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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/25/2025 has been entered.
Response to Amendment
Applicant’s response and amendments to the claims received 12/04/2024 have been acknowledged. Claims 1, 5, 7, 27, and 79 have been amended. Claim 82 is newly added.
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.
Enablement
Claims 1, 5, 7, 25, 27, 30, and 78-82 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.
Claims 1 and 79 are broadly drawn to an anti-FcRn x CD32a bispecific antibody that 1) selectively inhibits the interaction between FcRn, type I Fc receptor (CD32a), and immune-complexed (IC) IgG; 2) selectively binds both FcRn and CD32a to prevent interaction with IC IgG; and 3) is selective for IC IgG and does not modulate the binding of FcRn to monomeric IgG. The claimed bispecific antibody further does not result in hypogammaglobulinemia per claim 81.
While the specification teaches that FcRn, IgG, and FcyR can form a ternary complex under acidic conditions (see, e.g., Para. 0252 and Para. 0292 of Example 3) and hypothesizes that a bispecific that binds to both FcRn and FcyR could permit the selective targeting and thus depletion of ICs while sparing monomeric IgG from degradation such that hypogammaglobulinemia is prevented (Para. 0253-0254), there is no evidence showing that the claimed bispecific antibody achieves this selectivity. In particular, there does not appear to be any data presented showing (i) a tested bispecific antibody causes preferential uptake/degradation of ICs versus monomeric IgG, (ii) the bispecific localizes only to IC-containing endosomes while leaving FcRn recycling of monomeric IgG intact, or (iii) that epitope/valency/linker choices of the bispecific antibody reliably produce the asserted selectivity.
Indeed, the CD32a binding arm MDE-8 of the claimed bispecific antibody prevents the engagement of immune-complexed IgG with FcyRIIa (CD32a) (Para. 0263). Thus, the claimed bispecific antibody would be expected to block uptake of IC IgG rather than facilitate its selective trafficking into acidic endosomes where it can interact with FcRn. Further, monomeric IgG continues to enter FcRn endosomes via fluid-phase pinocytosis (Pyzik et al, see “FcRn as a recycling receptor” section on Pages 4-5; Figure 2 legend), and the FcRn-binding arm of the bispecific would be expected to block recycling of all IgG – including monomeric IgG – present in those compartments and thus lead to hyogammaglobulinemia. Thus, without further evidence artisans would not reasonably expect the claimed bispecific anti-FcRn x CD32a antibody to selectively target IC IgG but not modulate the interaction between FcRn and monomeric IgG, thus sparing monomeric IgG from degradation and preventing hypogammaglobulinemia.
The reported in-vivo findings with the anti-FcRn antibody DVN24—showing reduced inflammation at low doses without measurable serum IgG loss (Para. 0307-0308)—can be explained by pharmacologic dose effects and do not establish a mechanistic selectivity for immune complexes. For example, the FcRn inhibitory antibodies rozanolixizumab and SYNT1001 (presently claimed) causes a dose-dependent decrease in circulating IgG levels (see Kiessling et al, Abstract; and Blumberg et al, see “Pharmacodynamics” section on Page 4, respectively). This data does not support the hypothesis that the claimed bispecific antibody comprising the FcRn binding domain of SYNT001 and the CD32a binding domain of MDE-8 can selectively target immunocomplexed IgG while sparing monomeric IgG.
Accordingly, while the specification describes the structural combination of known FcRn- and CD32A-binding domains, it does not enable one of ordinary skill in the art to make and use such bispecific antibodies with the claimed functional property of preferential immune-complex targeting.
Claim 7 recites that the bispecific antibody construct can be a dAb2-IgG, dAb-IgG, or dAb-Fc-dAb.
It is well-known in the art that, in order to bind antigen, an antibody or antigen-binding fragment must have six complementarity defining regions (CDRs) (Janeway, see selection, in particular section 3-6) (Janeway, Charles A. "Immunobiology: The Immune System in Health and Disease." 2001). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chain, and not either alone, that determines the final antigen specificity. The antigen-binding domains of the claimed bispecific antibody are derived from conventional antibodies that require six CDRs as stipulated by independent claim 1 or 79; yet, the bispecific construct can contain domain antibodies (dAb) per claim 7. A domain antibody (dAb) has only a single domain (VH or VL) and thus at most only three CDRs (see Bates et al, Section 2.3.2) (Bates, Adam, and Christine A. Power. "David vs. Goliath: the structure, function, and clinical prospects of antibody fragments." Antibodies 8.2 (2019): 28.). Thus, domain antibodies (dAb) have less than the six CDRs required for antigen binding by a conventional antibody domain. Thus, artisans would not reasonably expect a bispecific antibody construct that comprises a dAb having less than six CDRs required for antigen binding to be capable of binding to the target antigens.
