DETAILED ACTION
This action is in response to papers filed on 05/09/2025. Claims 15-17, 19-23, 31-32, 69, and 90-96 of Wei et al., 17623246 (12/28/2021) are pending examination on the merits: claims 15, 17, 19-23, and 31-32 are amended; claims 1-14, 18, 24-30, 33-68, and 70-79 are canceled; claims 90-96 are newly added; and claims 94 and 96 are withdrawn. Claims 15-17, 19-23, 31-32, 69, 90-93 and 95 are rejected.
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 .
Priority
This application is a 371 of PCT/US2020/040198 (06/29/2020) which claims benefit of 62/868,820 (06/28/2019).
Election/Restriction
REQUIREMENT FOR UNITY OF INVENTION
In a response filed on 05/09/2025, Applicant elected memantine as the glutamate receptor antagonist. Applicant also requested that ketamine as the glutamate receptor antagonist is also included in the search and examination, and argues that a search burden would not impose any additional search burden. Applicant also identified memantine as the glutamate receptor antagonist to read on claims 15-17, 19-23, 31-32, 69, 90-93 and 95. Applicant’s Remarks at page 2.
Examiner’s Response
Applicant’s election of species is acknowledged.
Regarding Applicant’s Election, MPEP 818.01 discloses that Election in reply to a requirement for restriction may be made either with or without an accompanying traverse of the requirement. The absence of any statement indicating whether the requirement to restrict is traversed or the failure to provide reasons for traverse will be treated as an election without traverse. Therefore, Applicant’s response is treated as an election without traverse.
Regarding Applicant’s request for the search of ketamine as a second species, ketamine and memantine are structurally different glutamate receptor antagonists. Applicant is required under 35 U.S.C. 121 to elect a single species, for prosecution on the merits, to which the claims shall be restricted if no generic claim is finally held to be allowable. As such, search and examination are limited to memantine as the glutamate receptor antagonist. In addition, claims 94 and 96 are hereby withdrawn as claims that do not read on the elected species.
Specification
The current title reads: “NTRANASAL DANTROLENE ADMINISTRATION FOR TREATMENT OF ALZHEIMER'S DISEASE”. The letter “I” is missing from “NTRANSAL”.
The following title is suggested: “INTRANASAL DANTROLENE ADMINISTRATION FOR TREATMENT OF ALZHEIMER'S DISEASE”, where “I” is reinstated.
Information Disclosure Statement
The Information Disclosure Statements (IDS) submitted on 12/28/2021, 06/14/2022, and 08/06/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 95 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 95 currently recites:
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The claim has a misplaced period after 3-MEP-PCP.
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.
Claim 23 is 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.
The limitation is merely a statement of intended result, and does not impose a structural or method step limitation on the claimed invention.
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 § 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.
Claims 15-17, 23, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Wei et. al, Grant NIH/R01-AG061447-02 (“Wei”).
Regarding claim 15, Wei teaches a method for improving and/or slowing the decline of cognitive function after onset of neuropathology and cognitive dysfunction, wherein said neuropathology and cognitive dysfunction are caused by Alzheimer's Disease (AD) (page 1, para. 1, “Clinical trials for the treatment of Alzheimer's disease (AD)... Our central hypothesis is that intranasal dantrolene inhibits the excessive activation of RYRs and NMDARs in AD and promotes adult neurogenesis"), the method comprising intranasally administering to a subject in need thereof an amount of dantrolene (page 1, para.1, "Ca2+ dysregulation may be an alternative mechanism. In familial AD (FAD), calcium homeostasis is disrupted by overactivation of NMDA (NMDAR) and ryanodine (RYR) receptors leading to increased cytosolic calcium and subsequent cognitive dysfunction and neuropathology... Our preliminary studies suggested that intranasal dantrolene administration abolished memory loss in 5XFAD ... The overall objective of this study is to investigate the effects and underlying mechanisms of dantrolene ... as well as the effects of intranasal dantrolene administration on adult neurogenesis and cognitive function in AD transgenic mice”) effective to inhibit over-activation of NMDA receptor and/or ryanodine receptor (RyR) (page 1, para. 1, "In familial AD (FAD), calcium homeostasis is disrupted by overactivation of NMDA (NMDAR) and ryanodine (RYR) receptors leading to increased cytosolic calcium and subsequent cognitive dysfunction and neuropathology... Our central hypothesis is that intranasal dantrolene inhibits the excessive activation of RYRs and NMDARs in AD and promotes adult neurogenesis". Claim 15 is obvious.
