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 Applicant's amendment, filed on 03/22/2024, is acknowledged.
3. Claims 1-6, 17, 38, 45 and 73 are pending.
4. Applicant’s IDS, filed 03/22/2024, is acknowledged.
5. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
6. Claims 1, 6, 38, 73 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 20150050278.
The `278 publication teaches large phage display libraries (each with more than 10 to 10 individuals) were constructed by three different ways: (a) randomly mutating residues in the CH2 domain of monomeric Fc (K246, R301, V303, V305); (b) randomly mutating residues in CH2 domain (K246, R301, V303, V305) as well as CH3 domain (residues 389 to 393, NNYKT) of monomeric Fc; (c) randomly mutating residues in CH2 domain (K246, R301, V303, V305), and naturally occurring heavy chain CDR3s were grafted into CH3 domain (residues 389 to 393) of monomeric Fc [0324]. The `278 publication further teaches monomeric Fc domains were generated wherein one or two residues around amino acid 16 (K), amino acid 71 (R) to 75 (V), 159 (N) to 163 (T) were mutated. In some cases, a CDR was inserted between residues 159 (N) to 163 (T), which are in CH3 domain to replace the original amino acids. It should be noted that residue 16 corresponds to residue 246 in IgG1 numbering system, etc. The sequences of the antigen binders are shown in FIG. 9 [0331]. Fig. 9 shows mutants of monomeric Fc at position 246 as 246T, 246S, 248L.
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The `278 publication teaches detectable compound or composition that is conjugated directly or indirectly to another molecule, such as an antibody, Fc domain or CH2 or CH3 domain molecule, to facilitate detection of that molecule. Specific, non-limiting examples of labels include fluorescent tags, enzymatic linkages, and radioactive isotopes [0101] . Monomeric Fc domains and CH3 domains can be conjugated to other compounds including, but not limited to, enzymes, paramagnetic beads, colloidal paramagnetic beads, haptens, fluorochromes, metal compounds, radioactive compounds or drugs [0188] [0219]. A peptide linker (short peptide sequence) can optionally be included between the Fc (or CH3 domain) molecule and the effector molecule [097] [0187]. The linker is capable of forming covalent bonds to both the protein and to the effector molecule [0189].
The `278 publication teaches antigen binding monomeric Fc domains, antigen binding monomeric CH3 domains, Fc domain molecules, and CH3 domain molecules a have enormous potential for diagnosis and/or treatment of any of a number of diseases or conditions for which an antibody is of use. For example, they can be used for the treatment of cancer, infectious disease (such as viral, bacterial, fungal or parasitic infections), [0172], [0194] [0253]
The reference teachings anticipate the claimed invention.
7. Claims 1, 6, 38, 73 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2017040380.
The `380 publication teaches a polypeptide comprising an aglycosylated mutant or variant human IgG Fc domain capable of binding human FcyRIIb; and comprising substitution mutations of glutamine at position 246 (K246Q) [0012]. The `380 publication teaches Fc-Bn2 polypeptide that has six mutations, K246Q, T260A, L351Q, Q386R, P396F, and V397M. Fc-Bnl7 has 8 mutations, K246Q, T260A, N315S, I336M, K340R, Q342D, A378T, Q386R [00208]. The `380 further teaches the polypeptide B57 comprising E233Q; L235H; G236R; G237V; K246R; M252V; K288M; E294K; Y296H; T307A; P352L; E388G; F404L (see Table 5).
Claim 38 is included because the `380 publication teaches variant Fc domain (E) is desired to link the molecule to at least one (n) agent (A) (e.g., anti-tumor agents, therapeutic enzymes) to form a conjugate to enhance the unity of the molecule, it is conventional to link (L) or covalently bind or complex at least one desired molecule or moiety [0034] [0085], [0093]. While the reference does not teach that the (L) is conjugated to variant Fc domain via lysine, it is well Conjuaged Fc linker utilize K246 and K248 to a obtain site-specific conjugate. Since K246 is mutated, then K248 among other lysine residues are left for the conjugation.
Moreover, the `380 publication teaches the use of a polypeptide in the treatment of diseases such as an infection including a bacterial infection or a viral infection [0019] [0022].
The reference teachings anticipate the claimed invention.
