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 .
Election/Restrictions and Claim Status
Applicants’ amendments and arguments filed 4/24/26 are acknowledged. Any objection or rejection from the 1/28/26 office action that is not addressed below is withdrawn based on the amendments.
Previously, oxyma (additive), DIC (condensing agent) and the compound of example 1 (peptide compound) were elected.
Claims 3-4 and 13-14 have been canceled.
Claim 16 does not read on the elected peptide since the elected peptide is not cyclized.
Newly added claim 22 refers to a ‘second peptide’. The elected compound is a dipeptide so there would be no second peptide. As such, claim 22 is drawn to a non-elected species.
Claims 16 and 22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10/27/25.
The elected peptide was not found in the prior art in the context of the instant claims. The search was extended in accord with MPEP 803.02.
Claims 1-2, 5-12, 15, 17-21 and 23-24 are being examined.
Priority
The priority information is found in the filing receipt dated 6/22/23.
Claim Rejections - 35 USC § 112
This 112 rejection is a new rejection necessitated by the addition of new claim 24.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 24 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 24 recites a variety of options for the first amino acid, the N-terminal amino acid of the first peptide, and/or the C-terminal amino acid of the first peptide including numerous options that recites ‘Me’. The required structure is unclear. Page 17 of the specification (see Fmoc-MeLeu-OH) includes an example where Me is an alpha-methyl group. Page 17 of the specification (see Fmoc-MeVal-OH) includes an example where Me is an N-methyl group. As such, it is unclear if ‘Me’ is to be interpreted as either an alpha-methyl group or an N-methyl group or if it is to be interpreted as only an alpha-methyl group or as only an N-methyl group.
Claim 24 recites a variety of options for the first amino acid, the N-terminal amino acid of the first peptide, and/or the C-terminal amino acid of the first peptide and recites ‘Aze(2)’. The specification (page 14) defines Aze, but the structure shown for Fmoc-Aze(2)-OH (page 18) only appears to include a single repeat of Aze. It is unclear if the 2 in ‘Aze(2)’ is to include 2 repeats of Aze. If so, the structure on page 18 for Fmoc-Aze(2)-OH only includes a single repeat of Aze. As such, the scope of Aze(2) is unclear.
Claim 24 recites a variety of options for the first amino acid, the N-terminal amino acid of the first peptide, and/or the C-terminal amino acid of the first peptide and refers to ‘pip’, ‘aze’, ‘pyrro’ and ‘mor’. The definition section (pages 14-15) refers to Pip, Aze, Pyrro and Mor. It is unclear if for example pip is the same as Pip. Further, claim 24 refers to ‘cpent’, ’26-bicyc’, ‘bzl’ and ‘bMe’. However, none of these terms are defined.
Claim 24 recites a variety of options for the first amino acid, the N-terminal amino acid of the first peptide, and/or the C-terminal amino acid of the first peptide and refers to OtBu and Boc for example. The point of attachment of these groups is unclear. Page 18 recites an example with the OtBu on the side chain (Fmoc-Thr(tBu)-OH) and page 17 recites an example with the OtBu on the terminal end (Fmoc-MeAsp(OH)-OtBu). Claim 24 recites MeLys(Boc). It is unclear if the Boc as attached to the side chain or to the terminal end.
Claim Rejections - 35 USC § 103
Claims were previously rejected based on the references cited below. Since the claims have been amended and new claims added the rejection is updated to correspond to the instant claims.
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) 1-2, 5-12, 15, 17-21 and 23-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Takahashi (US 2010/0184952) in view of Obrecht et al. (US 2015/0051183; ‘Obrecht’).
Takahashi teach methods of peptide synthesis (section 0031) specifically methods that remove impurities (abstract). Takahashi teach a coupling step as part of the peptide synthesis that uses amino acids (section 0184), a condensing agent (section 0187) and an activating agent (section 0189) as well as a solvent (section 0190). Takahashi teach a specific example in which 2.89 mmol of Fmoc-Phe-OH, 2.25 mmol H-Ala-OtBu.HCl, 0.55 mmol HOBt and 3.03 mmol EDC.HCl were added together in DMF (example 7 sections 0234-0235). Takahashi teach peptide synthesis including another addition step to make Fmoc-Ser(tBu)-Phe-Ala-OtBu (sections 0234-0235).
Takahashi does not teach an example with an amino acid as in claim 1.
Takahashi recognizes that the order of addition of amino acids is not particularly limited (section 0184). Takahashi teach that the amounts of the amino acids can be varied to limit excess and teach that generally 0.9 to 4 equivalents of one amino acid to another can be used (section 0185). Takahashi teach that the activator promotes the reaction and suppresses side reactions (section 0188) and that generally 0 to 4 equivalents of activator to amino acid can be used (section 0189). Takahashi teach the condensing agent for formation of the peptide (section 0184) and teach that the amount used is generally 0.8 to 4 equivalents of amino acid (section 0187). Takahashi teach that the amino acid is not limited and includes Pro and beta-Ala (sections 0149-0150). Takahashi teach methods specifically for compounds protected with an Fmoc group (abstract). Takahashi teach the use of amino protecting groups specifically Fmoc because it provides many advantages (section 0005). Takahashi teach that Fmoc is utilized for solid phase synthesis (section 0007).
