Detailed Action
Claims 1-12, 14-19 are rejected to and under examination.
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
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Rejections - 35 USC § 112
Claims 1-12, and 14-19 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 a method of treating Alzheimer’s Disease or dementia in a human subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, or a pharmaceutically acceptable salt thereof, does not reasonably provide enablement for a method of prevention of Alzheimer’s Disease or dementia in human subjects who do not already have or show signs of the disease, comprising administering to the subject a pharmaceutical composition comprising ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, or a pharmaceutically acceptable salt thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art predictability of the art and the amount of experimentation necessary. 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 1, on which the rest of the Applicant’s claims depend, is drawn to a method of treating Alzheimer's Disease or dementia in a human subject, comprising administering to the subject a pharmaceutical composition comprising ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, or a pharmaceutically acceptable salt thereof; wherein the load dose of the compound or pharmaceutically acceptable salt thereof is between 5 to 25 mg; and wherein the compound or pharmaceutically acceptable salt thereof is administered to the subject at a daily dose of 5 to 25 mg.
However, the nature of the invention is complex in that the Applicant defines treatment as “any form of intervention where a compound is administered to a subject suffering from, or at risk of suffering from, or potentially at risk of suffering from the disease or disorder in question”, and prophylactic treatment or prevention of a multifactorial disease such as Alzheimer’s Disease or dementia is undeterminable and not a guaranteed outcome.
Breadth of the Claims: The claims are broad in that the claims recite a method for
prevention of Alzheimer's Disease or dementia (broad and multifactorial diseases) in a human subject, comprising administering to the subject a pharmaceutical composition comprising ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, or a pharmaceutically acceptable salt thereof; wherein the load dose of the compound or pharmaceutically acceptable salt thereof is between 5 to 25 mg; and wherein the compound or pharmaceutically acceptable salt thereof is administered to the subject at a daily dose of 5 to 25 mg. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the Specification and Existence of Working Examples: The specification describes using HTL0018318, the Applicant’s claimed compound, in humans with and without concurrent administration of Donepezil, and shows cognitive improvements in human subjects.
However, no working examples are given for a method of preventing Alzheimer’s Disease or dementia. While it is noted that the applicant has shown relevant activity against Alzheimer’s Disease and dementia, the applicant is not enabled for prevention of Alzheimer’s Disease and dementia as claimed.
Predictability and State of the Art: The state of the art at the time the invention was made was unpredictable and underdeveloped. It is known in the art that
the development of Alzheimer’s Disease and dementia is highly dependent on multiple unpredictable factors including individual genetic disposition, demographic, environmental exposures, etc. Due to the unpredictable nature of Alzheimer’s Disease and dementia the applicant does not disclose a method of preventing Alzheimer's Disease or dementia in a human subject, comprising administering to the subject a pharmaceutical composition comprising ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, or a pharmaceutically acceptable salt thereof; wherein the load dose of the compound or pharmaceutically acceptable salt thereof is between 5 to 25 mg; and wherein the compound or pharmaceutically acceptable salt thereof is administered to the subject at a daily dose of 5 to 25 mg.
CDC. Reducing Risk for Dementia, Alzheimer's Disease and Dementia, [online], [retrieved on 12/23/2025]. https://www.cdc.gov/alzheimers-dementia/prevention/index.html (Year:2024) - Explains that there are identified risk factors for Alzheimer’s.
Alzheimer’s Association. Can Alzheimer’s Disease Be Prevented? [online], [retrieved on 12/23/2025]. https://www.alz.org/alzheimers-dementia/research and progress/prevention#prevention - Explains that Alzheimer’s Disease and dementia are not known to be preventable at this time.
Amount of Experimentation Necessary: The quantity of experimentation necessary to carry out the claimed invention is high, as the skilled artisan could not rely on the prior art or instant specification to teach how to prevent Alzheimer’s Disease and dementia using the Applicant’s claimed compound in a method to prevent Alzheimer’s Disease or dementia in a human subject. In order to carry out the claimed invention, one of ordinary skill in the art would have to administer the claimed compound as a regular, prophylactic dosing over the course of a long enough period of time under conditions where it would be certain that Alzheimer’s Disease or dementia would develop, which would be an impossible experimental setup due to the duration and the lack of a true control group.
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 1-12, and 14-19 are not considered to be fully enabled by the instant specification.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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) 1-12, and 14-19 are rejected under 35 U.S.C. 103 as being unpatentable over Congreve, M. S., et. al. (US Patent No. 10,030,035 B2; Issued 07/24/2018).
