leasDETAILED 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 .
Applicant’s amendment, filed 12/18/2025, is acknowledged.
Claims 5-7, 14, 22, 23, and 25-40 are cancelled.
Claims 1-4, 8-13, 15-21, 24, and 41-46 are currently pending.
Claims 1, 21, 24, and 46 are independent claims.
Claims 42-45 stand withdrawn, and newly added claim 46 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions and/or species.
Claims 1-4, 8-13, 15-21, 24, and 41 are under examination as reading on the elected invention of an ABPC comprising an anti-DLL3 binding domain and the species of MYT2829 conjugated to a toxin.
Applicant’s amendments and remarks, filed 12/18/2025, have obviated the previous 35 U.S.C. § 103 rejections.
In view of the amendments and remarks filed on 12/18/2025, the following rejections remain.
Claim Rejections - 35 USC § 112
Claims 8 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claim 8 are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The amino acid sequence Markush groupings in claim 8 contains 7 groups of pH-sensitive antibody variants generated from different parental antibodies that are structurally distinct (claim 8(a)-(g)).
Additionally, Applicant is advised that the Office limits up to 25 ABSS query sequences search per application, the instant application comprises unreasonable number of sequences to be searched. Claim 8(a) alone 65 amino acid sequences. The Office limits the search up to 25 SEQ ID Nos per request.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 9-13, 15-21, 24, and 41 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for pH-sensitive anti-DLL3 antibodies comprising VH and VL amino acid sequences of the following antibodies: MYT0643, MYT0645, MYT0647-MYT0648, MYT0650-MYT0652, MYT0655-MYT0657, MYT0660, MYT0669-MYT0670, MYT0673, MYT0675, MYT0677, MYT0678, MYT1533, MYT1534, MYT1537, MYT1540, MYT1541, MYT1542, MYT1544, MYT1547, MYT1550, MYT155 l, MYT1554, MYT1555, MYT1556, MYT1557, MYT1182, MYT1183, MYT1185, MYT1186, MYT1187, MYT1188, MYT1189, MYT1190, MYT1192, MYT1193, MYT1194, MYT1195, MYT1196, MYT1198, MYT1199, MYT1200, MYT1201, MYT4262-4281, MYT2800-2845, MYT3054, MYT3057, MYT3058, MYT3060, MYT3061, MYT3065, MYT3066, MYT3067, MYT3068, MYT3070, MYT3072, MYT3073, MYT3075, MYT3076, MYT3077, MYT3078, MYT3080, MYT3082, MYT3083, MYT3084, MYT3090, MYT3093, MYT3095, MYT3104, MYT3105, MYT3106, MYT3107, MYT3109, MYT3399-MYT3424, MYT4175, MYT4176, MYT4177, MYT4178, MYT4180, MYT4181, MYT4182, MYT4184, MYT4185, MYT4187, MYT4190-4199, MYT3493-MYT3513, MYT3183, MYT3185, MYT3187, MYT3189-MYT3194, MYT3196, MYT3197, MYT3198, MYT3200, MYT3202, MYT3210, MYT3212, MYT3214, MYT3218, MYT3220, MYT3222, MYT3227, MYT3231, MYT3234, MYT3235, MYT3236, MYT3237, JVIYT3245, MYT3246, MYT3248, MYT3250, MYT4346-MYT4366, MYT4368, MYT4369, MYT4370, MYT4372, MYT3526-MYT3530, MYT3532, MYT3534, MYT3536-MYT3537, MYT3539-MYT3543, MYT3545, MYT3547, MYT3549-3551, MYT3897, MYT3902-MYT3906, MYT3924, MYT3927-MYT3931, MYT3933, MYT3935, MYT3938, MYT3940, MYT3943, MYT3944, MYT3948-MYT3953, MYT3955, MYT3760, MYT3790, MYT3792, MYT3793, MYT3797, MYT3798, MYT3806, MYT3807, MYT3828, MYT3831, MYT3833, MYT3836, MYT3838, MYT3839, MYT3840, MYT3841, MYT3843, MYT3844, MYT3846, MYT3848, MYT3849, MYT3850, MYT3853, MYT3858, MYT3861, MYT3863, MYT3865, MYT3866, MYT3867, MYT3870, MYT3873-MYT3877, MYT3879, MYT3881, MYT3883, MYT3886, MYT3888, MYT3890, MYT3891, MYT3112, MYT3115, MYT3117, MYT3118, MYT3122, MYT3124, MYT3125, MYT3126, MYT3129, MYT3130, MYT3131, MYT3134, MYT3137, MYT3139, MYT3140, MYT3143, MYT3145, MYT3146, MYT3148, MYT3150, MYT3151, MYT3153, MYT3154, MYT3160, MYT3161, MYT3163, MYT3164, MYT3167, MYT3172, MYT3173, MYT3177, MYT3514-3525, does not reasonably provide enablement for a broad genus of antibodies comprising the VH and VL pairs recited in instant claim 1, wherein the VH and/or VL include one or more histidine mutations at the CDR residue positions recited in instant claims 1-4, 9-13, 15-21, 24, and 41 with the functions of “specifically binding DLL3 or an epitope of DLL3 presented on the surface of a target mammalian cell” and “the dissociation rate of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is faster than the dissociation rate at a pH of about 7.0 to about 8.0; or the dissociation constant (KD) of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is greater than the KD at a pH of about 7.0 to about 8.0”. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. This is a new grounds of rejection necessitated by Applicant’s amendments.
