DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
The rejections of claims 12 and 91 are moot in view of the cancelation of the claims.
The rejection of claims 6, 15, 81 and 84-87 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the amendment to claims 6, 15 and 84-87 removing the range of % identities and to claim 81 removing the “such as” phrase.
The rejection of claim 91 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in view of the cancelation of claim 91.
The rejection of claim(s) 1, 6, 42, 47, 81, 83-85 and 88-91 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0158772 A1 (Thompson) in view of US Patent 9,486,520 B2 (Borrebaeck) and Moran et al. (Curr. Opin. Immunol. 25:230–237, 2013) and US 2015/0175707 A1 (Jong) is withdrawn in view of the cancelation of claim 91 and amendment incorporating the limitations of claim 12 in claim 1.
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.
A) Claims 1, 6, 15, 42, 47, 81, 83-90 and 92-95 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 10, 14, 19, 22-24, 28-30, 34, 40, 45, 47, 73 and 80 of copending Application No. 18/549,346 (‘346) (reference application) for the reasons set forth in the previous Office action.
Although the claims at issue are not identical, they are not patentably distinct from each other because claims of both applications require a binding agent that binds both CD40 and CD137 and have the same VH and VL sequences. The instant claims are drawn to a multispecific antibody comprising a CD40-binding site comprising a VH of SEQ ID NO:117 and VL of SEQ ID NO:121 and a CD137-binding site comprising a VH of SEQ ID NO:123 and VL of SEQ ID NO:127, which are identical respectively to SEQ ID NO: 9, 10, 19 and 20 of ‘346. While the claims of ‘346 are drawn to a method of treating cancer or a composition comprising the binding agent (claim 73), the instantly claimed multispecific antibody is anticipated by the composition and its use in the methods of ‘346. Additionally, both applications claim wherein the first and second heavy chains comprise one or more substitutions of amino acids in the positions corresponding to positions L234, L235, D265, N297, and P331 in a human IgG1 heavy chain according to EU numbering, are not L, L, D, N, and P, respectively (see claims 29 and 30 of ‘346, and instant claims 42 and 47). Both claim wherein each of the heavy chain (CH) regions has at least one of the amino acids substituted in the positions corresponding to a position selected from the group consisting of T366, L368, K370, D399, F405, Y407, and K409 in a human IgG1 heavy chain according to EU numbering and the first and said second CH are not substituted in the same positions (claims 19, 22, 23, 28, 30, 34 of ‘346 and instant claims 88-91).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
B) Claims 1, 6, 15, 42, 47, 81, 83-90 and 92-95 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 8, 11, 15, 20, 23-24, 26, 30, 35, 41, 48, 78, 79, 81, 85 and 86 of copending Application No. 18/579,086 (‘086) (reference application) for the reasons set forth in the previous Office action.
Although the claims at issue are not identical, they are not patentably distinct from each other because claims of both applications require a binding agent that binds both CD40 and CD137 and have the same VH and VL sequences. The instant claims are drawn to a multiispecific antibody comprising a CD40-binding site comprising respectively a VH of SEQ ID NO:117 or 6 and VL of SEQ ID NO:121 or 7 and a CD137-binding site comprising a VH of SEQ ID NO:123 or 69 and VL of SEQ ID NO:127 or 70, which are identical respectively to SEQ ID NO: 9 or 6, 10 or 7, 19 or 17 and 20 or 18 of ‘086. While the claims of ‘086 are drawn to a method of treating cancer or a kit comprising the binding agent (claims 78, 79, 81 and 86), the instantly claimed multispecific antibody is anticipated by the kit comprising the CD40xCD137 binding agent and the binding agent’s use in the methods of ‘086. Additionally, both applications claim wherein the first and second heavy chains comprise one or more substitutions of amino acids in the positions corresponding to positions L234, L235, D265, N297, and P331 in a human IgG1 heavy chain according to EU numbering, are not L, L, D, N, and P, respectively (see claims 24, 26, and 30 of ‘086, and instant claims 42 and 47). Both claim wherein each of the heavy chain (CH) regions has at least one of the amino acids substituted in the positions corresponding to a position selected from the group consisting of T366, L368, K370, D399, F405, Y407, and K409 in a human IgG1 heavy chain according to EU numbering and the first and said second CH are not substituted in the same positions (claims 20, 23, 24, 30 of ‘086 and instant claims 88-91).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
C) Claims 1, 6, 15, 42, 47, 81, 83-90 and 92-95 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 39, 40, 43-51, 63, 85 and 90 of copending Application No. 18/861,928 (‘928) (reference application) for the reasons set forth in the previous Office action.
Although the claims at issue are not identical, they are not patentably distinct from each other because claims of both applications require a binding agent that binds both CD40 and CD137 and have the same VH and VL sequences. The instant claims are drawn to a multispecific antibody comprising a CD40-binding site comprising respectively a VH of SEQ ID NO:117 or 6 and VL of SEQ ID NO:121 and a CD137-binding site comprising a VH of SEQ ID NO:123 and VL of SEQ ID NO:127, which are identical respectively to SEQ ID NO: 49, 50, 56 and 57 of ‘928. While the claims of ‘928 are drawn to a method of treating cancer or a kit or a pharmaceutical composition comprising the binding agent (claims 1-3, 39, 40, 43, 44, 63, 85 and 90), the instantly claimed multispecific antibody is anticipated by the kit comprising the CD40xCD137 binding agent and the binding agent’s use in the methods of ‘928. Additionally, both applications claim wherein the first and second heavy chains comprise one or more substitutions of amino acids in the positions corresponding to positions L234, L235, D265, N297, and P331 in a human IgG1 heavy chain according to EU numbering, are not L, L, D, N, and P, respectively (see claims 46-47, 49 of ‘928, and instant claims 42 and 47). Both claim wherein each of the heavy chain (CH) regions has at least one of the amino acids substituted in the positions corresponding to a position selected from the group consisting of T366, L368, K370, D399, F405, Y407, and K409 in a human IgG1 heavy chain according to EU numbering and the first and second CH are not substituted in the same positions (claims 48-51 of ‘928 and instant claims 88-91).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
D) Claims 1, 6, 15, 42, 47, 81, 83-90 and 92-95 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 82 and 90-101 (added by amendment 6/11/2026) of copending Application No. 19,133,873 (‘873) (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because claims of both applications claim a binding agent that binds both CD40 and CD137 and have the same VH and VL sequences. The method of ‘873 of using the binding agent renders obvious the binding agent itself. The instant claims are drawn to a multispecific antibody comprising a CD40-binding site comprising a VH of SEQ ID NO:117 and VL of SEQ ID NO:121 and a CD137-binding site comprising a VH of SEQ ID NO:123 and VL of SEQ ID NO:127, which are identical respectively to SEQ ID NO: 9, 10, 19 and 20 of ‘873 (see claim 90). Additionally, the claims specify wherein the first and second heavy chains comprise a substitution of one or more amino acids in the positions corresponding to positions L234, L235, D265, N297, and P331 in a human IgG1 heavy chain according to EU numbering are not L, L, D, N, and P, respectively (see claim 97 of ‘873, and instant claims 42 and 47). Both claim wherein each of the heavy chain (CH) regions has at least one of the amino acids substituted in the positions corresponding to a position selected from the group consisting of T366, L368, K370, D399, F405, Y407, and K409 in a human IgG1 heavy chain according to EU numbering and the first and said second CH are not substituted in the same positions (claims 93-95 of ‘873 and instant claims 88-91).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant requests (p.10 of REMARKS) that the rejections under provisional nonstatutory double patenting be held in abeyance until all other rejections have been resolved. The request has been fully considered but is not persuasive. Even though the rejections under provisional and nonprovisional nonstatutory double patenting are the only remaining rejections, they cannot be held in abeyance and are maintained for the reasons of record.
a) Claims 1, 6, 15, 42, 47, 81, 83-90 and 92-95 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 10,457,735 B2 (‘735) in view of Moran et al. (Curr. Opin. Immunol. 25:230–237, 2013) and US 2015/0175707 (Jong) for the reasons set forth in the previous Office action.
