DETAILED ACTION
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 .
All previous objections and rejections not reiterated herein were overcome by claim amendments and arguments, filed March 3rd, 2026, have been fully considered and found persuasive. As such all objections and rejections not reiterated herein have been withdrawn.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in the instant Application No. 18/035245, filed on May 3rd, 2023. Acknowledgment is made to the certified translation of Foreign Priority Application KR 10-2020-0146677 filed November 5th, 2020. Therefore instant claims 1, 3 – 6, and 9 have been afforded an effective filing date of November 5th, 2020, which is the filing date for KR 10-2020-0146677 which provides the instant claims support.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3 – 6, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2008/144061 A2 to Held et. al. (herein after Held’061; cited on the ISR form) in view of Mao et. al. ((2017), Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer’s Disease, ACS Chem. Neurosci, 9, 328 – 345; cited on the ISR form).
Regarding claims 1, 3 – 6,and 9, Held’061 teach pharmaceutical compositions (claim 6) and methods for the treatment of various conditions, disorders, and diseases, and more particularly relates to the treatment of such conditions, disorders, and diseases using therapeutic agents that include a phosphodiesterase-5 inhibitor (PI-5) in combination with one or more agents (page 4 paragraph 00015) wherein the agent is selected from a list that includes cholinesterase Inhibitors (Cls) (page 4 paragraph 00016). Furthermore, Held’061 teach embodiments wherein the PI-5 is Cialis, that is tadalafil (claim 1 ) (page 5 paragraph 00019), and the CI medication is Aricept, that is donepezil (claim 1) (page 5 paragraph 00022).
Moreover, Held’061 teach that the agents, which include tadalafil and donepezil can be administered separately (claim 3) (page 6 paragraph 00029) or in a combined form (claim 4) (page 6 paragraph 00030) such as a once-weekly patch, a monthly patch, a long-term injection, a combined pill, or an implant (page 6 paragraph 00027). Additionally, Held’061 teach that Cialis, that is tadalafil can be administered at a dosage ranging from 2 mg to 120 mg per day (page 21 paragraph 000141). Also Held’061 teach that Aricept, that is donepezil, can be administered at a dosage ranging from 5 – 100 mg per day (page 22 paragraph 000155). Furthermore, Held’061 teach that the active agents can be administered orally (claim 4) (page 24 paragraph 000166).Moreover, Held’061 teach that the compositions are used in methods of treating neurodegenerative disease (page 6 paragraph 00028). Specifically, Held’061 teach that neurodegenerative disease includes Alzheimer’s disease (claims 1 and 9) (page 6 paragraphs 00031 and 00032). Additionally, Held’061 teach that autopsy changes seen in patients with advanced dementia represent a final common pathway of initially reversible dysfunction in the cortex and neo-cortex, the cognitive areas of the human brain (page 15 paragraph 000108). Likewise, Held’061 teach that the proposed pharmaceutical combination effects “neuro-restoration” of neurosynaptic defects in these areas (page 15 paragraph 000108). Thus one of ordinary skill in the art could envisage that the restoring neurosynaptic defects there is an inherent improving of cognitive function.
Moreover, the preamble, “for preventing, treating or improving Alzheimer's disease or cognitive impairment” recited in claims 1, 3 – 6, and 9 is interpreted as an intended use drawn to a composition. During examination, statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether or not the recited purpose or intended use results in a structural difference (or, in the case of process claims, manipulative difference) between the claimed invention and the prior art. If so, the recitation serves to limit the claim. See, e.g., In re Otto, 312 F.2d 937, 938, 136 USPQ 458, 459 (CCPA 1963)(MPEP 2111.02(II)). However, since the recitations of, “for preventing, treating or improving Alzheimer's disease or cognitive impairment” recited in claims 1, 3 – 6, and 9 do not provide a structural limitations for the composition the recitations are interpreted as intended use.
