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 1, 3-4, 6-19, 24, and 26-27 are pending. Instant claim 27 is new.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/31/2025 has been entered.
Claim Rejections Maintained or Necessitated by New Claims
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.
The rejection of claims 1, 3-4, 6-9, 11-14, 17-19, 24 and 26 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 is maintained.
Regarding instant claims 1, 3-4, 6-9, 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 1, 3-4, 6-9, 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 1, 3-4, 6-9, 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 1, 3, 6-9, 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 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 claims 7-9) 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 claims 1 and 3).
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:
1. The applied art fails to teach the claimed combination
None of the applied art, whether considered individually or in combination, teaches the claimed subject matter and would not have guided a person of ordinary skill in the subject art to the claimed subject matter with a reasonable expectation of success.
The Examiner alleges that Kinneer 2017 teaches a method of treating multiple
myeloma with MEDI2228. Kinneer '983 teaches the sequence of 15B2GL of the present application (Id., pp. 4-5). Kinneer 2017 and Kinneer '983 do not describe combinations with any other agent. The Examiner admits that Kinneer 2017 does not teach such combination as well (Id., p. 6).
The Office alleges that Richardson teaches "bortezomib is a proteosome inhibitor approved for treatment of multiple myeloma" (Id., p. 6). Richardson describes bortezomib, in combination with specific chemotherapeutic agents, including DNA cross-linkers like melphalan and mitoxantrone (Richardson, Tables 1-2, p. 600). Richardson does not teach or suggest combining bortezomib with an ADC. In fact, there is no enabling disclosure in Richardson for such a combination. The Examiner asserts that 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, however, merely mentions "possible synergy shown with doxorubicin ... ", (Id., Table 2).Richardson does not mention combination with anti-BCMA ADC nor that any combination with bortezomib would yield a synergistic effect, particularly a large molecule such as the claimed anti-BCMA ADC of the present application. A skilled artisan would not have understood Richardson as standing for the broad proposition asserted by the Examiner. Rather, the present application is the only evidence that bortezomib, when combined with the claimed anti-BCMA ADC, has an unexpected and synergistic effect (See., e.g., specification, Figures 5-8). Thus, there is no suggestion or motivation to combine the anti-BCMA ADC of Kinneer 2017 with the proteasome inhibitor bortezomib, and the applied art provides no basis or guidance for a person having ordinary skill in the art to assume that any and every combination with bortezomib would yield a beneficial result. The other applied art does not remedy this deficiency.
The Examiner asserts that the combination of Kinneer 2017 and Richardson would have rendered the claimed subject matter obvious because, "Richardson taught: la) bortezomib is a proteasome inhibitor approved for treatment of multiple myeloma; 1 b) additive and synergistic activity has been demonstrated in preclinical studies of bortezomib plus several drugs with DNA crosslinking agents including melphalan, mitoxantrone, and bendamustine; le) bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates in multiple myeloma; ld) toxicities from combination therapy are predictable and manageable and comparable to those seen with bortezomib therapy ... "( Office Action, pp. 8-9). However, the applied art does not enable such inferences as discussed below.