The claims at issue are not identical but they are not patentably distinct from each other because the patent claims a method of inducing T cell activation by administering an antibody that binds both CD40 and CD137, and the instant claims are drawn to a multispecific antibody which is anticipated by the antibody used in the patented method wherein the VH and VL of each antibody antigen-binding domain are identical to those of the instantly claimed multispecific antibody that binds both CD40 and CD137. The instant claims are drawn to a multispecific antibody comprising a CD40-binding site comprising a VH of SEQ ID NO:6 and VL of SEQ ID NO:7 and a CD137-binding site comprising a VH of SEQ ID NO:69 and VL of SEQ ID NO:70, which are identical respectively to SEQ ID NO:2321, 2322, 2241 and 2242 of ‘735, which inherently comprise the CDRs therein (claims 1-3 of ‘735, instant claims 1, 6, 12, 15, 83-87, 92-95). ‘735 does not claim wherein the antibody comprises two heavy chains comprising human IgG1 Fc domains, including wherein there is at least one amino acid substitution in the positions corresponding to positions L234, L235, D265, N297, and P331 in a human IgGl heavy chain according to EU numbering, are not L, L, D, N, and P, respectively, (instant claims 42 and 47) and/or a substitution of at least one of T366, L368, K370, D399, F405, Y407, and K409 according to EU numbering and for the latter substitution wherein the first and said second CH are not substituted in the same positions (instant claims 88-91). Nor does ‘735 claim a kit comprising the multispecific antibody ad instructions (instant claim 81).
Moran et al. teaches that antibody immunotherapy for tumors helps to overcome immune suppression by increasing the number and function of antigen presenting cells (APCs) and T cells, leading to tumor regression (p. 230, col. 2, second paragraph). “Optimal activation of naïve T cells requires a strong T cell receptor peptide antigen-MHC interaction along with engagement of costimulatory molecules expressed by APCs… [T]hus costimulation is indispensable for a functional T cell response.” (p. 230, col. 2, third paragraph). It is taught that 4-1BB (CD137) is expressed on activated T cells, NK cells and other activated cells, including endothelial cells of some tumors. Agonist 4-1BB antibody therapies are CD8 T cell-dependent, promoting long-term anti-tumor memory T cell survival (p. 233, col. 2, first paragraph). 4-1BB agonist antibody has been shown to increase activated T cell infiltration into tumors in a tumor-bearing mouse (p. 230, last paragraph). CD40 is constitutively expressed on APCs and its activation promotes antigen presentation and cytokine production (Fig. 1 and p. 234, col. 1, third paragraph). “In addition, as was observed with anti-4-1BB antibody therapy, targeting CD40 with an agonist antibody also allowed T cells to overcome tolerance and promote tumor eradication in mouse models of disease [48–50] as CD40 is also expressed at the surface of a wide array of primary tumors. Therefore, targeting CD40 might exert its anti-tumor activity by two distinct mechanisms; directly, antiCD40 induces antibody-dependent phagocytosis of tumor cells and inhibits CD40-CD40L induced tumor proliferation and indirectly by activating the anti-tumor immune response via APC maturation.” (p. 234, end of col. 1) In a study with mice and humans, an agonistic CD40 antibody with gemcitabine showed dendritic cell- and T cell-independent antitumor activity, instead acting on CD40-expressing macrophages. “These results demonstrate and highlight the importance of both innate and adaptive immune responses in mediating tumor regression. Moreover, the pleiotropic effects of mAb therapies that target this and other TNFR family members make them ideal targets for single agent and combination immunotherapy.” (p. 234, col. 2, third paragraph)
US 2015/0175707 (Jong) teaches antibodies with modification in their IgG Fc regions to either promote heterodimerization of two different heavy/light chain pairs or to reduce Fc receptor binding by the Fc region. In [0345] it teaches:
[0345] Thus, in one embodiment the present invention relates to a heterodimeric protein according to the present invention, wherein [0346] the amino acid in a position selected from K409, T366, L368, K370, D399, F405, and Y407 is not K, T, L, K, D, F and Y, respectively, in the first polypeptide, and [0347] the amino acid in a position selected from F405, T366, L368, K370, D399, Y407, and K409 is not F, T, L, K, D, Y and K, respectively, in the second polypeptide.
[0348] In a particular embodiment of the heterodimeric protein, the amino acid in position K409 is R in the first polypeptide, and the amino acid in position F405 is L in the second polypeptide.
Additionally, the antibody may comprise a substitution at L234, L235, D265, N297 ([0316]). “[0256] Based on this knowledge several variants were described to make Fc-domain inactive for interactions with Fcgamma receptors and C1q for therapeutic antibody development.
[0254] In another embodiment such further mutations may be mutations which inhibit or reduce the effector functions of the dimeric protein. In clinical applications where engagement of the immune system is not required and may even cause unwanted side-effects the first and/or second polypeptide of the dimeric protein may then be further mutated in the CH2 domain to abolish C1q and/or FcGammaReceptor interactions.
[0257] For IgG1 mutating L234A and L235A and P331S were described (Hezareh M, et al., J Virol 2001, 75:12161-12168, Xu D et al. Cell Immunol 2000, 200:16-26, Shields R L, et al. J Biol Chem 2001, 276:6591-6604) and L234A combined with L235A was used in the clinic (Herold K C, et al. Diabetes 2005, 54:1763-1769). Hence, in one embodiment, the amino acid in at least one position corresponding to L234, L235 and P331, may be A, A and S, respectively.
[0258] Also mutating these same positions to L234F and L235E was described to result in Fc-domains with abrogated interactions with FcGammaReceptors and C1q (Oganesyan Acta Cryst. (2008). D64, 700-704, Canfield & Morrison, 1991 J Exp Med.; 173:1483-91., Duncan, 1988 Nature 332:738-40). Hence, in one embodiment, the amino acids in the positions corresponding to L234 and L235, may be F and E, respectively.
[0259] Mutating position D265A showed decreased binding to all Fc.gamma.Receptors and prevented ADCC (Shields R L et al. J Biol Chem 2001, 276:6591-6604). Hence, in one embodiment, the amino acid in a position corresponding to D265, may be A.
[0260] Binding to C1q could be abrogated by mutating positions D270, K322, P329, and P331 (Idusogie et al., J Immunol 2000, 164:4178-4184). Mutating these positions to either D270A or K322A or P329A or P331A made the antibody deficient in CDC activity. Hence, in one embodiment, the amino acids in at least one position corresponding to D270, K322, P329 and P331, may be A, A, A, and A, respectively.
