RESPONSE TO APPLICANT’S AMENDMENT
1. Applicant's amendment, filed 08/04/2026, is acknowledged.
2. Claims 1, 3-5, 14-23, 26, 29, 32-33 and 36-40 are pending.
3. Claims 19, 32-33,37, 39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
4. Claims 1, 3-5, 14-18, 20-23, 26, 29, 36, 38, 40 are under examination as they read on the following species i) dosing regimen of 800 µg on day 1 (first dose), 4.5 mg on day 3 (second dose), 9 mg on day 5 (third dose), and18 mg on days 8, 15, and 22 (target dose), whereby the third dose is required.
(ii) wherein the method further comprises subsequent cycles at a dose of 18 mg on days 1, 8, 15, and 22.
(iii) multiple myeloma as the BCMA-positive neoplasm.
(iv) BCMA antibody comprising the HCDRs and LCDRs of SEQ ID NOs: 171-176, VH and VL of SEQ ID NOs: 177 and 178, target-binding domain and proteins of SEQ ID NO: 179 and 661 and ) CD3 antibody comprising the HCDRs and LCDRs of SEQ ID NOs: 636-638, 633-635, VH and VL of SEQ ID NOs: 639 and 641, target-binding domain and proteins of SEQ ID NO: 642 and 661.
5. Applicant’s IDS, filed 08/04/2026, is acknowledged.
6. The following new grounds of rejection are necessitated by the amendment submitted 08/04/2026.
7. The following is a quotation of 35 U.S.C. 112(b) (Pre AIA , 35 U.S.C. 112, second paragraph):
(B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
8. Claim 5 stands rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
The recitation “about X mg/day” in claim 5 is indefinite for reciting. It is unclear how many “mg” constitutes “about”. One of skill in the art would not know if applicant meant 0.1 mg, 0.2 mg or 0.4, or even more constitutes “about”.
Applicant’s arguments, filed 08/04/2026, have been fully considered, but have not been found convincing.
Applicant submits that claim 5 has been amended to remove “about”. However, claim 5 still recited “about”.
9. 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.
10. Claims 1, 3-5, 14-18, 20-23, 26, 29, 36, 38, 40 are rejected under 35 U.S.C. 103 as being unpatentable over US20210139584A1 in view of US 20230398147 and optionally in view of Cho et al. (17th International Myeloma Workshop, page e54, September 12-15, 2019, abstract no. OAB-081).
The `584 publication teaches and claims methods of treating or ameliorating a BCMA positive neoplasm such as multiple myeloma, comprising administering an antibody construct comprising a first domain which binds to BCMA, a second domain which binds to CD3 and a third domain which extends the half-life of the antibody construct, wherein the antibody construct is administered at a minimum dose of 800 μg/day in at least one cycle, wherein one cycle comprises at least three individual administrations of the antibody construct, wherein one cycle has
a) about 25 to about 30 days,
b) about 26 or 27 to about 29 days, or
c) about 28 days,
wherein the antibody construct is administered in one or two dose steps during the first cycle, wherein a first dose is between 800 μg/day and 1200 μg/day, an optional second dose is between 2500 μg/day and 5000 μg/day, preferably about 3000 μg/day or about 4500 μg/day, and a last dose (target dose) is between 6500 μg/day and 12 mg/day, such as 6500 μg/day, 7000 μg/day, 7500 μg/day, 8000 μg/day, 8500 μg/day, 9000 μg/day, 9500 μg/day, 10 mg/day, 11 mg/day or 12 mg/day, wherein the antibody construct is administered during the second cycle and optionally during any subsequent cycle at constant dose, a) an antibody or antibody construct comprising a domain which binds to BCMA on the surface of a target cell, wherein said domain comprises a VH region comprising CDR-H1 as depicted in SEQ ID NO: 171, CDR-H2 as depicted in SEQ ID NO: 172, and CDR-H3 as depicted in SEQ ID NO: 173, and a VL region comprising CDR-L1 as depicted in SEQ ID NO: 174, CDR-L2 as depicted in SEQ ID NO: 175, and CDR-L3 as depicted in SEQ ID NO: 176;
b) an antibody or antibody construct comprising a domain which binds to BCMA on the surface of a target cell, wherein said domain comprises a VH region as depicted in SEQ ID NO: 177, and a VL region as depicted in SEQ ID NO: 178;
c) an antibody construct comprising a domain which binds to BCMA on the surface of a target cell, wherein said domain comprises the amino acid sequence as depicted in SEQ ID NO: 179; or
