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 .
DETAILED ACTION
Final Rejection
Claim Status
Claims 17-20 and 33 were pending in the prior Office Action.
Upon amendment entry, Claims 21-32 and 34-45 stay withdrawn.
Claims 17-20 and 33 are currently pending examination.
Priority Status
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No foreign priority was claimed in the Instant Application.
Examiner Responses to Arguments/Amendments
The issues raised in the Office Action, are addressed below:
I. Claim Amendments –
Upon Amendment entrance, Claim 17 was amended with an additional limitation:
A pharmaceutical composition comprising: a phosphodiesterase 5 inhibitor or a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof;
wherein a molar ratio of the phosphodiesterase 5 inhibitor or the pharmaceutically acceptable salt thereof, the solvate thereof, or the hydrate thereof and the acetylcholinesterase inhibitor or the pharmaceutically acceptable salt thereof, the solvate thereof, or the hydrate thereof is about 5:1, about 2:1, about 1:1, about 1:2, or about 1:5,
and wherein the pharmaceutical composition is configured to inhibit IL-1β activity or TNFα activity, or reduce intracellular Αβ via administration to a subject in need thereof.
Upon Amendment entrance, Claim 33 was amended with an additional limitation:
A pharmaceutical composition: mirodenafil or a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof; and
one or more of donepezil or a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof, galantamine or a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof, or rivastigmine or a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof,
wherein a molar ratio of mirodenafil or the pharmaceutically acceptable salt thereof, the solvate thereof, or the hydrate thereof and the one or more of donepezil or the pharmaceutically acceptable salt thereof, the solvate thereof, or the hydrate thereof, galantamine or the pharmaceutically acceptable salt thereof, the solvate thereof, or the hydrate thereof, or rivastigmine or the pharmaceutically acceptable salt thereof, the solvate thereof, or the hydrate thereof is about 5:1, about 2:1, about 1:1, about 1:2, or about 1:5,
and wherein the pharmaceutical composition is configured to inhibit IL-1β activity or TNFα activity, or reduce intracellular Αβ via administration to a subject in need thereof.
II. Claim Rejections - 35 USC § 112 -
In view of the Applicant’s amendment, the 35 U.S.C. 112(a) rejection over Claims 18-20, and 33 is withdrawn.
III. Claim Rejections - 35 USC § 103 -
Applicant' s arguments, filed 02/17/2026 with respect to claims have been fully considered but they are not persuasive for the following reasons:
Applicant argues: The motivation to combine the benefits of both types of inhibition, increasing both acetylcholine and cGMP levels, results in improving cognitive function more effectively offer a rationale for synergistic benefits."
Applicant respectfully disagrees. One skilled in the relevant art would not arrive at each and every feature of present claims 17 and 33, especially in view of the newly recited features that "a molar ratio of the phosphodiesterase 5 inhibitor or the pharmaceutically acceptable salt thereof, the solvate thereof, or the hydrate thereof and the acetylcholinesterase inhibitor or the pharmaceutically acceptable salt thereof, the solvate thereof, or the hydrate thereof is about 5:1, about 2:1, about 1:1, about 1:2, or about 1:5" and "the pharmaceutical composition is configured to inhibit ILlP activity or TNFa activity, or reduce intracellular Ap via administration to a subject in need thereof."
Examiner disagrees.
In the pharmaceutical composition of a PD5 inhibitor, the recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. The claim states both components of a PDE5 inhibitor and an ACHE inhibitor. Based on the prior art the components can be combined in about 1:1 ratio or about 1:2 ratio for a dual-target combination. The reference of Mao disclosed a Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5). Indicating that “the substituent group at the N-atom of piperazine-2,5-dione was replaceable for PDE5 inhibitory activity while retaining the parent nucleus to maintain PDE5 inhibitory activity.” In the assessment of the concentration needed for effective inhibition, Compound 1p, 1q and 1w give ratio of about 1:1 and about 1:2 for AChE:PDE5 activity (1q - 0.075 AChE:0.153 PDE5 is a ratio about 1:2).
As such, it would therefore be obvious to combine Ahmed & Aravaca (Prong A of KSR) since combining prior art elements according to known methods yields predictable results. In the prior art combination, the patient populations have cardiovascular issues or neurological issues, which Ahmed discloses by inhibiting PDE5, cGMP (cyclic GMP) increases, which can lead to vasodilation and has neuroprotective effects by activating pathways that support memory, and neuroplasticity.
