DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims / Response to Amendments
The Amendments and Remarks filed 02/25/2026 in response to the Office Action of 11/25/2025 are acknowledged and have been entered.
Claims 16, 18, 20, 23-33, 42, 50, 51, 56-64, 67, 68, 75, 83, and 84 are currently pending.
Claims 16, 18, 20, 23-33, 56, 58, 59, 67 and 68 have been amended by Applicant.
Claims 16, 18, 20, 23-33, 42, 50, 51, 56-64, 67, 68, 75, 83, and 84 are currently under examination in the instant Office Action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
This Office Action contains New Rejections Necessitated by Amendments.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/25/2026 is being considered by the examiner.
Specification Objections - Withdrawn
The drawing objections are withdrawn because Applicant has amended and submitted corrected drawings.
The nucleotide and/or amino acid sequence disclosures objection is withdrawn because Applicant has amended the specification to include sequence identifier for the amino acid sequence (Gly4-Ser1)2, submitted a substituted specification and submitted a corrected Sequence Listing File.
The specification objections of typographical error and use of trademarks are withdrawn because Applicant has corrected the error and submitted an amended specification.
Claim Objections - Withdrawn
The objection of claims 56 and 59 are withdrawn because Applicant has corrected the informalities.
Claim Rejections - Withdrawn
The rejection of claims 33, 58, 59, 67, 68, 75, 83 and 84 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), second paragraph has been withdrawn because Applicant has amended the claims appropriately.
The rejection of claim 68 under 35 U.S.C. 112(d) or 35 U.S.C. 112 (pre-AlA), fourth paragraph has been withdrawn because Applicant has amended the claim appropriately.
The rejection of claims 16-33, 42, 50, 51, 56-68, 75, 83, and 84 under 35 U.S.C. 103 as being unpatentable over Vu et al. (WO2017021450A1 Date Published 2017-02-09) in view of Kufer et al. (US20110275787A1 Date Published 2011-11-10) has been withdrawn because Applicant has amended the instant claims.
The “First" rejections under nonstatutory double patenting of claims 16-33, 42, 50, 51, 56-68, 75, 83, and 84 over claims 1 and 5 of US Patent No. US11124577B2 in view of Kufer et al. (US20110275787A1 Date Published 2011-11-10) and Vu et al. (WO2017021450A1 Date Published 2017-02-09) has been withdrawn because Applicant has amended the instant claims.
The “Second" rejections under nonstatutory double patenting of claims 16-33, 42, 50, 51, 56-68, 75, 83, and 84 over 1-18 and 20-21 of US Patent No. US1110683369 in view of Kufer et al. (US20110275787A1 Date Published 2011-11-10) and Vu et al. (WO2017021450A1 Date Published 2017-02-09) has been withdrawn because Applicant has amended the instant claims.
The “Third" rejections under nonstatutory double patenting of claims 16-33, 42, 50, 51, 56-68, 75, 83, and 84 over claims 24-41 of copending Application No. 18/057,566 in view of Kufer et al. (US20110275787A1 Date Published 2011-11-10) and Vu et al. (WO2017021450A1 Date Published 2017-02-09) has been withdrawn because Applicant has amended the instant claims.
The “Fourth" rejections under nonstatutory double patenting of claims 16-33, 42, 50, 51, 56-68, 75, 83, and 84 over claims 1-2 and 6-11 of copending Application No. 17/798,983 in view of Kufer et al. (US20110275787A1 Date Published 2011-11-10) and Vu et al. (WO2017021450A1 Date Published 2017-02-09) has been withdrawn because Applicant has amended the instant claims.
New Objections Necessitated by Amendments
Claims 33 and 67 are objected to because of the following informalities.
Claim 33 recited in line 4 the phrase “….the second maintenance dose is administered first weekly, then biweekly,……”. Because this “second maintenance dose” is in fact subsequent doses of the “second maintenance dose”, it is suggested that the phrase be amended to recite “…. the subsequent second maintenance doses are administered first weekly, then biweekly,….”. The same suggestion is given to claim 67 which also recites the same phrase on Pg 10 lines 10-11.
New Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 103 – Necessitated by Amendments
Claims 16, 18, 20, 23-33, 42, 50, 51, 56-64, 67, 68, 75, 83, and 84 are rejected under 35 U.S.C. 103 as being unpatentable over Vu et al. (WO2017021450A1 Date Published 2017-02-09) in view of Wierda et al. (Cancer. 2011 Jan 1;117(1):116-24), Frampton et al. (Drugs 63, 1229–1243; 2003), Chu et al. (US20180134798A1 Date Published 2018-05-17) and Bittner et al. (BioDrugs (2018) 32:425–440).
Vu et al. teaches a bispecific antibody against BCMA and CD3 (Pg. 8 line 11). They teach that the bispecific antibody comprises within the BCMA binding portion a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, a CDR3H region of SEQ ID NO:17, a CDR1L region of SEQ ID NO:27, a CDR2L region of SEQ ID NO:28 and a CDR3L region of SEQ ID NO:20 (Pg. 7 lines 16-19 and 24-25 and claim 5) as well as a BCMA VH region of SEQ ID NO:10 and a BCMA VL region of SEQ ID NO:14 (Pg. 8 lines 11-14 and claim 6). They also teach that the bispecific antibody is characterized in that the VH of the anti-CD3 antibody portion comprises the heavy chain CDRs of SEQ ID NOs: 1, 2 and 3 as CDR1H, CDR2H and CDR3H respectively, and the VL comprises the light chain CDRs of SEQ ID NOs: 4, 5 and 6 as CDR1L, CDR2L and CDR3L respectively, as well as the VH and VL are of SEQ ID NO:7 and 8 respectively (Pg. 11 lines 1-8 and claim 8).
Vu et al. also teach that the bispecific antibody consists of one CD3-Fab, and one BCMA-Fab and one Fc portion, wherein the CD3-Fab and the BCMA-Fab are linked via their C-termini to the hinge region of said Fc portion and a second BCMA-Fab, which is linked with its C-terminus to the N-terminus of the CD3-Fab, such that the bispecific antibody comprises the format of BCMA-Fab-Fc-CD3-Fab-BCMA-Fab and wherein both BCMA-Fabs comprise amino acid substitutions E123R AND Q124K in the constant domain CL, and amino acid substitutions K147E and K213E in the constant domain CH1 (numberings according to Kabat) (Pg. 13 lines 16-26). They teach that the second BCMA-Fab is linked via its C-terminus to the N-terminus of the Fab fragment of the CD3-Fab wherein the linkage is formed between the CH1 of the BCMA-Fab and the VL of CD3-Fab, resulting in the CD3-Fab comprising a VL/VH crossover, in other words the VL and VH domains in the CD3-Fab are replaced by each other (Pg. 13 lines 28-32 and Pg. 15 lines 3-6), thus placing the CD3-Fab VL domain at the N-terminus position. Furthermore, Vu et al. teach that the bispecific antibody named Mab42 consists of the polypeptide sequences as set forth in SEQ ID NOs: 48, 55, 56, 57 and 57 (Pg. 15 lines 14-15 and 20-21 and Pg. 30 lines 19-21).
Sequence alignments of the SEQ ID NOs for the BCMA binding VH (SEQ ID NO: 10), VL (SEQ ID NO: 14), CDR1H (SEQ ID NO: 21), CDR2H (SEQ ID NO: 22), CDR3H (SEQ ID NO: 17), CDR1L (SEQ ID NO: 27), CDR2L (SEQ ID NO: 28) and CDR3L (SEQ ID NO: 20) and the CD3 binding VH (SEQ ID NO: 7), VL (SEQ ID NO: 8), CDR1H (SEQ ID NO: 1), CDR2H (SEQ ID NO: 2), CDR3H (SEQ ID NO: 3), CDR1L (SEQ ID NO: 4), CDR2L (SEQ ID NO: 5) and CDR3L (SEQ ID NO: 6), and the five polypeptide sequences of the bispecific antibody Mab42 (SEQ ID NOs: 48, 55, 56, 57 and 57) as taught by Vu et al. with instant claimed antibody that binds to BCMA and CD3 comprising a BCMA binding VH of SEQ ID NO: 10, VL of SEQ ID NO: 14, CDR1H of SEQ ID NO: 21, CDR2H of SEQ ID NO: 22, CDR3H of SEQ ID NO: 17, CDR1L of SEQ ID NO: 27, CDR2L of SEQ ID NO: 28 and CDR3L of SEQ ID NO: 20, and the CD3 binding VH of SEQ ID NO: 7, VL of SEQ ID NO: 8, CDR1H of SEQ ID NO: 1, CDR2H of SEQ ID NO: 2, CDR3H of SEQ ID NO: 3, CDR1L of SEQ ID NO: 4, CDR2L of SEQ ID NO: 5 and CDR3L of SEQ ID NO: 6, and comprising five polypeptide sequences of SEQ ID NOs: 48, 55, 56, 57 and 57 showed that all the amino acid sequences of Vu et al. have 100% identities to instantly claimed amino acid sequences (alignments not shown).
