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 . Claims 1-14 filed December 10, 2025 are currently pending. Claim 1 is independent.
Election/Restrictions
Applicant’s election without traverse of Formula (I) in the reply filed on 12/10/2025 is acknowledged.
Claim 8 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/10/2025.
Priority
Acknowledgement is made of the national stage entry of PCT/EP2021/075967 filed 09/21/2021, which claims foreign priority to Application 2026511 filed 09/21/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/05/2023, 05/23/2024, 12/19/2024, 01/07/2025 and 7/10/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112-Paragraph D
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 5 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 5 is directed to a compound of Formula (I). Said claim fails to further limit the scope of the claim from which it depends (claim 1), as claim 1 is only directed to compounds of Formula (I) due to the cancellation of Formula (II) in the response of 12/10/2025. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claim(s) 1-7, 11, 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Van Der Graaf (WO2014/098586 published 06/26/2014) and Bunsawat (Exp. Physiol. Vol. 105 pages 1384-1395 published August 2020).
Van Der Graaf (WO2014/098586 published 06/26/2014) teaches compounds of Formula (I). Van Der Graaf teaches that said compounds are efficacious at treating heart failure and preserving against oxidative stress (page 5 line 30 to page 6 line 5, page 8 lines 25-30; page 9 lines 1-15, claims 1, 5-6). Embraced within the compounds of Formula (I) include compound SUL-136 (page 18 lines 1 to page 19 line 30). Compound SUL-136 reads on the presently claimed structural limitations: R1 is H R2-R3 come together with the N atom to form a saturated optionally substituted non-aromatic 5-8 member ring with 1 N and R2-R3 contain 4 carbons (page 37).
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The difference between the present claims and that of Van Der Graaf is that Van Der Graaf does not specifically teach administering a compound of Formula (I) to treat heart failure with a reduced ejection fraction.
Bunsawat (Exp. Physiol. Vol. 105 pages 1384-1395 published August 2020) teaches that patients with heart failure with reduced ejection fraction (HFrEF) are characterized by macrovascular dysfunction and elevated oxidative stress. Oxidative stress contributes to endothelial dysfunction by scavenging the vasodilator nitric oxide (NO), limiting NO bioavailability and hindering endothelium-dependent vasodilation (page 3). Bunsawat teaches that administration of compounds that inhibit oxidative stress to HFrEF patients restore macrovascular function in patients with HFrEF, mitigate oxidative stress and yield a two-fold increase in brachial artery flow-mediated dilation, thereby treating the disorder in the subject in need (abstract, pages 9-11).
Therefore, one of ordinary skill in the art of treating heart failure with reduced ejection fraction, knowing that patients with heart failure with reduced ejection fraction (HFrEF) are characterized by macrovascular dysfunction and elevated oxidative stress and that administering compounds that inhibit oxidative stress are efficacious at improving macrovascular function in the HFrEF patient as taught by Bunsawat, said artisan would have found it prima facie obvious to administer compound SUL-136 of Van Der Graaf to treat the afflicted heart failure patient.
MPEP 2143 provides rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the present case, it was known in the art that administering compounds that inhibit oxidative stress is an efficacious strategy at improving macrovascular function in an HFrEF patient, thereby treating the patient. Considering compound SUL-136 of Van Der Graaf is art-recognized as efficacious at treating heart failure and preserving against oxidative stress, said artisan would have predicted that administration of SUL-136 to a patient with HFrEF would have reduced oxidative stress, thereby improving macrovascular function in the patient and treated the disease.
Regarding the limitation wherein the patient comprising heart failure with a reduced ejection fraction has a preserved ejection fraction of about 40% or lower (claims 13-14), as evidenced by page 1 of the specification, patients suffering from heart failure with preserved ejection fraction demonstrate values of ≥50% while values below 40% are considered a reduced LVEF (HFrEF). As shown in Table 1 of Bunsawat, HFrEF patients and HFrEF patients with left ventricular ejection fraction (LVEF) of 32% were treated with the oxidative stress inhibitory compounds, which read on the patient population of claims 13-14.
Claim(s) 1-7, 9-11 and 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Van Der Graaf (WO2016/188766 published 01/12/2016) and Bunsawat (Exp. Physiol. Vol. 105 pages 1384-1395 published August 2020).