[0261] An alternative approach to minimize the interaction of the Fc-domain with FcgammaReceptors and C1q is by removal of the glycosylation site of an antibody. Mutating position N297 to eg Q, A, and E removes a glycosylation site which is critical for IgG-Fcgamma receptor interactions (Tao and Morrison, J Immunol. 1989 Oct. 15; 143(8):2595-601, Bolt S et al., Eur J Immunol 1993, 23:403-411). Hence, in one embodiment, the amino acid in a position corresponding to N297, may be Q, A or E.
[0262] Alternatively, human IgG2 and IgG4 subclasses are naturally compromised in their interactions with C1q and FcgammaReceptors. However, residual interactions with Fc.gamma.Receptors (FcgammaReceptors) have been described (Parren et al., J Clin Invest 1992, 90:1537-1546.). Mutations abrogating these residual interactions have been described for both isotypes and result in reduction of unwanted side-effects associated with FcR binding. For IgG2 mutating L234A and G237A was described (Cole M S et al. J Immunol 1997, 159:3613-3621 and for IgG4 L235E was described (Reddy M P et al., J Immunol 2000, 164:1925-1933). Hence, in one embodiment, the amino acid in a position corresponding to L234 and G237 in a human IgG2 heavy chain, may be A and A, respectively. In one embodiment, the amino acid in a position corresponding to L235 in a human IgG4 heavy chain, may be E.”
[0266] Combining sets of mutations described above may result in an even more inert Fc-domain, for instance combining mutations L234F, L235E, D265A; or L234F, L235E, N297Q and D265A in an IgG1 Fc-domain or other variations generated by the information described above. Hence, in one embodiment, the amino acids in at least one or a combination of positions corresponding to L234, L235, D265; or L234, L235, N297 and D265, may be F, E, A, F, E, Q and A, respectively.
Such a multispecific antibody would have been obvious because agonist antibodies that bind CD40 and CD137 (4-1BB) had been shown to be effective in the treatment of cancer to overcome immune suppression as taught by Moran et al., each having similar but distinct antitumor effects. It would have been obvious wherein the bispecific antibody was a human IgG1 antibody in which each Fc region has one or more substitutions different between the two Fc region to promote heterodimerization so that each arm of the antibody comprises a different antibody binding site, i.e., one binding CD40 and one binding CD137, for example having a substitution of F405 in one Fc and K409 in the other as taught by Jong. It further would have been obvious wherein the Fc regions had reduced Fc receptor binding, particularly Fcgamma receptor-binding, in order to reduce unwanted side-effects associated with Fc receptor binding, for example having a combination of substitutions of L234F, L235E, D265A. It further would have been obvious to have a kit comprising the bispecific antibody binding CD40 and CD137 and instructions for use because this would facilitate tumor treatment or for detection of the antigens to which the antibody bound. Note that the intended use of the kit of instant claim 81 does not appear to change the contents of the kit.
b) Claims 1, 6, 15, 42, 47, 81, 83-90 and 92-95 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 10-20 of U.S. Patent No. 10,927,181 B2 (‘181) in view of Moran et al. (Curr. Opin. Immunol. 25:230–237, 2013) and US 2015/0175707 (Jong) for the reasons set forth in the previous Office action.
While the claims at issue are not identical, they are not patentably distinct from each other because both the patent claims an agonistic binding agent binding both CD40 and CD137, wherein the encoded VH and VL of each antigen-binding domain are identical to those of the instantly claimed multispecific antibody that binds both CD40 and CD137. The instant claims are drawn to a multispecific antibody comprising a CD40-binding site comprising a VH of SEQ ID NO:6 and VL of SEQ ID NO:7 and a CD137-binding site comprising a VH of SEQ ID NO:69 and VL of SEQ ID NO:70, which are identical respectively to SEQ ID NO:2321, 2322, 2241 and 2242 of ‘181, which inherently comprise the CDRs therein (claims 1-5, 13 and 17 of ‘181, instant claims 1, 6, 12, 15, 83-87, 92-95). ‘181 also claims a composition and kit comprising the agonistic bispecific binding agent (claims 10-12, 14-16 and 18-20 of ‘181, instant claim 81), but does not claim wherein the binding agent comprises two heavy chains comprising human IgG1 Fc domains, including wherein there is at least one amino acid substitution in the positions corresponding to positions L234, L235, D265, N297, and P331 in a human IgGl heavy chain according to EU numbering, are not L, L, D, N, and P, respectively (instant claims 42 and 47) and/or a substitution of at least one of T366, L368, K370, D399, F405, Y407, and K409 according to EU numbering and for the latter substitution wherein the first and second CH are not substituted in the same positions (instant claims 88-91).
Moran et al. teaches that antibody immunotherapy for tumors helps to overcome immune suppression by increasing the number and function of antigen presenting cells (APCs) and T cells, leading to tumor regression (p. 230, col. 2, second paragraph). “Optimal activation of naïve T cells requires a strong T cell receptor peptide antigen-MHC interaction along with engagement of costimulatory molecules expressed by APCs… [T]hus costimulation is indispensable for a functional T cell response.” (p. 230, col. 2, third paragraph). It is taught that 4-1BB (CD137) is expressed on activated T cells, NK cells and other activated cells, including endothelial cells of some tumors. Agonist 4-1BB antibody therapies are CD8 T cell-dependent, promoting long-term anti-tumor memory T cell survival (p. 233, col. 2, first paragraph). 4-1BB agonist antibody has been shown to increase activated T cell infiltration into tumors in a tumor-bearing mouse (p. 230, last paragraph). CD40 is constitutively expressed on APCs and its activation promotes antigen presentation and cytokine production (Fig. 1 and p. 234, col. 1, third paragraph). “In addition, as was observed with anti-4-1BB antibody therapy, targeting CD40 with an agonist antibody also allowed T cells to overcome tolerance and promote tumor eradication in mouse models of disease [48–50] as CD40 is also expressed at the surface of a wide array of primary tumors. Therefore, targeting CD40 might exert its anti-tumor activity by two distinct mechanisms; directly, antiCD40 induces antibody-dependent phagocytosis of tumor cells and inhibits CD40-CD40L induced tumor proliferation and indirectly by activating the anti-tumor immune response via APC maturation.” (p. 234, end of col. 1) In a study with mice and humans, an agonistic CD40 antibody with gemcitabine showed dendritic cell- and T cell-independent antitumor activity, instead acting on CD40-expressing macrophages. “These results demonstrate and highlight the importance of both innate and adaptive immune responses in mediating tumor regression. Moreover, the pleiotropic effects of mAb therapies that target this and other TNFR family members make them ideal targets for single agent and combination immunotherapy.” (p. 234, col. 2, third paragraph)
US 2015/0175707 (Jong) teaches antibodies with modification in their IgG Fc regions to either promote heterodimerization of two different heavy/light chain pairs or to reduce Fc receptor binding by the Fc region. In [0345] it teaches:
[0345] Thus, in one embodiment the present invention relates to a heterodimeric protein according to the present invention, wherein [0346] the amino acid in a position selected from K409, T366, L368, K370, D399, F405, and Y407 is not K, T, L, K, D, F and Y, respectively, in the first polypeptide, and [0347] the amino acid in a position selected from F405, T366, L368, K370, D399, Y407, and K409 is not F, T, L, K, D, Y and K, respectively, in the second polypeptide.