Claims 1-4, 9-13, 15-21, 24, and 41 are rejected under 35 § U.S.C. 112(a) as not enabled for the same reasons discussed in the Office Action mailed on 7/28/2025.
Applicant’s amendments and remarks, filed 12/18/2025, have been fully considered, but have been found to be not persuasive.
Applicant has amended the claims to recite “a histidine at one position” instead of “a histidine at one or more positions”, and points to support for the pH sensitive anti-DLL3 clone VH/VL sequences in the instant specification (remarks pg. 1-20).
This has been found to be not persuasive. The instant claims currently encompass a broad genus of antibodies with the recited CDR regions and undefined framework regions in the variable region and the indicated CDR histidine substitutions. For example, the elected species of antibody is a variant rovalpituzumab comprising a VH of SEQ ID NO: 81 and a VL of SEQ ID NO: 77. SEQ ID NO: 81 is the VH of rovalpituzumab with two residues in the CDRs mutated to histidine, and SEQ ID NO: 77 is the VL of rovalpituzumab with one residue in the CDRs mutated to histidine (Example 13, Figure 11, and pg. 422-423).
Therefore, the instant claims encompass a genus of antibodies with both variable CDR regions and variable framework regions with the recited functions of “specifically binding DLL3 or an epitope of DLL3 presented on the surface of a target mammalian cell” and “the dissociation rate of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is faster than the dissociation rate at a pH of about 7.0 to about 8.0; or the dissociation constant (KD) of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is greater than the KD at a pH of about 7.0 to about 8.0”. As discussed in the Office Action mailed on 7/28/2025, the instant specification does not enable this broad genus of antibodies with the recited functions.
Additionally, one with ordinary skill in the art would appreciate that while the CDR regions are critical for antigen binding, the framework region of antibodies do influence antibody binding to an antigen. For example, Chien et al. (PNAS USA. 1989 Jul;86(14):5532-6. doi: 10.1073/pnas.86.14.5532) teaches that a single amino acid substitution in the VH framework region abolished the binding of the S017 to its cognate antigen phosphocholine (Abstract, Results, Figure 3). Additionally, Foote et al. (J Mol Biol. 1992 Mar 20;224(2):487-99. doi: 10.1016/0022-2836(92)91010-m) teaches that specific framework residue mutations in the variable domain of an antibody can significantly affect the conformation of the CDR regions and interaction with an antigen (Abstract, pg. 488, Fig. 1).
Given that the instant claims encompass antibodies with variant CDR regions and variant framework regions, and given that neither the prior art nor the instant specification provide guidance on what other framework sequences would lead to functional antibodies with these variant CDR regions, undue experimentation would be required by one with ordinary skill in the art to make the broad genus of antibody structures recited in the claims with the functions of “specifically binding DLL3 or an epitope of DLL3 presented on the surface of a target mammalian cell” and “the dissociation rate of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is faster than the dissociation rate at a pH of about 7.0 to about 8.0; or the dissociation constant (KD) of the first antigen-binding domain at a pH of about 4.0 to about 6.5 is greater than the KD at a pH of about 7.0 to about 8.0”.
Amending the claims to recite the VH/VL sequences of the variant pH sensitive anti-DLL3 antibody clones disclosed in the instant specification and mentioned in the Applicant’s remarks filed on 12/18/2025, such as in amended claim 8, would resolve this issue.
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 8 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 8 depends on claim 1. Claim 1 recites “…wherein the heavy chain variable domain includes a histidine at one position in SEQ ID NO: 1 selected from the group consisting of: 27, 29, 31, 32, 34, 35, 50, 53, 54, 55, 58, 97, 98, 101, 103, 105, and 106…” However, SEQ ID NO: 81 (claim 8(a) and the elected species of VH) contains two histidine at positions 29 and 54. It is currently unclear how a heavy chain comprising a histidine at one recited position in claim 1 can have histidine at more than one of the recited positions.
Conclusion
No claim is allowed.
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 ALEC JON PETERS whose telephone number is (703)756-5794. The examiner can normally be reached Monday-Friday 8:30am - 6:00pm EST.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641