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 .
DETAILED ACTION
Claims 3-4, 6-7, 11-14, 17-19, 24, and 26-27 are pending.
Claims 1 and 8-9 are canceled.
Rejections Withdrawn
The rejections to claims 1 and 8-9 are moot in view of claim cancelation.
The rejection to claims 3-4, 6-7, 11-14, 17-19, 24, and 26-27 under 35 USC §103 is withdrawn in view of claim amendment.
The rejection to claims 3-4, 6-7, 11-14, 17-19, 24, and 26-27 under nonstatutory double patenting is withdrawn in view of claim amendment.
Claim Rejections Necessitated by Amendment
Claim Rejections – 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 3-4, 6-7, 11-14, 17-19, 24 and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Kinneer K et al. (Blood (2017) 130 (Supplement 1): 3153., IDS reference) hereafter Kinneer 2017 and Richardson PG et al. (Curr Opin Oncol 2006 18:598–608, reference of record) hereafter Richardson and evidenced by Kinneer K et al. (Leukemia 2019 33, 766–771, IDS reference) hereafter Kinneer Leukemia and WO2019/025983 (Kinneer K et al., IDS reference) hereafter Kinneer ‘983.
Regarding instant claims 3-4, 6-7, 11-14, 17-19, 24 and 26, Kinneer 2017 taught MEDI2228 is an antibody drug conjugate (ADC) that targets BCMA and is composed of a fully human antibody site-specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer via a protease-cleavable linker (abstract). Regarding instant claims 3, 6-7, 11-14, 17-19, 24 and 26, Kinneer 2017 taught a method of administering MEDI2228 to a subject with multiple myeloma was effective in vivo (abstract). Regarding instant claims 4, Kinneer 2017 taught a method of administering MEDI2228 to multiple myeloma cells in vitro was effective (abstract). Regarding instant claim 7, Kinneer 2017 taught B-cell maturation antigen (BCMA, TNFRSF17) is a suitable therapeutic target for the treatment of MM due to its restricted expression on normal plasma cells and universal expression in myeloma cells (abstract). Regarding instant claim 7, Kinneer 2017 taught MEDI2228 was highly active in multiple myeloma cell lines with high (~19,000 receptors/cell) or low (~930 receptors/cell) expression of BCMA. Regarding instant claims 3-4, 6-7, 11-14, 17-19, 24 and 26, Kinneer Leukemia evidenced MEDI2228 has the structure:
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(Kinneer Leukemia Fig. 2A), wherein the structure conjugated is PBD tesirine (Kinneer Leukemia, page 768, right column, third paragraph) and the antibody component BCMA-Ab1 (Kinneer Leukemia, page 770, left column, second paragraph), which is further evidenced as 15B2GL site-specifically conjugated to an engineered cysteine inserted after position 239 (C239i) in the CH2 constant domain of the BCMA antibody of the M2 antibody in the instant specification (instant specification, page 40, lines 11-21) in the heavy chain constant region of instant SEQ ID NO:11 (instant specification, page 47, Table), which is further comprised of a human kappa constant region comprising instant SEQ ID NO:12 (instant specification, page 47, Table), wherein the sequence of 15B2GL is evidenced by Kinneer ‘983 as comprising:
a VH of SEQ ID NO:7
EVQLVESGGGLVKPGGSLRLSCAASGFTFRSYSMNWVRQAPGKGLEWVSSISGSSNYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGGNYYVEYFQYWGQGTLVTVSS
a VL of SEQ ID NO:8
EIVLTQSPGTLSLSPGERATLSCRASQYISSNYLAWYQQKPGQAPRLLIYGASNRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPITFGQGTKLEIK
Kinneer 2017 taught MEDI2228 is rapidly internalized and trafficked to lysosomes and upon release, the warhead binds to the minor-groove and cross-links DNA, leading to DNA damage and apoptotic cell death (abstract). Kinneer taught MEDI2228 is active in the presence of bone marrow stromal cells, which have been shown to play a role in chemotherapy resistance, and in cell models resistant to lenalidomide (abstract).
Kinneer 2017 did not teach a composition of an ADC targeting BCMA in combination with a proteasomal inhibitor, but this is obvious in view of Richardson.
Kinneer 2017 was silent to the expression of BCMA in the multiple myeloma cells in the subjects administered MEDI2228, but it would be obvious to treat multiple myeloma cells that had overexpression of BCMA in view of Kinneer 2017.
Richardson taught bortezomib is a proteasome inhibitor approved for treatment of multiple myeloma (page 598, right column, first paragraph). Richardson taught bortezomib has been consistently shown to prolong time to progression (TTP) compared with patients' prior therapy (page 598, right column, first paragraph).
Richardson taught additive and synergistic activity has been demonstrated in preclinical studies of bortezomib plus conventional and novel therapies (page 600, left to right column bridging sentence). Regarding instant claim 6 and 26, Richardson taught the nuclear factor-kB (NF-kB) pathway, which is constitutively active in myeloma cells, is responsible for proliferation and survival and for the antiapoptotic response to stressors such as chemotherapy and that inhibition of the NF-kB pathway by bortezomib causes cellular apoptosis and sensitizing cells to other chemotherapeutic agents (page 599, Figure 1 legend). Richardson taught bortezomib can overcome or reverse chemoresistance and enhance sensitivity to specific agents, including melphalan and mitoxantrone, which are the DNA crosslinking agents (page 600, right column, first paragraph). Richardson taught reversal of chemoresistance has potentially great clinical significance, as it would allow for the reintroduction of agents to which multiple myeloma had previously become refractory (page 600, right column, first paragraph). Richardson taught combination bortezomib and the DNA cross-linking agent melphalan resulted in 1,000,000-fold increase in sensitivity to in U266/LR7 and RPMI8226/LR5 melphalan-resistant myeloma cell lines; enhanced sensitivity to melphalan in MM.1S cell line and in patient cells (page 600, Table 1). Richardson taught combination bortezomib and the DNA cross-linking agent mitoxantrone resulted in 100,000-fold increase in sensitivity to mitoxantrone in RPMI8226/MR20 mitoxantrone-resistant myeloma cell line (page 600, Table 1). Richardson taught improved activity with combination administration of bortezomib plus the DNA crosslinking agent, bendamustine, for treatment of multiple myeloma (page 605, right column, first paragraph). Richardson taught a strong body of evidence has emerged demonstrating the efficacy and safety of bortezomib-based therapies across a broad spectrum of patient populations (page 606, right column, last paragraph). Richardson taught bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates in multiple myeloma (abstract). Richardson taught toxicities from combination therapy are predictable and manageable and comparable to those seen with bortezomib monotherapy.
Regarding instant claims 3, 6-7, 11-14, 17-19, 24 and 26-27, it would have been obvious for a person having ordinary skill in the art to take the method of Kinneer 2017 of administering a subject with multiple myeloma a composition of MEDI2228, which is a BCMA targeting ADC composed of a fully human antibody site-specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine (PBD) – and: 1) to further include in the composition the proteasome inhibitor bortezomib of Richardson; 2) to treat multiple myeloma cells with increased expression level of BCMA; and 3) administer bortezomib prior to or simultaneously with the ADC.
