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 .
Priority
The present application claims priority to the following applications: CN 02110184080.0, CN 202111503546.5, CN 202111664079.4, and PCT/CN2022/075740, with effective filing dates of 10 February 2021, 10 December 2021, 31 December 2021, and 10 February 2022, respectively.
Claim Status
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 28 July 2026 has been entered.
This Office Action is in response to Applicant’s Request for Continued Examination filed, 28 July 2026, wherein the Applicant amended claims 20 and 21 and added new claim 28. Claims 2-4, 8-11, 13-19, and 25 were canceled previously.
Claims 1, 5-7, 12, 20-24, and 26-28 are pending.
Information Disclosure Statement
The Information Disclosure Statement filed 12 June 2026 and the references cited therein were considered in the Advisory Action mailed 26 June 2026.
Claim Interpretation
The Examiner notes that claims 24 and 26-27 recite a method for preventing and/or treating a cardiovascular or cerebrovascular disease via administering a compound of Formula (I). Sawada (J. Cerebral Blood Flow, 2014, 34(2), 235-241, see IDS filed 10 Aug 2023) teaches that SMTP-7 has profibrinolytic activity and promotes clot clearance (page 239, column 1, paragraph 2; page 239, column 2, paragraph 3). Cleveland Clinic 4 (“Thrombosis,” Cleveland Clinic¸ 2026, <my.clevelandclinic.org/health/diseases/22242-thrombosis>, accessed 18 Aug 2026) teaches that thrombosis is a condition where one or more blood clots form in the blood vessels or heart and that the clot can cause an array of cardiovascular and cerebrovascular events depending upon clot origin or travel (page 1, paragraph 1; page 1, paragraph 6 and bullet points 1-5). Because SMTP-7 (the parent drug) has profibronlytic activity (breakdown of clots), SMTP-7 would be able to prevent clot formation, which would prevent cardiovascular and/or cerebrovascular disease.
Rejections Withdrawn
Claim Rejections – 35 U.S.C. § 103
1. Claims 20-21 were rejected as being unpatentable over Sawada (J. Cerebral Blood Flow, 2014, 34(2), 235-241, see IDS filed 10 Aug 2023) in view of Pirali (J. Med. Chem., 2019, 62, 5276-5297, of record, see PTO-892 filed 16 Dec 2025). Applicant’s amendments, see pages 2-3, with respect to claims 20-21 has been fully considered. The rejection of claims 20-21 as being unpatentable over Sawada in view of Pirali has been withdrawn.
Rejections New/Modified or Maintained
Claim Rejections – 35 U.S.C. § 103
1. (Maintained) Claims 1, 5-7, 12, 24, and 26-27 were rejected as being unpatentable over Sawada (J. Cerebral Blood Flow, 2014, 34(2), 235-241, see IDS filed 10 Aug 2023) in view of Pirali (J. Med. Chem., 2019, 62, 5276-5297, of record, see PTO-892 filed 16 Dec 2025).
Applicant's arguments and declaration filed 12 June 2026 have been fully considered but they are not persuasive.
Applicant argues that a person of ordinary skill in the art lacks motivation to deuterate SMTP-7. Applicant asserts that Sawada does not identify any metabolic liability, short half-life, poor bioavailability, or other pharmacokinetic deficiency that would motivate a person having ordinary skill in the art to pursue deuterium modification. Applicant further asserts in Pirali that designing a successful deuterated drug is far from straightforward and the translation from concept to practice is often unpredictable. Applicant then asserts in the Rule 1.132 Declaration that “according to Annex 1, SMTP-7 is almost not metabolized by conventional CYP450 enzymes” and that the “primary clearance pathway of SMTP-7 in vivo is the ‘glucuronidation’ mediated by UGT1A1 enzyme” (point 11, page 5). Applicant further asserts that only the δ-deuterated SMTP exhibits a significant qualitative improvement in pharmacokinetic performance and therapeutic effect on cerebral infarction compared to original drug (SMTP-7) and that the pharmacokinetic properties of the other three deuterated compounds (α, β, and γ-deuterated compound) are essentially equivalent to or even worse than the original drug (point 16, page 5).