On the Examiner's 1 a) point, there are a myriad of medicines, both in the clinic and approved by a health authority, that are therapeutically useful in the treatment of multiple myeloma. While Richardson may teach one specific drug, bortezomib, can be used for the treatment of multiple myeloma, the Examiner fails to explain why a person of ordinary skill in the art would have (1) selected an anti-BCMA ADC, and specifically the anti-BCMA ADC of the present application, (2) selected a proteasome inhibitor, specifically bortezomib, from among countless possible anti-cancer drug combinations available, and (3) had any reasonable expectation that such a combination would be any more advantageous or therapeutically efficacious than any other possible combination. As stated earlier, Kinneer 2017 does not teach combining the ADC recited in the independent claims with bortezomib. Richardson also does not teach combining a proteasome inhibitor with any large molecule or an ADC. Thus, there is no trail or blaze mark to guide a person of ordinary skill in the subject art to combine the specifically claimed anti-BCMA ADC with bortezomib. Even if it were assumed, arguendo, that such a combination might be possible, there is no evidence from any of the applied art that such a combination would have a reasonable expectation of success. There are many examples of therapeutic combinations that individually show efficacy, but in combination do not yield significantly improved or even therapeutically beneficial results. In the present case, the applied art does not offer any evidence or suggestion that the combination of an anti-BCMA ADC and bortezomib would provide any advantageous effect or therapeutic efficacy over a monotherapy treatment. Kinneer 2017 offers no guidance on a combination with any drug. Richardson also offers no guidance for a combination with a large molecule such as an ADC. Richardson does not address the unique properties of ADCs, including their targeted delivery, internalization, and payload release, which distinguish them from conventional small molecule chemotherapeutics. At best, Richardson merely teaches bortezomib in combination with specific chemotherapeutic agents, including small molecule DNA cross-linkers like melphalan and mitoxantrone, and steroids, but does not mention or suggest the use of bortezomib with an ADC, and specifically an anti-BCMA-targeting ADC (Richardson, Tables 1-2, p. 600). A person of ordinary skill in the art would not have reasonably extrapolated the effect reported in Richardson to a combination with the panacea of anticancer drugs regardless of target, modality, indication, and patient population. These features introduce significant unpredictability into drug combinations that would have to be experimentally and clinically vetted before being considered viable. To select an efficacious treatment plan among all the potential anti-cancer agents would require infinite, exhausting experimentation, to arrive at the claimed combination. None of the applied art teaches the combination of the presently claimed ADC and bortezomib, nor would the applied art have led a person having ordinary skill in the subject art to appreciate the synergistic effect of the claimed combination. The applied art provides no reason to select an anti-BCMA-targeting ADC as the agent to combine with bortezomib, nor does it suggest that such a combination would yield any benefit. The other applied art does not remedy the deficiencies of Kinneer 2017 and Richardson. Kinneer '983 teaches an ADC that includes an anti-BCMA antibody conjugated to pyrrolobenzodiazepine (PBD). It does not mention combining the anti-BCMA ADC with another agent, particularly a proteasome inhibitor, and specifically bortezomib. Kinneer Leukemia describes the presence of BCMA in "patients with MM resistant to the combinations of bortezomib, prednisone, and cyclophosphamide (MM284); bortezomib, prednisone, and dexamethasone or mitoxantrone and dexamethasone treatment regimens (MM221, MM230)" (Kinneer Leukemia, p. 768). This statement is acknowledging that presence of the antigen BCMA in patients who have developed resistance to certain regimens. Nowhere within this reference is there a suggestion to treat such resistance with the presently claimed combination. Kinneer Leukemia provides no reasonable expectation that treatment with an anti-BCMA ADC and bortezomib would have any beneficial effect. It offers no teaching or suggestion to do so. A person having ordinary skill in the subject art would not have been guided to or selected the presently claimed combination to treat a B-cell malignancy based upon Kinneer Leukemia and Kinneer '983. Accordingly, the Examiner's 1 a) point fails to establish a prima facie case of obviousness. The disclosure of Kinneer 2017 would not have guided a person having ordinary skill in the art to select the claimed ADC in combination with bortezomib, from among the myriad of potential anti-cancer agents that might be combinable. Bortezomib monotherapy being useful to treat multiple myeloma does not render it obvious to combine with every other anti-cancer agent in existence, nor would all such combinations, even if conceivable, be reasonably expected to be successful. The Examiner alleges in point lb) an additive and a synergistic activity in preclinical studies of bortezomib plus drugs with DNA crosslinking agents including melphalan, mitoxantrone, and bendamustine (Office Action p. 35). The only mention of a "synergy" event in Richardson is with a combination of bortezomib and doxorubicin, which is a chemotherapy drug (Richardson, Table 2, p. 603). There is simply no scientific or clinical basis to conclude from the applied art that bortezomib could or would be combinable with any anti-cancer agent. Richardson provides absolutely no teaching or guidance towards a combination with a large molecule anti-cancer agent, nor an ADC, nor an anti-BCMA ADC. The Examiner offers