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 .
Status of Claims
Claims 11-32 are pending in the application as of the response filed 11/21/2025. Previously examined claims 1-10 are cancelled. Claims 11-32 are newly added. Claims 11-32 are examined herein.
The claim objection and 35 U.S.C. 112(b) rejection of previous record are rendered moot in view of the cancellation of claims 1-10.
The 35 U.S.C. 102 rejections of previous record are rendered moot in view of the cancellation of claims 1-10.
The drawing objections of previous record are withdrawn in consideration of the replacement drawings submitted 11/21/2025.
In view of the pending claims, the following new rejections are made necessitated by the claim amendments.
Applicant’s arguments are based on the rejections of previous record that are rendered moot in view of the cancellation of all previously examined claims. Applicant’s arguments have been addressed to the extent to which they are applicable to the current new rejections.
Priority
This application is a 371 of PCT/IB2021/058487 filed 09/17/2021 and claims foreign priority to FRANCE 20/09509 filed 09/18/2020.
In consideration of Applicant's submission of an English translation to support the claim for foreign priority, the effective filing date of claims 11-32 is 09/18/2020.
Claim Objections
Claim 16 is objected to because of the following informalities:
In claim 16, line 3, the claim should read “detected in a healthy subject”.
Appropriate correction is required.
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.
Claims 12, 21, 29 and 32 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.
Regarding claims 12 and 29, the claims recite the limitation “wherein the TRPA1 calcium channel inhibitor is selected from the group consisting of HC030031, Chembridge- 5861528, A-967079, AP-18, GRC-17536, CB-625, ODM-108, GSK205 and GDC-0334”. However, the structure of the inhibitor compounds “ODM-108” and “CB-625” have not been disclosed in the prior art. Therefore, there is no way for a person of ordinary skill in the art to decipher/search for these compounds. The metes and bounds of the claim is indefinite.
For the purpose of applying prior art, claims 12 and 29 have been interpreted without the limitations “ODM-108”, “CB-625” appearing in the claim.
Regarding instant claims 21 and 32, the claims recite “wherein the TRPA1 calcium channel inhibitor is administered chronically, in particular daily”. The inclusion of the exemplary claim language “in particular” renders the claim indefinite. It is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
For the purpose of applying prior art, claims 21 and 32 have been interpreted to read “wherein the TRPA1 calcium channel inhibitor is administered daily”.
Response to Arguments
Applicants argue on pages 7-8 of the response filed 11/21/2025, that “In particular, the reference by E. Villemure et al. (2021) (submitted herewith), identifying the structure of GDC-0334 [compound (1)], was published on July 19, 2021 … i.e., prior to the filing date of the present application. Thus, the structure of GDC-0334 has been disclosed in the prior art. Regarding the ODM-108 inhibitor, Chen (submitted herewith) discloses that the ODM-108 inhibitor was used in clinical trials (Chen section 2.12) by Orion and establishes a link with the patent applications covering such an inhibitor. Chen additionally identifies the lead compounds in those patent applications. The ODM-108 inhibitor is identifiable by its code name, clinical trials have been conducted, and results have been published using the ODM-108 inhibitor. Additionally, the product designated by this code name cannot vary over time. Thus, a PHOSITA would have been able to easily locate and use the ODM-108 inhibitor. Similarly, CB-325 is disclosed in D4 and D6 (documents of the International search report filed in the August 11, 2023 IDS, alternatively listed as non-patent literature #3 and #1 respectively) ”.
Applicant's arguments have been fully considered but they are not persuasive.
With due respect, it is noted that GDC-0334 was not mentioned in the 35 U.S.C. 112(b) rejection of previous record.
