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 Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 6, 14, and 15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains 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.
Claim 6 is broadly drawn to a variant IgG Fc region consisting of two Fc domains, wherein one or both Fc domains comprise 252Y, 254T, 256E, 433K, and 434Y mutations according to Eu numbering.
The specification teaches that anti-IgE antibodies reformatted in human IgG1 Fc equipped with the ABDEG mutations had a higher affinity to FcRn at pH 6 and pH 7 compared to wild-type human IgG1 (Example 4, Part IV: FcRn Binding ELISA, Page 79-80). The anti-IgE-ABDEG antibodies, in particular clone 18E2His2-hIgG1-ABDEG, induced clearance of IgG and IgE in a non-disease model compared to a non-IgE clone with ABDEG mutation which promoted IgG but not IgE depletion and omalizumab which was unable to promote either IgE or IgG depletion (Example 7). ABDEG antibodies also reduced clinical disease activity in a murine model of bullous pemphigoid induced by IgG and IgE autoantibodies (Example 13).
There is no evidence provided in the specification that the claimed variant IgG Fc region comprising the 252Y, 254T, 256E, 433K, and 434Y mutations was ever made, tested, and shown to exhibit increased affinity for human FcRn at both pH 6.0 and pH 7.4 commensurate in scope with claim 6.
While the specification describes that certain mutations may increase FcRn affinity (see Section B, part I: Variant Fc domains and FcRn binding fragments thereof, including Page 27, Ln. 4-33), it does not provide actual evidence that the presently claimed combination of IgG Fc substitutions – 252Y, 254T, 256E, 433K, and 434Y –would inherently or predictably yield this functional property. In the art, FcRn affinity is heavily dependent on the identity of the substitution at a given position Even when single substitutions show increased affinity, combinations may be non-additive, neutralizing, or even detrimental. For example, whereas combination of 428L with 434S and 259I has been reported to provide synergistic improvements in FcRn binding, substitutions such as 252Y or 434M negatively impacted affinity when combined with 428L. Likewise, a substitution that increased affinity in one isotype (e.g. 434T in IgG1) did not necessarily confer improvement in another isotype (e.g. IgG2) (Chamberlain et al, see Example 3, Para. 0196). Thus, increased FcRn binding affinity in one context does not reasonably predict the outcome in others. Given the level of unpredictability in combining Fc mutations, and the absence of further guidance provided in the specification, persons of ordinary skill in the art would be required to engage in additional trial and error research to determine whether the claimed Fc variant would in fact provide increased FcRn affinity at pH 6.0 and pH 7.4 and across different IgG isotypes commensurate in scope of claim 6.
Further, claims 14 and 15 are broadly drawn to a method of treating an antibody-mediated disorder, including an autoimmune disorder, in a subject comprising administering the recited variant IgG Fc region to the subject.
Variant IgG Fc regions having mutations that confer increased affinity for FcRn (e.g. ABDEG mutations) can act as FcRn antagonists and thereby reduce endogenous IgG levels (Page 24 of specification, Ln. 15-27). As such, these variant IgG Fc regions can be effective for treating IgG-mediated autoimmune or antibody-driven disorders where IgG autoantibodies cause tissue damage. However, IgG is not the key pathogenic mediator in all autoimmune or antibody-mediated diseases.
Indeed, many immune and allergic conditions are instead driven primarily by IgE binding to mast cells/basophils and triggering rapid degranulation, histamine release, and acute allergic inflammation independent of IgG. For example, classic type I hypersensitivity disorders are characterized by an immediate IgE-mediated immune response to typically harmless environmental antigens, producing a wide range of clinical manifestations, including urticaria, allergic rhinitis, asthma, food allergies, atopic dermatitis, angioedema, and, in severe cases, anaphylaxis—a potentially life-threatening emergency (Abbas et al, see Introduction). In some subsets, chronic spontaneous urticaria is mediated by IgE autoantibodies against self-allergens (type I CSU) (Wong et al, 3rd paragraph of Introduction on Page 18). Thus, the claimed variant IgG Fc regions which target IgG would not be therapeutically beneficial in the treatment of antibody-mediated diseases or autoimmune disorders in which other immunoglobulin isotypes (e.g. IgE) underlie pathogenesis absent of evidence provided to the contrary.
