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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/05/2026 has been entered.
Response to Amendments
The amendments made to the claims 05/05/2026 have been entered.
Status of Claims
Claims currently pending and under examination are claims 7-15.
Modified Rejections
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 7-15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Puzzo (J. Neurosci, 2009, 29(25), of the record).
In regards to claim 7, Puzzo on p. 8075, para 2 discloses administration of sildenafil to affect hippocampal cGMP levels where it states “Preclinical studies have shown that the selective PDE5 inhibitors sildenafil…and vardenafil raise hippocampal cGMP levels and improve memory in aged rats and mice.” Puzzo in sec. Drug Administration discloses administration of sildenafil to hippocampal slices where it states “In one experimental series, we assessed the acute effects of PDE inhibition on synaptic dysfunction by perfusing hippocampal slices with sildenafil (50 nM).
Puzzo on p. 8082, right col., para. 3 states “ELISA of extracts of cerebral cortices revealed a reduction in human Aβ40 and Aβ42 levels in sildenafil treated APP/PS1 mice after 3 week treatment with 3 mg/kg and 6 mg/kg sildenafil at 3 months and 7-10 months.”
In regards to claim 15, Puzzo on p. 8078-8079, sec. Acute effects of sildenafil on the cognitive function of APP/Pδ1 mice teaches that “Sildenafil treatment improved contextual learning in the transgenic animals.”
In regards to claims 8-14, the language of the claims implies that the claimed elements are effects that are brought on by the composition of claim. Essentially, the claim elements are consequence of administering the composition comprising sildenafil and would be made obvious by the combination Puzzo which makes obvious administering sildenafil to treat Alzheimer’s Disease.
Therefore, it would have been prima facie obvious at the time of the effective filing date for one of ordinary skill in the art to have taken the teachings of Puzzo and arrive at the instant claims with a reasonable assumption of success. Puzzo teaches administering a PDE5 inhibitor, specifically sildenafil, to treat cognitive loss.
Regarding claims 8-15, the MPEP section 2112, subsections I and III state:
I. SOMETHING WHICH IS OLD DOES NOT BECOME PATENTABLE UPON THE DISCOVERY OF A NEW PROPERTY
“[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable.
III. A REJECTION UNDER 35 U.S.C. 102 AND 103 CAN BE MADE WHEN THE PRIOR ART PRODUCT SEEMS TO BE IDENTICAL EXCEPT THAT THE PRIOR ART IS SILENT AS TO AN INHERENT CHARACTERISTIC
Where applicant claims a composition in terms of a function, property or characteristic and the composition of the prior art is the same as that of the claim but the function is not explicitly disclosed by the reference, the examiner may make a rejection under both 35 U.S.C. 102 and 103. “There is nothing inconsistent in concurrent rejections for obviousness under 35 U.S.C. 103 and for anticipation under 35 U.S.C. 102.” In re Best, 562 F.2d 1252, 1255 n.4, 195 USPQ 430, 433 n.4 (CCPA 1977). This same rationale should also apply to product, apparatus, and process claims claimed in terms of function, property or characteristic. Therefore, a 35 U.S.C. 102 and 103 rejection is appropriate for these types of claims as well as for composition claims.
In the instant case, the claims only require administering sildenafil. The limitations found in claims 8-15 are all drawn to features that are effects of administering the sildenafil. While the reference does not explicitly discuss said limitations, they are all inherent features of administering sildenafil. Therefore Puzzo reads on the instant claims.
Maintained Claim Rejection - 35 USC § 103
Claim(s) 7-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Puzzo (J. Neurosci, 2009, 29(25), of the record) in view of Naef (WO2018/215433 A1, of the record).
KSR Rationales
The MPEP in section 2143, subsection I gives examples of Rationales for supporting a conclusion of obvious. These rationales are non-exhaustive and include (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Claim 7 is drawn to a method of reducing amyloid beta (Aβ) in a hippocampal neuronal cell in a subject in need, the method comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective dose of a compound selected from the group consisting of mirodenafil, sildenafil….or a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof, wherein the therapeutically effective dose reduces accumulation of Aβ in the hippocampal neuronal cell.”
Claims 8-15 are drawn to effects of administering the sildenafil or mirodenafil and include inhibiting formation of Aβ aggregation (claim 8), inhibiting β-Amyloidogenic Processing through BACE-1 reduction (claim 9), reducing extracellular formation and accumulation of amyloid beta monomer, oligomer, and/or amyloid beta fibril and plague (claim 10), reducing neuronal cell death and enhances neurogenesis, synaptogenesis, or angiogenesis (claim 11), restoring synaptic plasticity (claim 12), suppresses DKK-1 (claim 13), activates autophagy (claim 14), and improving behavioral or cognitive function (claim 15). The dependent claims are all drawn to functions of the claimed method.