Congreve teaches the Applicant’s claimed compound, ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (See e.g. col. 26; Table 1; Example 2-2) encompassing both stereoisomers as claimed in claims 2 and 3, and having activity as muscarinic M1 and M4 receptor agonists at higher selectivity than M2 and M3 receptors (See e.g. col. 3; line 66- col.4; line 3). Congreve also teaches that this mechanism is relevant in Alzheimer’s and dementia (See e.g. col. 1; lines 40-61), that ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate is administered to human subjects in need thereof (See e.g. col. 26; line 4), claims a method of treating dementia in a subject in need thereof using ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (See claim 10), and mentions that the dementia may be dementia with Lewy bodies (See e.g. col. 18; Line 57).
It would have been obvious to one skilled in the art, before the Applicant’s effective filling date, to modify Congreve’s teaching of the Applicant’s claimed compound and stereoisomers, the mechanism as a muscarinic M1 and M4 receptor agonist, and that this mechanism is relevant in treating Alzheimer’s Disease and dementia with or without Lewy bodies, to arrive at the Applicant’s claimed method of using ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, in a composition to treat Alzheimer’s Disease or dementia with or without Lewy bodies in a human subject.
Congreve also teaches that the pharmaceutical compositions may contain a sufficient amount of ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate to provide a desired level of biological activity, and may contain between 1 nanogram to 2 grams of the claimed compound, and that oral dosage forms may contain 1 mg to 2 g, or preferably 10 mg to 1g (See e.g. col. 25; line 54 - col. 26; line 2).
According to MPEP 2144.05, "In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)".
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical."[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)
It would have been obvious to one skilled in the art, before the Applicant’s effective filling date, to routinely optimize Congreve’s taught dosing range of 1 mg to 2 g ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, to arrive at the applicant’s various claimed dosing ranges of 5 mg to 25 mg ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, in a method of treating Alzheimer's Disease or dementia, with or without Lewy bodies, in a human subject, comprising administering to the subject a pharmaceutical composition comprising the compound ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, or a pharmaceutically acceptable salt thereof, once ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate and its mechanism of action as a M1 and M4 muscarinic receptor agonist, since dosing is a result-effective variable.
Congreve also teaches donepezil as a positive control from which to compare the effects of ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (See e.g. col. 87; line 35-38), as it is a standard of care in Alzheimer’s treatment, along with other cholinesterase inhibitors.
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
It would have been obvious, prior to the Applicant’s effective filing date, to use a cholinesterase inhibitor such as donepezil, in the Applicant’s method of treating Alzheimer's Disease or dementia, with or without Lewy bodies, in a human subject, comprising administering to the subject a pharmaceutical composition comprising the compound ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, or a pharmaceutically acceptable salt thereof, as donepezil and other cholinesterase inhibitors are routine compounds for treatment of Alzheimer’s and dementia, supported by Congreve’s use of donepezil as a positive control for an experiment testing Alzheimer’s symptoms.
Congreve teaches that the claimed compound can be further converted into a pharmaceutically acceptable salt (See e.g. col. 84; lines 5). Congreve also teaches that the claimed compound can be in a composition with pharmaceutically acceptable excipients such as, “carriers (e.g. a solid, liquid or semi-solid carrier), adjuvants, diluents (e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents), granulating agents, binders, flow aids, coating agents, release-controlling agents (e.g. release retarding or delaying polymers or waxes), binding agents, disintegrants, buffering agents, lubricants, preservatives, anti-fungal and antibacterial agents, antioxidants, buffering agents, tonicity-adjusting agents, thickening agents, flavouring agents, sweeteners, pigments, plasticizers, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions”(See e.g. col. 24; lines 29-41). Congreve also teaches that the claimed compound can be in a pharmaceutically acceptable dosage form suitable for oral administration, such as “tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches (See e.g. col. 24; lines 60-64).
It would have been obvious, prior to the Applicant’s effective filing date, to use Congreve’s teachings of using ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate in various pharmaceutically acceptable salts, excipients, and oral dosage forms, to arrive at the Applicant’s claims of using various pharmaceutically acceptable salts, excipients, and oral dosage forms, in a method of treating Alzheimer's Disease or dementia, with or without Lewy bodies, in a human subject, comprising administering to the subject a pharmaceutical composition comprising the compound ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, or a pharmaceutically acceptable salt thereof.
One skilled in the art would have had sufficient teaching, suggestion, or motivation, before the Applicant’s effective filling date, to modify the teachings of Congreve to arrive at the Applicant’s method of treating Alzheimer’s Disease or dementia with or without Lewy bodies, in a human subject. This method involves administering to the subject a pharmaceutical composition comprising the compound ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, or a pharmaceutically acceptable salt thereof such as the hydrochloride salt, in routinely optimized doses, in pharmaceutically acceptable carriers, excipients and routine oral dosage forms such tablets, as well as administration with a standard of care cholinesterase inhibitor such as donepezil.
Conclusion
No claims are allowed.
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/OROD MOTEVALLI/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628