DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant's election without traverse of claims 1-3, 8-11, 15, 17, 19 and 21-26, drawn to an isolated monoclonal antibody which selectively binds to glycosylated CTLA-4 relative to glycosylated form of CTLA-4, and further election of the species of isolated monoclonal antibody in the reply filed on 06/09/2025 is acknowledged.
Claims 4-7, 12-14, 16, 18, 20, 30-35 and 38 are canceled.
Claims 1-3, 8-11, 15, 17, 19, 21-29 and 36-37 are pending.
Claims 27-29 and 36-37 are withdrawn from consideration under 37 CFR 1.142(b) as being drawn to nonelected invention and species.
Claims 1-3, 8-11, 15, 17, 19 and 21-26 are currently under examination.
Priority
3. Applicant' s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 36/5(c), or 386(c) is acknowledged. This application is a 371 of PCT/US2020/052949 filed 09/25/2020 which claims benefit of US Provisional Application No. 62/906,500 filed 09/26/2019. Claims 1-3, 8-11, 15, 17, 19 and 21-26 have an effective filing date of 09/26/2019.
Specification
4. The disclosure is objected to because of the following informalities: The specification recites “FIGS. 6A and B.” (page 9 of the specification, ¶33, line 1), however there is only one panel of figure 6. The specification references FIG. 5 to demonstrate STC1807’s binding specificity as shown through western blot analysis (pg. 77, ¶243), but the western blot image in the drawings is actually FIG. 6. Additionally, the specification references FIG.6 for the binding kinetics plot (pgs. 77-78, ¶244), which is actually FIG.5 in the drawings.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
5. 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.
6. Claims 2, 3, 11, 15, 17, 19 and 22 are 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.
7. Claim 2 appears to recite alternative limitations for glycosylation positions, “… wherein the antibody selectively binds to CTLA-4 glycosylated at positions N113 or N145 or N113 and N1145 relative to unglycosylated CTLA-4”. Taken as a whole, the majority of the instant disclosure recites two glycosylation positions (N113 and N145), but this claim recites a third position as “N1145”; while this is likely a typo, this “N1145” position is also recited in the specification (page 19, ¶ 70), making unclear if this was intended as an N-glycosylation site for CTLA-4. Additionally, the “and/or” relationship between the alternative limitations (shown in bold above) of claim 2 is unclear due to missing punctuation, or even a clear delineation between the alternatives. For instance, assuming “N1145” is a typographical error, one would likely interpret this as only claiming the following 3 alternative glycosylation positions; (i) N113 alone, (ii) N145 alone or (iii) both N113 and N145.
Appropriate correction is required.
8. Claim 3 recites, “…wherein the antibody blocks the binding of CTLA-4 to CD86 with the neutralizing activity (decreased half-maximal effective concentrations EC50) 2 to 10 higher than the EC50 exhibited by…”. It is not clear how to interpret this claim due to the lack of a comparable metric in the limitation. For instance, a neutralizing effect of “2 to 10 times” higher is not the same as a neutralizing effect of “2 to 10 fold” or “2 to 10 log” higher than the EC50 exhibited by the control antibody.
Appropriate correction is required.
9. Claim 3 is further indefinite for reciting the alternative limitation, “…or wherein the antibody binds to glycosylated CTLA-4 with a Kd less ten times the Kd exhibited relative to ipilimumab”. If the bold section was written as intended, the examiner does not understand how to interpret this limitation.
Appropriate correction is required.
10. Claims 11, 15 and 17 recite amino acid sequence SEQ ID NOs for the VH/VL complimentary determining regions. These claims are indefinite because of suspected typographical errors in how the Applicant has defined the CDRs throughout the specification. For instance, within the VH region defined by SEQ ID NO: 3; the differences between the sets of CDR H1-H3 are due to different methods of delineating the CDRs (e.g. Chothia vs Kabat). However, CDR H1 defined by Kabat (SEQ ID NO: 11) is the same sequence as CDR H3 defined by Chothia, Kabat and AbM (all are defined as SEQ ID NO: 8). This appears to be a mistake as SEQ ID NO: 11 does not align properly with the other CDR H1 sequences (see alignments below) and is most likely the result of typographical error by the Applicant.