d) an antibody construct having the amino acid sequence as depicted in SEQ ID NO: 661, wherein the antibody construct competes for binding to CD3 with or which binds to the same epitope of CD3 as:
a) an antibody or antibody construct comprising a domain which binds to CD3 on the surface of a T cell, wherein said domain comprises a VH region comprising CDR-H1 as depicted in SEQ ID NO: 636, CDR-H2 as depicted in SEQ ID NO: 637, and CDR-H3 as depicted in SEQ ID NO: 638, and a VL region comprising CDR-L1 as depicted in SEQ ID NO: 633, CDR-L2 as depicted in SEQ ID NO: 634, CDR-L3 as depicted in SEQ ID NO: 635;
b) an antibody or antibody construct comprising a domain which binds to CD3 on the surface of a T cell, wherein said domain comprises a VH region as depicted in SEQ ID NO: 639, and a VL region as depicted in SEQ ID NO: 641;
c) an antibody construct comprising a domain which binds to CD3 on the surface of a T cell, wherein said domain comprises the amino acid sequence as depicted in SEQ ID NO: 642; or
d) an antibody construct having the amino acid sequence as depicted in SEQ ID NO: 661 (see published claims 1-31).
The `584 published that in this FIH study with ongoing dose escalation and MTD not yet identified, AMG 701, an HLE antibody construct targeting CD3 and BCMA, showed encouraging activity in patients with heavily pre-treated R/R MM [0518].
The reference teachings differ from the claimed invention only in the recitation that the target dose of the protein (construct) from 12.5 mg/day to 24 mg/day.
The `147 publication teaches AMG 701 is an HLE BiTE® molecule that binds both B-cell maturation antigen (BCMA) and CD3 and comprises a single chain IgG Fc domain (extends the half-life of the BiTE). The amino acid sequence of AMG 701 is set forth in SEQ ID NO: 50. This study is a phase 1 open-label, dose-exploration study to evaluate the safety, tolerability, and efficacy of AMG 701 in patients who have relapsed/refractory multiple myeloma [0272]. [0296] Patients are dosed in each of four cohorts as follows: [0297] Cohort 1: priming dose of 8.4 mg administered by continuous IV infusion over 7 days (e.g. 1.2 mg/day for 7 days) on cycle 1 day 1 to day 7 followed by administration of a target dose of 12 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0298] Cohort 2A: priming dose of 16.1 mg administered by continuous IV infusion over 7 days (e.g. 2.3 mg/day for 7 days) on cycle 1 day 1 to day 7 followed by administration of a target dose of 12 mg to 18 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0299] Cohort 2B: priming dose of 4.6 mg administered by continuous IV infusion over 2 days (e.g. 2.3 mg/day for 2 days) on cycle 1 day 1 to day 2, followed by administration of a boost dose of 0.8 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 3, followed by administration of a target dose of 12 mg to 18 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0300] Cohort 3: priming dose of 9.2 mg administered by continuous IV infusion over 2 days (e.g. 4.6 mg/day for 2 days) on cycle 1 day 1 to day 2, followed by administration of a boost dose of 1.6 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 3, followed by administration of a target dose of 12 mg to 18 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0322], [0322]. Without being bound by theory, these continuous IV priming dosing regimens are believed, based on PK simulations, to achieve the serum free AMG 701 projected efficacious exposures within 2 to 4 days, but more importantly they are also predicted to avoid any rapid increase in free AMG 701 serum exposures as seen with short-term 60-minute IV infusions with a sharp increase in free AMG 701 serum concentrations, e.g. a peak serum concentration (Cmax) within 1 hour of infusion start. A slow ramp up in free AMG 701 concentrations and delaying the time to Cmax is believed to reduce the risk of CRS. These cIV priming dosing regimens are believed to enable optimal T cell engagement of target cells during week 1, without rapid increases in serum concentrations of free AMG 701, which have been associated with induction of Grade 2 and higher CRS following initial cycle 1 doses of AMG 701 administered by 60-min IV infusions [0294].