The claims therefore fail to satisfy the enablement requirement of 35 U.S.C. § 112(a).
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, 5, 25, 27, 30, and 78-82 are rejected under 35 U.S.C. 103 as being unpatentable over Blumberg et al (WO2015164605A1, of record), hereinafter Blumberg, Van de Winkel et al (WO2006039418, of record), hereinafter Van de Winkel, Hearn et al (WO2016183352A1, of record), hereinafter Hearn, Yang et al (Yang, Fa, Weihong Wen, and Weijun Qin. "Bispecific antibodies as a development platform for new concepts and treatment strategies." International journal of molecular sciences 18.1 (2016): 48, of record), hereinafter Yang, and Kim et al (US20160017058A1, of record), hereinafter Kim.
Blumberg teaches a bispecific antibody for treating an immune-mediated disease in a subject comprising a first binding domain that binds to a Fcy receptor and a second binding domain that binds to FcRn, wherein the subject is human and the antibodies are human antibodies (see entire document, in particular, Abstract, Summary of Invention, specifically Para. 0008 and Para. 0022, and Claims).
Blumberg does not specifically teach that the first binding domain binds to the human type I Fc receptor CD32a and a human FcRn.
However, Van de Winkel teaches anti-CD32 antibodies that inhibit FcyRIIa ligand binding, down-modulate surface expression of FCyRIIa, inhibit autoimmune hemolytic anemia, and binds the FcyRIIa-H131 variant specifically (see entire document, in particular, Abstract, Claims, Summary of Invention, and Claims). In particular, disclosed are the anti-CD32a antibody MDE-8 having the CDRs of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, corresponding to SEQ ID NOs: 4, 26, 48, 70, 92, and 116 of the instant claims (see entire document, in particular, Summary of Invention and Pages 26-27).
Hearn further teaches the anti-human FcRn antibody SYNT001 for use in treating autoimmune disorders, which comprises six CDRs having the amino acid sequences of SEQ ID NOs: 2, 4, 55, 6, 8, and 68, corresponding to SEQ ID NOs: 171, 173, 189, 192, 194, and 200 of the instant claims, and bind to an epitope of FcRn that overlaps the binding site for the Fc domain of IgG and reduce or inhibit binding of FcRn to IgG and IgG as an immune complex (see entire document, in particular, Abstract, Summary of Invention, Para. 0018, and Claim 8). Blockade of FcRn-IgG interaction can be used to promote degradation of pathogenic IgG antibodies such as to treat IgG mediated autoimmune diseases as well as inhibit production of inflammatory cytokines by innate immune cells and antigen activated T cells (Para. 0006-0010).
Yang further teaches that in a bispecific antibody the interchain linker determines the movement flexibility between the two antigen-binding domain and optimize the ability of the antigen-binding domains to bind both the target antigens (see entire document, in particular, Section 2.1).
Kim further teaches bispecific antibody formats in which the first and second antigen-binding domains (referred to as X and Y) are separated, e.g. via a linker, such that the distance between the domains is less than or equal to about 50, 45, 43, 42, 41, or 40 angstroms (see entire document, in particular, Para. 0009, Para. 0015, and Para. 0116).