8. Claims 1 and 38 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US20160008485.
The `485 publication teaches mutant human Fc domain comprising K246C (published SEQ ID NO: 6-GGPSVFLFPPCPKDTLMISRT) (See published claim 1, Table 13, row #1, Table 14, row #1, Examples 5-6, page 66 and Fig. 15F). The `485 publication teaches cysteine residues with either an optimal predicted pKa range between 9.5 and 11.5, and/or a predicted side chain solvent accessibility between 15 and 60, may mimic the properties of the conjugated cysteine mutants such as E380C, K392C, I398C, V422C and L443C (numbering using the Eu index of Kabat). Since these properties (pKa and predicted side chain solvent accessibility) are correlated, it is difficult to establish which criteria are associated with the desired biological outcomes, including, but not limited to, low propensity to aggregate and facile conjugation to linkers and payloads [0601] [0604]. The `485 publication teach that the cytotoxic agent (e.g., an auristatin, a maytansinoid and a calicheamicin [0024]) is conjugated to the polypeptide via a linker such as mc, mc-val-cit, mc0val0citoPABC, Mal0PEG2C2, Mal-PEG3C2 and Mal-PEG6C2 [0022]-[00025], [0070].
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The reference teachings anticipate the claimed invention.
9. Claims 1-6, 38, 45 and 73 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 20230364251.
The `251 publication teaches an Fc domain monomer in the conjugates include a K246X mutation, wherein X is not a Lys, most preferably wherein X is selected from Ser, Gly, Ala, Thr, Asn, Gln, Arg, His, Glu, or Asp. An Fc domain monomer in the conjugates include one or more mutations that enhance binding to an Fc receptor (e.g., the FcRn receptor), such as M252Y/S254T/T256E (“YTE”), V309D/Q311H/N434S (“DHS”), and/or M428L/N434S (“LS”), wherein the numbering is according to the EU index as in Kabat. Also, the `251 publication teaches amino acid substitutions are relative to a wild-type Fc monomer amino acid sequence, e.g., wild-type human IgG1 or IgG2. The `251 publication also teaches an F domain monomer in the conjugates include a C220S mutation. [0253], [0255], [0255].
The `251 publication teaches a conjugate of formula: wherein E is an Fc domain, the squiggly line in formula (M-I) is covalently bound to a lysine residue of each E [0006]-[0015].
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Wherein E may be conjugated to 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different therapeutic agents. E is conjugated to a first therapeutic agent, and a second therapeutic agent. Each A1 the first therapeutic agent and of the second therapeutic agent are independently selected from any structure [0242].
The `251 publication provides methods for the synthesis of conjugates useful for the treatment of diseases and conditions related thereto comprising administering the conjugates to a subject pose a high risk of infections. [0002]-[0003]
The reference teachings anticipate the claimed invention
10. 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.
11. Claims 1-6, 38, 45 and 73 are rejected under 35 U.S.C. 103 as being unpatentable over US 20150050278, or WO2017040380, each in view of Wang et al (Protein Cell 2018, 9(1):63-73) and Lee et al. (Nature Communications volume 10, Article number: 5031 (2019).
The teachings of the `278 and `380 publications have been discussed, supra.
The reference teachings differ from the claimed invention only in the recitation that the monomeric mutant Fc comprising K246X further comprises mutations M252Y/S254T/T256E (“YTE”) in claims 2-3, V309D/Q311H/N434S (“DHS”) in claims 2 and 4, and M428L/N434S (“LS”) in claims 2 and 5.
Wang et al teaches modifications in the Fc region that increase half-life that increased FcRn binding at pH 6 including M252Y/S254T/T256E (YTE) and M428L and N434S (LS) (see Table 1).
Lee et al teach engineered Fc domains that confer a longer circulation half-life by virtue of more favorable pH-dependent binding to hFcRn are of great therapeutic interest. Lee et al developed a pH Toggle switch Fc variant containing the L309D/Q311H/N434S (DHS) substitutions, which exhibits markedly improved pharmacokinetics relative to both native IgG1 and widely used half-life extension variants, both in conventional hFcRn transgenic mice and in new knock-in mouse strains. engineered specifically to recapitulate all the key processes relevant to human antibody persistence in circulation. DHS-IgG retains intact effector functions, which are important for the clearance of target pathogenic cells and also has favorable developability.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to introduce mutations M252Y/S254T/T256E (“YTE”), V309D/Q311H/N434S (“DHS”), and M428L/N434S (“LS”) taught by Wang et al and Lee et al references to increase half-life of the monomeric Fc variants taught by the `278 publication.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
12. Claims 1, 6, 17, 38, 73 are rejected under 35 U.S.C. 103 as being unpatentable over US 20150050278, or WO2017040380, each in view of US10035853B2.
The teachings of the `278 and `380 publications have been discussed, supra.
The reference teachings differ from the claimed invention only in the recitation that the monomeric mutant Fc comprising K246X further comprises a serine substitution at position 220 (i.e., C220S) in claim 17.