Obrecht teach structures with medical applications that can be made by combinatorial chemistry in solution or solid phase (abstract) and recognizes methods of peptide synthesis including those that use Fmoc (section 0283). Obrecht teach specific examples that include combining peptides including Fmoc-NMe-beta-Ala-OH (Table 22a example 193h page 144). On page 200, Obrecht shows the compound containing NMe-beta-Ala (85h-Ex. 193h). Obrecht shows that preparation of Fmoc-NMe-beta-Ala-OH was known (section 0445). Obrecht teach that the solid support is preferably a trityl resin (section 0261) and teach the synthesis of precursors on solid support (sections 0282-0283).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the teachings of Takahashi based on the specific suggestions of Takahashi. With respect to the amounts of the components to use, Takahashi teach that the amounts of the amino acids can be varied to limit excess and teach that generally 0.9 to 4 equivalents of one amino acid to another can be used (section 0185). Takahashi teach that the activator promotes the reaction and suppresses side reactions (section 0188) and that generally 0 to 4 equivalents of activator to amino acid can be used (section 0189). Takahashi teach the condensing agent for formation of the peptide (section 0184) and teach that the amount used is generally 0.8 to 4 equivalents of amino acid (section 0187). Thus, based on the specific suggestions of Takahashi one would have been motivated to use various amounts to limit excess of amino acid, promote the reaction and suppress the side reaction. Since Takahashi teach that the amino acid is not limited and includes Pro and beta-Ala (sections 0149-0150) one would have been motivated to use such amino acids. Since Takahashi teach methods specifically for compounds protected with an Fmoc group (abstract) and teach the use of amino protecting groups specifically Fmoc because it provides many advantages (section 0005) and teach that Fmoc is utilized for solid phase synthesis (section 0007) one would have applied the method for such purposes. Further, since Takahashi teach that the amino acid is not limited and includes Pro and beta-Ala (sections 0149-0150) one would have been motivated to use the method for known peptide containing compounds such as those of Obrecht. Obrecht recognizes methods of peptide synthesis including those that use Fmoc (section 0283). Obrecht teach specific examples that include combining peptides including Fmoc-NMe-beta-Ala-OH (Table 22a example 193h page 144). On page 200, Obrecht shows the compound containing NMe-beta-Ala (85h-Ex. 193h). Since Obrecht teach that the solid support is preferably a trityl resin (section 0261) one would have been motivated to use such resin. One would have had a reasonable expectation of success since the components and methods of adding them together were known (compare example 7 of Takahashi and section 0445 of Obrecht).
In relation to the condensing agent as recited in claims 1, 11 and 24, Takahashi teach a specific example in which 3.03 mmol EDC.HCl was used (section 0234). Takahashi teach that EDC is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (section 0062) which is instant EDCI-HCl.
In relation to the additive as recited in claims 1, 10 and 24, Takahashi teach a specific example in which 0.55 mmol HOBt was used (example 7 sections 0234-0235).
In relation to the first amino acid amounts as recited in claims 1 and 24, Takahashi teach a specific example in which 2.89 mmol of Fmoc-Phe-OH was used (example 7 sections 0234-0235). Instant claim 1 does not distinguish the first or second amino acid and Takahashi refers to 2 amino acids that are added (section 0234) so either amino acid could be considered the first.
In relation the sequence of the first amino acid of claims 1 and24, Obrecht teach specific examples that include combining peptides including Fmoc-NMe-beta-Ala-OH (Table 22a example 193h page 144). On page 200, Obrecht shows the compound containing NMe-beta-Ala (85h-Ex. 193h). Obrecht shows that preparation of Fmoc-NMe-beta-Ala-OH was known (section 0445). The NMe-beta-Ala of Obrecht is interpreted as meeting the limitation of bMeAla as recited in claim 24.
In relation to the second amino acid as recited in claims 1 and 24, Takahashi teach a specific example in which 2.25 mmol H-Ala-OtBu.HCl was used (example 7 sections 0234-0235). Instant claim 1 does not distinguish the first or second amino acid and Takahashi refers to 2 amino acids that are added (section 0234) so either amino acid could be considered the first. Obrecht teach specific examples that include combining peptides including Fmoc-NMe-beta-Ala-OH and a Beta-branched amino acid beta3-homoPhe (Table 22a example 193h page 144). Further, Obrecht refers to advantages in stability and teach the use of multiple Nmethylated amino acids (section 0014) and teach that N-methyl derivatives even if not explicitly listed are part of the embodiment (section 0219) thus suggesting an N-alkylamino acid.
In relation to the amounts and ratios of claim 1, the moles of the additive (0.55 mmol HOBt) is smaller than the number of moles of the second amino acid (2.25 mmol H-Ala-OtBu.HCl) (section 0234). The molar ratio of condensing agent (3.03 mmol EDC.HCl) to second amino acid (2.25 mmol H-Ala-OtBu.HCl) is 1.35.