In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to Applicant’s arguments that a person of ordinary skill in the art lacks motivation to deuterate SMTP-7, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). Further, in response to Applicant’s assertion that the Office’s stated motivation is conclusory, the Office previously articulated motivations to combine the references of Sawada and Pirali (see the Action filed 16 Dec 2025) and accordingly reiterates herein. In this case, one of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Sawada teaches the performance of SMTP-7 and salts thereof in animal models of thrombosis and stroke,
-Sawada teaches motivations to improve the pharmacokinetic profile of SMTP-7, because high doses (100 mg/kg) of SMTP-7 result in significantly enhanced bleeding and plasma Pm-AP levels as compared to a lower dose of SMTP-7 (10 mg/kg, which is pharmacologically active and affects the fibronlytic system minimally in normal animals) (page 240, column 2, paragraph 1);
-while Sawada states that the SMTP-7 dose at 10 mg/kg (the pharmacologically active dose) may minimally affect the fibrinolytic system in animals, a person of ordinary skill in the art would understand that Sawada is establishing the dosing range (via the 100 mg/kg dose) and thus the toxicity associated with each dose, which is important in pharmacokinetic studies and translation of active pharmaceutical ingredients from murine model to humans (page 240, column 2, paragraph 1; Figure 4),
-Pirali teaches the landscape of deuteration in drug development and that deuteration is now considered common practice,
-Pirali teaches motivations to deuterate: slow down drug metabolism, improve the pharmacokinetic profile of drugs, and prolong drug release,
-Pirali teaches success of compounds incorporating alkyl deuteration at the methylene unit adjacent to saturated heterocycles: Compounds 12 (
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, Figure 4, page 5280), 26 (
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, Figure 4, page 5280), and 30 (
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, Figure 6, page 5281),
-Pirali teaches success of deuteration directly on saturated heterocycles:
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(Compound 16, Figure 3, page 5280) and
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(Compound 53, Figure 12, page 5283),
-Pirali teaches success of deuteration in alkenyl chains:
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(Compound 92, Figure 21, page 5290),
-while Pirali states that the outcome of deuteration is unpredictable, Pirali also states that the outcome actually depends on the effect that the deuterated compound has compared to the ancestor, on the data that support the claims, and on the prior art of the nondeuterated compounds (page 5292, column 1, paragraph 2),
-Pirali also states that a critical appraisal of the literature suggests that deuterium is entering the medicinal chemist’s toolbox, and it is foreseeable that drugs will be increasingly endowed with deuterium atoms in the future (page 5292, column 1, paragraph 4),
-Pirali further teaches that deuterium incorporation is particularly appropriate for those soft spots that suffer from strict and rigid structure−activity relationships, where no change in steric hindrance or electronegativity is tolerated and that both intuition and rigor are necessary for selecting compounds and positions that might be amenable to precision deuteration, which is well within the competence of a person of ordinary skill in the art (page 5292, column 1, paragraph 4; page 5292, column 2, paragraph 1), and
-Pirali further teaches that deuterium isosteric replacement will come of age akin to fluorine and will be a great opportunity for medical chemists: fluorine appeared in less than 2% of drugs in the 1970s but is now in as many as 25% of approved drugs and that this same phenomenon will occur with deuterium (page 5292, column 2, paragraph 2).
As such, a person or ordinary skill would have been motivated to combine the teachings of Sawada and Pirali to develop deuterated SMTP-7 derivatives. Further, because claim 1 is a compound claim and does not recite a physiological effect, a person of ordinary skill in the art simply requires a reason to make the compound, which the combination of Sawada and Pirali provides (Sawada: page 240, column 2, paragraph 1; Pirali: page 5278, column 1, paragraph 1; page 5278, column 2, paragraph 3; page 5281, column 2, paragraph 2).
In response to Applicant’s assertion that SMTP-7 undergoes a different metabolism mechanism (point 11, page 5), it is unclear to which Annex 1 Applicant is referring. Because Applicant’s argument is unclear, the Examiner cannot accurately address the argument.
