INDOLE DERIVATIVES AS SEROTONERGIC AGENTS USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO

§102 §103 §112

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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/13/2026 has been entered. Status of the Claims Per Applicant’s amendment to the claims, submitted on 07/13/2026, claims 5, 7-9, 11-17, 19-20, 28-29, 31-35, and 42-51 are canceled, and claims 52-81 are newly added. Currently, claims 52-81 are pending in the instant application. Information Disclosure Statement The information disclosure statement (IDS) submitted on 07/13/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. Election/Restrictions Per the Election Requirement submitted on 08/13/2026, Applicant has elected the following species: A single compound: Compound I-21: PNG media_image1.png 126 177 media_image1.png Greyscale A single disease to be treated: depression The elected species read on claims 52-53, 55-58, 61, 64-66, 68-71, 74, 76-77, and 79-81. Accordingly, claims 54, 59-60, 62-63, 67, 72-73, 75, and 78 are withdrawn from consideration. The elected compound appears to be free of the art. However, the claims cannot be rejoined, as the claims pending examination are not in condition for allowance. Claim Objections – Withdrawn In light of Applicant’s amendment to the claims, the objections are hereby withdrawn. All previous claims have been canceled. Accordingly, the outstanding objections are now moot. Claim Rejections - 35 USC § 112 Second Paragraph - Withdrawn In light of Applicant’s amendment to the claims, the rejections are hereby withdrawn. All previous claims have been canceled. Accordingly, the outstanding rejections are now moot. Claim Rejections - 35 USC § 102 – Withdrawn In light of Applicant’s amendment to the claims, the rejections are hereby withdrawn. All previous claims have been canceled. Accordingly, the outstanding rejections are now moot. Claim Rejections - 35 USC § 103 - Withdrawn In light of Applicant’s amendment to the claims, the rejections are hereby withdrawn. All previous claims have been canceled. Accordingly, the outstanding rejections are now moot. Claim Rejections - 35 USC § 103 – New Grounds of Rejection 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. Claim(s) 52, is/are rejected under 35 U.S.C. 103 as being unpatentable over Chadeayne (previously referenced) in view of Martino (previously referenced). Claim 52 recites a compound of Formula (I): PNG media_image2.png 269 405 media_image2.png Greyscale Chadeayne teaches compositions comprising serotonergic drugs, and methods of use for said composition in treating depressive disorders. Among the serotonergic drugs taught by Chadeayne is N,N-Dimethyl-5-methylthio-T (page 30, claim 3), represented by the following structure: PNG media_image3.png 298 495 media_image3.png Greyscale The above compound meets the following limitations of Formula (I): X is S R1-R5 are each H R6 is CH3 R7-R10 are each H R11 is CH3 The only limitation of the instant claim not met by the compound of Chadeayne is variable R12. While the limitation of R12 does not include CH3 in its Markush group, it does indicate CD3, which is a deuterated analog. While Chadeayne does not explicitly teach compounds of the instant claim, it would have been obvious for a person of ordinary skill in the art to arrive at such compounds because the instant claim encompasses compounds which are deuterated analogs of N,N-Dimethyl-5-methylthio-T, and Martino teaches that such deuterium replacements are a commonplace technique in the art, and are used to manipulate pharmacodynamic or pharmacokinetic properties of pharmaceutical compounds. Accordingly, there would have been reasonable expectation of success in utilizing such deuterated analogs to treat depressive disorders. Martino provides an overview on the use of deuterium in pharmaceutical drug discovery. In particular, Martino indicates that the replacement of hydrogen for deuterium may provide improvements to the pharmacokinetic or toxicity profile of drugs, thereby providing benefits to safety and efficacy (page 1)1. Such improvements are indicated to be a result of the deuterium kinetic isotope effect (DKIE) wherein C-D bonds are more stable and difficult to cleave relative to original C-H bonds (pages 2-3)2. Furthermore, Martino indicates that such deuterated compounds are bioisosteres of their source compounds, meaning that they elicit similar biological effects despite being structurally distinct (page 2)3. Accordingly, there would be reasonable expectation that deuteration of the compounds of Chadeayne would yield bioisosteric compounds