This is obvious because Richardson taught: 1a) bortezomib is a proteasome inhibitor approved for treatment of multiple myeloma; 1b) additive and synergistic activity has been demonstrated in preclinical studies of bortezomib plus several drugs with DNA crosslinking agents including melphalan, mitoxantrone, and bendamustine; 1c) bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates in multiple myeloma; 1d) toxicities from combination therapy are predictable and manageable and comparable to those seen with bortezomib monotherapy; 2) MEDI2228 targets BCMA to deliver the toxic DNA cross-linker payload PBD and MEDI2228 was highly active in multiple myeloma cell lines with high (~19,000 receptors/cell) or low (~930 receptors/cell) expression of BCMA; and 3) Richardson taught the nuclear factor-kB (NF-kB) pathway, which is constitutively active in myeloma cells, is responsible for proliferation and survival and for the antiapoptotic response to stressors such as chemotherapy and that inhibition of the NF-kB pathway by bortezomib causes cellular apoptosis and sensitizing cancer cells to other chemotherapeutic agents. Thus, administration of bortezomib just prior to or simultaneously with the ADC would block the antiapoptotic response and sensitize the cancer cells to the toxic DNA cross-linker payload PBD of the ADC.
This would produce a method of administering a subject with multiple myeloma that had increased expression of BCMA (instant claim 7) a composition of:
MEDI2228, which is a BCMA targeting ADC composed of a fully human antibody site-specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine (PBD) (instant claim 17) and has the structure:
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, which has the structure of tesirine also known as SG3249 (instant claims 18-19); and the antibody sequence comprising Kinneer ‘983 VH SEQ ID NO:7 and VL SEQ ID NO:8, which is identical to instant VH SEQ ID NO:7 and instant VL SEQ ID NO:8 and comprises the VH CDR1-3 of instant SEQ ID NO:1-3 and VL CDR1-3 of instant SEQ ID NO:4-6 (instant claim 11), wherein the conjugation site is at an engineered cysteine inserted after position 239 (C239i) of the BCMA antibody (instant claim 12) in the heavy chain constant region of instant SEQ ID NO:11 (instant claim 13), wherein the antibody further contains a human kappa light chain region comprising instant SEQ ID NO:12 (instant claim 14); and
the proteasome inhibitor bortezomib,
wherein administration of bortezomib is just prior to or simultaneously with the ADC (instant claims 6 and 26), which would naturally provide an enhanced suppression of the B-cell malignancy multiple myeloma when compared with an otherwise identical composition medicament lacking the proteasome inhibitor bortezomib, which would naturally provide an enhanced suppression wherein the enhanced suppression is an enhanced delay in tumor growth (instant claim 24) (instant claim and 3). This method would naturally treat multiple myeloma, which is a B-cell malignancy wherein the malignant B-cell is a part of a tumor and after twenty four days post-treatment with the therapeutic combination, the tumor volume is reduced by at least 50% as evidenced by Figure 7 of the instant specification (instant claim 27).
There is a reasonable expectation of success because: 1) bortezomib is already known to be effective against multiple myeloma; 1b) combination bortezomib and the DNA cross-linking agent melphalan resulted in 1,000,000-fold increase in sensitivity to in melphalan-resistant myeloma cell lines; enhanced sensitivity to melphalan in MM.1S cell line and in patient cells; combination bortezomib and the DNA cross-linking agent mitoxantrone resulted in 100,000-fold increase in sensitivity to mitoxantrone in RPMI8226/MR20 mitoxantrone-resistant myeloma cell lines; 1c) bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates in multiple myeloma; 1d) toxicities from combination therapy are predictable and manageable and comparable to those seen with bortezomib monotherapy; 2) MEDI2228 targets BCMA to deliver the toxic DNA cross-linker payload PBD and MEDI2228 was highly active in multiple myeloma cell lines with high (~19,000 receptors/cell) or low (~930 receptors/cell) expression of BCMA; and 3) Richardson taught the nuclear factor-kB (NF-kB) pathway, which is constitutively active in myeloma cells, is responsible for proliferation and survival and for the antiapoptotic response to stressors such as chemotherapy and that inhibition of the NF-kB pathway by bortezomib causes cellular apoptosis and sensitizing cancer cells to other chemotherapeutic agents. Thus, administration of bortezomib just prior to or simultaneously with the ADC would block the antiapoptotic response and sensitize the cancer cells to the toxic DNA cross-linker payload PBD of the ADC. Thus, combination of i) MEDI2228; and ii) bortezomib; would effectively target the PBD crosslinking agent to BCMA expressing multiple myeloma cells and the bortezomib would reasonably be expected to effectively improve multiple myeloma cell killing as seen with other combinations of DNA crosslinking agents.
Regarding instant claim 4, it would have been obvious for a person having ordinary skill in the art to take the method of Kinneer 2017 of administering multiple myeloma cells in vitro a composition of MEDI2228, which is a BCMA targeting ADC composed of a fully human antibody site-specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine (PBD) – and: 1) to further include in the composition the proteasome inhibitor bortezomib of Richardson.
This is obvious because Richardson taught: 1a) bortezomib is a proteasome inhibitor approved for treatment of multiple myeloma; 1b) additive and synergistic activity has been demonstrated in preclinical studies of bortezomib plus several drugs with DNA crosslinking agents including melphalan, mitoxantrone, and bendamustine; 1c) bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates in multiple myeloma.
This would produce a method of enhancing ADC suppression of multiple myeloma that had expression of BCMA in vitro by contacting the BCMA-expressing multiple myeloma cell with a composition of:
MEDI2228, which is a BCMA targeting ADC composed of a fully human antibody site-specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine (PBD) and has the structure:
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,
the proteasome inhibitor bortezomib,
which would naturally provide an enhanced suppression of the B-cell malignancy multiple myeloma when compared with an otherwise identical composition lacking the proteasome inhibitor bortezomib (instant claim 4).
There is a reasonable expectation of success because: 1) bortezomib is already known to be effective against multiple myeloma; 1b) combination bortezomib and the DNA cross-linking agent melphalan resulted in 1,000,000-fold increase in sensitivity to in melphalan-resistant myeloma cell lines; enhanced sensitivity to melphalan in MM.1S cell line and in patient cells; combination bortezomib and the DNA cross-linking agent mitoxantrone resulted in 100,000-fold increase in sensitivity to mitoxantrone in RPMI8226/MR20 mitoxantrone-resistant myeloma cell lines; and 1c) bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates in multiple myeloma. Thus, combination of i) MEDI2228; and ii) bortezomib; would effectively target the PBD crosslinking agent to BCMA expressing multiple myeloma cells and the bortezomib would reasonably be expected to effectively improve multiple myeloma cell killing as seen with other combinations of DNA crosslinking agents.