Vu et al. also teaches that the bispecific antibody can be used for the treatment of plasma cell disorders such as multiple myeloma (MM) or other plasma cell disorders expressing BCMA such as systemic lupus erythematosus (SLE), plasma cell leukemia or AL-amyloidosis (Pg. 19 lines 5-25 and claims 20 and 21). Therefore, Vu et al. teaches treating disorders that are associated with BCMA expression, in other words treating BCMA-associated disorders as recited in instant claim 16, treating BCMA-expressing B-cell cancer as recited in instant claim 63, as well as treating multiple myeloma as recited in instant claim 67, by administering a bispecific antibody that binds to BCMA and CD3 with the characteristics and SEQ ID NOs as described above.
Vu et al. further teaches that the bispecific antibody against CD3 and BCMA is administered once or twice a week via subcutaneous administration in the dose range of 0.1 to 2.5, preferably to 25 mg/m2/week, preferably to 250 mg/m2/week (Pg. 21 lines 1-4). They teach that the anti-BCMAxCD3 TCBcv antibody has shown efficacy with once-a-week administration by subcutaneous administration (Pg. 45 lines 7-8).
Vu et al. does not specifically teach a method for treating a BCMA-associated disorder in a patient in need thereof, comprising subcutaneously administering to the patient said bispecific antibody that binds to BCMA and CD3 in a dosing regimen comprising:(i) administering a first starting dose of from about 1.5 mg to about 4.5 mg of the antibody to the patient at a starting phase, wherein the first starting dose is administered to the subject one time; (ii) administering a first maintenance dose of from about 4.5 mg to about 25 mg of the antibody to the patient at a maintenance phase, wherein the first maintenance dose is higher than the first starting dose and is administered to the patient one time and (iii) administering a second maintenance dose of the antibody to the patient at the maintenance phase, wherein the second maintenance dose is administered to the patient one or more times, wherein the second maintenance dose is the same as or higher than the first maintenance dose, and wherein the steps (i)-(iii) are performed in the specified order.
Vu et al. also does not specifically teach the said method wherein the first starting dose is a single starting dose of the starting phase; wherein the first maintenance dose is first administered 3 days after the administration of the single starting dose, and the second maintenance dose is first administered 4 days after the administration of the first maintenance dose; or wherein the first maintenance dose is first administered 3 days after the administration of the single starting dose, and the second maintenance dose is first administered 4 days after the administration of the first maintenance dose, then the second maintenance dose is administered first weekly, then biweekly, then every four weeks after the first administration of the second maintenance dose, wherein the second maintenance dose is administered two or more times.
Vu et al. further does not specifically teach the said method wherein the starting phase comprises a second starting dose that is from about 1.5 mg to about 4.5 mg; or wherein the second maintenance dose is a maximum dose; or wherein the second maintenance dose is higher than the first maintenance dose; or wherein the second maintenance dose is higher than 10 mg; or wherein the second maintenance dose is about 25 mg or from 20 mg to 30 mg; or wherein the first starting dose is about 3 mg, the first maintenance dose is about 6 mg, and the second maintenance dose is a maximum dose; or wherein the first starting dose is about 3 mg, the first maintenance dose is about 6 mg, and the second maintenance dose is higher than the first maintenance dose; or wherein the first starting dose is about 3 mg, the first maintenance dose is about 6 mg, and the second maintenance dose is higher than 10 mg; or wherein the first starting dose is about 3 mg, the first maintenance dose is about 6 mg, and the second maintenance dose is about 25 mg or from 20mg to 30 mg; or wherein the first maintenance dose is about 6 mg, and the second maintenance dose is the same as the first maintenance dose; or
Vu et al. also further does not specifically teach the said method wherein the method further comprises administering a steroid and/or an antipyretic, an analgesics and/or an antibiotics; wherein the steroid is a corticosteroid or dexamethasone; or wherein the patient has developed or is at risk of developing an adverse event associated with the administration of the antibody.
Moreover, Vu et al. does not specifically teach a method for treating multiple myeloma in a patient, comprising subcutaneously administering to the patient said bispecific antibody that comprises (a) a first BCMA-Fab and a second BCMA-Fab that each specifically binds to BCMA, (b) a CD3-Fab that specifically binds to CD3, and (c) an Fc portion, in a dosing regimen comprising:(i) administering a starting dose of the antibody to the patient, wherein the starting dose is about 3 mg and is administered to the patient one time;(ii) administering a first maintenance dose of the antibody to the patient, wherein the first maintenance dose is about 6 mg and is administered to the patient one time; and (iii) administering a second maintenance dose of the antibody to the patient, wherein the second maintenance dose is about 25 mg or from 20 mg to 30 mg wherein the second maintenance dose is administered to the patient one or more times, and wherein the steps (i)-(iii) are performed in the specified order; wherein the first maintenance dose is administered 3 days after the administration of the starting dose, the second maintenance dose is first administered 4 days after the administration of the first maintenance dose, then the second maintenance dose is administered first weekly, then biweekly, then every four weeks after the first administration of the second maintenance dose.
However, these deficiencies are made up in the teachings of Wierda et al., Frampton et al., Chu et al. and Bittner et al.
Wierda et al. teaches self-administered, subcutaneous alemtuzumab for the treatment of residual disease in patients with chronic lymphocytic leukemia (CLL) (Title and Abstract). They teach that the treatment consisted of a single-agent of subcutaneously administered alemtuzumab at doses of 3 mg, 10 mg, and 30 mg on Days 1, 2, and 3, respectively, followed by 30 mg subcutaneously 3 times weekly for a total of 12 doses, including the initial dose escalation (Pg 3 third full paragraph lines 1-3). They also teach that premedication can comprise 650 mg oral acetaminophen, a well-known antipyretic and analgesics, and trimethoprim/sulfamethoxazole, a well-known antibiotics (Pg 3 third full paragraph lines 7-9). They further teach that comparison between intravenous and subcutaneous administration of alemtuzumab showed a trend toward a higher response rate with subcutaneous alemtuzumab, where majority of treatment-related adverse events were grade 1 or 2 (Abstract Results and Table 6). They also further teach that alemtuzumab can be self-administered safely by patients (Abstract Conclusions and Pg 8 lines 3-4). As taught by Frampton et al., alemtuzumab is a humanized monoclonal antibody against CD52 (Abstract).
Chu et al. teaches methods of dosing anti-CD20/anti-CD3 bispecific antibodies for treatment of cancers (Title and Abstract). They teach that the bispecific antibody can be administered subcutaneously to the subject at a dose of between about 0.5 mg to about 40 mg (paragraph [0094]). They also teach a method of treating a subject having a cancer (e.g., a B cell proliferative disorder) comprising administering to the subject said bispecific antibody that binds to CD20 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, wherein the C1D1 and the C1D2 are each no greater than the C1D3, and wherein the C1D1 is between about 0.0056 mg to about 12.50 mg, the C1D2 is between about 0.0125 mg to about 20.00 mg, and the C1D3 is between about 0.0500 mg to about 50 mg, and the second dosing cycle comprises a single dose (C2D1) of the bispecific antibody, wherein the C2D1 is equal to or greater than the C1D3 and is between about 0.0500 mg to about 50 mg (paragraph [0087]). They further teach that (a) the C1D1 can be between about 1.0 mg to about 3.0 mg, the C1D2 can be between about 2.0 mg to about 6.0 mg, and the C1D3 can be between about 6.0 mg to about 50.0 mg, and (b) the C2D1 can be between about 6.0 mg to about 50.0 mg (paragraph [0087]). They also further teach that the dosing regimen can include a first dosing cycle of three weeks such that the C1D1, the C1D2, and the C1D3 are administered on or about Days 1, 8, and 15, respectively, of the first dosing cycle; a second dosing cycle of three weeks such that the C2D1 is administered on or about Day 1 of the second dosing cycle; and can further comprise 1 to 14 additional dosing cycles (paragraphs [0091], [0092] and [0093]).