[0348] In a particular embodiment of the heterodimeric protein, the amino acid in position K409 is R in the first polypeptide, and the amino acid in position F405 is L in the second polypeptide.
Additionally, the antibody may comprise a substitution at L234, L235, D265, N297 ([0316]). “[0256] Based on this knowledge several variants were described to make Fc-domain inactive for interactions with Fcgamma receptors and C1q for therapeutic antibody development.
[0254] In another embodiment such further mutations may be mutations which inhibit or reduce the effector functions of the dimeric protein. In clinical applications where engagement of the immune system is not required and may even cause unwanted side-effects the first and/or second polypeptide of the dimeric protein may then be further mutated in the CH2 domain to abolish C1q and/or FcGammaReceptor interactions.
[0257] For IgG1 mutating L234A and L235A and P331S were described (Hezareh M, et al., J Virol 2001, 75:12161-12168, Xu D et al. Cell Immunol 2000, 200:16-26, Shields R L, et al. J Biol Chem 2001, 276:6591-6604) and L234A combined with L235A was used in the clinic (Herold K C, et al. Diabetes 2005, 54:1763-1769). Hence, in one embodiment, the amino acid in at least one position corresponding to L234, L235 and P331, may be A, A and S, respectively.
[0258] Also mutating these same positions to L234F and L235E was described to result in Fc-domains with abrogated interactions with FcGammaReceptors and C1q (Oganesyan Acta Cryst. (2008). D64, 700-704, Canfield & Morrison, 1991 J Exp Med.; 173:1483-91., Duncan, 1988 Nature 332:738-40). Hence, in one embodiment, the amino acids in the positions corresponding to L234 and L235, may be F and E, respectively.
[0259] Mutating position D265A showed decreased binding to all Fc.gamma.Receptors and prevented ADCC (Shields R L et al. J Biol Chem 2001, 276:6591-6604). Hence, in one embodiment, the amino acid in a position corresponding to D265, may be A.
[0260] Binding to C1q could be abrogated by mutating positions D270, K322, P329, and P331 (Idusogie et al., J Immunol 2000, 164:4178-4184). Mutating these positions to either D270A or K322A or P329A or P331A made the antibody deficient in CDC activity. Hence, in one embodiment, the amino acids in at least one position corresponding to D270, K322, P329 and P331, may be A, A, A, and A, respectively.
[0261] An alternative approach to minimize the interaction of the Fc-domain with FcgammaReceptors and C1q is by removal of the glycosylation site of an antibody. Mutating position N297 to eg Q, A, and E removes a glycosylation site which is critical for IgG-Fcgamma receptor interactions (Tao and Morrison, J Immunol. 1989 Oct. 15; 143(8):2595-601, Bolt S et al., Eur J Immunol 1993, 23:403-411). Hence, in one embodiment, the amino acid in a position corresponding to N297, may be Q, A or E.
[0262] Alternatively, human IgG2 and IgG4 subclasses are naturally compromised in their interactions with C1q and FcgammaReceptors. However, residual interactions with Fc.gamma.Receptors (FcgammaReceptors) have been described (Parren et al., J Clin Invest 1992, 90:1537-1546.). Mutations abrogating these residual interactions have been described for both isotypes and result in reduction of unwanted side-effects associated with FcR binding. For IgG2 mutating L234A and G237A was described (Cole M S et al. J Immunol 1997, 159:3613-3621 and for IgG4 L235E was described (Reddy M P et al., J Immunol 2000, 164:1925-1933). Hence, in one embodiment, the amino acid in a position corresponding to L234 and G237 in a human IgG2 heavy chain, may be A and A, respectively. In one embodiment, the amino acid in a position corresponding to L235 in a human IgG4 heavy chain, may be E.”
[0266] Combining sets of mutations described above may result in an even more inert Fc-domain, for instance combining mutations L234F, L235E, D265A; or L234F, L235E, N297Q and D265A in an IgG1 Fc-domain or other variations generated by the information described above. Hence, in one embodiment, the amino acids in at least one or a combination of positions corresponding to L234, L235, D265; or L234, L235, N297 and D265, may be F, E, A, F, E, Q and A, respectively.
Such a multispecific antibody would have been obvious because agonist antibodies that bind CD40 and CD137 (4-1BB) had been shown to be effective in the treatment of cancer to overcome immune suppression as taught by Moran et al., each having similar but distinct antitumor effects. It would have been obvious wherein the bispecific antibody was a human IgG1 antibody in which each Fc region has one or more substitutions different between the two Fc region to promote heterodimerization so that each arm of the antibody comprises a different antibody binding site, i.e., one binding CD40 and one binding CD137, for example having a substitution of F405 in one Fc and K409 in the other as taught by Jong. It further would have been obvious wherein the Fc regions had reduced Fc receptor binding, particularly Fcgamma receptor binding, in order to reduce unwanted side-effects associated with Fc receptor binding, for example having a combination of substitutions of L234F, L235E, D265A.
c) Claims 1, 6, 15, 42, 47, 81, 83-90 and 92-95 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,084,882 B2 (‘882) for the reasons set forth in the previous Office action.
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim a multispecific antibody that binds both CD40 and CD137 and has the same VH and VL sequences. The multispecific antibody comprising a CD40-binding site comprising a VH of SEQ ID NO:117 and VL of SEQ ID NO:121 and a CD137-binding site comprising a VH of SEQ ID NO:123 and VL of SEQ ID NO:127, which inherently comprise the CDRs therein (claims 1, 2, 5-11 of ‘882, instant claims 1, 6, 12, 15, 83-87, 92-95). Additionally, the claims specify wherein the first and second heavy chains comprise one or more amino acids in the positions corresponding to positions L234, L235 and/or D265 in a human IgGl heavy chain according to EU numbering, are not L, L, D, N, and P, respectively (see claim1 of ‘882, and instant claims 42 and 47). Additionally, the claims specify the antibody comprises a human IgG1 heavy chain comprising at substitution of at least one of T366, L368, K370, D399, F405, Y407, and K409, more specifically F405 and K409, according to EU numbering, and wherein said first and said second CH are not substituted in the same positions (claims 1, 3 and 4 of ‘882 and instant claims 88-91). A kit comprising the multispecific antibody and instructions (instant claim 81) would have been obvious for detection of the antigens to which the antibody bound.