Therefore, the specification is not enabled over the full scope of the claims.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 6 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 6 recites that that “the variant IgG Fc region binds to human FcRn with increased affinity at both pH 6.0 and pH 7.4” but does not specify the reference point or baseline to which increased affinity is compared. It is unclear whether “increase affinity” is relative to wild-type IgG Fc, another Fc variant, or some other reference standard. Since the claim does not provide a clear standard for measuring or determining “increased affinity”, a person of ordinary skill in the art would not be able to ascertain the metes and bounds of the claim with reasonable certainty. Thus, scope of claim 6 is indefinite.
Claim Rejections - 35 USC § 103
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.
Claims 1-15 are rejected under 35 U.S.C. 103 as being unpatentable over Ulrichts et al (US20150218239A1), hereinafter Ulrichts, in view of Yeung et al (Yeung, Yik Andy, et al. "Engineering human IgG1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates." The Journal of Immunology 182.12 (2009): 7663-7671.), hereinafter Yeung.
Ulrichts discloses FcRn antagonist compositions comprising a variant Fc region that specifically binds to FcRn with increased affinity and reduced pH dependence relative to the native Fc region, wherein 1) the Fc region is a human IgG1 Fc region and consists of two Fc domains and 2) the Fc domains comprise the amino acid sequence of SEQ ID NO: 1, 2 or 3 having 252Y, 254T, 256E, 433K, and 434F, mutations per EU numbering (Abstract, Para. 0008-0009, Para. 0039-0040, Para. 0065-0066, Para. 0069, Para. 0070). Since both Fc domains can comprise the same mutations, the variant Fc region can be a homodimer. Polynucleotides encoding the FcRn antagonists, expression vectors comprising the polynucleotides, and host cells comprising the vectors are also disclosed (Para. 0098-0105). Methods of making FcRn antagonists culturing host cells under conditions appropriate to the production of the FcRn antagonists are further provided (Para. 0098 and Para. 0102). Lastly, disclosed are methods of treating antibody-mediated disorders (e.g. autoimmune diseases) using these FcRn antagonists (see Abstract).
Ulrichts does not teach that the variant IgG Fc regions comprise the 434Y rather than the 434F mutation.
However, Yeung teaches that the human IgG1 variants comprising the N434W, N434Y, and N434F mutations had the highest affinities toward human FcRn at pH 6.0 relative to wild-type according to the following ranking: N434W > N434Y>N434F (see “Saturation Mutagenesis at N434” section and Figure 1). Thus, the N434Y mutant has greater affinity for human FcRn compared to the N434F mutant.
It would have been obvious to one of ordinary skill in the art to modify the variant IgG Fc region disclosed by Ulrichts such that it comprises the N434Y mutation (rather than the N434F mutation). One of ordinary skill in the art would have been motivated to do so since human IgG1 variants comprising the N434Y mutation has greater affinity for human FcRn compared to those having the N434F mutation as taught by Yeung. Additionally, it would have been obvious to artisans to substitute N434F mutation in the variant IgG Fc region disclosed by the Ulrichts with the N434Y mutation disclosed by Yeung since they have the same function and can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Per the instant claims, the minimal structure required for a variant IgG Fc region to have increased binding to FcRn at both pH 6.0 and 7.4 are the 252Y, 254T, 256E, 433K, and 434Y mutations per EU numbering. As such, variant IgG Fc regions made by the combined teachings of Ulrichts and Yeung can bind to FcRn at both pH 6.0 and 7.4. Further, there are no more than 10 (or no more than 5) amino acid substitutions in the Fc domains of the variant Fc region –252Y, 254T, 256E, 433K, and 434Y – taught by Ulrichts in view of Yeung. Therefore, one of ordinary skill in the art would reasonably expect that a variant IgG Fc region comprising the 252Y, 254T, 256E, 433K, and 434Y mutations per EU numbering can effectively bind to FcRn and treat IgG-driven antibody disorders.
