DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims 1, 32, 90-92, 97-99, 109, 111, 121, 132, 134, 139-140, 144, 147-149, 159-160, 163, 166-167, 169-170, 173, 177, and 179 are pending in this application.
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Claims 1, 32, 99, 132, 134, 139-140, 144, 149, 163, 166-167, 169-170, 173, 177, and 179 are withdrawn. Claims 2-31, 33-89, 93-96, 100-108, 110, 112-120, 122-131, 133, 135-138, 141-143, 145-146, 150-158, 161-162, 164-165, 171-172, 174-176, 178, and 180-202 are cancelled.
Response to Amendment
The amendments filed on 31 Aug. 2026 have been entered.
Response to Arguments
In view of Applicants amendments, the rejection of claims 90-92, 97-98, 109, 111, 121, and 147-148 under 35 USC 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter is withdrawn.
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.
Claim(s) 90-92, 97-98, 109, 111, 121, 147-148, and 159-160 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kolodych et al. (WO 2019/008164 A1; published 10 Jan. 2019), in view of Krenske et al. (JACS; published 2012) and Kim et al. (Bioconjugate Chem.; published 16 Apr. 2020) for the reasons cited in the Office action filed on 7 May 2026.
Claim(s) 90-92, 97-98, 109, 111, 121, 147-148, and 159-160 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kolodych et al. (WO 2019/008164 A1; published 10 Jan. 2019), in view of Krenske et al. (JACS; published 2012) and Kim et al. (Bioconjugate Chem.; published 16 Apr. 2020), in further view of Kang et al. (ACS Cent. Sci.; published 19 Mar. 2021) for the reasons cited in the Office action filed on 7 May 2026.
Applicants’ Arguments
Applicants assert that the cited references fail to teach or suggest the enamine N-oxide core recited in claim 90 and the rationale for combining them is inconsistent and driven by impermissible hindsight. The Kang reference constitutes a disclosure made by the inventor not more than one year before the effective filing date and is excepted from prior art under 35 USC 102(b)(1)(A). Kolodych contains no disclosure of a hydroxylamine, retro-Cope or reverse Cope elimination, an enamine, or an N-oxide. Neither Krenske nor Kim supply the missing features or provide a reason to make the substitution the Examiner proposes. Far from directing a person of ordinary skill in the art toward a stable, isolable enamine N-oxide suitable for bioconjugation, Krenske teaches that the enamine N-oxide is a transient intermediate that spontaneously converts to a different product. Krenske notes that an alkyne must be used in the reaction. The TCO used by Kim is a strained alkene, not an alkyne. Because Krenske teaches that only alkynes yield an enamine N-oxide upon reverse Cope elimination, the skilled artisan would not use the alkene proposed by Kim because Krenskr suggests that such a reaction will not produce the desired enamine N-oxide. Applicants assert impermissible hindsight. Krenske does not teach or suggest that the N-methylation would yield a stable, isolable enamine N-oxide suitable for bioconjugation. The alleged advantages of the combination are not found in the cited art.
Applicants’ arguments filed 31 Aug. 2026 have been fully considered but they are not persuasive. The Kang reference is prior art because the Kang references names Sheldon T Cheung and Andrew Wong-Rolle who are not listed as inventors in the present application. See MPEP 2153.01(a). In the case, wherein an application name fewer joint inventors than a publication (e.g., the application names joint inventors A and B, and the publication names authors A, B, and C), the publication should be treated as prior art under AIA 35 USC 102(a)(1) unless there is evidence of record that an exception applies.