VH SEQ ID 3 1 EVQLQQSGAELVRPGALVKLSCKASGFNIKDYYMNWVKQRPEQGLEWIGW 50
CDR1 Chothia 1 -------------------------GFNIKDY------------------ 50
CDR1 AbM 1 -------------------------GFNIKDYYMN--------------- 50
CDR1 Contact 1 -----------------------------KDYYMN--------------- 50
VH SEQ ID 3 81 LQLSSLTSEDTAVYYCARKWSYTMDYWGQGTSVTVSS 117
CDR1 Kabat 81 ------------------KWSYTMDY----------- 117
According to Table 2 of the specification on page 18, the Kabat CDR H1 should comprise amino acid positions 31-35 of SEQ ID NO: 3 as depicted in the underlined section below:
VH SEQ ID 3 1 EVQLQQSGAELVRPGALVKLSCKASGFNIKDYYMNWVKQRPEQGLEWIGW 50
It is unclear what the Applicant intended to claim as the Kabat CDR H1 sequence, or even how this amino acid sequence (SEQ ID NO: 8) could be delineated as a CDR H1 by any numbering method. For these reasons, claims 11, 15 and 17 are rejected for being indefinite for not clearly defining the CDRs of the isolated antibody of the instant invention. Claim 19 is included in this rejection because it depends upon claim 15, and incorporates the indefiniteness of claim 15 by dependency. Appropriate correction is required.
11. Claim 22 recites the limitation "The isolated antibody of claim, wherein…" in the first line of claim 22. There is insufficient antecedent basis for this limitation in the claim, because it is unclear which claim is being referenced as the independent claim. For the purposes of compact prosecution and prior art, this claim will be examined as being dependent on base claim 1; however, this does not relieve applicant from the burden of responding to this rejection for indefiniteness.
Appropriate correction is required.
12. 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.
13. Claims 1-3, 9-11, 15, 17, 19 and 22-26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. Base claim 1 recites “an isolated monoclonal antibody” that is capable of selectively binding to glycosylated CTLA-4 relative to unglycosylated form of CTLA-4, which encompasses a genus of agents. Claims 2-3, 9-10 and 22-26 are dependent from Claim 1, and do not materially limit the genus of agents. For instance the genus of antibodies in dependent claims 9 and 10 only require 90% identity to amino acid sequence SEQ ID NOs for variable heavy and variable light regions; this allows for up to 10% variability, even in complimentary determining regions, and are therefore included in this rejection. Claims 2-3, 11, 15, 17, 19 and 22-26 also depend from claim 1 and do not materially limit this genus of agents, especially in consideration of the indefiniteness rejections (outlined above) and are therefore included in this rejection. In total, claims 1-3, 9-10, 11, 15, 17 and 22-26 do not require that the genus of the claims possess any particular structure or other distinguishing feature that is characteristic of the genus as a whole. Therefore the claims are drawn to a genus of “isolated monoclonal antibodies” for which there is inadequate written description.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see MPEP 2163(II)(3)(a)(i)(A), reduction to drawings MPEP 2163(II)(3)(a)(i)(B), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus MPEP 2163(II)(3)(a)(i)(C).
In the instant case, the only identifying characteristic present in the claim is a recitation of requisite activity (e.g., selectively binding to glycosylated CTLA-4 relative to unglycosylated form of CTLA-4)---------------. There is not even identification of any particular portion of a structure that must be conserved for said activity. Regarding the genus of the claims the specification describes only one specific species within the genus claimed (STC1807).
The specification discloses a hybridoma screening approach for the production of monoclonal antibodies specifically binding to glycosylated CTLA-4. Out of the more than 3000 monoclonal antibody (mAb)-producing hybridomas, 65 mAb-producing candidate hybridomas were selected by FACS for their binding to CTLA-4 WT or 2NQ (non-glycosylated form) expressing 293T cells; among those candidates only one mAb, named STC1807, blocked the binding of CTLA-4 to CD86 (see fig. 4) (examples 2, ¶240-242). Three antibodies (STC1836, STC1837 and STC1838) were shown to inhibit the interaction between CTLA-4 and CD86 in 293T cells expressing CTLA-4 (example 3, ¶245; FIG. 7A-D). The neutralizing effect on the interaction between CTLA-4 and CD86 was also demonstrated with a humanized chimeric antibody of STC1807 compared to ipilimumab (an anti-CTLA-4 antibody), each demonstrating comparable effects (example 3, ¶246; FIG. 8A-D). The binding affinity of the lead antibody STC1807 was also compared to ipilimumab, indicating that STC1807 displayed a stronger binding affinity (example 5, ¶248; FIG. 10). The lead antibody STC1807 also demonstrated a greater effect on T cell proliferation (by measuring secretion of IFN-γ and IL-2 in T cell culture supernatant) compared to ipilimumab (example 6, ¶249; FIG. 11).
