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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 10, 2026 has been entered.
DETAILED ACTION
3. Claims 20 – 21, 24, and 27 – 49 are pending in this application. Applicant’s Amendment and Remarks, filed March 10, 2026, is entered, wherein claims 20, 27 – 29, 31 – 41, and 43 – 49 are amended, claims 1 – 19, 22 – 23, and 25 – 26 are canceled, and claims 27 – 49 are withdrawn.
Claims 20 – 21 and 24 are examined on the merits herein.
Priority
This application is a continuation application of PCT/IB2023/056716, filed June 28, 2023, which claims benefit of domestic application 63/368,278, filed June 29, 2022.
Withdrawn Rejections
5. The rejection of claims 20 – 21 and 24 in the previous Office Action, mailed October 10, 2025, on the ground of nonstatutory double patenting as being unpatentable over claims 17 – 19 of copending Application No. 19/003,405 in view of Wu with evidence provided by Goto et al. has been considered and is withdrawn in view of the amended claim 20.
The rejection of claims 20 – 21 and 24 in the previous Office Action, mailed October 10, 2025, on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2 and 4 – 5 of copending Application No. 18/492,734 in view of Wu with evidence provided by Goto et al. has been considered and is withdrawn in view of the amended claim 20.
The rejection of claims 20 – 21 and 24 in the previous Office Action, mailed October 10, 2025, on the ground of nonstatutory double patenting as being unpatentable over claims 17 – 19 and 24 of copending Application No. 18/991,922 in view of Ahmed et al. has been considered and is withdrawn in view of the amended claim 20.
Claim Rejections - 35 USC § 102
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 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.
Claims 20 – 21 and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mayoux et al. (WO2016/174155A1) with evidence provided by Ahmed et al. (Saudi Pharmaceutical Journal, March 2022, page 863 – 873, cited in the previous Office Action mailed October 10, 2025).
a. Independent claim 20 is directed to a pharmaceutical composition comprising a PDE5 inhibitor and a SGLT2 inhibitor, wherein the molar ratio of PDE5 inhibitor and SGLT2 inhibitor is about 50:1, about 10:1, about 5:1, about 2:1, about 1:1, about 1:2, about 1:5, or about 1:10, wherein the pharmaceutical composition is configured to inhibit IL-1β or TNF-α activity. Dependent claim 21 is directed to the pharmaceutical composition, wherein the PDE5 inhibitor comprises sildenafil. Dependent claim 24 is directed to the pharmaceutical composition, wherein the SGLT2 inhibitor comprise empagliflozin.
Mayoux et al. teach a pharmaceutical composition comprising a SGLT2 inhibitor and a PDE5 inhibitor (Abstract). The PDE5 inhibitor may be sildenafil (page 15, para. 1). The SGLT2 inhibitor may be empagliflozin (page 15, para. 2), wherein the preferred amount of empagliflozin is in a range from 1 to 50 mg for once daily oral administration (page 17, para. 3). A preferred amount of sildenafil is in a range from 25 to 100 mg on demand for oral administration (page 19, para. 5).
According to Ahmed et al., empagliflozin exhibits anti-inflammatory effect that can be attributed to the diminished activity of NF-κB, which suppresses proinflammatory mediators TNF-α and IL-1β expression (page 870, Left Col., para. 1; Right Col., para. 1). The molar ratio of sildenafil and empagliflozin is 1.05:1 when sildenafil is 31.6 mg and empagliflozin is 30 mg.
For the reasons above, Mayoux et al. with evidence provided by Ahmed et al. anticipates the claimed invention.
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:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. Considering objective evidence present in the application indicating obviousness or
nonobviousness.
Claims 20 – 21 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (US9750743B2, cited in the previous Office Action mailed October 10, 2025) in view of Ahmed et al. (Saudi Pharmaceutical Journal, March 2022, page 863 – 873, cited in the previous Office Action mailed October 10, 2025).
b. Regarding claims 20 – 21 and 24, Kim et al. teach a pharmaceutical composition for inhibiting brain neuron apoptosis, comprising (i) a pharmaceutically effective amount of phosphodiesterase type 5 (PDE 5) inhibitor and (ii) a pharmaceutically acceptable carrier (Col. 3, lines 33 – 37). In one embodiment, the PDE 5 inhibitor is mirodenafil (Col. 3, line 67; Col. 4, line 1). The PDE 5 inhibitor may be administered in a dose of 0.5 – 2 mg/kg to a subject in need of inhibition of brain neuron apoptosis and the position may be administered orally or parenterally. The administration may be conducted once a day (Col. 6, lines 2 – 5; lines 24 – 25). The composition can be applied to the prevention or treatment of brain nerve disease (Col. 4, lines 62 – 64), wherein the brain nerve disease is neuronal degenerative disease, ischemic stroke, cognitive dysfunction, or motor dysfunction (Col. 5, lines 12 – 14). The neuronal degenerative disease is dementia, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (Col. 5, lines 15 – 18).
