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 .
Applicant’s amendments and remarks filed 9-12-25 are acknowledged.
Claims 11-16 and 166-178 are pending and under examination.
Claims 11-14 and 173-178 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4-8 of U.S. Patent No. 10550193.
Claims 11-14 and 166-178 stand rejected, and amended claims 15 and 16 are rejected, on the ground of nonstatutory double patenting as being unpatentable over claims 4-8, 15, 17-20, 27 and 28 of U.S. Patent No. 10550193 in view of Chao et al. (Cancer Management and Research 2013:5 251–269) and Wong et al. (Haematologica. 2013 Dec;98(12):1930–1938, supplemental pages included, document has been renumbered as pages 1-27).
Applicant acknowledged the above stated rejections of records but did not set forth a substantive argument as to why said rejection should be withdrawn. Thus, the rejection stands for the reasons of record. Amended claims 15 and 16 are rejected for the reasons of record and further in view of the teachings of Chao (of record) that clinical resistance to rituximab has been observed in multiple NHL subtypes.
Claims 11-16 and 166-178 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 10662244 in view of Chao et al. (Cancer Management and Research 2013:5 251–269), Wong et al. (Haematologica. 2013 Dec;98(12):1930–1938, supplemental pages included, document has been renumbered as pages 1-27)(all of record), and further in view of Davis et al. (WO2014121087, cited on an IDS),
as evidenced by:
Neijseen et al. (WO2012143524A2, cited herewith);
Nezu et al. (WO2012073985A1, the English language national stage entry under 35 U.S.C. § 371 of the ‘985 application into the USA which corresponds to 20140112914, both cited on an IDS);
Dixit et al. (WO2015006749, cited on an IDS);
Bargou et al. (Science, 2008, Vol 321, pages 974-977, cited on an IDS);
Chen et al. (20150166661, cited on an IDS); and
Van den Brink et al. (20160168247, cited on an IDS).
As a preliminary matter, please consider the following knowledge in the prior art of bispecific tumor binding x T-cell binding antibodies that retain tumor cell killing ability, even when said bispecific antibodies comprise diminished Fc-mediated ADCC and CDC activities, thereby mitigating on-target but off-tumor toxicity.
Neijseen taught bispecific antibodies comprising a Her2 binding domain, a CD3 binding domain, and a modified Fc region, wherein the modified Fc region (i) promotes dimerization of one Her2 binding domain with one CD3 binding domain, and (ii) is effector-function deficient with respect binding Fcγ receptor expressing accessory cells such as neutrophils, monocytes/macrophage, DC and NK cells (see, e.g., Examples 20-21, Example 27).
More particularly, Neijseen taught:
(i) the Fc-domain can be made effector-function deficient, e.g., by an N297Q mutation, or
(ii) in the alternative “residual Fc activity was further removed” by mutagenizing the Fc domains as follows: L234F, L235E, D265A, N297Q and P331S, thereby creating a variant referred to as “LFLEDANQPS.”
(see page 132-33 bridging paragraph).
Neijseen further shows effector-function deficient, bispecific anti-Her2/anti-CD3 antibodies having either the N297Q or the LFLEDANQPS mutations were capable of activating T-cell cytokine production in the presence of Her2-expressing target cells (see Figs. 20, 23, and text at Example 30). Moreover, while the bispecific anti-Her2/anti-CD3 antibody having an N297Q mutation exhibited some Fc-mediated activation of T-cells in assays comprising PBMC alone, the bispecific version having the LFLEDANQPS mutations did not show any significant Fc-mediated activation of T-cells in the same assay (see page 142, penultimate paragraph, page 144, 1st full paragraph, Figs. 17 and 21). Likewise, an effector-function deficient, bispecific anti-Her2/anti-CD3 antibody having the N297Q mutation (Her2 x huCLB-T3/4 N297Q) was able to treat a Her2-expressing cancer in vivo (see Figs. 33A and B).
The ability of bispecific anti-CD3 x anti-TAA antibody having diminished ability to bind Fcγ receptor to nonetheless activate the cytotoxic activity of CD3-expressing T cells in the presence of TAA-expressing target cells described by Neijseen was consistent with several other prior art (prior to 3-19-14) teachings.
For example, Nezu taught and exemplified an Fc “silent” bispecific anti-GPC3 x anti-CD3 antibody (“GPC3 ERY8-2”) which is fully capable of mediating tumor cell killing in vivo (see paragraphs 325, 326, 332 and SEQ ID NO: 42, which is the GPC3 ERY8-2 having the Fc silencing mutations L234A, L235A and N297A).
As yet another example, Dixit showed a bispecific anti-CD3 x anti-CD19 antibody having certain Fc mutations that diminish FcγR-binding (see clone 6754 in Fig. 2 having L234A and L235A) depletes B-cell from the peripheral blood, bone marrow and spleen of NSG mice containing a CD34+ humanized immune system (see Example 16 and paragraph 333). This reference also describes how the 6754 clone and another FcγR knockout anti-CD3 x anti-CD19 bispecific, the 1661 clone, effectively deplete human B-cell cancers in the NSG mouse model (see Figs. 9 and 16), as well as depleting human B-cell in a whole blood assay (see Fig. 7A).
Likewise, Bargou taught a bispecific antibody comprising tandem anti-CD3 and anti-CD19 scFvs, said bispecific antibody lacking an Fc domain, was capable of depleting B-cells in human patients, see, e.g., Fig. 1A.
In addition, Chen taught bispecific anti-CD3 x anti-Her2 antibodies can be produced with a number of different techniques, such as a “knobs into holes” format (see paragraphs 147, 1272, 1402), and further teaches such antibodies can have a human IgG1 heavy chain paired with a lambda or kappa light chain (see paragraph 1261 and 388), said IgG1 heavy chain having one or more amino acid modifications intended to reduce or inhibit CDC, ADCC and ADCP (see paragraphs 68, 94, 1261-64 and claims 53-55).