While the examiner appreciates Applicant’s directing attention to the Chen et al. and Talavera et al. references (#1 and #3 references in the IDS, respectively) regarding the structures of ODM-108 and CB-325, it is nevertheless, noted that these references do not disclose the structures of ODM-108 and/or CB-325. Chen et al. explicitly states that “The structure of CB-625 has not been disclosed” (Pg. 651, second column, last paragraph – Pg. 652, first column, continued paragraph). Further, while the clinical trials may reference ODM-108 by its code name, the structure has not been disclosed. There is no way a person of ordinary skill in the art would have been able to search for these compounds to ensure that the there is no prior art that falls within the scope of instant claims 12 and 29 with respect to these specific TRPA1 calcium channel inhibitors, namely ODM-108 and/or CB-325.
Since the structure of ODM-108 and/or CB-325 were not disclosed before the effective filing date of the instant claims, i.e., 18 September 2020, the 35 U.S.C. 112(b) rejections with respect to said TRPA1 calcium channel inhibitor compounds are being maintained for the currently amended claims being examined.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 11-13, 16-26 and 29-32 are rejected under 35 U.S.C. 103 as being unpatentable over Svensson et al. (WO 2014/184248 A2, 20 November 2014, hereinafter Svensson, in the IDS) in view of Bosson et al. (TRPA1 channels promote astrocytic Ca2+ hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-β peptide, 06 July 2017, hereinafter Bosson, in the IDS).
Regarding instant claims 11-13, Svensson teaches methods for treating diseases mediated by the transient receptor potential (TRP) family of ion channels (Pg. 1, Lns. 3-7). Svensson teaches a method for the treatment of a subject suffering from a disorder/disease/condition, especially treatment of Alzheimer's disease whereby an effective amount of a compound according to Formula (I), is administered to a patient in need of such treatment (Pg. 15, Ln. 33 – Pg. 16, Ln. 4; Claim 15; Claim 11). Svensson teaches the compounds of Formula (I) are inhibitors of TRPA1 useful in therapy, especially for treatment of Alzheimer's disease (Pg. 16, Lns. 12-15; Pg. 14, Lns. 22-24). Svensson teaches the term “therapy” encompasses mitigating the condition including “prophylaxis” (i.e., preventing progression of the condition) (Pg. 16, Lns. 5-11).
Svensson do not teach wherein the subject is at a prodromal stage of Alzheimer's disease, and wherein the TRPA1 calcium channel inhibitor prevents an occurrence of neuronal hyperactivity in the subject.
Bosson teaches astrocytes play a crucial role in the early stages of Alzheimer's disease (AD) pathology by contributing to synaptic dysfunction through TRPA1 channels and amyloid-β oligomer (Aβo) toxicity (Abstract; Pg. 11, first column, last paragraph – second column, continued paragraph). Bosson teaches in an AD mouse model (APP/PS1–21 mouse), astrocyte calcium hyperactivity takes place at the beginning of Aβ production, depends on TRPA1 channels and is linked to CA1 neurons hyperactivity (Abstract; Pg. 11, second column, continued paragraph - Pg. 11, second column, second full paragraph, Fig. 5; Pg. 15, first column, continued paragraph). Bosson teaches the application of a TRPA1 blocker, HC 030031 strongly reduced sEPSCs frequency in APP/PS1–21 mice as soon as 5 min after its bath perfusion (Pg. 15, first column, first full paragraph – Pg. 15, first column, second full paragraph, Fig. 7, especially Fig. 7f) (i.e., the strong reduction of spontaneous excitatory postsynaptic currents (sEPSCs) frequency in APP/PS1–21 mice by HC-030031 (a TRPA1 channel inhibitor) directly indicates a reduction in neuronal hyperactivity). Moreover, the studies of Bosson are done in young 1-month old APP/PS1–21 mice/hippocampal slices therefrom, which indicates an early stage of AD, wherein the amyloid beta (Aβ) pathology is present in the hippocampus but is not yet aggregated into plaques (Pg. 11, second column, continued paragraph, Fig. 5a; Pg. 16, second column, first full paragraph) (i.e., this represents a prodromal stage of AD). Bosson emphasizes that astrocytes are implicated far before astrogliosis and inflammatory processes and modulating TRPA1 channel activity, may represent a novel target to hamper early dysfunction in AD (Pg. 17, second column, last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Svensson and Bosson, to have modified the method of Svensson by substituting the TRPA1 inhibitor with the TRPA1 inhibitor (HC 030031) to treat a subject at a prodromal stage of AD as taught by Bosson, to arrive at the instant method claims, wherein the TRPA1 calcium channel inhibitor prevents an occurrence of neuronal hyperactivity in the subject, with a reasonable expectation of success.
