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 claims 96-102 (Group II) in the reply filed on 06/23/2026 is acknowledged.
Claims 83-95 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/23/2026.
Accordingly, claims 96-102 are pending and under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The earliest effective filing date to which the instant application is entitled is 12/18/2020.
Information Disclosure Statement
Receipt of an information disclosure statement on 06/16/2023 is acknowledged. The information disclosure statement filed 06/16/2023 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered, as indicated by lining through the reference(s) at issue.
Drawings
The drawings filed 06/16/2023 are acceptable.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code at paragraphs [0159], [0160], and [0161]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
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 – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). See Tables 3 and 4.
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 sequence identifiers, 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 Objections
Claim 97 is objected to because of the following informalities:
Claim 97 recites “the method of claim 96, wherein the cell is a located in a brain of an individual” (bolded emphasis added), which appears to incorporate an unintentional typographical error introducing a rogue “a” prior to “located.” In order to comport with standard grammatical and/or linguistic conventions, it would be remedial to amend the instant claim language to correct the unintentional typographical error such that the rogue “a” prior to “located” is removed therefrom.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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 96-101 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 increasing expression of FOXG1 in a cell by administering an antisense oligonucleotide comprising a sequence that hybridizes to a target nucleic acid sequence located within positions 2000-2100 or 2900-3000 of a human FOXG1 nucleic acid, thereby restoring expression of haploinsufficient FOXG1 (as in FOXG1 syndrome) does not reasonably provide enablement for restoring expression of haploinsufficient FOXG1 (as in FOXG1 syndrome) by decreasing expression of FOXG1 in a cell (which is encompassed by the instant claim term “modulating”) by administering an antisense oligonucleotide comprising a sequence that hybridizes to a target nucleic acid sequence located within positions 2000-2100 or 2900-3000 of any FOXG1 nucleic acid. 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/or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Claims 96-101 are drawn to a method of modulating expression of a FOXG1 in a cell, which encompasses both increasing and decreasing expression of a FOXG1 in a cell, wherein said modulation is achieved by contacting the cell with a composition comprising an antisense oligonucleotide, wherein the antisense oligonucleotide comprises a sequence that hybridizes to a target nucleic acid sequence located within positions 2000-2100 or 2900-3000 of a FOXG1 nucleic acid. This modulation of expression is further recited to take place in the brain of an individual such as a human, wherein said individual comprises a mutated FOXG1 gene or has a FOXG1 disease or disorder such as FOXG1 syndrome. The nature of the invention is complex in that per the instant claim language, one of ordinary skill in the art must be able to design antisense oligonucleotides targeting positions 2000-2100 or 2900-3000 of a FOXG1 nucleic acid such that said antisense oligonucleotides are capable of both increasing and decreasing (i.e. modulating) FOXG1 expression in a cell.
Breadth of the claims: The claims broadly encompass the administration of an antisense oligonucleotide targeting positions 2000-2100 or 2900-3000 of a FOXG1 nucleic acid, wherein said targeting must both increase and decrease (i.e. modulate) FOXG1 expression in a cell. The complex nature of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples: The specification describes design and administration of antisense oligonucleotides that increase FOXG1 expression (Examples 1-4) by targeting the positions highlighted in Figure 2. These examples are aligned with the principles disclosed at paragraph [0003] of the instant specification, which teaches that the instant invention is drawn to antisense oligonucleotides that target FOXG1 to increase the amount of functional FOXG1 protein in a cell, thereby restoring or increasing FOXG1 function. While the instant specification discloses antisense oligonucleotides that decrease FOXG1 expression (see Figure 2), these antisense oligonucleotides broadly do not target the instantly claimed positions of a FOXG1 nucleic acid; whereas, antisense oligonucleotides targeting the instantly claimed positions of a FOXG1 nucleic acid generally show a trend of increased FOXG1 expression. This consistent up- or downregulation of FOXG1 depending on the targeted position(s) is aligned with established principles in the field, as set forth below.