For example, at paragraph 1262 Chen taught (emphasis added), “In certain embodiments, the invention contemplates an anti-CD3 antibody variant that possesses some but not all effector functions, which make it a desirable candidate for applications in which the half life of the antibody in vivo is important yet certain effector functions (such as complement
and ADCC) are unnecessary or deleterious,” and at paragraph 1264 Chen teaches human IgG1 Fc substitutions such as L234A and L235A.
Finally, see the teachings of Van den Brink which are consistent with those of Neijseen, Nesu, Dixit, Bargou and Chen, describing how a bispecific antibody with binding domains for CD3 and a tumor target antigen can have an “inert” Fc region to block non-specific, Fe-mediated activation of the T-cell while retaining the ability to be activated by targeted, or target-specific, T-cell activation (see paragraph paragraphs 0241-243).
Given the knowledge in the art set forth above, it would have been obvious to the ordinarily skilled artisan that Fcγ receptor-binding activity of bispecific molecules such as CD20 x CD3, can be diminished while retaining effective tumor target cell-dependent T-cell activation. Thus, the ordinarily skilled artisan was well aware prior to applicant’s effective priority date that bispecific anti-TAA x anti-CD3 antibodies, such as bispecific anti-CD20 x anti-CD3 antibodies, do not require Fc effector function to be activated by, and, in turn, to lyse TAA-expressing target cells.
The nonstatutory double patenting rejection that follows is set forth in the context of the above knowledge of the prior art.
The claims of the ‘244 are drawn to a method of treating or ameliorating a human-CD20 positive B cell cancer in a subject, comprising administering a first dose of a bispecific antibody…
wherein the bispecific antibody comprises a first antigen-binding domain that binds human CD3, a second antigen-binding domain that binds human CD20, and a chimeric Fc domain tethered to each of the first and second antigen-binding domains, and wherein the first antigen-binding domain (A1) that specifically binds human CD3 comprises three heavy chain complementarity determining regions (A1-HCDR1, A1-HCDR2, A1-HCDR3) and three light chain complementarity determining regions (A1-LCDR1, A1-LCDR2, A1-LCDR3), and wherein the second antigen-binding domain (A2) that specifically binds human CD20 comprises three heavy chain complementarity determining regions (A2-HCDR1, A2-HCDR2 and A2-HCDR3) and three light chain complementarity determining regions (A2-LCDR1, A2-LCDR2 and A2-LCDR3); wherein
(a) A1-HCDR1 comprises the amino acid sequence of SEQ ID NO: 12;
(b) A1-HCDR2 comprises the amino acid sequence of SEQ ID NO: 14;
(c) A1-HCDR3 comprises the amino acid sequence of SEQ ID NO: 16;
(d) A1-LCDR1 comprises the amino acid sequence of SEQ ID NO: 20;
(e) A1-LCDR2 comprises the amino acid sequence of SEQ ID NO: 22;
(f) A1-LCDR3 comprises the amino acid sequence of SEQ ID NO: 24;
(g) A2-HCDR1 comprises the amino acid sequence of SEQ ID NO: 4;
(h) A2-HCDR2 comprises the amino acid sequence of SEQ ID NO: 6;
(i) A2-HCDR3 comprises the amino acid sequence of SEQ ID NO: 8;
(j) A2-LCDR1 comprises the amino acid sequence of SEQ ID NO: 20;
(k) A2-LCDR2 comprises the amino acid sequence of SEQ ID NO: 22; and
(l) A2-LCDR3 comprises the amino acid sequence of SEQ ID NO: 24.
Reference dependent claim 17 further specifies that the first antigen-binding domain that specifically binds human CD3 comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:18, and the second antigen-binding domain that specifically binds human CD20 comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO:18, said SEQ ID NOs: 10, 18 and 2 being identical to SEQ ID NOs: 10, 18 and 2 of the instant claims.
Likewise, reference dependent claims 12-15 further specify that the method of treating or ameliorating a human-CD20 positive B cell cancer in a subject of reference claim 1 is a method,
“…wherein the bispecific antibody comprises a chimeric heavy chain constant (CH) region, wherein: (a) the chimeric CH region binds to human FcγRIIA and human FcγRIIB, and (b) the chimeric CH binds with lower to no affinity to human FcγRI and human FcγRIII, compared to an antibody comprising a wild-type CH region,” (reference claim 12);
“…wherein the bispecific antibody comprises a chimeric hinge,” (reference claim 13);
“…wherein the chimeric hinge comprises: (a) a human IgG2 lower hinge amino acid sequence comprising PCPAPPVA (SEQ ID NO: 52) from positions 228 to 236 (EU numbering); (b) a human IgG1 or a human IgG4 upper hinge amino acid sequence from positions 216 to 227 (EU numbering); (c) a chimeric hinge amino acid sequence EPKSCDKTHTCPPCPAPPVA (SEQ ID NO: 53); or (d) a chimeric hinge amino acid sequence ESKYGPPCPPCPAPPVA (SEQ ID NO: 54),” (reference claim 14); and
“…wherein the bispecific antibody comprises: (a) a human IgG4 CH2 domain amino acid sequence from positions 237 to 340 (EU numbering); (b) a human CH3 domain derived from a human IgG1 CH3 domain or a human IgG4 CH3 domain; (c) a human IgG1 CH1 domain and a human IgG1 CH3 domain; or (d) a human IgG4 CH1 domain and a human IgG4 CH3 domain,” (reference claim 15).
