DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 6/24/2026 has been entered.
AIA Status of the Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Newly submitted claim 19 is directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: in Applicant’s Telephonic Response to a Requirement for Restriction/Election on 9/19/2025, Applicant elected Compound I-28 as a single compound species. New claim 19 is drawn to a compound of formula (I) according to claim 1 that does not include Applicant’s elected Compound I-28.
Since Applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claim 19 is withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should Applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Response to Arguments
Applicant’s elected species, Compound I-28 having the following structure:
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reads upon claims 1-6 and 8-13.
As discussed in the Action mailed on, 10/17/2025, the elected species is determined to be free of the art and non-obvious. In particular, the closest prior art is considered to be Qabar et al (US 2005/0250780; of record) which teach “[r]everse-turn mimetics” (Abstract) including the following compound:
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(Page 35, Table 2)
which, as indicated by arrows, differs from Applicant’s elected compound species Compound I-28 in the following three ways:
(i) comprising -CH2- as opposed to the instantly claimed -O- in the structure core;
(ii) comprising a C4 alkyl group as opposed to a C5 alkyl group at variable Q; and
(iii) comprising a substituted arylalkyl group as opposed to the instantly claimed unsubstituted cycloalkylalkyl at variable R33.
It would not have been obvious to modify the prior art compound of Qabar et al in these three ways to arrive at Applicant’s instantly elected compound species.
Accordingly, in the Action mailed on 10/17/2025, the search was expanded as called for under current Office Markush practice – a compound-by-compound search – to the following compound species, all of which were rejected under 35 U.S.C. 103(a):
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(b)
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(c)
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and (d)
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The rejections based thereon were MAINTAINED and made final in the Action mailed on 3/24/2026.
In Applicant’s response, filed 6/24/2026, Applicant traverses the rejections of the above compounds. As summarized by Applicant, “the above prior art molecules differ from the elected species by possessing a -CH2- linker in place of the -O- linker in the elected species” and the rejection “relies on Williams et al., Hevey et al., and Ueda et al. for allegedly teaching or suggesting that -CH2- and -O- are known interchangeable bioisosteres, and based on this view, one skilled in the art would have been motivated to replace the -CH2- moiety... with -O- to arrive at the claimed compounds” (Applicant Arguments, Page 17). However, as argued by Applicant, “none of the cited references teach or suggest compounds that have Notching signaling inhibitory activity” (Applicant Arguments, Page 17). Rather, “Compound (a)... described in Qabar et al... [exhibits] tachykinin antagonistic activity”, “Compound (b)... described in Kahn et al... [exhibits] opiate receptor binding antagonistic behavior”, “Compound (c)... described in Kahn et al... [exhibits] opiate receptor binding antagonistic behavior”, and “Compound (d)... described in Kouji et al... [exhibits] blocking the TCF4/β-catenin transcription pathway through inhibition of CBP” complex of Wnt pathway (Applicant Arguments, Pages 18-19).
Yet, it is not necessary that the prior art suggest the combination of references to achieve the same advantage or result discovered by Applicant (in this case, Notch signaling inhibitory activity). Rather, the reason or motivation to modify a reference to arrive at the claimed invention can be for a different purpose or to solve a different problem (in this case, tachykinin antagonistic activity, opiate receptor binding antagonistic behavior, or blocking the TCF4/β-catenin transcription pathway through inhibition of CBP complex of Wnt pathway) (see, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention). The fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious (see Ex parte Obiaya, 227 USPQ 58 (Bd. Pat. App. & Inter. 1985)).
Applicant, however, further argues that “the specific structural modifications disclosed in the present application provide unexpectedly superior Notch signaling inhibitory activity that is neither disclosed nor suggested in the cited references” (Applicant Arguments, Page 18).
It is well settled that a showing of unexpected results is generally sufficient to overcome a prima facie case of obviousness (In re Albrecht, 514 F.2d 1389 (CCPA 1975)). However, as recognized by the court in In re Schulze, 346 F.2d 600 (CCPA 1965), mere arguments are not sufficient to demonstrate unexpected results. Rather, unexpected results must be established by factual evidence by comparing the claimed invention with that of the closest prior art. In re Burckel, 592 F.2d 1175 (CCPA 1979). As discussed by the court in In re De Blauwe, 736 F.2d 699 (Fed. Cir. 1994), “the absence of tests comparing [Applicant’s claimed invention] with those of the closest prior art… constitute mere argument”.
In the instant case, has not compared the Notch signaling inhibitory activity of the instantly claimed compounds with those of the cited prior art and provided evidence of unexpected Notch signaling inhibitory activity.
