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/Restriction
A Markush search for “heat shock protein inhibitor” (Hsp inhibitor) and “mTOR inhibitor” still exists. The Markush search is extended to rapamycin and 17-AGG.
Now amended claims 20-21 and 66-69 are withdrawn as the current Hsp inhibitor is not a shRNA, or an inhibitor nucleic acid.
Current Status of 18/009,645
This Office Action is responsive to the claims of 05/26/2026.
Claims 1, 9, 15, 16, 37, 39-40, 42, 45-46, 51, and 70 are examined on the merits.
Priority
This application is a national stage entry of PCT/US2021/036402, which claims priority to US provisional application 63/037,946.
The instant claims find support from the provisional application. Therefore, the effective filing date is 06/11/2020.
Response to Arguments
Applicants’ claim amendments and Remarks of 05/26/2026 are acknowledged and have been considered.
Any rejection and/or objection not specifically addressed or modified below is herein withdrawn.
Claims 22, 36, 77, and 81 have been canceled.
In regard to the 112(d) rejection, this rejection is withdrawn as Applicants have amended the previously rejected claims to depend from an independent claim.
In regard to the 102 rejection, this rejection is withdrawn. Applicants deleted the mTOR inhibitor MCI-186.
In regard to the 103 rejection, this rejection is withdrawn. Applicants remarks with Examiner’s Reply are summarized below:
Applicants submit that Cincinnati Children’s Hospital was “Last Updated” in 6/2025 and thus is not prior art.
Applicants submit that claim 51 is not obvious over the cited references. LI teaches away from the administration of this combination.
Applicants point out LI Page E24, left column, and Figure 2A, where LI states that cells remained viable after 72 H of treatment.
LI also concludes that “this combination did not seem to be effective in our cell system” on page E27 right col.
After reviewing LI again, Examiner agrees and withdraws this rejection.
Response to Amendment
Nucleotide and/or Amino Acid Sequence Disclosures
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).
NOTE, Claims 20 and 21 lack proper sequence compliance. They should have a SEQ ID Number associated with the RNA sequences shown.
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 Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 9, 16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by YUAN (Yuan et al., “Target-of-rapamycin complex 1 (Torc1) signaling modulates cilia size and function through protein synthesis regulation”, PNAS, February 7, 2012).
YUAN investigates whether TSC signaling functions autonomously in KV cells to regulate cilia length, YUAN generated chimeric dorsal forerunner cells in which tsc1a is knocked down (bottom of page 2021 to top of 2022). YUAN teaches that administering rapamycin normalized ciliation in an abnormally long KV cilia phenotype back to a wild-type length in zebrafish embryo (abstract and Figure 1’s G). Examiner also understands this is a method of reducing a ciliation defect in a cell (page 2024). YUAN teaches treatment with rapamycin in knockdown of tsc1a embryos, which resulted in short KV cilia (page 2022). Examiner understands that treating the embryos would also treat KV cells. Therefore, YUAN anticipates a method of normalizing ciliation or reducing a ciliation defect in a cell, comprising contacting the cell with rapamycin, which anticipates claim 1.
YUAN teaches the reference is abnormally long compared to a reference (i.e. wild-type) (this anticipates claim 9). Examiner notes that “increased or normalized ciliation” inherently requires a reference to be increased or normalized to, and that anticipated claim 1 inherently anticipates claim 9.
YUAN teaches the cell is in vivo. This anticipates claim 16.
Claim(s) 37, 39-40, 45, 46, 51, 70 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by SHA (Sha et al., “Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy”, J. Exp. Med. 2017) and as evidenced by NGUYEN (Nguyen et al., “mTOR Hyperactivity Levels Influence the Severity of Epilepsy and Associated Neuropathology in an Experimental Model of Tuberous Sclerosis Complex and Focal Cortical Dysplasia”, J Neurosci, April 3, 2019) and as evidenced by PARK (Park et al., “Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination”, Cell Press, 2018).
SHA teaches administering 17AAG (which is another name for the instant 17-AGG) in Tsc1flox/flox;GFAP-Cre conditional knockout mice (Tsc1GFAPCKO), which is a well-established mouse model of TSC (page 555). SHA teaches that the 17AAG treated mice lived longer than the controls (page 555).
NGUYEN is relied upon for the beneficial teaching that TSC is a mTORopathy (abstract).
This anticipates treating a subject (mouse) with TSC by administering 17-AGG (claims 37, 46, and 51).
SHA teaches the neurodevelopment disorder is caused by a mutation in a mTOR gene (TSC1 on page 555). This anticipates claims 39 and 40.
PARK is relied upon for the beneficial teaching that Tuberous Sclerosis Complex (a neurodevelopmental disorder of instant claim 46, and caused by TSC2) is associated with a decrease in neuronal cilia length and number (“defective neuronal ciliogenesis was observed in brain tissues from tuberous sclerosis complex (TSC) patients” Results and Figures S1C and D).
This anticipates claim 45.
SHA anticipates this method is done in vivo (mice on page 555). This anticipates claim 70. Additionally, cells are only in vitro or in vivo. Physically, no other option exists.
