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
FORMAL MATTERS
The Office Action mailed October 29, 2025 is withdrawn in view of newly discovered reference(s) and restarts the period to respond.
Claim Status
Applicant’s amendment filed February 26, 2026 has been received and entered.
Claims 11-12, 15, and 18 have been amended.
Claims 1-2, 14, 17, and 19 were previously canceled.
Claims 3-13, 15-16, 18, and 20-25 are pending and under consideration.
Election/Restrictions
Applicant is reminded that claims 3-10 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 September 29, 2025.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Claims 11-13, 15-16, 18, and 20-25 are under examination.
Priority
This application is a 371 of PCT/IL2021/050100 filed on January 28, 2021, which claims the benefit of Foreign Application ISRAEL 272389 filed on January 30, 2020.
Claim Objections
Claims 11, 18, and 23 are objected to because of the following informalities:
Claim 11 (line 3) - remove the space between “95” and the percentage symbol (%).
Claim 11 (line 4) - should read “complementarity”.
Claim 11 (lines 6-7) - should read “N-terminus to C-terminus orientation”.
Claim 18 (lines 2-3) - should read “a therapeutically effective amount of a binding moiety of the antibody…”.
Claim 23 (line 2) - should read “cis-acting”.
Appropriate correction is required.
Claim Rejections
In view of the Applicant’s claim amendments, the previous grounds of rejection are withdrawn. The following are new grounds of rejection made after additional search and further consideration. However, Applicant’s arguments relevant to the new grounds of rejection will be addressed below.
Claim Rejections - 35 USC § 112(b)
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.
Claim 12 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 12 recites the antibody comprises at least one amino acid substitution selected from S238D, S239D, 1332E, A330L, S298A, E33A, L334A, G236A, and L235V.
It is unclear whether the recited E33A substitution is correct, or if it should read E333A? Although the instant specification also recites E33A, the substitutions recited in claim 11 are listed in chronological order, except for E33A, making it unclear if it is a typographical error or if it is the intended substitution. If E33A is correct, Applicant is advised to make said substitution the first listed so all are in the correct chronological order.
Appropriate correction is required.
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.
Claims 11-12, 16, 18, and 20-25 are rejected under 35 U.S.C. 103 as being unpatentable over Lazar et al. (PNAS, 2006; 103(11):4005-4010) (“Lazar”), as evidenced by Addgene Vector Database (Plasmid: pcDNA3.1/Zeo(+); https://www.addgene.org/vector-database/2110/, accessed 29 May 2026) (“Addgene”), Herceptin Product Insert (2003), and FDA Rituxan Labeling (2019).
The instant claims are drawn to an anti PD-L1 antibody comprising an of a human IgG1 isotype Fc region with at least 95% identity to SEQ ID NO: 2, comprising heavy chain complementarity determining regions as set forth in SEQ ID NOs: 18-20 and light chain complementarity determining regions as set forth in SEQ ID NOs: 21-23, wherein the Fc region comprises at least one mutation and/or modification, which specifically enhances binding affinity of said Fc region to human FcgRIIA and/or FcgRIIIA as compared to the wild type Fc region, wherein said mutation is selected from the group consisting of S239D, I332E, A330L, S298A, E33A, L334A, G236A and L235V according to EU nomenclature. The antibody is for treating cancer, inflammatory disease or infectious disease in a subject, wherein the cancer is a solid tumor cancer, comprising administering a therapeutically effective amount of a binding moiety of the antibody which binds a cancer antigen. Further claimed is an isolated polynucleotide comprising a nucleic acid sequence encoding the antibody, a cis-acting regulatory sequence for driving expression of said nucleic acid sequence, a cell comprising the nucleic acid construct, and methods for producing the antibody comprising culturing the cells in a cell culture under conditions which allow expression of said antibody, and recovering the antibody from said cell culture.
Lazar teaches methods for enhancing the antitumor potency of monoclonal antibodies (mAbs) through enhancement of their ability to mediate cellular cytotoxic effector functions such as antibody dependent cell-mediated cytotoxicity (ADCC). Lazar used a combination of computational structure-based protein design methods coupled with high-throughput protein screening to optimize the FcgR binding capacity of IgG1 mAbs [Introduction].
Lazar constructed variants of the anti-CD52 antibody alemtuzumab, which were expressed and purified, and screened for FcgR affinity. Variants comprising single mutants S239D and I332E and double and triple mutants S239D/I332E and S239D/I332E/A330L (EU numbering) demonstrate significant enhancements in binding affinity to human FcgRIIIa (instant claims 11 (partial), 12 The same increase in binding affinity was observed when Lazar made the same mutations in the anti-HER2 antibody trastuzumab, the anti-CD20 Ab rituximab, the anti-EGFR Ab cetuximab, and all other antibodies tested [Results, pg 4005-4006].
