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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/4/25 has been entered.
Election/Restrictions and Claim Status
Applicants’ arguments filed 12/4/25 are acknowledged.
Previously, Group 1 and the species of SEQ ID NO:5 were elected.
Claims 2-4 and 9-15 have been canceled.
Claims 5-6 and 8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/19/24.
Claims 1 and 7 are being examined.
Priority
The priority information is found in the filing receipt dated 3/7/24.
Claim Rejections - 35 USC § 103
The rejection below is maintained from the previous office action.
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.
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.
Claim(s) 1 and 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shimamura et al. (NPL citation A29 of IDS 3/1/24; ‘Shimamura’) in view of Hall et al. (‘NPL citation A15 of IDS 3/1/24; ‘Hall’) in view of Bokvist et al. (US 2008/0096811; ‘Bokvist’).
Shimamura teach that chemerin is a natural ligand for ChemR23 (abstract). Shimamura teach that chemerin-9 (chemerin148-156) is degraded and inactivated in plasma (abstract). Shimamura teach that analogs were tested to identify stable versions (abstract). Shimamura teach that the analog yFLPsQFa(Tic)S (figure 1 analog 17) showed enhanced plasma exposure and prolonged half-life (abstract and page 1537 4th paragraph). Shimamura teach that replacement of Ala with N-methyl-L-Ala or N-methyl-D-Ala resulted in improvement in the net metabolic stability (page 1533 last paragraph and Table 3). Shimamura teach that the results suggest that the bond between Phe148-Leu149 is a target for proteolysis (page 1532 first paragraph and figure 3 and page 1534 first paragraph of second column). Shimamura teach modifications at the terminal ends of the peptide including acetylation at the N-terminus and teach that analog 4 had better activity than analog 2 or 5 (Table 1 page 1534).
Shimamura does not teach an example where the third amino acid is NMe-Leu (Shimamura teach Leu) nor does Shimamura teach the phenylpropanoyl at the N-terminus of SEQ ID NO:5.
Hall teach a peptide that is limited by its susceptibility to degradation and for which an increase in stability is desired (abstract). Hall teach that N-methylation is known to be a tool for increasing stability among other desirable properties (page 1748 first complete paragraph). Hall shows that the sequences of interest comprise ‘Phe-Leu’ (Table 1). Hall teach that when Leu was modified by N-methylation that there was a huge increase in stability while retaining biological activity (abstract and compound 21 of Tables 1-2 and figure 1).
Bokvist teach peptides and uses thereof (abstract). Bokvist teach N-terminal modifications for advantages including to provide stability (section 0403). Bokvist teach acetyl and 3-phenylpropionyl as modifications to improve stability (section 0405). In section 0111 and claim 55, Bokvist teach that a preferable N-terminal modification is 3-phenylpropionyl. In section 0113, Bokvist teach a peptide with an acetyl N-terminus as well as a peptide with a 3-phenylpropionyl N-terminus (SEQ ID NOs: 355 and 358 which are also named P32 and P90). Bokvist teach that P90 had among the best activity (table 1 page 26).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the teachings of Shimamura based on the specific suggestions of Shimamura. Shimamura teach that chemerin-9 (chemerin148-156) is degraded and inactivated in plasma (abstract). Shimamura teach that the results suggest that the bond between Phe148-Leu149 is a target for proteolysis (page 1532 first paragraph and figure 3 and page 1534 first paragraph of second column). Since Hall also teach a peptide comprising Phe-Leu and teach that when Leu was modified by N-methylation that there was a huge increase in stability while retaining biological activity (abstract and compound 21 of Table 1 and figure 1) one would have been motivated to incorporate such modification into the compound of Shimamura. Shimamura teach the analog yFLPsQFa(Tic)S (figure 1 analog 17). When the Leu is modified to NMeLeu the resulting compound is yF(NMeL)PsQFa(Tic)S. Since Shimamura teach making and assaying the compounds (sections 2.2 and 2.9) one would have been motivated to make and assay such compound. With respect to the N-terminal end, Shimamura teach modifications at the N-terminal end of the peptide including acetylation and teach that analog 4 had better activity than analog 2 or 5 (Table 1 page 1534). Further, Bokvist teach acetyl and 3-phenylpropionyl as modifications to improve stability (section 0405). In section 0111 and claim 55, Bokvist teach that a preferable N-terminal modification is 3-phenylpropionyl. In section 0113, Bokvist teach a peptide with an acetyl N-terminus as well as a peptide with a 3-phenylpropionyl N-terminus (SEQ ID NOs: 355 and 358 which are also named P32 and P90). Thus one would have been motivated to make known substitutions especially because Shimamura teach that analogs were tested to identify stable versions (abstract). One would have had a reasonable expectation of success since methods of making were known (see section 2.2 of Shimamura).