Double Patenting
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.
Claims 1-8 and 13-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 15, 17, 25, 26, 43, 44, 49, 55-56, 63-67, 69, 72, and 75 of copending Application No. 17598033 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims either anticipate or are obvious variants over the instant claims.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite an anti-IgE antibody comprising a variant human IgG1 Fc region consisting of two identical Fc domains (i.e. homodimer), wherein the variant Fc domains bind to human -FcRn with increased affinity at pH 6.0 and pH 7.4 relative to wildtype human IgG1 Fc domain (co-pending claims 1, 17, 25, and 26). Further recited is a pharmaceutical composition comprising the anti-IgE antibody with the variant IgG1 Fc domain and methods of treating antibody-mediated disorders in a subject, including autoimmune disorders, comprising administering the anti-IgE antibody with the variant IgG1 Fc domain to the subject ) (co-pending claims 67, 69, and 72). The variant Fc domains can comprise the mutations recited in the instant claims, including 252Y, 254T, 256E, 433K, and 434Y according to EU numbering (co-pending claim 8, part ii, in particular). Thus, the variant Fc domains have no more than 5 amino acid substitutions as compared to wild-type Fc domain.
Thus, the co-pending claims meet the limitations of the instant claims.
Claims 1-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 4, 9, 19, 21, 26, 27, 30, 34, 35, 39, 46, 49, 53, 55, 58, 61, and 63-65 of copending Application No. 18774570 (reference application) in view of Ulrichts et al (US20150218239A1), hereinafter Ulrichts, in view of Yeung et al (Yeung, Yik Andy, et al. "Engineering human IgG1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates." The Journal of Immunology 182.12 (2009): 7663-7671.), hereinafter Yeung.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite a method of treating an autoantibody-mediated disease in a subject comprising administering to the subject FcRn antagonist (co-pending claims 4, 9, 65).
The co-pending claims do not teach that the FcRn antagonist is a variant human IgG1 Fc region comprising 252Y, 254T, 256E, 433K, and the 434Y mutations, wherein both Fc domains of the Fc region comprise identical mutation to form a homodimer. Further, the co-pending claims do not recite polynucleotides, vectors, or host cells encoding the FcRn antagonists nor methods of making the FcRn antagonists.
However, Ulrichts teaches FcRn antagonist compositions comprising a variant Fc region that specifically binds to FcRn with increased affinity and reduced pH dependence relative to the native Fc region, wherein 1) the Fc region is a human IgG1 Fc region and consists of two Fc domains and 2) the Fc domains comprise the amino acid sequence of SEQ ID NO: 1, 2 or 3 having 252Y, 254T, 256E, 433K, and 434F, mutations per EU numbering (Abstract, Para. 0008-0009, Para. 0039-0040, Para. 0065-0066, Para. 0069, Para. 0070). Since both Fc domains can comprise the same mutations, the variant Fc region can be a homodimer. Polynucleotides encoding the FcRn antagonists, expression vectors comprising the polynucleotides, and host cells comprising the vectors are also disclosed (Para. 0098-0105). Methods of making FcRn antagonists culturing host cells under conditions appropriate to the production of the FcRn antagonists are further provided (Para. 0098 and Para. 0102).
Yeung further teaches that the human IgG1 variants comprising the N434W, N434Y, and N434F mutations had the highest affinities toward human FcRn at pH 6.0 relative to wild-type according to the following ranking: N434W > N434Y>N434F (see “Saturation Mutagenesis at N434” section and Figure 1). Thus, the N434Y mutant has greater affinity for human FcRn compared to the N434F mutant.
