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. A request for continued examination under 37 CFR 1.114 was filed in this application after appeal to the Patent Trial and Appeal Board, but prior to a decision on the appeal. 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examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the appeal has been withdrawn pursuant to 37 CFR 1.114 and prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant’s submission filed on March 20, 2026 has been entered.
Claims 2, 3, 9, 16, 21, and 22 have been canceled.
Claims 1, 4-8, 10-15, and 17-20 are pending.
Claims 12, 13, 15, and 17-20 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on June 21, 2023.
Claims 1, 4-8, 10, 11, and 14 are currently under consideration as they read on the originally elected invention.
3. In view of applicant’s amendment, following rejections are set forth.
4. 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.
5. 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.
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.
6. Claims 1, 4-8, 10, 11, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Monet (WO 2016/177984, published on November 10, 2016) as evidenced by Monet (US 2018/0030111, the ‘111 application) in view of Chamberlain et al. (US 2007/0135620), Liu et al. (US 2014/0112926) and Isoda et al. (PLOS One, 2015, October 7, 10(10):e0140120.doi:1371/journal.pone.0140120, pages 1-17) for the reasons of record.
It is noted that Monet (WO 2016/177984) is in French. However, given that the ‘111 application is the national stage under 35 U.S.C. 371 of PCT international application PCT/FR2016/051068 that is published as Monet (WO 2016/177984), the ‘111 application is deemed to be the English translation of Monet (WO 2016/177984). Thus, the rejection is based on the content of the ’111 application.
The instant claims are drawn to a variant of human IgG1 G1m1 A3A-184AY polypeptide comprising amino acid sequence of SEQ ID NO:15. Amino acid sequence of SEQ ID NO:15 differs from the naturally occurring Fc of human IgG1 G1m1 allotype in six amino acid substitutions K334N, P352S, A378V, V397M, N434Y and Y296W (e.g. see pages 23-24 of the specification as-filed).
The ‘111 application teaches an Fc variant comprising at least one mutation selected from among K334N, P352S, A378V, V397M, 434S, and K290E (e.g. see [0009]). The ‘111 application discloses that the Fc variants exhibit increased binding affinity to at least one Fc receptor including FcγRIII (e.g. see [0103]). The Fc variants bank are constructed using Fc region (amino acids 226-447) from human IgG1 allotype G1m1.17 as the parent (e.g. see [0110]).
After several rounds of mutant bank selections, eighteen new variants of interest were constructed including A3A-184A consisting substitutions K334N, P352S, A378V, and V397M (e.g. see Table 2 in page 13).
The Fc variants of interest were then introduced into the Fc region of a human anti-CD20 antibody; CD20 is a tumor antigen (e.g. see [0142]). In Table 10, the ‘111 application discloses an Fc variant A3A-184A consisting of K334N, P352S, V397M, and A378V, see copy below:
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Note that variant A3A-184A is one of the two variants in Table 10 to exhibit over 30 readings in ADCC assay indicating strongest ADCC activity among the Fc variants disclosed in Table 10 of the ‘111 application.
The ’111 application further teaches a pharmaceutical composition comprising the Fc variant and at least one pharmaceutically acceptable excipient (e.g. see claim 62). The ‘111 application teaches that the parent human IgG1 can be G1m3 or G1M1.17, the two known human IgG1 allotypes (e.g. see [0154]). As such, the prior art parent IgG1 Fc would have the same sequences as the instantly claimed parent from which the recited SEQ ID NO:15 is made.
The teachings of the ‘111 application differ from the instant invention by not teaching additional substitution 434Y and Y296W.
Chamberlain teaches that the Fc variant N434Y has particularly strong binding to FcRn and that single variant N434Y has 16-fold increase in binding and combining N434Y with other mutations led to even stronger binding (e.g. see [0197]).
Liu et al. teaches an Fc-containing protein comprising a binding region and a variant Fc region from a wildtype Fc of human IgG1, wherein the variant Fc region comprises an amino acid substitution Y296W and wherein the Fc-containing protein binds tumor antigen such as HER-2/neu (e.g. see [0005]-[0008] and claims 53 and 59).
Liu et al. teach that the Fc-containing protein can be an antibody (e.g. see [0036]) or an Fc fusion protein (e.g. see [0037]). Liu et al. teach a pharmaceutical composition comprising the Fc-containing protein and a pharmaceutically acceptable carrier (e.g. see [0009] and claim 65).