Response to Arguments
Applicant argues Figures 5-8 of the present specification show a surprising synergistic effect for the combination of BCMA-ADC and bortezomib in multiple myeloma models (MM1S, H929, JJN3, RPMI8226 (low BCMA expressing cell models), and ANBL6-BR (bortezomib-resistant model)). Since synergy arises across diverse multiple myeloma cell lines, encompassing low BCMA, high BCMA, and drug-resistant disease models, it confirms the therapeutic effect is broadly applicable and not limited to any particular antibody species or drug conjugation chemistry. Without acquiescing the merits of the assertions by the Office and solely to expedite prosecution, independent claims 3 and 4 are amended herein to recite multiple myeloma, which aligns the scope of the claims in the manner alleged by the Office to be commensurate with the examples of the specification
The Office asserts that the combination of a BCMA-targeting ADC with bortezomib would be obvious because Richardson taught combining bortezomib with "DNA-crosslinking agents." However, none of the cited art teaches or suggests combining bortezomib with an ADC, let alone a BCMA-targeting ADC. The applied art does not teach or otherwise suggest that such ADC-bortezomib combinations would yield a synergistic effect, particularly in a low-BCMA expressing multiple myeloma model, a bortezomib-resistant multiple myeloma model, or patient-derived tumor xenografts (Fig. 7). Richardson reports synergy with a limited set of small-molecule agents (e.g., melphalan, mitoxantrone) that directly affect global DNA damage pathways, not with large biologics, targeted antibodies, or ADC frameworks. The predictability of such combinations is low, particularly for ADCs, which exhibit complex pharmacokinetics, intracellular trafficking, payload release profiles, antigen targeting, and tumor internalization dynamics. The small molecules disclosed by Richardson are cytotoxic agents that distribute systemically in a subject, which stands in contrast to the targeted mechanism by which an ADC functions. A person having ordinary skill in the subject art would not have inferred that bortezomib's effects on NF-KB would synergize with the targeted delivery of a potent DNA crosslinking payload via an ADC to BCMA expressing cells. The applied art provides no teaching, suggestion, or motivation for this pairing.
The Office alleges that toxicities from combination therapy are predictable, manageable, and comparable to those seen with bortezomib therapy. (Office Action, p. 7). There is little, if any, experimental evidence to support such a broad statement. Richardson references only a limited number of specific small molecule categories that may be combined with bortezomib, including steroids, alkylating agents, and doxorubicin. Even if Richardson provided experimental evidence supporting each of those combinations, which it does not, it contains no evidence or even a mention of combining bortezomib with an ADC, much less with a targeted anti-BCMA ADC as recited in the present claims. There is no basis to support the Office's assertion that such a combination would yield predictable results or constitute a manageable therapeutic regimen.
Accordingly, it is believed that applied art, whether considered individually or in combination, does not render obvious the presently claimed subject matter. Withdrawal of the rejections is respectfully requested.
In response, Applicant's arguments filed 4/16/2026 have been fully considered, but they are not persuasive. The obvious rational is above. The Applicant’s arguments regarding synergy of the combination of DNA crosslinking agents and bortezomib do not support all species of the subject matter of instant claims 3-4, 6-7, 11-14, 17-19, 24 and 26-27 which require an ADC with a DNA crosslinking agent and bortezomib. These claims do not require the specific species of ADC comprising the PBD DNA crosslinking agent tested in multiple myeloma cells. Instant Fig 5-6 shows results of the combination of ADC M2 in combination with bortezomib, but instant claims 3-4, 6-7, 11-14, 17-19, 24 and 26-27 do not require the crosslinking agent to be ADC M2, which is the anti-BCMA ADC prepared through site-specific conjugation of the PBD dimer, tesirine (SG3249), to the BCMA Ab1 (instant specification, page 40, lines 11-16). Fig 7-8 show the combination of ADC M2 in combination with bortezomib in vivo results in synergistic cancer cell death for MM1S multiple myeloma tumors.
Thus, the surprising synergistic effects are only shown when treating multiple myeloma cells wherein the treatment comprised bortezomib and the ADC M2, which is the anti-BCMA ADC prepared through site-specific conjugation of the PBD dimer, tesirine (SG3249), to the BCMA Ab1 (instant specification, page 40, lines 11-16), which is comprised of a sequence of a heavy chain CDR1-3 of instant SEQ ID NO:1-3, and a light chain CDR of instant SEQ ID NO:4-6. MPEP 716.02(d) requires unexpected results to be commensurate in scope with the claimed invention. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." The current scope of the claims are not commensurate with the surprising synergistic results.
Regarding “synergy arises across diverse multiple myeloma cell lines, encompassing low BCMA, high BCMA, and drug-resistant disease models, it confirms
the therapeutic effect is broadly applicable and not limited to any particular antibody species or drug conjugation chemistry” –
As described above, Kinneer 2017 taught a method of administering MEDI2228 to a subject with multiple myeloma was effective in vivo (abstract) and MEDI2228 was highly active in multiple myeloma cell lines with high (~19,000 receptors/cell) or low (~930 receptors/cell) expression of BCMA. Kinneer taught MEDI2228 is active in the presence of bone marrow stromal cells, which have been shown to play a role in chemotherapy resistance, and in cell models resistant to lenalidomide (abstract). Kinneer 2017 taught MEDI2228 is rapidly internalized and trafficked to lysosomes and upon release, the warhead binds to the minor-groove and cross-links DNA, leading to DNA damage and apoptotic cell death (abstract). Thus, effective treatment of MEDI2228 of multiple myeloma cells with high or low BCMA and in models of chemotherapy resistance was known.
Further, the benefits of bortezomib were taught by Richardson above, wherein Richardson taught: A) additive and synergistic activity has been demonstrated in preclinical studies of bortezomib plus conventional and novel therapies (page 600, left to right column bridging sentence); B) the nuclear factor-kB (NF-kB) pathway, which is constitutively active in myeloma cells, is responsible for proliferation and survival and for the antiapoptotic response to stressors such as chemotherapy and that inhibition of the NF-kB pathway by bortezomib causes cellular apoptosis and sensitizing cells to other chemotherapeutic agents (page 599, Figure 1 legend); C) bortezomib can overcome or reverse chemoresistance and enhance sensitivity to specific agents, including melphalan and mitoxantrone, which are the DNA crosslinking agents (page 600, right column, first paragraph); D) combination bortezomib and the DNA cross-linking agent melphalan resulted in 1,000,000-fold increase in sensitivity to in U266/LR7 and RPMI8226/LR5 melphalan-resistant myeloma cell lines; enhanced sensitivity to melphalan in MM.1S cell line and in patient cells (page 600, Table 1); E) combination bortezomib and the DNA cross-linking agent mitoxantrone resulted in 100,000-fold increase in sensitivity to mitoxantrone in RPMI8226/MR20 mitoxantrone-resistant myeloma cell line (page 600, Table 1); F) improved activity with combination administration of bortezomib plus the DNA crosslinking agent, bendamustine, for treatment of multiple myeloma (page 605, right column, first paragraph); G) a strong body of evidence has emerged demonstrating the efficacy and safety of bortezomib-based therapies across a broad spectrum of patient populations (page 606, right column, last paragraph). Richardson taught bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates in multiple myeloma (abstract); and toxicities from combination therapy are predictable and manageable and comparable to those seen with bortezomib monotherapy.
