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 of “heat shock protein inhibitor” in the reply filed on 10/20/2025 is acknowledged. Applicants did not elect with or without traverse. Additionally, applicants did not elect a singular compound of “heat shock protein inhibitor” and a singular compound of mTOR inhibitor.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Examiner searched the claims and found prior art for MCI-186 and rapamycin (as a species of mTOR inhibitor) and 17-AGG as a species of heat shock protein inhibitor.
Current Status of 18/009,645
This Office Action is responsive to the claims of 12/09/2022.
Claims 1, 9, 15, 16, 20, 21, 22, 36, 37, 39-40, 42, 45-46, 51, 66, 68-70, 77, and 81 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.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/23/2024, and 12/09/2022, are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 20-21 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 20-21 are dependent on now canceled claim 19. Therefore, claims 20-21 effectively do not depend on any independent claim.
Claim 39 depends on now canceled claim 3. Therefore, claim 39 (and its dependent claim 40) effectively do not depend on any independent claim.
Claim 66 depends on now canceled claim 60. Claims 67-69 also depend from claim 60 or 66. Therefore, claims 66-69 effectively do not depend on any independent claim.
Claim 81 depends on now canceled claim 76. Therefore, claim 81 effectively does not depend on any independent claim.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 22, 77 and 81 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by ZHANG (Zhang et al., “Edaravone Reduces Iron-Mediated Hydrocephalus and Behavioral Disorder in Rat by Activating the Nrf2/HO-1 Pathway”, Journal of Stroke and Cerebrovascular Diseases, December 2018) as evidenced by PubChem (“MCI-186”, PubChem, 03/25/2005).
Zhang anticipates a method of injecting Edaravone into ventricles of rats, which results in reduction in ependymal cilia damage (abstract, page 3512, and 3514). Zhang anticipates edaravone application significantly ameliorated iron-induced ependymal cilia damage (page 3514 left col).
PubChem is relied upon for the beneficial teaching that Edaravone is also known as MCI-186.
This anticipates a method of contacting a cell which normalizes ciliation in a cell of claim 1.
Zhang anticipates the ciliation is increased relative to an untreated cell (page 3512 1st col 3rd paragraph and figure 2C). This anticipates claim 9.
Zhang anticipates a method of injecting Edaravone (AKA MCL-186) into ventricles of rats (abstract, page 3512, and 3514). The cell is in vivo (anticipates claim 16).
Edaravone is part of a pharmaceutical composition (“intraventricular FeCl3 injection with Edaravone treatment” page 3512). This anticipates claim 22.
The phrase in instant claim 77 (“for the treatment of a subject with a neurodevelopmental disorder”) is interpreted as intended use. Nothing precludes the use as claimed. The second half of the claim (after the “and/or”) is optional given that Zhang anticipates the first part of the claim (mTOR inhibitor MCI-186 is disclosed by Zhang). This anticipates claim 77.
The instructions for use of the one of more compounds in the kit of claim 77 do not have patentable weight because the printed material is not functionally or structurally related to the associated physical substrate. In a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals. See MPEP 2111.05. This anticipates claim 81.
Claim(s) 1, 15, 36, 37, 45, 46, and 70 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by DING (Ding et al., “Edaravone attenuates neuronal apoptosis in hippocampus of rat traumatic brain injury model via activation of BDNF/TrkB signaling pathway”, Arch Med Sci. November 18, 2019) as evidenced by XIONG (Xiong et al., “Traumatic Brain Injury-Induced Ependymal Ciliary Loss Decreases Cerebral Spinal Fluid Flow”, J Neurotrauma., August 15, 2014).
Ding anticipates that rats were treated for traumatic brain injury (TBI) with edaravone (abstract). This anticipates claim 36 (the composition of claim 22 is a pharmaceutical composition containing edaravone) and claim 46 (traumatic brain injury). Applicants define that neurodevelopment disorder includes a traumatic brain injury (instant claim 46) and define a mTORopathy includes a traumatic brain injury in the instant specification page 24. Ding also anticipates claim 37.
XIONG is relied upon for the beneficial teaching that TBI causes a dramatic decrease in neuron cilia (abstract and introduction). This anticipates claim 45.
The method is in vivo (rats; anticipates claim 70).
Ding anticipates that the administration of edaravone was able to inhibit neural apoptosis in the hippocampus in a rat TBI model (conclusions). This is a method comprising contacting the cell (in a rat) with edaravone.