However, reference claims 1-17 of the ‘244 do not recite a method for treating a B-cell cancer in a subject, the method comprising: (a) selecting a subject who is afflicted with a cancer, such as a Non-Hodgkin’s Lymphoma (NHL) patient, that is resistant to, or incompletely responsive to anti-CD20 monospecific therapy alone; and (b) administering to the subject a therapeutic amount of a bispecific antibody comprising a first antigen-binding domain that binds human CD3, a second antigen-binding domain that binds human CD20, and a chimeric heavy chain constant region tethered to each of the first and second antigen-binding domains, wherein the heavy chain constant region comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30 and SEQ ID NO:32.
With respect to selecting a subject who is afflicted with a cancer, such as a Non-Hodgkin’s Lymphoma (NHL) patient, that is resistant to, or incompletely responsive to anti-CD20 monospecific therapy alone for treatment according to the methods of reference claims 1-17, at page 252, right col., Chao teaches:
“…rituximab acts in part by engaging Fc receptors on immune effector cells, such as natural killer cells and macrophages, and stimulates such effector functions as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and induction of apoptosis.4 While therapeutic outcomes has dramatically improved in the post-rituximab era, there is increasing evidence of rituximab resistance. Clinical resistance to rituximab is generally defined as a lack of response to a rituximab-containing treatment regimen or clinical progression after 6 months of such a regimen. Diminished response rates to rituximab in patients with prior rituximab treatments have been observed in multiple NHL subtypes. In patients with relapsed FL or low-grade NHL who had previously received single agent rituximab, only 40% of patients responded with rituximab retreatment.5
…Poorer outcomes were specifically seen in previously treated rituximab patients who relapsed or progressed during the first year. These data and others highlight the clinical concern that salvage regimens for relapsed/refractory patients may not be as effective in the era of rituximab usage in front-line regimens. Thus, overcoming rituximab resistance has been a major focus of recent therapeutic development. Several mechanisms of rituximab resistance have been postulated. These include resistance in antibody effector mechanisms (ADCC, CDC, and induction of apoptosis), Fc-receptor polymorphisms, downregulation or loss of CD20 expression, and altered antibody pharmacokinetics.8 To address these issues, one major treatment strategy has been the development of novel anti-CD20 antibodies that more effectively engage immune effectors….”
In the “Bispecific antibodies” section Chao further teaches, “Blinatumomab has been clinically studied in both NHL and acute lymphoblastic leukemia. The first phase I study of 62 NHL patients treated with the recommended dose of blinatumomab demonstrated an ORR of 82% across NHL subtypes, with over 60% of responders maintaining durable response up to 3 years out from therapy (Table 1)53,” wherein the data of Table 1 features a study where “R/R NHL” was successfully treated with blinatumomab.
Consistent with the teachings of Chao that “novel anti-CD20 antibodies that more effectively engage immune effectors” would be desirable as a remedy for rituximab resistance due to, e.g., resistance in antibody effector mechanisms (ADCC, CDC, and induction of apoptosis), at page 10, Wong teaches the use of a bispecific antibody capable of forcing a “conjugate between T cells and CLL cells (Online Supplementary Figure S8),” such as the CD3xC19 bispecific antibody blinatumomb, and the ordinarily skilled artisan would understand that treatment with a bispecific CD3xCD20 antibody, like that of the reference claims, would be reasonably expected to be effective for treating rituximab resistant B-cell cancer.
Given the reference methods of treating a CD20-positive B-cell cancer in a subject, the method comprising administering to the subject a therapeutic amount of bispecific antibody as recited in reference claims 1-17 of the ‘244, and further given the knowledge in the art illustrated by the teachings of Chao et al. and Wong et al. set forth above, it would have been obvious to the ordinarily skilled artisan, and the ordinarily skilled artisan would have been motivated to treat a B-cell cancer patient who is afflicted with a cancer that is resistant to, or incompletely responsive to anti-CD20 monospecific therapy alone by following the steps of reference claims 1-17 of the ‘244, since as taught by Wong / Chao the mechanism of action of a bispecific antibody that binds to a T-cell and redirects the T-cell into close proximity with a cancer target cells is very different from that of other agents such as the rituximab anti-CD20 antibody.
With respect to practicing the methods of reference claims 1-17 by administering to the subject a therapeutic amount of a bispecific antibody comprising a first antigen-binding domain that binds human CD3, a second antigen-binding domain that binds human CD20, and a chimeric heavy chain constant region tethered to each of the first and second antigen-binding domains, wherein the heavy chain constant region comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30 and SEQ ID NO:32, as taught by Davis at paragraph 0006, “For certain antibody therapies, it may be advantageous to engineer the Fc receptor binding properties so as to activate all, some, or none of the available effector mechanisms, without affecting the antibody's pharmacokinetic properties…. Another setting in which reduced binding to Fc receptors could be desirable is when the antibody is bispecific, and its desired therapeutic properties arise from the different binding specificities. For example, a common usage of bispecific antibodies is to combine a tumor targeting specificity with a T cell activating specificity in order to trigger tumor-specific T cell killing. In this case, if the Fc portion binds to an Fc receptor, then potentially that could trigger undesirable killing of cells bearing Fc receptors by T cells, or killing of T cells by Fc receptor-bearing cells such as natural killer cells or macrophages.” (emphasis added).