Aravaca discloses inhibitors like donepezil, rivastigmine, and galantamine (which are approved to treat Alzheimer's disease) work by increasing AChE levels, which is important for memory and cognition. The combination of Ahmed & Aravaca as discussed above - through Prong A of KSR - already has motivation in the prior art for a dual-target (combination) inhibitors of AChE and PDE5 in the treatment of Alzheimer's disease (AD).
As evidenced in Mao, dual-target AChE/PDE5 inhibitors are good candidate drugs for Alzheimer's disease (AD). This supports the dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier (BBB) penetrability. Also (pg. 331, col. 1, para. 1) tadalafil, a selective PDE5 inhibitor was found to have AChE inhibition. In those studies, tadalafil and derivatives synthesized aided in reversing cognitive dysfunction in animal models.
Based on the above, in the Ahmed & Aravaca combination, the use of a PDE5 inhibitor (like mirodenafil) combined with the use of AChE inhibitor (like rivastigmine) enhances cholinergic neurotransmission addressing cognitive deficits, which may be compounded by cerebrovascular deficiencies. The motivation to combine the benefits of both types of inhibition, increasing both acetylcholine and cGMP levels, results in improving cognitive function more effectively offer a rationale for synergistic benefits.
The Applicant’s arguments are not persuasive.
IV. New Rejections –
The 35 USC § 103 rejection is withdrawn because Applicant amended independent Claims 17 and 33 with an additional limitations.
This necessitated a new rejection.
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 17 and 33 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, Claims 17 and 33 recites the following molar ratios for the range/limitation: wherein a molar ratio of the phosphodiesterase 5 inhibitor or the pharmaceutically acceptable salt thereof, the solvate thereof, or the hydrate thereof and the acetylcholinesterase inhibitor or the pharmaceutically acceptable salt thereof, the solvate thereof, or the hydrate thereof is about 5:1, about 2:1, about 1:1, about 1:2, or about 1:5.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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.
Graham vs. Deere, Test for Obviousness
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.
Joint Inventors
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.
Claim(s) 17-20 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over WS Ahmed, (Biomed Pharmacother. 2021 Feb;134:111128; hereinafter “Ahmed”) and in view of Y. Aravaca, (J Pharmacol Exp Ther. 2009 Dec;331(3):1014-24; hereinafter “Aravaca”) and in further view of F. Mao, et al (ACS Chem Neurosci. 2018 Feb 21;9(2):328-345; hereinafter “Mao”).
With respect to Claims 17-19 and 33, Ahmed discloses a pharmaceutical composition comprising: at least one phosphodiesterase 5 inhibitor.
With respect to Claims 17-19, and 33, Ahmed discloses wherein the phosphodiesterase 5 inhibitor (PDE5, abstract) comprises mirodenafil (pg. 111128, col. 2, paras. 1 and 2). Mirodenafil has been used in trials studying the treatment and supportive care of kidney diseases, urologic diseases renal insufficiency, and erectile dysfunction. Kidney diseases, urologic diseases, and erectile dysfunction (ED) share common causes related to vascular, hormonal, and neurological issues, and are frequently linked to other comorbidities. Further, the prior art delves into the structure of PDE5, how its function is regulated, and discusses the clinically available inhibitors that target phosphodiesterase 5, aiming to better understand the structural bases of their affinity and specificity.
Ahmed does convey “…in addition to PDE5, some of these inhibitors can selectively inhibit other enzymes including acetylcholine esterase.” Ahmed though fails to disclose “…and an acetylcholinesterase inhibitor as active ingredients, and pharmaceutically acceptable salts, solvates, hydrates of said phosphodiesterase 5 inhibitor and said acetylcholinesterase inhibitor” and “wherein a molar ratio of the phosphodiesterase 5 inhibitor is about 5:1, about 2:1, about 1:1, about 1:2, or about 1:5,”
Aravaca discloses for Claims 17-20 and 33, wherein the acetylcholinesterase (AChE) inhibitor comprises rivastigmine (pg. 1015, col. 2, full para. 2; Donepezil, rivastigmine, or huperzine A was injected intramuscularly (indicating a pharmaceutical composition) in a hind limb in volumes not exceeding 0.5 ml/kg, before or after subcutaneous injection of soman). Rivastigmine is a centrally acting acetylcholinesterase inhibitor that increases the availability of acetylcholine by slowing its breakdown. It is approved for the symptomatic management of mild to moderate Alzheimer’s disease and dementia associated with Parkinson’s disease, aiming to improve cognitive function by enhancing cholinergic transmission in the brain.