The rejection of claims on the grounds of non-statutory obvious type double patenting over 18/014,556 (now U.S. Patent No. 12,703,707) is WITHDRAWN in view of Applicant’s amendments to the claims in 18/014,556 (now U.S. Patent No. 12,703,707).
Claim Rejections - 35 USC § 103
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.
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 1-6 and 8-13 are rejected under 35 U.S.C. 103(a) as being unpatentable over Qabar et al (US 2005/0250780; of record) in view of Williams et al (Foye’s Principles of Medicinal Chemistry, 5th Ed., Pages 59-63, 2002; of record), Hevey et al (Biomimetics 4:53 (23 pages), 2019; of record) and Ueda et al (Bioorg Med Chem Lett 27:4705-4709, 2017; of record).
Claim 1 is drawn to a compound of formula (I) which embraces the following compound species
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wherein Q is formula I-1wherein R1a is alkyl and R1b is hydrogen; U is -(C(O))-; R2 is substituted alkyl; R4a is substituted alkyl or arylalkyl; R4b is hydrogen; R3 is -W31-W32-R33- wherein W31 is -C(O)-, W32 is -O- and R33 is substituted alkyl or substituted arylalkyl; and R5 is hydrogen - which reads on claims 1-6 and 8-13.
Qabar et al teach “[r]everse-turn mimetics” (Abstract) including the following compound species
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(Page 35, Table 2) which differs from the instantly claimed compound in comprising a -CH2- in place of the instantly claimed -O- as indicated by arrow.
Yet, as taught by Williams et al “[w]hen a lead compound is first discovered for a particular disease state, it often lacks the required potency and pharmacokinetic properties suitable for making it a viable clinical candidate… The medicinal chemist therefore must modify the compound to reduce or eliminate these undesirable features without losing the desired biological activity. Replacement or modification of functional groups with other groups having similar properties is known as isosteric or bioisosteric replacement” (Page 59). Although it is clear that "the use of bioisosteric replacement (classical or nonclassical) in drug development is highly dependent upon the biological system being investigated” and that “[n]o hard and fast rules exist to determine what bioisosteric replacement is going to work with a given molecule” it is also clear that “some generalizations have been possible” (Page 60). Notably, one such generalization is that -CH2- and -O- can replace each other (Page 60, Table 2.8, Page 61, Table 2.9, Page 63, Table 2.10, Reference 45).
As similarly taught by Hevey et al – also noting that “[b]ioisosteric replacement of functional groups is commonly used in medicinal chemistry to improve the desired properties of a molecule” (Page 6, Section 4) – one common bioisosteric replacement is -CH-2- for -O- (Page 6, Table 2).
And, significantly, Ueda et al (see Page 4705, Figure 1) specifically teach replacing -CH-2- with -O- in the mimetic compound C699 (comprising the same core as Qabar et al) to provide the structurally and functionally related compound mS-11 (having the instantly claimed core):
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In view of all the foregoing, it would have been obvious to a person of ordinary skill in the art at the time the invention was made to replace -CH-2- with -O- in the compound taught by Qabar et al with to arrive at the instantly claimed compound. The person of ordinary skill in the art at the time the invention was made would have been motivated to make the bioisosteric modifications in an effort to synthesize similar compounds that retain biological activity, but have improved physiochemical properties and better pharmacokinetic behavior, with a reasonable expectation of success.
As such, claims 1-6 and 8-13 are rejected as prima facie obvious.
Claims 1-6 and 8-13 are ADDITIONALLY rejected under 35 U.S.C. 103(a) as being unpatentable over Kahn et al (US 6,013,458; of record) in view of Williams et al (Foye’s Principles of Medicinal Chemistry, 5th Ed., Pages 59-63, 2002; of record), Hevey et al (Biomimetics 4:53 (23 pages), 2019; of record) and Ueda et al (Bioorg Med Chem Lett 27:4705-4709, 2017; of record).
Claim 1 is drawn to a compound of formula (I) which embraces the following compound species
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wherein Q is I-1 wherein R1a is alkyl and R1b is hydrogen; U is -(C(O))-; R2 is substituted alkyl or arylalkyl; R4a is substituted alkyl or arylalkyl; R4b is hydrogen; R3 is -W31-W32-R33- wherein W31 is -C(O)-, W32 is -O- and R33 is substituted alkyl or arylalkyl; and R5 is hydrogen - which reads on claims 1-6 and 8-13.
Kahn et al teach “compounds which mimic the secondary structure of reverse-turn regions of biologically active peptides and proteins” (Abstract) including the following compound species
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(Column 27, Table I, Compound 8) which differs from the instantly claimed compound in comprising a -CH2- in place of the instantly claimed -O- as indicated by arrow.