Predictability and state of the art: The instant specification defines the term “antisense oligonucleotide” at paragraph [0048], disclosing that antisense oligonucleotides refer to oligonucleotides capable of modulating expression of a target gene by hybridizing to a target nucleic acid, wherein the antisense oligonucleotide is preferably single stranded. This broad definition invokes a number of oligonucleotide-based therapies, as reviewed in Drongitis et al., 2025 (hereinafter Drongitis). While Drongitis post-dates the earliest effective filing date of the instant application, it is hereby applied for evidentiary purposes to establish the state of the art regarding RNA-based therapies for neurodevelopmental disorders.
Figure 1 of Drongitis depicts various strategies for RNA-based therapies in neurodevelopmental disorders, including antisense oligonucleotides (ASOs), which modulate the target gene expression by triggering mRNA cleavage by RNAse H or by modulating RNA splicing, thereby resulting in mRNA downregulation and splicing correction, respectively. In the former case, the ASO targets a specified coding portion of the specified mRNA, and in the latter case, the ASO targets an exon/intron junction to effect splicing correction. AntagoNATs, on the other hand bind non-coding antisense RNAs to induce their degradation, thereby facilitating strong activation of mRNA transcription with resultant up-regulation at the protein level. Small RNA interference is mediated by double-stranded RNA (dsRNA) molecules, which are processed into small fragments by DICER to ultimately target the specified mRNA for cleavage, thereby resulting in mRNA downregulation. While the definition of “antisense oligonucleotide” from the instant specification (set forth above) is preferentially drawn to single-stranded oligonucleotides, this definition does not require that these oligonucleotides be single-stranded. In further embodiments, SINEUPs are antisense long non-coding RNAs (lncRNAs) with a dual-domain structure with a target-specific antisense region that binds to the 5’ UTR of the mRNA and an effector domain derived from an inverted SINEB2 element, thereby facilitating the recruitment of ribosomes to boost protein synthesis. Exon-specific U1snRNAs modulate target gene expression by facilitating splicing correction by targeting cryptic 5’ splice sites, thereby promoting the use of mutated or weak 5’ splice sites, leading to exon inclusion. Finally, saRNAs are small activating RNAs that can bind to the promoter of their target genes and thus regulate gene expression at the transcriptional level, thereby leading to transcription activation.
In summary, it is well-known in the field that there are many types of oligonucleotides that meet the instant definition of “antisense oligonucleotide,” and further that each type of oligonucleotide mediates a distinct functional outcome from the targeted nucleic acid by targeting distinct regions of the targeted nucleic acid (i.e. the functional outcome is determined by how and where the nucleic acid is targeted). Therefore, the instant claim language of “modulating” expression of a FOXG1 in a cell by targeting specific positions of a FOXG1 nucleic acid is at odds with the state of the art, as targeting specific positions would predictably lead to one functional outcome: either increasing expression of FOXG1 or decreasing expression of FOXG1, but not both, as is encompassed by the instant claim language.
Furthermore, while Hettige and Ernst, 2019 (hereinafter Hettige) discloses that FOXG1 dosage is linked to intellectual disability and epilepsy (when in excess) as well as to severe intellectual disability, epilepsy, microcephaly, and delayed motor development (when deficient), FOXG1 syndrome (recited at instant claim 101) specifically is known to be due to deficient levels of FOXG1, as it is a disorder of haploinsufficiency (also reviewed in Akol et al., 2022). Therefore, the state of the art establishes that one of ordinary skill in the art would reasonably predict that increasing expression of FOXG1 would have utility in correcting FOXG1 syndrome, although such interventions do not currently exist at the clinical level (reviewed in Akol et al., 2022).