Cho et al teach that in an NCI-H929 xenograft model, AMG 701, dose-dependently, blocked tumor growth 5d after the first injection and completely eradicated tumor growth after 3 injections at all dose levels (0.02, 0.2, 2 mg/kg), without drug-related adverse effects in the host. Next, mice were treated, from d15 until end of study, with (i) len once daily, (ii) AMG 701 once weekly or (iii) a combination of len and AMG 701 (see abstract).
Given that the all dose levels (0.02, 0.2, 2 mg/kg), blocked tumor growth 5d after first injection and completely eradicated tumor growth after 3 injections without drug-related adverse effects in the host, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal concentrations of components because concentration is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Further, if there are any differences between Applicant’s claimed method and that suggested by the combined teaching of the prior art, the differences would appear minor in nature. The prior art teach all the various permutations of concentration including the target dose of protein from 12.5 mg/day to 18 mg/day, it would be conventional and within the skill of the art to identify the claimed concentrations of AMG 701. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP §§ 2144.05 part II A.
The US 20230398147 indicates that targeting dose of AMG 701 at 18 mg/day intravenous (IV) after priming dose and intermediate doses previously been considered, and used, with AMG 701 therapies, those of primary skill in the art would have had a reasonable expectation of success in using the claimed anti-BCMA X CD3 antibody, AMG 701 regimen as claimed.
There is no evidence that the method of used described in the instant claims would differ in an unexpected manner from those described in the references.
The experimentation needed to arrive at the subject matter claimed was "nothing more than routine" application of a well-known problem-solving strategy, we must conclude it is not invention. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1368 (Fed. Cir. 2007).
The prior art provides the reason, means, and expectation of success in choosing the claimed dose escalation for the claimed AMG 701, and the claimed doses escalation are not dramatically different from the doses taught in the prior art if they were administered as dose escalation comprising a target dose of >12.5 mg/kg.
The Board stated that "all that remained to be achieved over the prior art was the determination that a specific dose within a previously suggested dose range, and its corresponding dosing schedule, would have been safe and effective for the treatment of human patients." Genzyme Therapeutic Prods. v. Biomarin Pharms., No. 2015-1720.
"[I]t is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456 (CCPA 1955); see also In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003). "Only if the 'results of optimizing a variable' are 'unexpectedly good' can a patent be obtained for the claimed critical range." In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997) (quoting In re Antonie, 559 F.2d 618, 620 (CCPA 1977)). "[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276 (CCPA 1980).
An improvement in the art would have been obvious if “it is likely the product not of innovation but of ordinary skill and common sense.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007). Finding workable or optimal ranges is generally understood as within the capabilities of the ordinary artisan. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1368 (Fed. Cir. 2007) (discovery of an optimum value of a variable in a known process is usually obvious.). The idea that optimizing an ordinary variable does not by itself constitute a patentable advance was also stated in In re Geisler, 43 USPQ2d 1362: “…“it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Only if the “results of optimizing a variable” are “unexpectedly good” can a patent be obtained for the claimed critical range. In re Antonie, 559 F.2d 618, 620, 195 USPQ 6, 8 (CCPA 1977); see also In re Dillon , 919 F.2d 688, 692, 16 USPQ2d 1897, 1901 (Fed.Cir. 1990) (in banc).” Note MPEP §2144.05IIA on this issue.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant’s arguments, filed 08/04/2026, have been fully considered, but have not been found convincing.
Applicant submits that the `147 publication refers only to dosing regimens for BCMA XC3 proteins in which intermediate dose exceeds the first dose is administered between the priming dose and the target dose as recited in claim 1.
However the rejection has been modified to address Applicant’s amendment.
11. Claims 1, 3-5, 14-18, 20-23, 26, 29, 36, 38, 40 are rejected under 35 U.S.C. 103 as being unpatentable over Harrison et al (Blood (Nov. 5, 2020) 136 (Supplement 1, of record) : 28) and/or US 20210139584 (of record) and/or US 20230398147 (of record), in view of in view of Goldstein et al (Blood Adv (Sept. 4,2020) 4 (17): 4180–4194, of record) and optionally in view of Cho et al. (17th International Myeloma Workshop, page e54, September 12-15, 2019, abstract no. OAB-081).
