DETAILED 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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on January 30, 2026 has been entered.
Application Status
The amended claims filed on January 30, 2026 are entered. Claims 52-53, 55-57, 59-61, 63-65, and 67-68 are pending. Claims 52, 56, 60, and 64 have been amended. Claims 64-65 and 67-68 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 52-53, 55-57, 59-61, and 63 are under examination herein.
It is noted that an accepted Power of Attorney is not on record for the instant application.
Claim Rejections Withdrawn
The rejection of claims 52, 56, and 60 under 35 U.S.C. § 102 as being anticipated by Schneider (U.S. Patent No. 8,496,937) is withdrawn in view of Applicant's claim amendments reciting a VH having “at least 85% sequence identity” to the amino acid sequence of SEQ ID NO: 168.
The rejection of claims 51, 55-56, 59-60, and 63 under 35 U.S.C. 103 as being unpatentable over Schneider (U.S. Patent No. 8,496,937) as applied to claims 52, 56, and 60, further in view of Crescioli (Current Allergy & Asthma Reports (2016) 16: 7) is withdrawn in view of Applicant's claim amendments reciting a VH having “at least 85% sequence identity” to the amino acid sequence of SEQ ID NO: 168.
NEW CLAIM REJECTIONS NECESSITATED BY CLAIM AMENDMENT
Claim Rejections - 35 USC § 102
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.
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.
Claims 52, 56, and 60 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Torgov (US 2016/0015828 A1).
Torgov teaches antibody-drug conjugates comprising antibodies specific for Delta-like ligand 3 (DLL3) (e.g., Abstract; ¶ 0015-0026; claims 1-9). Torgov discloses an ADC comprising an anti-DLL3 antibody or immunoreactive fragment comprising a VH having the amino acid sequence of SEQ ID NO: 75 (which shares 87.3% sequence identity to instant SEQ ID NO: 168) and a VL having the amino acid sequence of SEQ ID NO: 121 (which shares 86.3% sequence identity to instant SEQ ID NO: 176) (e.g., ¶ 0029; claim 9), anticipating claim 52. See respective alignments between the instantly claimed sequences (Qy) and those of Torgov (Db) below.
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Torgov further provides for nucleic acid molecules that encode the antibodies of the invention as well as whole cells comprising the same (e.g., ¶ 0144-0156), anticipating claims 56 and 60.
Claim Rejections - 35 USC § 103
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.
(1)
Claims 52, 55-56, 59-60, and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Torgov (US 2016/0015828 A1; supra) as applied to claims 52, 56, and 60 above, further in view of Crescioli (Current Allergy & Asthma Reports (2016) 16: 7; cited in PTO-982 mailed July 31, 2025).
The teachings of Torgov are recited in the 35 U.S.C. § 102 rejection above. In addition, Torgov teaches that the anti-DLL3 antibodies of the invention may comprise an antibody heavy chain comprising an IgG4 heavy chain (e.g., ¶ 0105, 0149).
However, Torgov does not expressly teach that the anti-DLL3 antibodies of the invention comprise a human IgG4 heavy chain constant region sequence comprising the substitution S228P (numbered according to EU numbering).
Crescioli teaches that Fab-arm exchange (FAE) is a process unique to IgG4 antibody molecules in which two IgG4 molecules exchange a heavy chain-light chain unit with an IgG4 molecule of a different specificity to form a new bispecific IgG4 entity (e.g., page 4). Crescioli teaches that two structural features of IgG4, specifically the core hinge sequence at residues 226-229 (which comprises a “CPSC” sequence motif) and the CH3-CH3 domain interface at residue 409, are responsible for the ability of IgG4 molecules to undergo FAE (e.g., page 4; Figure 1a). By contrast, the IgG1 core hinge comprises a CPPC sequence motif at residues 226-229 and does not undergo FAE (e.g., page 4). Crescioli discloses that the S228P mutation in IgG4 renders the IgG4 core hinge more IgG1-like and diminishes FAE in vitro and in vivo (e.g., page 4; page 8). Crescioli notes that IgG4 is a preferential subclass in the design of therapeutic antibodies when the recruitment of immune cells is undesired or unnecessary, and that incorporating the S228P mutation into IgG4 could be a design consideration to prevent therapeutic IgG4 antibodies from undergoing FAE with endogenous IgG4 antibodies (e.g., page 8).
Based on the further teachings of Crescioli, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the anti-DLL3 IgG4 antibody taught by Torgov to incorporate an S228P mutation in the heavy chain constant region. The skilled artisan would have been motivated to do so because Crescioli teaches that IgG4 antibodies can participate in FAE due in part to a CPSC sequence motif in the core hinge region, and the mutation of S228P renders the hinge more IgG1-like and minimizes the chance that the therapeutic IgG4 antibody would undergo FAE with an endogenous IgG4 antibody. There would have been a reasonable expectation of success because incorporating the substitution of S228P (according to EU numbering) into the IgG4 heavy chain would constitute applying a known technique to a known product ready for improvement to yield a predictable result.
(2)
Claims 52, 56, and 60 are rejected under 35 U.S.C. 103 as being unpatentable over Schneider (U.S. Patent No. 8,496,937; cited in PTO-892 mailed July 31, 2025) in view of Lombana (Scientific Reports (2015) 5: Article 17488).