From the specification, it is clear that Applicant is in possession of a single species of isolated monoclonal antibody capable of specifically binding glycosylated CTLA-4 compared to the unglycosylated form (discussed above). However, the scope of the claims is not limited to those species but also includes a vast number of antibodies, and the specification fails to provide a representative number of species within the recited genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, or representative number of species, the specification does not provide adequate written description of the claimed genus.
Claim Rejections - 35 USC § 102
14. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
15. Claims 1-3 and 22-26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WANG et al (WO 2018/209701 A1; published 11/22/2018; same patent family as CN 108948194 A, listed on the IDS filed 06/17/2025).
Regarding claim 1, WANG teaches novel monoclonal antibodies to CTLA-4 (title) that were assessed for binding selectivity to extracellular domain of CTLA-4 with and without glycosylation site mutations at positions (i) N113, (ii) N145 or (iii) N113 and N145 (page 42, last ¶). The results of WANG show the anti-CTLA-4 antibody (named W3162-1.146.19-z12-IgG1K) displayed significant reduction in binding to mutated CTLA-4 N145Q (Fig 17B), indicating that the glycan (Figure 18E) on N145 of CTLA-4 is the epitope of W3162-1.146.19-z12-IgG1K (see pg. 44, lines 5-17). Therefore, WANG teaches a monoclonal antibody with selective binding affinity to glycosylated CTLA-4 relative to unglycosylated form of CTLA-4, thereby anticipating instant claim 1.
Regarding claim 2, WANG teaches the antibody of claim 1 (discussed above); WANG also shows that the selective binding affinity to glycosylated CTLA-4 relative to unglycosylated form was due to the N145 glycosylation site of CTLA-4 (also discussed above), thereby anticipating instant claim 2.
Regarding claim 3, WANG teaches the antibody of claim 1 (see above); said antibody displayed a binding affinity (KD) of 5.05 nM to glycosylated CTLA-4, falling within the range 0.1-10 nM, as recited in the first alternative limitation of instant claim 3. Claim 3 recites additional limitations in the alternative form (separated by “or”), several of which are indefinite (see rejections under 35 U.S.C. 112(b) detailed above). For all of these reasons, WANG anticipates instant claim 3.
Regarding claim 22, WANG teaches the antibody of claim 1 (see above); said antibody is defined as an IgG antibody (see all of example 2, where the antibodies are detected in various assays using anti-human IgG antibodies; see also the name of the antibody W3162-1.146.19-z12-IgG1K, which denotes it is an IgG1 antibody). Therefore, WANG anticipates instant claim 22.
Regarding claim 23, WANG teaches the antibody of claim 1 (see above); said antibody includes antibody fragments such as Fab, F(ab')2, Fv, scFv, Fd, dAb, and other antibody fragments that retain antigen-binding function, i.e., the ability to bind CTLA-4 specifically (pg. 18, line 26 through pg. 19, line 5). Therefore, WANG anticipates instant claim 23.
Regarding claim 24, WANG teaches the antibody of claim 1 (see above); said antibody being a humanized antibody (e.g., see example 4; see claim 18). Therefore, WANG anticipates instant claim 24.
Regarding claim 25, WANG teaches the antibody of claim 1 (see above); said antibody was also taught by WANG to be used in an immunoconjugate linked to a therapeutic agent (e.g., claim 28). Therefore, WANG anticipates instant claim 25.
Regarding claim 26, WANG teaches the antibody of claim 1 (see above); said antibody or antibody conjugate being combined with a pharmaceutically acceptable excipient, diluent and carrier as part of a pharmaceutical composition (e.g., claim 29). Therefore, WANG anticipates instant claim 26.
Conclusion
15. An isolated monoclonal antibody which selectively binds to glycosylated CTLA-4 relative to unglycosylated form of CTLA-4, wherein the VH domain has an amino acid sequence of SEQ ID NO: 3 and the VL has an amino acid sequence of SEQ ID NO: 5, as recited in claim 8, appears to be free of prior art. However, this claim is objected to for being dependent on a rejected independent claim, claim 1.
16. No claim is allowed.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES L MCLELLAN whose telephone number is (703)756-1906. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm. *Compressed day off on first Friday of each Bi-week.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at (571) 272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAMES LYLE MCLELLAN/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
