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 .
Examiner’s Comment
This final Office action replaces the final Office action mailed October 02, 2025. It is identical to the previous final Office action with the exception that this Office action indicates that claims 9-12, 14-17, 44 and 45 are objected to as being dependent upon a rejected base claim (see “Allowable Subject Matter” below). These claims were inadvertently omitted from the previous Final Office action and the PTOL-326 accompanying it.
Response to Amendment
The rejection of claim 1 and dependent claims under 35 USC 112(b) is withdrawn in view of the amendment to claim 1 removing “together” and further clarifying the claim.
The rejection of claims under 35 USC 112(a) is withdrawn in view of the amendment to independent claims 1 and 41 reciting intravenous administration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
As stated in the previous Office action (p. 7) the disclosure of the prior-filed provisional applications, Application Nos. 63/605,368, 63/564,353 and 63/649,873, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, for one or more claims of this application. None of three provisional applications disclose a step-up dose of 2 mg etentamig. As a result, for the instantly claimed invention only prior-filed application 63/678,022, filed 07/31/2024, provides adequate support under 35 U.S.C. 112(a).
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.
Claim Rejections - 35 USC § 103
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.
Claim(s) 1, 3-8, 13, 21, 41-43, 47, 48 and 68-73 remain rejected under 35 U.S.C. 103 as being unpatentable over ClinicalTrials.gov Study NCT05650632 (version 20, https://clinicaltrials.gov/study/NCT05650632?term=NCT05650632&rank=1&tab=history&a=20#version-content-panelhttps://clinicaltrials.gov/study/NCT05650632?tab=table, 09 Nov. 2023), Lovely (https://www.onclive.com/view/bispecific-antibody-abbv-383-looks-to-fill-unmet-need-in-heavily-pretreated-multiple-myeloma, 27 Aug. 2022), Kumar et al. (Blood. 138(Supplement 1): 900, 2021) and VHA (https://www.va.gov/formularyadvisor/DOC_PDF/ CRE_Bispecific_Antibody_CRS_and_ICANS_Neurotoxicity_Guidance_Feb2024.pdf, Feb. 2024) and in light of the instant specification in paragraph [0075] for the reasons set forth in the previous Office action and as recast here to better address the amendment to the claims.
Clinical trial NCT05650632 was designed to study adverse events of intravenously (iv) administered ABBV-383 in adults with relapsed or refractory multiple myeloma (MM; Study Identification:Brief Title). Arm A, Part 1 examines different levels of step-up doses followed by a target dose of ABBV-383 every 28 days, with Part 2 using only the step-up dose identified in Part 1 followed by the target dose, and with infusion into the vein of the ABBV-383 target dose every 28 days for about 3 years (Study Design: Brief Summary). Cytokine release syndrome (CRS) events level grade 2 or greater will be measured (Outcome Measures: Primary Outcome Measures 1.) as well as number of CRS events (Outcome Measures: Secondary Outcome Measures 1.). NCT05650632 does not teach the dosage of the step-up or maintenance dose of ABBV-383 or a premedication dose of a corticosteroid before the step-up or maintenance dose of ABBV-383. It does not teach the percentage of patients likely to achieve objective response rate (ORR) or complete response (CR).
Lovely teaches results from treating patients having heavily pretreated relapsed or refractory multiple myeloma with bispecific anti-BCMA x anti-CD3 antibody ABBV-383 (first paragraph, p. 1/9, and third paragraph, p.2/9). Treatment with 60 mg resulted in an objective response (OR) of 60%, very good partial response (VGPR) of 14%, complete or stringent complete response (CR/sCR) of 29% and partial response (PR) of 17%, with the 12-month estimated response rate of 76.8% (second paragraph). However, at 60 mg cytokine release syndrome (CRS) was observed in 72% of patients, with serious CRS in 16/58 patients, after the first dose of the drug. “No patient experienced recurrence after the cycle 1.” (first paragraph, p. 2/9) In order to reduce CRS toxicity, some patients received an intravenous (iv) premedication dose of 10 mg dexamethasone 15-60 minutes before the bispecific antibody (fourth paragraph, p. 2/9). A group of 15 patients received the bispecific antibody at a dose of 0.025-1.8 mg, resulting in only 7% who had grade 2 CRS. As doses of ABBV-383 increased, so did the precent who had CRS (5.4-30 mg, n-28, yielded 18% grade 2 CRS and 21% grade 1; 40-50 mg, n=9, yielded 22% grade 2 CRS and 56% grade 1; fifth paragraph, p. 2/9). A hematologic cancer clinical researcher concludes (p. 5/9, last paragraph), “What we want is convenient dosing, every 3 to 4 weeks, which [ABBV-383] shows.”
