DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to an amendment filed 10/30/2025.
Claims 1-5, 7, 9, 13, 15-18, 21, 22, 29, 30 and 34-37 are pending. Claims 1-5, 7, 9 and 13, drawn to a method of stapling oner or more amino acid sequences by reacting a compound of Formula I with a compound of Formula II are under examination. Claims 15-18, 21, 22, 29, 30 and 34-37 are withdrawn from examination.
This application claims priority as a 371 filing of PCT/US2021/017839 which claims priority to U.S. Provisional Application No. 62/976,599, filed February 14, 2020.
Response to Amendments
Applicant's have submitted replacement drawings that are sufficient to overcome the objections to the drawings. The objections to the claims have been overcome. Applicants arguments are sufficient to overcome one of the rejections under 35 USC 112,b. The remaining rejections have not been overcome for reasons below.
Claim Rejections - 35 USC § 112, second paragraph
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.
Claims 4 and 5 recite the limitation "the amino acid sequence" in claim 1. There is insufficient antecedent basis for this limitation in the claim. The reference claim recites that there are one or more amino acid sequences. By referring to the amino acid sequence, it is not clear if all or one are included in claim 4 and 5. This rejection is maintained for reasons of record. The reference phrase “one or more amino acid sequences” in claim 1 is not supported by the recitation of “the amino acid sequence”.
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 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.
Claims 1-5, 7, 9 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Pentelute et al (US 20140113871) in view of Kobayshi et al (JACS, 2016, pages 14832-14835). This rejection is maintained for reasons below.
Stapling is a strategy used to Pentelute et al teach use of thiols and fluorinated compounds in stapling strategies. The reactions use a SH-linker-SH group to react with a fluorinated form of a peptide sequence (see 1B. approach 1). This methodically is shown in figure 5. As to Formula II, since p, q, r can be 0, the middle grouping can be a linker bond which is the formation in figure 5.
Kobayshi provides an improved chemical reactivity group between a fluoridated compound and a thiol group by providing a reactive compound called FAcK.
We demonstrated that fluoroacetamide installed on FAcK, previously thought inert to biological functional groups, actually reacted with the thiol group of cysteine when in proximity
FAcK meets the limitation of Formula 1 wherein F- X2, X1= NR1 and ( )n, n=4. FAcK was incorporated into proteins such as an Affibody protein (see page 14833, col 1) and reacted with a thiol group.
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Our results showed that when in close proximity, a condition often encountered
when small molecules bind with large biomolecules, fluoroacetamide reacted with the Cys thiol group readily under mild physiological conditions.
This reaction is performed at a pH of 7.4 with a 10:1 ratio (see page 14834, col 1).
Based on such teachings, it would have prima facie been obvious to one of ordinary skill in the art at the time the invention was made to use the FAcK reactive group in place of the fluoroaryl of Pentelute. Such a modification would have resulted in a composition encompassed by claims 1-5, 9 and 13. As noted above: 1) Pentelute teaches reaction of a thiol group matching Formula II in order to staple amino acid sequences; 2) Kobayshi teach improved treatment for reacting thiol groups where the molecule reactivity is readily occurring under mile conditions and . Thus, a person of ordinary skill in the art, absent evidence to the contrary, would have reasonably expected that the use of FAcK would be a substitution of one known element used in similar reactions for another.
The reaction requires a 10:1 ratio (see page 14834 of Kobayashi).
Response to Arguments
Applicants argue first that the references would not be suitable for use together as Pentelute requires the perfluorinated aromatic group to react with SH and combining the teachings of Kobayshi (Formula I) would remove this group. Secondly, applicants that Kobayshi explicitly requires pH of 8.8 for ideal conditions for reacting FAcK with a thiol. Applicants argue that they provide unexpected results that pH of 8.5 or below leads to success in stapling the amino acid.
As to the first, both Pentelute and Kobayshi are directed to covalent linkage between fluorinated compounds and Thiol (see abstract for Pentelute). Kobayshi teaches “we demonstrated that the “biologically inert” fluoroacetamide actually reacted with cysteine side chain selectively.” (page 14832, col 2). This is a feature that improves the reaction. Hence, one would substitute the FAcK in the scheme of Pentelute. The FAcK was incorporated (page 14833, col 2) into proteins (i.e. amino acid sequences) for linkage to a thiol group (SH). This reaction led to a bridge (staple) when tested in the same protein (see page 14835, col 1).
As to the nature of the pH, the disclosure actually states that the
0383] To identify the optimal pH range for this type of reaction, the pH (FIG. 4) was titrated and found that the reaction rate significantly increased with pH. The increased deprotonation of benzenethiol likely contributed to this effect.
Hence, the results show that pH 8.5 was an improvement over 7.5 but does not indicate that higher pH would not even increase the improvement more. In fact, example 5 uses pH 9.0 in at least two of the reactions and claims in original claims a pH above 7. Hence, clear unexpected results and results limited to only below pH 8.5 were not actually demonstrated in the instant disclosure as to pH use. However, to the point, teaching that the increase from 7.4 to 8.8 lead to an increase does not teach away as incubation at 7.4 was successful. The reference does not constitute teaching away (see Chemours Company FC, LLC v. Daikin Industries, Ltd. wherein the teaching of a “better” embodiment does not constitute a “teaching away” from alternative “feasible” solutions. The lower pH does not lead one of ordinary skill in the art in a different direction than the claimed invention. Teaching away is usually not met by mere disclosure of alternatives or even a description that some teaching is somewhat inferior. MPEP § 2143(E) and §2143.01(I).
Conclusion
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.
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/MARIA MARVICH/Primary Examiner, Art Unit 1634