Regarding claim 16, Wei teaches the method of claim 15, wherein the cognitive function is memory, learning, thinking, attention, perception, language use, reasoning, decision making, problem solving or a combination thereof (page 1, para 1, " ... Our preliminary studies suggested that intranasal dantrolene administration abolished memory loss... "). Claim 16 is obvious.
Regarding claim 17, Wei teaches the method of claim 15, wherein the AD is familial Alzheimer's disease (FAD) or sporadic Alzheimer's disease (SAD) (pg 1, para 1, "Ca2+ dysregulation may be an alternative mechanism. In familial AD (FAD), calcium homeostasis is disrupted by over activation of NMDA (NMDAR) and ryanodine (RYR) receptors leading to increased cytosolic calcium and subsequent cognitive dysfunction and neuropathology… Our preliminary studies suggested that intranasal dantrolene administration abolished memory loss in 5XFAD..."). Claim 17 is obvious.
Regarding claim 23, Wei teaches the method of claim 15. Claim 23 recitation is considered an inherent or expected result of the method already taught by the prior art. Wei teaches a method for the intranasal administration of dantrolene. There is no disclosure in the art that such administration necessarily causes the recited impairments. In the absence of evidence that the prior art method produces the excluded adverse effects, the limitation is merely an intended result and does not confer patentable weight. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). MPEP § 2112(I).
Regarding claim 31, Wei teaches the method of claim 15, wherein the cognitive dysfunction is short-term or long-term memory loss (page 1, para. 1, " ... Our preliminary studies suggested that intranasal dantrolene administration abolished memory loss... "). Claim 31 is obvious.
Claims 19-22 are rejected under 35 U.S.C. 103 as being unpatentable over Wei et. al, Grant NIH/R01-AG061447-02 (“Wei”), as applied above to claims 15-17, 23, and 31, in further view of Pinder et al., Drugs 13, 3–23 (1977) (“Pinder”) (Abstract), and Joynt et al., Arch Phys Med Rehabil. 1976 May;57(5):212-7 (“Joynt”) (“Abstract), and as evidenced by Silva et al., Journal of Neuromuscular Diseases 10 (2023) 1145–1149 (“Silva”).
Regarding claims 19-22, Wei teaches the method of claim 15, where dantrolene is used as a therapeutic agent for the treatment of AD by inhibiting the excessive activation of RYRs and NMDARs in AD and promoting adult neurogenesis. However, Wei does not teach the recited administration schedule of a pharmaceutical composition comprising dantrolene per claims 19-22, including the administration of dantrolene for over 2 years.
Pinder teaches the administration of dantrolene in the treatment of chronic central nervous system related disorders characterized by skeletal muscle spasticity, such as spinal cord injury, stroke, cerebral palsy and multiple sclerosis. Pinder also teaches that, “The dosage of dantrolene has been fixed in most controlled trials, though long-term studies have indicated the need for individualization of dosage. The initial dose is usually 25mg once daily, increasing to 25mg two, three or four times daily, and then by increments of 25mg up to as high as 100mg two, three or four times daily.” (Pinder, Summary).
Joynt also teaches the administration of dantrolene in treating muscle spasticity, where seventy-seven patients with muscle spasticity secondary to central nervous system pathology were treated with dantrolene sodium for periods of up to two years. (Joynt, Abstract).
While Pinder and Joynt teach the treatment of muscle spasticity by administering dantrolene sometimes daily, or for periods up to 2 years, to one of ordinary skill in the art, dantrolene is a known compound, with a known mechanism of action including RyR antagonism as discussed above by Wei. To a person of ordinary skill in the art, dantrolene’s mechanism of action, RyR antagonism, is shared and conserved across muscle spasticity and neurological diseases.
As evidenced by Silva, “Dantrolene is a muscle relaxant used for the treatment of MH [malignant hyperthermia] that selectively blocks the RyR1 channel, thus, relaxing the skeletal muscle.” This is well documented and known throughout the arts.
When mechanism is conserved across conditions, dosage optimization principles are therefore transferrable. The references therefore confirm that different administration frequencies, including daily, are routinely optimized are frequently optimized and takes into account the individual's specific needs and medical condition, and can be optimized to arrive at the claimed invention since dantrolene is known to act as an RyR antagonist across both AD and muscle spasticity.
Consistent with this reasoning, it would have been obvious to one of ordinary skill in the art to administer the pharmaceutical composition comprising dantrolene, as taught by Wei, in view of the administration schedules presented by Pinder and Joynt, and as evidenced by Silva, and arrive at the claimed invention per claims 19-22 by routine experimentation. Long-term administration of dantrolene is taught by Joynt, and dose frequency is routinely optimized for chronic use as taught by Pinder. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). Therefore, selecting the administration schedule per claims 19-22 would have been a predictable optimization of known variable parameters. Frequency and duration are considered results-effective parameters that would have been routinely optimized by a person of ordinary skill in the art. Applicant has not provided evidence that the claimed schedule, for example, produces unexpected clinical results, addresses a known dosing problem in AD patients, or is critical to the therapeutic effect of dantrolene. Absent of unexpected results, the claimed schedule is obvious over the prior art.
