DETAILED ACTION
This office action is in response to applicant’s filing dated July 29, 2026.
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 .
Status of Claims
Claims 1-20 are pending in the instant application. Acknowledgement is made of Applicant's remarks and amendments filed July 29, 2026.
Applicants elected without traverse Group I, drawn to a compound of formula (IV) in the reply filed on April 10, 2026. The requirement is still deemed proper. Claims 13, 14, and 17-20 remain withdrawn.
Applicant's election with traverse of Example 3: (2S,4R)1-[(3R)-5-chloro-1-[(2,4-dimeth-d6-oxyphenyl)sulfonyl]-2,3-dihydro-3-(2-methoxy-d3-phenyl)-2-oxo-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-d6-2-pyrrolidinecarboxamide in the reply filed on April 10, 2026 is acknowledged. The traversal has been addressed above.
The requirement is still deemed proper and is therefore made FINAL.
Example 3 is a compound of formula (IV) wherein R₁, R₂, R3, R6, R₈, R9, R₁₀, R₁₁, R₁₃, R₁₅, R₁₆, R₁₇, R₁₈, R₁9, R₂₀, R₂₁ and R₂₂ are hydrogen; R12 is chlorine; and R₂₃, R24, R₂₅, R₂₆, R₂₇, R₂₈, R₂9, R30, R31, R32, R33, R34, R35, R36, and R37 are enriched in deuterium. Example 3 reads on a compound of Formula (IV) wherein the enrichment in deuterium is 47%.
Claims 1-12, 15, and 16 are presently under examination as they relate to the elected species: Example 3.
Priority
The present application claims benefit US Provisional Application No. 63/513,158 filed on July 12, 2023 and claims benefit of foreign priority to EP 23185135.3 filed on July 12, 2023.
Objections and/or Rejections and Response to Arguments
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
Maintained Objections and/or Rejections
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
In the instant case, the abstract includes phrases which can be implied “The present invention relates to…”
Response to Arguments
Applicant argues:
The abstract has been amended thereby obviating the objection.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
The Examiner acknowledges that the amendment of the abstract deleted the term “said,” phraseology the MPEP notes as phraseology that should be avoided. However, as noted previously, the abstract contains phrases which can be implied which the MPEP explicitly states should be avoided.
“The present invention relates…”
“It further relates to a method of…”
“The present invention also relates to…”
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-12, 15, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Roux et al (US 6,730,695 B2, cited in the IDS filed January 12, 2026) in view of Oost et al (Bioorganic & Medicinal Chemistry Letters, 2011; 21:3828-3831, cited in a previous Office Action) and Pirali et al (J Med Chem, 2019; 62(11):5276-5297, cited in the IDS filed January 12, 2026).
Regarding claims 1-12, Roux teaches a compound of formula (I) (claim 1) and a compound of formula (I) is -(2S,4R)-1-[5-Chloro-1-[2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3yl]-4-hydroxy-N ,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer (claim 6 and Example 1, col 46). Example 1 differs from instantly elected compound in that R₁, R₂, R3, R6, R₈, R9, R₁₀, R₁₁, R₁₃, R₁₅, R₁₆, R₁₇, R₁₈, R₁9, R₂₀, R₂₁, R₂₂, R₂₃, R24, R₂₅, R₂₆, R₂₇, R₂₈, R₂9, R30, R31, R32, R33, R34, R35, R36, and R37 are hydrogen and the compound is not enriched with deuterium. However, Roux does teach the compounds of formula (I) also comprise those in which one or more hydrogen or carbon atoms have been replaced with their radioactive isotope, for example tritium or carbon-14; such labelled compounds are useful in metabolic or pharmacokinetic research studies, in biochemical assays as receptor ligands (col 19, lines 26-31). Thus, Roux suggests isotopes of the disclosed compounds. Roux does not explicitly teach the compound of Example 1 wherein the compound is enriched with deuterium as the elected compound is enriched.
However, Oost teaches the compound SSR149415 (Figure 1):
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which is the same as Example 1 taught by Roux. Moreover, Oost teaches SSR149415 exhibits a sub-optimal pharmacokinetic profile in rat; specifically, it displayed short half-life (<1 h) and high plasma clearance in rats, which is consistent with the high intrinsic clearance observed in liver microsomes, indicating extensive first-pass metabolism; in order to improve the sub-optimal pharmacokinetic profile, we sought to increase the metabolic stability of analogs from the oxindole series (page 3828, left). Thus, Oost teaches Example 1 has suboptimal pharmacokinetic profile with extensive first-pass metabolism.
