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 .
DETAILED ACTION
Claims 1, 4-5, 8, 10, 12, 15, 17, 19-23, 25-26, 33-35, 48-51, 60-71, 75-77, 82, 88-92, and 94-99 are pending in the instant application.
Claims 95-99 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/10/2026.
Claims 1, 4-5, 8, 10, 12, 15, 17, 19-23, 25-26, 33-34, 61-64, 66, 69-71, 75-77, 82, 88-92, and 94 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/10/2026.
Restriction Response
Applicant’s election without traverse of the compounds of Group I, Formula IV and the species:
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in the reply filed on 4/10/2026 is acknowledged. Claims 35, 48-51, 60, 65, and 67-68 are under review for the elected species.
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.
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.
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.
Claims 35, 48-51, 60, 65, and 67-68 are rejected under 35 U.S.C. 103 as being unpatentable over US 5,405,966 (Theodore LJ et al.), Wang W et al. (Int. J. Mol. Sci. 2021, 22(4), 1604), WO 2021/151984 (Kraiem M et al.), Nakada T et al. (Bioorganic & Medicinal Chemistry Letters 2016 26(6) 1542-1545), and Mondal D et al. (Tetrahedron Lett. 2018 Aug 14;59(40):3594–3599.).
‘966 taught antibody conjugates of trichothecene molecules (abstract).
‘966 taught the trichothecene as verrucarin A, wherein the structure is a macrocyclic trichothecene
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with an R’ of
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(column 6, Table 4).
‘966 taught conjugation of a macrocyclic trichothecene to a linker via a R’ group of
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wherein W is L1 or L2, wherein L1 or L2 comprise a nitrogen comprising linker of
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(column 13) and wherein Y is O or NH; R8 and R8’ are H; R1, R2, and R3 are H; and n’ is 0 to 10 (column 14, line 25-37). Thus, conjugation of a macrocyclic trichothecene of verrucarin A via a nitrogen at carbon 28 has been previously taught. ‘966 taught immunoconjugates of verrucarin A were effective against antigen positive cancer cells (column 18, lines 16-36).
‘966 did not teach: 1) the compound
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, but this is obvious in view of Wang, ‘984, Nakada, and Model.
Wang taught the verrucarin A structure
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(Fig. 1) and binding to the ribosome
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(Fig. 2).
Wang taught verrucarin A binds to the ribosome via core trichothecenes structural contacts on: i) O-C12,13-epoxide: ii) C6,7,8,9,10,11 ring, along with C16 methyl; iii) C6,7,8,9,10,11 ring, along with C16 methyl; and additional contacts (Table 1). Wang taught the verrucarin A binding pocket in the ribosome wherein the oxygen from C12,13 epoxide ring, the double bond between C9 and C10 in ring A were tightly contacted with the surface wall of the binding pocket and the tolerance of trichothecenes to substitutions is dictated by the architecture of the binding pocket formed by 25S rRNA (page 9, paragraph 1 and Figs. 3-4). Wang shows verrucarin A binding to the ribosome, which has space for a C28-OH bond out of plane for linker conjugation and a corresponding C27-CH3 in plane bond (Fig. 4).
‘984 taught an antibody drug conjugate comprising VC-exatecan wherein the structure comprised
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(page 92, Example 6) was effective against cancer cells in cell based assays and in vivo when administered to a subject with cancer (Fig. 5 and 8).
Nakada taught an antibody drug conjugate with the structure
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was effective (abstract, graphical abstract, and Fig. 2). Thus, N-C(O)-alkyl linkers attached to drug conjugates were previously shown to be effective for cancer treatment.
Mondal taught the cathepsin B cleavable Mc-Val-Cit-PAB-OH linker is utilized in an FDA approved antibody drug conjugate and many pre-clinical ADC candidates (abstract). Mondal taught hydrazone linkers are cleaved in the acidic environment of endosomes and lysosomes associated with tumor cells and chemically labile linkers often suffer from limited plasma stability (page 3594, right column, first paragraph). Mondal taught alternatively, peptide based linkers are designed as specific substrates for proteases that are highly expressed in cancer cells or the tumor microenvironment (page 3594, right column, first paragraph).