with potentially improved safety and/or efficacy. In the specific case of the compound of Chadeayne, such obviousness extends to the deuteration of the CH3 moiety corresponding to the R12 position. Given that Formula I of the instant claim encompasses deuterated analogs of the compound taught by Chadeayne, and that Martino provides ample motivation for deuteration of pharmaceutical compounds, it would have been prima facie obvious for a person of ordinary skill in the art to apply such deuteration to the compound of Chadeayne to arrive at a compound of the instant claim, because there would have been reasonable expectation that such a compound would be effective for treating depressive disorders and carry Martino’s aforementioned deuteration benefits. Claim 53 further limits the compound of claim 52 wherein R4 is H. The compound of Chadeayne meets the limitation wherein R4 is H. Claim 55 further limits the compound of claim 52 wherein R6 is CH3. The compound of Chadeayne meets the limitation wherein R6 is CH3. Claim 56 further limits the compound of claim 52 wherien R7-R10 are all H, or R7-R10 are all D. The compound of Chadeayne meets the limitation wherein each of R7-R10 are H. Claim 57 further limits the compound of claim 52 wherein R11 is selected from H, CH₃, CD₃, CH₂CH₃, CH₂CD₃, CH₂CH₂CH₃, CH(CH₃)₂, and CH(CD₃)₂. The compound of Chadeayne meets the limitation wherein R11 is CH3. Claim 58 further limits the compound of claim 52 wherein R11 is selected from CH₃, CD₃, CH₂CH₃, CH₂CD₃, CH₂CH₂CH₃, CH(CH₃)₂, and CH(CD₃)₂. The compound of Chadeayne meets the limitation wherein R11 is CH3. Claim 61 further limits the compound of claim 52 wherein R12 is CD₃, CH₂CH₃, CH₂CD₃, CD₂CD₃, CD₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, and CH(CD₃)₂. As discussed previously in the rejection of claim 52, Chadeayne in view of Martino would obviate at least a compound of the instant claim wherein R12 is CD3. Claim 64 further limits the compound of claim 52 wherein: PNG media_image4.png 397 649 media_image4.png Greyscale As discussed previously, the combined teachings of Chadeayne and Martino would obviate a compound wherein R4 and R5 are H, R6 is CH3, R7-R10 are each H, R11 is CH3, and R12 is CD3. Claim 65 recites a compound of Formula (I): PNG media_image5.png 264 412 media_image5.png Greyscale Chadeayne teaches compositions comprising serotonergic drugs, and methods of use for said composition in treating depressive disorders. Among the serotonergic drugs taught by Chadeayne is N,N-Dimethyl-5-methylthio-T (page 30, claim 3), represented by the following structure: PNG media_image3.png 298 495 media_image3.png Greyscale The above compound meets the following limitations of Formula (I): X is S R1-R5 are each H R6 is CH3 R7-R10 are each H R11 is CH3 The only limitation of the instant claim not met by the compound of Chadeayne is variable R12. While the limitation of R12 does not include CH3 in its Markush group, it does indicate CD3, which is a deuterated analog. While Chadeayne does not explicitly teach compounds of the instant claim, it would have been obvious for a person of ordinary skill in the art to arrive at such compounds because the instant claim encompasses compounds which are deuterated analogs of N,N-Dimethyl-5-methylthio-T, and Martino teaches that such deuterium replacements are a commonplace technique in the art, and are used to manipulate pharmacodynamic or pharmacokinetic properties of pharmaceutical compounds. Accordingly, there would have been reasonable expectation of success in utilizing such deuterated analogs to treat depressive disorders. Martino provides an overview on the use of deuterium in pharmaceutical drug discovery. In particular, Martino indicates that the replacement of hydrogen for deuterium may provide improvements to the pharmacokinetic or toxicity profile of drugs, thereby providing benefits to safety and efficacy (page 1)4. Such improvements are indicated to be a result of the deuterium kinetic isotope effect (DKIE) wherein C-D bonds are more stable and difficult to cleave relative to original C-H bonds (pages 2-3)5. Furthermore, Martino indicates that such deuterated compounds are bioisosteres of their source compounds, meaning that they elicit similar biological effects despite being structurally distinct (page 2)6. Accordingly, there would be reasonable expectation that deuteration of the compounds of Chadeayne would yield bioisosteric compounds with potentially improved safety and/or efficacy. In the specific case of the compound of Chadeayne, such obviousness extends to the deuteration of the CH3 moiety corresponding to the