This is consistent with the principles disclosed at paragraph [0003] of the instant specification, which teaches that the instant invention is drawn to antisense oligonucleotides that target FOXG1 to increase the amount of functional FOXG1 protein in a cell, thereby restoring or increasing FOXG1 function. However, as set forth above, the instant claim language encompasses both increasing and decreasing (i.e. modulating) FOXG1 expression, even though one of ordinary skill in the art would not reasonably predict that decreasing FOXG1 expression would have utility in correcting FOXG1 syndrome, as is instantly claimed.
Amount of experimentation necessary: The quantity of experimentation needed to carry out the full scope of the claimed method is large. One could not rely upon guidance provided in the instant disclosure or prior art, as neither the instant disclosure nor the prior art discloses antisense oligonucleotides that are capable of both increasing and decreasing target nucleic acid expression by targeting the same specified positions of said nucleic acid. Therefore, one of ordinary skill in the art would be required to design and validate novel antisense oligonucleotides of dual function without guidance from the instant disclosure and the prior art. Furthermore, one could not rely upon guidance from the instant disclosure or the prior art for methods of correcting FOXG1 syndrome by decreasing FOXG1 expression, as is encompassed by the instant claim language, given that the state of the art teaches that FOXG1 syndrome is a disease of haploinsufficiency, not of excess FOXG1 (although disorders of excess FOXG1 do also exist).
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 96-101 are not considered to be fully enabled by the instant disclosure.
Claim 102 is 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 increasing expression of FOXG1 by administering an antisense oligonucleotide comprising a sequence that hybridizes to a target nucleic acid sequence located within positions 2000-2100 or 2900-3000 of a human FOXG1 nucleic acid, thereby restoring expression of haploinsufficient FOXG1 for treatment of FOXG1 syndrome does not reasonably provide enablement for treating or ameliorating any FOXG1 disease or disorder in an individual by administering an antisense oligonucleotide comprising a sequence that hybridizes to a target nucleic acid sequence located within positions 2000-2100 or 2900-3000 of any FOXG1 nucleic acid, nor does it reasonably provide enablement for treating or ameliorating a FOXG1 disease or disorder in an individual at risk of having the FOXG1 disease or disorder. 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/or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Claim 102 is drawn to a method of treating or ameliorating a FOXG1 disease or disorder in an individual that has or it as risk of having the FOXG1 disease or disorder, said method comprising administering an antisense oligonucleotide comprising a sequence that hybridizes to a target nucleic acid sequence located within positions 2000-2100 or 2900-3000 of a FOXG1 nucleic acid, thereby treating or ameliorating a FOXG1 disease in the individual. The nature of the invention is complex in that per the instant claim language, one of ordinary skill in the art must be able to design antisense oligonucleotides targeting positions 2000-2100 or 2900-3000 of a FOXG1 nucleic acid such that said antisense oligonucleotides are capable of both increasing and decreasing (i.e. modulating) FOXG1 expression, thereby treating or ameliorating a FOXG1 disease or disorder.
Breadth of the claims: The claims broadly encompass the administration of an antisense oligonucleotide targeting positions 2000-2100 or 2900-3000 of a FOXG1 nucleic acid for purposes of treating or ameliorating a FOXG1 disease or disorder, wherein said targeting must both increase and decrease (i.e. modulate) FOXG1 expression such that both outcomes treat or ameliorate a FOXG1 disease or disorder. The complex nature of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples: The specification describes design and administration of antisense oligonucleotides that increase FOXG1 expression (Examples 1-4) by targeting the positions highlighted in Figure 2. These examples are aligned with the principles disclosed at paragraph [0003] of the instant specification, which teaches that the instant invention is drawn to antisense oligonucleotides that target FOXG1 to increase the amount of functional FOXG1 protein in a cell, thereby restoring or increasing FOXG1 function. While the instant specification discloses antisense oligonucleotides that decrease FOXG1 expression (see Figure 2), these antisense oligonucleotides broadly do not target the instantly claimed positions of a FOXG1 nucleic acid; whereas, antisense oligonucleotides targeting the instantly claimed positions of a FOXG1 nucleic acid generally show a trend of increased FOXG1 expression. No description is provided of any in vitro or in vivo disease modeling of how a FOXG1 disease or disorder responds to increased FOXG1 expression.