Svensson teaches methods for treating diseases mediated by the transient receptor potential (TRP) family of ion channels. Svensson teaches a method for the treatment of a subject suffering from a disorder/disease/condition, especially treatment of Alzheimer's disease by administering an effective amount of a TRPA1 inhibitor compound according to Formula (I), to a patient in need of such treatment. Svensson teaches the term “therapy” encompasses mitigating the condition including “prophylaxis” (i.e., preventing progression of the condition). Bosson teaches in an AD mouse model (APP/PS1–21 mouse), astrocyte calcium hyperactivity takes place at the beginning of Aβ production, depends on TRPA1 channels and is linked to CA1 neurons hyperactivity. Bosson teaches the application of a TRPA1 blocker, HC 030031 strongly reduced sEPSCs frequency in APP/PS1–21 mice, i.e., reduction in neuronal hyperactivity. The studies of Bosson are done in young 1-month old APP/PS1–21 mice/hippocampal slices therefrom, which indicates an early prodromal stage of AD. Bosson emphasizes modulating TRPA1 channel activity, may represent a novel target to hamper early dysfunction in AD.
Therefore, one of ordinary skill in the art would have been motivated to substitute the TRPA1 inhibitor compound in the method of Svensson, with the TRPA1 inhibitor inhibitor compound, HC 030031, as taught by Bosson to specifically treat an Alzheimer's disease patient population at a prodromal stage of Alzheimer's disease, to arrive at the instant method claims. The motivation being to counteract the effect of the Aβ overproduction in the hippocampus implicated in the early prodromal stages of AD, thereby rescuing synaptic plasticity and dysfunction (Abstract; Pg. 17, first column, last paragraph).
As stated in MPEP 2144.06 (II), “An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)”. In the instant case, the compounds of Formula (I) of Svensson and HC 030031 of Bosson are taught to be TRPA1 inhibitors used for the treatment of Alzheimer’s disease (AD), and are considered equivalents in the prior art.
Regarding instant claims 16-18, the teachings of Svensson in view of Bosson render the method of instant claim 11 prima facie obvious.
Svensson do not teach wherein the TRPA1 calcium channel inhibitor normalizes an astrocyte activity hyperactivity in a hippocampus of the subject to levels normally detected in a healthy subject; wherein the TRPA1 calcium channel inhibitor prevents irreversible neuronal dysfunction; to prevent mnesic decline.
Bosson teaches the administration of HC 030031 (a TRPA1 channel inhibitor) reduced the astrocytic Ca2+ hyperactivity induced by Aβo to basal levels/physiological state (Pg. 11, first column, first full paragraph – second full paragraph).
However, the limitations herein with respect to “wherein the TRPA1 calcium channel inhibitor normalizes an astrocyte activity hyperactivity in a hippocampus of the subject to levels normally detected in a healthy subject; wherein the TRPA1 calcium channel inhibitor prevents irreversible neuronal dysfunction; to prevent mnesic decline” are related to the mechanism of action of the agent, a TRPA1 channel inhibitor, such as HC 030031, in the treatment. The combined teachings of Svensson and Bosson teaches the active step of administering the same agent, a TRPA1 channel inhibitor, wherein the TRPA1 channel inhibitor is HC 030031, to the same patient population, a subject afflicted with Alzheimer’s disease at a prodromal stage of the disease. In the absence of evidence to the contrary, the method taught by the combined teachings of Svensson and Bosson, when practiced in treating a subject with Alzheimer’s disease at a prodromal stage of the disease, would have necessarily produced the same treatment effects. Therefore, the limitations of instant claims 16-18 are held unpatentable.