It would have been obvious to one of ordinary skill in the art to modify the bispecific anti- Fc gamma receptor x FcRn antibody for use in treating an immune-mediated disease in a human subject disclosed by Blumberg such that 1) the anti-FcyR binding domain is substituted with the anti-CD32a antibody MDE-8 disclosed by Van de Winkel; 2) the anti-FcRn binding domain is substituted with the anti-human FcRn antibody SYNT1001 disclosed by Hearn; and 3) the first and second antigen binding domains are separated via a linker at a distance between about 10 to 100 angstroms (Å) or 15 to 45 Å as taught by Yang and Kim. One of ordinary skill in the art would have been motivated to do so since the anti-CD32a antibodies can inhibit FcyRIIa ligand binding, down-modulate surface expression of FcyRIIa, and inhibit an autoimmune disorder and taught by Van de Winkel; and the anti-human FcRn antibody SYNT001 reduces/inhibits binding of FcRn to IgG and thus can be used to promote degradation of pathogenic IgG antibodies in autoimmune disorders and inhibit production of inflammatory cytokines by innate immune cells and antigen activated T cells as taught by Hearn. Further, 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). Artisans would have also been motivated to use an interchain linker between the antigen-binding domains of the bispecific antibody in order to optimize movement flexibility between the said domains and the ability of the antigen-binding domains to bind to both target antigens as taught by Yang. The courts have held that "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Thus, it would have been obvious to artisans to determine by routine experimentation the optimum distance between the FcRn and CD32a antigen-binding domains of the bispecific antibody. Of note, statements regarding i) the preferential binding of the claimed bispecific antibody to FcRn and CD32a to prevent interactions with immunocomplexed IgG (claim 1); ii) the selectivity of the claimed bispecific antibody for immunocomplexes but not monomeric IgG (claim 1); and iii) the prevention of hypogammaglobulinemia (claim 81) are statements of intended result that do not impart further limitations on the claimed structure and thus are not given patentable weight. Nevertheless, per the instant claims, the recited structure of the bispecific anti-FcRn x CD32a antibody is minimally required 1) to selectively inhibit interaction between a type I Fc receptor, FcRn, and an immunocomplexed antibody but not modulate the binding of FcRn to monomeric IgG antibodies and 2) to not result in hypogammaglobinemia. Thus, a bispecific anti-FcRn x CD32a antibody encompassed by the combined teachings of the cited art would have the presumed functional properties recited in the claims. Therefore, one of ordinary skill in the art would expect that a bispecific anti-CD32a x FcRn antibody having an interchain linker that gives a distance of 40 to 50 Å between the antigen-binding domains can effectively treat immune-mediated disorders in a subject.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Blumberg in view of Van de Winkel , Hearn, Yang, and Kim as applied to claims above 1, 5, 25, 27, 30, and 78-82 further in view of Carter et al (Carter, Paul. Journal of immunological methods 248.1-2 (2001): 7-15.), hereinafter Carter.
The teachings of Blumberg in view of Van de Winkel, Hearn, Yang, and Kim have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the bispecific antibody construct is a knob-into-holes format.
However, Carter teaches that production of bispecific IgG by the co-expression of two different antibodies is highly inefficient due to unwanted pairings of the component heavy and light chains. Due to the formation of homodimers, the purification of the desired bispecific antibody has a maximum possible yield of 50%. To overcome this problem, heavy chains can be remodeled for heterodimerization using “knob-into-holes” mutations. In this approach, a knob mutant is obtained by replacement of a small amino acid residue with a larger one (e.g. T366W) in the first CH3 domain, wherein the knob inserts into a hole in the second CH3 domain created by replacement of a large residue with a smaller one (e.g. Y407T) (see entire document, in particular, Abstract and Section 3.1).
It would have been obvious to one of ordinary skill in the art to use the “knobs-into-holes” technique to produce the bispecific anti-FcRn x CD32a antibodies taught by Blumberg in view of van de Winkel and Hearn. One of ordinary skill in the art would have been motivated to do so in order to promote heterodimerization of the corresponding heavy chains of two different antibodies and prevent the unwanted pairings of component heavy and light chains. Therefore, one of ordinary skill in the art would expect that the knobs-into-holes technique can effectively produce the bispecific anti-FcRn x CD32a antibodies taught by Blumberg in view of Van De Winkel, Hearn, Yang, and Kim at a higher yield.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 5, 25, 27, 30, and 78-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 10626175B2 in view of Blumberg et al (WO2015164605A1, of record), hereinafter Blumberg, Van de Winkel et al (WO2006039418, of record), hereinafter Van de Winkel, Yang et al (Yang, Fa, Weihong Wen, and Weijun Qin. "Bispecific antibodies as a development platform for new concepts and treatment strategies." International journal of molecular sciences 18.1 (2016): 48, of record), hereinafter Yang, and Kim et al (US20160017058A1, of record), hereinafter Kim.
The issued claims recite an anti-FcRn antibody or antigen-binding fragment having the CDRs of SEQ ID NOs: 2, 4, 55, 6, 8, and 10, corresponding to SEQ ID NOs: 171, 173, 189, 192, 194, and 200 of the instant claims (issued claim 1).