d) Claims 1, 6, 15, 42, 47, 81, 83-90 and 92-95 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11,440,966 B2 (‘966) for the reasons set forth in the previous Office action. Although the claims at issue are not identical, they are not patentably distinct from each other because both claim a multispecific antibody that binds both CD40 and CD137 and has the same VH and VL sequences. The multispecific antibody comprising a CD40-binding site comprising a VH of SEQ ID NO:117 and VL of SEQ ID NO:121 and a CD137-binding site comprising a VH of SEQ ID NO:123 and VL of SEQ ID NO:127, which inherently comprise the CDRs therein (claims 1, 7-11, 13-21 of ‘966, instant claims 1, 6, 12, 15, 83-87, 92-95). Additionally, both claim wherein the first and second heavy chains comprise one or more amino acids in the positions corresponding to positions L234, L235, D265, N297, and P331 in a human IgGl heavy chain according to EU numbering, are not L, L, D, N, and P, respectively (claims 1-3, 11, 17 of ‘966, and instant claims 42 and 47). Additional dependent claims specify the antibody comprises a human IgG1 heavy chain comprising at substitution of at least one of T366, L368, K370, D399, F405, Y407, and K409 according to EU numbering, and wherein said first and said second CH are not substituted in the same positions (claims 3, 6 and 12 of ‘873 and instant claims 88-91). A kit comprising the multispecific antibody and instructions (instant claim 81) would have been obvious for detection of the antigens to which the antibody bound.
e) Claims 1, 6, 15, 42, 47, 81, 83-90 and 92-95 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 and 11 of U.S. Patent No. 11,814,411 B2 (‘411) in view of Moran et al. (Curr. Opin. Immunol. 25:230–237, 2013) and US 2015/0175707 (Jong) for the reasons set forth in the previous Office action.
The claims at issue are obvious over those of the patent claims, which are drawn to a nucleic acid encoding a binding agent binding both CD40 and CD137, wherein the encoded VH and VL of each antigen-binding domain are identical to those of the instantly claimed multispecific antibody that binds both CD40 and CD137. The instant claims are drawn to a multispecific antibody comprising a CD40-binding site comprising a VH of SEQ ID NO:6 and VL of SEQ ID NO:7 and a CD137-binding site comprising a VH of SEQ ID NO:69 and VL of SEQ ID NO:70, which are identical respectively to SEQ ID NO:2321, 2322, 2241 and 2242 of ‘411, which inherently comprise the CDRs therein (claims 1-6 and 11 of ‘411, instant claims 1, 6, 12, 15, 83-87, 92-95). ‘411 does not claim wherein the binding agent comprises two heavy chains comprising human IgG1 Fc domains, including wherein there is at least one amino acid substitution in the positions corresponding to positions L234, L235, D265, N297, and P331 in a human IgGl heavy chain according to EU numbering, are not L, L, D, N, and P, respectively (instant claims 42 and 47) and/or a substitution of at least one of T366, L368, K370, D399, F405, Y407, and K409 according to EU numbering and for the latter substitution wherein the first and second CH are not substituted in the same positions (instant claims 88-91). Nor does ‘411 claim a kit comprising the multispecific antibody ad instructions (instant claim 81).
Moran et al. teaches that antibody immunotherapy for tumors helps to overcome immune suppression by increasing the number and function of antigen presenting cells (APCs) and T cells, leading to tumor regression (p. 230, col. 2, second paragraph). “Optimal activation of naïve T cells requires a strong T cell receptor peptide antigen-MHC interaction along with engagement of costimulatory molecules expressed by APCs… [T]hus costimulation is indispensable for a functional T cell response.” (p. 230, col. 2, third paragraph). It is taught that 4-1BB (CD137) is expressed on activated T cells, NK cells and other activated cells, including endothelial cells of some tumors. Agonist 4-1BB antibody therapies are CD8 T cell-dependent, promoting long-term anti-tumor memory T cell survival (p. 233, col. 2, first paragraph). 4-1BB agonist antibody has been shown to increase activated T cell infiltration into tumors in a tumor-bearing mouse (p. 230, last paragraph). CD40 is constitutively expressed on APCs and its activation promotes antigen presentation and cytokine production (Fig. 1 and p. 234, col. 1, third paragraph). “In addition, as was observed with anti-4-1BB antibody therapy, targeting CD40 with an agonist antibody also allowed T cells to overcome tolerance and promote tumor eradication in mouse models of disease [48–50] as CD40 is also expressed at the surface of a wide array of primary tumors. Therefore, targeting CD40 might exert its anti-tumor activity by two distinct mechanisms; directly, antiCD40 induces antibody-dependent phagocytosis of tumor cells and inhibits CD40-CD40L induced tumor proliferation and indirectly by activating the anti-tumor immune response via APC maturation.” (p. 234, end of col. 1) In a study with mice and humans, an agonistic CD40 antibody with gemcitabine showed dendritic cell- and T cell-independent antitumor activity, instead acting on CD40-expressing macrophages. “These results demonstrate and highlight the importance of both innate and adaptive immune responses in mediating tumor regression. Moreover, the pleiotropic effects of mAb therapies that target this and other TNFR family members make them ideal targets for single agent and combination immunotherapy.” (p. 234, col. 2, third paragraph)
US 2015/0175707 (Jong) teaches antibodies with modification in their IgG Fc regions to either promote heterodimerization of two different heavy/light chain pairs or to reduce Fc receptor binding by the Fc region. In [0345] it teaches:
[0345] Thus, in one embodiment the present invention relates to a heterodimeric protein according to the present invention, wherein [0346] the amino acid in a position selected from K409, T366, L368, K370, D399, F405, and Y407 is not K, T, L, K, D, F and Y, respectively, in the first polypeptide, and [0347] the amino acid in a position selected from F405, T366, L368, K370, D399, Y407, and K409 is not F, T, L, K, D, Y and K, respectively, in the second polypeptide.
[0348] In a particular embodiment of the heterodimeric protein, the amino acid in position K409 is R in the first polypeptide, and the amino acid in position F405 is L in the second polypeptide.
Additionally, the antibody may comprise a substitution at L234, L235, D265, N297 ([0316]). “[0256] Based on this knowledge several variants were described to make Fc-domain inactive for interactions with Fcgamma receptors and C1q for therapeutic antibody development.
[0254] In another embodiment such further mutations may be mutations which inhibit or reduce the effector functions of the dimeric protein. In clinical applications where engagement of the immune system is not required and may even cause unwanted side-effects the first and/or second polypeptide of the dimeric protein may then be further mutated in the CH2 domain to abolish C1q and/or FcGammaReceptor interactions.
[0257] For IgG1 mutating L234A and L235A and P331S were described (Hezareh M, et al., J Virol 2001, 75:12161-12168, Xu D et al. Cell Immunol 2000, 200:16-26, Shields R L, et al. J Biol Chem 2001, 276:6591-6604) and L234A combined with L235A was used in the clinic (Herold K C, et al. Diabetes 2005, 54:1763-1769). Hence, in one embodiment, the amino acid in at least one position corresponding to L234, L235 and P331, may be A, A and S, respectively.
[0258] Also mutating these same positions to L234F and L235E was described to result in Fc-domains with abrogated interactions with FcGammaReceptors and C1q (Oganesyan Acta Cryst. (2008). D64, 700-704, Canfield & Morrison, 1991 J Exp Med.; 173:1483-91., Duncan, 1988 Nature 332:738-40). Hence, in one embodiment, the amino acids in the positions corresponding to L234 and L235, may be F and E, respectively.
[0259] Mutating position D265A showed decreased binding to all Fc.gamma.Receptors and prevented ADCC (Shields R L et al. J Biol Chem 2001, 276:6591-6604). Hence, in one embodiment, the amino acid in a position corresponding to D265, may be A.