Regarding instant claim 19, the teachings of Svensson in view of Bosson render the method of instant claim 11 prima facie obvious.
Svensson do not teach wherein amyloid β peptide is overproduced in a hippocampus of the subject and the TRPA1 calcium channel inhibitor is administered from an onset of amyloid β peptide overproduction.
Bosson teaches astrocytic hyperactivity starting at the beginning of Aβ overproduction in the hippocampus, long before its aggregation into plaques in young APP/PS1–21 mice (~3–4 weeks) (Pg. 16, second column, first full paragraph; Pg. 17, first column, last paragraph). Bosson teaches this astrocytic hyperactivity is reversed by TRPA1 channel blockade.
. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Svensson and Bosson, to have administered the TRPA1 calcium channel inhibitor from an onset of amyloid β peptide overproduction, wherein the amyloid β peptide is overproduced in a hippocampus of the subject. The motivation being to reverse the astrocytic hyperactivity and associated neuronal hyperactivity that results from the Aβ overproduction, thereby hampering early dysfunction in AD (Pg. 17, first column, continued paragraph; Pg. 17, second column, continued paragraph).
Regarding instant claims 20-21, the teachings of Svensson in view of Bosson render the method of instant claim 11 prima facie obvious. Svensson teaches the TRPA1 inhibitor compounds may be administered by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, … intravenously, … transdermally, intracerebroventricularly (Pg. 15, Lns. 19-25). Svensson teaches the dosage administered will vary with the mode of administration, the treatment desired and the disorder indicated. Svensson teaches a daily dosage of the TRPA1 inhibitor compound in the range from 0.05 mg/kg to 100 mg/kg (this indicates the TRPA1 inhibitor may be administered daily). This renders the limitation of instant claims 20-21 prima facie obvious.
Regarding instant claims 22 and 29-30, Svensson teaches methods for treating diseases mediated by the transient receptor potential (TRP) family of ion channels (Pg. 1, Lns. 3-7). Svensson teaches a method for the treatment of a subject suffering from a disorder/disease/condition, especially treatment of Alzheimer's disease whereby an effective amount of a compound according to Formula (I), is administered to a patient in need of such treatment (Pg. 15, Ln. 33 – Pg. 16, Ln. 4; Claim 15; Claim 11). Svensson teaches the compounds of Formula (I) are inhibitors of TRPA1 useful in therapy, especially for treatment of Alzheimer's disease (Pg. 16, Lns. 12-15; Pg. 14, Lns. 22-24). Svensson teaches the term “therapy” encompasses mitigating the condition including “prophylaxis” (i.e., preventing progression of the condition) (Pg. 16, Lns. 5-11).
Svensson do not teach wherein the subject is at a prodromal stage of Alzheimer's disease with overproduction of amyloid β peptide in a hippocampus of the subject, and wherein an administration of TRPA1 calcium channel inhibitor from an onset of amyloid β peptide overproduction protects neurons of the subject from a toxicity of accumulation of amyloid beta peptide (Aβ) peptide in the hippocampus.
Bosson teaches astrocytes play a crucial role in the early stages of Alzheimer's disease (AD) pathology by contributing to synaptic dysfunction through TRPA1 channels and amyloid-β oligomer (Aβo) toxicity (Abstract; Pg. 11, first column, last paragraph – second column, continued paragraph). Bosson teaches in an AD mouse model (APP/PS1–21 mouse), astrocyte calcium hyperactivity takes place at the beginning of Aβ production, depends on TRPA1 channels and is linked to CA1 neurons hyperactivity (Abstract; Pg. 11, second column, continued paragraph - Pg. 11, second column, second full paragraph, Fig. 5; Pg. 15, first column, continued paragraph). Bosson teaches an early upregulation of the TRPA1 channel from the onset of Aβ secretion (Pg. 11, second column, first full paragraph; Pg. 15, first column, second full paragraph). Bosson teaches both the astrocytic calcium hyperactivity and neuronal hyperactivity observed at the onset of Aβ overproduction were attenuated by the administration of the TRPA1 inhibitor, HC 030031 (Pg. 13, first column, continued paragraph – second column, continued paragraph; Pg. 15, first column, first full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Svensson and Bosson, to have modified the method of Svensson by substituting the TRPA1 inhibitor with the TRPA1 inhibitor (HC 030031) to treat a subject at a prodromal stage of AD as taught by Bosson, to arrive at the instant method claims, wherein an administration of TRPA1 calcium channel inhibitor from an onset of amyloid β peptide overproduction protects neurons of the subject from a toxicity of accumulation of amyloid beta peptide (Aβ) peptide in the hippocampus, with a reasonable expectation of success.
