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
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 03/16/2026 has been entered.
Response to Amendment
Acknowledgment is made of the amendment filed on 03/16/2026, wherein claims 17 is amended with molar ratio instead of weight ratio of phosphodiesterase 5 inhibitor and NMDA receptor antagonist. It’s noted claim 17 still directed to broad combination genus comprising phosphodiesterase 5 inhibitor genus and NMDA receptor antagonist genus.
Election/Restrictions
Applicant elected Group I, claims 17-20 and 33, drawn to pharmaceutical composition; and species: a) mirodenafil as the species of phosphodiesterase 5 inhibitor; b) memantine as the species of NMDA-receptor; and c) dementia as the disease species on 04/28/2025.
Claims 21-32, 34-45 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention.
Status of Claims
Claims 17-45 are pending in the instant application.
Claims 21-32, 34-45 remain withdrawn.
Claims 17-20 and 33 are currently under examination.
Priority
This application 19/003/405 filed on 12/27/2024, is a continuation of PCT/IB2023/056712 filed 06/28/2023, which claims priority benefit of US provisional application No. 63/367,282 filed 06/29/2022.
Claim Objection
Claims 17 is objected to because of the following informalities:
Claims 17 recites " molar ratio of the phosphodiesterase 5 inhibitor or the pharmaceutically acceptable salt thereof, the solvate thereof, or the hydrate thereof and the NMDA-receptor antagonist or the pharmaceutically acceptable salt thereof, the solvate thereof, or the hydrate thereof” are redundant.
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 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 non-obviousness.
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 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 interpretation: Instant claims 17-20 and 33 are product claims wherein the intended use/function (e.g. inhibit TNFα activity or reduce intracellular Aβ ) do not necessarily contribute to the structural limitation of composition product. If the prior art composition is capable of performing the intended use/function, then it meets the limitation.
Claims 17-20 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (US 20150297599 A1, hereafter “Kim’599”, corresponding to US 9,750,743B2), in view of NAMZARIC 2014 label, Went et al. (US 8,580,858 B2) and Kabir et al. (International Journal of Molecular Sciences, 2020, 21, 3272; doi:10.3390/ijms21093272, Combination Drug Therapy for the Management of Alzheimer’s Disease).
Regarding phosphodiesterase 5 inhibitor component of claim 17-18, and mirodenafil of claims 19 and 33, Kim’599 disclosed a pharmaceutical composition comprising phosphodiesterase 5 inhibitor (e.g. mirodenafil) for inhibiting brain neuron apoptosis and treating neuronal degenerative disease associated with brain neuron apoptosis(e.g. dementia, Alzheimer's dementia etc.)(See abstract, [0004], [0049], claims 14-23).
Kim’599 disclosed dosage amount, dose form and administration regimen, etc. for the pharmaceutical composition comprising phosphodiesterase 5 inhibitor (e.g. 0.5-2 mg/kg)(See [0070]-[0083]). Kim’599 disclosed composition comprising mirodenafil administered at various amount (e.g. 2mg/kg) (See [0090]), and neuroprotective effects of mirodenafil in in-vivo test (See Example 1-2, Table 1, 3-10, Figures 4-8). A skilled artisan would know how to convert the dose (rat) for human subject, For example, 2 mg/kg of dose for rat could be calculated as 19.2 mg ( =2mg/kg x0.16 x 60kg) for human adult with normal weight of 60kg (See FDA guidance for dose conversion).
Kim’599 disclosed neuronal degenerative disease that could be prevented or treated by the phosphodiesterase 5 inhibitor, e.g. dementia, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis, wherein the dementia is AIDS-induced dementia, Lewy body dementia, frontotemporal dementia, multi-infarct dementia, semantic dementia, Alzheimer's dementia, and vascular dementia, etc. (See [0064], claim 17).
Kim’599 is silent about combining mirodenafil or other phosphodiesterase 5 inhibitor with NMDA-receptor (e.g. memantine), and ratio thereof.