Given that the prior art Fc-containing protein comprises the same amino acid substitution Y296W as the instantly claimed variant, the prior art Fc-containing protein would inherently exhibit the same functions, e.g. having an increased affinity for at least one FcγR including FcγRIIIa (CD16a) relative to the parent Fc.
Isoda et al. teach an anti-CD20 antibody comprising a human Fc region from IgG1, wherein the Fc region comprises amino acid substitution Y296W, and wherein the antibody exhibits increased binding to FcγRIIIa compared to the parent antibody without the Y296W substitution (e.g. see Abstract and Fig. 2 in page 8). CD20 is a well-known tumor antigen on B cell lymphoma (e.g. see Cell lines in page 2). Isoda et al. teach that he antibody Fc variant is in liquid composition together with buffers such as HBS which is considered carrier (e.g. see page 1st paragraph in page 4).
It would thus be obvious to one of ordinary skill in the art at the time the instant invention was filed to combine the teachings of the references to produce a human IgG Fc variant comprising K334N, P352S, V397M, A378V, N434Y, and Y296W for improved functions of the Fc region including increased binding affinity to FcγRIIIa and FcRn.
An ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, since amino acid substitution Y296W in the Fc region of human IgG was known to result in improved binding to FcγRIIIa as taught by Liu et al. and Isoda et al., and K334N, P352S, V397M, A378V, substitutions in the Fc region were shown to have improved binding to FcγRs as shown in the ‘111 application. Further, N434Y substitution in the Fc region is known to significantly improve the binding affinity to FcRn. As such, one skilled in the art could have combined Y296W and K334N, P352S, V397M, A378V, and N434Y substitutions by known methods of recombinant mutagenesis in the Fc region of human IgG with no change in their respective functions, and the combination would have yielded predictable results of an Fc variant comprising K334N, P352S, V397M, A378V, N434Y and Y296Wand have the function of improved binding to FcγRIIIa and FcRn.
Given that the prior art uses the same human IgG1 parent and mutated in the same positions with the same amino acid sequences as the instantly claimed Fc variant, the prior art Fc variant from the combined teachings of the references would inherently have the same amino acid sequence as the instantly claimed variant and the same function of relative affinity for FcRIIIa is increased by a ration at least equal to 2 compared to the parent polypeptide without the mutations.
Applicant’s arguments have been fully considered but have not been found persuasive.
Applicant argues that it has surprisingly found that het claimed Fc variants has increased affinity for all Fc receptors including FcγRI (CD64), FcγRIIIa (CD16a), and FcγRIIa (CD32a) relative to the parent polypeptide (in page 38) and the increase for FcγRIIIa by a ratio of at lease equal to 2 (in page 8, lines 18-22).
Applicant asserts that Monnet is applicant’s own earlier application and discloses variant A3A-184A with four mutations 334N, 353S, 378V, and 397M but no 434Y and 296W. In addition, applicant argues that Monnet does not teach the variant’s affinity to CD16a that is increased by a ration at least equal to 2 relative to the parent polypeptide.
Applicant argues Example 4 (pages 34-39) in the instant specification as-filed tested and compared the Fc variants and shows in Table 4 variant A3A-184EY_CHO (corresponding the claims on appeal) has an IC50 of 123 nM whereas the parent has IC50 of 282. As such, the recited Fc variant shows increased affinity for CD16a at least twice higher than the parent.
Applicant further points out that variant A3A-184AY-CHO without 296W substitution shows an IC50 of only 262 and asserts that the claimed variant further shows an increased affinity for CD16a at least twice higher than the variant A3A-184AY-CHO. Applicant asserts that these results are unexpected from the teachings of the prior art.
Applicant asserts that Chamberlain teaches 434Y mutation having improved binding to FcRn, but Chamberlain does not teach 434Y combined with the instantly recited mutations. Liu teaches 234Y/294L, 294Y or 298C/296W, but not the instant invention. Applicant asserts that Isoda teaches only mutation in position 296W but does not teach combining 296W with the mutations recited in the instant claims. Applicant argues there is no suggestion in the prior art for the unexpected and beneficial properties of the instant Fc variant.
Applicant further points to The Mondon declaration under 37 CFR 1.132 filed on September 9, 2024 for evidence of nonobviousness. The Mondon declaration has been fully addressed in the Office Action mailed on October 28, 2024.