Svensson teaches methods for treating diseases mediated by the transient receptor potential (TRP) family of ion channels. Svensson teaches a method for the treatment of a subject suffering from a disorder/disease/condition, especially treatment of Alzheimer's disease by administering an effective amount of a TRPA1 inhibitor compound according to Formula (I), to a patient in need of such treatment. Svensson teaches the term “therapy” encompasses mitigating the condition including “prophylaxis” (i.e., preventing progression of the condition). Bosson teaches in an AD mouse model (APP/PS1–21 mouse), astrocyte calcium hyperactivity takes place at the beginning of Aβ production, depends on TRPA1 channels and is linked to CA1 neurons hyperactivity. Bosson teaches an early upregulation of the TRPA1 channel from the onset of Aβ secretion. Bosson teaches both the astrocytic calcium hyperactivity and neuronal hyperactivity observed at the onset of Aβ overproduction were attenuated by the administration of the TRPA1 inhibitor, HC 030031.
Therefore, one of ordinary skill in the art would have been motivated to not only substitute the TRPA1 inhibitor compound in the method of Svensson, with the TRPA1 inhibitor compound, HC 030031, but also administer the TRPA1 inhibitor at the onset of Aβ production as taught by Bosson to specifically treat an Alzheimer's disease patient population at a prodromal stage of Alzheimer's disease, to arrive at the instant method claims. The motivation being to counteract the effect of the Aβ overproduction in the hippocampus implicated in the early prodromal stages of AD, thereby rescuing synaptic plasticity and dysfunction (Abstract; Pg. 17, first column, last paragraph).
With regard to the limitations “an administration of TRPA1 calcium channel inhibitor protects neurons of the subject from a toxicity of accumulation of amyloid beta peptide (Aβ) peptide in the hippocampus”, it is related to the mechanism of action of the agent, a TRPA1 channel inhibitor, such as HC 030031, in the treatment. The combined teachings of Svensson and Bosson teaches the active step of administering the same agent, a TRPA1 channel inhibitor, wherein the TRPA1 channel inhibitor is HC 030031, to the same patient population, a subject afflicted with Alzheimer’s disease at a prodromal stage of the disease with overproduction of amyloid β peptide in a hippocampus of the subject. Therefore, the method taught by the combined teachings of Svensson and Bosson, when practiced in treating a subject with Alzheimer’s disease at a prodromal stage of the disease, would have necessarily produced the same treatment effects. This renders the limitations of instant claim 22, prima facie obvious.
As stated in MPEP 2144.06 (II), “An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)”. In the instant case, the compounds of Formula (I) of Svensson and HC 030031 of Bosson are taught to be TRPA1 inhibitors used for the treatment of Alzheimer’s disease (AD), and are considered equivalents in the prior art.
Regarding instant claims 23-26, the teachings of Svensson in view of Bosson render the method of instant claim 22 prima facie obvious.
Svensson do not teach wherein the administration of TRPA1 calcium channel inhibitor stops or slows down neurodegeneration processes in the subject; prevents irreversible neuronal dysfunction in the subject; prevents progression of Alzheimer's disease; prevents mnesic decline.