Thus, a method of multiple myeloma treatment comprising administration of a composition of the known effective BCMA targeting ADC, MEDI2228, and bortezomib would be obvious with a reasonable expectation of success as described in the obvious rational above.
Regarding Richardson and a limited set of small-molecule agents, predictability, systemic distribution, and toxicity –
As described above, Kinneer 2017 taught effective treatment of MEDI2228 for multiple myeloma in vivo and with high or low BCMA and in models of chemotherapy resistance. Further, as described above, Kinneer 2017 taught MEDI2228 is rapidly internalized and trafficked to lysosomes and upon release, the warhead binds to the minor-groove and cross-links DNA, leading to DNA damage and apoptotic cell death (abstract). Thus, delivery of the pyrrolobenzodiazepine (PBD) dimer to multiple myeloma cells via MEDI2228 was known to be effective in vivo. As described above, Richardson taught: A) additive and synergistic activity has been demonstrated in preclinical studies of bortezomib plus conventional and novel therapies (page 600, left to right column bridging sentence); B) the nuclear factor-kB (NF-kB) pathway, which is constitutively active in myeloma cells, is responsible for proliferation and survival and for the antiapoptotic response to stressors such as chemotherapy and that inhibition of the NF-kB pathway by bortezomib causes cellular apoptosis and sensitizing cells to other chemotherapeutic agents (page 599, Figure 1 legend); C) bortezomib can overcome or reverse chemoresistance and enhance sensitivity to DNA crosslinking agents. Thus, a targeted DNA damaging agent delivered by an ADC would be obvious and expected to benefit from the combination with bortezomib. An ADC conjugated to a DNA damaging agent or a systemically administered DNA damaging agent would be expected to benefit from bortezomib combination. Bortezomib is known to be effective in multiple myeloma treatment and overcome or reverse chemoresistance and enhance sensitivity to DNA crosslinking agents in cancer cells and would be an obvious choice to combine with MEDI2228 as described above.
Further regarding toxicity, Richardson states (emphasis added),
“Bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates. Encouraging responses to bortezomib and its combinations are also seen in elderly patients, patients with adverse prognostic factors such as refractory disease and increased β2-microglobulin, patients with cytogenetic abnormalities such as chromosome 13 deletion, advanced bone disease, extramedullary involvement, and patients with renal impairment, including patients with renal failure requiring dialysis. Toxicities are predictable and manageable and comparable to those seen with bortezomib monotherapy.” (abstract)
and further describes toxicity of bortezomib and melphalan, wherein “Toxicities were manageable” (Richardson, page 605, left column, third paragraph). As described above, melphalan is a DNA crosslinking agent. Thus, bortezomib and DNA crosslinking agents can have manageable toxicities. Bortezomib and the DNA crosslinking agent bendamustine further show improved activity in multiple myeloma and toxicities that include mild fatigue and thrombocytopenia, plus three cases of manageable neuropathy in patients (Richardson, page 605, left to right column bridging paragraph), wherein the side effect of thrombocytopenia resulting from bortezomib therapy is noted by Richardson as transient and cyclical in nature with predictably platelet count recovery during each treatment cycle, with no evidence of cumulative toxicity (Richardson, page 606, left 6column, third paragraph). Thus, combination of an ADC that utilizes a DNA crosslinking agent to kill the targeted multiple myeloma cells and bortezomib is expected to have manageable toxicity. The targeting of the PBD DNA crosslinking agent by MEDI2228 to multiple myeloma cells would be expected to be beneficial for toxicity due to the multiple myeloma targeting properties of the ADC. Combination of the MEDI2228 with a DNA crosslinking payload and bortezomib would be better targeted to multiple myeloma cells.
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.
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Claims 3-4, 6-7, 11-14, 17-19, 24 and 26-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,912,782 in view of Kinneer K et al. (Blood (2017) 130 (Supplement 1): 3153., IDS reference) hereafter Kinneer 2017 and Richardson PG et al. (Curr Opin Oncol 2006 18:598–608, reference of record) hereafter Richardson and evidenced by Kinneer K et al. (Leukemia 2018 33, 766–771, IDS reference) hereafter Kinneer Leukemia and WO2019/025983 (Kinneer K et al., IDS reference) hereafter Kinneer ‘983.
‘782 taught a method of killing multiple myeloma cells comprising: contacting multiple myeloma cells that express BCMA with an ADC comprising a monoclonal antibody, directed against BCMA conjugated to a cytotoxin, wherein the monoclonal antibody comprises (a) a heavy chain variable region comprising an HCDR of SEQ ID NO: 1-3; and (b) a light chain variable region comprising an LCDR of SEQ ID NO: 4-6; wherein the ADC binds to BCMA on the multiple myeloma cells and kills the multiple myeloma cells in patented claim 1, wherein the multiple myeloma cells are in a human in patented claim 3 or in vitro in patented claim 4, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8 in patented claim 7, wherein the cytotoxin is PBD in patented claim 8 and 10, wherein the PBD is SG3249 having the following formula:
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in patented claim 11, and wherein the human has multiple myeloma and wherein a therapeutically effective amount of the ADC is administered to the human in patented claim 12.
‘782 did not teach: 1) a composition of an ADC targeting BCMA in combination with a proteasomal inhibitor; 2) wherein the BCMA in the multiple myeloma is overexpressed; 3) the linkage of the toxin to an inserted cysteine at 239 of the heavy chain constant region of instant SEQ ID NO:11; 3) the light chain further comprised a human kappa constant region of instant SEQ ID NO:12; and 4) wherein the multiple myeloma was resistant to lenalidomide or bortezomib, but this is obvious in view of Kinneer 2017 and Richardson.