Harrison et al teaches that patients with Relapsed/Refractory Multiple Myeloma (MM RR) or intolerant to ≥3 lines [proteasome inhibitor (PI), IMiD, anti-CD38 Ab as available] received AMG 701 IV infusions weekly in 4-week cycles until disease progression (PD). A 0.8-mg step dose was added prior to target doses ≥1.2 mg to prevent severe cytokine release syndrome (CRS). Target dose was achieved by day 8 or sooner with earlier escalation. The first 3 cohorts (dose 5-45 μg) had 1 patient each, the next cohorts (0.14-1.2 mg) had 3-4 patients each, and subsequent cohorts (1.6-12 mg) were to have 3-10 patients each. Minimal residual disease (MRD) was measured by next-generation sequencing (NGS, ≤10-5 per IMWG) or flow cytometry (≤3×10-5).
The response rate was 36% (16/45) at doses of 3-12 mg; at ≤1.6 mg (n=27), there was 1 response at 0.8 mg in a patient with low baseline soluble BCMA (sBCMA). With earlier dose escalation with 9 mg, the response rate was 83% (5/6, 3 PRs, 2 VGPRs), with 4/5 responders being triple refractory and 1 DLT of grade 3 CRS in this group. Across the study, responses included 4 stringent CRs (3 MRD-negative, 1 not yet tested), 1 MRD-negative CR, 6 VGPRs, and 6 PRs (Table). Median (Q1, Q3) time to response was 1.0 (1.0, 1.9) month, time to best response was 2.8 (1.0, 3.7) months, and response duration was 3.8 (1.9, 7.4) months, with maximum duration of 23 months; responses were ongoing at last assessment in 14/17 patients (Figure). MRD was tested in 4 patients (3 sCR, 1 CR) and all were negative (3 by NGS, 1 by flow); MRD negativity was ongoing at last observations up to 20 months later. AMG 701 exhibited a favorable PK profile in its target patient population of RR MM, with AMG 701 exposures increasing in a dose-related manner. Patient baseline sBCMA levels were identified as a determinant of AMG 701 free drug exposures; at higher doses, encouraging preliminary responses were seen even at the higher end of baseline sBCMA values.
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Claims 26 and 29, are included because AMG 701 comprises the claimed BCMA antibody comprising the HCDRs and LCDRs of SEQ ID NOs: 171-176, VH and VL of SEQ ID NOs: 177 and 178, target-binding domain and proteins of SEQ ID NO: 179 and 661 and ) CD3 antibody comprising the HCDRs and LCDRs of SEQ ID NOs: 636-638, 633-635, VH and VL of SEQ ID NOs: 639 and 641, target-binding domain and proteins of SEQ ID NO: 642 and 661.
The `584 publication teaches and claims methods of treating or ameliorating a B-cell maturation antigen (BCMA) positive neoplasm comprising administering an antibody construct comprising a first domain which binds to BCMA, a second domain which binds to CD3 and a third domain which extends the half-life of the antibody construct, wherein the antibody construct is administered at a minimum dose of 800 μg/day in at least one cycle, wherein one cycle comprises at least three individual administrations of the antibody construct, wherein the antibody construct is administered for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more cycles, wherein one cycle has a) about 25 to about 30 days, b) about 26 or 27 to about 29 days, or c) about 28 days, wherein the antibody construct is administered at a dose of about 800 μg/day to 12 mg per day, such as 1000 μg, 1200 μg, 1500 μg, 1600 μg, 2000 μg, 2500 μg, 3000 μg, 3500 μg, 4000 μg, 4500 μg, 5000 μg, 5500 μg, 6000 μg, 6500 μg, 7000 μg, 7500 μg, 8000 μg, 8500 μg, 9000 μg, 9500 μg, 10 mg, 11 mg or 12 mg per day, wherein the antibody construct is administered in one or two dose steps during the first cycle, wherein a first dose is between 800 μg/day and 1200 μg/day, an optional second dose is between 2500 μg/day and 5000 μg/day, preferably about 3000 μg/day or about 4500 μg/day, and a last dose (target dose) is between 6500 μg/day and 12 mg/day, such as 6500 μg/day, 7000 μg/day, 7500 μg/day, 8000 μg/day, 8500 μg/day, 9000 μg/day, 9500 μg/day, 10 mg/day, 11 mg/day or 12 mg/day. The `584 publication teaches that after a grade 3 dose-limiting toxicity (DLT) of cytokine release syndrome (CRS) at 1600 μg, for all target doses ≥1200 μg, an initial run-in dose of 800 μg was added, followed by step up to the target dose. 47 patients received AMG 701 at doses ranging from 5 to 6500 μg, with an 800 μg run-in dose used for step-up to target doses of ≥1200 μg; patients are yet to be enrolled at additional planned doses of 9000 and 12000 μg, see also FIG. 1 [0517].
