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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 September 5, 2025 has been entered.
Claim Status
Claim listing filed on September 5, 2025 is pending. Claims 1-25, 40, and 43 are canceled. Claims 26-38 and 48-56 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected species in the election made without traverse in the reply filed on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 6, 2024. Claims 39 and 41 are amended. Claims 39, 41-42, and 44-47 are examined upon their merits.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/05/2025 and 09/25/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Withdrawn Claim Rejections
Applicant’s cancelation of Claim 40 renders all previous rejections to this claim moot.
The rejection of claims 39, 41-42, and 44-47 under 35 U.S.C. 112(b) as being indefinite is withdrawn in view of Applicant’s amendments. Claim 39 is interpreted with the broadest reasonable interpretation to encompass any increase in KD, even a non-significant change. As of record in the final rejection filed 05/06/2025, the KD of human wild-type Fc to FcRn at pH 6.0 is known in the art to be 760 nM (Abdiche et al. MAbs. 2015, of record, abstract). Further, the KD to FcRn (Claims 39 and 41) is interpreted as an inherent function of the fusion polypeptide comprising the Fc region modifications outlined in Claim 39 (MPEP § 2112.01).
The rejection of Claims 39, 41-42, and 44-47 under 35 U.S.C. 103 as being unpatentable over Beffinger et al., Neuro-oncology (of record) in view of Burvenich et al., MAbs. 2016 (of record), and further in view of Lazar et al. US Patent No. 10,865,248 (of record) is withdrawn in view of Applicant’s remarks. In the remarks filed 09/05/2025 page 25 (item iv), Applicant cites Lobner and Wang to teach that the FcRn and C1q binding domains on Fc were known to be structurally distinct prior to the time of filing. Therefore, Examiner agrees that it is not obvious that mutations that disrupt C1q binding would also disrupt FcRn binding.
Claim Rejections - 35 USC § 103 (Modified)
Claims 39, 41-42, and 44-46 are rejected under 35 U.S.C. 103 as being unpatentable over Beffinger et al., Neuro-oncology 2017 (of record) in view of Burvenich et al., MAbs. 2016 (of record) and Cooper et al. Brain Res. 2013.
Beffinger teaches that IL-12 stimulates the cytotoxic function of lymphocytes and can trigger rejection of glioma (abstract). However, systemic IL-12 can quickly lead to severe adverse reactions, therefore it is necessary to administer the IL-12 with intratumor, intracranial, or CED administration (abstract). To further prevent IL-12 systemic toxicity, Beffinger teaches the administration of an IL-12Fc fusion protein directly to the brain where IL-12Fc was better retained in the brain than IL-12 (abstract). Beffinger proposes further testing of human IL-12 constructs in canine brain tumors (abstract).
Beffinger fails to teach modifications to the Fc region that reduce affinity to FcRn, specifically the mutations I253A and H435Q (Claims 39 and 45-46).
Burvenich teaches that the FcRn binding site on the Fc region of IgG1 contains I253, H310, and H435 (abstract), and that only a single mutation in this binding site is sufficient to no longer detect binding to human FcRn (abstract). The single mutation H435Q in the Fc region reduces affinity to FcRn by causing a shorter half-life in human FcRn transgenic mice (page 782, paragraphs 3 and 4). Similarly, the mutation I253A on human Fc is categorized as a non-binder to human FcRn (page 778 paragraph 4). Mutations at I253 and H435 can be combined to create a double mutant Fc with reduced binding to FcRn (Fig. 2F and Table 1). Burvenich additionally teaches that altering the IgG:FcRn interaction has increasingly been explored to improve the therapeutic applications of antibodies (introduction paragraph 1), and the interaction is important for antibody-based therapeutics with optimal pharmacokinetics for payload strategies used in the clinic (abstract).
While Burvenich teaches that reducing the binding affinity of Fc to FcRn is important for optimal pharmacokinetics and payload strategies, Burvenich does not teach a specific advantage for treating the central nervous system with modified Fc therapies. Cooper teaches that FcRn plays an important role in efflux of IgG from the rat brain into circulation (abstract). Following intra-cranial administration, levels of IgG comprising H435A (low-binding FcRn variant) did not change over 24 hours while the levels of IgG comprising N434A (high-binding FcRn variant) decreased significantly over time (discussion paragraph 1). Higher levels of N434A IgG were detected in serum compared to H435A after 24 hours (abstract). Therefore, Burvenich teaches that IgG with reduced affinity to FcRn has better retention in the brain and does not escape into the serum as compared to IgG with high affinity to FcRn.