[0260] Binding to C1q could be abrogated by mutating positions D270, K322, P329, and P331 (Idusogie et al., J Immunol 2000, 164:4178-4184). Mutating these positions to either D270A or K322A or P329A or P331A made the antibody deficient in CDC activity. Hence, in one embodiment, the amino acids in at least one position corresponding to D270, K322, P329 and P331, may be A, A, A, and A, respectively.
[0261] An alternative approach to minimize the interaction of the Fc-domain with FcgammaReceptors and C1q is by removal of the glycosylation site of an antibody. Mutating position N297 to eg Q, A, and E removes a glycosylation site which is critical for IgG-Fcgamma receptor interactions (Tao and Morrison, J Immunol. 1989 Oct. 15; 143(8):2595-601, Bolt S et al., Eur J Immunol 1993, 23:403-411). Hence, in one embodiment, the amino acid in a position corresponding to N297, may be Q, A or E.
[0262] Alternatively, human IgG2 and IgG4 subclasses are naturally compromised in their interactions with C1q and FcgammaReceptors. However, residual interactions with Fc.gamma.Receptors (FcgammaReceptors) have been described (Parren et al., J Clin Invest 1992, 90:1537-1546.). Mutations abrogating these residual interactions have been described for both isotypes and result in reduction of unwanted side-effects associated with FcR binding. For IgG2 mutating L234A and G237A was described (Cole M S et al. J Immunol 1997, 159:3613-3621 and for IgG4 L235E was described (Reddy M P et al., J Immunol 2000, 164:1925-1933). Hence, in one embodiment, the amino acid in a position corresponding to L234 and G237 in a human IgG2 heavy chain, may be A and A, respectively. In one embodiment, the amino acid in a position corresponding to L235 in a human IgG4 heavy chain, may be E.”
[0266] Combining sets of mutations described above may result in an even more inert Fc-domain, for instance combining mutations L234F, L235E, D265A; or L234F, L235E, N297Q and D265A in an IgG1 Fc-domain or other variations generated by the information described above. Hence, in one embodiment, the amino acids in at least one or a combination of positions corresponding to L234, L235, D265; or L234, L235, N297 and D265, may be F, E, A, F, E, Q and A, respectively.
Such a multispecific antibody would have been obvious because agonist antibodies that bind CD40 and CD137 (4-1BB) had been shown to be effective in the treatment of cancer to overcome immune suppression as taught by Moran et al., each having similar but distinct antitumor effects. It would have been obvious wherein the bispecific antibody was a human IgG1 antibody in which each Fc region has one or more substitutions different between the two Fc region to promote heterodimerization so that each arm of the antibody comprises a different antibody binding site, i.e., one binding CD40 and one binding CD137, for example having a substitution of F405 in one Fc and K409 in the other as taught by Jong. It further would have been obvious wherein the Fc regions had reduced Fc receptor binding, particularly Fcgamma receptor binding, in order to reduce unwanted side-effects associated with Fc receptor binding, for example having a combination of substitutions of L234F, L235E, D265A. It further would have been obvious to have a kit comprising the bispecific antibody binding CD40 and CD137 and instructions for use because this would facilitate tumor treatment or for detection of the antigens to which the antibody bound. Note that the intended use of the kit of instant claim 81 does not appear to change the contents of the kit.
f) Claims 1, 6, 15, 42, 47, 81, 83-90 and 92-95 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11,939,388 B2 (‘388) in view of Moran et al. (Curr. Opin. Immunol. 25:230–237, 2013) and US 2015/0175707 (Jong) for the reasons set forth in the previous Office action.
The claims at issue obvious over those of the patent claims, which are drawn to a nucleic acid encoding a multispecific antibody binding both CD40 and CD137, wherein the encoded VH and VL of each antigen-binding domain are identical to those of the instantly claimed multispecific antibody that binds both CD40 and CD137. The instant claims are drawn to a multispecific antibody comprising a CD40-binding site comprising a VH of SEQ ID NO:117 or 6 and VL of SEQ ID NO:121 or 7 and a CD137-binding site comprising a VH of SEQ ID NO:123 or 69 and VL of SEQ ID NO:127 or 70, which are identical respectively to the same numbered sequences of ‘388, which inherently comprise the CDRs therein (claims 1-6 and 11 of ‘388, instant claims 1, 6, 12, 15, 83-87, 92-95). The patent also claims an expression vector comprising the nucleic acid and host cell comprising the vector. ‘388 does not claim wherein the multispecific antibody comprises two heavy chains comprising human IgG1 Fc domains, including wherein there is at least one amino acid substitution in the positions corresponding to positions L234, L235, D265, N297, and P331 in a human IgGl heavy chain according to EU numbering, are not L, L, D, N, and P, respectively (instant claims 42 and 47) and/or a substitution of at least one of T366, L368, K370, D399, F405, Y407, and K409 according to EU numbering and for the latter substitution wherein the first and second CH are not substituted in the same positions (instant claims 88-91). Nor does ‘411 claim a kit comprising the multispecific antibody ad instructions (instant claim 81).
Moran et al. teaches that antibody immunotherapy for tumors helps to overcome immune suppression by increasing the number and function of antigen presenting cells (APCs) and T cells, leading to tumor regression (p. 230, col. 2, second paragraph). “Optimal activation of naïve T cells requires a strong T cell receptor peptide antigen-MHC interaction along with engagement of costimulatory molecules expressed by APCs… [T]hus costimulation is indispensable for a functional T cell response.” (p. 230, col. 2, third paragraph). It is taught that 4-1BB (CD137) is expressed on activated T cells, NK cells and other activated cells, including endothelial cells of some tumors. Agonist 4-1BB antibody therapies are CD8 T cell-dependent, promoting long-term anti-tumor memory T cell survival (p. 233, col. 2, first paragraph). 4-1BB agonist antibody has been shown to increase activated T cell infiltration into tumors in a tumor-bearing mouse (p. 230, last paragraph). CD40 is constitutively expressed on APCs and its activation promotes antigen presentation and cytokine production (Fig. 1 and p. 234, col. 1, third paragraph). “In addition, as was observed with anti-4-1BB antibody therapy, targeting CD40 with an agonist antibody also allowed T cells to overcome tolerance and promote tumor eradication in mouse models of disease [48–50] as CD40 is also expressed at the surface of a wide array of primary tumors. Therefore, targeting CD40 might exert its anti-tumor activity by two distinct mechanisms; directly, antiCD40 induces antibody-dependent phagocytosis of tumor cells and inhibits CD40-CD40L induced tumor proliferation and indirectly by activating the anti-tumor immune response via APC maturation.” (p. 234, end of col. 1) In a study with mice and humans, an agonistic CD40 antibody with gemcitabine showed dendritic cell- and T cell-independent antitumor activity, instead acting on CD40-expressing macrophages. “These results demonstrate and highlight the importance of both innate and adaptive immune responses in mediating tumor regression. Moreover, the pleiotropic effects of mAb therapies that target this and other TNFR family members make them ideal targets for single agent and combination immunotherapy.” (p. 234, col. 2, third paragraph)
US 2015/0175707 (Jong) teaches antibodies with modification in their IgG Fc regions to either promote heterodimerization of two different heavy/light chain pairs or to reduce Fc receptor binding by the Fc region. In [0345] it teaches:
[0345] Thus, in one embodiment the present invention relates to a heterodimeric protein according to the present invention, wherein [0346] the amino acid in a position selected from K409, T366, L368, K370, D399, F405, and Y407 is not K, T, L, K, D, F and Y, respectively, in the first polypeptide, and [0347] the amino acid in a position selected from F405, T366, L368, K370, D399, Y407, and K409 is not F, T, L, K, D, Y and K, respectively, in the second polypeptide.