Combination therapy is common practice in the field of treating neurological diseases. A skilled artisan would have known memantine/ NAMENDA is one of most commonly used NMDA receptor antagonist approved by FDA in 2003 for treating Alzheimer’s /dementia as s disclosed by instant specification (See page 3, [13]). "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) See MPEP 2144.06.
NAMZARIC is approved by FDA in 2014 for treatment of moderate to severe dementia of the Alzheimer’s. NAMZARIC comprises combination of 5-10mg twice daily or 14 mg or 28 mg memantine hydrochloride extended-release and 10 mg donepezil hydrochloride (cholinesterase inhibitor ) (See Indication, Dosage, and Dosage forms and strengths). The weight ratio of active ingredient donepezil to memantine hydrochloride is calculated about 1:1 or 2:1, or 1: 1.4 or 1: 2.8.
Regarding the amended molar ratio limitation, in the standard FDA-approved maintenance dose of Namzaric ( 28 mg of memantine hydrochloride and 10 mg of donepezil hydrochloride),
Memantine hydrochloride (Molecular weight is roughly 215.76 g/mol), dose of 28mg equals 0.13 mmol = 28 mg /215.76 g/mol.
Donepezil hydrochloride (Molecular weight is roughly 415.95 g/mol). dose of 10 mg equals 0.024 mmol = 10 mg /415.95 g/mol;
The molar ratio of donepezil hydrochloride to memantine hydrochloride is calculated to be about 1:5.4 (= 0.024 mmol/0.13 mmol) which falls within instant claimed molar ratio of about 1:5.
Went is the original patent of NAMZARIC. Went teaches composition comprising combination of N-Methyl-D-Aspartate receptor (NMDAr) antagonist (e.g. memantine) and a second agent such as acetylcholinesterase inhibitor (Ache l) (e.g. donepezil, rivastigmine, etc.) for treating CNS-related conditions(e.g. Alzheimer’s) (See abstract, Col. 2, lines 1-67; Col. 7, lines 46-67; Col. 8, lines 1-50; Col. 9, lines 1-25; Examples 1-12; claims 1-10). Went teaches various amount of memantine, e.g. 2.5 and 80 mg per day and donepezil ranges between 1 and 20 mg/day (See Col 11, lines 4- 30) and ratio thereof, e.g. preferably 1:10 to 10:1 by mass (See Col. 16, lines 11-16; Example 2, Table 3; Example 5- 7, Table 13). Went teaches combination of NMDAr antagonist and AChe provides additive effect, improves efficacy and avoids undesirable side effects of both drugs (Col. 12, lines 6- 30).
Kabir reviews combination therapy for management of Alzheimer’s disease which is a leading cause of dementia. Kabir and its incorporated references teach AD is a multifactorial disorder, major AD hallmark includes the accumulation of Aβ as senile plaques and aggregating hyperphosphorylated tau-mediated neurofibrillary tangles, etc. and combination of therapeutic agents are more effective as compared to single-agent therapy, for example, NAMZARIC, combination of memantine and donepezil(cholinesterase inhibitor, approved by FDA in 2014 (See Introduction). Kabir and incorporated references teach variety of combination therapy comprising memantine, one of most commonly used FDA-approved NMDA receptor antagonists for treating Alzheimer’s /dementia/ (See Table 1). Kabir teaches combination therapy targeting at different pathophysiological mechanisms actions (See Table 2), which may be more beneficial, wherein different pathophysiological mechanisms actions might increase drug efficacy by stimulating synergistic or additive actions (See page 12/23, Potential Benefits of Combination Therapies).
