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
RCE NonFinal
Request for Continued Examination
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Applicant’s submission filed on 02/05/2025 has been entered.
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Upon amendment entry, Claims 21-32 and 34-45 stay withdrawn.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:
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 selected from the group consisting of about 5:1, about 2:1, about 1:1, about 1:2, and 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:
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 selected from the group consisting of 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 § 103 -
Applicant' s arguments, filed 07/13/2026 with respect to claims, have been fully considered but they are not persuasive for the following reasons:
Prior Art:
WS Ahmed (Biomed Pharmacother. 2021 Feb;134:111128, hereinafter "Ahmed")
Y. Aravaca, (J Pharmacol Exp Ther. 2009 Dec;331(3):1014-24, hereinafter "Aravaca")
F. Mao et al. (ACS Chem Neurosci. 2018 Feb 21;9(2):328-345, hereinafter "Mao").
Applicant argues: The Office Action alleges that the presently claimed molar ratios constitute merely result-effective variables that would have been routinely optimized by one of ordinary skill in the art. Applicant respectfully disagrees.
The Office Action relies upon Mao as evidence that the presently claimed molar ratios would have been obvious because certain compounds disclosed in Mao exhibit both AChE inhibitory activity and PDE5 inhibitory activity. Applicant respectfully submits, however, that Mao is directed to a different subject matter than that presently claimed invention
Examiner disagrees.
Mao combines AChE inhibition (to increase brain acetylcholine levels and temporarily improve memory/cognition) with PDE5 inhibition (to elevate cAMP/cGMP, promoting neuroprotection, neuroplasticity, and CREB phosphorylation). Though Mao is directed to a different subject matter, there is connection in the dual target AChE and PDE5 inhibition can be used in neurological diseases which affects the activity of TNFα, intracellular Αβ and IL1β.
It is the Examiner’s position that the Instant case does not provide evidence of how combining a PDE5 inhibitor (PDE5) like mirodenafil with an acetylcholinesterase inhibitor (AChE) like rivastigmine synergistically enhances cholinergic neurotransmission and addresses cognitive/cerebrovascular deficits. If there is cascading hierarchy of evidence for unexpected results, the Applicant is invited to submit a Declaration under 37 C.F.R. § 1.132. In that, the Instant Specification does not demonstrate unexpected results for two distinct physiological systems - the cholinergic system (via AChE inhibition) and the nitric oxide/cGMP vascular pathway (via PDE5 inhibition).
Second, in response to Applicant’s argument arguments based on Mao used as prior art, the Examiner disagrees. In response, applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Third, as stated in a prior rejection, 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 Instant claims states both components of a PDE5 inhibitor and an ACHE inhibitor. Based on the prior art the components can be combined or optimized in about 1:1 ratio or about 1:2 ratio for a dual-target combination.
The combination of references, which includes Mao, disclosed a Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5). 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 and Mao (Prong A of KSR) since combining prior art elements according to known methods yields predictable results; also, one in the art would know how to optimize the molar ratios to present the inhibitors at different ratios to show how the inhibition at various concentrations benefits the patient overall.
In the prior art combination, the patient populations are disclosed to have cardiovascular issues or neurological issues. Therefore, Ahmed reads on inhibiting PDE5, cGMP (cyclic GMP) increases. Aravaca discloses inhibitors like donepezil, rivastigmine, and galantamine (which are approved to treat Alzheimer's disease; a neurological disease within the scope of the Instant Case) work by increasing AChE levels. The combination of Ahmed & Aravaca gives suggestion and motivation for a dual-target (combination) inhibitors of AChE and PDE5 inhibitors aimed at treatment of neurological diseases.
Mao adds to this combination with dual-target AChE/PDE5 inhibitors. This supports the dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier 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. So though tadafil is used in Mao, the combination with Ahmed & Aravaca, the use of a PDE5 inhibitor (like mirodenafil) combined with the use of AChE inhibitor (like rivastigmine) enhances cholinergic neurotransmission addressing cognitive deficits (all of which follows KSR – Prong B in substituting mirodenafil and rivastigimine for the PDE5 inhibitor and AChE inhibitor seen in the prior art.
The Applicant’s arguments are not persuasive.
III. RCE Nonfinal Rejection –
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.
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