Kumar et al. teach a multicenter phase I open-label dose-escalation/expansion study (NCT03933735) for patients with relapsed/refractory multiple myeloma. TNB-383B, a BCMA x CD3 T-cell engaging bispecific antibody, was administered intravenously every 3 weeks (Q3W). Dose expansion was initiated for select RP2D (recommended phase II dose) patients. “The RP2D of 60 mg Q3W was selected on the basis of tolerability, safety, PK, and clinical activity.” (Results, first paragraph) It is discussed that (Background), “TNB-383B … was designed to overcome the toxicity limitations of existing BCMA therapies.”
VHA teaches bispecific antibodies (BsAbs) include teclistamab and elrantamab, both of which bind BCMA (p.1, bottom). Cytokine Release Syndrome (CRS, p. 1, Definitions) is defined as “An exaggerated systemic inflammatory response triggered by the effects of T-cell engaging therapies like BsAbs that cause release of inflammatory cytokines.” It is discussed (p. 11, first paragraph) that step-up dosing of BsAb can help decrease the risk of CRS since CRS usually occurs in the first several days of BsAb therapy. Further (p. 11, second paragraph), premedication during the initial step-up dosing and subsequent cycles can help reduce CRS and is given 60 min. prior to the BsAb. Pretreatment is drug-specific and can be with corticosteroids (usually prednisone or dexamethasone; p. 11, second paragraph). The table on page 14 provides pre-medication information found in the FDA package labeling for a variety of BsAbs, with examples including 15-20 mg iv or oral (PO) dexamethasone.
The specification in paragraph [0075] states that ABBV-383 is also known as etentamig and TNB-383B.
It would have been obvious to the artisan of ordinary skill before the effective filing date of the invention to have practiced the method of NCT05650632 for the treatment of a human patient with multiple myeloma wherein the maintenance dose of etentamig was administered about every 28 days (Brief Summary) and was about 60 mg as taught by Lovely and by Kumar for the RP2D dose showing tolerability, safety, acceptable PK, and clinical activity. It further would have been obvious wherein the step-up dose of about 2 mg etentamig (about 1.8 mg) was administered in view of the teachings of Lovely wherein that dose and lower resulted in only 7% of patients with grade 2 CRS, but higher doses significantly increased the percent of patients with CRS. One of ordinary skill in the art would have expected a step-up dose to be helpful in reducing CRS because after one cycle of ABBV-383, i.e., after first exposure, there were no recurrences of CRS in patients (Lovely). Also, it would have been obvious to pretreat the patient with an oral or intravenous corticosteroid both before the step-up and the maintenance dose to reduce the risk or severity of CRS as taught by VHA and Lovely, which specifies 10 mg iv dexamethasone 15-60 minutes before etentamig administration. It would have been obvious wherein the premedication dose was either oral or iv as taught by VHA in reference to the FDA drug package labeling. Further, it would have been obvious to increase the premedication dose before the maintenance dose of etentamig relative to the much lower step-up dose, for example to about 20 mg dexamethasone, for a total of about 30 mg given during a dosing regimen cycle. As discussed by VHA, both a step-up dose and corticosteroid are means for reducing the incidence and/or severity of CRS. In view of the teachings of Lovely for treatment of MM with 60 mg etentamig, one skilled in the art would have reasonably expected that at least about 60% of treated patients would have achieved ORR and at least about 5% CR.