In relation to SEQ ID NO:5 of claim 1, as discussed above the compound suggested by the prior art is yF(NMeL)PsQFa(Tic)S. With respect to the N-terminal end, Shimamura teach modifications at the N-terminal end of the peptide including acetylation and teach that analog 4 had better activity than analog 2 or 5 (Table 1 page 1534). Further, Bokvist teach acetyl and 3-phenylpropionyl as modifications to improve stability (section 0405). In section 0111 and claim 55, Bokvist teach that a preferable N-terminal modification is 3-phenylpropionyl. In section 0113, Bokvist teach a peptide with an acetyl N-terminus as well as a peptide with a 3-phenylpropionyl N-terminus (SEQ ID NOs: 355 and 358 which are also named P32 and P90).
In relation to claim 7, Shimamura teach the peptides in a composition (section 2.9).
Response to Arguments - 103
Applicant's arguments filed 12/4/25 have been fully considered but they are not persuasive with respect to the rejection set forth above.
Although applicants argue that Shimamura alone does not teach the 3-Phenylpropionyl modification, the instant rejection is a multiple reference 103 rejection and as such any single reference does not necessarily anticipate the claims. 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). Bokvist teach N-terminal modifications for advantages including to provide stability (section 0403). Bokvist teach acetyl and 3-phenylpropionyl as modifications to improve stability (section 0405). In section 0111 and claim 55, Bokvist teach that a preferable N-terminal modification is 3-phenylpropionyl.
Although applicants argue that Shimamura cautions about chemical modifications, such section of Shimamura refers to replacing with a natural amino acid. The N-terminal modification to 3-phenylpropionyl is not a natural amino acid substitution.
Although applicants argue that Hall alone does not teach the 3-Phenylpropionyl modification, the instant rejection is a multiple reference 103 rejection and as such any single reference does not necessarily anticipate the claims. 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). Bokvist teach N-terminal modifications for advantages including to provide stability (section 0403). Bokvist teach acetyl and 3-phenylpropionyl as modifications to improve stability (section 0405). In section 0111 and claim 55, Bokvist teach that a preferable N-terminal modification is 3-phenylpropionyl.
Although applicants argue that Bokvist does not teach 3-phenylpropionyl as a preferred modification, section 0111 of Bokvist recites “Preferably, the N-terminal modification is the addition of a group selected from: acetyl, propionyl, butyryl, pentanoyl, hexanoyl, methionine, methionine sulfoxide, 3-phenylpropionyl”.
Although applicants argue that “P90 exhibits an (Alpha Screen), while P32 has an (Bokvist, Table 1)”, such argument is unclear and not persuasive. There is no requirement that the IC50 values of any substituted compounds must be identical to the parent.
Although applicants argue that Bokvist alone does not teach the all the claim limitations, the instant rejection is a multiple reference 103 rejection and as such any single reference does not necessarily anticipate the claims. 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).
Although applicants argue that the suggested modification would not lead to the claimed compound, Shimamura teach the analog yFLPsQFa(Tic)S (figure 1 analog 17) which comprises D-Tyr-Phe. Bokvist recites “Preferably, the N-terminal modification is the addition of a group selected from: acetyl, propionyl, butyryl, pentanoyl, hexanoyl, methionine, methionine sulfoxide, 3-phenylpropionyl”. Addition of 3-phenylpropionyl results in a compound comprising 3-phenylpropionyl-D-Tyr-Phe.