In treating live animals (page 555 also page 556 “injected”), SHA inherently teaches a method comprising contacting a cell with 17-AGG (a Hsp inhibitor). SHA also discloses that “the beneficial effects of Hsp90 inhibitor in neurodegenerative diseases have been attributed to the inhibition of Hsp90 activity and increased Hsp70 levels in affected neurons” (page 556).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 15-16, 37, 39-40, 42, 45-46, 51 and 70 is/are rejected under 35 U.S.C. 103 as being unpatentable over YUAN (Yuan et al., “Target-of-rapamycin complex 1 (Torc1) signaling modulates cilia size and function through protein synthesis regulation”, PNAS, February 7, 2012) as evidenced by NGUYEN (Nguyen et al., “mTOR Hyperactivity Levels Influence the Severity of Epilepsy and Associated Neuropathology in an Experimental Model of Tuberous Sclerosis Complex and Focal Cortical Dysplasia”, J Neurosci, April 3, 2019) and PARK (Park et al., “Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination”, Cell Press, 2018) and in view of SHA (Sha et al., “Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy”, J. Exp. Med. 2017).
Above, Claim(s) 1, 9, 16 taught by YUAN (Yuan et al., “Target-of-rapamycin complex 1 (Torc1) signaling modulates cilia size and function through protein synthesis regulation”, PNAS, February 7, 2012). Above, Claims 37, 39-40, 45, 46, 51, 70 taught by SHA as evidenced by NGUYEN and PARK.
YUAN teaches that TSC1 and TSC2 are the causal genes of Tuberous sclerosis Complex (TSC) (page 2021). YUAN also teaches administering rapamycin to cells that have TSC1 (page 2022). This helps teach claim 51.
It would have been obvious from YUAN’s teachings to arrive at a method of treating Tuberous sclerosis Complex (TSC), comprising administering rapamycin to a patient in need thereof. The artisan would have expected rapamycin to treat TSC in a patient in need thereof because rapamycin is effective in normalizing cilia length in the TSC cell model (YUAN page 2024). This teaches claim 51.
NGUYEN is relied upon for the beneficial teaching that TSC is a mTORopathy (abstract).
From YUAN’s method of treating Tuberous sclerosis Complex (TSC, which also is a mTORopathy as evidenced by NGUYEN), comprising administering rapamycin to a patient in need thereof, this teaches claim 37.
YUAN teaches the cell is in vivo of claim 70. Note, cells are only in vitro or in vivo. Physically, no other option exists.
YUAN teaches TSC is caused by TSC1 and TSC2 (page 2021). This teaches claims 39-40.
YUAN teaches that TSC1 and TSC2 form a complex that prevents the activation of target-of-rapamycin complex 1 (TORC1). This teaches claim 42.
YUAN teaches the neurodevelopmental disorder is Tuberous sclerosis complex (abstract and page 2021). This teaches claim 46.
PARK is relied upon for the beneficial teaching that Tuberous Sclerosis Complex (a neurodevelopmental disorder of instant claim 46) is associated with a decrease in neuronal cilia length and number (“defective neuronal ciliogenesis was observed in brain tissues from tuberous sclerosis complex (TSC) patients” Results and Figures S1C and D). This teaches claim 45.
SHA teaches administering 17AAG (which is another name for the instant 17-AGG) in Tsc1flox/flox;GFAP-Cre conditional knockout mice (Tsc1GFAPCKO), which is a well-established mouse model of TSC (page 555). SHA teaches that the 17AAG treated mice lived longer than the controls (page 555).
PARK is relied upon for the beneficial teaching that Tuberous Sclerosis Complex (caused by mutated TSC2 gene) is associated with a decrease in neuronal cilia length and number (“defective neuronal ciliogenesis was observed in brain tissues from tuberous sclerosis complex (TSC) patients” Results and Figures S1C and D).
YUAN teaches TSC is caused by mutations in TSC1 and TSC2 (page 2021).
Because SHA teaches a method of treating TSC in a subject in need thereof (mouse) by administering 17-AGG (page 555) and because TSC is associated with a decrease in neuronal cilia length and number (“defective neuronal ciliogenesis was observed in brain tissues from tuberous sclerosis complex (TSC) patients” (Results and Figures S1C and D from PARK), the artisan would expect 17-AGG to contact a cell (in a mouse). The artisan would expect 17-AGG to increase or normalize ciliation or reduce a ciliation defect in a cell because 17-AGG treats TSC. This teaches claims 1 and 15-16 (where the cell is a neuron and the cell is in a live mouse).
Note, due to how claim 1 is currently written, the “and/or” in claim 1, allows for selection of just 17-AAG alone without rapamycin.
However, the artisan would have found it obvious to combine rapamycin (mTOR inhibitor) and 17-AAG (Hsp inhibitor) in order to treat TSC. It is prima facie obvious to combine one treatment with another in order to form a composition to be used for the very same purpose (treating TSC). In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP 2144.06(I). This teaches the combination of both mTOR inhibitor and Hsp inhibitor in base claims 1, 37, and 51.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GILLIAN A HUTTER whose telephone number is (571)272-6323. The examiner can normally be reached M-F 7:30-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at 571-272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/G.A.H./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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