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 .
Status of the Claims/Application
Claims 1-43 and 48-55 are canceled. Claims 44-47 are currently amended. Claims 44-47 and 56-62 are currently pending and are under examination on the merits herein.
Priority
The instant application 18/052,131 filed on 11/02/2022 claims priority to US Provisional application 63/274,716 filed on 11/02/2021 and will be examined with an effective priority date of 11/02/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/11/2025 is acknowledged and is in compliance with the provisions of CFR 1.97. It has been considered by the examiner.
Withdrawn Rejections
Applicant’s amendments, see claims 44-47, filed 12/11/2025, with respect to the rejections of claims 44-62 under 35 USC 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new grounds of rejection is made in view of different interpretation of the previously applied references and newly found prior art references.
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.
Claims 44, 47 and 56-57are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. Fc-Engineering for Modulated Effector Functions-Improving Antibodies for Cancer Treatment. Antibodies (Basel). 2020 Nov 17;9(4):64, and further in view of EP2794658 B1 and Lesnik et al. Loop Grafting between Similar Local Environments for Fc-Silent Antibodies. J Chem Inf Model. 2020 Nov 23;60(11):5475-5486, herein further referred to as Liu, EP’658 and Lesnik respectively.
Regarding claim 44, Liu teaches that tislelizumab an hIgG4 anti-PD1 mAb having substitutions E233P/F234V/L235A/D265A/R409K (including F234V substitution) abrogated FcγR interactions (Liu pg. 18 para Sec. 5.4 para 2). Liu also teaches that durvalumab having triple mutations at L234F/L235E/P331S (including L235E substitution) also lost binding to all its FcγR (Liu pg. 19 para 1) and that the PD1:PD-L1 axis is of interest with regards to Fc-engineering for enhancing blockade to the PD1:PDL1 interaction without deletion of APC or PD-L1 expressing T cells (Liu pg. 18 Sec 5.4 para 3).
Liu does not specifically teach a combination of amino acid substitutions having D265G.
EP’658 teaches that an Fc variant with amino acid substitutions comprising D265G (E233P/L234V/L235A/ΔG236/D265G/A327Q/A330S), wherein the substitutions reduced its binding affinity to the Fc receptors, thereby reducing antibody directed cytotoxicity effector function (EP’658 pg. 19 para 0088 ln 39-42).
Lesnik teaches a method for reducing the immune effector functions of monoclonal antibodies wherein up 20 amino acids from a similar local environment was grafted as a method of substituting the amino acids. Lesnik teaches that this method reduces the immunogenicity and improves the stability of the variant antibody (Lesnik Abstract). Lesnik teaches Fc variants T3 and T4 having substitutions at D265G of a wild type IgG that has similar stability to the wild type IgG and lower affinity towards the FcγIIIa receptor in comparison to the S1 variant (D265A) that is widely known to have high Fc-silencing potential. Lesnik further teaches that the T4 variant was shown to be less immunogenic than the other variants or the wild type and that further experimentation can be carried out to demonstrate the new design approach (Lesnik pg. 5484 col 1 para 3- col 4 para 1).
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Liu in view of EP’658 and Lesnik with a reasonable degree of predictable success so as to use the substation of D265G instead of D265A in the amino acid substitution of Liu in order to reduce the immunogenicity and improve the stability of the Fc variant. As indicated by Liu, the PD1:PD-L1 axis is of interest for Fc engineering for enhancing blockade to the PD1:PDL1 interaction without deletion of APC or PD-L1 expressing T cells, and as illustrated by the example combination of Lesnik, the Fc variant comprising a substitution of D265G was shown to be less immunogenic and more stable that a D265A variant. Therefore, it would have been obvious for a skilled artisan to include a D265G substitution instead of the D265A in the Fc variant of Liu with a reasonable degree to predictable success that the claimed Fc variant comprising F234V/L235E/D265G targets the PD1:PD-L1 axis, thereby reducing its binding to the Fc receptors, reduce immunogenicity and improve its stability.