Predictability and state of the art: As set forth above, Hettige and Ernst, 2019 (hereinafter Hettige) discloses that FOXG1 dosage is linked to a number of neurodevelopmental disorders (Figure 1). For example, excess FOXG1 is linked to intellectual disability and epilepsy, while deficient FOXG1 (i.e. FOXG1 syndrome) is linked to severe intellectual disability, epilepsy, microcephaly, and delayed motor development (also reviewed in Akol et al., 2022). Hettige further discloses that FOXG1 dosage states cannot be modeled linearly or simplistically, as FOXG1 interacts with different players and may be governed by substrate affinity or phosphorylation states, meaning FOXG1 exerts its effects by how and when it is expressed, how FOXG1 is stabilized or degraded, and also is influenced by background genetics (see section “CONCLUSION”). Therefore, any therapeutic interventions targeting FOXG1 must take these considerations into account to avoid eliciting any undesirable phenotypic effects, meaning a simple increase (or decrease) of FOXG1 expression would not be reasonably predicted to fully treat the symptoms of improper FOXG1 expression. While Akol et al., 2022 (hereinafter Akol) post-dates the earliest effective filing date of the instant application, it is hereby applied for evidentiary purposes to establish the state of the art regarding treating of FOXG1 diseases or disorders such as FOXG1 syndrome. Akol discloses that although recent scientific advancements have opened promising and important new avenues in FOXG1 research, clinical interventions to treat FOXG1 diseases or disorders by targeting FOXG1 have not yet been realized (abstract). While Akol discloses that RNA therapies and antisense oligonucleotide therapies have been investigated, these investigations have resulted in only a few publications and no clinical treatments (page 5, paragraph 3). To date, most therapies of FOXG1 syndrome have aimed at treating symptoms, including seizures, with interventions such as hormonal therapy and anti-epileptic drugs (reviewed in Seltzer et al., 2014). As of the time of filing, no therapeutic intervention targeting FOXG1 with antisense oligonucleotides was known in the art, and the instant specification is silent as to the role of modulating (i.e. increasing) FOXG1 expression in treating FOXG1 diseases of disorders, including FOXG1 syndrome and FOXG1 overexpression.
Similarly, while Fimiani et al., 2016 (hereinafter Fimiani; as cited in Applicant IDS) discloses saRNA-driven activation of FOXG1 in vitro and in vivo, Fimiani merely contemplates therapeutic use of said saRNAs and does not offer any data demonstrating therapeutic utility of said saRNAs (abstract; discussion).
Furthermore, as set forth above, Drongitis discloses that there are many types of oligonucleotides that meet the instant definition of “antisense oligonucleotide” (paragraph [0048]), and further that each type of oligonucleotide mediates a distinct functional outcome from the targeted nucleic acid by targeting distinct regions of the targeted nucleic acid (i.e. the functional outcome is determined by how and where the nucleic acid is targeted) (see Figure 1). Therefore, one of ordinary skill in the art would reasonably predict that targeting positions 2000-2100 or 2900-3000 would result in only increased or decreased expression of FOXG1 such that diseases or disorders amenable to treatment with said antisense oligonucleotides must be drawn to only decreased or increased expression of FOXG1, respectively, in order to be effectively treated by the instantly claimed methods. One of ordinary skill in the art would not reasonably predict that an antisense oligonucleotide targeting the specified positions would be capable of treating any disease or disorder of FOXG1, which encompasses diseases or disorders involving both increased and decreased expression of FOXG1, as the instant claim language is not limited to diseases of disorders associated with decreased expression of FOXG1.