In response to Applicant’s arguments regarding unexpected success (i.e. pharmacokinetic performance), a showing of unexpected results must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997) (conclusory statements regarding unusually low immune response or unexpected biological activity that were unsupported by comparative data held insufficient to overcome prima facie case of obviousness). Rebuttal evidence may include evidence that the claimed invention was copied by others. See, e.g., In re GPAC, 57 F.3d 1573, 1580, 35 USPQ2d 1116, 1121 (Fed. Cir. 1995); Hybritech Inc. v. Monoclonal Antibodies, 802 F.2d 1367, 1380, 231 USPQ 81, 90 (Fed. Cir. 1986). See MPEP 2145. Applicant, indeed, shows unexpected pharmacokinetic performance and therapeutic effect on cerebral infarction for Compound 1 (the only δ-deuterated SMTP-7 derivative) but details that Compounds 2-4 (α, β, and γ-deuterated compounds) are essentially equivalent to or even worse than the original drug (Rule 1.132 Declaration, point 16, page 5).
Additionally, the evidence must be reasonably commensurate in scope with the claimed invention. See, e.g., In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990); In re Grasselli, 713 F.2d 731, 743, 218 USPQ 769, 777 (Fed. Cir. 1983). In other words, in order for evidence of secondary considerations to be accorded substantial weight, there must be a nexus, i.e., a legally and factually sufficient connection or correspondence between the submitted evidence and the claimed invention. Fox Factory, Inc. v. SRAM, LLC, 944 F.3d 1366, 1373, 2019 USPQ2d 483355 (Fed. Cir. 2019), cert. denied, 141 S.Ct. 373 (2020). "A presumption of nexus requires both that the product embodies the invention and is coextensive with it." Volvo Penta of the Americas, LLC v. Brunswick Corp., 81 F.4th 1202,1211-12, 2023 USPQ2d 1000 (Fed. Cir. 2023). Applicant notes that Compounds 2-4 do not exhibit the same unexpected success in pharmacokinetic performance and therapeutic effect on cerebral infarction as Compound 1 (Rule 1.132 Declaration, point 16, page 5). However, Compounds 1 and 2-4 all fall into the genus of Formula (I). Accordingly, the success of Compound 1 as demonstrated by Applicant is not commensurate in scope with the claims.
Accordingly, the rejection of claims 1, 5-7, 12, 24, and 26-27 as being unpatentable over Sawada in view of Pirali is maintained.
3. (Modified) Claim(s) 1, 5-7, 12, 22-24, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Sawada (J. Cerebral Blood Flow, 2014, 34(2), 235-241, see IDS filed 10 Aug 2023) and Pirali (J. Med. Chem., 2019, 62, 5276-5297, of record, see PTO-892 filed 16 Dec 2025) as applied to claims 1, 5-7, 12, 24, and 26-27 above, and further in view of Jones (U.S. Patent Publication No. 2020/0039965, published 6 Feb 2020, of record, see PTO-892 filed 16 Dec 2025).
Applicant's arguments filed 12 June 2026 have been fully considered but they are not persuasive.
Applicant argues that Jones relates exclusively to deuterated HSF1 inhibitors for the treatment of cancer – a compound class, therapeutic area, and mechanism of action entirely distinct from SMTP-7 and that there is no teaching that would lead a person having skill in the art to deuterate SMTP-7 at any particular position or to any particular isotopic purity level.
In response to Applicant’s argument that Jones is directed to a compound class, therapeutic area, and mechanism of action entirely distinct from SMTP-7, Jones teaches deuteration of similar moieties:
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([0127]). Thus, Jones builds upon Pirali and teaches successful deuteration of designed active pharmaceutical ingredients with better pharmacokinetics: compounds with improved clearance, stability, half-life, volume of distribution, and bioavailability as compared to the un-deuterated analogs in an abundance of at least 4000 times ([0009]; [0038]; [0055]). Further, Jones teaches motivations to deuterate: compounds suffering from poor ADME (absorption, distribution, metabolism, excretion) properties in vivo, which now have better ADME as the deuterated derivatives ([0008]-[0009]). Thus, Jones builds upon Sawada and Pirali to teach compounds with an abundance of at least 4000 times (60% isotopic purity).
Accordingly, claims 1, 5-7, 12, 22-24, and 26-27 are rejected as being unpatentable over Sawada and Pirali in view of Jones.