Yet, as taught by Williams et al “[w]hen a lead compound is first discovered for a particular disease state, it often lacks the required potency and pharmacokinetic properties suitable for making it a viable clinical candidate… The medicinal chemist therefore must modify the compound to reduce or eliminate these undesirable features without losing the desired biological activity. Replacement or modification of functional groups with other groups having similar properties is known as isosteric or bioisosteric replacement” (Page 59). Although it is clear that "the use of bioisosteric replacement (classical or nonclassical) in drug development is highly dependent upon the biological system being investigated” and that “[n]o hard and fast rules exist to determine what bioisosteric replacement is going to work with a given molecule” it is also clear that “some generalizations have been possible” (Page 60). Notably, one such generalization is that -CH2- and -O- can replace each other (Page 60, Table 2.8, Page 61, Table 2.9, Page 63, Table 2.10, Reference 45).
As similarly taught by Hevey et al – also noting that “[b]ioisosteric replacement of functional groups is commonly used in medicinal chemistry to improve the desired properties of a molecule” (Page 6, Section 4) – one common bioisosteric replacement is -CH-2- for -O- (Page 6, Table 2).
And, significantly, Ueda et al (see Page 4705, Figure 1) specifically teach replacing -CH-2- with -O- in the mimetic compound C699 (comprising the same core as Kahn et al) to provide the structurally and functionally related compound mS-11 (having the instantly claimed core):
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In view of all the foregoing, it would have been obvious to a person of ordinary skill in the art at the time the invention was made to replace -CH-2- with -O- in the compound taught by Kahn et al with to arrive at the instantly claimed compound. The person of ordinary skill in the art at the time the invention was made would have been motivated to make the bioisosteric modifications in an effort to synthesize similar compounds that retain biological activity, but have improved physiochemical properties and better pharmacokinetic behavior, with a reasonable expectation of success.
As such, claims 1-6 and 8-13 are rejected as prima facie obvious.
Claims 1-6 and 8-13 are ADDITIONALLY rejected under 35 U.S.C. 103(a) as being unpatentable over Kahn et al (US 6,184,223; of record), Kahn et al (US 6,413,963), Kahn et al (US 6,548,500; of record), and/or Kahn et al (US 7,598,253; of record) in view of Williams et al (Foye’s Principles of Medicinal Chemistry, 5th Ed., Pages 59-63, 2002; of record), Hevey et al (Biomimetics 4:53 (23 pages), 2019; of record) and Ueda et al (Bioorg Med Chem Lett 27:4705-4709, 2017; of record).
Claim 1 is drawn to a compound of formula (I) which embraces the following compound species
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wherein Q is I-1 wherein R1a is substituted alkyl or substituted arylalkyl and R1b is hydrogen; U is -(C(O))-; R2 is substituted alkyl or substituted arylalkyl; R4a is substituted alkyl; R4b is hydrogen; R3 is -W31-W32-R33- wherein W31 is -C(O)-, W32 is -O- and R33 is substituted alkyl or arylalkyl; and R5 is hydrogen - which reads on claims 1-6 and 8-13.
Kahn et al teach “compounds which mimic the secondary structure of reverse-turn regions of biologically active peptides and proteins” (Abstract) including the following compound species
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(Table 6) which differs from the instantly claimed compound in comprising a -CH2- in place of the instantly claimed -O- as indicated by arrow.
Yet, as taught by Williams et al “[w]hen a lead compound is first discovered for a particular disease state, it often lacks the required potency and pharmacokinetic properties suitable for making it a viable clinical candidate… The medicinal chemist therefore must modify the compound to reduce or eliminate these undesirable features without losing the desired biological activity. Replacement or modification of functional groups with other groups having similar properties is known as isosteric or bioisosteric replacement” (Page 59). Although it is clear that "the use of bioisosteric replacement (classical or nonclassical) in drug development is highly dependent upon the biological system being investigated” and that “[n]o hard and fast rules exist to determine what bioisosteric replacement is going to work with a given molecule” it is also clear that “some generalizations have been possible” (Page 60). Notably, one such generalization is that -CH2- and -O- can replace each other (Page 60, Table 2.8, Page 61, Table 2.9, Page 63, Table 2.10, Reference 45).
As similarly taught by Hevey et al – also noting that “[b]ioisosteric replacement of functional groups is commonly used in medicinal chemistry to improve the desired properties of a molecule” (Page 6, Section 4) – one common bioisosteric replacement is -CH-2- for -O- (Page 6, Table 2).