However, Kim et al. do not teach the composition comprising sodium-glucose cotransporter 2 (SGLT2) inhibitor, wherein the SGLT2 inhibitor is empagliflozin. Kim et al. do not teach the molar ratio of PDE 5 inhibitor and SGLT2 inhibitor is about 50:1, 10:1, 5:1, 2:1, 1:1, 1:2, 1:5, or 1:10.
Ahmed et al. teach that SGLT2 inhibitors are antidiabetic drug with antioxidant and anti-inflammatory properties. Ahmed et al. further teach that SGLT2 inhibitors have a neuroprotective effect in Parkinson’s disease. In the study, Ahmed et al found that both low and high doses of empagliflozin produce a neuroprotective effect against Parkinson’s disease rat model, with the high dose inducing a more significant effect. The oral dose of empagliflozin is 1 and 2 mg/kg/day (Abstract). Moreover, empagliflozin exhibits anti-inflammatory effect that can be attributed to the diminished activity of NF-κB, which suppresses proinflammatory mediators TNF-α and IL-1β expression (page 870, Left Col., para. 1; Right Col., para. 1).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine PDE 5 inhibitor, such as mirodenafil, as taught by Kim et al. with SGLT2 inhibitor, such as empagliflozin, in view of Ahmed et al. to administering the combination of mirodenafil and empagliflozin to treat Parkinson’s disease. It would have been obvious for one of ordinary skill in the art to do this because both drugs are known separately in the prior art for the purpose of treating Parkinson’s disease, and it would have been obvious to combine them to treat the same disease. The molar ratio is calculated to be 0.212:1 to 1.696:1 based on the oral dose disclosed by Kim et al. and Ahmed et al., which reads on the molar ratio limitation of claim 1. One would have performed routine experimentation to discover the best molar ratio of PDE5 inhibitor and SGLT2 inhibitor for optimal treatment characteristics. One of ordinary skill in the art would have had a reasonable expectation of success to combine PDE 5 inhibitor, such as mirodenafil, as taught by Kim et al. with SGLT2 inhibitor, such as empagliflozin, in view of Ahmed et al. because it is well known to combine drugs to treat the same disease.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed March 10, 2026, have been fully considered and are found to be not persuasive.
Regarding Kim et al. and Ahmed et al., Applicant argues that one skilled in the art would not arrive at each and every feature of present claim 20, especially in view of the newly recited “molar ratio” as well as the therapeutic effects. However, the argument is not persuasive. The previous rejection has been modified to include teachings of Kim et al. and Ahmed et al. that address the newly added features. Both Kim et al. and Ahmed et al. disclose the dosages of mirodenafil and empagliflozin, respectively, and the molar ratio is calculated based on these dosages for treating the same condition. Ahmed et al. also explicitly teach that empagliflozin exhibits inhibitory activity toward TNF-α and IL-1β. Therefore, the combination of Kim et al. and Ahmed et al. renders the claimed invention obvious.