In Example 2, Davis teaches the production of bispecific anti-CD3 x anti-CD20 antibodies wherein “Antibody 3,” also known as “Control Ab 5,” is antibody which “had its heavy chain constant regions replaced with chimeric constant heavy chain regions, the anti-CD20 arm having an heavy chain constant region amino acid sequence comprising SEQ ID NO: 30, and the anti-CD3 arm having a mutation in the CH3 domain of the CH (SEQ ID NO:37) to create Antibody 3
(also known herein as slgG1*);” likewise Davis further teaches, “Antibody 4” is antibody which “was created from bispecific antibody Control Ab 5 whereas heavy chain constant regions were replaced with chimeric CH, the anti-CD20 arm having an heavy chain constant region amino acid sequence comprising SEQ ID NO: 31, and the anti-CD3 arm having a mutation in the CH3 domain of the CH (SEQ ID NO:38) to create Antibody 4 (also known herein as slgG4*).” (see paragraphs 00216-217).
As further described in paragraph 00218, “The chimeric antibodies comprising constant regions of SEQ ID NO:30 or SEQ ID NO:31 (or bispecific antibodies comprising SEQ ID NO:30/37 or SEQ ID NO:31/38), and the control antibodies, were used in certain experiments set out in the Examples that follow.”
The ordinarily skilled artisan would instantly understand that if a given bispecific antibody is an IgG1 isotype then, except in very limited, non-physiologic conditions, stable pairing of the antibody constant domains requires that each heavy chain be an IgG1 isotype or have a structure that is primarily based upon an IgG1 isotype.
Likewise, the ordinarily skilled artisan would further instantly understand that if a given bispecific antibody is an IgG4 isotype then, except in very limited, non-physiologic conditions, stable pairing of the antibody constant domains requires that each heavy chain be an IgG4 isotype or have a structure that is primarily based upon an IgG4 isotype.
Given the above, the ordinarily skilled artisan would understand that “Antibody 3,” which is described as an “slgG1*” above, is a bispecific antibody having constant domains that are IgG1 isotype or have a structure that is primarily based upon an IgG1 isotype; more particularly Antibody 3 has a first heavy chain which has the CH1, upper and lower hinge and the Fc domains of SEQ ID NO: 30 and a second heavy chain which has the CH1, upper and lower hinge and the Fc domains of SEQ ID NO: 37.
Likewise, the ordinarily skilled artisan would understand that “Antibody 4,” which is described as an “slgG4*” above, is a bispecific antibody having constant domains that are IgG4 isotype or have a structure that is primarily based upon an IgG4 isotype; more particularly Antibody 4 has a first heavy chain which has the CH1, upper and lower hinge and the Fc domains of SEQ ID NO: 31 and a second heavy chain which has the CH1, upper and lower hinge and the Fc domains of SEQ ID NO: 38.
In Example 7, Davis describes how bispecific anti-CD3 x anti-CD20 Antibody 3 (sIgG1*), which comprises the constant regions of SEQ ID NOs: 30/37, and further how bispecific anti-CD3 x anti-CD20 Antibody 4 (sIgG4*), which comprises the constant regions of SEQ ID NOs: 31/38, exhibit no binding to human FcγRI (see Table 10) or to human FcγRIIIA(V176), FcγRIIIA(F176) or FcγRIIIB (see Table 11).
In Example 8, Davis describes how bispecific anti-CD3 x anti-CD20 Antibody 3 (sIgG1*), which comprises the constant regions of SEQ ID NOs: 30/37, and further how bispecific anti-CD3 x anti-CD20 Antibody 4 (sIgG4*), which comprises the constant regions of SEQ ID NOs: 31/38, have CDC activity which is “significantly diminished” against Daudi and Raji cells as compared to corresponding antibody having a wild-type heavy chain constant domain (see paragraph 00232).
Additionally, in Example 9 Davis describes how bispecific anti-CD3 x anti-CD20 Antibody 3 (sIgG1*), which comprises the constant regions of SEQ ID NOs: 30/37, and further how bispecific anti-CD3 x anti-CD20 Antibody 4 (sIgG4*), which comprises the constant regions of SEQ ID NOs: 31/38, “display reduced activity in ADCC assays measuring effector function.”
Given the reference claims are drawn to treating or ameliorating a human-CD20 positive B cell cancer in a subject comprising administering a bispecific antibody that binds CD20 and CD3 and further that comprises a chimeric Fc domain which mediates reduced ADCC / CDC, and further binds with lower to no affinity to human FcγRI and human FcγRIII, compared to an antibody comprising a wild-type CH region, and further given the teachings of Davis as viewed from the perspective of the knowledge in the art as illustrated by Neijseen, Nezu, Dixit, Bargou, Chen and Van den Brink, it would have been obvious to the ordinarily skilled artisan to practice the reference methods of treatment by administering CD20xCD3 bispecific antibodies comprising the particular chimeric Fc domains described by Davis which mediate diminished ADCC and diminished CDC compared to wild-type Fc, i.e., to use bispecific antibodies comprising SEQ ID NO:30/37 or SEQ ID NO:31/38 of Davis.
Note in this regard that these Fc domains of Davis are identical to Fc domains of the instant claims as follows:
SEQ ID NO: 26 of the instant claims = Davis SEQ ID NO: 31;
SEQ ID NO: 28 of the instant claims = Davis SEQ ID NO: 38;
SEQ ID NO: 30 of the instant claims = Davis SEQ ID NO: 30;
SEQ ID NO: 32 of the instant claims = Davis SEQ ID NO: 37;
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 11-16 and 166-178 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 and 13-18 of U.S. Patent No. 11155621 in view of Chao et al. (Cancer Management and Research 2013:5 251–269), Wong et al. (Haematologica. 2013 Dec;98(12):1930–1938, supplemental pages included, document has been renumbered as pages 1-27), Guo et al. (8597648) and P01834 (GenPept, Ig kappa chain C region, pages 1-4, 19-FEB-2014)(all of record), and further in view of Davis et al. (WO2014121087, cited on an IDS),
as evidenced by:
Neijseen et al. (WO2012143524A2, cited herewith);
Nezu et al. (WO2012073985A1, the English language national stage entry under 35 U.S.C. § 371 of the ‘985 application into the USA which corresponds to 20140112914, both cited on an IDS);
Dixit et al. (WO2015006749, cited on an IDS);
Bargou et al. (Science, 2008, Vol 321, pages 974-977, cited on an IDS);
Chen et al. (20150166661, cited on an IDS); and
Van den Brink et al. (20160168247, cited on an IDS).