Kolodych provides for peptide and lysozyme conjugates comprising a trans-tagging unit formed by cycloaddition reaction with complementary trans-tagging functions attached to TAMRA diagnostic agent. For example, Kolodych teaches compounds 3 and 16. Regarding the trans-tagging units formed by cycloaddition reaction, Kolodych is not limited to a particular trans-tagging units. At pg. 4, Kolodych lists some preferred embodiments, but the preferred embodiments are not limiting. At for example pgs 13 and 16, Kolodych teaches and suggests cyclooctynes as a cycloaddition amendable functional group capable of forming a trans tagging unit that conjugates the peptide or lysozyme to the diagnostic agent. Accordingly, a person of ordinary skill in the art absent hindsight analysis would have had reason and motivation to investigate other moieties capable of undergoing cycloaddition reaction with a cycloalkyne to form a peptide or lysozyme conjugate as claimed. Krenske teaches that alkynes take part in a reverse Cope elimination reaction, which is a cycloaddition reaction. In addition, Krenske teaches that alkyne are more reactive than alkenes. Regarding the formation of an enamine N-oxide, Krenske teaches that the immediate product of the cyclization reaction is an enamine N-oxide and when R is H, the N-oxide rearranges. In this case, a person of ordinary skill would have understood Krenske to teach that when R is not H, such as a generally considered bioequivalent Me, the enamine N-oxide does not/cannot rearrange to produce a nitrone and a reactive cation. Regarding reason and motivation to combine, at for example scheme 4, Krenske teaches the reverse Cope elimination reaction of an alkyne under mild conditions. A person of ordinary skill in the art would have understood from Krenske that hydroxylamines are suitable reaction partners for cyclooctyne conjugation moiety in Kolodych and that the first step in the reaction is formation of an enamine N-oxide that does not rearrange into a nitrone when R is not H such as a bioequivalent Me. It cannot be considered hindsight analysis when a recognized advantage is the reason to combine. A recognized advantage is the strongest reason to combine. MPEP 2144.II. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Kolodych so that the peptide or lysozyme is attached to TAMRA by a cycloaddition reaction using hydroxylamine and cyclooctyne reaction partners to form enamine N-oxide unit as a claimed because the enamine N-oxide as claimed would have been expected to advantageously enable a conjugation reaction selective to alkynes such that a peptide or lysozyme conjugate is form under mild conditions at neutral pH. There would have been a reasonable expectation of success since Krenske teaches and suggests that the enamine N-oxide does not rearrange when R is not H such as a Me. While Kim teaches the use of a cyclooctene as a reaction partner in a cycloaddition reaction that forms a conjugate, Krenske teaches that the alkynes are more reactive than alkenes. In addition, Krenske teaches and suggests that alkynes form an enamine N-oxide under mild conditions. At scheme 4, an alkene having terminal substituent groups did not undergo reverse Cope reaction at elevated temperature in toluene. Accordingly, a person of ordinary skill in the art would have had reason and motivation to modify the cyclooctene in Kim to form a cyclooctyne when using a reverse Cope reaction to conjugate a peptide or lysozyme to TAMRA because the cyclooctyne would have been expected to enable the formation of the peptide or lysozyme conjugate under mild conditions.
The teachings of Kang are similar Krenske. Kange provides additional reason and motivation to modify the conjugates of Kolodych to arrive at the claimed conjugates that use an enamine N-oxide formed by cycloaddition reaction to link a peptide or lysozyme to TAMRA. At scheme 1 and Fig. 2, Kang teaches that the retro Cope elimination reaction is mild, regioselective and has broad scope. It would have been further obvious to a person of ordinary skill in the art before the effective filing date to modify the conjugates of Kolodych so that a retro Cope cycloaddition reaction with a N,N-dialkylhydroxylamine such as N-Me-TAMRA-hydroxylamine (-N(OH)Me), and cyclooctyne such as the A2-NHC(O)(CH2)2-NH-C(O)-O-cyclooctyne taught by Kim, Kolodych, and Kang is used to the peptide to lysosome to arrive at the elected species because the retro Cope cycloaddition reaction would have been expected to advantageously enable simple, fast, and chemoselective conjugation with a broad range of substrates under mild conditions and near neutral pH.
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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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618
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