Discussion of Puzzo from the 102 rejection above is incorporated here.
Puzzo does not explicitly teach mirodenafil. This is addressed by Naef.
Naef discusses phosphodiesterase (PDE) inhibitors in combination with guanylate cyclase activators. Naef on p. 144, Table 1 teaches the % inhibition and IC50 of the compound sildenafil and mirodenafil. These values were measured in a Phosphodiesterase-5 activity assay as discussed on p. 143-144, Example 110.
Mirodenafil showed a % inhibition (at 5.0E-09 M) of 64.9% compared to sildenafil’s 49.9%. The IC50 value for mirodenafil was also measured at 3.4x10-10, which is an improvement over sildenafil’s 5.4x10-9.
Therefore, one of ordinary skill in the art would find motivation to replace sildenafil with mirodenafil for its improve pharmacokinetic values.
In regards to claims 8-14, the claim elements are consequence of administering the composition comprising mirodenafil and would be made obvious by the combination Puzzo and Naef which makes obvious administering mirodenafil to treat Alzheimer’s Disease.
Therefore, it would have been prima facie obvious at the time of the effective filing date for one of ordinary skill in the art to have combined the teachings of Puzzo and Naef and arrive at the instant claims with a reasonable assumption of success. Puzzo teaches administering a PDE5 inhibitor, specifically sildenafil, to reduce amyloid beta accumulation and Naef teaches the improved properties of mirodenafil over sildenafil.
One of ordinary skill in the art would find motivation to use mirodenafil in place of sildenafil as Naef teaches improved pharmacokinetic properties of mirodenafil.
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 7-15 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 9,271,916 in view of Puzzo (J. Neurosci, 2009, 29(25), of the record) in view of Naef (WO2018/215433 A1, of the record).
Dependent reference claim 3 states “The method of claim 2, wherein the PDE5 inhibitor is mirodenafil, or a pharmaceutically acceptable salt, solvate, or hydrate.”
Puzzo discloses sildenafil is effective to reduce Aβ levels in hippocampal neuronal cells. Naef teaches improved properties of mirodenafil. Puzzo also teaches daily administration over the course of a minimum of 3 weeks. Therefore, the instant claims are made obvious over the reference claims in view of the references cited.
Response to Arguments
Applicant’s arguments submitted 05/05/2026 have been considered but are not persuasive.
Applicant argues that “Puzzo, alone or in combination with Naef, does not disclose or suggest a method of reducing accumulation of amyloid beta in a hippocampal neuronal cell”.
Puzzo, as cited above, states “ELISA of extracts of cerebral cortices revealed a reduction in human Aβ40 and Aβ42 levels in sildenafil treated APP/PS1 mice after 3 week treatment with 3 mg/kg and 6 mg/kg sildenafil at 3 months and 7-10 months.”
Regarding the double patenting rejection over U.S Patent 9,271,916, applicant states the ‘916 patent is drawn to non-analogous art and is silent regarding reducing accumulation of amyloid beta in a hippocampal neuronal cell. The reference claims, specifically reference claim 3, is drawn to mirodenafil. Puzzo teaches a method of administration that directly results in the reduction of Aβ. Therefore, the reference claims in view of Puzzo and Naef make the instant claims obvious.
Additionally, applicant argues that “the examiner erroneously applies MPEP § 2112(I) states the old composition is not render patentably new by the discovery of a previously unappreciated property. MPEP section § 2112(I) is not applicable to methods using such composition as the Examiner erroneously interprets it.” Emphasis by applicant.
MPEP section 2112(III) states:
III. A REJECTION UNDER 35 U.S.C. 102 AND 103 CAN BE MADE WHEN THE PRIOR ART PRODUCT SEEMS TO BE IDENTICAL EXCEPT THAT THE PRIOR ART IS SILENT AS TO AN INHERENT CHARACTERISTIC
Where applicant claims a composition in terms of a function, property or characteristic and the composition of the prior art is the same as that of the claim but the function is not explicitly disclosed by the reference, the examiner may make a rejection under both 35 U.S.C. 102 and 103. “There is nothing inconsistent in concurrent rejections for obviousness under 35 U.S.C. 103 and for anticipation under 35 U.S.C. 102.” In re Best, 562 F.2d 1252, 1255 n.4, 195 USPQ 430, 433 n.4 (CCPA 1977). This same rationale should also apply to product, apparatus, and process claims claimed in terms of function, property or characteristic. Therefore, a 35 U.S.C. 102 and 103 rejection is appropriate for these types of claims as well as for composition claims.
The rejections are maintained.
New Rejections
Claim Rejections - 35 USC § 102
Claim(s) 7-15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dorsey (Expert Opinion on Pharmacotherapy, 2010, Vol. 11, Iss. 7) as supported by Kang (Alzheimer’s Research and Therapy, 2022, 14:92, of the record).