R12 position. Given that Formula I of the instant claim encompasses deuterated analogs of the compound taught by Chadeayne, and that Martino provides ample motivation for deuteration of pharmaceutical compounds, it would have been prima facie obvious for a person of ordinary skill in the art to apply such deuteration to the compound of Chadeayne to arrive at a compound of the instant claim, because there would have been reasonable expectation that such a compound would be effective for treating depressive disorders and carry Martino’s aforementioned deuteration benefits. Claim 66 further limits the compound of claim 65 wherein R4 is H and R5 is H. The compound of Chadeayne meets the limitation wherein R4 and R5 are each H. Claim 68 further limits the compound of claim 65 wherein R6 is CH3. The compound of Chadeayne meets the limitation wherein R6 is CH3. Claim 69 further limits the compound of claim 65 wherein R7-R10 are all H, or R7-R10 are all D. The compound of Chadeayne meets the limitation wherein R7-R10 are each H. Claim 70 further limits the compound of claim 65 wherein R11 is selected from H, CH₃, CD₃, CH₂CH₃, CH₂CD₃, CH₂CH₂CH₃, CH(CH₃)₂, and CH(CD₃)₂. The compound of Chadeayne meets the limitation wherein R11 is CH3. Claim 71 further limits the compound of claim 65 wherein R11 is selected from CH₃, CD₃, CH₂CH₃, CH₂CD₃, CH₂CH₂CH₃, CH(CH₃)₂, and CH(CD₃)₂. The compound of Chadeayne meets the limitation wherein R11 is CH3. Claim 74 further limits the compound of claim 65 wherein R12 is CD₃, CH₂CH₃, CH₂CD₃, CD₂CD₃, CD₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, and CH(CD₃)₂. The combined teachings of Chadeayne and Martino obviate at least a compound of claim 65 wherein R12 is CD3 as a deuterated analog of the compound of Chadeayne. Claim 76 further limits the compound of claim 65 wherein: PNG media_image6.png 222 638 media_image6.png Greyscale As discussed previously in the rejection of claim 65, the combined teachings of Chadeayne and Martino would obviate a compound wherein R4 and R5 are each H, R6 is CH3, R7-R10 are each H, R11 is CH3, and R12 is CD3. Claim 77 recites a compound selected from the recited table. As indicated previously in the rejections of claims 52 and 65, the combined teachings of Chadeayne and Martino obviate deuterated analogs of Chadeayne’s N,N-Dimethyl-5-methylthio-T: PNG media_image3.png 298 495 media_image3.png Greyscale Of the compounds recited in the instant claim, at least the following are considered as deuterated analogs of the above compound: PNG media_image7.png 553 485 media_image7.png Greyscale As indicated previously, deuterated analogs, such as the compounds above, would be reasonably expected by a person of ordinary skill in the art to have bioisosteric activity with the compound of Chadeayne. Accordingly, there would be a further reasonable expectation that such compounds would have the advantages of deuteration as taught by Martino and be effective in the treatment of depressive disorders. Claim 78 recites a compound selected from the recited table. As indicated previously in the rejections of claims 52 and 65, the combined teachings of Chadeayne and Martino obviate deuterated analogs of Chadeayne’s N,N-Dimethyl-5-methylthio-T: PNG media_image3.png 298 495 media_image3.png Greyscale Of the compounds recited in the instant claim, at least the following compound is considered as a deuterated analog of the above compound: PNG media_image8.png 160 486 media_image8.png Greyscale As indicated previously, deuterated analogs, such as the compound above, would be reasonably expected by a person of ordinary skill in the art to have bioisosteric activity with the compound of Chadeayne. Accordingly, there would be a further reasonable expectation that such compounds would have the advantages of deuteration as taught by Martino and be effective in the treatment of depressive disorders. Claim 79 recites a composition comprising one or more compounds of claim 52 and a pharmaceutically acceptable carrier. The teachings of Chadeayne are directed towards pharmaceutical compositions further comprising excipients (specification [0284])7. Claim 80 recites a method of treating a mental illness comprising administering a therapeutically effective amount of one or more compounds of claim 52, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the mental illness is selected from anxiety disorders, generalized anxiety disorder, social anxiety disorder, depression, cancer-related depression, major depressive disorder (MDD), treatment-resistant depression (TRD), postpartum depression (PPD), anxiety, alcohol addiction, drug addiction, opioid