no explanation of why a person having ordinary skill in the subject art would have a reasonable expectation of success of such combinations-absent hindsight to the present application-or have the unexpected and synergistic results described in the present application. As stated earlier, there are countless anti-cancer agents. Some of them will work synergistically, but many of them will not. Practically speaking, this is precisely why health authorities do not blindly authorize combining anti-cancer agents, even those with demonstrated safety and efficacy in a monotherapy setting. It requires considerable scientific and experimental testing to discern which combinations are viable. One cannot say, with any modicum of certainty, that a drug that works well in one combination setting will necessarily be successful in most other combination settings. Thus, the Examiner's point 1 b) makes an inferential error by asserting that a combination setting with specific molecules as described in Richardson is applicable broadly to the completely novel combination of the present application. Richardson simply does not provide evidence to enable such an extrapolation and would not have been viewed as providing such evidence by those of ordinary skill in the subject art. The Examiner's point le) alleges that bortezomib can be combined with a broad set of active agents resulting in enhanced response rates, including high complete response rates in multiple myeloma. (Office Action, p. 35). Richardson describes a combination with a few different agents (Richardson, Table 2, pp. 602-604). In these suggested agents, there is not a suggestion to combine with a large molecule, let alone an anti-BCMA ADC. As noted above, the list of agents is actually limited in scope as far as modality or compounds tested, and a person having ordinary skill in the art would not understand that list to mean that any combination of bortezomib with an anti-cancer agent will yield a beneficial effect as purported by the Office. None of the applied art provides any reason to believe that an ADC in combination with bortezomib would have been effective, let alone that it would be more likely to yield a synergistic effect than any other anti-cancer agent combination. In other words, a person having ordinary skill in the subject art would have had no basis to select the presently claimed combination over any other of the countless possible combinations. The Examiner's point ld) alleges that toxicities from combination therapy are predictable and manageable and comparable to those seen with bortezomib therapy. (Office Action, p. 35). The combinations of agents with bortezomib described in Richardson to be predictable and manageable include steroids, alkylating agents, and doxorubicin. There is no mentioned of a predictable and manageable combination with an immunomodulator such as ADC or a targeted anti-BCMA ADC. Further, as noted earlier, health authorities routinely require demonstration of safety and efficacy of agents that, while effective in monotherapy settings, have never been combined. A person having ordinary skill in the subject art would have had no basis to make any statement on safety or efficacy of the claimed combination based on the applied art or the monotherapy activity of anti-BCMA ADC or bortezomib, individually. Accordingly, the point ld) does not address the massive gap between the teachings of the applied art and the presently claimed subject matter. Therefore, none of the references, whether considered separately or in combination, teach or suggest combining the claimed anti-BCMA ADC with bortezomib to treat multiple myeloma and, therefore, do not render the presently claimed subject matter as obvious. Withdrawal of the rejection is respectfully requested.
In response, Applicant's arguments filed 10/31/2025 have been fully considered, but they are not persuasive. Regarding the applied art fails to teach the claimed combination with a reasonable expectation of success, the obvious rational above details why it would be obvious with a reasonable expectation of success 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.
While Kinneer 2017 and Kinneer '983 do not describe combinations with other agents, Richardson taught combination treatment with bortezomib and DNA crosslinking agents were effective for treating multiple myeloma. Thus, combination of:
the effective ADC of Kinneer 2017, MEDI2228, which is an ADC that targets BCMA and is comprised of a fully human antibody site-specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer and known to be effective in a subject with multiple myeloma in vivo (abstract); and
bortezomib, which Richardson taught is effective in multiple myeloma and effective when combined with DNA crosslinking agents,
would be expected to be effective.
Further, while Richardson does not mention combination with anti-BCMA ADC nor that any combination with bortezomib would yield a synergistic effect, the effective ADC of Kinneer 2017, MEDI2228, comprises an antibody site-specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer that is known to be effective in a subject with multiple myeloma in vivo. Thus, the ADC provides a targeted DNA crosslinking agent to multiple myeloma cells that would be expected to be effective when combined with bortezomib because Richardson taught bortezomib is effective in multiple myeloma and effective when combined with DNA crosslinking agents.
It is known that combination of bortezomib and DNA crosslinking agents is an effective combination. Richardson further 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).
A skilled artisan would have found it obvious to combine Kinneer 2017 and Richardson as described above and would be motivated to combine the references to produce an effective treatment of multiple myeloma as bortezomib combination treatments in multiple myeloma are previously known and would be expected to provide a beneficial result.