It would have been obvious to one of the ordinary skill in the art before the effective filing date of instantly claimed invention to combine the phosphodiesterase type 5 inhibitor (e.g. mirodenafil) taught by Kim’599 with commonly used FDA approved memantine for treating Alzheimer /dementia as taught by Namzaric, Went, Kabir, and arrive at the instant claimed invention with reasonable expectation of success. At the time the invention was made, it was known that phosphodiesterase type 5 inhibitor (e.g. mirodenafil) could be used for treating Alzheimer /dementia as taught by Kim’599. A skilled artisan would also have known memantine is FDA approved NMDA inhibitor for treating Alzheimer’s dementia that could be combined with other Alzheimer dementia medicine in combination therapy as taught by NAMZARIC label, Went and Kabir. Went is the original patent of NAMZARIC and teaches combination of memantine with donepezil at various amount and ratios. Dose exploration is within the knowledge of a skilled artisan. A skilled artisan would have known to explore the amount/ratio of phosphodiesterase type 5 inhibitor (e.g. mirodenafil) to memantine based on the teachings of prior art together with general knowledge of Alzheimer’s treatment and arrive at the range claimed in instant invention. Kim’599 disclosed 0.5-2 mg/kg of mirodenafil dose for rat which could be converted to 4.8-19.2 mg (x0.16 x 60kg ) for human adult with normal weight of 60kg (See FDA guidance of dose conversion). The weight ratio of mirodenafil to memantine would be calculated as about 1: 0.26 (19.2 mg/ 5mg) or 1: 0.52(19.2 mg/ 10mg). Went also teaches combination of memantine with donepezil at various amount and ratios. A skilled artisan would have known to explore/optimize the amount of mirodenafil and memantine at different molar ratio. Where 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. MPEP 2144.05.
A skilled artisan would be motivated to combine phosphodiesterase type 5 inhibitor (e.g. mirodenafil) taught by Kim’599 with memantine because both are directed to treatment for neurological disease (e.g. Alzheimer/dementia), and combination therapy targeting at different pathophysiological mechanisms actions increase drug efficacy by stimulating synergistic or additive actions for treating Alzheimer’s disease as indicated by Namzaric , Went and Kabir. A skilled artisan would reasonably expect the pharmaceutical composition comprising phosphodiesterase type 5 inhibitor (e.g. mirodenafil) and memantine based on combination of different mechanism provide an alternative synergistic combination therapy of Namzaric for treating Alzheimer’s dementia .
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of treating Alzheimer and dementia. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 17-20 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Choung et al. (WO2020201915A2, hereafter “Choung’915”, family member of US 20220168308A1), in view of NAMZARIC label 2014, Went et al. (US 8,580,858 B2) and Kabir et al. (International Journal of Molecular Sciences, 2020, 21, 3272; doi:10.3390/ijms21093272, Combination Drug Therapy for the Management of Alzheimer’s Disease).
Regarding phosphodiesterase 5 inhibitor component of claim 17-18, mirodenafil of claims 19 and 33, Choung’915 teaches a pharmaceutical composition comprising phosphodiesterase 5 inhibitor, e.g. mirodenafil, for reducing amyloid beta formation with multi-mechanism and for treating diseases associated with the accumulation of amyloid beta (e.g. Alzheimer’s disease, dementia) (See abstract; page 4, lines 9-32; page 5, lines 1-9; page 11, lines 3-16; claims 1-15).
Choung’915 disclosed dosage amount and administration regimen, etc. for the pharmaceutical composition comprising phosphodiesterase 5 inhibitor (See Example 13, page 41, lines 22-24; Example 17-2, page 47, lines 29-33). Choung’915 disclosed composition comprising mirodenafil administered at various amount (e.g. 4mg/kg), and effects/efficacy of mirodenafil in variety of in-vitro and in-vivo assay (See Examples 16- 23, Figures 4-29). Choung’915 teaches efficacy of mirodenafil on Tau expression and Aß Expression in Alzheimer's dementia animal model (See page 19, lines 17-30; Example 17, 19; Figures 20, 23 and 24). Choung’915 also teaches the improvement in cognitive and behavioral learning skills by mirodenafil in Alzheimer's dementia animal model (See page 20, lines 6-19; Example 24, Figure 28 and 29).
Choung’915 teaches pharmaceutical composition comprising phosphodiesterase 5 inhibitor with "one Drug, Multiple Targets/Mechanisms" for reducing amyloid beta formation with improved efficacy for treatment of Alzheimer's disease: (1) inhibition of Aß oligomer / fibril formation by reduction of Aß aggregation, (2 ) inhibition of ß - amyloidogenic processing decreased BACE- 1 … ( 6 ) inhibition of formation of AB Fibril / plaque by removal of intracellular toxic and soluble AB oligomers by activation of autophage” (see abstract; page 4, lines 9-32; page 5, lines 1-9; page 11, lines 3-31).