Regarding claim 47, and incorporating the analysis of claim 44 above, Liu teaches a substitution of a novel mutation P329G that was able to disrupt the interaction between hIgG and hFcγR (Liu pg. 16 paga 2), as well when in combination with other substitutions L234/L235A/P329G (LALA-PG), reduced the binding affinity to Fc gamma RIIB (Liu pg. 15 Tab 3).Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Liu and further in view of EP’658 and Lesnikwith a reasonable degree of predictable success use an amino acid substitution at position P329 in combination with the substitutions at F234V, L235E and D265G wherein the combination will reduce the binding to the Fc receptors. Therefore, a skilled artisan would have being able to perform routine experimentation and in view in view of the prior references to determine if such combination (F234V, L235E and D265G, P329G) teachings would reduce the Fc receptor binding affinity of the Fc variant.
Regarding claim 56 and 57, and incorporating the analysis of claim 44 above, Liu teaches that the exemplary antibody tislelizumab are hIgG4 having an S228P mutation in other to prevent F(ab) arm exchange (Liu pg. 18 para 5).
Claims 45 and 58-62 are rejected under 35 U.S.C. 103 as being unpatentable over Liu, EP’658 and Lesnik as applied to claim 44 above and further in view US 20090042291 A1 and Lund et al. Human Fc gamma RI and Fc gamma RII interact with distinct but overlapping sites on human IgG. J Immunol. 1991 Oct 15;147(8):2657-62, herein further referred to as US’291 and Lund respectively.
Regarding claim 45, and incorporating the analysis of claim 44 above, Liu teaches of combination substitution comprising G237A in an hIgG4 based design (V234A/G237A/P238S/H268A/V309L/A330S/P331S (IgG2c4d) mutations), that resulted in no detectable binding to any Fc receptors (Liu pg. 18 para 3).
US’291 teaches that substitutions at G237A reduces the binding affinity to FcγRI, FcγRIIaR and FcγRIIb (US’291 Fig. 49).
Lund teaches that human Fc gamma RI interacts with a site in the lower hinge of human IgG (residues 234-237) and that this interaction dictates Fc gamma RI-mediated superoxide generation. Lund further teaches that mutations at positions 234 and 237 resulted in the reductions in Fc gamma RII recognition and that deviation from the optimal motif 234-Leu-Leu-Gly-Gly-237 may then explain the human IgG subclass specificity profile for human Fc gamma RI and Fc gamma RII (Lund Abstract)
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Liu, EP’658 and Lesnik and further in view of US’291 and Lund with a reasonable degree of predictable success use an amino acid substitution at position G237A in combination with the substitutions at F234V, L235E and D265G wherein the combination will reduce the binding to the Fc receptors. As indicated by Lund the lower hinge region of the hIgG is critical for the interaction with the Fc gamma RI, and that substitutions on this region will showed reduction in the hIgG’s binding to the Fc receptors. Also, as indicated by US’291, G237A has been shown to reduce binding to Fc receptors. Furthermore, the hIgG4 example of Liu as indicated above comprising G237A substitution was able to reduce binding to Fc receptors. Therefore, a skilled artisan would have being able to perform routine experimentation by following the teaching of Liu, EP’658 and Lesnik in view of US’291 and Lund to determine if such combination comprising F234V/L235E/G237A/D265G would reduce the Fc receptor binding affinity of the Fc variant thereby improving the effectiveness of a PD1-PD-L1 antibody.
Regarding claims 58-61, and incorporating the analysis of claim 44 above, US’291 teaches that the invention can be an antibody comprising an isolated polypeptide (US’291 pg. 22 para 0189 ln 1-14). US’291 further teaches a nucleic acid encoding a polypeptide, a cell comprising the nucleic acid encoding and a method of culturing the cell for the production of the isolated polypeptide (US’291 pg. 43 para 0282).
Regarding claim 62, and incorporating the analysis of claim 44 above, US’291 teaches that the Fc variant may be used for therapeutic purposes for which the antibodies, Fc fusion proteins etc. maybe used (US’291 para 0332). US’291 further teaches that the isolated polypeptide can be administered or co-administered in an effective amount with one or more additional molecules comprising antibodies or Fcs that have therapeutic efficacy in treating of a disease or disorder such as cancer and autoimmune disease (US’291 pg. 51 para 0325 and 0332).