It would have been obvious to one of ordinary skill in the art to modify the FcRn antagonists of the co-pending claims such that the variant Fc region is a human IgG1 Fc region comprising 252Y, 254T, 256E, 433K, and the 434Y mutations, wherein both Fc domains of the Fc region have identical mutations to form a homodimer. One of ordinary skill in the art would have been motivated to do so since variant IgG Fc regions having the 252Y, 254T, 256E, 433K, and 434F have increased affinity and reduced pH dependence relative to the native Fc region as taught by Ulrichts. Further, the N434Y mutation has greater affinity for human FcRn compared to those having the N434F mutation as taught by Yeung. As such, artisans would have been further motivated to substitute N434F mutation in the variant IgG Fc region disclosed by the Ulrichts with the N434Y mutation disclosed by Yeung in order to obtain the enhanced FcRn binding affinity associated with the N434Y mutation. Additionally, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Per the instant claims, the minimal structure required for a variant IgG Fc region to have increased binding to FcRn at both pH 6.0 and 7.4 are the 252Y, 254T, 256E, 433K, 438L, and 434F mutations per EU numbering. As such, variant IgG Fc regions made by the combined teachings of the co-pending claims in view of Ulrichts and Yeung can bind to FcRn at both pH 6.0 and 7.4. Further, there are no 10 (or no more than 5) amino acid substitutions in the Fc domains of the variant Fc region -252Y, 254T, 256E, 433K, and 434Y, and taught by co-pending claims in view of Ulrichts and Yeung. Lastly, artisans would have been motivated to develop polynucleotides, vectors, host cells comprising the variant IgG Fc regions in order to make said variant IgG Fc regions according to methods provided by Ulrichts. Therefore, one of ordinary skill in the art would reasonably expect that a variant IgG Fc region comprising the 252Y, 254T, 256E, 433K, and 434Y mutations per EU numbering can effectively bind to FcRn and treat IgG-driven antibody disorders.
Claims 1-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 8-9, 11, 13, 17, 19-21, 27, 31, 33, 40, 45, 48, 49, 53, 56, 61, 63, 65, and 71-72 of copending Application No. 18810851 (reference application) in view of Ulrichts et al (US20150218239A1), hereinafter Ulrichts, in view of Yeung et al (Yeung, Yik Andy, et al. "Engineering human IgG1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates." The Journal of Immunology 182.12 (2009): 7663-7671.), hereinafter Yeung.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite a method of treating myositis (an autoimmune disease) in subject comprising administering to the subject an FcRn antagonist consisting of a variant Fc region (co-pending claim 1).
The co-pending claims do not teach that the FcRn antagonist is a variant human IgG1 Fc region comprising 252Y, 254T, 256E, 433K, and the 434Y mutations, wherein both Fc domains of the Fc region comprise identical mutation to form a homodimer. Further, the co-pending claims do not recite polynucleotides, vectors, or host cells encoding the FcRn antagonists nor methods of making the FcRn antagonists.
However, Ulrichts teaches FcRn antagonist compositions comprising a variant Fc region that specifically binds to FcRn with increased affinity and reduced pH dependence relative to the native Fc region, wherein 1) the Fc region is a human IgG1 Fc region and consists of two Fc domains and 2) the Fc domains comprise the amino acid sequence of SEQ ID NO: 1, 2 or 3 having 252Y, 254T, 256E, 433K, and 434F, mutations per EU numbering (Abstract, Para. 0008-0009, Para. 0039-0040, Para. 0065-0066, Para. 0069, Para. 0070). Since both Fc domains can comprise the same mutations, the variant Fc region can be a homodimer. Polynucleotides encoding the FcRn antagonists, expression vectors comprising the polynucleotides, and host cells comprising the vectors are also disclosed (Para. 0098-0105). Methods of making FcRn antagonists culturing host cells under conditions appropriate to the production of the FcRn antagonists are further provided (Para. 0098 and Para. 0102).
Yeung further teaches that the human IgG1 variants comprising the N434W, N434Y, and N434F mutations had the highest affinities toward human FcRn at pH 6.0 relative to wild-type according to the following ranking: N434W > N434Y>N434F (see “Saturation Mutagenesis at N434” section and Figure 1). Thus, the N434Y mutant has greater affinity for human FcRn compared to the N434F mutant.