The 20230398147 publication teaches AMG 701 is an HLE BiTE® molecule that binds both B-cell maturation antigen (BCMA) and CD3 and comprises a single chain IgG Fc domain (extends the half-life of the BiTE). The amino acid sequence of AMG 701 is set forth in SEQ ID NO: 50. This study is a phase 1 open-label, dose-exploration study to evaluate the safety, tolerability, and efficacy of AMG 701 in patients who have relapsed/refractory multiple myeloma [0272]. [0296] Patients are dosed in each of four cohorts as follows: [0297] Cohort 1: priming dose of 8.4 mg administered by continuous IV infusion over 7 days (e.g. 1.2 mg/day for 7 days) on cycle 1 day 1 to day 7 followed by administration of a target dose of 12 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0298] Cohort 2A: priming dose of 16.1 mg administered by continuous IV infusion over 7 days (e.g. 2.3 mg/day for 7 days) on cycle 1 day 1 to day 7 followed by administration of a target dose of 12 mg to 18 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0299] Cohort 2B: priming dose of 4.6 mg administered by continuous IV infusion over 2 days (e.g. 2.3 mg/day for 2 days) on cycle 1 day 1 to day 2, followed by administration of a boost dose of 0.8 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 3, followed by administration of a target dose of 12 mg to 18 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0300] Cohort 3: priming dose of 9.2 mg administered by continuous IV infusion over 2 days (e.g. 4.6 mg/day for 2 days) on cycle 1 day 1 to day 2, followed by administration of a boost dose of 1.6 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 3, followed by administration of a target dose of 12 mg to 18 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0322], [0322].
The `147 publication teaches that the first dose (e.g. priming dose) of AMG 701 is administered as a continuous IV infusion over the course of 2 or 7 days during the first week of cycle 1 followed by weekly short-term IV infusions (e.g. 60-minute IV infusions) of the target dose of AMG 701 beginning on day 8 of the cycle. AMG 701 is administered in 28-day cycles and the date of the first dose of AMG 701 is defined as day 1 in the cycle. Without being bound by theory, these continuous IV priming dosing regimens are believed, based on PK simulations, to achieve the serum free AMG 701 projected efficacious exposures within 2 to 4 days, but more importantly they are also predicted to avoid any rapid increase in free AMG 701 serum exposures as seen with short-term 60-minute IV infusions with a sharp increase in free AMG 701 serum concentrations, e.g. a peak serum concentration (Cmax) within 1 hour of infusion start. A slow ramp up in free AMG 701 concentrations and delaying the time to Cmax is believed to reduce the risk of CRS. These cIV priming dosing regimens are believed to enable optimal T cell engagement of target cells during week 1, without rapid increases in serum concentrations of free AMG 701, which have been associated with induction of Grade 2 and higher CRS following initial cycle 1 doses of AMG 701 administered by 60-min IV infusions [0294].
Cho et al teach that in an NCI-H929 xenograft model, AMG 701, dose-dependently, blocked tumor growth 5d after the first injection and completely eradicated tumor growth after 3 injections at all dose levels (0.02, 0.2, 2 mg/kg), without drug-related adverse effects in the host. Next, mice were treated, from d15 until end of study, with (i) len once daily, (ii) AMG 701 once weekly or (iii) a combination of len and AMG 701 (see abstract).
AMG 701 comprises all the claimed SEQ ID NOs, molecular weight and half-life.
The reference teachings differ from the claimed invention only in the recitation that the target dose from 12.5 mg/day to about 24mg/day in claim 1, or 18 mg/day in claims 4, 17, 19, 20.
Goldstein et al teach in a subcutaneous mouse xenograft model, at all doses tested, AMG 701 completely inhibited tumor formation (P < .001), as well as inhibited growth of established tumors (P ≤ .001) and extended survival in an orthotopic MM model (P ≤ .01). Dose-dependent pharmacokinetic and pharmacodynamic behavior was observed, with depletion of PC-specific genes reaching 93% in blood and 85% in BM.