Claims 46 rejected under 35 U.S.C. 103 as being unpatentableover Liu, EP’658 and Lesnik as applied to claim 44 above and further in view of Vafa et al. An engineered Fc variant of an IgG eliminates all immune effector functions via structural perturbations. Methods. 2014 Jan 1;65(1):114-26, herein further referred to as Vafa.
Regarding claim 46, and incorporating the analysis of claim 44 above, Liu teaches of Fc modification comprising A330S and P331S on IgG2m4 and IgG2c4d wherein there the was no effector function compared to wild types and reduced or no binding affinity to Fc receptors compare to wild type (Liu pg. 15 Tab 3 and pg. 18 para 2-3).
Vafa teaches of IgG2 sigma and IgG2m4 with changes to (IgG4) that reduced binding to Fc receptors (Vafa Abstract). Vafa also teaches that the F-G loop (residues 324-332) of an rIgG2 sigma_Fc that contains changes A33oS and P331S had a conformational (Vafa pg. 123 para 4 and Fig. 10) change which potentially lead to loss of effector function (Vafa pg. 123 Sec. 3.8).
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of 5Liu, EP’658 and Lesnik and further in view of Vafa with a reasonable degree of predictable success use an amino acid substitutions at positions A330S and P331S in combination with the substitutions at F234V, L235E and D265G wherein the substitution A330S and P331S will create a conformational change in the hinge region that will effectuate a loss of reduced binding to the Fc receptor thereby effectuating a loss of effector function. Furthermore, amino acids substitutions A330S and P331S are commonly used in the art to reduce binding affinity of Fc variant antibodies as shown by Liu (Liu Tab. 3). Therefore, an ordinary artisan would have being able to perform routine experimentation using the substitutions in the combination (F234V, L235E, D265G, A330S, P331S) reduce the Fc receptor binding affinity of the Fc variant as claimed.
Response to Arguments
Applicant’s amendments, see claims 44-47, filed 12/11/2025, with respect to the rejections of claims 44-62 under 35 USC 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new grounds of rejection is made in view of different interpretation of the previously applied references and newly found prior art references.
Prior arts US’5600, Baudino andBorrok have been removed to simplify the rejections submitted on 09/17/2025.
Regarding the applicants argument that the substitution D265G as thought by US’291 increases the binding affinity to the Fc regions and therefore a skilled artisan would not have been motivated to make the D265G substitution. D265A is known to be the most potent substitution to reduce Fc receptor binding and as indicated by Lesnik, and that an Fc variant with combination of substitutions comprising D265G was shown reduce the binding affinity and immunogenicity of the Fc variant (Lesnik pg. 5484 col 1 para 3- col 4 para 1). The examiner agrees with the applicant that a single substitution D265G as indicated by US’291 only reduced the binding affinity of FcγRI and C1q (US’291 Tab. 41 variant 44), but does not teach the binding affinity of D265G in the substitution combination as claimed. Nonetheless, as shown by Lesnik, D265G in combination with other substitutions have been shown to reduce Fc receptor binding as well as better immunogenicity compare to D265A substitution.
Applicant further argues that a POSA would not have being motivated to use substitutions 234V and L235E because the other amino acid substitutions at position L234 and L235 showed better reduction in binding affinity to the Fc receptor (Remarks pg. para 2-3) than L234V and L235E. The examiner respectfully disagrees. Although L234V and L235E have been shown to have a higher binding affinity to fc receptors compared to the other amino acid substitutions at the same positions (234 and 235), these substitutions have also being shown to reduce binding to FcγRIIa and C1q (US’291 Tab. 41 variant 119) for L234V, and all the Fc receptors except FcγRIIIa for L235E (US’291 Tab. 41 variant 425). Also, L234V and L235E have been used in prior teachings in combination with other amino acid substitutions to reduce the Fc receptor binding affinity of the Fc variant antibody as thought by Lund (Lund Abstract). Furthermore, as evidenced by Liu’s F234V substitution was used in a combination for Tislelizumab (an hIgG4 anti-PD1 mAB) wherein the Fcγ interactions was abrogated (Liu pg. 18 Sec 5.4 para 2) and another anti-PD1 mAb, durvalumab wherein L235E was used in combination with L234F and P331S to reduce the Fc receptor binding of the antibody (Lui Tab. 2). Given that Liu teaches that both substitutions at L234V (F234V for an IgG4) and L235E have being used in combinations with other substitutions to reduce Fc receptor binding in an anti-PD1 mAb, a skilled artisan would have been motivated to practice routine optimization to use these substitutions in combination with other substitutions that have been characterized and known in the art to obtain a combination of substitutions that can reduce the binding affinity to the Fc receptors of an anti-PD1 mAb.