Regarding the present application is the only evidence that bortezomib, when combined with the claimed anti-BCMA ADC, has an unexpected and synergistic effect (See., e.g., specification, Figures 5-8):
Fig 5-6 shows the combination of ADC M2 in combination with bortezomib results in synergistic cancer cell death for JJN3, RPMI8226, ANBL6-BR cells, MM1S and H929 cells, which are multiple myeloma cell lines. Fig 7 shows 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 Applicants arguments on point 1), 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 and bortezomib is already known to be effective against 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. 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 Richardson only mentions synergy shown with doxorubicin, Richardson taught “Preclinical findings indicating additive or synergistic activity of bortezomib plus conventional and novel agents for multiple myeloma appear to be supported by clinical studies of bortezomib-based combinations.” (abstract). Table 1 of Richardson further supports synergistic effects across a range of combinations including the DNA cross-linking agents melphalan, which produces a 1,000,000-fold increase in sensitivity, and mitoxantrone, which resulted in 100,000-fold increase in sensitivity to mitoxantrone in RPMI8226/MR20 mitoxantrone-resistant myeloma cell line. Thus, Richardson supports bortezomib and DNA crosslinking agent combination treatment synergy.
Regarding Applicants arguments: i) on point 1a); ii) there are countless anti-cancer agents and some of them will work synergistically; iii) Richardson does not address the unique properties of ADCs; iv) Richardson merely teaches bortezomib in combination with specific chemotherapeutic agents; v) a person of ordinary skill in the art would not have reasonably extrapolated the effect reported in Richardson to a combination with the panacea of anticancer drugs regardless of target, modality, indication, and patient population; vi) these features introduce significant unpredictability into drug combinations; vii) none of the applied art teaches the combination of the presently claimed ADC and bortezomib, nor would the applied art have led a person having ordinary skill in the subject art to appreciate the synergistic effect of the claimed combination; viii) the applied art provides no reason to select an anti-BCMA-targeting ADC as the agent to combine with bortezomib, nor does it suggest that such a combination would yield any benefit; ix) point 1 b) makes an inferential error; x) one cannot say, with any modicum of certainty, that a drug that works well in one; xi) point 1c); and xii) there is not a suggestion to combine with a large molecule, let alone an anti-BCMA ADC combination setting will necessarily be successful in most other combination settings:
the effective 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) is obvious to combine with bortezomib. As stated above, 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 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 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).Richardson taught bortezomib can overcome or reverse chemoresistance and enhance sensitivity to specific agents, including melphalan and mitoxantrone. 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 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. Thus, there are mechanistic reasons to combine a DNA crosslinking agent with bortezomib for multiple myeloma treatment. 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, ADC delivery of the DNA crosslinking PBD payload to the multiple myeloma cells is known. The targeting of multiple myeloma with the ADC delivers the DNA cross-linking PBD payload to the multiple myeloma cells that would combine with bortezomib to effectively kill the multiple myeloma cells.
Therefore, (1) the known effective 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) would be an effective method for treating multiple myeloma, wherein the addition of (2) bortezomib has mechanistic reasons to combine a DNA crosslinking agent for multiple myeloma treatment for a more effective treatment. The targeting of the multiple myeloma with the DNA cross-linking pyrrolobenzodiazepine (PBD) payload with the ADC provides a combination treatment of the DNA cross-linking PBD payload with bortezomib to the multiple myeloma cells. Kinneer taught MEDI2228 targets BCMA to deliver the toxic DNA cross-linker payload PBD and MEDI2228 was highly active in multiple myeloma cell lines. This combination (3) would have a reasonable expectation of being more effective.
Additionally, the Applicant’s arguments regarding unpredictability and reasonable expectations of success of the effects of the combination of DNA crosslinking agents and bortezomib do not support the subject matter of many of the current claims, wherein instant claims 1, 3-4, 6-9, 11-14, 24 and 26 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 1, 3-4, 6-9, 11-14, 24 and 26 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).