Regarding instant claims 35, 48-51, 60, 65, and 67-68, it would have been obvious for a person having ordinary skill in the art to take the ‘966 macrocyclic trichothecene verrucarin A with a linker for a drug conjugate wherein the structure is a macrocyclic trichothecene
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conjugated to a linker via a R’ group of
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wherein W is L2, wherein comprises a nitrogen comprising linker of
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, wherein Y is O or NH; R8 and R8’ are H; R1, R2, and R3 are H; and wherein n’ is 0 to 10 – and:
Exchange the
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in the linker for a MC-Val-Cit-PAB-O linker in view of ‘984, Nakada, and Mondal;
Change the stereochemistry of the C28-OH to above the plane and C27-CH3 to below the plane in view of Wang;
Conjugate the drug to the linker via an N-C(O)-alkyl rather than an N=N-C(O) linker in view of Nakada, and Mondal;
This is obvious because ‘966 taught immunoconjugates of verrucarin A were effective against antigen positive cancer cells and: 1a) ‘984 taught an antibody drug conjugate comprising VC-exatecan wherein the structure comprised
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was effective against cancer cells in cell based assays and in vivo when administered to a subject with cancer; 1b) Nakada also taught an MC-Val-Cit-PAB-O was effective against cancer cells; 1c) Mondal taught the cathepsin B cleavable Mc-Val-Cit-PAB-O linker is utilized in an FDA approved antibody drug conjugate and many pre-clinical ADC candidates and that peptide based linkers are designed as specific substrates for proteases that are highly expressed in cancer cells or the tumor microenvironment; 2) Changing the stereochemistry of the C28-NH to above the plane and C27-CH3 to below the plane would maintain core contacts with the ribosome for drug binding and have space for a C28-NH bond out of plane for linker conjugation and a corresponding C27-CH3 in plane bond; 3a) Nakada taught an N-C(O)-alkyl was effective; 3b) Mondal taught hydrazone linkers are cleaved in the acidic environment of endosomes and lysosomes associated with tumor cells and chemically labile linkers often suffer from limited plasma stability. Thus, an N-C(O)-alkyl attachment would be effective and thought to be more stable.
There is a reasonable expectation of success because ‘966 taught immunoconjugates of verrucarin A were effective against antigen positive cancer cells and: 1a) ‘984 taught an antibody drug conjugate comprising VC-exatecan wherein the structure comprised
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was effective against cancer cells in cell based assays and in vivo when administered to a subject with cancer; 1b) Nakada also taught an MC-Val-Cit-PAB-O ADC linker was effective against cancer cells; 1c) Mondal taught the cathepsin B cleavable Mc-Val-Cit-PAB-O linker is utilized in an FDA approved antibody drug conjugate and many pre-clinical ADC candidates and that peptide based linkers are designed as specific substrates for proteases that are highly expressed in cancer cells or the tumor microenvironment; 2) Changing the stereochemistry of the C28-NH to above the plane and C27-CH3 to below the plane would maintain core contacts with the ribosome for drug binding and have space for a C28-NH bond out of plane for linker conjugation and a corresponding C27-CH3 in plane bond; 3a) Nakada taught an N-C(O)-alkyl was effective; 3b) Mondal taught hydrazone linkers are cleaved in the acidic environment of endosomes and lysosomes associated with tumor cells and chemically labile linkers often suffer from limited plasma stability. Thus, an N-C(O)-alkyl attachment would be effective and thought to be more stable.
This would produce a compound linker for an antibody drug conjugate of
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wherein n is 0 to 10 which includes n = 2 and meets the claim limitations of the elected species in instant claims 35, 48-51, 60, 65, and 67-68.
Conclusion
Instant claims 35, 48-51, 60, 65, and 67-68.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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