Applicant summarizes Clinical Trial NCT0565032 (version 20) and argues (last paragraph of p. 10 and first paragraph of p. 11 of Remarks) that neither Lovely nor Kumar teach or suggest administration of ABBV-383 (etentamig) every 4 weeks (Q4W), as recited in independent claims 1 and 41, no step-up dosing of etentamig or the safety and effectiveness of the claimed 2 mg step-up dose of etentamig combined with a 60 mg maintenance dose of etentamig in four-week cycles. NCT0565032 is described as a clinical study where patients needing treatment of relapsed or refractory multiple myeloma (RRMM) received a step-up dose and then a target dose of etentamig every 28 days. The study does not teach the claimed step-up or maintenance dose of etentamig or premedication with corticosteroid. The study does not predict objective response rate (ORR) or complete response (CR). The argument has been fully considered but is not persuasive. In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). NCT0565032 teaches 28 day cycles (about four weeks) of etentamig, including different levels of a step-up dose followed by a target dose. Evaluation includes presence, frequency and severity of treatment-induced cytokine release syndrome (CRS). While the clinical study does not disclose some of the critical limitations of the claimed invention, it is maintained that prior art relied upon supports the obviousness of the invention. For example, Lovely teaches successful treatment of RRMM with 60 mg etentamig, but CRS was observed in 72% of the treated patients after the first 60 mg dose. Lovely premedicated some patients with dexamethasone (a corticosteroid) to reduce toxicity. Also, 15 patients received etentamig in the range of 0.25-1.8 mg, with only 7% having grade 2 CRS. This is much lower than those receiving etentamig in a dose of 5.4 to 30 mg (21% with grade 2 CRS) or 40-50 mg (22% having grade 2 and 56% having grade 1 CRS). Both NCT0565032 and Lovely support administration of etentamig for treatment of RRMM. Both support the use of a low first dose to decrease the risk of CRS. Lovely quotes a cancer researcher who says, “What we want is convenient dosing, every 3 to 4 weeks, which [ABBV-383] shows.” Additionally, Kumar teaches etentamig (a.k.a. TNB-383B) for treating RRMM intravenously administered every 3 weeks with a determined recommended phase II trial dose of 60 mg based on evaluation of tolerability, safety, PK and clinical activity. Kumar supports a maintenance dose of 60 mg and only looked at a single dosing frequency (Q3W). Lovely supports the use of about 2 mg (~1.8 mg) and also a dose of 60 mg with administration every 3 or 4 weeks. NCT0565032 supports 28-day etentamig treatment cycles. However, these are not the only references relied upon.
Applicant argues (p. 11, second paragraph) reference VHA only generally describes the use of different (non-etentamig) bispecific antibodies for treatment of B-cell cancers and that step-up dosing can decrease the risk of CRS. Further, the anti-BCMA bispecific antibodies teclistamab and elranatamab described by VHA require two step-up doses prior to the first maintenance dose. The argument has been fully considered but is not persuasive. The instant claims do not exclude multiple step-up doses because “the method comprises” (line 2 of claims 1 and 41) administration during a first cycle of: a step-up dose and maintenance dose of 2 and 60 mg etentamig, respectively. The claims do not exclude additional step-up doses of etentamig. Additionally, VHA was relied upon for its teaching that step-up dosing of a bispecific antibody can help reduce CRS and that CRS symptoms tend to diminish with subsequent doses. Also, premedication with a corticosteroid, e.g., dexamethasone or prednisone, prior to bispecific antibody administration can also increase treatment safety.