However, the limitations herein with respect to “wherein the administration of TRPA1 calcium channel inhibitor stops or slows down neurodegeneration processes in the subject; wherein the administration of TRPA1 calcium channel inhibitor prevents irreversible neuronal dysfunction in the subject; wherein the administration of TRPA1 calcium channel inhibitor prevents progression of Alzheimer's disease; wherein the administration of TRPA1 calcium channel inhibitor prevents mnesic decline” are related to the mechanism of action of the agent, a TRPA1 channel inhibitor, such as HC 030031, in the treatment. The combined teachings of Svensson and Bosson teaches the active step of administering the same agent, a TRPA1 channel inhibitor, wherein the TRPA1 channel inhibitor is HC 030031, to the same patient population, a subject afflicted with Alzheimer’s disease at a prodromal stage of the disease. In the absence of evidence to the contrary, the method taught by the combined teachings of Svensson and Bosson, when practiced in treating a subject with Alzheimer’s disease at a prodromal stage of the disease with overproduction of amyloid β peptide in a hippocampus of the subject, would have necessarily produced the same treatment effects. Therefore, the limitations of instant claims 23-26 are held unpatentable.
Regarding instant claims 31-32, the teachings of Svensson in view of Bosson render the method of instant claim 22 prima facie obvious. Svensson teaches the TRPA1 inhibitor compounds may be administered by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, … intravenously, … transdermally, intracerebroventricularly (Pg. 15, Lns. 19-25). Svensson teaches the dosage administered will vary with the mode of administration, the treatment desired and the disorder indicated. Svensson teaches a daily dosage of the TRPA1 inhibitor compound in the range from 0.05 mg/kg to 100 mg/kg (this indicates the TRPA1 inhibitor may be administered daily). This renders the limitation of instant claims 20-21 prima facie obvious.
Claims 14-15 and 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over Svensson et al. (WO 2014/184248 A2, 20 November 2014, hereinafter Svensson, in the IDS) in view of Bosson et al. (TRPA1 channels promote astrocytic Ca2+ hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-β peptide, 06 July 2017, hereinafter Bosson, in the IDS) as applied to claims 11-13, 16-26 and 29-32, in view of Haberman et al. (Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer’s Disease, 30 May 2017, hereinafter Haberman, in the IDS).
The teachings of Svensson and Bosson are set forth in the obviousness rejection above and incorporated herein by reference.
Regarding instant claims 14 and 27, the teachings of Svensson in view of Bosson render the method of instant claim 11 and instant claim 22 prima facie obvious.
Svensson do not teach wherein the subject has neuronal hyperactivity in a hippocampus detectable by brain imaging and mild memory disorders.
Bosson teaches neuronal hyperactivity in a hippocampus of young APP/PS1–21 mice (Pg. 15, first column, second full paragraph). Bosson teaches Fluo-4 imaging for measuring astrocytic calcium hyperactivity (Pg. 17, Additional files inset, second and third paragraph).
Haberman teaches neuronal hyperactivity in the hippocampus of AD subjects being central to cognitive decline in the prodromal stage of the disease (Pg. 663, second column, first paragraph; Pg. 667, second column, second full paragraph; Pg. 672, first column, last paragraph). Haberman teaches the prodromal phase being characterized by amnestic mild cognitive impairment (aMCI) (Pg. 662, second column, first full paragraph). Haberman teaches high-resolution fMRI to characterize the neuronal hyperactivity (Pg. 665, second column, first full paragraph; Fig. 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Svensson, Bosson and Haberman, to have detected the neuronal hyperactivity in the hippocampus by brain imaging and associated cognitive deficit in the prodromal stage of AD. The motivation being to prevent disease progression and accumulating AD pathology (Pg. 672, second column, first full paragraph).
Regarding instant claims 15 and 28, the teachings of Svensson in view of Bosson and Haberman render the method of instant claim 14 and instant claim 27 prima facie obvious.
Svensson do not teach wherein the TRPA1 calcium channel inhibitor restores a neuronal activity hyperactivity in the hippocampus to basal values.
Bosson teaches neuronal hyperactivity in the hippocampus of APP/PS1-21 mice were reversed to basal levels by TRPA1 channel inhibitor, HC 030031 (Pg. 15, first column, second full paragraph; Fig. 7f).