Schneider describes preparations containing isolated agonist anti-ectodysplasin isoform A1 (Eda-A1) receptor (EDAR) monoclonal antibodies and antigen-binding fragments thereof (e.g., Abstract). Relevant to claim 52, Schneider discloses anti-EDAR antibodies comprising the complex of a VH amino acid sequence of SEQ ID NO: 170 (which shares 81.7% sequence identity to instant SEQ ID NO: 168) and a VL amino acid sequence of SEQ ID NO: 187 (which shares 94.4% sequence identity to instant SEQ ID NO: 176) (e.g., col 25-26, 43-44). See respective sequence alignments below:
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Schneider further describes isolated nucleic acids encoding an isolated anti-EDAR antibody or antigen-binding fragment thereof of the invention as well as host cells comprising an expression vector comprising the same (e.g., col 5), relevant to claims 56 and 60.
However, Schneider does not describe an anti-EDAR antibody complex wherein the VH comprises an amino acid sequence having at least 85% sequence identity to instant SEQ ID NO: 168.
Lombana describes using a Bacterial Antibody Display (BAD) system to screen antibodies for variants that influence antibody expression and thermostability to improve yields for bringing therapeutics to the clinic (e.g., Abstract). Lombana teaches that several approaches have been used to increase antibody yields in Escherichia coli, including saturation mutagenesis of select positions in the antibody sequence. However, this approach increases the risk of introducing immunogenic sequences because the resulting amino acid changes are not found in the natural repertoire of antibodies (Introduction, page 1). Accordingly, Lombana investigated natural antibody diversity within a subgroup that occurs during the natural process of somatic hypermutation, since these changes are structurally desired and tolerated by the immune system (Introduction, page 1). Lombana focused on framework region variants for two therapeutically relevant antibodies against IL-13 and VEGF to maintain antibody affinity via the CDRs, concentrating on buried but not surface exposed residues of the framework regions (Introduction, page 2; Results, page 6). After demonstrating that better expressing antibodies are enriched using the BAD system (Results, pages 4-5; Figure 3), Lombana performed a BAD screen using 33 individual framework variants of an anti-IL-13 half-antibody (5 light chain variants, 28 heavy chain variants). The results illustrated that the IL-13 framework variants showed increased binding to IL-13 antigen, and several variants displayed increased functional expression and thermal stability relative to anti-IL-13 wildtype (WT) antibody (Results, pages 5-7; Figure 4). The highest expressing functional variants from E. coli also showed expression gains in a mammalian expression system, albeit to a slightly lesser extent than in E. coli (Results, page 7; Figure 4). Combining selected variants also had an additive effect on functional expression and thermal stability (Results, page 7; Figure 4). Lombana extended their analysis to an anti-VEGF.3 antibody derived from a different germline, analyzing 47 light chain framework variants and 36 heavy chain framework variants, and similarly showed that the variants had increased binding to VEGF relative to WT anti-VEGF antibody and conferred increasing functional expression in E. coli, and that high-expressing variants had improved thermostability (Results, pages 7-9; Figure 5). Double variants also displayed additive improvement of functional expression, and all variants showed improved protein stability relative to wildtype (Results, page 9; Figure 5).
Based on the further teachings of Lombana, it would have been obvious for one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at an anti-EDAR antibody complex comprising a VH having at least 85% sequence identity to the amino acid sequence of instant SEQ ID NO: 168 through the process of routine optimization. The skilled artisan would have been led to do so because modifying residues within the framework region of the antibody, particularly within non-surface exposed regions, can confer increased functional expression in a host system and improved thermal stability while also increasing affinity of the antibody for its target antigen and minimizing antibody immunogenicity, as demonstrated by Lombana. These qualities are useful for scaling up commercial production and increasing antibody formulation stability. There would have been a reasonable expectation of success because Lombana demonstrates that antibody framework residues (alone or in combination) identified during somatic hypermutation can be modified, while the CDR residues remain unchanged, to augment expression of the antibodies in a bacterial or mammalian host and improve their thermal stability.
(3)
Claims 52, 55-56, 59-60, and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Schneider (U.S. Patent No. 8,496,937; supra) in view of Lombana (Scientific Reports (2015) 5: Article 17488; supra) as applied to claims 52, 56, and 60 above, further in view of Crescioli (Current Allergy & Asthma Reports (2016) 16: 7; cited in PTO-982 mailed July 31, 2025).
The teachings of Schneider are recited in the 35 U.S.C. § 103 rejection above. In addition, Schneider teaches that the agonistic anti-EDAR antibodies of the invention may comprise an antibody heavy chain comprising an IgG4 heavy chain or a mutated IgG4 sequence that no longer undergoes heavy chain swapping (e.g., col 25, 47).
However, Schneider does not expressly teach that the anti-EDAR antibody of the invention comprises a human IgG4 heavy chain constant region sequence comprising the substitution S228P (numbered according to EU numbering).
The teachings of Lombana and Crescioli are discussed above.
Based on the additional teachings of Crescioli, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the anti-EDAR monoclonal IgG4 antibody taught by Schneider to incorporate an S228P mutation in the heavy chain constant region. The skilled artisan would have been motivated to do so because Crescioli teaches that IgG4 antibodies can participate in FAE due in part to a CPSC sequence motif in the core hinge region, and the mutation of S228P renders the hinge more IgG1-like and minimizes the chance that the therapeutic IgG4 antibody would undergo FAE with an endogenous IgG4 antibody. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized the suitability of incorporating the S228P mutation into an IgG4 core hinge for the purpose of minimizing heavy chain swapping as desired by Schneider.
Allowable Subject Matter
Claims 53, 57, and 61 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643