Lazar also measured the binding affinity of the trastuzumab Fc variants to the inhibitory receptor FcgRIIb finding that a combination of the A330L mutation with S239D/I332E provides increased FcgRIIIa affinity and reduced FcgRIIb affinity relative to the double variant, resulting in a significant improvement of the effector function [Results, pg. 4006] (instant claim 20).
Lazar further teaches that the trastuzumab, alemtuzumab, rituximab Fc variants demonstrated a substantial enhancement (between 2 and 3 logs) in ADCC activity over the wild-type antibodies when administered to human Her2+ breast cancer cells. Comparable enhancements in ADCC were observed in all other antibodies tested. Furthermore, enhancements in the ADCC activity of the trastuzumab S239D/I332E and S239D/I332E/A330L variant antibodies were even observed against cell lines expressing low levels of Her2, showing the enhancement is independent of antigen expression levels. Additionally, Lazar teaches that the triple trastuzumab and rituximab have enhanced ADCP and CDC activity [Results, pg. 4007].
Lastly, Lazar carried out B cell depletion experiments by administering the rituximab variants in a macaque immune system model, finding that the S239D/I332E variant had a significant increase in potency relative to WT rituximab, consistent with its enhanced receptor affinity and ADCC in vitro supporting its use in clinical trials against B cell malignancies [Discussion, pg. 4009] (instant claims 16, 18, 21).
Lazar teaches the mAb Fc variants are applicable to the entire patient population, with improvements in effector function and greater killing capacity at lower antigen expression levels resulting in promising implications for mAb therapy including expanding the population of patients responsive to treatment. Further, Lazar notes that the ability of an antibody to inhibit growth or signaling is not a requisite for success. Rather, the ability to inhibit tumor growth is dependent on the antibody’s engagement with the immune system through FcgR [Discussion, pg. 4009].
Lazar teaches the variable light and heavy chain genes for alemtuzumab, trastuzumab, and rituximab were constructed by using recursive PCR, and the genes were ligated into the vector pcDNA3.1Zeo (instant claims 22-23). Light and heavy chain encoding plasmids were prepared and cotransfected into 293T cells, and the subsequent expressed antibodies were harvested from the media and purified using protein A affinity chromatography [see attached: Supporting Text; Construction of Ab Variants] (instant claims 24-25).
Lazar does not explicitly teach that the plasmid pcDNA3.1Zeo comprises a cis-acting promoter.
However, Addgene teaches the commercially available plasmid pcDNA3.1Zeo+ comprises a CMV promoter, which is a cis-acting promoter that drives expression [see Addgene Vector Database - pcDNA3.1Zeo].
Trastuzumab is also known as Herceptin, and is indicated for use in treating HER2+ cancers such as breast cancer, which is a solid tumor cancer [see Herceptin Labeling, 2003].
Rituximab is also known as Rituxan, and is indicated for use in treating specific blood cancers (e.g. NHL, CLL) and autoimmune diseases ( e.g. rheumatoid arthritis) by depletion of harmful CD20-positive cells [see FDA Rituxan Labeling, 2019].
The teachings of Lazar differ from the present invention in that although S239D/I332E and S239D/I332E/A330L mutations in the Fc region of several human IgG1 monoclonal antibodies that confer enhanced binding to human FcgRIIIA resulting in improved ADCC activity over their wild-type counterparts is taught, the antibodies are not explicitly taught as being anti-PD-L1 antibodies such as avelumab comprising the CDRs recited in instant claim 11. Given that Lazar teaches the Fc mutations confer the same enhanced FcgRIIIA binding resulting in improved ADCC, ADCP, and CDC activities in all antibodies tested, one of ordinary skill in the art would have more than a reasonable expectation of success that making the same mutations in the Fc region of any IgG1 monoclonal antibody, including avelumab, would result in improved ADCC, ADCP, and CDC activities over the wild-type antibody. Lazar teaches these Fc mutations and subsequent enhancements to anti-tumor activity are independent of antigen target or expression levels, which makes it irrelevant to which monoclonal IgG antibody such Fc mutations are applied. Therefore, the invention as a whole was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Claims 13 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Lazar et al. (PNAS, 2006; 103(11):4005-4010) (“Lazar”) as applied to claims 11-12, 16, 18, and 20-25 above, in further view of Richards (Mol Can Ther, 2008; 7(8):2517-2527) (“Richards”).