And, significantly, Ueda et al (see Page 4705, Figure 1) specifically teach replacing -CH-2- with -O- in the mimetic compound C699 (comprising the same core as Kahn et al) to provide the structurally and functionally related compound mS-11 (having the instantly claimed core):
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In view of all the foregoing, it would have been obvious to a person of ordinary skill in the art at the time the invention was made to replace -CH-2- with -O- in the compound taught by Kahn et al with to arrive at the instantly claimed compound. The person of ordinary skill in the art at the time the invention was made would have been motivated to make the bioisosteric modifications in an effort to synthesize similar compounds that retain biological activity, but have improved physiochemical properties and better pharmacokinetic behavior, with a reasonable expectation of success.
As such, claims 1-6 and 8-13 are rejected as prima facie obvious.
Claims 1-6 and 8-13 are ADDITIONALLY rejected under 35 U.S.C. 103(a) as being unpatentable over Kouji et al (US 8,691,819; of record), Kouji et al (US 9,126,981; of record) and/or Kouji et al (US 9,682,996; of record) in view of Williams et al (Foye’s Principles of Medicinal Chemistry, 5th Ed., Pages 59-63, 2002; of record), Hevey et al (Biomimetics 4:53 (23 pages), 2019; of record) and Ueda et al (Bioorg Med Chem Lett 27:4705-4709, 2017; of record).
Claim 1 is drawn to a compound of formula (I) which embraces the following compound species
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wherein Q is I-1 wherein R1a is substituted alkyl or substituted heteroarylalkyl and R1b is hydrogen; U is -(C(O))-; R2 is substituted alkyl or substituted arylalkyl; R4a is alkyl; R4b is alkyl; R3 is -W31-W32-R33- wherein W31 is -C(O)-, W32 is -NH- and R33 is substituted alkyl or arylalkyl; and R5 is hydrogen - which reads on claims 1-6 and 8-13.
Kouji et al teach “[a]lpha-helix mimetic structures and compounds represented by the formula (I)” (Abstract) including the following compound species
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(see ACCESSION NUMBER 2010:504003, CAS RN 1222062-38-5) which differs from the instantly claimed compound in comprising a -CH2- in place of the instantly claimed -O- as indicated by arrow.
Yet, as taught by Williams et al “[w]hen a lead compound is first discovered for a particular disease state, it often lacks the required potency and pharmacokinetic properties suitable for making it a viable clinical candidate… The medicinal chemist therefore must modify the compound to reduce or eliminate these undesirable features without losing the desired biological activity. Replacement or modification of functional groups with other groups having similar properties is known as isosteric or bioisosteric replacement” (Page 59). Although it is clear that "the use of bioisosteric replacement (classical or nonclassical) in drug development is highly dependent upon the biological system being investigated” and that “[n]o hard and fast rules exist to determine what bioisosteric replacement is going to work with a given molecule” it is also clear that “some generalizations have been possible” (Page 60). Notably, one such generalization is that -CH2- and -O- can replace each other (Page 60, Table 2.8, Page 61, Table 2.9, Page 63, Table 2.10, Reference 45).
As similarly taught by Hevey et al – also noting that “[b]ioisosteric replacement of functional groups is commonly used in medicinal chemistry to improve the desired properties of a molecule” (Page 6, Section 4) – one common bioisosteric replacement is -CH-2- for -O- (Page 6, Table 2).
And, significantly, Ueda et al (see Page 4705, Figure 1) specifically teach replacing -CH-2- with -O- in the mimetic compound C699 (comprising the same core as Kouji et al) to provide the structurally and functionally related compound mS-11 (having the instantly claimed core):
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Indeed, Kouji et al generically teach that the -CH2- group in the compounds disclosed therein can alternatively be -O- (see Column 3, Line 40, variable G in Formula (I) and Column 4, Line 1).
In view of all the foregoing, it would have been obvious to a person of ordinary skill in the art at the time the invention was made to replace -CH-2- with -O- in the compound taught by Kahn et al with to arrive at the instantly claimed compound. The person of ordinary skill in the art at the time the invention was made would have been motivated to make the bioisosteric modifications in an effort to synthesize similar compounds that retain biological activity, but have improved physiochemical properties and better pharmacokinetic behavior, with a reasonable expectation of success.
As such, claims 1-6 and 8-13 are rejected as prima facie obvious.
Conclusion
All claims are drawn to the same invention claimed in the application prior to the entry of the submission under 37 C.F.R. 1.114 and could have been finally rejected on the grounds and art of record in the next Office Action if they had been entered in application prior to entry under 37 C.F.R. 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a Request for Continued Examination and the submission under 37 C.F.R. 1.114. See MPEP 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 C.F.R. 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 extension fee pursuant to 37 C.F.R. 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 CRAIG D RICCI whose telephone number is (571) 270-5864. The examiner can normally be reached on Monday through Thursday, and every other Friday, 7:30 am - 5:00 pm ET.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached on (571) 272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CRAIG D RICCI/Primary Examiner, Art Unit 1611
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