addiction, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and combinations thereof. The teachings of Chadeayne are directed towards the treatment of depressive disorders, including major depressive disorder (MDD) (specification [0376])8. As iterated previously, deuterated analogs of the compound of Chadeayne would be considered as obvious in view of the combination of the teachings of Chadeayne and Martino, and a person of ordinary skill in the art would have found it further obvious to use such deuterated analogs to treat at least MDD, as there would have been a reasonable expectation of success in treatment. Claim 81 recites a method of treating depression, comprising administering a therapeutically effective amount of one or more compounds of claim 52, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the depression is selected from cancer-related depression, major depressive disorder (MDD), treatment-resistant depression (TRD), postpartum depression (PPD), and combinations thereof. The teachings of Chadeayne are directed towards the treatment of depressive disorders, including major depressive disorder (MDD) (specification [0376]). As iterated previously, deuterated analogs of the compound of Chadeayne would be considered as obvious in view of the combination of the teachings of Chadeayne and Martino, and a person of ordinary skill in the art would have found it further obvious to use such deuterated analogs to treat at least MDD, as there would have been a reasonable expectation of success in treatment. Conclusion Claims 52-53, 55-58, 61, 64-66, 68-71, 74, 76-77, and 79-81 are rejected. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC TRAN whose telephone number is (571)272-7854. The examiner can normally be reached Mon-Fri 8:00-5:00. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached at (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /ERIC TRAN/Examiner, Art Unit 1629 /JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629 1 “Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural modification, known as deuteration, may improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts.” 2 “the C–D bond is associated with a reduced vibrational stretching frequency compared with the C–H bond, a lower ground-state energy and, in turn, a greater activation energy for cleavage (Fig. 1b). It follows that the C–D bond is more stable than the C–H bond (with a difference of 1.2–1.5 kcal mol−1) 25, and its cleavage occurs in a slower fashion. Such a difference in reactivity is quantified by the so-called deuterium kinetic isotope effect (DKIE)… : the higher the DKIE value, the slower the C–D bond breaking rate compared with that of C–H.” 3 “Arguably, the H to D substitution is one of the most conservative examples of bioisosterism. The two isotopes are very similar in terms of physicochemical properties, with D displaying a smaller molar volume (by 0.140 cm3  mol−1 per atom), a lower lipophilicity (ΔlogPoct −0.006), slightly altered pKa values (higher or lower depending on the specific compound) and C–D bonds being shorter than C–H bonds by 0.005 Å.” 4 “Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural modification, known as deuteration, may improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts.” 5 “the C–D bond is associated with a reduced vibrational stretching frequency compared with the C–H bond, a lower ground-state energy and, in turn, a greater activation energy for cleavage (Fig. 1b). It follows that the C–D bond is more stable than the C–H bond (with a difference of 1.2–1.5 kcal mol−1) 25, and its cleavage occurs in a slower fashion. Such a difference in reactivity is quantified by the so-called deuterium kinetic isotope effect (DKIE)… : the higher the DKIE value, the slower the C–D bond breaking rate compared with that of C–H.” 6 “Arguably, the H to D substitution is one of the most conservative examples of bioisosterism. The two isotopes are very similar in terms of physicochemical properties, with D displaying a smaller molar volume (by 0.140 cm3  mol−1 per atom), a lower lipophilicity (ΔlogPoct −0.006), slightly altered pKa values (higher or lower depending on the specific compound) and C–D bonds being shorter than C–H bonds by 0.005 Å.” 7 “In one embodiment , the methods and compositions disclosed herein comprise an excipient” 8 “In one embodiment , a depressive disorder is chosen from atypical depression , bipolar disorder , catatonic depression , depressive disorder due to a medical condition , major depressive disorder , postpartum depression , premenstrual dysphoric disorder , or seasonal affective disorder”