It would have been obvious to one of ordinary skill in the art to modify the FcRn antagonists of the co-pending claims such that the variant Fc region is a human IgG1 Fc region comprising 252Y, 254T, 256E, 433K, and the 434Y mutations, wherein both Fc domains of the Fc region have identical mutations to form a homodimer. One of ordinary skill in the art would have been motivated to do so since variant IgG Fc regions having the 252Y, 254T, 256E, 433K, and 434F have increased affinity and reduced pH dependence relative to the native Fc region as taught by Ulrichts. Further, the N434Y mutation has greater affinity for human FcRn compared to those having the N434F mutation as taught by Yeung. As such, artisans would have been further motivated to substitute N434F mutation in the variant IgG Fc region disclosed by the Ulrichts with the N434Y mutation disclosed by Yeung in order to obtain the enhanced FcRn binding affinity associated with the N434Y mutation. Additionally, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Per the instant claims, the minimal structure required for a variant IgG Fc region to have increased binding to FcRn at both pH 6.0 and 7.4 are the 252Y, 254T, 256E, 433K, 438L, and 434F mutations per EU numbering. As such, variant IgG Fc regions made by the combined teachings of the co-pending claims in view of Ulrichts and Yeung can bind to FcRn at both pH 6.0 and 7.4. Further, there are no 10 (or no more than 5) amino acid substitutions in the Fc domains of the variant Fc region -252Y, 254T, 256E, 433K, and 434Y, and taught by co-pending claims in view of Ulrichts and Yeung. Lastly, artisans would have been motivated to develop polynucleotides, vectors, host cells comprising the variant IgG Fc regions in order to make said variant IgG Fc regions according to methods provided by Ulrichts. Therefore, one of ordinary skill in the art would reasonably expect that a variant IgG Fc region comprising the 252Y, 254T, 256E, 433K, and 434Y mutations per EU numbering can effectively bind to FcRn and treat IgG-driven antibody disorders.
Claims 1-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 14, 20, 23, 26, 32-34, 38, 39, 43, 46-47, 51, 58, 60-71, and 73-74 of copending Application No. 18979921 (reference application) in view of Ulrichts et al (US20150218239A1), hereinafter Ulrichts, in view of Yeung et al (Yeung, Yik Andy, et al. "Engineering human IgG1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates." The Journal of Immunology 182.12 (2009): 7663-7671.), hereinafter Yeung.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite an FcRn antagonist comprising a variant IgG Fc region, wherein the variant IgG Fc region consists of two Fc domains to form a dimer, wherein the variant Fc region comprise one or more mutations of the amino acid residues forming the interface of the CH3 domain of the Fc domains (co-pending claim 1). Each Fc domain is a human IgG1 Fc domain (co-pending claim 14). Further recited are polynucleotides encoding the FcRn antagonist, expression vectors comprising the polynucleotides, host cells comprising the expression vectors, and a method for producing the FcRn antagonist comprising culturing the host cells under conditions which permit the expression of the FcRn antagonists (co-pending claims 67-70). Pharmaceutical compositions comprising the FcRn antagonist and methods for treating an antibody-mediated disorder in a subject are also recited (co-pending claims 71 and 74).
The co-pending claims do not teach that the FcRn antagonist is a variant human IgG1 Fc region comprising 252Y, 254T, 256E, 433K, and the 434Y mutations, wherein both Fc domains of the Fc region comprise identical mutation to form a homodimer. Additionally, the co-pending claims do not recite that the antibody-mediated disorder is an autoimmune disorder.
However, Ulrichts teaches FcRn antagonist compositions comprising a variant Fc region that specifically binds to FcRn with increased affinity and reduced pH dependence relative to the native Fc region, wherein 1) the Fc region is a human IgG1 Fc region and consists of two Fc domains and 2) the Fc domains comprise the amino acid sequence of SEQ ID NO: 1, 2 or 3 having 252Y, 254T, 256E, 433K, and 434F, mutations per EU numbering (Abstract, Para. 0008-0009, Para. 0039-0040, Para. 0065-0066, Para. 0069, Para. 0070). Since both Fc domains can comprise the same mutations, the variant Fc region can be a homodimer. Further, disclosed are methods of treating antibody-mediated disorders (e.g. autoimmune diseases) using these FcRn antagonists (see Abstract).