Regarding unexpected results, Applicant argues that the combination of Kim et al. and Ahmed et al. does not allow one skilled in the art to arrive at a conclusion that a synergistic effect can be expected at the specifically claimed ratios of PDE5 inhibitor and SGLT2 inhibitor. Applicant specifically points to figures 1 – 8, para. [0066] – [0067], and [0077] – [0085] in the specification, wherein synergistic effects for IL-1β and TNF-α inhibition and intracellular Aβ reduction are observed when utilizing concomitant administration of mirodenafil and empagliflozin in the claimed ratios. However, the argument is not persuasive. The data are limited to the specific pair mirodenafil and empagliflozin and therefore are not commensurate in scope with claims directed broadly to PDE5 inhibitors and SGLT2 inhibitors. Applicant has not shown a trend that would justify extrapolation across the full claim scope. For IL-1β, the reported combination in figure 2 for synergistic effect evaluation are only between 1.0 – 1.2, which illustrating that the therapeutic effects are additive and are only slightly above additivity. For example, at 2 μM mirodenafil and 2 μM empagliflozin, the reported decrease is 7.66%, whereas the sum of the individual decrease is 7.19% (4.33% + 2.86%); at 10 μM mirodenafil and 2 μM empagliflozin, the reported decrease is 24.05%, whereas the sum of the individual decrease is 22.44% (19.68% + 2.68%); and at 20 μM mirodenafil and 20 μM empagliflozin, the reported decrease is 71.56%, whereas the sum of the individual decrease is 69.30% (47.87% + 21.43%). For TNF-α, the reported combination in figure 4 for synergistic effect evaluation are only between 1.0 – 1.3. For example, at 10 μM mirodenafil and 20 μM empagliflozin, the reported decrease is 46.65%, whereas the sum of individual decrease is 46.04% (24.00% + 22.04%); and at 20 μM mirodenafil and 20 μM empagliflozin, the reported decrease is 74.69%, whereas the sum of individual decrease is 72.47% (50.43% + 22.04%). The reported decreases in both IL-1β and TNF-α show that there is only additive effect at 20 μM mirodenafil and 20 μM empagliflozin. The Aβ42 data are also inconsistent. Although some combinations are reported as synergistic, such as 1 μM mirodenafil and 1 μM empagliflozin with a combination index of 3.0, 1 μM mirodenafil and 10 μM empagliflozin with a combination index of 1.5, and 5 μM mirodenafil and 0.1 μM empagliflozin with a combination index of 1.6. Even assuming that Applicant has shown a greater-than-additive effect for certain tested mirodenafil and empagliflozin combinations, such a showing is not, by itself, sufficient to establish nonobviousness. As stated in MPEP § 716.02(a), Applicant must further show that the results are greater than those which would have been expected from the prior art to an unobvious extent and that the results provide a significant, practical advantage. However, Applicant has not made such a showing. The reported IL-1β and TNF-α values are only 1.1 to 1.3, with 1.0 also reported for certain tested combinations, indicating that many of the reported effects are only marginally above additivity. Thus, Applicant’s evidence shows, at most, limited and ratio-dependent effects for a single tested species pair, not robust or consistent unexpected results across the breadth of the presently claimed invention.
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 20 – 21 and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17 – 19 and 23 – 25 of copending Application No. 19/003,405 in view of Kim et al. (US9750743B2, cited in the previous Office Action mailed October 10, 2025) and Ahmed et al. (Saudi Pharmaceutical Journal, March 2022, page 863 – 873, cited in the previous Office Action mailed October 10, 2025).
a. Regarding claims 20 – 21 and 24, ‘405 teaches a pharmaceutical composition comprising at least one phosphodiesterase 5 inhibitor and at least one N-methyl-D-aspartate-receptor (NMDA-receptor) (claim 17). The phosphodiesterase 5 inhibitor comprises mirodenafil (claims 18 – 19). ‘405 teaches that the pharmaceutical composition is used for treating neurodegenerative disease, wherein the neurodegenerative disease is Parkinson’s disease, Alzheimer’s disease, dementia, Huntington’s disease, and amyotrophic lateral sclerosis (claims 24 – 25) and inhibiting beta-amyloid accumulation (claim 23).
However, ‘405 does not teach the composition comprising a SGLT2 inhibitor, wherein the SGLT2 inhibitor is empagliflozin as well as the molar ratio of PDE5 inhibitor and SGLT2 inhibitor.
Kim et al. teach a pharmaceutical composition for inhibiting brain neuron apoptosis, comprising (i) a pharmaceutically effective amount of phosphodiesterase type 5 (PDE 5) inhibitor and (ii) a pharmaceutically acceptable carrier (Col. 3, lines 33 – 37). In one embodiment, the PDE 5 inhibitor is mirodenafil (Col. 3, line 67; Col. 4, line 1). The PDE 5 inhibitor may be administered in a dose of 0.5 – 2 mg/kg to a subject in need of inhibition of brain neuron apoptosis and the position may be administered orally or parenterally. The administration may be conducted once a day (Col. 6, lines 2 – 5; lines 24 – 25). The composition can be applied to the prevention or treatment of brain nerve disease (Col. 4, lines 62 – 64), wherein the brain nerve disease is neuronal degenerative disease, ischemic stroke, cognitive dysfunction, or motor dysfunction (Col. 5, lines 12 – 14). The neuronal degenerative disease is dementia, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (Col. 5, lines 15 – 18).