It would therefore be obvious to combine Ahmed and Aravaca (Prong A of KSR) since combining prior art elements according to known methods yields predictable results. In the prior art combination, the patient populations have cardiovascular issues or neurological issues, which Ahmed discloses by inhibiting PDE5, cGMP (cyclic GMP) increases, which can lead to vasodilation and has neuroprotective effects by activating pathways that support memory, and neuroplasticity. Aravaca discloses inhibitors like donepezil, rivastigmine, and galantamine (which are approved to treat Alzheimer's disease) work by increasing AChE levels, which is important for memory and cognition.
The combination of Ahmed & Aravaca as discussed above - through Prong A of KSR - already has motivation in the prior art for a dual-target inhibitors of AChE and PDE5 in the treatment of Alzheimer's disease (AD). Both Ahmed & Aravaca intended use of the claimed invention. The prior art composition with its structures is capable of performing the intended use, thus it meets the claims.
Ahmed & Aravaca fail to disclose ““wherein a molar ratio of the phosphodiesterase 5 inhibitor is about 5:1, about 2:1, about 1:1, about 1:2, or about 1:5,”
molar ratio of the phosphodiesterase 5 inhibitor….and the acetylcholinesterase inhibitor…is about 5:1, about 2:1, about 1:1, about 1:2, or about 1:5.
Mao, teaches a dual-target AChE/PDE5 inhibitors are good candidate drugs for Alzheimer's disease (AD). This supports the dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier (BBB) penetrability. Also (pg. 331, col. 1, para. 1) tadalafil, a selective PDE5 inhibitor was found to have AChE inhibition. In those studies, tadalafil and derivatives synthesized aided in reversing cognitive dysfunction in animal models.
Based on the prior art, the components can be combined in about 1:1 ratio or about 1:2 ratio for a dual-target combination. The reference of Mao disclosed a Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) indicating that “the substituent group at the N-atom of piperazine-2,5-dione was replaceable for PDE5 inhibitory activity while retaining the parent nucleus to maintain PDE5 inhibitory activity.” In the assessment of the concentration needed for effective inhibition, several compounds showed ratio as addressed in the Instant Claim. In particular 1q for AChE:PDE5 activity (pg. 334; 1q - 0.075 AChE:0.153 PDE5 is a ratio about 1:2).
Based on the above, in the Ahmed, Aravaca & Mao combination, the use of a PDE5 inhibitor (like mirodenafil) combined with the use of AChE inhibitor (like rivastigmine) enhances cholinergic neurotransmission addressing cognitive deficits, which may be compounded by cerebrovascular deficiencies. The motivation to combine the benefits of both types of inhibition, increasing both acetylcholine and cGMP levels, results in improving cognitive function more effectively offer a rationale for synergistic benefits.
According to the MPEP, the molar ratio range presented occurs within the prior art, even if not explicitly stated, thus rendering it obvious. To optimize result-effective variables, it must be noted that the weight ratio, molar ratio, purification percentage, temperature, etc…at which a composition is directed, is itself a result-effective variable and will alter the production of by-products and the final desired yield of product depending on the ratio/desired starting quantities. Changes in the result-effective variables, in this case molar ratio of PDE5 inhibitor affects the overall behavior of the composition.
It would have been obvious to one of ordinary skill in the art to choose the instantly
claimed ratios through process optimization, since it has been held that where the general
conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges
involves only routine skill in the art. See In re Boesch, 205 USPQ 215 (CCPA 1980).See MPEP
2144.05 incorporated by reference herein.
However, it would have been prima facie obvious to one having ordinary skill in the art to arrive at an overlapping range because according to MPEP 2144.05.
Overlapping ranges:
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) (The prior art taught carbon monoxide concentrations of “about 1-5%” while the claim was limited to “more than 5%.” The court held that “about 1-5%” allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of “50 to 100 Angstroms” considered prima facie obvious in view of prior art reference teaching that “for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms].” The court stated that “by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range.”).
Conclusion
Claims 17-20 and 33 are rejected.
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 Josmalen M. Ramos-Lewis whose telephone number is (571)272-0084. The examiner can normally be reached M-F 9:30-5:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Josmalen M. Ramos-Lewis, Ph.D.
Patent Examiner
Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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