Amount of experimentation necessary: The quantity of experimentation needed to carry out the full scope of the claimed method is large. One could not rely upon guidance provided in the instant disclosure or prior art, as neither the instant disclosure nor the prior art discloses antisense oligonucleotides that are capable of treating any disease or disorder of FOXG1 (i.e. diseases or disorders associated with increased or decreased expression of FOXG1). Therefore, one of ordinary skill in the art would be required to design and validate novel antisense oligonucleotides of dual function (i.e. capable of increasing and decreasing expression of FOXG1) to treat diseases of disorders of FOXG1 associated with decreased or increased expression of FOXG1, respectively. One could not rely upon guidance from the instant disclosure, which does not disclose any therapeutic intervention, nor could one rely upon guidance from the prior art, as the prior art discloses that no FOXG1-specific therapies are currently known (reviewed in Akol, as set forth above).
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claim 102 is not considered to be fully enabled by the instant disclosure.
Regarding the limitations drawn to the treatment or amelioration of a FOXG1 disease or disorder in an individual at risk of having the FOXG1 disease or disorder, the Examiner notes that under broadest reasonable interpretation, the instant claim language reads on a method of prevention.
It should be made clear that the enabling specification must teach those skilled in the art to make and use the full scope of the claimed invention without undue experimentation. “Although not explicitly stated in section 112, to be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without "undue experimentation." Vaeck, 947 F.2d at 495, 20 USPQ2d at 1444; Wands, 858 F.2d at 736-37, 8 USPQ2d at 1404; In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (the first paragraph of section 112 requires that the scope of protection sought in a claim bear a reasonable correlation to the scope of enablement provided by the specification).” In re Wright (CAFC) 27 USPQ2d 1510 at 1513. Although a working example is not required to enable an invention, the skilled artisan must be able to practice the claimed invention without undue experimentation. See also, MPEP §2164.02, which states in part: The specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970). Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.
In this case, the claims are considered to encompass preventing a FOXG1 disease or disorder in a subject at risk of having the FOXG1 disease or disorder. Looking to the prior art for guidance, a search of the prior art did not identify any methods which utilize antisense oligonucleotides which could effectively prevent any FOXG1 disease or disorder in a subject. In fact, no prior art was identified which taught effective prevention of any FOXG1 disease or disorder using any agent similar to the agents utilized in the instant claims. The specification also does not provide any working example demonstrating prevention of any FOXG1 disease or disorder in a subject. Therefore, given the lack of knowledge present in the prior art and the lack of guidance provided in the specification with respect to preventing a FOXG1 disease or disorder, further experimentation would be required. Considering that the additional experimentation would require de novo experimentation without a guarantee of success, and further considering that any positive results (i.e., successful prevention of any FOXG1 disease or disorder in a subject) would amount to a significant advancement in the state of the art, the additional experimentation required is considered undue.
Furthermore, in In re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991), the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was appropriate given the relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. Such is the case here where there is a relatively incomplete understanding in the biotechnological field involved, as described above, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims.
Therefore, it is appropriate to reject the claims under 35 USC 112(a) for not being enabled to their full scope. It is noted that amending the claims to, for example, a method of treating FOXG1 syndrome in a subject in need thereof (as set forth above), would obviate this rejection.
Claim Rejections - 35 USC § 112(b)
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.
Claims 96-102 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
With regard to independent claims 96 (from which all other dependent claims directly or indirectly depend) and 102, the recitation of “positions 2000-2100 or 2900-3000 of a FOXG1 nucleic acid” (bolded emphasis added) is indefinite, as there are many FOXG1 nucleic acid species, including genomic sequences and transcriptomic sequences, not all of which are amenable to modulation of expression with an antisense oligonucleotide, as is instantly claimed. Furthermore, the recitation of specific targeted positions in a nucleic acid sequence requires a reference nucleic acid sequence in order to clearly define the metes and bounds of protection sought by the instant application.