Choung’915 and its incorporated reference teaches NMDA receptor antagonist, memantine (EbixaTM ) causes excitotoxicity to inhibit glutamate transportation system which blocks synaptic plasticity to effectively reduce neuronal degeneration. Memantine was confirmed to be effective in the moderate or more dementia and Lewy body dementia with relatively low side effect and was used with ChE inhibitors in mild and severe dementia than monotherapy (See page 2, lines 10-16).
Choung’915 is silent about combining mirodenafil or phosphodiesterase 5 inhibitor with NMDA-receptor (e.g. memantine).
Combination therapy is common practice in the field of treating neurological diseases. "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) See MPEP 2144.06.
The collective teachings of NAMZARIC label, Went and Kabir are elaborated in preceding 103 rejection and applied as before. NAMZARIC teaches combination of memantine and donepezil for treatment of moderate to severe dementia of the Alzheimer’s, wherein the amount/ molar ratio of donepezil hydrochloride to memantine hydrochloride could be calculated as about 1:5. Went is the original patent of NAMZARIC and teaches combination of memantine with donepezil at various amount and ratios that improve efficacy of both drugs. Kabir also teaches combination therapy targeting at different pathophysiological mechanisms actions might increase drug efficacy by stimulating synergistic or additive actions.
It would have been obvious to one of the ordinary skill in the art before the effective filing date of instantly claimed invention to combine the phosphodiesterase type 5 inhibitor (e.g. mirodenafil) taught by Choung’915 with commonly used FDA approved memantine for treating Alzheimer /dementia as taught by NAMZARIC, Went and Kabir, and arrive at the instant claimed invention with reasonable expectation of success. At the time the invention was made, it was known that phosphodiesterase type 5 inhibitor (e.g. mirodenafil) could be used for treating Alzheimer /dementia as taught by Choung’915 . A skilled artisan would also have known memantine is FDA approved NMDA inhibitor for treating Alzheimer’s dementia that could be combined with other Alzheimer dementia medicine in combination therapy as taught by NAMZARIC, Went and Kabir. A skilled artisan would know to explore the amount/ratio of phosphodiesterase type 5 inhibitor (e.g. mirodenafil) to memantine based on the teachings of prior art together and general knowledge of Alzheimer’s treatment and arrive the range claimed in instant invention.
Regarding the amended ratio limitation of phosphodiesterase 5 inhibitor to NAMENDA. Choung’915 disclosed various dosage amount of phosphodiesterase 5 inhibitor (e.g. mirodenafil, 4mg/kg). For example, 4 mg/kg of mirodenafil dose for rat taught by Choung’915 could be converted to 38.4 mg (= 4mg/kg x0.16 x 60kg ) for human adult with normal weight of 60kg (See FDA guidance of dose conversion). The weight ratio of mirodenafil to memantine would be calculated as about 1: 0.13 (38.4 mg/ 5mg) or 1: 0.26 (38.4 mg/ 10 mg). Went also teaches combination of memantine with donepezil at various amount and ratios. A skilled artisan would have known to explore/optimize the amount of mirodenafil and memantine at different molar ratio accordingly. Where 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. MPEP 2144.05.
A skilled artisan would be motivated to combine phosphodiesterase type 5 inhibitor (e.g. mirodenafil) taught by Choung’915 with memantine because both are directed to treatment for neurological disease (e.g. Alzheimer/dementia) and combination therapy targeting at different pathophysiological mechanisms actions might increase drug efficacy by stimulating synergistic or additive actions as indicated by NAMZARIC, Went and Kabir. A skilled artisan would reasonably expect the pharmaceutical composition comprising phosphodiesterase type 5 inhibitor (e.g. mirodenafil) and memantine (NMDA receptor antagonist) based on combination of different mechanism to provide an alternative synergistic combination therapy of NAMZARIC for treating dementia (Alzheimer’s dementia).
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of treating Alzheimer and dementia. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant’s remarks filed 03/16/2026 have been fully considered. Applicant’s argument against the reference on the record, Kim, Choung , NAMZARIC label and Kabir have been fully considered, but they are NOT persuasive.