Chu et al. also teaches that if the subject has a cytokine release syndrome (CRS) event following administration of the bispecific antibody, the method may further involve administering to the subject a corticosteroid such as dexamethasone (paragraphs 0130] and [0131]).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating BCMA-associated disorder, or to perform a combined method for treating multiple myeloma, in a patient, comprising subcutaneously administering to the patient a bispecific antibody that comprises (a) a first BCMA-Fab and a second BCMA- Fab that each specifically binds to BCMA, (b) a CD3-Fab that specifically binds to CD3, and (c) an Fc portion comprising the amino acid sequences as taught by Vu et al., in a subcutaneous dosing regimen for an anti-CD52 antibody as taught by Wierda et al. or for a bispecific anti-CD20/anti-CD3 antibody as taught by Chu et al. comprising a first starting dose, a first maintenance dose that is higher than the first starting dose administered to the patient once, and a second maintenance dose that is administered one or more times that is the same as or higher than the first maintenance dose that is performed in the said specific order, and the exact dosing regimen could be further optimized by routine dose escalation clinical studies based on the teachings of subcutaneous antibody administration provided by Wierda et al. and Chu et al. because Vu et al. teach a broad dosing range could be used for the BCMA/CD3 bispecific antibody (Pg. 21 lines 1-4) and because of the advantages of the bispecific trivalent BCMA and CD3 targeting antibody of Vu et al. which includes having potency and efficacy for killing low BCMA expressing MM cell lines and for killing MM cells in patient bone marrow aspirates and having favorable properties such as long elimination half-life, efficacy, low or no tendency to aggregation and can be manufactured with high purity and good yield (Pg. 45 lines 3-9); and because of the advantages of lower incidence of adverse events from subcutaneous administration compared to intravenous administration, proven effectiveness and safety, general preference by patients and healthcare providers and associated lowered healthcare cost for subcutaneous administration as taught by Bittner et al. (Abstract, Pg 431 left column first full paragraph and Pg 434 right column lines 5-8).
In addition, said combined method can further comprise administering the corticosteroid dexamethasone for when the subject has a cytokine release syndrome (CRS) event following administration of the bispecific antibody as taught by Chu et al. because Chu et al. teaches dexamethasone can be administered for the management of CRS events following administration of an anti-CD20/anti-CD3 bispecific antibody (paragraphs 0130], [0131 and [0133]-[0135]). Alternatively, said combined method can further comprise administering an antipyretic, an analgesics, and/or an antibiotics as taught by Wierda et al. as a premedication to administering an antibody therapeutic because Wierda et al. teaches that acetaminophen, an antipyretic and analgesics, is an effective supportive measure for local injection site reactions of subcutaneous antibody administration and that the antibiotics trimethoprim/sulfamethoxazole can be administrated for prophylaxis of bacterial infections in patients with CLL receiving subcutaneous antibody administration (Pg 3 third full paragraph lines 7-9 and Pg 8 first full paragraph lines 3-6).
This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Further, it would be conventional and routine for one to perform the combined method comprising subcutaneously administering to just any subject with BCMA-associated disorders the bispecific antibody of Vu et al. at initial dosages and maintenance doses or schedules as taught by Wierda et al. and Chu et al. to a subject with said disorders, including those encompassed by the claims, in order to optimize the combined method. “[W]here the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” /n re Aller, 220 F.2d 454, 456 (CCPA 1955) (Citing /n re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite, 168 F.2d 104 (CCPA 1948)). MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”
In the instant case, given the known function of each administered reagent to treat BCMA-associated disorders including multiple myeloma, it is well within the level of the ordinary skilled artisan to adjust the dosages and timing of administration for optimal therapeutic efficacy and safety, and to arrive at the dosages and timing of administration as instantly claimed, where the bispecific antibody is expected to provide therapeutic treatment. Further, varying dosage amounts and dosage schedules of the administered therapeutic reagents of the combined method are “result-effective variables” wherein the results are therapeutic benefit weighed against dose-limiting toxicities and the variables are the varying amounts and dosage schedules of the administered therapeutic reagents. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 02/25/2026, Applicant cites that Applicant respectfully disagrees and traverses the instant U.S.C. 103 rejection. Solely to expedite prosecution and without acquiescing to the instant rejection, Applicant has amended independent claims 1 and 67 to specify that the method comprises subcutaneously administering to the patient the antibody in a dosing regimen comprising: administering (i) a first starting dose; (ii) a first maintenance dose; and (iii) a second maintenance dose, wherein the steps are performed in the specific order, with specific amounts and frequencies.
Applicant also cited that the Office has not established a prima facie case of obviousness because the presumption of obviousness does not apply to the instant claims in view of Janssen Pharms., Inc. v. Teva Pharms. USA, Inc., 141 F.4th 1367 (Fed. Cir. 2025). Applicant continued that the Office has acknowledged that Vu does not disclose the claimed dosing regimen. Kufer cannot remedy the deficiency of this rejection as Kufer is completely silent regarding the claimed antibody and the claimed dosing regimen as amended. In Janssen, the Federal Circuit found that the "crucial choice made by Janssen [...] for the combination of loading doses is addressed to the relation between two dosage figures in a way that does not clearly fit within the presumption's focus on simply selecting a number or range overlapping a prior-art range of a variable or, even, a plurality of variables that overlap with prior- art ranges where the variables are properly considered separately from each other." See id. at 1378 (emphasis in original). Like Janssen, the choice made by the Applicant for the combination of subcutaneously administering the specific amounts and frequencies of a first starting dose, a first maintenance dose, and a second maintenance dose "in a way that does not clearly fit within the presumption's focus on" simply selecting a number or range within the broad dosing range disclosed in Vu or the general dosing regimen of a completely irrelevant antibody disclosed in Kufer.
Applicant concludes that, for at least the above reasons, the instant claims as amended are not obvious over the cited references.
Examiner’s Response: The amendments to the claims and the arguments found in the Reply of 02/25/2026 have been carefully considered, but are not deemed persuasive. The examiner disagrees and has now provided the above U.S.C. 103 rejection of amended claims based on Vu et al., Wierda et al., Frampton et al., Chu et al. and Bittner et al.
Double Patenting -Necessitated by Amendments
First NSDP: U.S. Patent No. US11124577B2
Claims 16, 18, 20, 23-33, 42, 50, 51, 56-64, 67, 68, 75, 83, and 84 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5 of US Patent No. US11124577B2 (herein after referred to as Patent ‘577) in view of Wierda et al. (Cancer. 2011 Jan 1;117(1):116-24), Frampton et al. (Drugs 63, 1229–1243; 2003), Chu et al. (US20180134798A1 Date Published 2018-05-17), Bittner et al. (BioDrugs (2018) 32:425–440), and Vu et al. (WO2017021450A1 Date Published 2017-02-09).
The Patent ‘577 claims are drawn in part to a method of treating multiple myeloma, comprising administering to a patient in need a therapeutically effective amount of a bispecific antibody comprising a first binding part specifically binding to human B cell maturation antigen (BCMA) and a second binding part specifically binding to human CD3ɛ (CD3), wherein the VH region CDR1H, CDR2H and CDR3H and the VL region CDR1L, CDR2L and CDR3L of the BCMA and CD3 binding parts are the same as the instant claims bispecific antibody that binds to BCMA and CD3 (Patent claims 1 and 5).
"Further, those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application (as distinguished from an obvious variation of the subject matter disclosed in the reference patent or application)." See MPEP 804.