Moreover, Pirali teaches deuterium is a rare, stable, nonradioactive isotope of hydrogen, which differs from protium by a single neutron (page 5276, left, 1st paragraph); the most straightforward application of deuterium substitution is to slow down drug metabolism, especially cytochrome P450 (CYP450)-mediated transformations (page 5278, left, 1st paragraph); ample literature is devoted to deuteration as a means to improve the PK profile of drugs (page 5278, right, 2nd paragraph); independent of PK parameters, deuteration of a soft-spot can be capitalized upon to reduce the formation of unwanted metabolites, as well as to increase the formation of desirable active metabolites, a phenomenon named metabolic shunting (page 5281, right, 3rd paragraph); the substitution of the acidic proton with deuterium at the chiral center of a single stereoisomer might decrease the rate of atom abstraction and afford a good strategy to stabilize chemically unstable stereoisomers (page 5283, right, 2nd paragraph); and deuteration can also be used as a means to expand knowledge, for example, to test the contribution of a metabolite to the action of a particular drug (page 5284, left, 3rd paragraph). Thus, Pirali teaches deuterium substitution is a known method utilized in drug design and known for use in improving bioavailability, drug stability, and PK profile. Moreover, Pirali teaches deutetrabenazine (figure 1); d6-tivozanib and d3-NVS-CRF38 (Figure 3); d3-ligand for GABAA-α6 (Figure 4); d3-analogue of dapagliflozin (Figure 5); d15-atazanavir and d6-dextrmethorphan (Figure 6); d9--tramadol (Figure 11); and d9-venlafaxine (Figure 18), all of which are deuterium enriched in the methoxy substituent of the compound. Pirali further teaches d9--tramadol (Figure 11) and d9-venlafaxine (Figure 18), each of which is deuterium enriched in the dimethylamide substituent of the compound. Thus, Pirali teaches it was known in the art to substitute deuterium in methoxy and dimethylamide moieties of a compound to produce deuterium enriched compounds. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to produce a deuterium enriched-SSR149415 compound wherein the methoxy moieties and the dimethylamide moieties are substituted with deuterium to arrive at the instantly elected compound with a reasonable expectation of success, since the prior art suggests formulating isotopes of structurally similar compounds including Example 1/SSR149415; Example 1/SSR149415 has suboptimal pharmacokinetic profile with extensive first-pass metabolism; deuterium substitution including deuterium substitutions in methoxy and dimethylamide moieties are known methods in drug design and known for use in improving bioavailability, drug stability, and PK profile.
Regarding claims 15 and 16, Roux teaches the compounds of formula (I) are generally administered in dosage units; the said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with one or more pharmaceutical excipients (col 21, lines 10-14). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to formulate the deuterium substituted Example 1/SSR149415 suggested by the cited art in a composition comprising a pharmaceutical excipient in view of the teachings of Roux.
Taken together, all this would result in the composition of claims 1-12, 15 and 16 with a reasonable expectation of success.
Response to Arguments
Applicant argues:
Roux only discloses compounds of formula (I) labeled with radioactive isotopes, e.g. for metabolic or pharmacokinetic research studies or in biochemical assays, thus obviously not for medical treatment. This disclosure has nothing to do with replacing hydrogens with deuterium, which is not radioactive, in order to provide a derivative of nelivaptan having improved pharmacological properties. Thus, the skilled person would not have considered compounds of formula (I) labeled with radioactive isotopes suitable for preparation of medicinal products as described in Roux, and neither does Roux.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
Applicants are reminded that it must be remembered that the references are relied upon in combination and are not meant to be considered separately as in a vacuum. It is the combination of all of the cited and relied upon references, which make up the state of the art with regard to the claimed invention. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference and it is not that the claimed invention must be expressly suggested in any one or all of the references; but rather the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, the examiner acknowledges that Roux does not explicitly teach the compound of Example 1 wherein the compound is enriched with deuterium as the elected compound is enriched or that the isotopes were deuterated isotopes. However, as set forth above, Roux does suggest isotopes of the disclosed compounds. Oost establishes Example 1, a compound of formula (IV) wherein R1, R2, R3, R6, R8, R9, R10, R11, R13, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36 and R37 are hydrogen, and R12, is halogen, wherein the compound has no deuterium has suboptimal pharmacokinetic profile with extensive first-pass metabolism. As set forth above, Pirali establishes that deuterium substitution is a known method utilized in drug design and known for use in improving bioavailability, drug stability, and PK profile and that it was known in the art to substitute deuterium in methoxy and dimethylamide moieties of a compound to produce deuterium enriched compounds. As set forth above, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to produce a deuterium enriched-SSR149415 compound wherein the methoxy moieties and the dimethylamide moieties are substituted with deuterium to arrive at the instantly elected compound with a reasonable expectation of success, since the prior art suggests formulating isotopes of structurally similar compounds including Example 1/SSR149415; Example 1/SSR149415 has suboptimal pharmacokinetic profile with extensive first-pass metabolism; deuterium substitution including deuterium substitutions in methoxy and dimethylamide moieties are known methods in drug design and known for use in improving bioavailability, drug stability, and PK profile.