Applicant’s argument against the reference on the record are similar as arguments filed in 08/20/2025. Applicant argues “both Kim and Choung do not disclose or suggest combining a phosphodiesterase 5 inhibitor with an NMDA-receptor antagonist. And Kabir fails to disclose or suggest the claimed molar ratios of the phosphodiesterase 5 inhibitor and the NMDA-receptor antagonist. Furthermore, Kim, Choung, and Kabir, alone or in combination, fail to disclose or suggest the claimed synergistic effect on TNFa inhibition or intracellular AB reduction on specific molar ratios...” (Remarks, page 14).
RESPONSE: As elaborated in previous office actions mailed on 05/20/2025 and 09/16/2025, "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) See MPEP 2144.06. Combination therapy is common practice in the field of treating neurological diseases as taught by NAMZARI and Kabir. NAMZARIC approved by FDA in 2014 comprises combination of 5-10mg twice daily or 14 mg or 28 mg memantine hydrochloride extended-release and 10 mg donepezil hydrochloride (cholinesterase inhibitor ) The weight ratio of active ingredient donepezil hydrochloride to memantine hydrochloride is about 1:1 or 2:1, or 1: 1.4 or 1: 2.8.
Regarding the amended molar ratio limitation, in the standard FDA-approved maintenance dose of Namzaric ( 28 mg of memantine hydrochloride and 10 mg of donepezil hydrochloride),
Donepezil hydrochloride (Molecular weight is roughly 415.95 g/mol). dose of 10 mg equals 0.024 mmol = 10 mg /415.95 g/mol;
Memantine hydrochloride (Molecular weight is roughly 215.76 g/mol), dose of 28mg equals 0.13 mmol = 28 mg /215.76 g/mol.
The molar ratio of donepezil hydrochloride to memantine hydrochloride is calculated to be about 1:5.4 (= 0.024 mmol/0.13 mmol) which falls within instant claimed molar ratio of about 1:5.
Kim’599 disclosed various dosage amount of phosphodiesterase 5 inhibitor (e.g. mirodenafil, 0.5-2 mg/kg)(See [0070]-[0083]). For example, 0.5-2 mg/kg of mirodenafil dose for rat could be converted to 4.8-19.2 mg (x 0.16 x 60kg ) for human adult with normal weight of 60kg (See FDA guidance of dose conversion). NAMENDA® and Namzaric label teach the dosage amount of memantine at 5 mg, 10 mg 14mg, 28mg. The weight ratio of mirodenafil to memantine could be calculated as about 1: 1 (4.8mg/ 5mg) or 1: 2 (4.8 mg/ 10mg). A skilled artisan would have known to explore/optimize the amount of mirodenafil and memantine at different molar ratio accordingly.
Choung’915 disclosed various dosage amount of phosphodiesterase 5 inhibitor (e.g. mirodenafil, 4mg/kg). For example, 4 mg/kg of mirodenafil dose for rat taught by Choung’915 could be converted to 38.4 mg (= 4mg/kg x0.16 x 60kg ) for human adult with normal weight of 60kg (See FDA guidance of dose conversion). The weight ratio of mirodenafil to memantine would be calculated as about 1: 0.13 (38.4 mg/ 5mg) or 1: 0.26 (38.4 mg/ 10 mg). Where 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. MPEP 2144.05. A skilled artisan would have known to explore/optimize the amount of mirodenafil and memantine at different molar ratio accordingly.
Applicant argues about unexpected result : “Kim, Choung, and Kabir, alone or in
combination, fail to disclose or suggest the claimed synergistic effect on TNFa inhibition
or intracellular AB reduction on specific molar ratios … On the other hand, the instant application not only teaches the combination a phosphodiesterase 5 inhibitor with an NMDA-receptor antagonist, but also provides in paragraphs [0063]-[0064] and FIGS. 3-4 that in the recited molar ratios in claim 17, the
combination of the phosphodiesterase 5 inhibitor and the NMDA-receptor antagonist clearly provides a synergistic effect on TNFa inhibition, evidenced by the "A+B" factor exceeding 1.0...” (Remarks, page 14-16).