Patent ‘577 specification discloses for the antibody specifically binding to BCMA, SEQ ID NOs: 10 and 14 are VH and VL domains comprising recited CDR1H region of SEQ ID NO: 21, CDR2H region of SEQ ID NO: 22 and CDR3H region of SEQ ID NO: 17 and CDR1L region of SEQ ID NO: 27, CDR2L region of SEQ ID NO: 28 and CDR3L region of SEQ ID NO: 20 respectively as recited in patented claim 1 and 5 (Column 56 lines 22-25 and Table 1A). Therefore, as defined by Patent ‘577 specification, anti-BCMA antibodies comprising recited CDRs in patented claims 1 and 5 include those comprising the VH and VL domains of SEQ ID NO: 10 and 14 respectively."
The specification of Patent ‘577 also discloses anti-CD3 antibodies comprising SEQ ID NOs: 7 and 8 are VH and VL domains comprising CDR1H, CDR2H and CDR3H of SEQ ID NO: 1, 2 and 3 respectively and CDR1L, CDR2L and CDR3L of SEQ ID NO: 4, 5 and 6 respectively of the anti CD3 antibody portion of the patented bispecific antibody against BCMA and CD3 (Column 28 lines 9-20 and Table 1A). Therefore, as defined by Patent ‘577 specification, the second binding part of the patented bispecific antibody that specifically binds to human CD3ɛ (CD3) can comprise the VH domain of SEQ ID NO: 7 comprising CDR1H, CDR2H and CDR3H of SEQ ID NOs: 1, 2 and 3 respectively, and the VL domain of SEQ ID NO: 8 comprising CDR1L, CDR2L and CDR3L of SEQ ID NOs: 4, 5 and 6 respectively.
Further, Patent ‘577 specification discloses a bispecific antibody specifically binding the extracellular domain of human BCMA and human CD3ɛ comprising heavy and light chain set of polypeptides as set forth in SEQ ID NO: 48, SEQ ID NO: 55, SEQ ID NO: 56, and SEQ ID NO: 57 (2x) (set 3 TCB of antibody 42; Column 59 lines 43-47 and 52-53; Table 1A Columns 44-51). The following are noted for each of these polypeptide chains:-
Patent ‘577 SEQ ID NO: 48 comprises anti-CD3 VH domain of SEQ ID NO: 7 comprising CDR1H, CDR2H and CDR3H of SEQ ID NOs: 1, 2 and 3 respectively;
Patent ‘577 SEQ ID NO: 55 comprises anti-BCMA VH domain of SEQ ID NO: 10 comprising recited (in patented claims 1 and 5) CDR1H region of SEQ ID NO: 21, CDR2H region of SEQ ID NO: 22 and CDR3H region of SEQ ID NO:17. Patent ‘577 SEQ ID NO: 55 also comprises anti-CD3 VL domain of SEQ ID NO: 8 comprising CDR1L, CDR2L and CDR3L of SEQ ID NOs: 4, 5 and 6 respectively;
Patent ‘577 SEQ ID NO: 56 comprises anti-BCMA VH domain of SEQ ID NO: 10 comprising recited (in patented claims 1 and 5) CDR1H region of SEQ ID NO: 21, CDR2H region of SEQ ID NO: 22 and CDR3H region of SEQ ID NO: 17;
Patent ‘577 SEQ ID NO: 57 comprises anti-BCMA VH domain of SEQ ID NO: 14 comprising recited (in patented claims 1 and 5) CDR1L region of SEQ ID NO: 27, CDR2L region of SEQ ID NO: 28 and CDR3L region of SEQ ID NO: 20.
Therefore, as defined by the specification of Patent ‘577, the bispecific antibody comprising recited CDRs of the first binding part specifically binding to BCMA of CDR1H region of SEQ ID NO: 21, CDR2H region of SEQ ID NO: 22 and CDR3H region of SEQ ID NO: 17 and CDR1L region of SEQ ID NO: 27, CDR2L region of SEQ ID NO: 28 and CDR3L region of SEQ ID NO: 20 include those comprising the polypeptides of SEQ ID NOs: 55, 56 and 57; while the bispecific antibody comprising the second binding part specifically binding to CD3 comprising of CDR1H, CDR2H and CDR3H of SEQ ID NO: 1, 2 and 3 respectively, and CDR1L, CDR2L and CDR3L of SEQ ID NO: 4, 5 and 6 respectively, include those comprising the polypeptide chains of SEQ ID NOs: 48 and 55.
Sequence alignments of Patent ‘577 BCMA binding VH (SEQ ID NO: 10) and VL (SEQ ID NO: 14), the CD3 binding VH (SEQ ID NO: 7), VL (SEQ ID NO: 8), CDR1H (SEQ ID NO: 1), CDR2H (SEQ ID NO: 2), CDR3H (SEQ ID NO: 3), CDR1L (SEQ ID NO: 4), CDR2L (SEQ ID NO: 5) and CDR3L (SEQ ID NO: 6), and the five polypeptide sequences of the bispecific antibody Mab42 (SEQ ID NOs: 48, 55, 56, 57 and 57) with instant claimed antibody that binds to BCMA and CD3 comprising a BCMA binding VH of SEQ ID NO: 10 and VL of SEQ ID NO: 14 (instant claims 42, 56 and 75), and the CD3 binding VH of SEQ ID NO: 7, VL of SEQ ID NO: 8, CDR1H of SEQ ID NO: 1, CDR2H of SEQ ID NO: 2, CDR3H of SEQ ID NO: 3, CDR1L of SEQ ID NO: 4, CDR2L of SEQ ID NO: 5 and CDR3L of SEQ ID NO: 6, and comprising five polypeptide sequences of SEQ ID NOs: 48, 55, 56, 57 and 57 (instant claim 84) showed that all the patented amino acid sequences and corresponding instant claimed amino acid sequences have 100% identities to each other.
The Patent ‘577 claims do not specifically recite a method for treating multiple myeloma or a BCMA-associated disorder in a patient in need thereof, comprising subcutaneously administering to the patient the patent bispecific antibody in a dosing regimen comprising: administering (i) a first starting dose; (ii) a first maintenance dose; and (iii) a second maintenance dose, wherein the steps are performed in the specific order.
The Patent ‘577 claims also do not specifically recite a method wherein the bispecific antibody comprises (a) a first BCMA-binding Fab and a second BCMA-binding Fab, (b) a CD-binding Fab, and (c) an Fc portion, wherein each of the first and second BCMA-Fabs comprises a constant domain CL and a constant domain CH1, and wherein (i) each of the CL of the first and second BCMA-Fabs comprises amino acid substitutions at positions 123 and 124, which are substituted by arginine (R) and lysine (K) respectively, wherein the amino acid positions are according to Kabat numbering(numbering according to Kabat); and(ii) each of the CH1 of the first and second BCMA-Fabs comprises amino acid substitutions at positions 147 and 213, which are substituted by glutamic acid (E), wherein the amino acid positions are according to EU index of Kabat; or wherein the N-terminus of the Fc portion is linked to each of the C-terminus of a CH1 domain of the first BCMA-Fab and the C-terminus of a CH1 domain of the CD3- Fab, and the N-terminus of the VL region of the CD3- Fab is linked to the C-terminus of a CH1 domain of the second BCMA-Fab.
The Patent ‘577 claims further do not specifically recite a method wherein the method further comprises administering a steroid and/or an antipyretic, an analgesics and/or an antibiotics; wherein the steroid is a corticosteroid or dexamethasone; or wherein the patient has developed or is at risk of developing an adverse event associated with the administration of the antibody.
However, these deficiencies are made up in the teachings of Wierda et al., Frampton et al., Chu et al., Bittner et al. and Vu et al.
The teachings of Wierda et al., Frampton et al., Chu et al., Bittner et al. and Vu et al. are discussed in the 103 rejection above.