4. (New) Claims 1, 5-7, 12, 20-21, 24, and 26-27 were rejected as being unpatentable over Sawada (J. Cerebral Blood Flow, 2014, 34(2), 235-241; of record, see IDS filed 10 Aug 2023) in view of Hasumi (Int. J. Mol. Sci., 19 Jan 2021, 22(954), 1-23; see IDS filed 12 June 2026) and Pirali (J. Med. Chem., 2019, 62, 5276-5297; of record, see PTO-892 mailed 16 Dec 2025) as evidenced by Cleveland Clinic 1 (“Cerebrovascular Disease,” Cleveland Clinic, https://my.clevelandclinic.org/health/diseases/24205-cerebrovascular-disease, accessed 25 Nov 2025; of record, see PTO-892 mailed 16 Dec 2025), Cleveland Clinic 2 (“Cardiovascular Disease,” Cleveland Clinic, https://my.clevelandclinic.org/health/diseases/21493-cardiovascular-disease, accessed 25 Nov 2025, of record, see PTO-892 mailed 16 Dec 2025), and Cleveland Clinic 3 (Cleveland Clinic (“Venous thromboembolism,” Cleveland Clinic, https://my.clevelandclinic.org/health/diseases/22614-venous- thromboembolism, accessed 25 Nov 2025; of record, see PTO-892 mailed 16 Dec 2025).
Sawada teaches how SMTP-7 and salts thereof perform in animal models of thrombosis
and stroke with the end goal of extrapolating to humans (page 235, column 1, paragraph 1; page
236, column 1, paragraph 1). Sawada specifically teaches the compound, SMTP-7:
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, which is pharmacologically active in thrombosis and stroke models (page 236, column 1, paragraph 1; page 240, column 2, paragraph 1). Sawada further teaches high doses (100 mg/kg) of SMTP-7 result in significantly enhanced bleeding and plasma Pm-AP levels as opposed to a SMTP-7 dose of 10 mg/kg, which is pharmacologically active and affects the fibronlytic system minimally in normal animals (page 240, column 2, paragraph 1).
Regarding claim 1, Sawada fails to teach the corrected stereochemistry of SMTP-7 and deuteration of SMTP-7.
Hasumi teaches that SMTP is a large family of small molecules derived from the fungus S. micropsora and that SMTP congeners with both plasminogen modulation activity and anti-inflamamtory activity ameliorate various aspects of ischemic stroke in rodents and primates (abstract). Hasumi teaches that the hemostatic system is finely regulated to achieve continuous blood circulation and prevent blood loss based on the balance between blood coagulation and fibronlysis (blood clot degradation; page 1, paragraph 1). Hasumi teaches antithrombotics, which inhibit blood clot formation, and thrombolytics, which accelerate the degradation of blood clots, are widely used to treat, control, or prevent thrombotic complications such as ischemic diseases of the heart, brain, lungs, and kidneys (page 1, paragraph 1). Hasumi teaches that SMTP promotes thrombolysis without causing excessive bleeding (page 1, paragraph 2). Hasumi teaches that the initial absolute stereochemistry was proposed utilizing NMR techniques using the simplest congener, SMTP-0, and its derivatives but that a recent investigation utilized a combination of NMR and crystallographic techniques proved an (8S,9R) configuration for an SMTP congener (page 4, paragraph 2). Hasumi teaches that all the SMTP congeners should be revised to (8S,9R) stereochemistry (page 4, paragraph 2). Hasumi teaches SMTP-7 has the following structure:
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(page 4, Figure 1).