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 the applied art does not offer any evidence or suggestion that the combination of an anti-BCMA ADC and bortezomib would provide any advantageous effect or therapeutic efficacy over a monotherapy treatment:
as described above, there are mechanistic reasons to combine a DNA crosslinking agent with bortezomib for multiple myeloma treatment. The targeting of the multiple myeloma with the DNA cross-linking pyrrolobenzodiazepine (PBD) payload with the ADC would provide a combination treatment of the DNA cross-linking PBD payload with bortezomib to the multiple myeloma cells. Bortezomib is a known multiple myeloma treatment, that is known to be more effective when combined with DNA crosslinking agents, and is known to inhibit pathways responsible for proliferation and survival and for the antiapoptotic response to stressors such as chemotherapy and sensitizes cells to other chemotherapeutic agents.
Regarding Kinneer Leukemia, 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)
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Regarding arguments of point 1d) and 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 to multiple myeloma cells would be expected to be beneficial to combination therapy.
Regarding health authorities routinely require demonstration of safety and efficacy of agents that, while effective in monotherapy settings, have never been combined, the combination of Kinneer 2017 and Richardson is obvious with a reasonable expectation of success as described above and bortezomib has been taught to have manageable toxicity for combination treatment with DNA crosslinking agents. The Applicant’s argument suggests that the claimed subject matter would not be enabled for safe human treatment in the absence of clinical testing in a trial. The teaching of Richardson that bortezomib combination treatment with DNA crosslinking agents has manageable toxicity supports the reasonable expectation of success.
Applicant argues: 2. Unexpected and synergistic effect is not predictable from the applied art. Applicant argues the claimed combination of anti-BCMA-targeting ADC and the proteasome inhibitor bortezomib yields a synergistic effect and an unexpected effect, neither of which would have been reasonably expected from the applied art. The combination of the claimed anti-BCMA ADC and bortezomib yields a synergistic effect that would not have been predictable prior to the present application or based on the applied art. The claimed combination is experimentally demonstrated across multiple cell lines, including those with varying levels of BCMA expression and drug resistance (Example 3, Figs. 5-8). RPMI8226 cell line expresses BCMA at a low level (See., e.g., specification Figure IA). Figures 5A and 5B of the present application demonstrate the surprising finding that combining the claimed anti-BCMA ADC and bortezomib has a higher apoptotic effect compared to a monotherapy of anti-BCMA ADC or bortezomib (Figure 5B). This synergistic effect was also demonstrated in vivo. Figures 7 and 8, show that the combination therapy of anti-BCMA ADC with bortezomib in patient-derived xenograft mice reduced tumor volume as compared to a monotherapy of either the anti-BCMA ADC or bortezomib. The Examiner has offered no assertion to the contrary of the results of the specification. The claimed combination of bortezomib and the anti-BCMA ADC is unexpected based on the prior art (no teaching suggestion in the prior art as noted earlier). The evidence in the specification is greater than the sum of the effects of monotherapy of each agent. In contrast to the data of the specification, the agents referenced in Richardson merely reduce the activity of NF-KB. The cited art is devoid of any data or rationale supporting the expectation that bortezomib would synergize with an anti-BCMA-targeting ADC. None of the other applied art that allegedly teaches an anti-BCMA ADC teaches a combination with bortezomib. The combination of a targeted biologic with a proteasome inhibitor presents unique and unpredictable challenges, including potential for altered pharmacokinetics, toxicity, and cellular response, none of which are addressed or even contemplated in the cited references. The presently claimed combination confers a synergistic effect that would not have been reasonably predicted from the applied art. The Examiner has not weighed the surprising synergy of the claimed combination against the closest prior art as required un MPEP 716.02. Given the lack of any teaching or suggestion by the applied art of the claimed combination, the recited claims are non-obvious over the applied art, whether considered separately or in combination. The applied art further lacks any teaching or suggestion of a synergy of the claimed combination, which further evinces a finding the presently claimed subject matter is non-obvious over the applied art. Unexpected effect The combination of the claimed anti-BCMA ADC and bortezomib yields an additional unexpected effect that would not have been predictable prior to the present application or based on the applied art. Figure 5B demonstrates that a bortezomib resistant tumor cell line (ANBL6-BR), when treated with the combination of the claimed anti-BCMA ADC and bortezomib, has a synergistic effect as evidenced by the enhanced killing of the combination compared to monotherapy with either agent. This surprising effect would not have been predictable from any of the applied art. Figures 5A and 5B show the surprising tumoricidal synergistic effects in a low expressing BCMA tumor cell line (RPMI8226) and a bortezomib resistant cell line (ANBL6-BR) by combining anti-BCMA ADC and bortezomib that is not seen when the cell lines are treated individually with either anti-BCMA ADC or bortezomib. A person having ordinary skill in the subject art would not have expected a bortezomib resistant cell line to show enhanced sensitivity to treatment with the combination of anti-BCMA ADC and bortezomib over a monotherapy of either agent. (Figure SA and Figure 5B). The examples of the specification of the present application, therefore, demonstrate that the claimed combination has a surprising enhanced anti-tumor effect regardless of expression of BCMA and/or resistance to bortezomib. For this additional reason, the applied art fails to provide a basis to arrive at the unexpected results of the presently claimed subject matter. Therefore, the claimed subject matter is non-obvious over the applied art.