The instant claims are drawn to an anti PD-L1 antibody comprising an of a human IgG1 isotype Fc region with at least 95% identity to SEQ ID NO: 2, comprising heavy chain complementarity determining regions as set forth in SEQ ID NOs: 18-20 and light chain complementarity determining regions as set forth in SEQ ID NOs: 21-23, wherein the Fc region comprises at least one mutation and/or modification, which specifically enhances binding affinity of said Fc region to human FcgRIIA and/or FcgRIIIA as compared to the wild type Fc region, wherein the modification is afucosylation or wherein said at least one mutation comprises G236A/S239D/A330L/I332E. The antibody is for treating cancer, inflammatory disease or infectious disease in a subject, wherein the cancer is a solid tumor cancer.
The teachings of Lazar are set forth above.
Lazar teaches a triple S239D/A330L/I332E mutation, but does not teach a quadruple G236A/S239D/A330L/I332E mutation in the Fc region of an IgG1 monoclonal antibody.
Richards teaches engineered Fc variants with diverse FcgR affinities, including a novel substitution G236A that provides selectively enhanced binding to FcgRIIa relative to FcgRIIb. Variants containing this substitution have up to 70-fold greater FcgRIIa affinity and 15-fold improvement in FcgRIIa/FcgRIIb ratio and mediate enhanced phagocytosis of antibody-coated target cells by macrophages. Specific double and triple combination variants with this substitution are simultaneously capable of exhibiting high NK-mediated ADCC and high macrophage phagocytosis. Richards teaches these enhancements can improve the performance of therapeutic antibodies targeting cancers [Abstract].
Richards combined the G236A mutation with I332E and S239D/I332E in the context of an anti-EpCAM antibody to generate additional Fc variants I332E/G236A and S239D/I332E/G236A (instant claim 13 (partial)). Richards teaches the G236A variant exhibits a marked enhancement in response and a slower off-rate relative to native IgG1. Addition of the G236A mutation to I332E and S239D/I332E imparts its unique profile to these variants, i.e. binding of I332E/G236A and S239D/I332E/G236A to FcgRIIa, and the ratios of FcgRIIa to FcgRIIb affinities are enhanced relative to the single and double variants, respectively [Results, pg. 2519].
Additionally, Richards teaches an afucosylated version of the IgG1 anti-EpCAM antibody, wherein removal to fucose from the complex carbohydrate attached at N297 improves binding only to FcgRIIa (instant claim 15). The ADCC for the afucosylated antibody and the I332E/G236A and S239D/I332E double mutants was correlated with their FcgRIIIa affinity.
It would have been obvious to one of ordinary skill in the art before the effective filing date to combine the methods of Lazar that teach an S239D/I332E/A330L triple mutant with enhanced binding to human FcgRIIIa with those of Richards that teach the addition of G236A mutation in the S239D/I332E variant (S239D/I332E/G236A) resulted in 70-fold greater FcgRIIa affinity and 15-fold improvement in FcgRIIa/FcgRIIb. One would have a reasonable expectation of success in engineering an IgG1 variant comprising a combination of the mutations taught by Lazar and Richards to generate S239D/I332E/A330L/G236A variant having enhanced affinity for FcgRIIa and FcgRIIIa, from addition of G236A and A330L, respectively, to the S239D/I332E double mutant. A skilled artisan would also have a reasonable expectation of success in increasing the affinity of an IgG1 monoclonal antibody by afucosylation at N297 as evidenced by Richards that teaches afucosylation increased binding specifically to FcgRIIa. Having such Fc engineering capabilities will allow the optimal flexibility to target various cancers. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of the combined references.
Response to Arguments
Applicant argues in the reply received February 26, 2026 that it would not be obvious to make one or more mutations in the Fc region of the anti-PD-L1 antibody avelumab in order to enhance the binding activity to FcgRIIa and/or FcgRIIIa as presently claimed.
Applicant’s arguments were fully considered but were not deemed persuasive.
As taught by Lazar, the antibody target is irrelevant. Lazar teaches that every monoclonal antibody tested that had the triple S239D/I332E/A330L mutation in the Fc region had enhanced FcgRIIa binding, providing evidence that the Fc region mediates anti-tumor activity independently from antigen expression or specificity. Therefore, it would be obvious to make the recited Fc mutations in any IgG1 monoclonal antibody, including avelumab, if one wanted to increase binding to FcgRIIa.
Conclusion
No claim is allowed.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1644
/SAMIRA J JEAN-LOUIS/ Supervisory Patent Examiner, Art Unit 1642
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