Therefore, it would have been obvious to perform a combined method of treating a BCMA-associated disorder, or to perform a combined method for treating multiple myeloma, in a patient in need thereof, comprising administering to the patient a bispecific antibody as recited by the patented claims, wherein the administering is subcutaneous as taught by Vu et al. of the same bispecific antibody, also as taught by Wierda et al. in a subcutaneous dosing regimen for an anti-CD52 antibody, or as taught by Chu et al. in a subcutaneous dosing regimen for a bispecific anti-CD20/anti-CD3 antibody, comprising a first starting dose, a first maintenance dose that is higher than the first starting dose administered to the patient once, and a second maintenance dose that is administered one or more times that is the same as or higher than the first maintenance dose that is performed in the said specific order, and the exact dosing regimen could be further optimized by routine dose escalation clinical studies based on the teachings of subcutaneous antibody administration provided by Wierda et al. and Chu et al. because Vu et al. teach a broad dosing range could be used for the same BCMA/CD3 bispecific antibody (Pg. 21 lines 1-4) and because of the advantages of the bispecific trivalent BCMA and CD3 targeting antibody as taught by Vu et al. which includes having potency and efficacy for killing low BCMA expressing MM cell lines and for killing MM cells in patient bone marrow aspirates and having favorable properties such as long elimination half-life, efficacy, low or no tendency to aggregation and can be manufactured with high purity and good yield (Pg. 45 lines 3-9); and because of the advantages of lower incidence of adverse events from subcutaneous administration compared to intravenous administration, proven effectiveness and safety, general preference by patients and healthcare providers and associated lowered healthcare cost for subcutaneous administration as taught by Bittner et al. (Abstract, Pg 431 left column first full paragraph and Pg 434 right column lines 5-8).
In addition, the said combined method can further comprise administering the corticosteroid dexamethasone for when the subject has a cytokine release syndrome (CRS) event following administration of the bispecific antibody as taught by Chu et al. because Chu et al. teaches dexamethasone can be administered for the management of CRS events following administration of an anti-CD20/anti-CD3 bispecific antibody (paragraphs 0130], [0131 and [0133]-[0135]). Alternatively, said combined method can further comprise administering an antipyretic, an analgesics, and/or an antibiotics as taught by Wierda et al. as a premedication to administering an antibody therapeutic because Wierda et al. teaches that acetaminophen, an antipyretic and analgesics, is an effective supportive measure for local injection site reactions of subcutaneous antibody administration and that the antibiotics trimethoprim/sulfamethoxazole can be administrated for prophylaxis of bacterial infections in patients with CLL receiving subcutaneous antibody administration (Pg 3 third full paragraph lines 7-9 and Pg 8 first full paragraph lines 3-6).
Further, it would be conventional and routine for one to perform the combined method comprising subcutaneously administering to just any subject with BCMA-associated disorders the patented bispecific antibody at initial dosages and maintenance doses or schedules as taught by Wierda et al. and Chu et al. to a subject with said disorders, including those encompassed by the claims, in order to optimize the combined method. “[W]here the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” /n re Aller, 220 F.2d 454, 456 (CCPA 1955) (Citing /n re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite, 168 F.2d 104 (CCPA 1948)). MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”
In the instant case, given the known function of each administered reagent to treat BCMA-associated disorders including multiple myeloma, it is well within the level of the ordinary skilled artisan to adjust the dosages and timing of administration for optimal therapeutic efficacy and safety, and to arrive at the dosages and timing of administration as instantly claimed, where the bispecific antibody is expected to provide therapeutic treatment. Further, varying dosage amounts and dosage schedules of the administered therapeutic reagents of the combined method are “result-effective variables” wherein the results are therapeutic benefit weighed against dose-limiting toxicities and the variables are the varying amounts and dosage schedules of the administered therapeutic reagents.
Second NSDP: U.S. Patent No. US10683369B2
Claims 16, 18, 20, 23-33, 42, 50, 51, 56-64, 67, 68, 75, 83, and 84 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 and 20-21 of US Patent No. US1110683369B2 (herein after referred to as Patent ‘369) in view of Wierda et al. (Cancer. 2011 Jan 1;117(1):116-24), Frampton et al. (Drugs 63, 1229–1243; 2003), Chu et al. (US20180134798A1 Date Published 2018-05-17), Bittner et al. (BioDrugs (2018) 32:425–440) and Vu et al. (WO2017021450A1 Date Published 2017-02-09).
The Patent ‘369 claims are drawn in part to a monoclonal antibody specifically binding to human B cell maturation antigen (BCMA), wherein the VH region, VHCDR1H, VHCDR2H and VHCDR3H and the VL region, as well as VLCDR1L, VLCDR2L and VLCDR3L are the same as the instant claims BCMA-binding Fab (claims 1, 2, 3 and 20). Patent ‘369 claim 17 is drawn to a method of treatment of a plasma cell disorder comprising administering an antibody according to Patent claim 1 to a subject in need thereof. Patent claim 18 is drawn to a method of treatment of a plasma cell disorder according to Patent claim 17, wherein the plasma cell disorder is selected from the group consisting of multiple myeloma, systemic lupus erythematosus, plasma cell leukemia, and AL-amyloidosis.
The Patent ‘369 claims are drawn in part to a bispecific antibody specifically binding to BCMA and human CD3ε (CD3), wherein the VH region CDR1H, CDR2H and CDR3H and the VL region CDR1L, CDR2L and CDR3L of the BCMA and CD3 binding parts are the same as the instant claims bispecific antibody that binds to BCMA and CD3 (claims 4-16, and 21).
The Patent ‘369 claim 12 recites the bispecific antibody of Patent claim 4, characterized in comprising one Fab fragment of an anti-CD3 antibody, two Fab fragments of an anti-BCMA antibody and one Fc portion. The Patent ‘369 claims 13-15 are drawn to specific N-terminus and C-terminus orientation and linkage of the various parts of the said bispecific antibody that is the same as the instant claimed bispecific antibody.
The Patent ‘369 claim 16 is drawn to a bispecific antibody specifically binding to BCMA and to CD3, characterized in comprising a heavy and light chain set that is the same as instant claimed bispecific antibody (see instant claim 84).
The Patent ‘369 claim 16 is drawn to a bispecific antibody comprising SEQ ID NOs: 48, 55, 56 and 57 which matches exactly to instant SEQ ID NOs: 48, 55, 56 and 57 respectively (instant claim 84).
The Patent ‘369 claims do not specifically recite a method for treating multiple myeloma or a BCMA-associated disorder in a patient in need thereof, comprising subcutaneously administering to the patient the patent bispecific antibody in a dosing regimen comprising: administering (i) a first starting dose; (ii) a first maintenance dose; and (iii) a second maintenance dose, wherein the steps are performed in the specific order.
The Patent ‘369 claims also do not specifically recite a method wherein each of the two BCMA-Fabs of the bispecific antibody comprises a constant domain CL and a constant domain CH1, and wherein (i) each of the CL of the first and second BCMA-Fabs comprises amino acid substitutions at positions 123 and 124, which are substituted by arginine (R) and lysine (K) respectively, wherein the amino acid positions are according to Kabat numbering(numbering according to Kabat); and(ii) each of the CH1 of the first and second BCMA-Fabs comprises amino acid substitutions at positions 147 and 213, which are substituted by glutamic acid (E), wherein the amino acid positions are according to EU index of Kabat;
The Patent ‘369 claims further do not specifically recite a method wherein the method further comprises administering a steroid and/or an antipyretic, an analgesics and/or an antibiotics; wherein the steroid is a corticosteroid or dexamethasone; or wherein the patient has developed or is at risk of developing an adverse event associated with the administration of the antibody.
However, these deficiencies are made up in the teachings of Wierda et al., Frampton et al., Chu et al., Bittner et al. and Vu et al.
The teachings of Wierda et al., Frampton et al., Chu et al., Bittner et al. and Vu et al. are discussed in the 103 rejection above.
Therefore, it would have been obvious to perform a combined method of treating a BCMA-associated disorder, or to perform a combined method for treating multiple myeloma, in a patient in need thereof, comprising administering to the patient a bispecific antibody as recited by the patented claims, wherein the administering is subcutaneous as taught by Vu et al. of the same bispecific antibody, also as taught by Wierda et al. in a subcutaneous dosing regimen for an anti-CD52 antibody, or as taught by Chu et al. in a subcutaneous dosing regimen for a bispecific anti-CD20/anti-CD3 antibody, comprising a first starting dose, a first maintenance dose that is higher than the first starting dose administered to the patient once, and a second maintenance dose that is administered one or more times that is the same as or higher than the first maintenance dose that is performed in the said specific order, and the exact dosing regimen could be further optimized by routine dose escalation clinical studies based on the teachings of subcutaneous antibody administration provided by Wierda et al. and Chu et al. because Vu et al. teach a broad dosing range could be used for the same BCMA/CD3 bispecific antibody (Pg. 21 lines 1-4) and because of the advantages of the bispecific trivalent BCMA and CD3 targeting antibody as taught by Vu et al. which includes having potency and efficacy for killing low BCMA expressing MM cell lines and for killing MM cells in patient bone marrow aspirates and having favorable properties such as long elimination half-life, efficacy, low or no tendency to aggregation and can be manufactured with high purity and good yield (Pg. 45 lines 3-9); and because of the advantages of lower incidence of adverse events from subcutaneous administration compared to intravenous administration, proven effectiveness and safety, general preference by patients and healthcare providers and associated lowered healthcare cost for subcutaneous administration as taught by Bittner et al. (Abstract, Pg 431 left column first full paragraph and Pg 434 right column lines 5-8).