Van Der Graaf (WO2016/188766 published 01/12/2016) teaches compounds of Formula (II) including compound SUL-121 (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1-yl)methanone for restoring endothelial function and inhibiting oxidative stress by inhibiting reactive oxygen species (ROS), thereby treating organ failure (abstract, pages 3 lines 1-15, page 23 line 15 to page 24 line 35, Figures 5-6). Compound SUL-121 reads on the following structural limitations: R1 is H, R2 and R3 come together with the nitrogen to which they are attached to forming a saturated 5-8 membered heterocyclic ring (piperazine) (page 3 lines 1-15). As shown in Figures 5-7, compound SUL-121 is efficacious at restoring endothelial NO production in patients as well as reducing radical reactive oxygen species in the plasma of said patient (page 23 line 15 to page 24 line 35).
The difference between the present claims and that of Van Der Graaf is that Van Der Graaf does not specifically teach administering a compound of Formula (I) wherein the compound is SUL-121 to treat heart failure with a reduced ejection fraction.
Bunsawat (Exp. Physiol. Vol. 105 pages 1384-1395 published August 2020) teaches that patients with heart failure with reduced ejection fraction (HFrEF) are characterized by macrovascular dysfunction and elevated oxidative stress. Oxidative stress contributes to endothelial dysfunction by scavenging the vasodilator nitric oxide (NO), limiting NO bioavailability and hindering endothelium-dependent vasodilation (page 3). Bunsawat teaches that administration of compounds that inhibit oxidative stress to HFrEF patients restore macrovascular function in patients with HFrEF, mitigate oxidative stress and yield a two-fold increase in brachial artery flow-mediated dilation, thereby treating the disorder in the subject in need (abstract, pages 9-11).
Therefore, one of ordinary skill in the art of treating heart failure with reduced ejection fraction would have found it prima facie obvious to administer compounds of Formula (II) including compound SUL-121 to treat said patient comprising heart failure with reduced ejection fraction in view of the combined teachings of Van Der Graaf and Bunsawat, arriving at the presently claimed.
MPEP 2143 provides rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the present case, it was known in the art that administration of compounds that inhibit oxidative stress is an efficacious strategy at improving macrovascular function in an HFrEF patient, thereby treating the patient coupled with the knowledge that compounds of Formula (II) including compound SUL-121 are efficacious at preserving against oxidative stress and reducing radical reactive oxygen species in the plasma of said patient. As such, said artisan would have predicted that administration of SUL-121 to a patient with HFrEF would have reduced oxidative stress by inhibiting radical reactive oxygen species in the plasma of the patient, thereby improving macrovascular function in the patient and treated the disease.
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Regarding the limitation of claim 10 wherein compound SUL-121 is administered as the 2(R) enantiomer, compound SUL-121 embraces both the 2(R) and 2(S)-enantiomers of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1-yl)methanone. Accordingly, administration of compound SUL-121 taught by Van Der Graaf above reads on the administration of the 2(R) enantiomer.
Regarding the limitation wherein the patient comprising heart failure with a reduced ejection fraction has a preserved ejection fraction of about 40% or lower (claims 13-14), as evidenced by page 1 of the specification, patients suffering from heart failure with preserved ejection fraction demonstrate values of ≥50% while values below 40% are considered a reduced LVEF (HFrEF). As shown in Table 1 of Bunsawat, HFrEF patients and HFrEF patients with left ventricular ejection fraction (LVEF) of 32% were treated with the oxidative stress inhibitory compounds, which read on the patient population of claims 13-14.
Claim(s) 12 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of Van Der Graaf (WO2014/098586 published 06/26/2014) and Bunsawat (Exp. Physiol. Vol. 105 pages 1384-1395 published August 2020) as applied to claims 1-7, 9-11 and 13-14 in view of Tamby (WO2020/236736 published 11/16/2020 with priority to U.S. Provisional Application 62849936 filed 05/19/2019).
As disclosed above, the combination of Van Der Graaf and Bunsawat render obvious the administration of a compound of Formula (I) to treat heart failure with reduced ejection fraction (HFrEF) in a subject in need as it was known in the art that administering compounds that inhibit oxidative stress is an efficacious strategy at improving macrovascular function in an HFrEF patient, thereby treating the patient. As Van Der Graaf teaches that compounds of Formula (I) including compound SUL-136 are efficacious at treating heart failure and preserving against oxidative stress, said artisan would have predicted that administration of SUL-136 to a patient with HFrEF would have reduced oxidative stress, thereby improving macrovascular function in the patient and treated the disease.