Pirali teaches deuteration in drug design and why the pharmaceutical industry is interested in it (page 5277, column 1, paragraph 6). Pirali further teaches the example of BMS-986165 and the lack of mention of its deuterated nature in publication and states that this modification is now considered common practice in drug development (page 5277, column 2, paragraph 2). Pirali specifies that the salvaging of compounds via deuteration that previously showed weaknesses in their nondeuterated form (e.g. CTP-354) allows for revitalization of abandoned drug programs (page 5277, column 2, paragraph 3). Pirali further specifies deuteration substitution is to slow down drug metabolism, improve the pharmacokinetic profile of drugs, and prolong drug release (page 5278, column 1, paragraph 1; page 5278, column 2, paragraph 3; page 5281, column 2, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to select the compound of Sawada and Hasumi and the deuteration of Pirali to design deuterated SMTP-7 to arrive at instant claim 1. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Sawada teaches the performance of SMTP-7 and salts thereof in animal models of thrombosis and stroke,
-Sawada teaches motivations to improve the pharmacokinetic profile of SMTP-7, because high doses (100 mg/kg) of SMTP-7 result in significantly enhanced bleeding and plasma Pm-AP levels as compared to a lower dose of SMTP-7 (10 mg/kg, which is pharmacologically active and affects the fibronlytic system minimally in normal animals) (page 240, column 2, paragraph 1),
-while Sawada states that the SMTP-7 dose at 10 mg/kg (the pharmacologically active dose) may minimally affect the fibrinolytic system in animals, a person of ordinary skill in the art would understand that Sawada is establishing the dosing range (via the 100 mg/kg dose) and thus the toxicity associated with each dose, which is important in pharmacokinetic studies and translation of active pharmaceutical ingredients from murine model to humans (page 240, column 2, paragraph 1; Figure 4),
-Hasumi teaches that SMTP is a large family of small molecules derived from the fungus S. micropsora and that SMTP congeners with both plasminogen modulation activity and anti-inflamamtory activity ameliorate various aspects of ischemic stroke in rodents and primates,
-Hasumi teaches that the hemostatic system is finely regulated to achieve continuous blood circulation and prevent blood loss based on the balance between blood coagulation and fibronlysis (blood clot degradation),
-Hasumi teaches antithrombotics, which inhibit blood clot formation, and thrombolytics, which accelerate the degradation of blood clots, are widely used to treat, control, or prevent thrombotic complications such as ischemic diseases of the heart, brain, lungs, and kidneys,
-Hasumi teaches that SMTP promotes thrombolysis without causing excessive bleeding,
-Hasumi teaches that the initial absolute stereochemistry was proposed utilizing NMR techniques using the simplest congener, SMTP-0, and its derivatives but that a recent investigation utilized a combination of NMR and crystallographic techniques proved an (8S,9R) configuration for an SMTP congener,
-Hasumi teaches that all the SMTP congeners should be revised to (8S,9R) stereochemistry,
-Hasumi teaches SMTP-7 has the following structure:
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,
-Pirali teaches the landscape of deuteration in drug development and that deuteration is now considered common practice,
-Pirali teaches motivations to deuterate: slow down drug metabolism, improve the pharmacokinetic profile of drugs, and prolong drug release,
-Pirali teaches success of compounds incorporating alkyl deuteration at the methylene unit adjacent to saturated heterocycles: Compounds 12 (
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, Figure 4, page 5280), 26 (
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, Figure 4, page 5280), and 30 (
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, Figure 6, page 5281),
-Pirali teaches success of deuteration directly on saturated heterocycles:
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(Compound 16, Figure 3, page 5280) and
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(Compound 53, Figure 12, page 5283),
-Pirali teaches success of deuteration in alkenyl chains:
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(Compound 92, Figure 21, page 5290),
-while Pirali states that the outcome of deuteration is unpredictable, Pirali also states that the outcome actually depends on the effect that the deuterated compound has compared to the ancestor, on the data that support the claims, and on the prior art of the nondeuterated compounds (page 5292, column 1, paragraph 2),
-Pirali also states that a critical appraisal of the literature suggests that deuterium is entering the medicinal chemist’s toolbox, and it is foreseeable that drugs will be increasingly endowed with deuterium atoms in the future (page 5292, column 1, paragraph 4),
-Pirali further teaches that deuterium incorporation is particularly appropriate for those soft spots that suffer from strict and rigid structure−activity relationships, where no change in steric hindrance or electronegativity is tolerated and that both intuition and rigor are necessary for selecting compounds and positions that might be amenable to precision deuteration, which is well within the competence of a person of ordinary skill in the art (page 5292, column 1, paragraph 4; page 5292, column 2, paragraph 1), and
-Pirali further teaches that deuterium isosteric replacement will come of age akin to fluorine and will be a great opportunity for medical chemists: fluorine appeared in less than 2% of drugs in the 1970s but is now in as many as 25% of approved drugs and that this same phenomenon will occur with deuterium (page 5292, column 2, paragraph 2).