In response, Applicant's arguments filed 10/31/2025 have been fully considered, but they are not persuasive. 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 1, 3-4, 6-9, 11-14, 24 and 26 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 1, 3-4, 6-9, 11-14, 24 and 26 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 shows 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.
Claims 1, 3-4, 6-9, 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 as applied to claims 1, 3-4, 6-9, 11-14, 17-19, 24 and 26 above.
Kinneer 2017, Kinneer Leukemia, and Kinneer ‘983 and Richardson are described above.
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.
Regarding instant claim 27, it would have been obvious for a person having ordinary skill in the art to perform the method of Kinneer 2017 and Richardson above of administering a subject with multiple myeloma that had increased expression of BCMA 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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, which has the structure of tesirine also known as SG3249; and
the proteasome inhibitor bortezomib,
wherein administration of bortezomib is just prior to or simultaneously with the ADC, 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.
This method would naturally treat multiple myeloma, which is a B-cell malignancy wherein the malignant B-cell is a part of a tumour 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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
The rejection of claims 1, 3-4, 6-9, 11-14, 17-19, 24 and 26 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 is maintained.
‘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 1, 3-4, 6-9, 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 1, 3-4, 6-9, 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 1, 3-4, 6-9, 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 1, 3, 6-9, 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 ‘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 claims 7-9) 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 claims 1 and 3).
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 neither the '782 patent nor the '892 application claims, alone or in combination with the applied art, recite or suggest the specific combination of a BCMA-targeting ADC with a proteasome inhibitor, such as bortezomib, as required by the pending claims. The '782 patent and '892 application describe the use of the anti-BCMA ADC as a monotherapy. Neither reference suggests combining the anti-BCMA ADC with another agent, including bortezomib.
The Office Action relies on Kinneer 2017, Richardson, Kinneer Leukemia, and
Kinneer '983 to argue that it would have been obvious to combine an anti-BCMA targeting ADC with a proteasome inhibitor (Office Action, pp. 19-22, 29-32). However, as discussed in detail in the response to the § 103 rejection, these references do not teach or suggest the claimed combination, nor do they provide a reasonable expectation of success for such a combination. The cited art does not disclose or suggest the synergistic effects, or the specific clinical advantages demonstrated by the present application.
The present application provides experimental evidence that the claimed
combination of a BCMA-targeting ADC and a proteasome inhibitor results in unexpected
synergy and enhanced efficacy, including in drug-resistant multiple myeloma cell lines
(See, e.g., specification, Example 3, Figs. 5-8). These results are not taught or suggested by the reference claims or the cited art and further support the patentable distinction of the pending claims.
Therefore, the pending claims are patentably distinct from the claims of the '782
patent and the '892 application, even when considered in view of the cited art. The
applied art does not teach or suggest the specific combination of an anti-BCMA-targeting ADC and bortezomib, nor does it provide a reasonable expectation of the unexpected results demonstrated herein. Applicants respectfully request withdrawal of the nonstatutory double patenting rejections.
In response, Applicant's arguments filed 10/31/2025 have been fully considered, but they are not persuasive. The obvious rational above indicates why it would have been obvious with a reasonable expectation of success 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 or administering multiple myeloma cells in vitro 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.
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 1, 3-4, 6-9, 11-14, 24 and 26 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 1, 3-4, 6-9, 11-14, 24 and 26 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 shows 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.
Claims 1, 3-4, 6-9, 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.