However, Held’061 fails to explicitly teach a composition wherein the weight ratio of (i) donepezil or the pharmaceutically acceptable salt thereof; and (ii) tadalafil or the pharmaceutically acceptable salt thereof is 5 : 1 to 30 : 1 (claim 1) nor does Held’061 teach a composition wherein the combination formulation includes (i) 2.5 to 23 mg of donepezil or the pharmaceutically acceptable salt thereof; and (ii) 0.1 to 2.5 mg of tadalafil or the pharmaceutically acceptable salt thereof (claim 5).
Nonetheless, as stated above Held’061 teach that Cialis, that is tadalafil can be administered at a dosage ranging from 2 mg to 120 mg per day (page 21 paragraph 000141). Also Held’061 teach that Aricept, that is donepezil, can be administered at a dosage ranging from 5 – 100 mg per day (page 22 paragraph 000155). Both the dosage ranges of tadalafil and donepezil, taught by Held’061 overlap with the dosage ranges recited in claim 5. Thus 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)(MPEP 2144.05(I)). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)(MPEP 2144.05(I)).
Nevertheless, Mao et. al. teach that Alzheimer’s disease (AD) (claims 1 and 9) is a long-term and incurable neurodegenerative brain disorder clinically characterized by dysmnesia, loss of speech, and behavioral abnormalities (page 328 column 1 paragraph 1). Furthermore, Mao et. al. teach that due to AD complex pathogenesis, a single target drug cannot cure this disease fundamentally; thus a dual or multiple target drug that is involved in two or more aspects of AD pathogenesis may generate a synergistic effect and ultimately achieve an ideal therapeutic effect (page 328 column 1 paragraph 1). Mao et. al. teach that the current anti-AD therapeutic arsenal approved by the United States Food and Drug Administration (FDA) consists of four drugs which include donepezil (claims 1, 4, and 6) which only ameliorate the symptoms of cognitive function (claim 9) but do not cure the disease or reverse its progression (page 329 column 1 paragraph 1). Furthermore, Mao et. al. teach that three of the four drugs, which includes donepezil, are acetylcholinesterase (AChE) inhibitors (page 329 column 1 paragraph 1). Moreover, Mao et. al. teach that although inadequate for curing AD, inhibition of AChEs remains the most successful strategy and has been shown to be transiently capable of improving memory and cognitive function (claims 1 and 9) in AD patients (page 329 column 1 paragraph 1).
Additionally, Mao et. al. teach that phosphodiesterases (PDEs) comprise a group of enzymes that are responsible for the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are intracellular second messengers that are closely associated with cellular functions such as neurotransmitter release, neuroplasticity and neuroprotection (page 329 column 2 paragraph 1). More specifically, Mao et. al. teach PDE5, special cGMP hydrolytic enzyme, as promising therapeutic target in AD, and a PDE5 inhibitor may be a good therapeutic strategy for the treatment of AD patients (page 330 column 1 paragraph 2). Mao et. al. teach that PDE5 inhibitors, such as sildenafil and tadalafil (claims 1, 4, and 6) possess potent anti-AD effects in different mouse models of AD, significantly reversing cognitive impairment and improving learning and memory (page 330 column 1 paragraph 2). In addition, Mao et. al. teach that research has indicated that the effects of AChE and PDE5 inhibitors on object recognition memory in rats is different and dissociable (page 330 column 1 paragraph 2 and column 2 paragraph 1). Thus, Mao et.al. teach that AChE/PDE5 dual inhibitors could play a synergistic anti-AD effect and may supply a new perspective and breakthrough for the treatment of AD (page 330 column 1 paragraph 2).
Furthermore, Mao et. al. teach that tadalafil has an IC50 (µM) value of 26.159 ± 1.300 (0.026159 M) and donepezil has an IC50 (µM) value of 0.013 ± 0.150 (1.3 x 10-5M) against rat cortex acetylcholinesterase (AChE) (page 330 Table 1). Moreover, Mao et.al. teach that for the assay, the volume comprised contained 50 μL of 0.1 M phosphate buffer, 50 μL of 0.2% 5,5′-dithiobis (2-nitrobenzoic acid) (DTNB, Sigma), 109 or 99 μL of deionized water, 10 μL of rat cortex homogenate or 20 μL of rat serum, and 30 μL of 2 mM acetylthiocholine iodide (Sigma) or 40 μL of 2 mM butyrylthiocholine (Sigma) as the substrate of the AChE or BuChE enzymatic reaction, respectively with 1 μL an appropriate concentration of compound (1 nM to 10 mM) (page 342 column 2 paragraph 2). Thus, Mao et. al. teach that the total volume in each well of the assay was 250 μL or 2.50 x 10-4 L.