In relation to claim 2, the molar ratio of the additive (0.55 mmol HOBt) to the second amino acid (2.25 mmol H-Ala-OtBu.HCl) (section 0234) is 0.24.
In relation to claim 5, the molar ratio of the second amino acid (2.25 mmol H-Ala-OtBu.HCl) to the first amino acid (2.89 mmol of Fmoc-Phe-OH) (section 0234) is 0.78.
In relation to the amounts and ratios of the claims including claims 6-9 and 17-18, Takahashi teach that the amounts of the amino acids can be varied to limit excess and teach that generally 0.9 to 4 equivalents of one amino acid to another can be used (section 0185). Takahashi teach that the activator promotes the reaction and suppresses side reactions (section 0188) and that generally 0 to 4 equivalents of activator to amino acid can be used (section 0189). Takahashi teach the condensing agent for formation of the peptide (section 0184) and teach that the amount used is generally 0.8 to 4 equivalents of amino acid (section 0187). Thus, Takahashi generally recognizes a range of amounts up to 4 equivalents and suggest the agents for specific purposes (see MPEP 2144.05 II A). Further, MPEP 2144.05 recognizes that where the claimed ranges overlap or lie inside ranges disclosed by the prior art a prima facie case of obviousness exists.
In relation to claim 12, Takahashi teach peptide synthesis including another addition step to make Fmoc-Ser(tBu)-Phe-Ala-OtBu (sections 0234-0235) which comprises Ala and Phe.
In relation to claim 15, Takahashi teach that the amino acid is not limited and includes Pro and beta-Ala (sections 0149-0150). Proline is an N-alkylamino acid. Obrecht teach specific examples that include combining peptides including Fmoc-NMe-beta-Ala-OH (Table 22a example 193h page 144). On page 200, Obrecht shows the compound containing NMe-beta-Ala (85h-Ex. 193h). Obrecht shows that preparation of Fmoc-NMe-beta-Ala-OH was known (section 0445).
In relation to claim 19, Takahashi teach a specific example in which components were added together in DMF (example 7 sections 0234-0235).
In relation to claims 20-21 and 23-24, Takahashi teach methods specifically for compounds protected with an Fmoc group (abstract). Takahashi teach the use of amino protecting groups specifically Fmoc because it provides many advantages (section 0005). Takahashi teach that Fmoc is utilized for solid phase synthesis (section 0007). Obrecht teach that the solid support is preferably a trityl resin (section 0261). Obrecht refers to advantages in stability and teach the use of multiple Nmethylated amino acids (section 0014) and teach that N-methyl derivatives even if not explicitly listed are part of the embodiment (section 0219).
Response to Arguments - 103
Applicant's arguments filed 4/24/26 have been fully considered but they are not persuasive with respect to the rejection set forth above.
Although applicants argue about a motivation to use or combine the references, Takahashi teach that the amounts of the amino acids can be varied to limit excess and teach that generally 0.9 to 4 equivalents of one amino acid to another can be used (section 0185). Takahashi teach that the activator promotes the reaction and suppresses side reactions (section 0188) and that generally 0 to 4 equivalents of activator to amino acid can be used (section 0189). Takahashi teach the condensing agent for formation of the peptide (section 0184) and teach that the amount used is generally 0.8 to 4 equivalents of amino acid (section 0187). Thus, based on the specific suggestions of Takahashi one would have been motivated to use various amounts to limit excess of amino acid, promote the reaction and suppress the side reaction. Since Takahashi teach that the amino acid is not limited and includes Pro and beta-Ala (sections 0149-0150) one would have been motivated to use such amino acids. Since Takahashi teach methods specifically for compounds protected with an Fmoc group (abstract) and teach the use of amino protecting groups specifically Fmoc because it provides many advantages (section 0005) and teach that Fmoc is utilized for solid phase synthesis (section 0007) one would have applied the method for such purposes. Further, since Takahashi teach that the amino acid is not limited and includes Pro and beta-Ala (sections 0149-0150) one would have been motivated to use the method for known peptide containing compounds such as those of Obrecht.
Although applicants argue that Takahashi only teach coupling methods generically, MPEP 2123 recognizes that a reference may be relied upon for all that it would have reasonably suggested. The specific teachings of Takahashi are discussed in detail above.
Although applicants argue about the teachings of the references alone, 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 about difficult sequences and yields, it is noted that the features upon which applicant relies (i.e., difficult sequences and yields) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Although applicants argue that there would not have been a reasonable expectation of success, one would have had a reasonable expectation of success since the components and methods of adding them together were known (compare example 7 of Takahashi and section 0445 of Obrecht). Takahashi teach that the amino acid is not limited and includes Pro and beta-Ala (sections 0149-0150).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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RONALD T. NIEBAUER
Primary Examiner
Art Unit 1658
/RONALD T NIEBAUER/Examiner, Art Unit 1658
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