As such, a person or ordinary skill would have been motivated to combine the teachings of Sawada, Hasumi, and Pirali to develop deuterated SMTP-7 derivatives.
Regarding claim 5, Pirali teaches deuterated alkyl analogs, such as R29 is deuterium (page 5278, column 1, paragraph 1; Figure 2, page 5278; Figure 4, page 5280; Table 3, pages 5288- 5289; Figure 2, page 5278; Figure 3, page 5280; Figure 4, page 5280).
Regarding claim 6, Pirali teaches deuterated alkyl analogs, such as R30, R31 are deuterium (page 5278, column 1, paragraph 1; Figure 2, page 5278; Figure 3, page 5280; Figure 4, page 5280; Table 3, pages 5288-5289).
Regarding claim 7, Pirali teaches deuterated alkyl analogs, such as R34, R35 are deuterium (page 5278, column 1, paragraph 1; Figure 2, page 5278; Figure 3, page 5280; Figure 4, page 5280; Table 3, pages 5288-5289).
Regarding claim 12, Pirali teaches deuterated alkyl analogs, such as R32, R33 are deuterium (page 5278, column 1, paragraph 1; Figure 2, page 5278; Figure 3, page 5280; Figure 4, page 5280; Table 3, pages 5288-5289).
Regarding claim 20, Pirali teaches deuterated analogs of aryl rings, heterocycles, alkyl, and alkenyl, such as:
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(page 5278, column 1, paragraph 1; Figure 2, page 5278; Figure 3, page 5280; Figure 4, page 5280; Figure 9, page 5282; Figure 11, page 5282; figure 17, page 5285; Figure 18, page 5286).
Regarding claim 21, Pirali teaches success of compounds incorporating alkyl deuteration at the methylene unit adjacent to saturated heterocycles: Compounds 12 (
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, Figure 4, page 5280), 26 (
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, Figure 4, page 5280), and 30 (
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, Figure 6, page 5281). Additionally, Pirali teaches success of deuteration of alkyl chains: Compounds 19 and 20 (
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; Figure 3, page 5280). Pirali also teaches success of deuteration in alkenyl chains:
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(Compound 92, Figure 21, page 5290).
Regarding claim 24, Sawada teaches the use of SMTP-7 to treat thrombosis and stroke (page 235, column 1, paragraph 1; page 236, column 1, paragraph 1), which are cardiovascular and cerebrovascular diseases, as evidenced by Cleveland Clinic 1 (page 1, paragraph 1) and Cleveland Clinic 2 (page 1, paragraph 1).
Regarding claim 26, Sawada teaches that SMTP-7 effectively ameliorates embolic stroke in rodent models (page 235, column 1, paragraph 2), which embolic stroke is an example of a thromoboembolic disease, as evidenced by Cleveland Clinic 3 (page 1, paragraph 1).
Regarding claim 27, Sawada teaches that SMTP-7 effectively ameliorates embolic stroke in rodent models (page 235, column 1, paragraph 2).
5. (New) Claim(s) 1, 5-7, 12, 20-24, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Sawada (J. Cerebral Blood Flow, 2014, 34(2), 235-241; of record, see IDS filed 10 Aug 2023) in view of Hasumi (Int. J. Mol. Sci., 19 Jan 2021, 22(954), 1-23; see IDS filed 12 June 2026) and Pirali (J. Med. Chem., 2019, 62, 5276-5297; of record, see PTO-892 mailed 16 Dec 2025) as evidenced by Cleveland Clinic 1 (“Cerebrovascular Disease,” Cleveland Clinic, https://my.clevelandclinic.org/health/diseases/24205-cerebrovascular-disease, accessed 25 Nov 2025; of record, see PTO-892 mailed 16 Dec 2025), Cleveland Clinic 2 (“Cardiovascular Disease,” Cleveland Clinic, https://my.clevelandclinic.org/health/diseases/21493-cardiovascular-disease, accessed 25 Nov 2025, of record, see PTO-892 mailed 16 Dec 2025), and Cleveland Clinic 3 (Cleveland Clinic (“Venous thromboembolism,” Cleveland Clinic, https://my.clevelandclinic.org/health/diseases/22614-venous- thromboembolism, accessed 25 Nov 2025; of record, see PTO-892 mailed 16 Dec 2025) as applied to claims 1, 5-7, 12, 20-21, 24, and 26-27 above, and further in view of Jones (U.S. Patent Publication No. 2020/0039965, published 6 Feb 2020, of record, see PTO-892 filed 16 Dec 2025).