The issued claims do not recite a composition comprising a first and second antigen binding domain that specifically binds CD32a and human FcRn to selectively inhibit interaction between a type I Fc receptor, FcRn, and an immunocomplexed antibody, wherein the anti-CD32a binding domain has the CDRs of MDE-8.
However, Blumberg teaches a bispecific antibody for treating an immune-mediated disease in a subject comprising a first binding domain that binds to a Fcy receptor and a second binding domain that binds to FcRn, wherein the subject is human and the antibodies are human antibodies (see entire document, in particular, Abstract, Summary of Invention, specifically Para. 0008 and Para. 0022, and Claims).
Van de Winkel further teaches anti-CD32 antibodies that inhibit FcyRIIa ligand, down modulates surface expression of FCyRIIa, inhibit autoimmune hemolytic anemia, and binds the FcyRIIa-H131 variant specifically (see entire document, in particular, Abstract, Claims, Summary of Invention, and Claims). In particular, disclosed are the anti-CD32a antibody MDE-8 having the CDRs of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, corresponding to SEQ ID NOs: 4, 26, 48, 70, 92, and 116 of the instant claims (see entire document, in particular, Summary of Invention and Pages 26-27).
Yang further teaches that in a bispecific antibody the interchain linker determines the movement flexibility between the two antigen-binding domain and optimize the ability of the antigen-binding domains to bind both the target antigens (see entire document, in particular, Section 2.1).
Kim further teaches bispecific antibody formats in which the first and second antigen-binding domains (referred to as X and Y) are separated, e.g. via a linker, such that the distance between the domains is less than or equal to about 50, 45, 43, 42, 41, or 40 angstroms (see entire document, in particular, Para. 0009, Para. 0015, and Para. 0116).
It would have been obvious to one of ordinary skill in the art to modify the anti-FcRn antibody of the issued claims into a bispecific anti- Fc gamma receptor x FcRn format disclosed by Blumberg wherein the first antigen binding domain is substituted with the anti-CD32a antibody MDE-8 disclosed by Van de Winkel; and the first and second antigen binding domains are separated via a linker at a distance between about 10 to 100 angstroms (Å) or 15 to 45 Å as taught by Yang and Kim. One of ordinary skill in the art would have been motivated to do so to effectively treat an immune-mediated disease in a human subject. Further, 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). In addition, artisans would have been motivated to use an interchain linker between the antigen-binding domains of the bispecific antibody in order to optimize movement flexibility between the said domains. The courts have held that "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Thus, it would have been obvious to artisans to determine by routine experimentation the optimum distance between the FcRn and CD32a antigen-binding domains of the bispecific antibody. Of note, statements regarding i) the preferential binding of the claimed bispecific antibody to FcRn and CD32a to prevent interactions with immunocomplexed IgG (claim 1); ii) the selectivity of the claimed bispecific antibody for immunocomplexes but not monomeric IgG (claim 1); and iii) the prevention of hypogammaglobulinemia (claim 81) are statements of intended result that do not impart further limitations on the claimed structure and thus are not given patentable weight. Nevertheless, per the instant claims, the recited structure of the bispecific anti-FcRn x CD32a antibody is minimally required 1) to selectively inhibit interaction between a type I Fc receptor, FcRn, and an immunocomplexed antibody but not modulate the binding of FcRn to monomeric IgG antibodies and 2) to not result in hypogammaglobinemia. Thus, a bispecific anti-FcRn x CD32a antibody encompassed by the combined teachings of the cited art would have the presumed functional properties recited in the claims. Therefore, one of ordinary skill in the art would expect that a bispecific anti-CD32a x FcRn antibody having an interchain linker that gives a distance of 40 to 50 Å between the antigen-binding domains can effectively treat immune-mediated disorders in a subject.
Claim 7 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 10626175B2 in view of Blumberg, Van de Winkel, Yang, and Kim, as applied to claims above 1, 5, 25, 27, 30, and 78-82 and further in view of Carter et al (Carter, Paul. Journal of immunological methods 248.1-2 (2001): 7-15.), hereinafter Carter.
The teachings of the issued claims in view of Blumberg, Van de Winkel, Yang, and Kim have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the bispecific antibody construct is a knob-into-holes format.