As a preliminary matter, please consider the following knowledge in the prior art of bispecific tumor binding x T-cell binding antibodies that retain tumor cell killing ability, even when said bispecific antibodies comprise diminished Fc-mediated ADCC and CDC activities, thereby mitigating on-target but off-tumor toxicity.
Neijseen taught bispecific antibodies comprising a Her2 binding domain, a CD3 binding domain, and a modified Fc region, wherein the modified Fc region (i) promotes dimerization of one Her2 binding domain with one CD3 binding domain, and (ii) is effector-function deficient with respect binding Fcγ receptor expressing accessory cells such as neutrophils, monocytes/macrophage, DC and NK cells (see, e.g., Examples 20-21, Example 27).
More particularly, Neijseen taught:
(i) the Fc-domain can be made effector-function deficient, e.g., by an N297Q mutation, or
(ii) in the alternative “residual Fc activity was further removed” by mutagenizing the Fc domains as follows: L234F, L235E, D265A, N297Q and P331S, thereby creating a variant referred to as “LFLEDANQPS.”
(see page 132-33 bridging paragraph).
Neijseen further shows effector-function deficient, bispecific anti-Her2/anti-CD3 antibodies having either the N297Q or the LFLEDANQPS mutations were capable of activating T-cell cytokine production in the presence of Her2-expressing target cells (see Figs. 20, 23, and text at Example 30). Moreover, while the bispecific anti-Her2/anti-CD3 antibody having an N297Q mutation exhibited some Fc-mediated activation of T-cells in assays comprising PBMC alone, the bispecific version having the LFLEDANQPS mutations did not show any significant Fc-mediated activation of T-cells in the same assay (see page 142, penultimate paragraph, page 144, 1st full paragraph, Figs. 17 and 21). Likewise, an effector-function deficient, bispecific anti-Her2/anti-CD3 antibody having the N297Q mutation (Her2 x huCLB-T3/4 N297Q) was able to treat a Her2-expressing cancer in vivo (see Figs. 33A and B).
The ability of bispecific anti-CD3 x anti-TAA antibody having diminished ability to bind Fcγ receptor to nonetheless activate the cytotoxic activity of CD3-expressing T cells in the presence of TAA-expressing target cells described by Neijseen was consistent with several other prior art (prior to 3-19-14) teachings.
For example, Nezu taught and exemplified an Fc “silent” bispecific anti-GPC3 x anti-CD3 antibody (“GPC3 ERY8-2”) which is fully capable of mediating tumor cell killing in vivo (see paragraphs 325, 326, 332 and SEQ ID NO: 42, which is the GPC3 ERY8-2 having the Fc silencing mutations L234A, L235A and N297A).
As yet another example, Dixit showed a bispecific anti-CD3 x anti-CD19 antibody having certain Fc mutations that diminish FcγR-binding (see clone 6754 in Fig. 2 having L234A and L235A) depletes B-cell from the peripheral blood, bone marrow and spleen of NSG mice containing a CD34+ humanized immune system (see Example 16 and paragraph 333). This reference also describes how the 6754 clone and another FcγR knockout anti-CD3 x anti-CD19 bispecific, the 1661 clone, effectively deplete human B-cell cancers in the NSG mouse model (see Figs. 9 and 16), as well as depleting human B-cell in a whole blood assay (see Fig. 7A).
Likewise, Bargou taught a bispecific antibody comprising tandem anti-CD3 and anti-CD19 scFvs, said bispecific antibody lacking an Fc domain, was capable of depleting B-cells in human patients, see, e.g., Fig. 1A.
In addition, Chen taught bispecific anti-CD3 x anti-Her2 antibodies can be produced with a number of different techniques, such as a “knobs into holes” format (see paragraphs 147, 1272, 1402), and further teaches such antibodies can have a human IgG1 heavy chain paired with a lambda or kappa light chain (see paragraph 1261 and 388), said IgG1 heavy chain having one or more amino acid modifications intended to reduce or inhibit CDC, ADCC and ADCP (see paragraphs 68, 94, 1261-64 and claims 53-55).
For example, at paragraph 1262 Chen taught (emphasis added), “In certain embodiments, the invention contemplates an anti-CD3 antibody variant that possesses some but not all effector functions, which make it a desirable candidate for applications in which the half life of the antibody in vivo is important yet certain effector functions (such as complement
and ADCC) are unnecessary or deleterious,” and at paragraph 1264 Chen teaches human IgG1 Fc substitutions such as L234A and L235A.
Finally, see the teachings of Van den Brink which are consistent with those of Neijseen, Nesu, Dixit, Bargou and Chen, describing how a bispecific antibody with binding domains for CD3 and a tumor target antigen can have an “inert” Fc region to block non-specific, Fe-mediated activation of the T-cell while retaining the ability to be activated by targeted, or target-specific, T-cell activation (see paragraph paragraphs 0241-243).
Given the knowledge in the art set forth above, it would have been obvious to the ordinarily skilled artisan that Fcγ receptor-binding activity of bispecific molecules such as CD20 x CD3, can be diminished while retaining effective tumor target cell-dependent T-cell activation. Thus, the ordinarily skilled artisan was well aware prior to applicant’s effective priority date that bispecific anti-TAA x anti-CD3 antibodies, such as bispecific anti-CD20 x anti-CD3 antibodies, do not require Fc effector function to be activated by, and, in turn, to lyse TAA-expressing target cells.