Although applicants argue that the properties of YW-111, MPEP 716.02(b) recognizes that the burden is on the applicant to establish results are unexpected and significant and be of statistical significance. Page 6 of the 12/4/25 reply does not report any details about any statistical significance.
With respect to the stability (and the modification of Leu to NMe-Leu), Shimamura teach that the results suggest that the bond between Phe148-Leu149 is a target for proteolysis (page 1532 first paragraph and figure 3 and page 1534 first paragraph of second column). Hall teach that N-methylation is known to be a tool for increasing stability among other desirable properties (page 1748 first complete paragraph). Hall shows that the sequences of interest comprise ‘Phe-Leu’ (Table 1). Hall teach that when Leu was modified by N-methylation that there was a huge increase in stability while retaining biological activity (abstract and compound 21 of Tables 1-2 and figure 1). Thus, incorporation of NMe-Leu after a Phe (see compounds YW-111 and YW-125 as compared to YW-3) to lead to increased stability is not unexpected. MPEP 716.02(c) states that expected beneficial results are evidence of obviousness.
With respect to the EC50 (and the modification at the N-terminal end), Table 1 of Shimamura shows that analog 4 has an N-terminal modification (adding an acetyl group) and has an EC50 of 47nM while the corresponding analogs without an N-terminal modification (analogs 2 and 5) have EC50 values of greater than 10000 nM and 240 nM. Thus, the N-terminal modification leading to improved EC50 is not necessarily unexpected. MPEP 716.02(c) states that expected beneficial results are evidence of obviousness. From such data there is no basis to conclude unexpected results or unexpected results commensurate in scope with the claims.
With respect to arguments about synergy, instant claim 1 is drawn to a single compound not a combination of compounds. Further, as discussed in the preceding paragraphs multiple modifications were known and known to have beneficial effects. From such data there is no basis to conclude unexpected results or unexpected results commensurate in scope with the claims.
Although applicants argue that there is no incentive to combine modifications, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the teachings of Shimamura based on the specific suggestions of Shimamura. Shimamura teach that chemerin-9 (chemerin148-156) is degraded and inactivated in plasma (abstract). Shimamura teach that the results suggest that the bond between Phe148-Leu149 is a target for proteolysis (page 1532 first paragraph and figure 3 and page 1534 first paragraph of second column). Since Hall also teach a peptide comprising Phe-Leu and teach that when Leu was modified by N-methylation that there was a huge increase in stability while retaining biological activity (abstract and compound 21 of Table 1 and figure 1) one would have been motivated to incorporate such modification into the compound of Shimamura. Shimamura teach the analog yFLPsQFa(Tic)S (figure 1 analog 17). When the Leu is modified to NMeLeu the resulting compound is yF(NMeL)PsQFa(Tic)S. Since Shimamura teach making and assaying the compounds (sections 2.2 and 2.9) one would have been motivated to make and assay such compound. With respect to the N-terminal end, Shimamura teach modifications at the N-terminal end of the peptide including acetylation and teach that analog 4 had better activity than analog 2 or 5 (Table 1 page 1534). Further, Bokvist teach acetyl and 3-phenylpropionyl as modifications to improve stability (section 0405). In section 0111 and claim 55, Bokvist teach that a preferable N-terminal modification is 3-phenylpropionyl. In section 0113, Bokvist teach a peptide with an acetyl N-terminus as well as a peptide with a 3-phenylpropionyl N-terminus (SEQ ID NOs: 355 and 358 which are also named P32 and P90). Thus one would have been motivated to make known substitutions especially because Shimamura teach that analogs were tested to identify stable versions (abstract). One would have had a reasonable expectation of success since methods of making were known (see section 2.2 of Shimamura).
Although applicants argue that there is no prediction of potency and stability, the instant claims are not drawn to methods of predicting potency and stability. The claim limitations are met for the reasons discussed above.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 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 CFR 1.114. See MPEP § 706.07(b). 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 RONALD T NIEBAUER whose telephone number is (571)270-3059. The examiner can normally be reached M - F 6:30 - 2:30 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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RONALD T. NIEBAUER
Primary Examiner
Art Unit 1658
/RONALD T NIEBAUER/Examiner, Art Unit 1658
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