Yeung further teaches that the human IgG1 variants comprising the N434W, N434Y, and N434F mutations had the highest affinities toward human FcRn at pH 6.0 relative to wild-type according to the following ranking: N434W > N434Y>N434F (see “Saturation Mutagenesis at N434” section and Figure 1). Thus, the N434Y mutant has greater affinity for human FcRn compared to the N434F mutant.
It would have been obvious to one of ordinary skill in the art to modify the FcRn antagonists of the co-pending claims such that the variant Fc region is a human IgG1 Fc region comprising 252Y, 254T, 256E, 433K, and the 434Y mutations, wherein both Fc domains of the Fc region have identical mutations to form a homodimer and the antibody-mediated disease treated is an autoimmune disease. One of ordinary skill in the art would have been motivated to do so since variant IgG Fc regions having the 252Y, 254T, 256E, 433K, and 434F have increased affinity and reduced pH dependence relative to the native Fc region and can be used to treat autoimmune diseases as taught by Ulrichts. Further, the N434Y mutation has greater affinity for human FcRn compared to those having the N434F mutation as taught by Yeung. As such, artisans would have been further motivated to substitute N434F mutation in the variant IgG Fc region disclosed by the Ulrichts with the N434Y mutation disclosed by Yeung in order to obtain the enhanced FcRn binding affinity associated with the N434Y mutation. Additionally, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Per the instant claims, the minimal structure required for a variant IgG Fc region to have increased binding to FcRn at both pH 6.0 and 7.4 are the 252Y, 254T, 256E, 433K, 438L, and 434F mutations per EU numbering. As such, variant IgG Fc regions made by the combined teachings of the co-pending claims in view of Ulrichts and Yeung can bind to FcRn at both pH 6.0 and 7.4. Further, there are no 10 (or no more than 5) amino acid substitutions in the Fc domains of the variant Fc region -252Y, 254T, 256E, 433K, and 434Y, and taught by co-pending claims in view of Ulrichts and Yeung. Therefore, one of ordinary skill in the art would reasonably expect that a variant IgG Fc region comprising the 252Y, 254T, 256E, 433K, and 434Y mutations per EU numbering can effectively bind to FcRn and treat IgG-driven antibody disorders.
Claims 1-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over 1, 6, 8, 9, 11, 14-16, 23, 24, 38-41, 44-45, 47-50, 56, 59, 62, 63, 66, 68, and 72 of copending Application No. 19200764 (reference application) in view of Ulrichts et al (US20150218239A1), hereinafter Ulrichts, in view of Yeung et al (Yeung, Yik Andy, et al. "Engineering human IgG1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates." The Journal of Immunology 182.12 (2009): 7663-7671.), hereinafter Yeung.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite a method of treating lupus nephritis (an autoimmune disease) in a subject comprising administering to the subject a human FcRn antagonist consisting of a variant Fc region (co-pending claim 1).
The co-pending claims do not teach that the FcRn antagonist is a variant human IgG1 Fc region comprising 252Y, 254T, 256E, 433K, and the 434Y mutations, wherein both Fc domains of the Fc region comprise identical mutation to form a homodimer. Further, the co-pending claims do not recite polynucleotides, vectors, or host cells encoding the FcRn antagonists nor methods of making the FcRn antagonists.
However, Ulrichts teaches FcRn antagonist compositions comprising a variant Fc region that specifically binds to FcRn with increased affinity and reduced pH dependence relative to the native Fc region, wherein 1) the Fc region is a human IgG1 Fc region and consists of two Fc domains and 2) the Fc domains comprise the amino acid sequence of SEQ ID NO: 1, 2 or 3 having 252Y, 254T, 256E, 433K, and 434F, mutations per EU numbering (Abstract, Para. 0008-0009, Para. 0039-0040, Para. 0065-0066, Para. 0069, Para. 0070). Since both Fc domains can comprise the same mutations, the variant Fc region can be a homodimer. Polynucleotides encoding the FcRn antagonists, expression vectors comprising the polynucleotides, and host cells comprising the vectors are also disclosed (Para. 0098-0105). Methods of making FcRn antagonists culturing host cells under conditions appropriate to the production of the FcRn antagonists are further provided (Para. 0098 and Para. 0102).