Regarding instant claims 3-4, 6-7, 11-14, 17-19, 24 and 26, Kinneer 2017 taught MEDI2228 is an antibody drug conjugate (ADC) that targets BCMA and is composed of a fully human antibody site-specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer via a protease-cleavable linker (abstract). Regarding instant claims 3, 6-7, 11-14, 17-19, 24 and 26, Kinneer 2017 taught a method of administering MEDI2228 to a subject with multiple myeloma was effective in vivo (abstract). Regarding instant claims 4, Kinneer 2017 taught a method of administering MEDI2228 to multiple myeloma cells in vitro was effective (abstract). Regarding instant claim 7, Kinneer 2017 taught B-cell maturation antigen (BCMA, TNFRSF17) is a suitable therapeutic target for the treatment of MM due to its restricted expression on normal plasma cells and universal expression in myeloma cells (abstract). Regarding instant claim 7, Kinneer 2017 taught MEDI2228 was highly active in multiple myeloma cell lines with high (~19,000 receptors/cell) or low (~930 receptors/cell) expression of BCMA. Regarding instant claims 3-4, 6-7, 11-14, 17-19, 24 and 26, Kinneer Leukemia evidenced MEDI2228 has the structure:
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(Kinneer Leukemia Fig. 2A), wherein the structure conjugated is PBD tesirine (Kinneer Leukemia, page 768, right column, third paragraph) and the antibody component BCMA-Ab1 (Kinneer Leukemia, page 770, left column, second paragraph), which is further evidenced as 15B2GL site-specifically conjugated to an engineered cysteine inserted after position 239 (C239i) in the CH2 constant domain of the BCMA antibody of the M2 antibody in the instant specification (instant specification, page 40, lines 11-21) in the heavy chain constant region of instant SEQ ID NO:11 (instant specification, page 47, Table), which is further comprised of a human kappa constant region comprising instant SEQ ID NO:12 (instant specification, page 47, Table), wherein the sequence of 15B2GL is evidenced by Kinneer ‘983 as comprising:
a VH of SEQ ID NO:7
EVQLVESGGGLVKPGGSLRLSCAASGFTFRSYSMNWVRQAPGKGLEWVSSISGSSNYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGGNYYVEYFQYWGQGTLVTVSS
a VL of SEQ ID NO:8
EIVLTQSPGTLSLSPGERATLSCRASQYISSNYLAWYQQKPGQAPRLLIYGASNRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPITFGQGTKLEIK
Kinneer 2017 taught MEDI2228 is rapidly internalized and trafficked to lysosomes and upon release, the warhead binds to the minor-groove and cross-links DNA, leading to DNA damage and apoptotic cell death (abstract). Kinneer taught MEDI2228 is active in the presence of bone marrow stromal cells, which have been shown to play a role in chemotherapy resistance, and in cell models resistant to lenalidomide (abstract).
Richardson taught bortezomib is a proteasome inhibitor approved for treatment of multiple myeloma (page 598, right column, first paragraph). Richardson taught bortezomib has been consistently shown to prolong time to progression (TTP) compared with patients' prior therapy (page 598, right column, first paragraph).
Richardson taught additive and synergistic activity has been demonstrated in preclinical studies of bortezomib plus conventional and novel therapies (page 600, left to right column bridging sentence). Regarding instant claim 6 and 26, Richardson taught the nuclear factor-kB (NF-kB) pathway, which is constitutively active in myeloma cells, is responsible for proliferation and survival and for the antiapoptotic response to stressors such as chemotherapy and that inhibition of the NF-kB pathway by bortezomib causes cellular apoptosis and sensitizing cells to other chemotherapeutic agents (page 599, Figure 1 legend). Richardson taught bortezomib can overcome or reverse chemoresistance and enhance sensitivity to specific agents, including melphalan and mitoxantrone, which are the DNA crosslinking agents (page 600, right column, first paragraph). Richardson taught reversal of chemoresistance has potentially great clinical significance, as it would allow for the reintroduction of agents to which multiple myeloma had previously become refractory (page 600, right column, first paragraph). Richardson taught combination bortezomib and the DNA cross-linking agent melphalan resulted in 1,000,000-fold increase in sensitivity to in U266/LR7 and RPMI8226/LR5 melphalan-resistant myeloma cell lines; enhanced sensitivity to melphalan in MM.1S cell line and in patient cells (page 600, Table 1). Richardson taught combination bortezomib and the DNA cross-linking agent mitoxantrone resulted in 100,000-fold increase in sensitivity to mitoxantrone in RPMI8226/MR20 mitoxantrone-resistant myeloma cell line (page 600, Table 1). Richardson taught improved activity with combination administration of bortezomib plus the DNA crosslinking agent, bendamustine, for treatment of multiple myeloma (page 605, right column, first paragraph). Richardson taught a strong body of evidence has emerged demonstrating the efficacy and safety of bortezomib-based therapies across a broad spectrum of patient populations (page 606, right column, last paragraph). Richardson taught bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates in multiple myeloma (abstract). Richardson taught toxicities from combination therapy are predictable and manageable and comparable to those seen with bortezomib monotherapy.
Regarding instant claims 3, 6-7, 11-14, 17-19, 24 and 26-27, it would have been obvious for a person having ordinary skill in the art to take the method of ‘782 patented claims of 1, 3, 7-8, 10-12 of killing multiple myeloma cells that express BCMA by administering a human with multiple myeloma a therapeutically effective amount of an ADC comprising a monoclonal antibody, directed against BCMA conjugated to a cytotoxin, wherein the monoclonal antibody comprises the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8, wherein the cytotoxin is the PBD SG3249 having the following formula:
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– and: 1) to further include in the composition the proteasome inhibitor bortezomib of Richardson; 2) treat multiple myeloma cells that had BCMA overexpressed because ‘782 and Kinneer 2017 taught that was that target of the ADC; 3) use the linkage of the toxin to an inserted cysteine at 239 of the heavy chain constant region of instant SEQ ID NO:11 of MEDI2228 of Kinneer 2017; 4) include in the light chain a human kappa constant region of instant SEQ ID NO:12 of MEDI2228 of Kinneer 2017; and 5) administer bortezomib prior to or simultaneously with the ADC.
This is obvious because:
Richardson taught: 1a) bortezomib is a proteasome inhibitor approved for treatment of multiple myeloma; 1b) additive and synergistic activity has been demonstrated in preclinical studies of bortezomib plus several drugs with DNA crosslinking agents including melphalan, mitoxantrone, and bendamustine; 1c) bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates in multiple myeloma; 1d) toxicities from combination therapy are predictable and manageable and comparable to those seen with bortezomib monotherapy;
The ADC of ‘782 and Kinneer 2017 taught BCMA was that target of the ADC;
Kinneer 2017 taught MEDI2228, which has the same VH and VL antibody domain and PBD SG3249 drug conjugate and linker, was effective at treating multiple myeloma and used linkage to an inserted cysteine at 239 of the heavy chain constant region of instant SEQ ID NO:11
Kinneer 2017 taught MEDI2228, which has the same VH and VL antibody domain and PBD SG3249 drug conjugate and linker, was effective at treating multiple myeloma and used a human kappa constant region of instant SEQ ID NO:12; and
Richardson taught the nuclear factor-kB (NF-kB) pathway, which is constitutively active in myeloma cells, is responsible for proliferation and survival and for the antiapoptotic response to stressors such as chemotherapy and that inhibition of the NF-kB pathway by bortezomib causes cellular apoptosis and sensitizing cancer cells to other chemotherapeutic agents. Thus, administration of bortezomib just prior to or simultaneously with the ADC would block the antiapoptotic response and sensitize the cancer cells to the toxic DNA cross-linker payload PBD of the ADC.