Regarding claim 1 recitation, for a composition wherein the weight ratio of (i) donepezil or the pharmaceutically acceptable salt thereof; and (ii) tadalafil or the pharmaceutically acceptable salt thereof is 5 : 1 to 30 : 1 (claim 1), as stated above, the prior art of Held’061 taught that Cialis, that is tadalafil can be administered at a dosage ranging from 2 mg to 120 mg per day (page 21 paragraph 000141). Also Held’061 taught that Aricept, that is donepezil, can be administered at a dosage ranging from 5 – 100 mg per day (page 22 paragraph 000155). Moreover, Mao et. al. teach that tadalafil has an IC50 (µM) value of 26.159 ± 1.300 (0.026159 M) and donepezil has an IC50 (µM) value of 0.013 ± 0.150 (1.3 x 10-5M) against rat cortex acetylcholinesterase (AChE) (page 330 Table 1). Thus both the prior art of Held’061 and Mao et. al. teach effective ranges for donepezil and tadalafil in separate compositions. Given that the skill level of one of ordinary skill in the art is relatively high it would stand the reason that it would have been obvious to one such artisan to try a combination of ratios within the dosage range taught by Held’016 and the IC50 values taught by Mao et. al. Moreover, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)(MPEP 2144.05(II(A)).
Therefore, it would have been obvious before the effective filing date of the instant application to modify the composition and method of Held’061 for a composition comprising donepezil and tadalafil in view of Mao et. al. that is to optimize the ranges of donepezil and tadalafil to get weight ratios of 5 : 1 to 20 : 1. One of ordinary skill in the art would have been motivated to make this modification to determine the most effective ratio of donepezil and tadalafil. One of ordinary skill in the art would have had a reasonable expectation of success because the prior art of Held’061 and Mao et. al. teach that separately donepezil and tadalafil demonstrate efficacy; therefore, in combining donepezil and tadalafil there is a minimal expectation that the composition would work just as good as the separate compositions.
Response to Arguments
Applicant's arguments and declaration filed March 3rd, 2026, with regards to the 35 USC § 103 rejection of instant claims 1, 3 – 6, and 9 have been fully considered but they are not persuasive.
Applicant argues that the present invention demonstrates that the combination of donepezil and tadalafil has a significant synergistic treatment effect compared to either donepezil or tadalafil alone (see applicants’ arguments page 6 paragraph 6). Moreover, the applicant argues that the present invention has experimentally and quantitatively identified and exemplified a synergistic treatment effect on Alzheimer's disease of cognitive impairment at the weight ratio of donepezil and tadalafil in the range of 5: 1 to 30: 1 (see FIGS. IA to 3 of the present invention) (see applicants’ arguments page 8 paragraph 4).
The examiner agrees that the combination of Tadalafil at 10 nM+ Donepezil at 100 nM+ A-beta shows at least an order of magnitude difference compared to the combinations of Tadalafil at 10 nM+ A-beta and Donepezil at 100 nM+ A-beta as shown in Figure 1 and Table 1 (see applicants’ arguments page 7). However, the results shown are not commensurate in scope to the instant claims. Specifically, it is uncertain whether the presence of A-beta with Tadalafil at 10 nM+ Donepezil at 100 nM provides the unexpected synergistic effect. Moreover, in Figure 1 the vehicle seems to have the same effect as the combination of Tadalafil at 10 nM+ Donepezil at 100 nM+ A-beta. Thus given these issues the argument of unexpected synergistic effect is unpersuasive.