Ahmed et al. teach that SGLT2 inhibitors are antidiabetic drug with antioxidant and anti-inflammatory properties. Ahmed et al. further teach that SGLT2 inhibitors have a neuroprotective effect in Parkinson’s disease. In the study, Ahmed et al found that both low and high doses of empagliflozin produce a neuroprotective effect against Parkinson’s disease rat model, with the high dose inducing a more significant effect. The oral dose of empagliflozin is 1 and 2 mg/kg/day (Abstract). Moreover, empagliflozin exhibits anti-inflammatory effect that can be attributed to the diminished activity of NF-κB, which suppresses proinflammatory mediators TNF-α and IL-1β expression (page 870, Left Col., para. 1; Right Col., para. 1).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the at least one N-methyl-D-aspartate-receptor (NMDA-receptor) in the composition as taught by ‘405 with SGLT-2, such as empagliflozin, in view of Ahmed et al. because both drugs are known separately in the art for the purpose of treating Parkinson’s disease. It would have been obvious for one to substitute equivalent drug known to treat the same disease. The molar ratio is calculated to be 0.212:1 to 1.696:1 based on the oral dose disclosed by Kim et al. and Ahmed et al., which reads on the molar ratio limitation of claim 1. One would have performed routine experimentation to discover the best molar ratio of PDE5 inhibitor and SGLT2 inhibitor for optimal treatment characteristics. Therefore, one of ordinary skill in the art would have had a reasonable expectation of success to modify ‘405 with Ahmed et al. because it is well known to combine drugs to treat the same disease.
This is a provisional nonstatutory double patenting rejection.
Claims 20 – 21 and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2, 4 – 5, and 7 – 9 of copending Application No. 18/492,734 in view of Kim et al. (US9750743B2, cited in the previous Office Action mailed October 10, 2025) and Ahmed et al. (Saudi Pharmaceutical Journal, March 2022, page 863 – 873, cited in the previous Office Action mailed October 10, 2025).
b. Regarding claims 20 – 21 and 24, ‘734 teaches a composition comprising a phosphodiesterase 5 inhibitor and a glucocorticoid receptor (GR) antagonist (claim 1). The phosphodiesterase 5 inhibitor comprises mirodenafil (claims 2 and 4 – 5). The pharmaceutical composition may inhibit accumulation of beta-amyloid (claim 7) and is used for treating neurodegenerative disease, wherein the disease is Parkinson’s disease (claims 8 – 9).
However, ‘734 does not teach the composition comprising a SGLT2 inhibitor, wherein the SGLT2 inhibitor is empagliflozin as well as the molar ratio of PDE5 inhibitor and SGLT2 inhibitor.
Kim et al. teach a pharmaceutical composition for inhibiting brain neuron apoptosis, comprising (i) a pharmaceutically effective amount of phosphodiesterase type 5 (PDE 5) inhibitor and (ii) a pharmaceutically acceptable carrier (Col. 3, lines 33 – 37). In one embodiment, the PDE 5 inhibitor is mirodenafil (Col. 3, line 67; Col. 4, line 1). The PDE 5 inhibitor may be administered in a dose of 0.5 – 2 mg/kg to a subject in need of inhibition of brain neuron apoptosis and the position may be administered orally or parenterally. The administration may be conducted once a day (Col. 6, lines 2 – 5; lines 24 – 25). The composition can be applied to the prevention or treatment of brain nerve disease (Col. 4, lines 62 – 64), wherein the brain nerve disease is neuronal degenerative disease, ischemic stroke, cognitive dysfunction, or motor dysfunction (Col. 5, lines 12 – 14). The neuronal degenerative disease is dementia, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (Col. 5, lines 15 – 18).