Claims 91-92 are rejected under 35 U.S.C. 103 as being unpatentable over Wei et. al, Grant NIH/R01-AG061447-02 (“Wei”), as applied above to claims 15-17, 19-23, and 31, in further view of Oo et al., Mol Pharmacol. 2015 Jul;88(1):57-63 (“Oo”).
Regarding claims 91-92, Wei teaches the method of claim 91. Wei teaches in the Abstract that intranasal dantrolene inhibits the excessive activation of RYRs and NMDARs in AD and promotes adult neurogenesis. Wei, page 1, para. 1 teaches that intranasal administration of dantrolene resulted in the reversal of memory decline, evidencing therapeutic effectiveness. Claim 91 adds no distinction over Wei, and is thus obvious.
While Wei teaches inhibiting ryanodine receptors (RyR) generically in the brain, Wei does not expressly disclose wherein the RyR is selected from the group consisting of the Type 1, Type 2, Type 3, and combinations thereof. However, since dantrolene binds to the conserved cytoplasmic region of all mammalian RyR isoforms, a person of ordinary skill in the art would reasonably expect inhibition of RyR-1, RyR-2, and RyR-3.
Nonetheless, Oo teaches “dantrolene inhibition of RyR1 and RyR2” (Oo, Abstract).
Therefore, restricting the receptor to known subtypes does not confer patentable distinction over the prior art as dantrolene is known to act on RyR-1 and RyR-2. As in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007) (“When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). A person of ordinary skill would reasonably expect dantrolene to affect any RyR subtype known to be expressed in the brain, including the exact three (3) subtypes recited. No new or unexpected results are shown. Claim 92 is also obvious.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Wei et. al, Grant NIH/R01-AG061447-02 (“Wei”), as applied above to claims 15-17, 19-23, 31, and 91-92, and in further view of Girard et al., (2014), Hippocampus, 24: 762-772 (“Girard”).
Regarding claim 32, Wei teaches the method of claim 31. Wei teaches the method of treating 5XFAD transgenic mouse models of AD using intranasal administration of dantrolene. Although Wei does not expressly teach that the memory loss is hippocampal-dependent or hippocampal-independent memory loss, the same 5XFAD mouse model used in Wei is well-established in the art as exhibiting early on-set hippocampus-dependent memory impairment, as taught by Girard.
Girard teaches in the title and Abstract, the “Onset of hippocampus-dependent memory impairments in 5XFAD transgenic mouse model of Alzheimer's disease”. As discussed by Girard, “The 5XFAD mice are an early-onset transgenic model of Alzheimer's disease (AD) in which amyloid plaques are first observed between two and four months of age in the cortical layer five and in the subiculum of the hippocampal formation.”. In the study, memory deficits appeared at 4 months of age in correlation with an increased astrogliosis and amyloid plaque formation. “This early impairment in learning and memory related to the hippocampal dysfunction is particularly suited to assess preclinical therapeutic strategies aiming to delay or suppress the onset of AD.”. Abstract.
Consistent with this reasoning, it would have been obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to apply the intranasal dantrolene treatment of Wei to the same 5XFAD mouse model disclosed by Girard with reasonable expectation that the treatment would address the known hippocampal-dependent cognitive deficits exhibited by the model. Since Wei already administers the therapeutic agent to the same disease model, and Girard clarifies the nature of the memory impairment in that model, the combination merely represents the predictable use of a known treatment in a known AD model exhibiting a known phenotype. Accordingly, the features of claim 32 relating to hippocampal-dependent memory loss would have been obvious over Wei in view of Girard.
Claim 90 is rejected under 35 U.S.C. 103 as being unpatentable over Wei et. al, Grant NIH/R01-AG061447-02 (“Wei”), as applied above to claims 15-17, 19-23, 31-32, and 91-92, and in further view of Lista et al., Journal of Alzheimer’s Disease. 2015;47(2):291-317.