Applicant argues (paragraph bridging pp. 11-12) that the claimed 2 mg step-up dose and about 4-week cycle yield unexpected results not predictable from the cited references. Incidence and severity of CRS with etentamig is lower than other BCMA-binding bispecific antibodies as discussed by VHA, with 60 mg Q4W etentamig showing 43% overall CRS incidence, teclistamab 72% and elrantamab 58% (specification Table 15). These two drugs rely on two step-up doses to achieve results that are not as effective as 60 mg Q4W etentamig regimen with a single step-up dose of about 2 mg (30% overall CRS incidence; Table 28 of specification). The argument has been fully considered but is not persuasive. One thing VHA shows is that different bispecific antibodies have different biophysical properties. Applicant’s point that etentamig is superior to teclistamab and elrantamab in terms of CRS incidence with treatment is acknowledged. However, this is not surprising as supported by Lovely and by the initiation of clinical trial NCT0565032, because the skilled artisan would not have conducted a clinical trial for which they expect inferior results compared to existing treatments. Lovely quotes Dr. Voorhees, a hematologist/oncologist, as noting two distinguishing features of etentamic (p. 2/9, third paragraph). “[ABBV-383] harbors 2 BCMA-binding domains to better engage its target and it also utilizes a lower affinity CD3-binding domain with the strategy [being to] try and mitigate the potential CRS [which] can occur with these therapeutics ….” Lovely also discusses (paragraph bridging pp. 5/9-6/9) that another clinical cancer researcher compared other agents for treatment of MM and even though the overall response rate of etentamig was similar to other agents such as elranatamab and REG-5458, etentamig and REG-5458 had the lowest CRS. In view of the language of the instant claims allowing for steps/doses in addition to a first premedication dose of corticosteroid and an about 2 mg step-up dose of etentamig followed by one or more additional premedication doses of corticosteroid and an about 60 mg maintenance does of etentamig due to the method “comprising”, and in view of the prior art supporting the better effects of etentamig on CRS compared to other MM agents such as elrantamab, and as well as the known advantage of having one or more step-up doses to decrease the risk of CRS, the prior art relied upon as a whole makes obvious the claimed methods in view of their breadth and supports the reasonable expectation of reduced severity and occurrence of CRS therewith.
Applicant agues (p. 12, second through fourth paragraphs, and first paragraph of p. 13) that the results are unexpected in light of paragraph [0075] of the specification because the prior art relied on fails “to teach or suggest the success seen in the administration of the Q4W regimen of about 2 mg step-up dose of ABBV-383 and the maintenance dose of about 60 mg ABBV-383. A 60 mg Q3W regimen of ABBV-383 achieves a 71% patient CRS rate whereas a 2 mg step-up dose and 60 mg Q4W achieves a patient CRS rate of 39% with SUD [step-up dose] and 30% with SUD + Dex. (See Specification at FIG. 13A).” MPEP §§ 2141.02 and 2145 are discussed as saying a finding of obviousness is not appropriate when there is no suggestion to combine references and references teach away from the claimed invention. Also, unexpected results can serve to rebut a determination of obviousness. “Here, in view of the prior art cited and discussed above, a skilled person would not have foreseen that using fewer step up doses, i.e. a single step-up dose of an entirely different drug, (i.e., etentamig), would lead to safe and effective treatment of multiple myeloma or decrease the risk of Cytokine Release Syndrome (CRS) in patients. More specifically, the combination of a) a step-up dose, b) a longer treatment cycle, and c) a corticosteroid more than halved the incidence of CRS (71% to 30%) while maintaining treatment of the underlying condition—an unexpected, unpredictable result, and one which provides significant benefits to patients suffering from multiple myeloma.” The argument has been fully considered but is not persuasive. First, any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986) MPEP § 716.2 In this instance it is maintained that with the breadth of the claims, the differences are not unexpected in view of the teachings and suggestions of the prior art. Further, as discussed in MPEP 716.02(d) (see In re Clements, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)): “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.”” In response to Applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a method comprising a first cycle wherein there is a single step-up dose of etentagmic and which step-up dose is about 2 mg and a maintenance dose of about 60 mg etentamig, with a premedication dose of a corticosteroid before each etentamig dose, wherein the first cycle has a duration of about four weeks) are not recited in the rejected claim(s). Were the claims limited to wherein in the first cycle, which is about 4 weeks, there was a single step-up dose of etentamig, wherein the step-up dose was about 2 mg, and one maintenance dose of about 60 mg etentamig, with the recited premedication corticosteroid doses, then the unexpected results would be commensurate in scope with the claims. Otherwise, it is maintained for the reasons of record and as discussed above the prior art relied upon in the rejection supports both the claimed method and the reasonable expectation of the method reducing the incidence of one or more adverse events, such as CRS, compared to in the absence of a step-up dose and as compared to other BCMA-CD3 bispecific antibodies.
Allowable Subject Matter
Claims 9-12, 14-17, 44 and 45 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
June 17, 2026
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