The nonstatutory double patenting rejection that follows is set forth in the context of the above knowledge of the prior art.
621 claims 1 and 13 are drawn to,
1. A method for treating a B-cell cancer in a subject, comprising: administering to the subject an anti-CD20 antibody; and subsequently administering to the subject a bispecific anti-CD3×CD20 antibody, wherein the bispecific anti-CD3×CD20 antibody is a fully human bispecific antibody comprising a first antigen-binding domain that specifically binds human CD3, and a second antigen-binding domain that specifically binds human CD20; wherein the first antigen-binding domain comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1250, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:1258; and wherein the second antigen-binding domain comprises a HCVR comprising the amino acid sequence of SEQ ID NO:1242, and a LCVR comprising the amino acid sequence of SEQ ID NO:1258;
and
13. A method for treating a B-cell cancer in a subject, comprising: administering to the subject an anti-CD20 antibody; and subsequently administering to the subject a bispecific anti-CD3×CD20 antibody, wherein the bispecific anti-CD3×CD20 antibody is a fully human bispecific antibody comprising a first antigen-binding domain that specifically binds human CD3, and a second antigen-binding domain that specifically binds human CD20; wherein the first antigen-binding domain comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1282, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:1290; and wherein the second antigen-binding domain comprises a HCVR comprising the amino acid sequence of SEQ ID NO:1242, and a LCVR comprising the amino acid sequence of SEQ ID NO:1290.
SEQ ID NO: 1242 is identical to SEQ ID NO: 2 of the instant claims.
However, the reference claims do not explicitly teach the light chain of SEQ ID NO: 18 nor do the reference claims explicitly recite a method for treating a B-cell cancer in a subject, such as Non-Hodgkin’s Lymphoma (NHL), the method comprising: (a) selecting a subject who is afflicted with a cancer that is resistant to, or incompletely responsive to anti-CD20 monospecific therapy alone; and (b) administering to the subject a therapeutic amount of a bispecific antibody comprising a first antigen-binding domain that binds human CD3, a second antigen-binding domain that binds human CD20, and a chimeric heavy chain constant region tethered to each of the first and second antigen-binding domains, wherein the heavy chain constant region comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30 and SEQ ID NO:32.
The following alignment illustrates the difference in the light chain variable regions (LCVR) of instant SEQ ID NO: 18 as compared to SEQ ID NOs: 1250 and 1282 of the ‘621:
sin18 -EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIP 59
1258 AEIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIP 60
1290 -EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIP 59
***********************************************************
sin18 ARFSGSGSGTEFTLTISSLQSEDFAVYYCQHYINWPLTFGGGTKVEIKR 108
1258 ARFSGSGSGTEFTLTISSLQSEDFAVYYCQHYINWPLTFGGGTKVEIK- 108
1290 ARFSGSGSGTEFTLTISSLQSEDFAVYYCQHYINWPLTFGGGTKVEIK- 107
************************************************
However, this difference is not consequential and it would have been obvious to the ordinarily skilled artisan a C-terminal arginine residue could be considered part of any given LCVR given the knowledge in the art illustrated by Guo at SEQ ID NO: 8 which shows a fully human light chain terminating with “Arg” at position 110, wherein the human antibody light chain constant region (CL) of Guo begins with “TVAAPSVF…” (see SEQ ID NO: 4) which lies downstream of the human light chain terminating “Arg” residue as shown in Guo SEQ ID NO: 12 which is the amino acid sequence of light chain of fully human antibody 4H16:
sin8 DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPS 60
sin4 ------------------------------------------------------------ 0
sin12 DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPS 60
sin8 RFSGSGSGTDFTFTISSLQPEDIATYYCQQYDNLPPELTFGGGTKVEIKR---------- 110
sin4 --------------------------------------------------TVAAPSVFIF 10
sin12 RFSGSGSGTDFTFTISSLQPEDIATYYCQQYDNLPPELTFGGGTKVEIKRTVAAPSVFIF 120
sin8 ------------------------------------------------------------ 110
sin4 PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST 70
sin12 PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST 180
sin8 ------------------------------------ 110
sin4 LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 106
sin12 LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 216
Additionally, as taught by P01834, the human Ig kappa chain C region begins with the sequence “TVAAPS…” and since this sequence is joined to the light chain variable domain via mRNA splicing the upstream Arg residue is part of the human antibody LCVR.
Thus, given the reference claims and the knowledge of LCVR in art as illustrated by Guo, it would have been obvious to the ordinarily skilled artisan that any given LCVR could potentially include the C-terminal R residue present, e.g., in SEQ ID NO: 18 of the instant claims.
Furthermore, with respect to treating a B-cell cancer in a subject, such as Non-Hodgkin’s Lymphoma (NHL), the method comprising: (a) selecting a subject who is afflicted with a cancer that is resistant to, or incompletely responsive to anti-CD20 monospecific therapy alone; and (b) administering to the subject a therapeutic amount of a bispecific antibody comprising a first antigen-binding domain that binds human CD3, a second antigen-binding domain that binds human CD20, and a chimeric heavy chain constant region tethered to each of the first and second antigen-binding domains, the teachings of Chao and Wong are relevant.