The claims of the ‘782 patent in view of Kinneer 2017 and Richardson teach the limitations of claims 1, 3-4, 6-9, 11-14, 17-19, 24 and 26 for the reasons set forth above.
The claims of ‘782, Kinneer 2017, Kinneer Leukemia, and Kinneer ‘983 and Richardson are described above.
‘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 claim 27, it would have been obvious for a person having ordinary skill in the art to perform the method of ‘782, Kinneer 2017 and Richardson above of administering a subject with multiple myeloma that had increased expression of BCMA a composition of:
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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, which has the structure of tesirine also known as SG3249; 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
the proteasome inhibitor bortezomib,
wherein administration of bortezomib is just prior to or simultaneously with the ADC, 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.
This method would naturally treat multiple myeloma, which is a B-cell malignancy wherein the malignant B-cell is a part of a tumour 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.
The provisionally rejected claims 1, 3-4, 6-9, 11-14, 17-19, 24 and 26 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 is maintained.
‘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 1, 3, 6-9, 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 1, 4-5, 7-8, and 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 ‘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 claims 7-9) 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 claims 1 and 3).
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 neither the '782 patent nor the '892 application claims, alone or in combination with the applied art, recite or suggest the specific combination of a BCMA-targeting ADC with a proteasome inhibitor, such as bortezomib, as required by the pending claims. The '782 patent and '892 application describe the use of the anti-BCMA ADC as a monotherapy. Neither reference suggests combining the anti-BCMA ADC with another agent, including bortezomib.
The Office Action relies on Kinneer 2017, Richardson, Kinneer Leukemia, and
Kinneer '983 to argue that it would have been obvious to combine an anti-BCMA targeting ADC with a proteasome inhibitor (Office Action, pp. 19-22, 29-32). However, as discussed in detail in the response to the § 103 rejection, these references do not teach or suggest the claimed combination, nor do they provide a reasonable expectation of success for such a combination. The cited art does not disclose or suggest the synergistic effects, or the specific clinical advantages demonstrated by the present application.
The present application provides experimental evidence that the claimed
combination of a BCMA-targeting ADC and a proteasome inhibitor results in unexpected
synergy and enhanced efficacy, including in drug-resistant multiple myeloma cell lines
(See, e.g., specification, Example 3, Figs. 5-8). These results are not taught or suggested by the reference claims or the cited art and further support the patentable distinction of the pending claims.
Therefore, the pending claims are patentably distinct from the claims of the '782
patent and the '892 application, even when considered in view of the cited art. The
applied art does not teach or suggest the specific combination of an anti-BCMA-targeting ADC and bortezomib, nor does it provide a reasonable expectation of the unexpected results demonstrated herein. Applicants respectfully request withdrawal of the nonstatutory double patenting rejections.
In response, Applicant's arguments filed 10/31/2025 have been fully considered, but they are not persuasive. The obvious rational above indicates why it would have been obvious with a reasonable expectation of success for a person having ordinary skill in the art to take the method of ‘892 claims 1, 4-5, 7-8, and 12-13 of killing multiple myeloma cells that express BCMA by administering a human with multiple myeloma or administering multiple myeloma cells in vitro 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.
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 1, 3-4, 6-9, 11-14, 24 and 26 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 1, 3-4, 6-9, 11-14, 24 and 26 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 shows 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.
Claims 1, 3-4, 6-9, 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.
The claims of copending ‘892 in view of Kinneer 2017 and Richardson teach the limitations of claims 1, 3-4, 6-9, 11-14, 17-19, 24 and 26 for the reasons set forth above.
The claims of copending ‘892, Kinneer 2017, Kinneer Leukemia, and Kinneer ‘983 and Richardson are described above.
‘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.
Regarding instant claim 27, it would have been obvious for a person having ordinary skill in the art to perform the method of administering a subject with multiple myeloma that had increased expression of BCMA a composition of:
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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, which has the structure of tesirine also known as SG3249; 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
the proteasome inhibitor bortezomib,
wherein administration of bortezomib is just prior to or simultaneously with the ADC, 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.
This method would naturally treat multiple myeloma, which is a B-cell malignancy wherein the malignant B-cell is a part of a tumour 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.
Conclusion
No claims are allowed.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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