Applicant argues:
The prior art does not suggest formulating isotopes of structurally similar compounds including Example 1/SSR149415. As discussed above, Roux only discloses compounds of formula (I) labeled with radioactive isotopes, e.g. for metabolic or pharmacokinetic research studies or in biochemical assays, thus obviously not for medical treatment. In fact, as confirmed in Pirali, deuterium is a rare, stable, nonradioactive isotope of hydrogen. Thus, combining the disclosure of Pirali, which discloses the use of nonradioactive isotopes, with the disclosure of Roux, which requires the modification with radioactive isotopes, would render Roux unfit for its intended purpose.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
Roux teaches compounds of formula (I) also comprise those in which one or more hydrogen atoms have been replaced with their radioactive isotopes and such labelled compounds are useful in metabolic or pharmacokinetic research studies, in biochemical assays as receptor ligands. Thus, Roux teaches the isotopically labeled compounds are alternatively useful to those that are not and in particular are useful in metabolic or pharmacokinetic research and biochemical assays. It was known in the art that deuterated compounds are useful as isotopically labeled compounds as evidenced by Pirali. Pirali teaches incorporation of deuterium in place of protium has been exploited in many different disciplines in life sciences, including proteomics, metabolomics, and diagnostics. Thus, the skilled artisan would recognize that modification of the compounds of Roux with the nonradioactive isotope, deuterium, to form a nonradioactive isotope of the disclosed compounds would result in a compound useful for metabolic or pharmacokinetic research and biochemical assays and would not result in compounds unfit for the intended purpose disclosed in Roux.
Applicant argues:
Nonobviousness can be shown when a person of ordinary skill in the art would not have reasonably predicted the claimed invention based on the prior art, and the resulting invention would not have been expected." Pirali itself teaches the unpredictability of the incorporation of deuterium and thus provides objective evidence on non- obviousness. Pirali does not mention SSR149415, let alone that deuterium enriched- SSR149415 as presently claimed and which shows an improved pharmacological profile as shown in Figure 2 of the application.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
Obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). In the instant case, Roux establishes that isotopes of the disclosed compounds were known in the art and how to make them. Oost Example 1, a non-isotopically modified compound of formula (IV) has suboptimal pharmacokinetic profile with extensive first-pass metabolism. As set forth above, Pirali establishes that deuterium substitution is a known method utilized in drug design and known for use in improving bioavailability, drug stability, and PK profile and that it was known in the art to substitute deuterium in methoxy and dimethylamide moieties of a compound to produce deuterium enriched compounds. As set forth above, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to produce a deuterium enriched-SSR149415 compound wherein the methoxy moieties and the dimethylamide moieties are substituted with deuterium to arrive at the instantly elected compound with a reasonable expectation of success, since the prior art suggests formulating isotopes of structurally similar compounds including Example 1/SSR149415; Example 1/SSR149415 has suboptimal pharmacokinetic profile with extensive first-pass metabolism; deuterium substitution including deuterium substitutions in methoxy and dimethylamide moieties are known methods in drug design and known for use in improving bioavailability, drug stability, and PK profile. The skilled artisan would have had a reasonable expectation of success in formulating deuterium substituted compounds of Roux, one would formulate additional compounds having similar properties.
Conclusion
Claims 1-12, 15, and 16 are rejected.
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RAYNA B RODRIGUEZ whose telephone number is (571)272-7088. The examiner can normally be reached 8am-5:00pm, Monday - Thursday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached at 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Rayna Rodriguez/ Primary Examiner, Art Unit 1628
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