First, regarding the breadth of nucleic acid species encompassed by the recitation of “a FOXG1 nucleic acid,” as is known to those of ordinary skill in the art, nucleic acids encompass both DNA and RNA, generally wherein the genome is comprised of DNA and the transcriptome is comprised of RNA. Furthermore, as is known to those of ordinary skill in the art, antisense oligonucleotides are generally designed to target RNA-not DNA (reviewed in Bennett 2019: see section “ANTISENSE OLIGONUCLEOTIDES: MOLECULAR MECHANISMS”). It is therefore unclear how an antisense oligonucleotide, as instantly claimed, could modulate the expression of FOXG1 by targeting DNA, which is a nucleic acid species that reads on the instantly claimed “FOXG1 nucleic acid.” While the instant specification discloses that the targeted nucleic acid molecule may be an RNA molecule such as an mRNA molecule at least at paragraphs [0006] and [0025], the instant claim language is not restricted to an RNA molecule such as an mRNA molecule. In fact, the instant specification defines the term “FOXG1” explicitly to encompass DNA at paragraph [0046]). Therefore, given that antisense oligonucleotides are generally not known to target DNA, it is considered that the recitation of “an antisense oligonucleotide…comprising a sequence that hybridizes to a target nucleic acid sequence located within positions 2000-2100 or 2900-3000 of a FOXG1 nucleic acid,” which may properly be interpreted to recite targeting of a genomic FOXG1 nucleic acid (i.e. DNA), is indefinite.
Furthermore, regarding the recitation of specific targeted positions in a nucleic acid sequence, such positions do not have meaning on their own. They are only imparted meaning in the context of a defined reference nucleic acid sequence. In the instant case, even if one limits the instantly claimed FOXG1 nucleic acid to FOXG1 mRNA specifically, FOXG1 mRNA is found in numerous species, including humans (NCBI Reference Sequence: NM_005249.4), mice (NCBI Reference Sequence: NM_008241.1), cattle (NCBI Reference Sequence: XM_024982051.1), and naked mole rats (NCBI Reference Sequence: XM_004864051.3). As shown in the multiple sequence alignment of the Appendix, while certain regions of FOXG1 (such as the 3’ UTR) show a great degree of sequence conservation, other regions are much more divergent (also reviewed in Kumamoto and Hanashima, 2017), meaning the same positions in different sequences do not necessarily comprise the same, conserved sequence amenable to antisense targeting. Furthermore, cattle FOXG1 mRNA (NCBI Reference Sequence: XM_024982051.1) only comprises 2480 base pairs, meaning antisense oligonucleotides targeting 2900-3000, as instantly claimed, are impossible to synthesize, thereby rendering the metes and bounds of protection sought by the instant claim language indefinite.
Additionally, some species such as zebrafish are known to express multiple forms of FOXG1. As disclosed in Zhao et al., 2009, zebrafish express three forms of FOXG1 (FOXG1a, FOXG1B, and FOXG1C) with different functions, wherein FOXG1b is most closely related to mouse FOXG1 (Figure 2; page 269, column 1, paragraph 1). In the absence of reference to a particular FOXG1 nucleic acid sequence, it is impossible for one of ordinary skill in the art to ascertain those FOXG1 species amenable to modulation via targeting with antisense oligonucleotides.
It would be remedial to amend the instant claim language to recite clearly defined positions of a specific FOXG1 nucleic acid, thereby clearly delineating the metes and bounds of protection sought by the instant application. For purposes of examination and in the interest of compact prosecution, the Examiner has interpreted the instant claim set to recite targeting of a human FOXG1 mRNA (i.e. NCBI Reference Sequence: NM_005249.4).
Claim 98 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 98 recites the limitation “the individual” in line 1. There is insufficient antecedent basis for this limitation in the claim. For purposes of examination and in the interest of compact prosecution, the Examiner has interpreted instant claim 98 to depend from instant claim 97, which recites “an individual,” thereby establishing antecedent basis for the individual of instant claim 98. It would be remedial to amend the instant claim language such that there is proper antecedent basis for each and every claim term.
Conclusion
No claims are allowed.