RESPONSE: Applicant’s argument of unexpected result has been fully considered. For the effect of combination of AR 1001 (mirodenafil) and memantine on Aβ reduction in instant Figures 1-4, it’s noted there is no alleged synergistic effect for combination comprising higher concentration of mirodenafil and memantine, for example 20uM of mirodenafil in combination with 20 uM of memantine (molar ratio 1:1) wherein “ A+B” factor is 1.0 (See Figure 2).
Kabir and its incorporated reference teach amyloid pathology is one of multiple targets of combination therapy strategy for treating Alzheimer’s disease(See Table 2) and teaches targeting at different pathophysiological mechanisms actions may be more beneficial by stimulating synergistic or additive actions (See page 12/23,Potential Benefits of Combination Therapies). Choung’915 teaches a pharmaceutical composition comprising phosphodiesterase 5 inhibitor, e.g. mirodenafil, for reducing amyloid beta formation with multi-mechanism and for treating diseases associated with the accumulation of amyloid beta (e.g. Alzheimer’s disease, dementia)(See Figures 23-26). A skilled artisan would know to explore the combination of phosphodiesterase 5 inhibitor ( e.g. mirodenafil) and memantine, measure the effect of combination on the amyloid pathway and expect the combination stimulate synergistic or additive actions of different targets as NAMZARIC. As such, instant alleged synergistic effect of different targets is not unexpected. Please note instant claims are product claims wherein the intended specific function (e.g. inhibit TNFa activity, reducing amyloid beta formation/accumulation) are the property/direct result of the composition which do not necessarily contribute to the structural limitation of composition product. If the combination/ composition made obvious based on the combined teachings of prior art is capable of performing the intended use/function, then it meets the limitation.
More importantly, instant claims are directed to vast combination genus comprising phosphodiesterase 5 inhibitor genus and NMDA-receptor antagonist genus. As stated in MPEP 716.02(d): “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”. Instant specification only discloses working example for combination of mirodenafil with memantine. Instant specification does not disclose working example for combination of mirodenafil with other NMDA-receptor antagonist. Instant specification does not disclose working example for combination of other PDE5 inhibitor with memantine or other NMDA-receptor antagonist. The alleged synergistic effect of specific combination comprising mirodenafil and memantine at specific concentration and ratio thereof, does not commensurate with the scope the vast combination genus comprising phosphodiesterase 5 inhibitor genus and NMDA-receptor antagonist genus.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 17-20 and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 9750743B2, in view of NAMZARIC label and Went et al. (US 8,580,858 B2).
Reference claims are directed to a method for inhibiting brain neuron apoptosis in a subject in need thereof, comprising administering a composition containing a phosphodiesterase type 5 inhibitor that is mirodenafil or a pharmaceutically acceptable salt, solvate, or hydrate thereof in an effective amount to the subject.
Reference claim 4 further recites the neuronal degenerative disease is selected from the group consisting of dementia, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
Reference claims are silent about mirodenafil or other phosphodiesterase type 5 inhibitor, in combination of with memantine, or NMDA-receptor inhibitor and ratio thereof .
"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) See MPEP 2144.06.
Combination therapy is common practice in the field of treating neurological diseases. The collective teachings of NAMZARIC label and Went are elaborated in preceding 103 rejection and applied as before. A skilled artisan would have known Namzaric approved in 2014 comprises combination of 5-10mg twice daily or 14 mg or 28 mg memantine hydrochloride extended-release and 10 mg donepezil hydrochloride (cholinesterase inhibitor ). The ratio of active ingredient donepezil to memantine hydrochloride is calculated about 1:1 or 2:1, or 1: 1.4 or 1: 2.8 (which falls within instant claimed range). Went is the original patent of NAMZARIC and teaches combination of memantine with donepezil at various amount and ratios.