Dorsey in sec. 3.1, p. 1113 states “Mirodenafil is a PDE5i recently approved for use in Korea for the treatment of ED. Compared with sildenafil, mirodenafil demonstrated a significantly higher Cmax and area under the curve (AUC) in both the plasma and corpus cavernosum tissue of rats…The pharmacologic properties of mirodenafil in 20 young, healthy Korean men with and without concurrent consumption of alcohol have also been studied.”
While Dorsey makes no mention of reducing amyloid beta accumulation, Kang in its abstract states “mirodenafil is demonstrated to improve cognitive behavior in the APP-C105 mouse model. Mirodenafil not only reduced the Aβ and phosphorylated tau burdens in vivo, but also ameliorated AD pathology induced by Aβ through modulation of the cGMP/PKG/CREB signaling pathway, glycogen synthase kinase 3β (GSK-3β activity), GR transcriptional activity, and the Wnt/β-catenin signaling in neuronal cells. Interestingly, homodimerization and nuclear localization of GR were inhibited by mirodenafil, but not by other PDE5 inhibitors. In addition, only mirodenafil reduced the expression levels of the Wnt antagonist dickkopf-1 (Dkk-1), thus activating the Wnt/β-catenin signaling.”
The MPEP sec 2112, subsections I-III state:
I. SOMETHING WHICH IS OLD DOES NOT BECOME PATENTABLE UPON THE DISCOVERY OF A NEW PROPERTY
“[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable.
II. INHERENT FEATURE NEED NOT BE RECOGNIZED AT THE RELEVANT TIME
There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) (“[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention.”); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed. Cir. 1999)
III. A REJECTION UNDER 35 U.S.C. 102 AND 103 CAN BE MADE WHEN THE PRIOR ART PRODUCT SEEMS TO BE IDENTICAL EXCEPT THAT THE PRIOR ART IS SILENT AS TO AN INHERENT CHARACTERISTIC
Where applicant claims a composition in terms of a function, property or characteristic and the composition of the prior art is the same as that of the claim but the function is not explicitly disclosed by the reference, the examiner may make a rejection under both 35 U.S.C. 102 and 103. “There is nothing inconsistent in concurrent rejections for obviousness under 35 U.S.C. 103 and for anticipation under 35 U.S.C. 102.” In re Best, 562 F.2d 1252, 1255 n.4, 195 USPQ 430, 433 n.4 (CCPA 1977). This same rationale should also apply to product, apparatus, and process claims claimed in terms of function, property or characteristic. Therefore, a 35 U.S.C. 102 and 103 rejection is appropriate for these types of claims as well as for composition claims.
As claim 7 requires only the administration of mirodenafil and/or sildenafil, the disclosure of Dorsey embraces the instant claims.
Note: The Kang publication shares authors with the inventors of the instant application. While the Kang publication is dated after the effective filing date, the information provided in Kang is used to support the inherency arguments above. Essentially, Kang identifies new properties of an old composition and/or method.
Double Patenting
U.S. Patent 12,485,124
Claims 7-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 12,485,124 (previously app. 18/906,967). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims require administering mirodenafil.
The reference claims are drawn to a method for treating Alzheimer’s Disease (AD) in a subject in need comprising administering a composition comprising a therapeutically effective dose of mirodenafil.
The instant claims are broader in that they claim administration of either mirodenafil or sildenafil. The additional limitation of the instant claims, which is “wherein the therapeutically effective dose restores Synaptic plasticity by Wnt signaling activation through DKK-1 inhibition” is a result of administering the mirodenafil. Therefore, the instant claims are made obvious in view of the reference claims.
Co-pending application 19/347,194
Claims 7-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 7-10 and 12-16 of copending Application No. 19/347,194 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The reference claims are drawn to a method of reducing accumulation of amyloid beta (Aβ) in a hippocampal neuronal cell in a subject in need, comprising administering a therapeutically effective dose of mirodenafil. The instant claims are drawn to an identical method except that the method comprising administering either sildenafil or mirodenafil.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Examiner’s Comments
Claim 12 states “The method of claim 7, wherein the therapeutically effective dose restores synaptic plasticity through DKK-1 inhibition.”
Applicant elected mirodenafil. At examiner’s discretion, search and examination were expanded to include sildenafil. Currently, claim 12 is enabled only for mirodenafil as Kang (cited above) states “only mirodenafil reduced the expression levels of the Wnt antagonist dickkopf-1 (Dkk-1)…”.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUISALBERTO GONZALEZ whose telephone number is (571)272-1154. The examiner can normally be reached M-F 8:30-5:30.
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/LUISALBERTO GONZALEZ/Examiner, Art Unit 1624
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