However, Carter teaches that production of bispecific IgG by the co-expression of two different antibodies is highly inefficient due to unwanted pairings of the component heavy and light chains. Due to the formation of homodimers, the purification of the desired bispecific antibody has a maximum possible yield of 50%. To overcome this problem, heavy chains can be remodeled for heterodimerization using “knob-into-holes” mutations. In this approach, a knob mutant is obtained by replacement of a small amino acid residue with a larger one (e.g. T366W) in the first CH3 domain, wherein the knob inserts into a hole in the second CH3 domain created by replacement of a large residue with a smaller one (e.g. Y407T) (see entire document, in particular, Abstract and Section 3.1).
It would have been obvious to one of ordinary skill in the art to use the “knobs-into-holes” technique to produce the bispecific anti-FcRn x CD32a antibodies taught by the issued claims in view of Blumberg, Van de Winkel, Yang, and Kim. One of ordinary skill in the art would have been motivated to do so in order to promote heterodimerization of the corresponding heavy chains of two different antibodies and prevent the unwanted pairings of component heavy and light chains. Therefore, one of ordinary skill in the art would expect that the knobs-into-holes technique can effectively produce the bispecific anti-FcRn x CD32a antibodies taught by issued claims in view of Blumberg, Van de Winkel, Yang, and Kim at a higher yield.
Response to Arguments
Applicant's arguments filed 07/25/2025 have been fully considered but they are not persuasive.
With respect to the 103 rejections, Applicant argues that it was known in the art that anti-FcRn agents bind to and deplete all IgG-with no differentiation reported between effects on monomeric IgG and immunocomplexed IgG. The Blumberg reference is clear that the goal of their treatments is “decreasing the IgG levels” -generically and with no reference to any kind specificity. Applicant notes that immunocomplexed IgG represents a very small portion of total IgG; thus, when a reference reports, e.g. a 50% reducing in serum or total IgG, the reduction must be primarily a reduction in monomeric IgG.
Applicant further argues that the Office is not permitted to argue that Blumberg's antibodies could have been specific for immunocomplexed IgG since Blumberg does not teach that their anti-FcRn agents have specificity for immunocomplexed IgG. Therefore, Applicant asserts that any such activity which is merely theorized by the Office and not disclosed in the art cannot form the basis of an obviousness rejection.
Thus, it is a matter of record that on the basis of the cited art and the evidence provided by Applicant, that the established function of an anti-FcRn antibody, alone or in combination with other antibodies, was to bind FcRn, thereby reducing IgG levels without regard to the type of IgG, and thus to cause hypogammaglobulinemia. Nothing in the cited art suggests that specificity for the type of IgG was possible, much less how to achieve it. One of ordinary skill in the art, combining any anti-FcRn and anti- CD32a with a linker of any size (assuming merely en arguendo that there was a teaching and/or motivation to do so), would predict the result of a bispecific reagent that would - according to the established function of anti-FcRn agents - reduce the level of all IgG and lead to hypogammaglobulinemia.
Applicant further argues that the claimed compositions are more than predictable use of prior art elements according to their established functions, stating that the claimed bispecific antibody would not have been predicted to have the ability to selectively target IC IgG without modulating binding of FcRn binding to monomeric IgG, thereby reducing the occurrence of hypogammaglobulinemia. Applicant further submits that the cited art does not teach how to specifically interfere with the small subset of IgG antibodies that form an immune complex with antigen and cause autoimmune diseases through their interactions with FcRn and classical Fcy receptors such as CD32a. Such activities can only be optimally inhibited if both FcRn and CD32a are simultaneously blocked on a cell that expresses both of these receptors. Agents that only inhibit FcRn will reduce circulating IgG antibodies but not optimally inhibit the activities of IgG immune complexes that are associated with autoimmune diseases including their ability to stimulate inflammatory cytokines and cause tissue damage. Thus, full interruption of an IgG immune complex induced inflammatory cascade requires dual blockade of FcRn and FcyR as achieved with a bispecific antibody. None of the foregoing is taught or suggested by the cited art, and the instant claims are therefore more than the predictable use of prior art elements according to their established functions.
Lastly, Applicant argues that the Office is improperly relying on routine experimentation doctrine, stating that the art does not teach or suggest the possibility of the specificity and improved safety profile of the claimed compositions. Thus, there was no basis for predicting such results, and the significance of the results clearly exceed the threshold the CCPA established for "different in kind." Accordingly, the recited compositions are not the result of routine optimization.