It would have been obvious to one of the ordinary skill in the art to combine the phosphodiesterase type 5 inhibitor (e.g. mirodenafil) taught by reference claims with commonly known FDA approved memantine for treating Alzheimer /dementia as taught by Namzaric and Went, and further explore the dose amount/ratio as taught by Namzaric and Went together with optimization based on general knowledge of treating Alzheimer /dementia, and arrive at the instant claimed invention with reasonable expectation of success. A skilled artisan would know to explore the amount/ratio of phosphodiesterase type 5 inhibitor (e.g. mirodenafil) to memantine based on the teachings of prior art together and general knowledge of Alzheimer’s treatment. A person of ordinary skill in the art would have expected the combination of phosphodiesterase type 5 inhibitor (e.g. mirodenafil) with NMDA-receptor inhibitor (e.g. memantine) provide an alternative combination therapy in treating Alzheimer /dementia.
The instant application shares one common inventor/applicant/assignee with the reference patent. Based on the record, instant application is not related to the reference patent, thus no 35 USC 121 shield exists.
Claims 17-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 10064865B2, in view of NAMZARIC label and Went et al. (US 8,580,858 B2).
Reference claims are directed to a method for inhibiting brain neuron apoptosis in a subject in need thereof, comprising administering a composition containing a phosphodiesterase type 5 inhibitor selected from the group consisting of udenafil, dasantafil, or avanafil in an effective amount to the subject.
Reference claim 4 further recites the neuronal degenerative disease is selected from the group consisting of dementia, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
Reference claims are silent about phosphodiesterase type 5 inhibitor in combination of with memantine, or NMDA-receptor inhibitor.
"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) See MPEP 2144.06. Combination therapy is common practice in the field of treating neurological diseases. The collective teachings of NAMZARIC and Went are elaborated in preceding 103 rejection and applied as before.
It would have been obvious to one of the ordinary skill in the art to combine the phosphodiesterase type 5 inhibitor (e.g. mirodenafil) taught by reference claims with commonly known FDA approved memantine for treating Alzheimer /dementia as taught by Namzaric and Went, and further explore the dose amount/ratio as taught by Namzaric and Went together with optimization based on general knowledge of treating Alzheimer /dementia, and arrive at the instant claimed invention with reasonable expectation of success. A skilled artisan would know to explore the amount/ratio of phosphodiesterase type 5 inhibitor (e.g. mirodenafil) to memantine based on the teachings of prior art together and general knowledge of Alzheimer’s treatment and arrive the range claimed in instant invention. The person of ordinary skill in the art would have expected the combination of phosphodiesterase type 5 inhibitor (e.g. mirodenafil) with NMDA-receptor inhibitor (e.g. memantine) provide an alternative combination therapy in treating Alzheimer /dementia.
The instant application shares one common inventor/applicant/assignee with the reference patent. Based on the record, instant application is not related to the reference patent, thus no 35 USC 121 shield exists.
Claims 17-20 and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of US patent No.12485124B2, in view of NAMZARIC label and Went et al. (US 8,580,858 B2).
Reference claims are directed to a method for treating Alzheimer’s disease in a subject in need thereof, comprising administering to the subject a composition containing an effective amount of mirodenafil and salt thereof.
Reference claims do not teach phosphodiesterase type 5 inhibitor in combination of with memantine, or NMDA-receptor inhibitor.
Combination therapy is common practice in the field of treating neurological diseases. The collective teachings of NAMZARIC and Went are elaborated in preceding 103 rejection and applied as before.
It would have been obvious to one of the ordinary skill in the art to combine the phosphodiesterase type 5 inhibitor (e.g. mirodenafil) taught by reference claims with commonly known FDA approved memantine for treating Alzheimer /dementia as taught by Namzaric and Went, and further explore the dose amount/ratio as taught by Namzaric and Went together with optimization based on general knowledge of treating Alzheimer /dementia, and arrive at the instant claimed invention with reasonable expectation of success. A skilled artisan would have reasonably expected the combination of phosphodiesterase type 5 inhibitor (e.g. mirodenafil) with NMDA-receptor inhibitor (e.g. memantine) provide an alternative combination therapy in treating Alzheimer /dementia.
The instant application shares one common inventor/applicant/assignee with the reference patent. Based on the record, instant application is not related to the reference patent, thus no 35 USC 121 shield exists.