Regarding the applicant’s argument (Remarks pg. 8 para 1), that Liu teaches a combination of comprising D265A and not D265G, and that D265G will have a different effect in the combination to D265A and are not interchangeable. Also that the substitution at position 234 with phenylalanine (F) is different from the valine (V). Examination acknowledges these differences that substitutions D265A and D265G have in a combination and the argument as persuasive. Upon further consideration and new found art, Liu teaches a combination of that uses substitution F234V to reduce Fc receptor binding affinity (Liu pg. 18 Sec 5.4 para 2). Furthermore, as indicated in the rejection above EP’658 showed that D265G was used in a combination to reduce the Fc receptor binding affinity (EP’658 pg. 19 para 0088 ln 39-42). Therefore, a skilled artisan would have being motivated to use the D265G and F234V substitutions in a combination of substitutions for an anti-PD1 mAb to reduce the binding affinity of the antibody to its Fc receptors.
In regards to applicant’s argument that Baudino discloses D265A and Borrok teaches that a L235E substitution lacks thermostability (Remarks pg. 8 para 2), they are persuasive and therefore the rejection based on the analysis of the claim in view of Baudino and Borrok have been withdrawn. However, upon further consideration and newly found prior art, D265G and L235E have been shown to be used in combination with other substitutions in anti-PD1 mAb that reduced binding affinity to it Fc receptors.
Regarding the applicant’s argument that for the reasons stated (Remarks pg. 8 para 3) a skilled artisan would not have been motivated to use the amino acid substitutions F234V, L235E and D265G to reduce the binding affinity of the antibody to its Fc receptors. The examiner respectfully points out that “it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose...The idea of combining them flows logically from their having been individually taught in the prior art." (See MPEP 2144.06). Furthermore, a teaching, suggestion, or motivation to combine references that is found in the prior art is an appropriate rationale for determining obviousness. KSR, 550 U.S. at 418, 82 USPQ2d at 1396. However, it is just one of a number of valid rationales for doing so. (See MPEP 2143).
Regarding the applicants argument that applicant unexpectedly discovered that the combination F234V, L235E and D265G mutations significantly reduces Fc receptors affinity and thereby decrease Fc effector functions (Remarks pg. 8 para 4 – pg. 10), examiner respectfully disagrees. Although the specific combination of substitution does not appear to be present in the art, it is common for a skilled artisan to use different combinations in which either F234V (as in Liu pg. 18 Sec 5.4 para 2), L235E (as in Lui Tab. 2)and/or D256G (as in Lesnik pg. 5484 col 1 para 3- col 4 para 1) have been used in order to reduce the Fc receptor binding affinity. Therefore, a skilled artisan would have being motivated to using F234V, L235E and D265G substitutions to reduce the binding affinity of an anti-PD1 mAb with a predictable level of success given that all these substitutions have being used in order combinations. Furthermore, where there is a reason to modify or combine the prior art to achieve the claimed invention, the claims may be rejected as prima facie obvious provided there is also a reasonable expectation of success. The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. (See MPEP 2143.02).
Conclusion
No Claims 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 EMMANUEL LED YOUTCHOM PENDIE whose telephone number is (571)272-6313. The examiner can normally be reached Mon - Fri: 8AM - 5PM CST.
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/EMMANUEL LED YOUTCHOM PENDIE/ Examiner, Art Unit 1647
/JOANNE HAMA/ Supervisory Patent Examiner, Art Unit 1647