The difference between the present claims and that of the combination of Van Der Graaf and Bunsawat is that the combination of Van Der Graaf and Bunsawat does not specifically teach administering said regimen in combination with one or more common measures to treat heart failure.
Tamby teaches treating systolic dysfunction in patients with heart failure with reduced ejection fraction and heart failure with preserved ejection fraction (HFpEF). Tamby teaches that heart failure with preserved ejection fraction is the result of the heart pumping normally but is too stiff to fill properly ([0004]-[0009]). Tamby teaches administration of a compounds of Formula (I) to treat both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction (HFpEF) ([0012]-[0016], [0028] claims 1-2, 7-9, 32-36). Tamby teaches that the compound of Formula (I) improves left ventricular ejection fraction and left ventricular stroke volume in said heart failure patients ([0028], [0146]-[0159], Table 6).
Therefore, one of ordinary skill in the art prior to the time of the invention would have found it prima facie obvious to combine Formula (I) of Tamby to the heart failure with reduced ejection fraction treating regimen comprising the heart failure treating and oxidative stress inhibiting compounds of Formula (I) of Van Der Graaf and Bunsawat above, arriving at the presently claimed methodology.
Motivation to administer the compositions together flows logically from the very fact each agent or combination of agents was known in the prior art to have the same therapeutic utility of treating heart failure patients with reduced ejection fraction and, in turn, raises the reasonable expectation of success, that when combined, a composition comprising the heart failure treating and oxidative stress inhibiting compounds of Formula (I) of Van Der Graaf and Bunsawat and Formula (I) of Tamby, said composition would be efficacious at treating heart failure with reduced ejection fraction. The instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose (MPEP 2144.06).
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 1-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10 of U.S. Patent No. 12,156,862 in view of Tamby (WO2020/236736 published 11/16/2020 with priority to U.S. Provisional Application 62849936 filed 05/19/2019).
Claim 1 of U.S. Patent 12,156,862 is directed to the method of treating heart failure with preserved ejection fraction in a subject in need thereof comprising administering a therapeutically effective amount of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)piperazin-1-yl)methanone to a subject in need thereof. As evidenced by col 7 lines 50-65, col. 9 lines 40-50 of U.S. Patent 12,156,862 and Figure 6 (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)piperazin-1-yl)methanone corresponds to the enantiomers SUL-150 and SUL-150, which reads on the following claimed limitations: R1 is H, R2 and R3 and the nitrogen they are attached to form a saturated 5-8 membered ring.
The difference between the present claims and that of claims 1 and 10 of U.S. Patent 12,156,862 is that the present claims do not specifically teach administering 6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)piperazin-1-yl)methanone to treat heart failure with preserved ejection fraction in a subject in need thereof.
Tamby teaches treating systolic dysfunction in patients with heart failure with reduced ejection fraction and heart failure with preserved ejection fraction (HFpEF). Tamby teaches that heart failure with preserved ejection fraction is the result of the heart pumping normally but is too stiff to fill properly ([0004]-[0009]). Tamby teaches administration of a compounds of Formula (I) to treat both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction (HFpEF) ([0012]-[0016], [0028] claims 1-2, 7-9, 32-36). Tamby teaches that the compound of Formula (I) improves left ventricular ejection fraction and left ventricular stroke volume in said heart failure patients ([0028], [0146]-[0159], Table 6).
Therefore, one of ordinary skill in the art of treating heart failure with reduced ejection fraction comprising administering compound SUL-150 as taught by claims 1-14 of the instant claims, said skilled artisan would have found it prima facie obvious that administration of the heart failure with reduced ejection fraction treating SUL-150 would effectively treat heart failure with preserved ejection fraction, arriving at the methodology of claims 1 and 10 of U.S. Patent 12,156,862 in view of Tamby.
MPEP 2143 provides rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the present case, considering Tamby teaches that compounds that are efficacious at treating heart failure with reduced ejection fraction are also efficacious at treating heart failure with preserved ejection fraction (HFpEF) (claims 1-2, 7-9, 32-36), said skilled artisan would have predicted that administration of the heart failure with reduced ejection fraction treating SUL-150 of the instant claims would have also effectively treated heart failure with preserved ejection fraction as embraced in claims 1 and 10 of U.S. Patent 12,156,862.
Conclusion
In view of the rejections set forth above, no claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GEORGE W KOSTURKO whose telephone number is (571)270-5903. The examiner can normally be reached M-F 9:00-5:30.
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/GEORGE W KOSTURKO/Primary Examiner, Art Unit 1621