Claims 17-20 and 33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 7- 15 of copending Application No. 17/593,842, in view of NAMZARIC label and Went et al. (US 8,580,858 B2). This is a provisional nonstatutory double patenting rejection.
Reference claims are directed to a method for treating Alzheimer in a subject in need thereof, comprising administering a composition containing a phosphodiesterase type 5 inhibitor selected from the group consisting of mirodenafil, sildenafil, etc. and salt thereof.
Reference claims 8-10 recite inhibition of Aβ aggregation/formation.
Reference claims do not teach phosphodiesterase type 5 inhibitor in combination of with memantine, or NMDA-receptor inhibitor.
Combination therapy is common practice in the field of treating neurological diseases. The collective teachings of NAMZARIC and Went are elaborated in preceding 103 rejection and applied as before.
It would have been obvious to one of the ordinary skill in the art to combine the phosphodiesterase type 5 inhibitor (e.g. mirodenafil) taught by reference claims with commonly known FDA approved memantine for treating Alzheimer /dementia as taught by Namzaric and Went, and further explore the dose amount/ratio as taught by Namzaric and Went together with optimization based on general knowledge of treating Alzheimer /dementia, and arrive at the instant claimed invention with reasonable expectation of success. A skilled artisan would know to explore the amount/ratio of phosphodiesterase type 5 inhibitor (e.g. mirodenafil) to memantine based on the teachings of prior art together and general knowledge of Alzheimer’s treatment and arrive the range claimed in instant invention. The person of ordinary skill in the art would have expected the combination of phosphodiesterase type 5 inhibitor (e.g. mirodenafil) with NMDA-receptor inhibitor (e.g. memantine) provide an alternative combination therapy in treating Alzheimer /dementia.
The instant application shares one common inventor/applicant/assignee with the reference patent. Based on the record, instant application is not related to the reference patent, thus no 35 USC 121 shield exists.
Claims 17-20 and 33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-19 and 21-33 of copending Application No. 18/991,922, in view of NAMZARIC label and Went et al. (US 8,580,858 B2). This is a provisional nonstatutory double patenting rejection.
Reference claims are directed to a pharmaceutical composition comprising at least one phosphodiesterase 5 inhibitor, and at least one acetylcholinesterase inhibitor as active ingredients at different ratio, and a method for treating neuroinflammation and neurodegenerative disease in a subject in need thereof, comprising administering to the subject aforementioned composition containing phosphodiesterase 5 inhibitor and salt thereof.
Reference claim 18 and19 recites phosphodiesterase 5 inhibitor comprises mirodenafil.
Reference claim 24 further recites the neuronal degenerative disease is comprises dementia, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
Reference claims do not teach phosphodiesterase type 5 inhibitor in combination of with memantine, or NMDA-receptor inhibitor.
Combination therapy is common practice in the field of treating neurological diseases. The collective teachings of NAMZARIC and Went are elaborated in preceding 103 rejection and applied as before.
It would have been obvious to one of the ordinary skill in the art to combine the phosphodiesterase type 5 inhibitor (e.g. mirodenafil) taught by reference claims with commonly known FDA approved memantine for treating Alzheimer /dementia as taught by Namzaric and Went, and further explore the dose amount/ratio as taught by Namzaric and Went together with optimization based on general knowledge of treating Alzheimer /dementia, and arrive at the instant claimed invention with reasonable expectation of success. A skilled artisan would know to explore the amount/ratio of phosphodiesterase type 5 inhibitor (e.g. mirodenafil) to memantine based on the teachings of prior art together and general knowledge of Alzheimer’s treatment and arrive the range claimed in instant invention. The person of ordinary skill in the art would have expected the combination of phosphodiesterase type 5 inhibitor (e.g. mirodenafil) with NMDA-receptor inhibitor (e.g. memantine) provide an alternative combination therapy in treating Alzheimer /dementia.
The instant application shares one common inventor/applicant/assignee with the reference patent. Based on the record, instant application is not related to the reference patent, thus no 35 USC 121 shield exists.
Conclusion
No claim is allowed.
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/LIYUAN MOU/Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628
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