Claim 97 is objected to.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Antisense-mediated modulation of FOXG1 expression is known in the art. For example, Duggan et al., 2008 (hereinafter Duggan; as cited in Applicant IDS) discloses antisense morpholino-mediated knockdown of FOXG1 in zebrafish (Figure 6). A BLAST search of the morpholino sequences of Duggan (disclosed at page 5230, column 1, paragraph 3) did not return matches to the instantly claimed positions of FOXG1. While Duggan does disclose probes meeting the definition of the instantly claimed “antisense oligonucleotide” targeting FOXG1 at the specified residues (disclosed at page 5230, column 1, paragraph 5), these probes are explicitly drawn to in situ hybridization and do not modulate expression of FOXG1, as instantly claimed. Thus, it is considered that Duggan does not anticipate the instantly claimed invention.
While Duggan is drawn to the knockdown of FOXG1, Fimiani et al., 2016 (hereinafter Fimiani; as cited in Applicant IDS) is drawn to RNA activation of FOXG1 (abstract), wherein said activation is achieved by providing artificial miRNA sequences that appreciably upregulate FOXG1 expression while complying with endogenous gene tuning even in vivo, although therapeutic application requires further troubleshooting (Figure 1; page 7, paragraph 9). However, the artificial miRNA sequences that activate FOXG1 expression disclosed in Fimiani do not target the instantly claimed positions of FOXG1 and therefore it is considered that Fimiani does not anticipate the instantly claimed invention.
Expanding on these principles, it is thus known in the art that therapeutic upregulation of FOXG1 has the potential to treat FOXG1 disorders such as FOXG1 syndrome (reviewed in Fimiani), and it is further known that such upregulation may be achieved by small activating RNAs, such as those disclosed in Fimiani. It is further known that small activating RNAs can function by blocking miRNA binding to the 3’ UTR of a target gene, thereby derepressing the target gene and upregulating expression of the same (reviewed in Wang, 2011: abstract; Figure 1). Prior to the effective filing date of the instant application, FOXG1 was known to comprise multiple miRNA binding sites in the highly conserved 3’ UTR, including miR-9 and miR-33, which regulate FOXG1 post-transcriptionally (Bredenkamp et al., 2007: abstract; page 228, column 1, paragraph 2). miRNA-422a has also been implicated in FOXG1 expression (Zhang et al., 2015). More recently, miR-9-3p has been experimentally verified to regulate FOXG1 expression by targeting the 3’ UTR thereof (Zhen et al., 2020), as has miRNA-378a-3p (Zhang and Wu, 2020). Neither the binding site for miR-9-3p nor miR-378a-3p is predicted to occur at the specified positions of FOXG1. While database searches such as miRDB indicate that FOXG1 is predicted to comprise numerous miRNA binding sites, many of these predicted binding sites have yet to be experimentally investigated and/or verified.
Therefore, while one of ordinary skill in the art would be motivated based on the state of the prior art to target FOXG1 for therapeutic upregulation by targeting the 3’ UTR, for example to block miRNA binding to the same, nothing in the prior art fairly teaches or suggests targeting the specified positions of FOXG1 of the instant application. While targeting the 3’ UTR is generally known in the art, the 3’ UTR of FOXG1 is relatively long (1,538 bases in humans per NM_005249.4; 923 bases in mice per NM_008241.1; 934 bases in cattle per XM_024982051.1; 920 bases in naked mole rats per XM_004864051.3). Given that antisense oligonucleotides suitable for blocking miRNA binding sites are generally approximately 22 nucleotides in length (Wang, 2011: abstract), it is considered that it would constitute undue experimentation to design, test, and validate antisense oligonucleotides targeting all of the 3’ UTR in the absence of guidance from a particular miRNA binding site target, to which the prior art is silent at the instantly claimed positions.
Accordingly, it is considered that the prior art does not disclose a method of modulating FOXG1 expression by targeting the instantly claimed positions of FOXG1.
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/SARAH E ALLEN/Examiner, Art Unit 1637
/J. E. ANGELL/Primary Examiner, Art Unit 1637
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