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 1, 3 – 4, 6, and 9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3 – 4, 6 – 7, and 9 – 10 of copending Application No. 18/035403 to Lee et. al. (herein after Lee’403) in view of Mao et. al. ((2017), Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer’s Disease, ACS Chem. Neurosci, 9, 328 – 345; cited on the ISR form).
Lee’403 recite a composition for preventing, treating or improving Alzheimer's disease or cognitive impairment (instant claims 1, and 9) comprising: (i) donepezil (instant claims 1, 4, 6, and 9) or a pharmaceutically acceptable salt thereof; and (ii) sildenafil or a pharmaceutically acceptable salt thereof (reference claim 1); wherein the composition of (reference) claim 1, wherein (i) donepezil or the pharmaceutically acceptable salt thereof; and (ii) sildenafil or the pharmaceutically acceptable salt thereof are administered simultaneously or at different times (reference claim 3; instant claim 3); wherein the composition is in a combination formulation including (i) donepezil or a pharmaceutically acceptable salt thereof; and (ii) sildenafil or a pharmaceutically acceptable salt thereof (reference claim 4; instant claim 4); wherein the wherein the composition is a pharmaceutical composition or a food composition (reference claim 6; instant claim 6).
Moreover, Lee’403 recite a method for preventing, treating or improving Alzheimer's disease or cognitive impairment, the method comprising: administering the composition of (reference) claim 1 to a subject in need thereof (reference claim 9; instant claim 9) and a method for improving cognitive function, the method comprising: administering the composition of (reference) claim 7 to a subject in need thereof (reference claim 10).
However, Lee’403 fails to recite a composition (instant claims 1, 3 – 4, and 6) wherein a weight ratio of (i) donepezil or the pharmaceutically acceptable salt thereof; and (ii) tadalafil or the pharmaceutically acceptable salt thereof is 5 : 1 to 20 : 1 (instant claim 1) or method (instant claims 9) comprising tadalafil (instant claims 1, 3 – 4, 6, and 9).
Nevertheless, the teaching of Mao et. al. as the relate to the prior art rejection of the instant claims are given above and are incorporated here.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the method of copending Lee’403 for a composition comprising donepezil in view of Mao et. al., that is to substitute sildenafil with tadalafil and have the ratio of (i) donepezil and (ii) tadalafil as 5 : 1 to 20 : 1. One of ordinary skill in the art would have been motivated to make this modification and have a reasonable expectation of success because the prior art of Mao et.al. teach that both sildenafil and tadalafil are a PDE5 inhibitor, and both sildenafil and tadalafil possess potent anti-AD effects in different mouse models of AD, significantly reversing cognitive impairment and improving learning and memory.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed March 3rd, 2026, with regards to the provisional nonstatutory double patent rejection of instant claims 1, 3 – 6, and 9 over claims 1, 3 – 4, 6 – 7, and 9 – 10 of copending Application No. 18/035403 to Lee et. al. (herein after Lee’403) have been fully considered but they are not persuasive.
Applicant argues that each feature of the amended claims, as well as the technical significance associated therewith, as explained in response to the § 103 rejections, is neither taught nor suggested by the reference application or the cited references (see applicants’ remarks page 11 paragraph 2).
As stated previously in the prior art response, the examiner agrees that the combination of Tadalafil at 10 nM+ Donepezil at 100 nM+ A-beta shows at least an order of magnitude difference compared to the combinations of Tadalafil at 10 nM+ A-beta and Donepezil at 100 nM+ A-beta as shown in Figure 1 and Table 1 (see applicants’ arguments page 7). However, the results shown are not commensurate in scope to the instant claims. Specifically, it is uncertain whether the presence of A-beta with Tadalafil at 10 nM+ Donepezil at 100 nM provides the unexpected synergistic effect. Moreover, in Figure 1 the vehicle seems to have the same effect as the combination of Tadalafil at 10 nM+ Donepezil at 100 nM+ A-beta. Thus given these issues the argument of unexpected synergistic effect is unpersuasive.
Conclusion
Claims 1, 3 – 6, and 9 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 DAWANNA S WHITE whose telephone number is (703)756-4687. The examiner can normally be reached 7:00 am - 5:00 pm [EST] M - Th.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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