Sawada (J. Cerebral Blood Flow, 2014, 34(2), 235-241; of record, see IDS filed 10 Aug 2023) in view of Hasumi (Int. J. Mol. Sci., 19 Jan 2021, 22(954), 1-23; see IDS filed 12 June 2026) and Pirali (J. Med. Chem., 2019, 62, 5276-5297; of record, see PTO-892 mailed 16 Dec 2025) as evidenced by Cleveland Clinic 1 (“Cerebrovascular Disease,” Cleveland Clinic, https://my.clevelandclinic.org/health/diseases/24205-cerebrovascular-disease, accessed 25 Nov 2025; of record, see PTO-892 mailed 16 Dec 2025), Cleveland Clinic 2 (“Cardiovascular Disease,” Cleveland Clinic, https://my.clevelandclinic.org/health/diseases/21493-cardiovascular-disease, accessed 25 Nov 2025, of record, see PTO-892 mailed 16 Dec 2025), and Cleveland Clinic 3 (Cleveland Clinic (“Venous thromboembolism,” Cleveland Clinic, https://my.clevelandclinic.org/health/diseases/22614-venous- thromboembolism, accessed 25 Nov 2025; of record, see PTO-892 mailed 16 Dec 2025) are applied as discussed in the 35 U.S.C. 103 rejection above.
Regarding claim 22, while the combination of Sawada, Hasumi, and Pirali teach deuterated derivatives of SMTP-7, they differ from that of the instantly claimed invention in that they do not explicitly teach that compounds having a deuterium abundance that is at least 4000 times, which is equivalent to 60% incorporation (see the specification, page 8, lines 9-10).
It would have been prima facie obvious to one or ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to exemplify the compounds of Sawada, Hasumi, and Pirali with the abundance (isotopic purity) of at least 4000 times (60%), as taught by Jones, to arrive at the instantly claimed invention (page 2, [0038]; page 3, [0055]).
One of ordinary skill in the art would have been motivated to make deuterated analogs in an abundance of at least 4000 times (isotopic purity of 60%) with a reasonable expectation of success, because Jones teaches compounds suffering from poor ADME (absorption, distribution, metabolism, excretion) properties in vivo, which now have better ADME as the deuterated derivatives (page 1, [0008]-[0009]). Jones teaches deuteration of similar moieties:
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73
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, and
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([0127]). Thus, Jones teaches successful deuteration of designed active pharmaceutical ingredients with better pharmacokinetics: compounds with improved clearance, stability, half-life, volume of distribution, and bioavailability as compared to the un-deuterated analogs in an abundance of at least 4000 times ([0009]; [0038]; [0055]). Further, Jones teaches motivations to deuterate: compounds suffering from poor ADME (absorption, distribution, metabolism, excretion) properties in vivo, which now have better ADME as the deuterated derivatives ([0008]-[0009]). Thus, one of ordinary skill in the art would have been motivated to make such a selection, to predictably arrive at instant claim 22: deuterated derivatives of SMTP-7 in abundance of at least 4000 times.
Regarding claim 23, Jones teaches pharmaceutical compositions that have the compound in association with a pharmaceutically acceptable diluent or carrier (page 9, [0167]).
Allowable Subject Matter
Claim 28 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Applicant shows unexpected pharmacokinetic performance and therapeutic effect on cerebral infarction for Compound 1 (the only δ-deuterated SMTP-7 derivative; Rule 1.132 Declaration, point 16, page 5), which is the compound shown in claim 28.
Conclusion
No claim is allowed.
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/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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