Specifically, The Mondon declaration asserts that the primary reference Monnet only teaches mutant 334N/352S/378V/397M in Table 10 and mutants comprises these four substitutions and additional substitutions, e.g. 333G or 423Y in Table 11. Monet does not teach 434Y and 296W. As such, the Mondon declaration asserts that one of skill in the art would have no apparent reasons to modify Monet by adding N434Y and Y296W substitution and would not have a reasonable expectation of success in doing so and results in making applicant’s claimed variant A3A-184EY disclosed in Table 5 of the instant application.
The Mondon declaration cites Monnet et al. (Frontiers in Immunology 2021, Vol. 12, Article 728322 pages 1-18, reference on IDS), and states that in Table 1, it was shown that Y296W when combined with different mutations display different effects, for example, T5A-74A and T5A-74MA (differ from each other only by addition of Y296W) does not affect FcRn affinity and increased FcγRIIIa affinity only slightly. Similarly, A3A-184AY and A3A-184E (differ only by addition of Y296W) shows that FcRn affinity slightly decreased and FcγRIIIa affinity not significantly affected. The Mondon declaration also asserts that addition of N434Y substitution greatly improved FcRN binding but not significantly impacting FcγRIIIa binding. The Mondon declaration further asserts that the Chamberlain, Liu, and Isoda do not teach 334N/352S/378V/397M substitutions.
As such, applicant asserts that one of ordinary skill in the art would not have reasonably expect that the variant of Monnet when modified to include N434Y and Y296W mutations would exhibit the properties of A3A-184EY variant (consisting 334N, 352S, 378V, 397M. 434Y, and Y296W) would maintain the affinity for FcγRIIIa (CD16a).
Moreover, applicant argues that claims 4 and 5 are independently patentable because claim 4 further limits claim 1 by reciting the variants having an increased affinity for the FcRn receptor relative to that of the parent of a ratio at least equal to 2 and claim 5 recites that the variants having an increased affinity for at least one Fc receptor relative to that of the parent polypeptide of a ratio at least equal to 2.
As such, applicant asserts the rejection should be withdrawn.
This is not found persuasive for following reasons:
Contrary to applicant’s arguments against the references individually, note that One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. Where an applicant’s reply establishes that each of the applied references fails to teach a limitation and addresses the combined teachings and/or suggestions of the applied prior art, the reply as a whole does not attack the references individually as the phrase is used in Keller and reliance on Keller would not be appropriate. This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012). See MPEP 2145 IV.
Here, in contrast to the assertion made by the Mondon declaration, note that the question is not whether the references could be physically combined but whether the claimed inventions of the Fc variants comprising 334N/352S/378V/398M/434Y/296W is rendered obvious by the teachings of the prior art as a whole.
Contrary to applicant’s reliance on comparison of the instant Fc variant (with mutations 334N/352S/378V/397M/434Y/296W) to A3A-184AY (with mutations same mutations except 296W) wherein the instant Fc variant has better ADCC, note that the results of better ADCC activity is to be expected since mutation Y296W was shown to have increased binding to FcγRIIIa which correlates to enhanced ADCC activity as disclosed in Liu and Isoda. Each of the of the elements of the claims were taught by Monet except 434Y and 296W substitutions for enhanced effector functions such as ADCC.
The post filing date reference Monnet et al. (Frontiers in Immunology 2021, Vol. 12, Article 728322 pages 1-18, reference on IDS, cited by the Monnet Declaration) support that the combination substitutions are predictable. For example, Table 1 of the post filing date reference Monnet is copied below:
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Contrary to applicant’s arguments that adding N434Y to T5A-74A does not affect FcRn affinity and increased FcγRIIIa affinity only slightly, note that T5A-74A is not the variant as being claimed because it contains N315D and N361A (see copy of Table 1 above).
Consistent with the teachings of the prior art, K334N/P352S/A378V/V397M/N434Y improved the binding to FcRn compared to the wildtype or the same variant without N434Y. Adding Y296W/K334N/P352S/A378V/V397M improves its binding to FcγRIIIa compared to wild type or the variant without Y296W.
It was known in the art that the effector functions such as ADCC of the Fc variant can be further enhanced by Y296W substitution as disclosed in Liu and Isoda and by substitution 434Y to enhance FcRn binding as disclosed in Chamberlain.