This would produce a method of administering a subject with multiple myeloma that had increased expression of BCMA (instant claim 7) a composition of:
a BCMA targeting ADC composed of a fully human antibody site-specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine (PBD) (instant claim 17) and has the structure:
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, which has the structure of tesirine also known as SG3249 (instant claims 18-19); and the antibody sequence comprising VH SEQ ID NO:7 and VL SEQ ID NO:8, which is identical to instant VH SEQ ID NO:7 and instant VL SEQ ID NO:8 and comprises the VH CDR1-3 of instant SEQ ID NO:1-3 and VL CDR1-3 of instant SEQ ID NO:4-6 (instant claim 11), wherein the conjugation site is at an engineered cysteine inserted after position 239 (C239i) of the BCMA antibody (instant claim 12) in the heavy chain constant region of instant SEQ ID NO:11 (instant claim 13), wherein the antibody further contains a human kappa light chain region comprising instant SEQ ID NO:12 (instant claim 14); and
the proteasome inhibitor bortezomib,
wherein administration of bortezomib is just prior to or simultaneously with the ADC (instant claims 6 and 26), which would naturally provide an enhanced suppression of the B-cell malignancy multiple myeloma when compared with an otherwise identical composition medicament lacking the proteasome inhibitor bortezomib, which would naturally provide an enhanced suppression wherein the enhanced suppression is an enhanced delay in tumor growth (instant claim 24) (instant claim and 3). This method would naturally treat multiple myeloma, which is a B-cell malignancy wherein the malignant B-cell is a part of a tumor and after twenty four days post-treatment with the therapeutic combination, the tumor volume is reduced by at least 50% as evidenced by Figure 7 of the instant specification (instant claim 27).
There is a reasonable expectation of success because:
bortezomib is already known to be effective against multiple myeloma; 1b) combination bortezomib and the DNA cross-linking agent melphalan resulted in 1,000,000-fold increase in sensitivity to in melphalan-resistant myeloma cell lines; enhanced sensitivity to melphalan in MM.1S cell line and in patient cells; combination bortezomib and the DNA cross-linking agent mitoxantrone resulted in 100,000-fold increase in sensitivity to mitoxantrone in RPMI8226/MR20 mitoxantrone-resistant myeloma cell lines; 1c) bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates in multiple myeloma; 1d) toxicities from combination therapy are predictable and manageable and comparable to those seen with bortezomib monotherapy;
MEDI2228 targets BCMA to deliver the toxic DNA cross-linker payload PBD and MEDI2228 was highly active in multiple myeloma cell lines with high (~19,000 receptors/cell) or low (~930 receptors/cell) expression of BCMA.
Kinneer 2017 taught MEDI2228 was effective at treating multiple myeloma and used linkage to an inserted cysteine at 239 of the heavy chain constant region of instant SEQ ID NO:11
Kinneer 2017 taught MEDI2228 was effective at treating multiple myeloma and used a human kappa constant region of instant SEQ ID NO:12; and
Richardson taught the nuclear factor-kB (NF-kB) pathway, which is constitutively active in myeloma cells, is responsible for proliferation and survival and for the antiapoptotic response to stressors such as chemotherapy and that inhibition of the NF-kB pathway by bortezomib causes cellular apoptosis and sensitizing cancer cells to other chemotherapeutic agents. Thus, administration of bortezomib just prior to or simultaneously with the ADC would block the antiapoptotic response and sensitize the cancer cells to the toxic DNA cross-linker payload PBD of the ADC.
Thus, combination of i) the ‘782 and Kinneer 2017 ADC; and ii) bortezomib; would effectively target the PBD crosslinking agent to BCMA expressing lenalidomide-resistant multiple myeloma cells and the bortezomib would reasonably be expected to effectively improve lenalidomide-resistant multiple myeloma cell killing as seen with other combinations of DNA crosslinking agents.
Regarding instant claim 4, it would have been obvious for a person having ordinary skill in the art to take the method of ‘782 patented claims of 1, 4, 7-8, 10-11 of killing multiple myeloma cells that express BCMA by administering multiple myeloma cells in vitro an ADC comprising a monoclonal antibody, directed against BCMA conjugated to a cytotoxin, wherein the monoclonal antibody comprises the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8, wherein the cytotoxin is the PBD SG3249 having the following formula:
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– and: 1) to further include in the composition the proteasome inhibitor bortezomib of Richardson
This is obvious because Richardson taught: 1a) bortezomib is a proteasome inhibitor approved for treatment of multiple myeloma; 1b) additive and synergistic activity has been demonstrated in preclinical studies of bortezomib plus several drugs with DNA crosslinking agents including melphalan, mitoxantrone, and bendamustine; 1c) bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates in multiple myeloma.
This would produce a method of enhancing ADC suppression of multiple myeloma that had expression of BCMA in vitro by contacting the BCMA-expressing multiple myeloma cell with a composition of:
the ADC of ‘782, which is a BCMA targeting ADC composed of a fully human antibody site-specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine (PBD) and has the structure:
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,
the proteasome inhibitor bortezomib,
which would naturally provide an enhanced suppression of the B-cell malignancy multiple myeloma when compared with an otherwise identical composition lacking the proteasome inhibitor bortezomib (instant claim 4).
There is a reasonable expectation of success because: 1) bortezomib is already known to be effective against multiple myeloma; 1b) combination bortezomib and the DNA cross-linking agent melphalan resulted in 1,000,000-fold increase in sensitivity to in melphalan-resistant myeloma cell lines; enhanced sensitivity to melphalan in MM.1S cell line and in patient cells; combination bortezomib and the DNA cross-linking agent mitoxantrone resulted in 100,000-fold increase in sensitivity to mitoxantrone in RPMI8226/MR20 mitoxantrone-resistant myeloma cell lines; and 1c) bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates in multiple myeloma. Thus, combination of i) the ADC of ‘782; and ii) bortezomib; would effectively target the PBD crosslinking agent to BCMA expressing multiple myeloma cells and the bortezomib would reasonably be expected to effectively improve multiple myeloma cell killing as seen with other combinations of DNA crosslinking agents.
Response to Arguments
Applicant argues without acquiescing to the merits of the assertions in the Office Action and solely to expedite prosecution, it is believed that the amendment to independent claims 3 and 4 obviates the double patenting rejections. The applied references do not teach a combination therapy with bortezomib and a BCMA-ADC, nor does the applied art teach synergistic effects of the combination in the treatment of multiple myeloma, which are demonstrated in the present application.