It would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to administer an IL-12Fc fusion protein in the treatment of glioma as outlined in Beffinger wherein the Fc region comprises I253A and H435Q mutations that reduce affinity to FcRn as taught in Burvenich. Burvenich teaches that human Fc domains comprising mutations at I253 and H435 have reduced affinity to FcRn and that I253A and H435Q are known to individually reduce affinity to FcRn. Therefore, it is obvious to specifically combine the I253A and H435Q mutations to produce an IL-12Fc fusion protein with reduced affinity to FcRn. Cooper teaches the motivation to modify the Fc domain is because FcRn plays an important role in IgG efflux from the brain to the serum. Cooper teaches that an IgG comprising mutations that reduce Fc affinity to FcRn had longer retention in the brain as compared to IgG with high affinity to FcRn. Because Beffinger teaches that IL-12 retention in the brain is favorable to avoid systemic IL-12 toxicity problems, it would have been obvious to one of ordinary skill to modify the Fc domain to reduce affinity to FcRn for better retention in the brain.
Applicant's arguments filed September 5, 2025 have been fully considered but they are not persuasive.
Applicant argues that Beffinger does not disclose the Fc region comprising a modification at one or more of positions 253, 310, and 435 that result in reduced affinity to FcRn. However, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references (MPEP § 2145.IV). The rejection is based on Beffinger in view of Burvenich and Cooper wherein Burvenich teaches the recited technical features.
Applicant argues that mutations known to reduce Fc binding affinity to FcRn cannot be assumed to function in the same way when mutated Fc is fused to IL-12. Applicant supports this argument with experimental data showing that modified Fc has a KD of 1200% compared to wild-type Fc, and when the modified Fc is fused to IL-12, the KD is 230% of wild-type IL-12Fc. Examiner maintains that this data supports that mutations known to reduce binding affinity in Fc can be expected to have the same effect when fused to IL-12 with a reasonable expectation of success, because the modified IL-12Fc still had a 230% increase in KD compared to wild-type IL-12Fc. See UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 693, 2023 USPQ2d 448 (Fed. Cir. 2023): "A difference of degree is not as persuasive as a difference in kind – i.e., if the range produces ‘"a new property dissimilar to the known property,’" rather than producing a predictable result but to an unexpected extent." (MPEP § 716.02). Therefore, a difference in degree of binding reduction does not take away from the fact that both the Fc domain and the Fc fusion protein both had reduced FcRn affinity. Further, one of ordinary skill would understand that the Fc domain in the IL-12Fc fusion protein retains its structure and function, and the known mutations could be applied to reduce affinity to FcRn with a reasonable expectation of success. This reasoning is supported by the state of the art prior to filing which teaches a fusion protein comprising a functional domain (erythropoietin) fused to an Fc domain wherein the I253A mutation was made in the Fc portion of the fusion protein and resulted in the fusion protein having reduced affinity to FcRn (Bitonti et al. Proc Natl Acad Sci. 2004; abstract and page 9764 paragraph 1). The I253A Fc mutation had the same effect even when part of a fusion protein. The new art is cited solely in response to Applicant’s arguments to demonstrate that the Fc mutations can be applied to the IL-12Fc fusion protein with a reasonable expectation of success and is not a new grounds of rejection.
Applicant argues that the combination of Beffinger and Burvenich does not disclose a KD value of a modified IL-12Fc fusion polypeptide according to Claim 39. As stated in the “Withdrawn Claim Rejections” section above, the KD to FcRn (Claims 39 and 41) is interpreted as an inherent function of the fusion polypeptide comprising the Fc region modifications outlined in Claim 39 (MPEP § 2112.01). Because the teachings of Beffinger, Burvenich, and Cooper make obvious the structure of the fusion polypeptide of Claim 39, the inherent functional properties (KD) of the fusion polypeptide are also obvious.
Applicant argues that the claimed mutation triplets are selected from 8000 possible triplets of the 20 canonical amino acids, and asserting that the selected triplets have the claimed technical effect is an inadmissible ex post facto analysis. The teachings of Beffinger, Burvenich, and Cooper are applied to the fusion polypeptide comprising the double mutation I253A and H435Q, not a triplet mutation. Burvenich specifically teaches Fc domains comprising double mutations at I253 and H435 that have reduced affinity to FcRn and that I253A and H435Q as single mutations have reduced affinity to FcRn. Therefore, it is not using ex post facto analysis that one of ordinary skill could make an Fc mutant comprising I253A and H435Q with the reasonable expectation that the mutant would have reduced affinity to FcRn.
Applicant argues that it would not have been obvious to one of ordinary skill to modify the Fc domain to decrease affinity to FcRn because the motivation taught by Burvenich (such as decreased half-life) does not apply to scenarios of treating the CNS. Examiner relies on Cooper as outlined above to teach the motivation for reducing Fc affinity to FcRn as applied specifically to CNS administration.