In addition, the said combined method can further comprise administering the corticosteroid dexamethasone for when the subject has a cytokine release syndrome (CRS) event following administration of the bispecific antibody as taught by Chu et al. because Chu et al. teaches dexamethasone can be administered for the management of CRS events following administration of an anti-CD20/anti-CD3 bispecific antibody (paragraphs 0130], [0131 and [0133]-[0135]). Alternatively, said combined method can further comprise administering an antipyretic, an analgesics, and/or an antibiotics as taught by Wierda et al. as a premedication to administering an antibody therapeutic because Wierda et al. teaches that acetaminophen, an antipyretic and analgesics, is an effective supportive measure for local injection site reactions of subcutaneous antibody administration and that the antibiotics trimethoprim/sulfamethoxazole can be administrated for prophylaxis of bacterial infections in patients with CLL receiving subcutaneous antibody administration (Pg 3 third full paragraph lines 7-9 and Pg 8 first full paragraph lines 3-6).
Further, it would be conventional and routine for one to perform the combined method comprising subcutaneously administering to just any subject with BCMA-associated disorders the patented bispecific antibody at initial dosages and maintenance doses or schedules as taught by Wierda et al. and Chu et al. to a subject with said disorders, including those encompassed by the claims, in order to optimize the combined method. “[W]here the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” /n re Aller, 220 F.2d 454, 456 (CCPA 1955) (Citing /n re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite, 168 F.2d 104 (CCPA 1948)). MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”
In the instant case, given the known function of each administered reagent to treat BCMA-associated disorders including multiple myeloma, it is well within the level of the ordinary skilled artisan to adjust the dosages and timing of administration for optimal therapeutic efficacy and safety, and to arrive at the dosages and timing of administration as instantly claimed, where the bispecific antibody is expected to provide therapeutic treatment. Further, varying dosage amounts and dosage schedules of the administered therapeutic reagents of the combined method are “result-effective variables” wherein the results are therapeutic benefit weighed against dose-limiting toxicities and the variables are the varying amounts and dosage schedules of the administered therapeutic reagents.
Third NSDP: Application No. 18/057,566
Claims 16, 18, 20, 23-33, 42, 50, 51, 56-64, 67, 68, 75, 83, and 84 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24-41 of copending Application No. 18/057,566 (herein after referred to as Copending ‘566) in view of Wierda et al. (Cancer. 2011 Jan 1;117(1):116-24), Frampton et al. (Drugs 63, 1229–1243; 2003), Chu et al. (US20180134798A1 Date Published 2018-05-17), Bittner et al. (BioDrugs (2018) 32:425–440) and Vu et al. (WO2017021450A1 Date Published 2017-02-09).
Copending ‘566 claims 24-41 are drawn to the same instant claims bispecific antibody, comprising:(i) a first BCMA-Fab and a second BCMA-Fab, wherein each of the first and second BCMA-Fabs comprises a variable heavy chain (VH) region comprising a CDR1H region comprising the amino acid sequence of SEQ ID NO: 21, a CDR2H region comprising the amino acid sequence of SEQ ID NO: 22, and a CDR3H region comprising the amino acid sequence of SEQ ID NO: 17; and a variable light chain (VL) region comprising a CDR1L region comprising the amino acid sequence of SEQ ID NO: 27, a CDR2L region comprising the amino acid sequence of SEQ ID NO: 28, and a CDR3L region comprising the amino acid sequence of SEQ ID NO: 20; (ii) an CD3-Fab, wherein the CD3-Fab comprises a VH region comprising a CDR1H region comprising the amino acid sequence of SEQ ID NO: 1, a CDR2H region comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3H region comprising the amino acid sequence of SEQ ID NO: 3; and a VL region comprising a CDR1L region comprising the amino acid sequence of SEQ ID NO: 4, a CDR2L region comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3L region comprising the amino acid sequence of SEQ ID NO: 6; and (iii) an Fc part.
Copending ‘566 claim 25 is drawn to the same VH and VL regions for the first and second BCMA-Fabs as instant claims bispecific antibody as well as the to the same VH and VL regions for the CD3-Fab as instant claimed bispecific antibody (instant claims 42, 50, 56, 75, 83 and 84) .
Copending ‘566 claim 27 is drawn to specific amino acid substations at positions 123 and 124 of each of the CL domain of the BCMA-Fabs and positions 147 and 213 of each of the CH1 domain of the BCMA-Fabs that are the same as the instant claimed bispecific antibody (instant claim 58).
Copending ‘566 claim 28 is drawn to specific N-terminus and C-terminus orientation and linkage of the various parts of the said bispecific antibody that is the same as the instant claimed bispecific antibody (instant claim 59).
Copending ‘566 claims 33-35 are drawn to a method of treating a plasma cell disorder, including multiple myeloma, comprising administering the bispecific antibody of Patent claim 24 to a subject in need thereof.
In addition, copending ‘566 claim 29 is drawn to a bispecific antibody, which is the same bispecific antibody as the instant claims 58 and 59, comprising:(i) a first BCMA-Fab and a second BCMA-Fab, wherein each of the first and second BCMA-Fabs comprises a VH region comprising a CDR1H region comprising the amino acid sequence of SEQ ID NO: 21, a CDR2H region comprising the amino acid sequence of SEQ ID NO: 22, and a CDR3H region comprising the amino acid sequence of SEQ ID NO: 17; a VL region comprising a CDR1L region comprising the amino acid sequence of SEQ ID NO: 27, a CDR2L region comprising the amino acid sequence of SEQ ID NO: 28, and a CDR3L region comprising the amino acid sequence of SEQ ID NO: 20; a CL domain; and a CHI domain, and wherein (a) each of the CL domain of the first and second BCMA-Fabs comprises amino acid substitutions at positions 123 and 124, which are substituted by arginine (R) and lysine (K) respectively (numbering according to Kabat); and(b) each of the CH1 domain of the first and second BCMA-Fabs comprises amino acid substitutions at positions 147 and 213, which are substituted by glutamic acid (E) (numbering according to EU index of Kabat);(ii) an CD3-Fab, wherein the CD3-Fab comprises a VH region comprising the amino acid sequence of SEQ ID NO: 1, a CDR2H region comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3H region comprising the amino acid sequence of SEQ ID NO: 3; and a VL region comprising a CDR1L region comprising the amino acid sequence of SEQ ID NO: 4, a CDR2L region comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3L region comprising the amino acid sequence of SEQ ID NO: 6; and the VH region and the VL region of the CD3-Fab are replaced by each other; and (iii) an Fc part, wherein the N-terminus of the Fe part is linked to each of the C-terminus of the first BCMA-Fab and the C-terminus of the CD3-Fab, the N-terminus of the CD3-Fab is linked to the C-terminus of the second BCMA-Fab, and the VL region of the CD3-Fab is linked to the CHI domain of the second BCMA-Fab.
Copending ‘566 claims 36-38 are drawn to a method of treating a plasma cell disorder, including multiple myeloma, comprising administering the bispecific antibody of Patent claim 29 to a subject in need thereof.
Further, copending ‘566 claim 31 is drawn to a bispecific antibody, which is the same bispecific antibody as the instant claim 84, comprising five polypeptides comprising the amino acid sequences of SEQ ID NO: 48, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, and SEQ ID NO: 57 respectively. Copending ‘566 claims 39-41 are drawn to a method of treating a plasma cell disorder, including multiple myeloma, comprising administering the bispecific antibody of Patent claim 31 to a subject in need thereof.