In response, Applicant's arguments filed 4/16/2026 have been fully considered, but they are not persuasive. The obvious rational is above and identifies why the combination of ‘782 is obvious with a reasonable expectation of success in view of Kinneer 2017 and Richardson. As described above, Kinneer 2017 taught effective treatment of MEDI2228 for multiple myeloma in vivo and with high or low BCMA and in models of chemotherapy resistance. Further, as described above, Kinneer 2017 taught MEDI2228 is rapidly internalized and trafficked to lysosomes and upon release, the warhead binds to the minor-groove and cross-links DNA, leading to DNA damage and apoptotic cell death (abstract). Thus, delivery of the pyrrolobenzodiazepine (PBD) dimer to multiple myeloma cells via MEDI2228 was known to be effective in vivo. As described above, Richardson taught: A) additive and synergistic activity has been demonstrated in preclinical studies of bortezomib plus conventional and novel therapies (page 600, left to right column bridging sentence); B) the nuclear factor-kB (NF-kB) pathway, which is constitutively active in myeloma cells, is responsible for proliferation and survival and for the antiapoptotic response to stressors such as chemotherapy and that inhibition of the NF-kB pathway by bortezomib causes cellular apoptosis and sensitizing cells to other chemotherapeutic agents (page 599, Figure 1 legend); C) bortezomib can overcome or reverse chemoresistance and enhance sensitivity to DNA crosslinking agents. Thus, a targeted DNA damaging agent delivered by an ADC would be obvious and expected to benefit from the combination with bortezomib.
Claims 3-4, 6-7, 11-14, 17-19, 24 and 26-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 12-13, 15-16, 18, and 22-28 of copending Application No. 18/414,892 in view of Kinneer K et al. (Blood (2017) 130 (Supplement 1): 3153., IDS reference) hereafter Kinneer 2017 and Richardson PG et al. (Curr Opin Oncol 2006 18:598–608, reference of record) hereafter Richardson and evidenced by Kinneer K et al. (Leukemia 2018 33, 766–771, IDS reference) hereafter Kinneer Leukemia and WO2019/025983 (Kinneer K et al., IDS reference) hereafter Kinneer ‘983.
‘892 taught a method of killing multiple myeloma cells comprising: contacting multiple myeloma cells that express BCMA with an ADC comprising a monoclonal antibody, directed against BCMA conjugated to a cytotoxin, wherein the monoclonal antibody comprises (a) a heavy chain variable region comprising an HCDR of SEQ ID NO: 1-3; and (b) a light chain variable region comprising an LCDR of SEQ ID NO: 4-6; wherein the ADC binds to BCMA on the multiple myeloma cells and kills the multiple myeloma cells in copending claim 1, wherein the multiple myeloma cells are in a human in copending claim 12 or in vitro in copending claim 13, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8 in copending claim 4, wherein the cytotoxin is PBD in copending claim 5 and 7, wherein the PBD is SG3249 having the following formula:
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in copending claim 8.
‘892 did not teach: 1) a composition of an ADC targeting BCMA in combination with a proteasomal inhibitor; 2) wherein the BCMA in the multiple myeloma is overexpressed; 3) the linkage of the toxin to an inserted cysteine at 239 of the heavy chain constant region of instant SEQ ID NO:11; 3) the light chain further comprised a human kappa constant region of instant SEQ ID NO:12; and 4) wherein the multiple myeloma was resistant to lenalidomide or bortezomib, but this is obvious in view of Kinneer 2017 and Richardson.
Kinneer 2017 and Richardson are described above.
Regarding instant claims 3, 6-7, 11-14, 17-19, 24 and 26, it would have been obvious for a person having ordinary skill in the art to take the method of ‘892 claims 3-4, 6-7, 11-14, 17-19, 24 and 26 of killing multiple myeloma cells that express BCMA by administering a human with multiple myeloma a therapeutically effective amount of an ADC comprising a monoclonal antibody, directed against BCMA conjugated to a cytotoxin, wherein the monoclonal antibody comprises the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8, wherein the cytotoxin is the PBD SG3249 having the following formula:
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– and: 1) to further include in the composition the proteasome inhibitor bortezomib of Richardson; 2) treat multiple myeloma cells that had BCMA overexpressed because ‘892 and Kinneer 2017 taught that was that target of the ADC; 3) use the linkage of the toxin to an inserted cysteine at 239 of the heavy chain constant region of instant SEQ ID NO:11 of MEDI2228 of Kinneer 2017; 4) include in the light chain a human kappa constant region of instant SEQ ID NO:12 of MEDI2228 of Kinneer 2017; and 5) administer bortezomib prior to or simultaneously with the ADC.
This is obvious because:
Richardson taught: 1a) bortezomib is a proteasome inhibitor approved for treatment of multiple myeloma; 1b) additive and synergistic activity has been demonstrated in preclinical studies of bortezomib plus several drugs with DNA crosslinking agents including melphalan, mitoxantrone, and bendamustine; 1c) bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates in multiple myeloma; 1d) toxicities from combination therapy are predictable and manageable and comparable to those seen with bortezomib monotherapy;
The ADC of ‘892 and Kinneer 2017 taught BCMA was that target of the ADC;
Kinneer 2017 taught MEDI2228, which has the same VH and VL antibody domain and PBD SG3249 drug conjugate and linker, was effective at treating multiple myeloma and used linkage to an inserted cysteine at 239 of the heavy chain constant region of instant SEQ ID NO:11
Kinneer 2017 taught MEDI2228, which has the same VH and VL antibody domain and PBD SG3249 drug conjugate and linker, was effective at treating multiple myeloma and used a human kappa constant region of instant SEQ ID NO:12; and
Richardson taught the nuclear factor-kB (NF-kB) pathway, which is constitutively active in myeloma cells, is responsible for proliferation and survival and for the antiapoptotic response to stressors such as chemotherapy and that inhibition of the NF-kB pathway by bortezomib causes cellular apoptosis and sensitizing cancer cells to other chemotherapeutic agents. Thus, administration of bortezomib just prior to or simultaneously with the ADC would block the antiapoptotic response and sensitize the cancer cells to the toxic DNA cross-linker payload PBD of the ADC.
This would produce a method of administering a subject with multiple myeloma that had increased expression of BCMA (instant claim 7) a composition of:
a BCMA targeting ADC composed of a fully human antibody site-specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine (PBD) (instant claim 17) and has the structure:
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, which has the structure of tesirine also known as SG3249 (instant claims 18-19); and the antibody sequence comprising VH SEQ ID NO:7 and VL SEQ ID NO:8, which is identical to instant VH SEQ ID NO:7 and instant VL SEQ ID NO:8 and comprises the VH CDR1-3 of instant SEQ ID NO:1-3 and VL CDR1-3 of instant SEQ ID NO:4-6 (instant claim 11), wherein the conjugation site is at an engineered cysteine inserted after position 239 (C239i) of the BCMA antibody (instant claim 12) in the heavy chain constant region of instant SEQ ID NO:11 (instant claim 13), wherein the antibody further contains a human kappa light chain region comprising instant SEQ ID NO:12 (instant claim 14); and
the proteasome inhibitor bortezomib,
wherein administration of bortezomib is just prior to or simultaneously with the ADC (instant claims 6 and 26), which would naturally provide an enhanced suppression of the B-cell malignancy multiple myeloma when compared with an otherwise identical composition medicament lacking the proteasome inhibitor bortezomib, which would naturally provide an enhanced suppression wherein the enhanced suppression is an enhanced delay in tumor growth (instant claim 24) (instant claim and 3). This method would naturally treat multiple myeloma, which is a B-cell malignancy wherein the malignant B-cell is a part of a tumor and after twenty five days post-treatment with the therapeutic combination, the tumor volume is reduced by at least 50% as evidenced by Figure 7 of the instant specification (instant claim 27).
