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 .
Claim Status
Claim listing filed on December 2, 2025 is pending. Claims 1-20 are canceled. Claims 27-45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected species in the election made without traverse in the reply filed on December 4, 2024. Claims 21-26 and 46-47 are examined upon their merits.
Claim Rejections - 35 USC § 103 (Maintained)
The rejection of Claims 21, 23-24, and 46 under 35 U.S.C. 103 as being unpatentable over Burvenich et al., MAbs. 2016 (of record), and further in view of Bosques et al. US 2022/0153833 (of record) is maintained.
Applicant's arguments filed December 2, 2025 have been fully considered but they are not persuasive. Applicant argues that the “obvious-to-try” test requires that a person of ordinary skill (1) confronts a finite number of identified solutions, (2) that are predictable, and (3) pursues them with a reasonable expectation of success. Applicant argues that these criteria were not met because one of ordinary skill would not have had any clear or predetermined starting variant based on Burvenich, nor could the potential alternatives be regarded as well-characterized and previously known. The starting point taught by Burvenich is that the FcRn binding site on the Fc region of IgG1 contains I253, H310, and H435 (abstract, of record), and that only a single mutation in this binding site is sufficient to no longer detect binding to human FcRn (abstract, of record). Burvenich teaches that I253A, I253D, I253P, and H435A single mutations all abolish Fc binding to FcRn to the same extent that the double mutation combination I253A/H435A abolishes Fc binding to FcRn (Table 1 and Figure 2, of record). Therefore, it is obvious that single mutations that disrupt FcRn binding can be combined into a double mutant that has the same function. Burvenich teaches three I253 mutations that disrupt FcRn binding (I253A, I253D, I253P) and three H435 mutations that disrupt FcRn binding (H435A, H435Q, H435R) (Table 1; Fig. 2; pg 782, paragraphs 3 and 4; of record). Therefore, there are 16 possible I253 mutations and 16 possible H435 mutations not taught by Burvenich, and evaluating 32 finite single mutations is well within the number that is reasonable to try according to Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 82 USPQ2d 1321 (Fed. Cir. 2007) (MPEP § 2143.1.E). Further, from the teachings of Burvenich, there is a reasonable expectation of success that any amino acid substitution at these residues will disrupt the binding pocket and decrease affinity of Fc to FcRn. The teachings of Bosques support this expectation of success by teaching that I253 can be substituted with any natural amino acid or non-natural amino acid to decrease the binding of a modified Fc domain to FcRn. One of ordinary skill could make the mutations at I253 and H435 in Fc and evaluate Fc binding to FcRn using methods standard in the art prior to the time of filing. Thus, all three criteria of the obvious-to-try test as listed above (1-3) are met.
Applicant argues that varying an amino acid at I253 and varying an amino acid at A435 results in 19 x 19 = 361 possible variants to evaluate which is significantly more than is obvious to try. This logic is on the basis that combining different I253 mutations with different H435 mutations into a double mutant may cause Fc to bind to FcRn in a significantly different manner than the single mutants do on their own. On the contrary, Burvenich teaches that a double mutant comprising two single mutations that each disrupt FcRn binding is expected to also disrupt FcRn binding to the same extent. Therefore, one of ordinary skill would understand that it is unnecessary to evaluate 361 possible double mutants when the functional activity of the single mutants is an accurate indicator of double mutant function (i.e. it is obvious to combine two single mutants that disrupt FcRn binding to form a double mutant that disrupts FcRn binding).
Applicant argues that the present case aligns with the case law of Takeda v. Alphapharm as taught in MPEP § 2143.1.E wherein the Federal Circuit found that the claimed invention was not obvious because there was no finite number of identified, predictable solutions to the recognized need, and no reasonable expectation of success. Examiner disagrees that the instant scenario aligns with Takeda v. Alphapharm because the teachings of Burvenich and Bosques do direct one of ordinary skill to a finite number of FcRn binding pocket residues wherein a finite number of amino acid substitutions can be made to disrupt Fc binding to FcRn with a reasonable expectation of success. The expectation of success is specifically supported by different I253 amino acid substitutions ablating FcRn binding to the same extent (Burvenich Fig. 2 and Table 1, of record) which shows that the binding disruption is robust to variation in amino acid substitutions.