There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Chemical properties are inherent to their compounds. See MPEP 2112.01 (II). Products of identical chemical composition can not have mutually exclusive properties. A chemical, edaravone, and its properties, increasing or normalizing ciliation or reducing a ciliation defect in a cell, are inseparable. This anticipates claim 1 and 15 (where the cell is a neuron).
Claim(s) 22, 36, 42 and 46 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Raedt (Raedt et al., “Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors”, Cancer Cell, 2011 Sep 13) as evidenced by MALONE (Malone et al., “Defining Key Signaling Nodes and Therapeutic Biomarkers in NF1-Mutant Cancers”, Cancer Discovery, September 1, 2014).
Raedt anticipates a composition of rapamycin (mTOR inhibitor) and IPI-504 (Hsp inhibitor) (Figure 2). This composition was administered to animals (Figure 2E and page 4). Because this composition was administered to treat tumors in animals via IP injections (page 10), Examiner understands that there was a pharmaceutically acceptable carrier and that this composition was a pharmaceutical composition. This anticipates claim 22.
Raedt anticipates treating an animal model of Malignant Peripheral Nerve Sheath Tumor (MPNST), which is a brain tumor (page 2). This is a neurodevelopmental disorder of claim 46. This anticipates claims 36 and 46.
Raedt anticipates targeting mTOR activity (page 8).
MALONE is relied upon for the beneficial teaching that mTORC1 is a criterial mediator of malignancy in MPNST (Abstract). This anticipates claim 42.
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) 51 is rejected under 35 U.S.C. 103 as being unpatentable over LI (Li et al., “Synthetic lethality of combined glutaminase and Hsp90 inhibition in mTORC1-driven tumor cells”, PNAS, December 18, 2014) in view of CINCINNATI CHILDREN’s (“Tuberous Sclerosis (TSC)”, Cincinnati Children’s Hospital, April 29, 2016) as evidenced by MERCK (“17-(Allylamino)-17-demethoxygeldanamycin”, Merck, accessed in February, 2026). Note there is a retraction from LI after the effective filing date in 2023; Examiner has not cited the retracted duplicate data. Regardless LI’s retraction would not have been known at the time of the effective filing date.
LI teaches that the deregulation of the mTORCl pathway is found in tuberous sclerosis complex (TSC) (Abstract).
CINCINNATI CHILDREN’s teaches that Tuberous Sclerosis Complex treatment is an mTOR inhibitor (page 3).
CINCINNATI CHILDREN’S does not teach a specific mTOR inhibitor or a Hsp inhibitor.
LI teaches that mTORC1 inhibitor rapamycin generally suppresses proliferation rather than induce apoptosis (abstract).
LI teaches that the small-molecule screen has revealed that the combination of glutaminase(GLS) and heat shock protein 90 (Hsp90) inhibitors selectively triggers death of TSC2-deficient cells (abstract).
LI also teaches that a combination of rapamycin and 17-AAG (also referred to as 17-N-allylamino-17-demethoxygeldanamycin) administered to mouse embryonic fibroblasts that are TSC2 negative (page 23 right col).
MERCK is relied upon for the beneficial teaching that 17-AAG (also referred to as 17-N-allylamino-17-demethoxygeldanamycin) is also known as 17-Allylamino-geldanamycin (PAGE 1).
LI teaches that combination (of rapamycin and 17-AAG) induced death in cells with activated mTORC1 via the loss of TSC1/2 (Discussion page E26-27). TSC is caused by TSC2 gene mutation (LI page E21).
LI does not anticipate treating tuberous sclerosis complex.
Because tuberous sclerosis complex uses the mTORCl pathway (LI Abstract) and because Tuberous Sclerosis Complex treatment is an mTOR inhibitor (Cincinnati children’s page 3), the artisan would have been motivated to administer rapamycin (an mTOR inhibitor) in order to treat tuberous sclerosis complex (TSC). The artisan would have expected that the mTOR inhibitor to be an effective treatment for TSC.
The artisan would have found it obvious to combine rapamycin (mTOR inhibitor) and 17-AAG (Hsp inhibitor) in order to treat TSC. Both compounds are known to be effective in suppressing growth (rapamycin; LI abstract) or inducing apoptosis (LI teaches that the combination of glutaminase(GLS) and heat shock protein 90 inhibitors (17-AAG is the one used) selectively triggers death of TSC2-deficient cells, which is the animal model for TSC (LI abstract and E26-27)). Both suppressing growth and inducing apoptosis are needed to treat TSC. However, the artisan would have expected that at the very least the mTOR inhibitor to be an effective treatment for 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 claim 51.
Conclusion
No claims are allowable as written.
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/G.A.H./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625