Ahmed et al. teach that SGLT2 inhibitors are antidiabetic drug with antioxidant and anti-inflammatory properties. Ahmed et al. further teach that SGLT2 inhibitors have a neuroprotective effect in Parkinson’s disease. In the study, Ahmed et al found that both low and high doses of empagliflozin produce a neuroprotective effect against Parkinson’s disease rat model, with the high dose inducing a more significant effect. The oral dose of empagliflozin is 1 and 2 mg/kg/day (Abstract). Moreover, empagliflozin exhibits anti-inflammatory effect that can be attributed to the diminished activity of NF-κB, which suppresses proinflammatory mediators TNF-α and IL-1β expression (page 870, Left Col., para. 1; Right Col., para. 1).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute a glucocorticoid receptor (GR) antagonist in the composition as taught by ‘734 with SGLT-2, such as empagliflozin, in view of Ahmed et al. because both drugs are known separately in the art for the purpose of treating Parkinson’s disease. It would have been obvious for one to substitute equivalent drug known to treat the same disease. The molar ratio is calculated to be 0.212:1 to 1.696:1 based on the oral dose disclosed by Kim et al. and Ahmed et al., which reads on the molar ratio limitation of claim 1. One would have performed routine experimentation to discover the best molar ratio of PDE5 inhibitor and SGLT2 inhibitor for optimal treatment characteristics. Therefore, one of ordinary skill in the art would have had a reasonable expectation of success to modify ‘734 with Ahmed et al. because it is well known to combine drugs to treat the same disease.
This is a provisional nonstatutory double patenting rejection.
Claims 20 – 21 and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17 – 19, 22, and 24 of copending Application No. 18/991,922 in view of Kim et al. (US9750743B2, cited in the previous Office Action mailed October 10, 2025) and Ahmed et al. (Saudi Pharmaceutical Journal, March 2022, page 863 – 873, cited in the previous Office Action mailed October 10, 2025).
c. Regarding claims 20 – 21 and 24, ‘922 teaches a pharmaceutical composition comprising at least one PDE 5 inhibitor and at least one acetylcholinesterase inhibitor active ingredients (claim 17), wherein the PDE 5 inhibitor comprises mirodenafil (claims 18 – 19). The composition may inhibit accumulation of beta-amyloid (claim 22) and is intended for treating Parkinson’s disease (claim 24).
However, ‘922 does not teach the composition comprising a SGLT2 inhibitor, wherein the SGLT2 inhibitor is empagliflozin as well as the molar ratio of PDE5 inhibitor and SGLT2 inhibitor.
Kim et al. teach a pharmaceutical composition for inhibiting brain neuron apoptosis, comprising (i) a pharmaceutically effective amount of phosphodiesterase type 5 (PDE 5) inhibitor and (ii) a pharmaceutically acceptable carrier (Col. 3, lines 33 – 37). In one embodiment, the PDE 5 inhibitor is mirodenafil (Col. 3, line 67; Col. 4, line 1). The PDE 5 inhibitor may be administered in a dose of 0.5 – 2 mg/kg to a subject in need of inhibition of brain neuron apoptosis and the position may be administered orally or parenterally. The administration may be conducted once a day (Col. 6, lines 2 – 5; lines 24 – 25). The composition can be applied to the prevention or treatment of brain nerve disease (Col. 4, lines 62 – 64), wherein the brain nerve disease is neuronal degenerative disease, ischemic stroke, cognitive dysfunction, or motor dysfunction (Col. 5, lines 12 – 14). The neuronal degenerative disease is dementia, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (Col. 5, lines 15 – 18).
Ahmed et al. teach that SGLT2 inhibitors are antidiabetic drug with antioxidant and anti-inflammatory properties. Ahmed et al. further teach that SGLT2 inhibitors have a neuroprotective effect in Parkinson’s disease. In the study, Ahmed et al found that both low and high doses of empagliflozin produce a neuroprotective effect against Parkinson’s disease rat model, with the high dose inducing a more significant effect. The oral dose of empagliflozin is 1 and 2 mg/kg/day (Abstract). Moreover, empagliflozin exhibits anti-inflammatory effect that can be attributed to the diminished activity of NF-κB, which suppresses proinflammatory mediators TNF-α and IL-1β expression (page 870, Left Col., para. 1; Right Col., para. 1).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute at least one acetylcholinesterase inhibitor in the composition as taught by ‘922 with SGLT-2, such as empagliflozin, in view of Ahmed et al. because both drugs are known separately in the art for the purpose of treating Parkinson’s disease. It would have been obvious for one to substitute equivalent drug known to treat the same disease. The molar ratio is calculated to be 0.212:1 to 1.696:1 based on the oral dose disclosed by Kim et al. and Ahmed et al., which reads on the molar ratio limitation of claim 1. One would have performed routine experimentation to discover the best molar ratio of PDE5 inhibitor and SGLT2 inhibitor for optimal treatment characteristics. Therefore, one of ordinary skill in the art would have had a reasonable expectation of success to modify ‘922 with Ahmed et al. because it is well known to combine drugs to treat the same disease.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is found to be allowable.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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