The `853 patent teaches site-specific antibody conjugation methods. The `853 patent teaches the interchain disulfide bond between the light and heavy chain of IgG1 are formed between C214 of the kappa lambda light chain and C220 in the upper hinge region of the heavy chain (Fig. 1). The `853 patent teaches that the cysteine at position 220 (C220O of the IgG heavy chain is deleted or substituted. The C220 on the heavy chain is substituted with serine (C220S) to provide the desired free cysteine in the light chain (col., 18 lines 8+ and Tables 2, 9-10, SEQ ID NO: 500, Examples 6-7, hSC16.56ss1, Fig. 6A-B). The `853 patent teach an engineered human IgG1/kappa anti-SEZ6 antibody was constructed, wherein the cysteine in the upper hinge region of the heavy chain (C220), which forms an interchain disulfide bond with the light chain, was substituted with serine (C220S) resulting in an antibody (hSC17.200ss1) having two unpaired cysteines to which cytotoxins could be conjugated. The amino acid sequence of the entire engineered heavy chain is shown in Fig. 6A as SEQ ID NO: 515.
Those of skill in the art would have had a reason to introduce C220S substitution as taught by the `853 patent in the Fc region taught by `278 and `380 publications to provide additional unpaired cysteine to which cytotoxins could be conjugated.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
13. The following is a quotation of 35 U.S.C. 112(a) (Pre-AIA 35 U.S.C. 112, first paragraph):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
14. Claim 73 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as containing subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification does not reasonably provide enablement for methods of treating or preventing an infection in a subject, the method comprising administering to the subject the pharmaceutical composition comprising conjugate comprising the variant Fc domain monomer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The specification at page 53, under viral infections discloses that the compounds and pharmaceutical compositions described herein (e.g., a conjugate of formula (1) or a fusion protein described herein) can be used to treat a viral infection (e.g., viral meningitis, herpessimplex virus (HSV) 1,HSV 2, Epstein-Barr virus, varicella-zoster virus, poliovirus, coxsackievirus, West Nile virus, Lacrosse virus, western equine encephalitis, eastern equine encephalitis, Powassan virus, rabies virus, respiratory syncytial virus (RSV), dengue, a beta coronavirus (e.g., COVID-19), zika virus, or an influenza viral infection, such as influenza A, B, C, or parainfluenza).
Page 41, under Conjugates of the disclosure discloses that synthetic conjugates useful in the treatment of a condition or disorder described herein (e.g., a respiratory disorder, a hepatic disorder, a central nervous system disorder, a muscular disorder, a skin disorder, an ocular disorder, a vascular disorder, or an infection (e.g., a viral infection, a fungal infection, or a bacterial infection)). The conjugates disclosed herein (e.g., conjugates described by formula (1)), include a variant Fc domain conjugated to one or more therapeutic agents (e.g., one or more small molecule therapeutic agents). Without being bound by theory, in some aspects, conjugates described herein bind to a surface exposed target of an infectious pathogen (e.g., a viral particle, a fungi, or a bacterium) through the interactions between the therapeutic agent in the conjugates and proteins on the surface of the infectious pathogen.
The specification does not provide empirical data to show the efficacy of any conjugate comprising any K246X variant Fc domain monomer on any infection in a subject. No working empirical data demonstrating that the conjugate comprising any K246X variant Fc domain monomer treat and/or prevent any infection in a subject.
The specification lacks empirical data on the in vivo efficacy of conjugate comprising any K246X variant Fc domain monomer. It is noted that the specification does not provide exemplification or animal model to treat a subject with conjugate comprising any K246X variant Fc domain monomer. There is no correlation on this record between the claimed method and a practical method of in vivo use in currently available form for subject suffering from infection.
It is not enough to rely on in vitro studies where a person having ordinary skill in the art has no basis for perceiving those studies as constituting recognized screening procedures with clear relevance to methods of ex vivo use in humans or animals (emphasis added). Ex parte Maas, 9 USPQ2d 1746. There must be a rigorous correlation of pharmacological activity between the disclosed in vitro use and an in vivo or ex vivo use to establish practical methods of in vivo use.
If the use disclosed is of such nature that the art is unaware of successful treatments with chemically analogous compounds, a more complete statement of how to use must be supplied.
The determination that "undue experimentation" would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988).
The scope of the required enablement varies inversely with the degree of predictability involved, but even in unpredictable arts, a disclosure of every operable species is not required. A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements...However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims.” MPEP § 2164.03.
The instant claims are drawn to a large genus of methods which have not been developed yet to the point where a specific benefit exists in currently available form.
Furthermore, regarding in vivo methods which rely on generally unpredictable mechanisms, ''The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.'' In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction'' refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling (MPEP 2164.03).'' The MPEP also states that physiological activity can be considered inherently unpredictable.
Further, in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297-1303 (CAFC 2005), the court states “If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the 'inventor' would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis.”