The copending ‘566 claims do not specifically recite a method for treating multiple myeloma or a BCMA-associated disorder in a patient in need thereof, comprising subcutaneously administering to the patient the copending claims bispecific antibody in a dosing regimen comprising: administering (i) a first starting dose; (ii) a first maintenance dose; and (iii) a second maintenance dose, wherein the steps are performed in the specific order.
The copending ‘566 claims also do not specifically recite a method wherein the method further comprises administering a steroid and/or an antipyretic, an analgesics and/or an antibiotics; wherein the steroid is a corticosteroid or dexamethasone; or wherein the patient has developed or is at risk of developing an adverse event associated with the administration of the antibody.
However, these deficiencies are made up in the teachings of Wierda et al., Frampton et al., Chu et al., Bittner et al. and Vu et al.
The teachings of Wierda et al., Frampton et al., Chu et al., Bittner et al. and Vu et al. are discussed in the 103 rejection above.
Therefore, it would have been obvious to perform a combined method of treating a BCMA-associated disorder, or to perform a combined method for treating multiple myeloma, in a patient in need thereof, comprising administering to the patient a bispecific antibody as recited by the copending claims, wherein the administering is subcutaneous as taught by Vu et al. of the same bispecific antibody, also as taught by Wierda et al. in a subcutaneous dosing regimen for an anti-CD52 antibody, or as taught by Chu et al. in a subcutaneous dosing regimen for a bispecific anti-CD20/anti-CD3 antibody, comprising a first starting dose, a first maintenance dose that is higher than the first starting dose administered to the patient once, and a second maintenance dose that is administered one or more times that is the same as or higher than the first maintenance dose that is performed in the said specific order, and the exact dosing regimen could be further optimized by routine dose escalation clinical studies based on the teachings of subcutaneous antibody administration provided by Wierda et al. and Chu et al. because Vu et al. teach a broad dosing range could be used for the same BCMA/CD3 bispecific antibody (Pg. 21 lines 1-4) and because of the advantages of the bispecific trivalent BCMA and CD3 targeting antibody as taught by Vu et al. which includes having potency and efficacy for killing low BCMA expressing MM cell lines and for killing MM cells in patient bone marrow aspirates and having favorable properties such as long elimination half-life, efficacy, low or no tendency to aggregation and can be manufactured with high purity and good yield (Pg. 45 lines 3-9); and because of the advantages of lower incidence of adverse events from subcutaneous administration compared to intravenous administration, proven effectiveness and safety, general preference by patients and healthcare providers and associated lowered healthcare cost for subcutaneous administration as taught by Bittner et al. (Abstract, Pg 431 left column first full paragraph and Pg 434 right column lines 5-8).
In addition, the said combined method can further comprise administering the corticosteroid dexamethasone for when the subject has a cytokine release syndrome (CRS) event following administration of the bispecific antibody as taught by Chu et al. because Chu et al. teaches dexamethasone can be administered for the management of CRS events following administration of an anti-CD20/anti-CD3 bispecific antibody (paragraphs 0130], [0131 and [0133]-[0135]). Alternatively, the said combined method can further comprise administering an antipyretic, an analgesics, and/or an antibiotics as taught by Wierda et al. as a premedication to administering an antibody therapeutic (Pg 3 third full paragraph lines 7-9).
Further, it would be conventional and routine for one to perform the combined method comprising subcutaneously administering to just any subject with BCMA-associated disorders the patented bispecific antibody at initial dosages and maintenance doses or schedules as taught by Wierda et al. and Chu et al. to a subject with said disorders, including those encompassed by the claims, in order to optimize the combined method. “[W]here the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” /n re Aller, 220 F.2d 454, 456 (CCPA 1955) (Citing /n re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite, 168 F.2d 104 (CCPA 1948)). MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”
In the instant case, given the known function of each administered reagent to treat BCMA-associated disorders including multiple myeloma, it is well within the level of the ordinary skilled artisan to adjust the dosages and timing of administration for optimal therapeutic efficacy and safety, and to arrive at the dosages and timing of administration as instantly claimed, where the bispecific antibody is expected to provide therapeutic treatment. Further, varying dosage amounts and dosage schedules of the administered therapeutic reagents of the combined method are “result-effective variables” wherein the results are therapeutic benefit weighed against dose-limiting toxicities and the variables are the varying amounts and dosage schedules of the administered therapeutic reagents.
This is a provisional nonstatutory double patenting rejection.
Fourth NSDP: Application No. 17/798,983
Claims 16, 18, 20, 23-33, 42, 50, 51, 56-64, 67, 68, 75, 83, and 84 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6-11 of copending Application No. 17/798,983 (herein after referred to as Copending ‘983) Wierda et al. (Cancer. 2011 Jan 1;117(1):116-24), Frampton et al. (Drugs 63, 1229–1243; 2003), Chu et al. (US20180134798A1 Date Published 2018-05-17), Bittner et al. (BioDrugs (2018) 32:425–440) and Vu et al. (WO2017021450A1 Date Published 2017-02-09).
Copending ‘983 claims are drawn to a method of treating or managing an autoimmune disorder, the method comprising administering to a patient in need thereof a multispecific antibody, wherein the multispecific antibody binds to B-cell maturation antigen (BCMA) and an antigen that promotes the activation of one or more T cells. This overlaps with instant claims reciting using a multispecific antibody with the same specificity towards BCMA and towards CD3, which is an antigen that promotes activation of T cells, for treating BCMA-associated disorder wherein known BCMA-associated autoimmune disorders include systemic lupus erythematosus (SLE), myasthenia gravis (MG) and rheumatoid arthritis (RA).
Copending ‘983 claim 6 is drawn to the method of copending claim 1, wherein bispecific antibody is a trivalent bispecific antibody comprising two Fab fragments of an anti-BCMA antibody (BCMA Fab), one Fab fragment of an anti-CD3 antibody (CD3 Fab), and one Fc portion, which comprises the same domains as the bispecific antibody of the instant claims.
Copending ‘983 claim 7 is drawn to the method of copending claim 1, wherein the multispecific antibody comprises an anti-BCMA antibody or an antigen-binding fragment thereof comprising a heavy chain complementarity-determining region 1 (CDR1H) region comprising the amino acid sequence of SEQ ID NO:21, a heavy chain complementarity-determining region 2(CDR2H) comprising the amino acid sequence of SEQ ID NO: 22, a heavy chain complementarity-determining region 3 (CDR3H) comprising the amino acid sequence of SEQ ID NO: 17, a light chain complementarity-determining region 1 (CDR1L) comprising the amino acid sequence of SEQ ID NO:27, a light chain complementarity-determining region 2(CDR2L) comprising the amino acid sequence of SEQ ID NO:28, and a light chain complementarity-determining region 3 (CDR3L) comprising the amino acid sequence of SEQ ID NO:20; which is the same BCMA-binding antibody encompassed by the instant claims bispecific antibody.
Copending ‘983 claim 8 is drawn to a method of claim 1, wherein the multispecific antibody comprises an anti-BCMA antibody or an antigen-binding fragment thereof comprising a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90% identical to, at least 95% identical to, at least 99% identical to, or identical to the amino acid sequence of SEQ ID NO: 10; and a light chain variable region (VL) comprising an amino acid sequence that is at least 90% identical to, at least 95% identical to, at least 99% identical to, or identical to the amino acid sequence of SEQ ID NO: 14; which is the same BCMA-binding antibody encompassed by the instant claims bispecific antibody.
Copending ‘983 claim 9 is drawn to the method of claim 1, wherein the multispecific antibody comprises an anti-CD3 antibody or an antigen-binding fragment thereof comprising a CDR1H comprising the amino acid sequence of SEQ ID NO:1, a CDR2H comprising the amino acid sequence of SEQ ID NO:2, a CDR3H comprising the amino acid sequence of SEQ ID NO:3, a CDR1L comprising the amino acid sequence of SEQ ID NO:4, a CDR2L comprising the amino acid sequence of SEQ ID NO:5, and a CDR3L comprising the amino acid sequence of SEQ ID NO:6; which is the same CD3-binding antibody encompassed by the instant claims bispecific antibody.