Therefore, the limitations of instant claims 15 and 28 are rendered prima facie obvious.
Alternately, the limitations herein with respect to “wherein the TRPA1 calcium channel inhibitor restores a neuronal activity hyperactivity in the hippocampus to basal values” is related to the mechanism of action of the agent, a TRPA1 channel inhibitor, such as HC 030031, in the treatment. The combined teachings of Svensson, Bosson and Haberman teaches the active step of administering the same agent, a TRPA1 channel inhibitor, wherein the TRPA1 channel inhibitor is HC 030031, to the same patient population, a subject afflicted with Alzheimer’s disease at a prodromal stage of the disease/subject with overproduction of amyloid β peptide in a hippocampus of the subject. In the absence of evidence to the contrary, the method taught by the combined teachings of Svensson, Bosson and Haberman, when practiced in treating a subject with Alzheimer’s disease at a prodromal stage of the disease, would have necessarily produced the same treatment effects. Therefore, the limitations of instant claims 15 and 28 are held unpatentable.
Response to Arguments
Applicants argue on pages 10-11 of the response dated 11/21/2025, that “Bosson does not provide any motivation for a PHOSITA to conclude that the inhibitor has a neuroprotective effect in the treatment and/or prevention of early stages of Alzheimer's disease in subjects at the prodromal stage of the disease. Rather, a PHOSITA would have tested the curative effect of TRPA1 inhibition on more advanced stages of the disease, with a view to reversing the disease since this was approach taken in Bosson”. Applicants argue that “Furthermore, Bosson fails to disclose any information on the treatment with HC030031 on the therapeutic effect in vivo”. Applicants argue “Bosson fails to disclose this prophylactic effect on one hand, and treatment by restoring damage observed in the prodromal stage on the other hand, due to the neuroprotective effect. Bosson additionally fails to even suggest this because Bosson fails to disclose in vivo data and tests on CA1 neuronal activity”.
Applicant's arguments have been fully considered but they are not persuasive.
As clearly discussed in the 103 rejections above, the Bosson reference provides sufficient motivation to a person of ordinary skill in the art to utilize the TRPA1 calcium channel inhibitor in the treatment of prodromal stages of Alzheimer’s disease. The combined teachings of Svensson, Bosson and Haberman, render all the limitations of instant claims 11-32, prima facie obvious.
Firstly, it is noted that all the studies of Bosson are done in young 1-month old APP/PS1–21 mice/hippocampal slices therefrom, which indicates an early stage of AD, wherein the amyloid beta (Aβ) pathology is present in the hippocampus but is not yet aggregated into plaques – this corresponds to a prodromal stage of AD. Therefore, contrary to Applicant’s contention that a PHOSITA would only have considered the use of a TRPA1 inhibitor in more advanced stages of the disease, Bosson provides sufficient motivation for using the TRPA1 inhibitor, HC 030031 in the prodromal stages of AD.
Secondly, the examiner notes that it is well within the skill of one of ordinary skill in the art of pharmaceutical treatments to extrapolate the results of research done in a mouse model of AD, to human treatments. Therefore, the results of Bosson are directly translatable to in vivo treatments.
Finally, the examiner notes that Bosson teaches recording spontaneous EPSCs in APP/PS1–21 mice at the onset of Aβ overproduction, and observe an increase in the neuronal activity in CA1 neurons (Pg. 15, first column, first full paragraph). Bosson teaches both astrocytic calcium hyperactivity and associated neuronal hyperactivity that occur at the beginning of Aβ overproduction is reversed by blocking the TRPA1 channel with HC 030031 (a TRPA1 channel inhibitor).
Applicants are encouraged to present a clear and convincing evidence of nonobviousness or unexpected results to overcome the rejections of record.
Conclusion
Claims 11-32 are rejected.
Claim 16 is objected to.
No claims are allowed.
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 PADMAJA S RAO whose telephone number is (571)272-9918. The examiner can normally be reached on 9:00-5:30pm EDT.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney L Klinkel can be reached on (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/PADMAJA S RAO/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627