[0348] In a particular embodiment of the heterodimeric protein, the amino acid in position K409 is R in the first polypeptide, and the amino acid in position F405 is L in the second polypeptide.
Additionally, the antibody may comprise a substitution at L234, L235, D265, N297 ([0316]). “[0256] Based on this knowledge several variants were described to make Fc-domain inactive for interactions with Fcgamma receptors and C1q for therapeutic antibody development.
[0254] In another embodiment such further mutations may be mutations which inhibit or reduce the effector functions of the dimeric protein. In clinical applications where engagement of the immune system is not required and may even cause unwanted side-effects the first and/or second polypeptide of the dimeric protein may then be further mutated in the CH2 domain to abolish C1q and/or FcGammaReceptor interactions.
[0257] For IgG1 mutating L234A and L235A and P331S were described (Hezareh M, et al., J Virol 2001, 75:12161-12168, Xu D et al. Cell Immunol 2000, 200:16-26, Shields R L, et al. J Biol Chem 2001, 276:6591-6604) and L234A combined with L235A was used in the clinic (Herold K C, et al. Diabetes 2005, 54:1763-1769). Hence, in one embodiment, the amino acid in at least one position corresponding to L234, L235 and P331, may be A, A and S, respectively.
[0258] Also mutating these same positions to L234F and L235E was described to result in Fc-domains with abrogated interactions with FcGammaReceptors and C1q (Oganesyan Acta Cryst. (2008). D64, 700-704, Canfield & Morrison, 1991 J Exp Med.; 173:1483-91., Duncan, 1988 Nature 332:738-40). Hence, in one embodiment, the amino acids in the positions corresponding to L234 and L235, may be F and E, respectively.
[0259] Mutating position D265A showed decreased binding to all Fc.gamma.Receptors and prevented ADCC (Shields R L et al. J Biol Chem 2001, 276:6591-6604). Hence, in one embodiment, the amino acid in a position corresponding to D265, may be A.
[0260] Binding to C1q could be abrogated by mutating positions D270, K322, P329, and P331 (Idusogie et al., J Immunol 2000, 164:4178-4184). Mutating these positions to either D270A or K322A or P329A or P331A made the antibody deficient in CDC activity. Hence, in one embodiment, the amino acids in at least one position corresponding to D270, K322, P329 and P331, may be A, A, A, and A, respectively.
[0261] An alternative approach to minimize the interaction of the Fc-domain with FcgammaReceptors and C1q is by removal of the glycosylation site of an antibody. Mutating position N297 to eg Q, A, and E removes a glycosylation site which is critical for IgG-Fcgamma receptor interactions (Tao and Morrison, J Immunol. 1989 Oct. 15; 143(8):2595-601, Bolt S et al., Eur J Immunol 1993, 23:403-411). Hence, in one embodiment, the amino acid in a position corresponding to N297, may be Q, A or E.
[0262] Alternatively, human IgG2 and IgG4 subclasses are naturally compromised in their interactions with C1q and FcgammaReceptors. However, residual interactions with Fc.gamma.Receptors (FcgammaReceptors) have been described (Parren et al., J Clin Invest 1992, 90:1537-1546.). Mutations abrogating these residual interactions have been described for both isotypes and result in reduction of unwanted side-effects associated with FcR binding. For IgG2 mutating L234A and G237A was described (Cole M S et al. J Immunol 1997, 159:3613-3621 and for IgG4 L235E was described (Reddy M P et al., J Immunol 2000, 164:1925-1933). Hence, in one embodiment, the amino acid in a position corresponding to L234 and G237 in a human IgG2 heavy chain, may be A and A, respectively. In one embodiment, the amino acid in a position corresponding to L235 in a human IgG4 heavy chain, may be E.”
[0266] Combining sets of mutations described above may result in an even more inert Fc-domain, for instance combining mutations L234F, L235E, D265A; or L234F, L235E, N297Q and D265A in an IgG1 Fc-domain or other variations generated by the information described above. Hence, in one embodiment, the amino acids in at least one or a combination of positions corresponding to L234, L235, D265; or L234, L235, N297 and D265, may be F, E, A, F, E, Q and A, respectively.
Such a multispecific antibody would have been obvious because agonist antibodies that bind CD40 and CD137 (4-1BB) had been shown to be effective in the treatment of cancer to overcome immune suppression as taught by Moran et al., each having similar but distinct antitumor effects. It would have been obvious wherein the bispecific antibody was a human IgG1 antibody in which each Fc region has one or more substitutions different between the two Fc region to promote heterodimerization so that each arm of the antibody comprises a different antibody binding site, i.e., one binding CD40 and one binding CD137, for example having a substitution of F405 in one Fc and K409 in the other as taught by Jong. It further would have been obvious wherein the Fc regions had reduced Fc receptor binding, particularly Fcgamma receptor binding, in order to reduce unwanted side-effects associated with Fc receptor binding, for example having a combination of substitutions of L234F, L235E, D265A. It further would have been obvious to have a kit comprising the bispecific antibody binding CD40 and CD137 and instructions for use because this would facilitate tumor treatment or for detection of the antigens to which the antibody bound. Note that the intended use of the kit of instant claim 81 does not appear to change the contents of the kit.
g) Claims 1, 6, 15, 42, 47, 81, 83-90 and 92-95 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,077,596 B2 (‘596) for the reasons set forth in the previous Office action.
Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims require a binding agent that binds both CD40 and CD137 and has the same VH and VL sequences. The multispecific antibody of both sets of claims comprising a CD40-binding site comprising respectively a VH of SEQ ID NO:117 or 6 and VL of SEQ ID NO:121 or 7 and a CD137-binding site comprising a VH of SEQ ID NO:123 or 69 and VL of SEQ ID NO:127 or 70 (instant claims 1, 6, 12, 15, 83-87 and 92-95, claims 1-11, 16, 17, 19 and 20 of ‘596). While the claims of ‘596 are drawn to a method of treating cancer, the instantly claimed multispecific antibody is anticipated by the kit comprising the CD40xCD137 binding agent and the binding agent’s use in the methods of ‘596. Additionally, both claim wherein each of the heavy chain (CH) regions has at least one of the amino acids substituted in the positions corresponding to a position selected from the group consisting of T366, L368, K370, D399, F405, Y407, and K409 in a human IgG1 heavy chain according to EU numbering, and wherein said first and said second CH are not substituted in the same positions (claims 13-15 and 18 of ‘96 and instant claims 88-91). The patent does not claim wherein the first and second heavy chains comprise one or more amino acids in the positions corresponding to positions L234, L235, D265, N297, and P331 in a human IgGl heavy chain according to EU numbering, are not L, L, D, N, and P, respectively (see instant claims 42 and 47) or a kit comprising the multispecific antibody (instant claim 81).