At page 252, right col., Chao teaches:
“…rituximab acts in part by engaging Fc receptors on immune effector cells, such as natural killer cells and macrophages, and stimulates such effector functions as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and induction of apoptosis.4 While therapeutic outcomes has dramatically improved in the post-rituximab era, there is increasing evidence of rituximab resistance. Clinical resistance to rituximab is generally defined as a lack of response to a rituximab-containing treatment regimen or clinical progression after 6 months of such a regimen. Diminished response rates to rituximab in patients with prior rituximab treatments have been observed in multiple NHL subtypes. In patients with relapsed FL or low-grade NHL who had previously received single agent rituximab, only 40% of patients responded with rituximab retreatment.5
…Poorer outcomes were specifically seen in previously treated rituximab patients who relapsed or progressed during the first year. These data and others highlight the clinical concern that salvage regimens for relapsed/refractory patients may not be as effective in the era of rituximab usage in front-line regimens. Thus, overcoming rituximab resistance has been a major focus of recent therapeutic development. Several mechanisms of rituximab resistance have been postulated. These include resistance in antibody effector mechanisms (ADCC, CDC, and induction of apoptosis), Fc-receptor polymorphisms, downregulation or loss of CD20 expression, and altered antibody pharmacokinetics.8 To address these issues, one major treatment strategy has been the development of novel anti-CD20 antibodies that more effectively engage immune effectors….”
In the “Bispecific antibodies” section Chao further teaches, “Blinatumomab has been clinically studied in both NHL and acute lymphoblastic leukemia. The first phase I study of 62 NHL patients treated with the recommended dose of blinatumomab demonstrated an ORR of 82% across NHL subtypes, with over 60% of responders maintaining durable response up to 3 years out from therapy (Table 1)53,” wherein the data of Table 1 features a study where “R/R NHL” was successfully treated with blinatumomab.
Consistent with the teachings of Chao that “novel anti-CD20 antibodies that more effectively engage immune effectors” would be desirable as a remedy for rituximab resistance due to, e.g., resistance in antibody effector mechanisms (ADCC, CDC, and induction of apoptosis), at page 10, Wong teaches the use of a bispecific antibody capable of forcing a “conjugate between T cells and CLL cells (Online Supplementary Figure S8),” such as the CD3xC19 bispecific antibody blinatumomb, and the ordinarily skilled artisan would understand that treatment with a bispecific CD3xCD20 antibody, like that of the reference claims, would be reasonably expected to be effective for treating rituximab resistant B-cell cancer.
Given the reference methods of treating a CD20-positive B-cell cancer in a subject, the method comprising administering to the subject a therapeutic amount of bispecific antibody as recited in reference claims 1-6 and 13-18 of the ‘621, and further given the knowledge in the art illustrated by the teachings of Chao et al. and Wong et al. set forth above, it would have been obvious to the ordinarily skilled artisan, and the ordinarily skilled artisan would have been motivated to treat a B-cell cancer patient, such as Non-Hodgkin’s Lymphoma (NHL) cancer patient, who is afflicted with a cancer that is resistant to, or incompletely responsive to anti-CD20 monospecific therapy alone by following the steps of reference claims 1-6 and 13-18 of the ‘621, since as taught by Wong / Chao the mechanism of action of a bispecific antibody that binds to a T-cell and redirects the T-cell into close proximity with a cancer target cells is very different from that of other agents such as the rituximab anti-CD20 antibody.
With respect to practicing the methods of reference claims 1-6 and 13-18 by administering to the subject a therapeutic amount of a bispecific antibody comprising a first antigen-binding domain that binds human CD3, a second antigen-binding domain that binds human CD20, and a chimeric heavy chain constant region tethered to each of the first and second antigen-binding domains, wherein the heavy chain constant region comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30 and SEQ ID NO:32, as taught by Davis at paragraph 0006, “For certain antibody therapies, it may be advantageous to engineer the Fc receptor binding properties so as to activate all, some, or none of the available effector mechanisms, without affecting the antibody's pharmacokinetic properties…. Another setting in which reduced binding to Fc receptors could be desirable is when the antibody is bispecific, and its desired therapeutic properties arise from the different binding specificities. For example, a common usage of bispecific antibodies is to combine a tumor targeting specificity with a T cell activating specificity in order to trigger tumor-specific T cell killing. In this case, if the Fc portion binds to an Fc receptor, then potentially that could trigger undesirable killing of cells bearing Fc receptors by T cells, or killing of T cells by Fc receptor-bearing cells such as natural killer cells or macrophages.” (emphasis added).
In Example 2, Davis teaches the production of bispecific anti-CD3 x anti-CD20 antibodies wherein “Antibody 3,” also known as “Control Ab 5,” is antibody which “had its heavy chain constant regions replaced with chimeric constant heavy chain regions, the anti-CD20 arm having an heavy chain constant region amino acid sequence comprising SEQ ID NO: 30, and the anti-CD3 arm having a mutation in the CH3 domain of the CH (SEQ ID NO:37) to create Antibody 3
(also known herein as slgG1*);” likewise Davis further teaches, “Antibody 4” is antibody which “was created from bispecific antibody Control Ab 5 whereas heavy chain constant regions were replaced with chimeric CH, the anti-CD20 arm having an heavy chain constant region amino acid sequence comprising SEQ ID NO: 31, and the anti-CD3 arm having a mutation in the CH3 domain of the CH (SEQ ID NO:38) to create Antibody 4 (also known herein as slgG4*).” (see paragraphs 00216-217).
As further described in paragraph 00218, “The chimeric antibodies comprising constant regions of SEQ ID NO:30 or SEQ ID NO:31 (or bispecific antibodies comprising SEQ ID NO:30/37 or SEQ ID NO:31/38), and the control antibodies, were used in certain experiments set out in the Examples that follow.”
The ordinarily skilled artisan would instantly understand that if a given bispecific antibody is an IgG1 isotype then, except in very limited, non-physiologic conditions, stable pairing of the antibody constant domains requires that each heavy chain be an IgG1 isotype or have a structure that is primarily based upon an IgG1 isotype.