In response to Applicant’s arguments, the Examiner reiterates that the combined teachings of the prior art disclose bispecific antibodies comprising the FcRn-binding domain of SYNT001 and the CD32a-binding domain of MDE-8. Further, optimal spacing/orientation between the binding domains can be achieved via routine optimization. Therefore, it would have been obvious to produce the claimed bispecific antibodies with FcRn- and CD32a-binding arms positioned at the recited distances by routine experimentation. By Applicant’s own submission, “full interruption of an IgG immune complex induced inflammatory cascade requires dual blockade of FcRn and FcyR as achieved with a bispecific antibody”. As such, unlike anti-FcRn agents, the bispecific FcRn x FcyR antibody taught by the combined teachings of the prior art would “optimally inhibit the activities of IgG immune complexes that are associated with autoimmune diseases including their ability to stimulate inflammatory cytokines and cause tissue damage”.
However, while the claimed structure would have been obvious to prepare based on the combined art teachings, the specification fails to enable the claimed functional result—namely, that such bispecific antibodies are selective for immune-complexed IgG and do not modulate FcRn binding to monomeric IgG such that hypogammaglobulinemia is prevented (as discussed further in the 112(a) enablement rejection above). The specification teaches that FcRn, IgG, and FcyR can form a ternary complex in an acidified intracellular environment and uses this finding as a basis to predict the functionality of a bispecific FcRn x FcyR antibody having the claimed structure; however, it does not provide actual evidence of that the claimed bispecific antibody selectively targets IC IgG while sparing monomeric IgG. The CD32a binding arm MDE-8 of the claimed bispecific antibody prevents the engagement of immune-complexed IgG with FcyRIIa (CD32a); and thus, the claimed bispecific antibody would be expected to block uptake of IC IgG rather than facilitate its selective trafficking into acidic endosomes where it can interact with FcRn. Further, monomeric IgG continues to enter FcRn endosomes via fluid-phase pinocytosis, and the FcRn-binding arm of the bispecific would be expected to block recycling of all IgG – including monomeric IgG – present in those compartments and thus lead to hypogammaglobulinemia. In view of the foregoing and absent of further evidence, artisans would not reasonably expect the claimed bispecific anti-FcRn x CD32a antibody to selectively target IC IgG while sparing monomeric IgG to prevent hypogammaglobulinemia.
Even if FcRn and CD32a were co-expressed on the cell surface (as applicant appears suggest at the beginning of the 2nd paragraph on Page 7 of the Remarks), the specification still does not provide a mechanism of action to explain how the claimed bispecific antibody would selectively target immune-complexed IgG and promote its degradation while sparing monomeric IgG in view of the activities of the FcRn and CD32a binding arms of said antibody.
As such, the specification itself has failed to demonstrate the alleged specificity and improved safety profile of the claimed compositions, and the claimed structure at least can be achieved via routine experimentation. Accordingly, the claimed structure is taught by the prior art, but the purported functional property is not enabled across the full scope of the claims under 35 U.S.C. §112(a).
With respect to the rejections made under double patenting, Applicant argues that the ‘175 patent is alleged to teach no more than an anti-FcRn antibody or antigen-binding fragment. Applicant asserts that for at least the foregoing reasons regarding the 35 USC 103 rejection this does not relieve the deficiencies of the cited prior art.
In response to Applicant’s arguments, the Examiner notes that the issued claims are not limited to monospecific antibodies. The term ‘antibody’ or ‘antigen-binding fragment’ is not specifically defined within the context of the issued specification and thus does not exclude bispecific or multispecific antibody formats. Further, the term ‘comprising’ recited in the claims is open-ended and does not exclude additional unrecited elements (see MPEP 2111.03). As such, the antibody of the issued claims can be modified into a bispecific format that not only binds to FcRn but also FcyR (e.g. CD32a) in order to treat immune-mediated diseases as taught by the combined teachings of the prior art. The Examiner further maintains position against Applicant’s argument regarding the alleged selectivity of the claimed bispecific anti-FcRn x CD32a antibody for immunocomplexed IgG as discussed above. Thus, the double patenting rejection over the ‘175 patent is maintained.
Applicant has requested that the non-statutory double patenting rejections are held in abeyance until allowable subject matter has been indicated. Since no terminal disclaimers have been filed and no amendments have been made to the instant claims such that they represent patentably distinct inventions, the double patenting rejections previously set forth over the issued patent is maintained.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641