Applicant argues that the teachings of Bosques are not enabled because Bosques teaches all 20 canonical amino acid substitutions at I253 without constructing and testing any of the variants. Examiner relies on Bosques to teach the understanding in the art that any amino acid substitution could be made at I253 (19 finite substitutions) to disrupt FcRn binding and alter half-life with a reasonable expectation of success. The teachings of Bosques as relied upon in the obvious-to-try rationale are not required to provide absolute predictability by constructing and evaluating every I253 variant. As supported by MPEP § 2145, absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. Applicant’s arguments are not persuasive, and the rejection is maintained.
The rejection of Claims 22 and 25 under 35 U.S.C. 103 as being unpatentable over Burvenich et al., MAbs. 2016 (of record) in view of Bosques et al. US 2022/0153833 (of record) as applied to Claims 21, 23-24, and 46 above, and further in view of Campbell et al. WO 2017/220990 (of record) is maintained.
Applicant's arguments filed December 2, 2025 have been fully considered but they are not persuasive. Applicant argues that the working examples of Campbell consistently describe IL-2 fusions to anti-PD-L1 antibodies and generically list other cytokines such as IL-12 with no reasoning why IL-12 would function equivalently to IL-2 in that context. One of ordinary skill would understand that IL-2 and IL-12 are both proinflammatory cytokines that enhance anti-tumor immunity which is why Campbell teaches immunocytokines comprising an anti-PD-L1 antibody fused to a cytokine (abstract, of record). The anti-PD-L1 antibody enables the immune system to recognize and eliminate cancer cells, and the cytokine (IL-2 or IL-12) promotes the anti-cancer immune response.
Applicant argues that Burvenich/Bosques teach reducing FcRn binding to alter serum half-life wherein Campbell teaches the opposite effect - employing Fc mutations to increase FcRn binding and prolong half-life. Campbell teaches that the antibodies can be modified “to increase or decrease serum half-life” (page 88, lines 1-2; emphasis added). Campbell goes on to teach that in some embodiments biological half-life can be increased, and in other embodiments the Fc region is mutated to decrease the biological half-life (page 88, lines 1-10). One of ordinary skill would understand that it can be advantageous to increase half-life or decrease half-life depending on the therapeutic context. Decreasing half-life can be advantageous to manage toxicity and allows for precise control of the therapeutic window. Note, new sections of Campbell are cited solely in reply to Applicant’s arguments and not as a new grounds of rejection. Applicant’s arguments are not persuasive, and the rejection is maintained.
The rejection of Claims 26 and 47 under 35 U.S.C. 103 as being unpatentable over Burvenich et al., MAbs. 2016 (of record) in view of Bosques et al. US 2022/0153833 (of record) as applied to Claims 21, 23-24, and 46 above, and further in view of Marasco et al. US 2017/0290911 (of record), Vidarsson et al. Front. Immunol. 2014 (of record), and Ghetie et al. Annu Rev Immunol. 2000 (of record) is maintained.
Applicant's arguments filed December 2, 2025 have been fully considered but they are not persuasive. Applicant argues that even though FcRn-binding residues are conserved among IgG subclasses, conservation alone does not create predictability for complex receptor-binding behavior. One of ordinary skill would understand that structure dictates function, and because the FcRn binding pocket of Fc is structurally and functionally conserved between IgG1 and IgG4, mutations made to the FcRn binding pocket of IgG1 can be made in IgG4 with a reasonable expectation of success.
Applicant argues that the references provide no data that the I253N and H435Q mutations would produce the same quantitative effect in IgG4, particularly in combination with S228P, which is an argument that a reasonable expectation of success is insufficient and absolute predictability is required to be taught by the art. As stated above, absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient (MPEP § 2145). Applicant’s arguments are not persuasive, and the rejection is maintained.
Double Patenting (Maintained)
The provisional rejection of claims 21-24, 26, and 46-47 on the ground of nonstatutory double patenting as being unpatentable over claims 26-28, 30-32, 48, and 50 of copending U.S. App. No. 17/599,921 is maintained.
Applicant's arguments filed December 2, 2025 state that no action appears required as both cases are still pending and claim scope may change. Examiner agrees and maintains the rejection, because the most recently filed copending claims recite the same elements of the instant claims.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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 SARAH COOPER PATTERSON whose telephone number is (703)756-1991. The examiner can normally be reached Monday - Friday 8:00am - 5:00pm EST.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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