Likewise, the ordinarily skilled artisan would further instantly understand that if a given bispecific antibody is an IgG4 isotype then, except in very limited, non-physiologic conditions, stable pairing of the antibody constant domains requires that each heavy chain be an IgG4 isotype or have a structure that is primarily based upon an IgG4 isotype.
Given the above, the ordinarily skilled artisan would understand that “Antibody 3,” which is described as an “slgG1*” above, is a bispecific antibody having constant domains that are IgG1 isotype or have a structure that is primarily based upon an IgG1 isotype; more particularly Antibody 3 has a first heavy chain which has the CH1, upper and lower hinge and the Fc domains of SEQ ID NO: 30 and a second heavy chain which has the CH1, upper and lower hinge and the Fc domains of SEQ ID NO: 37.
Likewise, the ordinarily skilled artisan would understand that “Antibody 4,” which is described as an “slgG4*” above, is a bispecific antibody having constant domains that are IgG4 isotype or have a structure that is primarily based upon an IgG4 isotype; more particularly Antibody 4 has a first heavy chain which has the CH1, upper and lower hinge and the Fc domains of SEQ ID NO: 31 and a second heavy chain which has the CH1, upper and lower hinge and the Fc domains of SEQ ID NO: 38.
In Example 7, Davis describes how bispecific anti-CD3 x anti-CD20 Antibody 3 (sIgG1*), which comprises the constant regions of SEQ ID NOs: 30/37, and further how bispecific anti-CD3 x anti-CD20 Antibody 4 (sIgG4*), which comprises the constant regions of SEQ ID NOs: 31/38, exhibit no binding to human FcγRI (see Table 10) or to human FcγRIIIA(V176), FcγRIIIA(F176) or FcγRIIIB (see Table 11).
In Example 8, Davis describes how bispecific anti-CD3 x anti-CD20 Antibody 3 (sIgG1*), which comprises the constant regions of SEQ ID NOs: 30/37, and further how bispecific anti-CD3 x anti-CD20 Antibody 4 (sIgG4*), which comprises the constant regions of SEQ ID NOs: 31/38, have CDC activity which is “significantly diminished” against Daudi and Raji cells as compared to corresponding antibody having a wild-type heavy chain constant domain (see paragraph 00232).
In Example 9 Davis describes how bispecific anti-CD3 x anti-CD20 Antibody 3 (sIgG1*), which comprises the constant regions of SEQ ID NOs: 30/37, and further how bispecific anti-CD3 x anti-CD20 Antibody 4 (sIgG4*), which comprises the constant regions of SEQ ID NOs: 31/38, “display reduced activity in ADCC assays measuring effector function.”
Finally, in Example 10 Davis demonstrates the bispecific anti-CD3 x anti-CD20 Antibody 3 (sIgG1*) and the bispecific anti-CD3 x anti-CD20 Antibody 4 (sIgG4*) antibodies have measured terminal half-lives “typical of monoclonal antibodies dosed in cynomolgus monkey,” i.e., these antibodies have an “apparent terminal half-life…estimated to be between 8.14-14.0 days.”
Given the reference claims are drawn to treating or ameliorating a human-CD20 positive B cell cancer in a subject comprising administering a bispecific antibody that binds CD20 and CD3, it would have been obvious to the ordinarily skilled artisan to administer the reference bispecific antibody in a form that comprises the chimeric Fc domain which mediates reduced ADCC / CDC while retaining tumor cell killing ability and a long terminal half-life. In this regard, given the teachings of Davis as viewed from the perspective of the knowledge in the art as illustrated by Neijseen, Nezu, Dixit, Bargou, Chen and Van den Brink, it would have been obvious to the ordinarily skilled artisan to practice the reference methods of treatment by administering CD20xCD3 bispecific antibodies comprising the particular chimeric Fc domains described by Davis which mediate diminished ADCC and diminished CDC compared to wild-type Fc, i.e., to use bispecific antibodies comprising SEQ ID NO:30/37 or SEQ ID NO:31/38 of Davis.
Note in this regard that these Fc domains of Davis are identical to Fc domains of the instant claims as follows:
SEQ ID NO: 26 of the instant claims = Davis SEQ ID NO: 31;
SEQ ID NO: 28 of the instant claims = Davis SEQ ID NO: 38;
SEQ ID NO: 30 of the instant claims = Davis SEQ ID NO: 30;
SEQ ID NO: 32 of the instant claims = Davis SEQ ID NO: 37;
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 11-16 and 166-178 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of U.S. Patent No. 12054557 in view of Chao et al. (Cancer Management and Research 2013:5 251–269) and Wong et al. (Haematologica. 2013 Dec;98(12):1930–1938, supplemental pages included, document has been renumbered as pages 1-27)(all of record), and further in view of Davis et al. (WO2014121087, cited on an IDS),
as evidenced by:
Neijseen et al. (WO2012143524A2, cited herewith);
Nezu et al. (WO2012073985A1, the English language national stage entry under 35 U.S.C. § 371 of the ‘985 application into the USA which corresponds to 20140112914, both cited on an IDS);
Dixit et al. (WO2015006749, cited on an IDS);
Bargou et al. (Science, 2008, Vol 321, pages 974-977, cited on an IDS);
Chen et al. (20150166661, cited on an IDS); and
Van den Brink et al. (20160168247, cited on an IDS).
As a preliminary matter, please consider the following knowledge in the prior art of bispecific tumor binding x T-cell binding antibodies that retain tumor cell killing ability, even when said bispecific antibodies comprise diminished Fc-mediated ADCC and CDC activities, thereby mitigating on-target but off-tumor toxicity.
Neijseen taught bispecific antibodies comprising a Her2 binding domain, a CD3 binding domain, and a modified Fc region, wherein the modified Fc region (i) promotes dimerization of one Her2 binding domain with one CD3 binding domain, an