Copending ‘983 claim 10 is drawn to the method of claim 9, wherein the anti-CD3 antibody or antigen-binding fragment thereof comprising a VH comprising an amino acid sequence that is at least 90% identical to, at least 95% identical to, at least 99% identical to, or identical to the amino acid sequence of SEQ ID NO:7; and a VL comprising an amino acid sequence that is at least 90% identical to, at least 95% identical to, at least 99% identical to, or identical to the amino acid sequence of SEQ ID NO:8; which is the same CD3-binding antibody encompassed by the instant claims bispecific antibody.
Copending ‘983 claim 11 is drawn to the method of claim 1, wherein the multispecific antibody comprises five polypeptides comprising the amino acid sequences of SEQ ID NO: 48, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57 and SEQ ID NO: 57 respectively; which are the same polypeptides encompassed by the instant claim’s bispecific antibody (instant claim 84).
The copending ‘983 claims do not specifically recite a method for treating multiple myeloma or a BCMA-associated disorder in a patient in need thereof, comprising subcutaneously administering to the patient the copending claims bispecific antibody in a dosing regimen comprising: administering (i) a first starting dose; (ii) a first maintenance dose; and (iii) a second maintenance dose, wherein the steps are performed in the specific order.
The copending ‘983 claims also do not specifically recite a method wherein the bispecific antibody which comprises (a) a first BCMA-binding Fab and a second BCMA-binding Fab, (b) a CD-binding Fab, and (c) an Fc portion, wherein each of the first and second BCMA-Fabs comprises a constant domain CL and a constant domain CH1, and wherein (i) each of the CL of the first and second BCMA-Fabs comprises amino acid substitutions at positions 123 and 124, which are substituted by arginine (R) and lysine (K) respectively, wherein the amino acid positions are according to Kabat numbering(numbering according to Kabat); and(ii) each of the CH1 of the first and second BCMA-Fabs comprises amino acid substitutions at positions 147 and 213, which are substituted by glutamic acid (E), wherein the amino acid positions are according to EU index of Kabat; or wherein the N-terminus of the Fc portion is linked to each of the C-terminus of a CH1 domain of the first BCMA-Fab and the C-terminus of a CH1 domain of the CD3-Fab, and the N-terminus of the VL region of the CD3-Fab is linked to the C-terminus of a CH1 domain of the second BCMA-Fab.
The copending ‘983 claims further do not specifically recite a method wherein the method further comprises administering a steroid and/or an antipyretic, an analgesics and/or an antibiotics; wherein the steroid is a corticosteroid or dexamethasone; or wherein the patient has developed or is at risk of developing an adverse event associated with the administration of the antibody.
However, these deficiencies are made up in the teachings of Wierda et al., Frampton et al., Chu et al., Bittner et al. and Vu et al.
The teachings of Wierda et al., Frampton et al., Chu et al., Bittner et al. and Vu et al. are discussed in the 103 rejection above.
Therefore, it would have been obvious to perform a combined method of treating a BCMA-associated disorder, or to perform a combined method for treating multiple myeloma, in a patient in need thereof, comprising administering to the patient a bispecific antibody as recited by the copending claims, wherein the administering is subcutaneous as taught by Vu et al. of the same bispecific antibody, also as taught by Wierda et al. in a subcutaneous dosing regimen for an anti-CD52 antibody, or as taught by Chu et al. in a subcutaneous dosing regimen for a bispecific anti-CD20/anti-CD3 antibody, comprising a first starting dose, a first maintenance dose that is higher than the first starting dose administered to the patient once, and a second maintenance dose that is administered one or more times that is the same as or higher than the first maintenance dose that is performed in the said specific order, and the exact dosing regimen could be further optimized by routine dose escalation clinical studies based on the teachings of subcutaneous antibody administration provided by Wierda et al. and Chu et al. because Vu et al. teach a broad dosing range could be used for the same BCMA/CD3 bispecific antibody (Pg. 21 lines 1-4) and because of the advantages of the bispecific trivalent BCMA and CD3 targeting antibody as taught by Vu et al. which includes having potency and efficacy for killing low BCMA expressing MM cell lines and for killing MM cells in patient bone marrow aspirates and having favorable properties such as long elimination half-life, efficacy, low or no tendency to aggregation and can be manufactured with high purity and good yield (Pg. 45 lines 3-9); and because of the advantages of lower incidence of adverse events from subcutaneous administration compared to intravenous administration, proven effectiveness and safety, general preference by patients and healthcare providers and associated lowered healthcare cost for subcutaneous administration as taught by Bittner et al. (Abstract, Pg 431 left column first full paragraph and Pg 434 right column lines 5-8).
In addition, the said combined method can further comprise administering the corticosteroid dexamethasone for when the subject has a cytokine release syndrome (CRS) event following administration of the bispecific antibody as taught by Chu et al. because Chu et al. teaches dexamethasone can be administered for the management of CRS events following administration of an anti-CD20/anti-CD3 bispecific antibody (paragraphs 0130], [0131 and [0133]-[0135]). Alternatively, said combined method can further comprise administering an antipyretic, an analgesics, and/or an antibiotics as taught by Wierda et al. as a premedication to administering an antibody therapeutic because Wierda et al. teaches that acetaminophen, an antipyretic and analgesics, is an effective supportive measure for local injection site reactions of subcutaneous antibody administration and that the antibiotics trimethoprim/sulfamethoxazole can be administrated for prophylaxis of bacterial infections in patients with CLL receiving subcutaneous antibody administration (Pg 3 third full paragraph lines 7-9 and Pg 8 first full paragraph lines 3-6).
Further, it would be conventional and routine for one to perform the combined method comprising subcutaneously administering to just any subject with BCMA-associated disorders the patented bispecific antibody at initial dosages and maintenance doses or schedules as taught by Wierda et al. and Chu et al. to a subject with said disorders, including those encompassed by the claims, in order to optimize the combined method. “[W]here the general conditions of a claims are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” /n re Aller, 220 F.2d 454, 456 (CCPA 1955) (Citing /n re Dreyfus, 73 F.2d 931 (CCPA 1934); In re Waite, 168 F.2d 104 (CCPA 1948)). MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”
In the instant case, given the known function of each administered reagent to treat BCMA-associated disorders including multiple myeloma, it is well within the level of the ordinary skilled artisan to adjust the dosages and timing of administration for optimal therapeutic efficacy and safety, and to arrive at the dosages and timing of administration as instantly claimed, where the bispecific antibody is expected to provide therapeutic treatment. Further, varying dosage amounts and dosage schedules of the administered therapeutic reagents of the combined method are “result-effective variables” wherein the results are therapeutic benefit weighed against dose-limiting toxicities and the variables are the varying amounts and dosage schedules of the administered therapeutic reagents.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
In the Reply of 02/25/2026, Applicant respectfully requests that the nonstatutory double patenting rejections of:
Claims 16-33, 42, 50, 51, 56-68, 75, 83, and 84 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5 of U.S. Patent No. 11,124,577 in view of Kufer and Vu;
Claims 16-33, 42, 50, 51, 56-68, 75, 83, and 84 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18, 20, and 21 of U.S. Patent No. 10,683,369 in view of Kufer and Vu;
Claims 16-33, 42, 50, 51, 56-68, 75, 83, and 84 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24-41 of co-pending US Application No. 18/057,566 in view of Kufer and Vu;
Claims 16-33, 42, 50, 51, 56-68, 75, 83, and 84 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 6-11 of co-pending US Application No. 17/798,983 in view of Kufer and Vu;
be held in abeyance until all other rejections and objections are overcome. Applicant will address these double patenting rejections upon the indication of otherwise allowable subject matter.
Examiner’s Response: The amendments to the claims and the arguments found in the Reply of 02/25/2026 have been carefully considered, but are not deemed persuasive. Firstly, the rejections cannot be held in abeyance. Secondly, the examiner has now provided the above non-statutory double patenting rejections of amended claims over U.S. Patent No. 11,124,577, U.S. Patent No. 10,683,369, co-pending US Application No. 18/057,566 and co-pending US Application No. 17/798,983, in view of Wierda et al., Frampton et al., Chu et al., Bittner et al. and Vu et al.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/YIE CHIA LEE/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642
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