Yeung further teaches that the human IgG1 variants comprising the N434W, N434Y, and N434F mutations had the highest affinities toward human FcRn at pH 6.0 relative to wild-type according to the following ranking: N434W > N434Y>N434F (see “Saturation Mutagenesis at N434” section and Figure 1). Thus, the N434Y mutant has greater affinity for human FcRn compared to the N434F mutant.
It would have been obvious to one of ordinary skill in the art to modify the FcRn antagonists of the co-pending claims such that the variant Fc region is a human IgG1 Fc region comprising 252Y, 254T, 256E, 433K, and the 434Y mutations, wherein both Fc domains of the Fc region have identical mutations to form a homodimer. One of ordinary skill in the art would have been motivated to do so since variant IgG Fc regions having the 252Y, 254T, 256E, 433K, and 434F have increased affinity and reduced pH dependence relative to the native Fc region as taught by Ulrichts. Further, the N434Y mutation has greater affinity for human FcRn compared to those having the N434F mutation as taught by Yeung. As such, artisans would have been further motivated to substitute N434F mutation in the variant IgG Fc region disclosed by the Ulrichts with the N434Y mutation disclosed by Yeung in order to obtain the enhanced FcRn binding affinity associated with the N434Y mutation. Additionally, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Per the instant claims, the minimal structure required for a variant IgG Fc region to have increased binding to FcRn at both pH 6.0 and 7.4 are the 252Y, 254T, 256E, 433K, 438L, and 434F mutations per EU numbering. As such, variant IgG Fc regions made by the combined teachings of the co-pending claims in view of Ulrichts and Yeung can bind to FcRn at both pH 6.0 and 7.4. Further, there are no 10 (or no more than 5) amino acid substitutions in the Fc domains of the variant Fc region -252Y, 254T, 256E, 433K, and 434Y, and taught by co-pending claims in view of Ulrichts and Yeung. Lastly, artisans would have been motivated to develop polynucleotides, vectors, host cells comprising the variant IgG Fc regions in order to make said variant IgG Fc regions according to methods provided by Ulrichts. Therefore, one of ordinary skill in the art would reasonably expect that a variant IgG Fc region comprising the 252Y, 254T, 256E, 433K, and 434Y mutations per EU numbering can effectively bind to FcRn and treat IgG-driven antibody disorders.
Claims 1, 3, 4, 6, and 7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over 1, 4, 5, 7-9, 13-15, and 19-20 of copending Application No. 19256452 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims either anticipate or are obvious variants over the instant claims.
This is a provisional nonstatutory double patenting rejection.
The co-pending claims recite a heterodimeric protein comprising a human IgG1 Fc region, wherein the human IgG1 Fc region comprising i) a first Fc domain having amino acids Y,T, E, W, K, and Y at EU positions 252, 254, 256, 366, 433, and 434, respectively; and ii) a second Fc domain having the amino acids Y, T, E, S, A, V, K, and Y at EU positions 252, 254, 256, 366, 368, 407, 433, and 434 (co-pending claim 1). Per the instant claims, the minimal structure required for a variant IgG Fc region to have increased binding to FcRn at both pH 6.0 and 7.4 are the 252Y, 254T, 256E, 433K, 438L, and 434F mutations per EU numbering. As such, variant IgG Fc regions of the co-pending claims can bind to FcRn at both pH 6.0 and 7.4. Further, there are no 10 amino acid substitutions in the Fc domains of the variant Fc region taught by co-pending claims.
Thus, the co-pending claims meet the limitations of instant claims 1, 3, 4, 6, and 7.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641