Claim Rejections - 35 USC § 103 (New)
Claims 39, 41-42, and 44-47 are rejected under 35 U.S.C. 103 as being unpatentable over Beffinger et al., Neuro-oncology 2017 (of record) in view of Burvenich et al., MAbs. 2016 (of record) and Cooper et al. Brain Res. 2013 as applied to Claims 39, 41-42, and 44-46 above, and further in view of Bosques US 2022/0153833 (filed March 2017).
The teachings of Beffinger, Burvenich, and Cooper as they apply to Claims 39, 41-42, and 44-46 are outlined in the rejection above and teach a method of treating glioma by administering an IL-12Fc fusion protein wherein the Fc domain comprises I253A and H435Q mutations. Beffinger, Burvenich, and Cooper fail to teach wherein said Fc region comprises SEQ ID NO: 004 (Claim 47) which is wild-type human Fc with I253N and H435Q mutations (specification Table 1). Note, Claim 47 specifically states “wherein said Fc region is or comprises a sequence characterized by SEQ ID NO: 004” and this is interpreted to mean the Fc region comprises SEQ ID NO: 004.
Bosques teaches Fc domain mutations that decrease the binding of the modified Fc domain to FcRn by modifying position I253 (paragraph [0230]). The mutation can comprise any natural amino acid substitution (I253A, I253C, I253D, I253E, I253F, I253G, I253H, I253K, I253L, I253M, I253N, I253P, I253Q, I253R, I253S, I253T, I253V, I253W, or I253Y) (paragraph [0231]).
It would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the IL-12Fc polypeptide comprising Fc mutations I253A and H435Q as taught by Beffinger, Burvenich, and Cooper to comprise the I253N mutation instead of I253A as taught by Bosques. Burvenich teaches that the FcRn binding site on Fc comprises residues I253, H310, and H435, and a single mutation in these three residues is sufficient to disrupt binding to FcRn (abstract; of record). Burvenich also teaches mutating I253 to different amino acids such as I253A, I253D, and I253P (Figure 2; of record). Considering Burvenich alone, there are only 16 other possible natural amino acids that could be substituted at I253 that Burvenich did not evaluate. A person having ordinary skill in the art would only have to evaluate a finite number of I253 substitutions (16) to arrive at the claimed invention. In Pfizer, Inc. V. Apotex, Inc., 480 F.3d 1348, 82 USPQ2d 1321 (Fed. Cir. 2007), the court ruled that evaluating a group of 53 anions known to form pharmaceutically acceptable salts would be an acceptable number to form a “reasonable expectation of success” (MPEP § 2143.I.E). Even considering all 16 possible I253 substitutions, this finite number is much lower than what the case law teaches is obvious to try. Further, the teachings of Bosques support that any natural amino acid substitution at I253 has a reasonable expectation to reduce binding affinity to FcRn. Absolute predictability is not a 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. “Good science and useful contributions do not necessarily result in patentability.” PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342 (Fed. Cir. 2007). MPEP § 2145. From the teachings of Beffinger, Burvenich, Cooper, and Bosques, one of ordinary skill could have tried substituting the I253A mutation with the I253N mutation with a reasonable expectation of success in achieving reduced FcRn binding affinity. The motivation to reduce FcRn binding affinity is to retain the IL-12Fc fusion protein in the brain and avoid systematic leakage into the serum as taught by Cooper and Beffinger.
Applicant's arguments filed September 5, 2025 have been fully considered but they are not persuasive.
Applicant argues that the Pfizer v. Apotex case is law is not comparable to the present case because the besylate anion is an established counterion in pharmaceutically acceptable salts, and the I253N mutation cannot be regarded as an established mutation for reducing the FcRn affinity of an IgG Fc region. Examiner maintains that the state of the art prior to filing does establish a reasonable expectation of success that the I253N mutation would reduce binding affinity to FcRn. Burvenich teaches that I253 is in the binding domain for FcRn and a single mutation can disrupt binding. Burvenich specifically teaches that I253A, I253D, and I253P all reduce binding to FcRn. Bosques further supports this teaching by stating that any natural amino acid mutation at I253 is expected to reduce binding to FcRn which includes I253N. Therefore, the case law directed to an ‘obvious to try’ rationale does apply to the instant scenario.
Double Patenting (Maintained)
The provisional rejection of Claims 39, 41-42, and 44-47 on the ground of nonstatutory double patenting as being unpatentable over claims 28-35 of copending U.S. App. No. 17/599,856 is maintained.
Applicant's arguments filed September 5, 2025 have been fully considered but they are not persuasive. Applicant traverses the double patenting rejection in view of the remarks and amendments. However, both sets of claims are still directed to a method of treating glioma by administering an IL-12/Fc fusion protein comprising a modified Fc region wherein the Fc region comprises SEQ ID NO: 004 (NHQ). The rejection is maintained.
Conclusion
No claim is allowed.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675