Each of the of the elements of the claims were explicitly taught by Monet, Liu, and Isoda for enhanced effector functions such as enhanced binding to FcRn and ADCC.
Once again, the ‘111 application explicitly teaches human IgG1 Fc variant A3A-184A consisting of K334N/P352S/V397M/A378V exhibits increased binding to Fcγ receptors CD16aF (3.40), CD16aV (4.74), CD32aH (3.25), CD32aR (5.03) (e.g. see Table 2 in page 13), and enhanced ADCC activity (30.9) (e.g. in Table 10).
Chamberlain teaches that the Fc variant N434Y has particularly strong binding to FcRn and that single variant N434Y has 16-fold increase in binding and combining N434Y with other mutations led to even stronger binding (e.g. see [0197]).
Both Liu et al. and Isoda et al. teach Y296W substitution in the Fc region of human IgG1 antibodies increases the Fc’s affinity to FcγRIIIa (CD16a) relative to the parent Fc.
As such, one of ordinary skill in the art would be motivated to modify the Fc variant disclosed in Monet in view of Chamberlain, Liu and Isoda with a reasonable expectation of success, because the modification would enhance ADCC further and improve binding to FcRn. The combination would yield predictable results of an Fc variant comprises all six recited substitutions with enhanced ADCC function compare to the Fc variant disclosed in Monet without 434Y and 296W substitutions. All that is required is a reasonable expectation of success, not absolute predictability of success. See In re O’Farrell, 853 F.2d 894,903 (Fed. Cir. 1988).
Given that the properties of a compound cannot be separated from the compound, see In re Papesch, 315 F.2d 381,391 (CCPA 1963) (“a compound and all its properties are inseparable), the Fc variant resulted from the combined teachings of the prior art would have the same functions as the instantly recited polypeptide including those recited in instant claims 4 and 5, e.g. the affinity for FcRn or FcγRI and FcRIIa is increased by a ratio at least equal to 2 relative to the parent polypeptide. The mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979).
As such, applicant’s arguments have not been found persuasive.
7. Claims 1, 4-8, 10, 11, and 14 stand rejected under 35 U.S.C. 103 as being unpatentable over Monnet (WO 2016/177984, published on November 10, 2016) as evidenced by Monet (US 2018/0030111, the ‘111 application) in view of Chamberlain et al. (US 2007/0135620), Liu et al. (US 2014/0112926), Isoda (PLOS One, 2015, October 7, and Fontayne (US 2013/0122546) for the reasons of record.
The instant claims are drawn to a variant of human IgG1 G1m1 A3A-184AY polypeptide comprising amino acid sequence of SEQ ID NO:16. SEQ ID NO:16 corresponds to variant A3A-184EY (SEQ ID NO:15) with a signal peptide (SEQ ID NO:12) at the N-terminus (see pages 23-24 of the specification as-filed).
The teachings of Monnet as evidenced by the ‘111 application, Chamberlain, Liu, and Isoda have been discussed, above.
The reference teachings differ from the instant invention by not disclose a signal sequence encompassed by SEQ ID NO:16 as recited in claim 1.
Fontayne teaches a signal peptide for producing a recombinant polypeptide in an expression system. Specifically, Fontayne teaches signal peptide of SEQ ID NO:1 that is identical to the signal peptide in the N-terminal of the instant SEQ ID NO 16 (e.g. see [0049]). Fontayne teaches that the signal peptide is more advantageous in higher eukaryotic cell lines for recombinant polypeptide production such as antibody production (e.g. see [0072] and [0175]).
It would thus be obvious to one or ordinary skill in the art at the time the invention was filed to combine the teachings of the references to produce the IgG1 Fc variant disclosed in combined teachings of the ‘111 application, Chamberlain, Liu and Isoda using the signal peptide sequence disclosed in Fontayne. One of ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, since the ‘111 application and Chamberlain teach human IgG1 Fc variant with improved effector functions and Fontayne teaches signal peptide suitable for producing antibody in higher eukaryotic cell lines. As such, using the signal peptide to produce the human IgG1 Fc variant would be well within the skill of an ordinary artisan.
Applicant’s arguments and the Examiner’s rebuttal are essentially the same as above.
8. No claim is allowed.
9. All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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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/CHUN W DAHLE/Primary Examiner, Art Unit 1641