Regarding claim 90, Wei teaches the method of claim 15. Wei teaches a method for improving and/or slowing the decline of cognitive function after onset of neuropathology and cognitive dysfunction, wherein said neuropathology and cognitive dysfunction are caused by Alzheimer's Disease (AD) (page 1, para. 1, “Clinical trials for the treatment of Alzheimer's disease (AD)... Our central hypothesis is that intranasal dantrolene inhibits the excessive activation of RYRs and NMDARs in AD and promotes adult neurogenesis"), the method comprising intranasally administering to a subject in need thereof an amount of dantrolene (page 1, para.1, "Ca2+ dysregulation may be an alternative mechanism. In familial AD (FAD), calcium homeostasis is disrupted by overactivation of NMDA (NMDAR) and ryanodine (RYR) receptors leading to increased cytosolic calcium and subsequent cognitive dysfunction and neuropathology... Our preliminary studies suggested that intranasal dantrolene administration abolished memory loss in 5XFAD ... The overall objective of this study is to investigate the effects and underlying mechanisms of dantrolene ... as well as the effects of intranasal dantrolene administration on adult neurogenesis and cognitive function in AD transgenic mice”) effective to inhibit over-activation of NMDA receptor and/or ryanodine receptor (RyR) (page 1, para. 1, "In familial AD (FAD), calcium homeostasis is disrupted by overactivation of NMDA (NMDAR) and ryanodine (RYR) receptors leading to increased cytosolic calcium and subsequent cognitive dysfunction and neuropathology... Our central hypothesis is that intranasal dantrolene inhibits the excessive activation of RYRs and NMDARs in AD and promotes adult neurogenesis".
While Wei repeatedly refers to Alzheimer’s disease without restriction to any specific subtype, and thus broadly teaches treatment of AD patients generally, Wei does not expressly teach wherein the AD is sporadic Alzheimer’s disease (SAD).
Lista teaches that the vast majority of AD cases are sporadic. Specifically, Lista states, “Most forms of Alzeihmer’s disease (AD are sporadic (sAD)…” (Abstract); that is, “over 95% of AD cases are sporadic” (page 298). Lista therefore establishes that sporadic AD is the predominant clinical form of AD, and represents the expected patient population in AD therapeutic treatment.
Consistent with this reasoning, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention, to apply the method taught by Wei to patients with sporadic AD, because Wei teaches treatment of AD broadly, and Lista establishes that the overwhelming majority of AD cases are sporadic. Therefore, since sporadic AD is the predominant AD subtype, the selection of sAD patients would have been an obvious and routine clinical choice. The limitation of claim 90 merely restricts the treated patient population to a known, expected subset of the disease already taught by Wei. The limitation does not change the mechanism, dosage, route of administration, or therapeutic effect of dantrolene, nor does Applicant identify any unexpected results associated with treating sporadic AD versus familial AD. Accordingly, claim 90 is rendered obvious over Wei in view of Lista.
Claims 69, 93 and 95 are rejected under 35 U.S.C. 103 as being unpatentable over Wei et. al, Grant NIH/R01-AG061447-02 (“Wei”), as applied above to claims 15-17, 19-23, 31-32, and 90-92, and in further view of Went et al., US 20100311697 (“Went”).
Regarding claim 69, Wei teaches the method of claim 15, but does not teach further administering a therapeutically effective amount of a glutamate receptor antagonist to the subject.
Went teaches administering a therapeutically effective amount of a glutamate receptor antagonist (Went Abstract, "The present invention provides novel methods and
compositions for the treatment and prevention of CNS-related conditions. One of the CNS-related conditions treated by the methods and compositions of the invention is Alzheimer's disease"; Went para [0041], "Any NMDAr antagonist can be used in the methods and compositions of the invention ... "; Went paras [0042]-[0043], "Further NMDAr antagonists that may be employed include, for example, ketamine ... aptiganel" and memantine. Therefore, it would have been obvious to one of ordinary skill in the art to combine these references and incorporate the glutamate receptor antagonist by routine experimentation to optimize the treatment of Alzheimer's disease, because both references teach treating Alzheimer's disease (Wei, page 1, para 1; Went, Abstract).
Regarding claims 93 and 95, Wei in view of Went teach the method of claim 69. Wei in view of Went teach the elected species memantine, as well as ketamine as the glutamate receptor antagonist (Went paras [0041]-[0043]). Went further teaches wherein the glutamate receptor antagonist is an agent that blocks the NMDA receptor by competitive antagonism at a glutamate-binding site or is an agent that blocks the
NMDA receptor by noncompetitive antagonism at a glycine, phencyclidine and/or magnesium binding site. Claims 93 and 95 are obvious.
Conclusion
Claims 15-17, 19-23, 31-32, 69, 90-93 and 95 are rejected.
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/C A/Examiner, Art Unit 1622
November 13, 2025
/DANAH AL-AWADI/Primary Examiner, Art Unit 1615