The MPEP states that the issue of "correlation" is also dependent on the state of the prior art. In other words, if the art is such that a particular model is recognized as correlating to a specific condition, then it should be accepted as correlating unless the examiner has evidence that the model does not correlate. Even with such evidence, the examiner must weigh the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition. See MPEP 2164.02.
The burden of enabling the prevention of a disease (i.e. the need for additional testing) would be greater than that of enabling a treatment due to the need to screen those mammals susceptible to such diseases and the difficulty of proof that the administration of the drug was the agent that acted to prevent the condition. Further, the specification does not provide guidance as to how one skilled in the art would go about screening those patients susceptible to infection within the scope of the presently claimed invention. Nor is sufficient guidance provided as to a specific protocol to be utilized in order to prove the efficacy of the presently claimed conjugate comprising K246X mutant in preventing infection state.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
16. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
17. Claims 1-6, 17, 38, 45 and 73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 9-12, 18-22, 24, 28-35 of copending Application No. 18281205 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the `205 application are directed to conjugates comprising an Fc domain monomer comprising an amino acid substitution at position 246, wherein the amino acid at position 246 is not a lysine (illustrated as E on the formulates), wherein the Fc domain monomer further comprises amino acid substitutions at positions (i) 252, 254, and 256, (ii) 309, 311, and 434, or (iii) 428 and 434, and wherein the substitution at position 252 is a tyrosine, the substitution at position at position 254 is a threonine, the substitution at position 256 is a glutamic acid, the substitution at position 309 is an aspartic acid, the substitution at position at position 311 is a histidine, the substitution at positions 428 is a leucine, and the substitution at position 434 is a serine, wherein the Fc domain monomer comprises:an amino acid that is not lysine at position 246; a tyrosine at position 252; a threonine at position 254; and a glutamic acid at position 256, wherein the Fc domain monomer comprises:an amino acid that is not lysine at position 246; an aspartic acid at position 309; a histidine at position 311; and a serine at position 434, wherein the Fc domain monomer comprises:an amino acid that is not lysine at position 246; a methionine leucine at position 428; and a serine at position 434, wherein the amino acid at position 246 is selected from serine, glycine, alanine, threonine, asparagine, glutamine, arginine, histidine, glutamic acid, or aspartic acid, wherein the Fc domain monomer further comprises a serine substitution at position 220, wherein the Fc domain monomer comprises the amino acid sequence of any one of SEQ ID NOs: 1-29, wherein the squiggly line connected to E indicates that the L of each Ai-L-A2 is covalently attached to a nitrogen atom of a solvent- exposed lysine of E, wherein n is 2, and each E dimerizes to form an Fc domain. The `205 application also claims method for the treatment of a subject having an influenza viral infection or presumed to have an influenza viral infection, the method comprising administering to the subject an effective amount of the conjugate, the population of conjugates, or the pharmaceutical composition
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
18. No claim is allowed.
19. The art made of record and not relied upon is considered pertinent to applicant's disclosure:
(i) US20090041770.
The `770 publication teaches a polypeptide comprising human IgG1Fc substitutions at position K246H and K246S (see [0019] and Fig. 10a, rows 1-2, Fig. 13). This crystal structure of rat Fc bound to rat FcRn was solved using an Fc dimer with one monomer containing the mutations T252G/1253G/T254G/ H31OE/H433E/H435E, which disrupt FcRn binding, and one monomer containing a wild-type Fc monomer.
(ii) US 20070111260 A1
The `260 publication shows under FIG. 6. The fluorescence intensity profile of stained HEK-293 cells expressing Fc variants of an anti-EphA2 fusion antibody comprising a DAF vGPI. HEK-293 cells expressing a wild type (A and D), K246E Fc variant (B and E) of an anti-EphA2 fusion antibody comprising a DAF vGPI were analyzed by flow cytometry. When stained with Fc.gamma.RIIIA-streptavidin fusion protein/FITC conjugated anti-streptavidin antibody, only cells expressing wild type or K246E Fc variant antibodies displayed fluorescence intensity that was significantly higher than that of observed for the control HEK-293 cells [0020].
(iii) US 20190352396 A1
The `396 publication teaches and claims a polypeptide comprising a human antibody Fc domain, the Fc domain comprising the following amino acid substitutions according to the Kabat numbering system: a) 8 amino acid substitutions of S298G, T299A, K3261, A327Y, L328G, E382V, N390D and M428L; and b) one or more additional amino acid substitution selected from a group consisting of C226R, F243L, K246E, T250I, I253N, V264E, T307S, C347R, T350A, S400T and N421S (see published claim 1).
(iv) 20180037634 A1
The `634 publication teaches under TABLE, exemplary Fc mutations FcMut029 comprising K246N_P247A and FcMut030 comprising K246N_P247A_D376N [0077], [0082].
20. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 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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February 2, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644