There is a reasonable expectation of success because:
bortezomib is already known to be effective against multiple myeloma; 1b) combination bortezomib and the DNA cross-linking agent melphalan resulted in 1,000,000-fold increase in sensitivity to in melphalan-resistant myeloma cell lines; enhanced sensitivity to melphalan in MM.1S cell line and in patient cells; combination bortezomib and the DNA cross-linking agent mitoxantrone resulted in 100,000-fold increase in sensitivity to mitoxantrone in RPMI8226/MR20 mitoxantrone-resistant myeloma cell lines; 1c) bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates in multiple myeloma; 1d) toxicities from combination therapy are predictable and manageable and comparable to those seen with bortezomib monotherapy;
MEDI2228 targets BCMA to deliver the toxic DNA cross-linker payload PBD and MEDI2228 was highly active in multiple myeloma cell lines with high (~19,000 receptors/cell) or low (~930 receptors/cell) expression of BCMA.
Kinneer 2017 taught MEDI2228 was effective at treating multiple myeloma and used linkage to an inserted cysteine at 239 of the heavy chain constant region of instant SEQ ID NO:11
Kinneer 2017 taught MEDI2228 was effective at treating multiple myeloma and used a human kappa constant region of instant SEQ ID NO:12; and
Richardson taught the nuclear factor-kB (NF-kB) pathway, which is constitutively active in myeloma cells, is responsible for proliferation and survival and for the antiapoptotic response to stressors such as chemotherapy and that inhibition of the NF-kB pathway by bortezomib causes cellular apoptosis and sensitizing cancer cells to other chemotherapeutic agents. Thus, administration of bortezomib just prior to or simultaneously with the ADC would block the antiapoptotic response and sensitize the cancer cells to the toxic DNA cross-linker payload PBD of the ADC.
Thus, combination of i) the ‘892 and Kinneer 2017 ADC; and ii) bortezomib; would effectively target the PBD crosslinking agent to BCMA expressing lenalidomide-resistant multiple myeloma cells and the bortezomib would reasonably be expected to effectively improve lenalidomide-resistant multiple myeloma cell killing as seen with other combinations of DNA crosslinking agents.
Regarding instant claim 4, it would have been obvious for a person having ordinary skill in the art to take the method of ‘892 claims of 1, 4-5, 7-8, and 13 of killing multiple myeloma cells that express BCMA by administering multiple myeloma cells in vitro an ADC comprising a monoclonal antibody, directed against BCMA conjugated to a cytotoxin, wherein the monoclonal antibody comprises the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8, wherein the cytotoxin is the PBD SG3249 having the following formula:
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– and: 1) to further include in the composition the proteasome inhibitor bortezomib of Richardson
This is obvious because Richardson taught: 1a) bortezomib is a proteasome inhibitor approved for treatment of multiple myeloma; 1b) additive and synergistic activity has been demonstrated in preclinical studies of bortezomib plus several drugs with DNA crosslinking agents including melphalan, mitoxantrone, and bendamustine; 1c) bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates in multiple myeloma.
This would produce a method of enhancing ADC suppression of multiple myeloma that had expression of BCMA in vitro by contacting the BCMA-expressing multiple myeloma cell with a composition of:
the ADC of ‘892, which is a BCMA targeting ADC composed of a fully human antibody site-specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine (PBD) and has the structure:
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,
the proteasome inhibitor bortezomib,
which would naturally provide an enhanced suppression of the B-cell malignancy multiple myeloma when compared with an otherwise identical composition lacking the proteasome inhibitor bortezomib (instant claim 4).
There is a reasonable expectation of success because: 1) bortezomib is already known to be effective against multiple myeloma; 1b) combination bortezomib and the DNA cross-linking agent melphalan resulted in 1,000,000-fold increase in sensitivity to in melphalan-resistant myeloma cell lines; enhanced sensitivity to melphalan in MM.1S cell line and in patient cells; combination bortezomib and the DNA cross-linking agent mitoxantrone resulted in 100,000-fold increase in sensitivity to mitoxantrone in RPMI8226/MR20 mitoxantrone-resistant myeloma cell lines; and 1c) bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates in multiple myeloma. Thus, combination of i) the ADC of ‘892; and ii) bortezomib; would effectively target the PBD crosslinking agent to BCMA expressing multiple myeloma cells and the bortezomib would reasonably be expected to effectively improve multiple myeloma cell killing as seen with other combinations of DNA crosslinking agents.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant argues without acquiescing to the merits of the assertions in the Office Action and solely to expedite prosecution, it is believed that the amendment to independent claims 3 and 4 obviates the double patenting rejections. The applied references do not teach a combination therapy with bortezomib and a BCMA-ADC, nor does the applied art teach synergistic effects of the combination in the treatment of multiple myeloma, which are demonstrated in the present application.
In response, Applicant's arguments filed 4/16/2026 have been fully considered, but they are not persuasive. The obvious rational is above and identifies why the combination of ‘892 is obvious with a reasonable expectation of success in view of Kinneer 2017 and Richardson. As described above, Kinneer 2017 taught effective treatment of MEDI2228 for multiple myeloma in vivo and with high or low BCMA and in models of chemotherapy resistance. Further, as described above, Kinneer 2017 taught MEDI2228 is rapidly internalized and trafficked to lysosomes and upon release, the warhead binds to the minor-groove and cross-links DNA, leading to DNA damage and apoptotic cell death (abstract). Thus, delivery of the pyrrolobenzodiazepine (PBD) dimer to multiple myeloma cells via MEDI2228 was known to be effective in vivo. As described above, Richardson taught: A) additive and synergistic activity has been demonstrated in preclinical studies of bortezomib plus conventional and novel therapies (page 600, left to right column bridging sentence); B) the nuclear factor-kB (NF-kB) pathway, which is constitutively active in myeloma cells, is responsible for proliferation and survival and for the antiapoptotic response to stressors such as chemotherapy and that inhibition of the NF-kB pathway by bortezomib causes cellular apoptosis and sensitizing cells to other chemotherapeutic agents (page 599, Figure 1 legend); C) bortezomib can overcome or reverse chemoresistance and enhance sensitivity to DNA crosslinking agents. Thus, a targeted DNA damaging agent delivered by an ADC would be obvious and expected to benefit from the combination with bortezomib.
Conclusion
No claims are allowed.
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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/J.J.S./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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