Moran et al. teaches that antibody immunotherapy for tumors helps to overcome immune suppression by increasing the number and function of antigen presenting cells (APCs) and T cells, leading to tumor regression (p. 230, col. 2, second paragraph). “Optimal activation of naïve T cells requires a strong T cell receptor peptide antigen-MHC interaction along with engagement of costimulatory molecules expressed by APCs… [T]hus costimulation is indispensable for a functional T cell response.” (p. 230, col. 2, third paragraph). It is taught that 4-1BB (CD137) is expressed on activated T cells, NK cells and other activated cells, including endothelial cells of some tumors. Agonist 4-1BB antibody therapies are CD8 T cell-dependent, promoting long-term anti-tumor memory T cell survival (p. 233, col. 2, first paragraph). 4-1BB agonist antibody has been shown to increase activated T cell infiltration into tumors in a tumor-bearing mouse (p. 230, last paragraph). CD40 is constitutively expressed on APCs and its activation promotes antigen presentation and cytokine production (Fig. 1 and p. 234, col. 1, third paragraph). “In addition, as was observed with anti-4-1BB antibody therapy, targeting CD40 with an agonist antibody also allowed T cells to overcome tolerance and promote tumor eradication in mouse models of disease [48–50] as CD40 is also expressed at the surface of a wide array of primary tumors. Therefore, targeting CD40 might exert its anti-tumor activity by two distinct mechanisms; directly, antiCD40 induces antibody-dependent phagocytosis of tumor cells and inhibits CD40-CD40L induced tumor proliferation and indirectly by activating the anti-tumor immune response via APC maturation.” (p. 234, end of col. 1) In a study with mice and humans, an agonistic CD40 antibody with gemcitabine showed dendritic cell- and T cell-independent antitumor activity, instead acting on CD40-expressing macrophages. “These results demonstrate and highlight the importance of both innate and adaptive immune responses in mediating tumor regression. Moreover, the pleiotropic effects of mAb therapies that target this and other TNFR family members make them ideal targets for single agent and combination immunotherapy.” (p. 234, col. 2, third paragraph)
US 2015/0175707 (Jong) teaches antibodies with modification in their IgG Fc regions to reduce Fc receptor binding by the Fc region. The antibody may comprise a substitution at L234, L235, D265, N297 ([0316]). “[0256] Based on this knowledge several variants were described to make Fc-domain inactive for interactions with Fcgamma receptors and C1q for therapeutic antibody development.
[0254] In another embodiment such further mutations may be mutations which inhibit or reduce the effector functions of the dimeric protein. In clinical applications where engagement of the immune system is not required and may even cause unwanted side-effects the first and/or second polypeptide of the dimeric protein may then be further mutated in the CH2 domain to abolish C1q and/or FcGammaReceptor interactions.
[0257] For IgG1 mutating L234A and L235A and P331S were described (Hezareh M, et al., J Virol 2001, 75:12161-12168, Xu D et al. Cell Immunol 2000, 200:16-26, Shields R L, et al. J Biol Chem 2001, 276:6591-6604) and L234A combined with L235A was used in the clinic (Herold K C, et al. Diabetes 2005, 54:1763-1769). Hence, in one embodiment, the amino acid in at least one position corresponding to L234, L235 and P331, may be A, A and S, respectively.
[0258] Also mutating these same positions to L234F and L235E was described to result in Fc-domains with abrogated interactions with FcGammaReceptors and C1q (Oganesyan Acta Cryst. (2008). D64, 700-704, Canfield & Morrison, 1991 J Exp Med.; 173:1483-91., Duncan, 1988 Nature 332:738-40). Hence, in one embodiment, the amino acids in the positions corresponding to L234 and L235, may be F and E, respectively.
[0259] Mutating position D265A showed decreased binding to all Fc.gamma.Receptors and prevented ADCC (Shields R L et al. J Biol Chem 2001, 276:6591-6604). Hence, in one embodiment, the amino acid in a position corresponding to D265, may be A.
[0260] Binding to C1q could be abrogated by mutating positions D270, K322, P329, and P331 (Idusogie et al., J Immunol 2000, 164:4178-4184). Mutating these positions to either D270A or K322A or P329A or P331A made the antibody deficient in CDC activity. Hence, in one embodiment, the amino acids in at least one position corresponding to D270, K322, P329 and P331, may be A, A, A, and A, respectively.
[0261] An alternative approach to minimize the interaction of the Fc-domain with FcgammaReceptors and C1q is by removal of the glycosylation site of an antibody. Mutating position N297 to eg Q, A, and E removes a glycosylation site which is critical for IgG-Fcgamma receptor interactions (Tao and Morrison, J Immunol. 1989 Oct. 15; 143(8):2595-601, Bolt S et al., Eur J Immunol 1993, 23:403-411). Hence, in one embodiment, the amino acid in a position corresponding to N297, may be Q, A or E.
[0262] Alternatively, human IgG2 and IgG4 subclasses are naturally compromised in their interactions with C1q and FcgammaReceptors. However, residual interactions with Fc.gamma.Receptors (FcgammaReceptors) have been described (Parren et al., J Clin Invest 1992, 90:1537-1546.). Mutations abrogating these residual interactions have been described for both isotypes and result in reduction of unwanted side-effects associated with FcR binding. For IgG2 mutating L234A and G237A was described (Cole M S et al. J Immunol 1997, 159:3613-3621 and for IgG4 L235E was described (Reddy M P et al., J Immunol 2000, 164:1925-1933). Hence, in one embodiment, the amino acid in a position corresponding to L234 and G237 in a human IgG2 heavy chain, may be A and A, respectively. In one embodiment, the amino acid in a position corresponding to L235 in a human IgG4 heavy chain, may be E.”
[0266] Combining sets of mutations described above may result in an even more inert Fc-domain, for instance combining mutations L234F, L235E, D265A; or L234F, L235E, N297Q and D265A in an IgG1 Fc-domain or other variations generated by the information described above. Hence, in one embodiment, the amino acids in at least one or a combination of positions corresponding to L234, L235, D265; or L234, L235, N297 and D265, may be F, E, A, F, E, Q and A, respectively.
Such a multispecific antibody would have been obvious because agonist antibodies that bind CD40 and CD137 (4-1BB) had been shown to be effective in the treatment of cancer to overcome immune suppression as taught by Moran et al., each having similar but distinct antitumor effects. It would have been obvious wherein the bispecific antibody was a human IgG1 antibody in which each Fc region has one or more substitutions two reduced binding to an Fc receptor, particularly Fcgamma receptor-binding in order to reduce unwanted side-effects associated with Fc receptor binding, for example having a combination of substitutions of L234F, L235E, D265A. A kit comprising the bispecific antibody binding CD40 and CD137 and instructions for use would have further been obvious because this would facilitate tumor treatment or for detection of the antigens to which the antibody bound. Note that the intended use of the kit of instant claim 81 does not appear to change the contents of the kit.
Applicant requests (p.11 of REMARKS) that the rejections under double patenting be held in abeyance until all other rejections have been resolved. The request has been fully considered but is not persuasive. Even though the rejections under provisional and nonprovisional nonstatutory double patenting are the only remaining rejections, they cannot be held in abeyance and are maintained for the reasons of record.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
June 18, 2026
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