Given that at all doses tested, AMG 701 completely inhibited tumor formation, further the Harrison et al, US 20210139584 and US 20230398147 applicant indicates a success using 12 mg/day target dose in the treatment of MM, those of skilled in the art would use 18 mg/day as the target dose with reasonable expectation of success since lower doses were efficient to inhibited MM, then a higher target dose of up to 24 mg/day would also be effective in treating. If one skilled in the art, based upon knowledge of compounds having similar physiological or biological activity, would be able to discern an appropriate dosage or method of use.
The US 20230398147 indicate that targeting dose of AMG 701 at 18 mg/day intravenous (IV) after priming dose and intermediate doses previously been considered, and used, with AMG 701 therapies, those of primary skill in the art would have had a reasonable expectation of success in using the claimed HLE anti-BCMA X CD3 antibody, AMG 701 regimen as claimed.
The claimed dose escalation of 800µg/day on d1, 2nd dose of 405 mg/day on d3, 3rd dose of 9 mg on d5 and the target dose of 18 mg/day on d8 , 18, 22 is considered obvious variation of the prior art does regimen to reduce the risk of CRS and effectively treat MM. A person who has ordinary skill in the art would have found it obvious to determine the optimum dose regimen for AMG 701 BiTE that enhances anti-tumor effect and reduce the risk of CRS of result-effective variables known in the art. Recognition that a property (promoting anti-tumor effect and reducing the riski of CRS) is affected by the variable (dose regimen of AMG 701) is sufficient to find the variable result-effective. The Board stated that "all that remained to be achieved over the prior art was the determination that a specific dose within a previously suggested dose range, and its corresponding dosing schedule, would have been safe and effective for the treatment of human patients." Genzyme Therapeutic Prods. v. Biomarin Pharms., No. 2015-1720. The experimentation needed to arrive at the subject matter claimed was "nothing more than routine" application of a well-known problem-solving strategy, we must conclude it is not invention. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1368 (Fed. Cir. 2007).
It would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal concentrations of components because concentration is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP §§ 2144.05 part II A.
The teachings of Harrison et al, US 20210139584 and US 20230398147 demonstrate that not only were the criteria for priming dosing followed by target doses known in the art, it is known that these criteria had been met for AMG 701 antibody. Those skilled in the art would have had a reasonable expectation that the claimed treatment regimen of the AMG-701 would have been successful.
When other methods similar to the claimed method have been successful, the court has determined there would have been a reasonable expectation of success. For example, in Velander v. Garner, 348 F.3d 1359, 1379 (Fed. Cir. 2003), a reasonable expectation of success was found for a method of producing a particular protein when several other proteins had been produced in a similar way.
The court has also determined that the availability of specific instructions to achieve the claimed subject matter can form the basis for a reasonable expectation of success. In Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1367-68 (Fed. Cir. 2007), a reasonable expectation of success was found where the prior art included several references with directions for narrowing the possible salts previously approved and the result could be verified by routine trial-and-error procedures.
"[I]t is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456 (CCPA 1955); see also In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003). "Only if the 'results of optimizing a variable' are 'unexpectedly good' can a patent be obtained for the claimed critical range." In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997) (quoting In re Antonie, 559 F.2d 618, 620 (CCPA 1977)). "[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276 (CCPA 1980). Appellants' claims and arguments fail under these tests.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant’s arguments, filed 08/04/2026, have been fully considered, but have not been found convincing.
Applicant submits that the cited documents do not teach or suggest administering a target dose of a BCMA x CD3 HLE bispecific T cell engaging molecule within the claimed range of 12.5 mg/day to about 24 mg/day with any reported efficacy, and a person of ordinary skill in the art would not have had a reasonable expectation of success in escalating the target dose into the claimed range.
This is not found persuasive because the `147 publication teaches the administration of a target dose of 12 mg to 18 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0300] and Cho et al teach that in an NCI-H929 xenograft model, AMG 701, dose-dependently, blocked tumor growth 5d after the first injection and completely eradicated tumor growth after 3 injections at all dose levels (0.02, 0.2, 2 mg/kg) (1.6, 16, 160 mg for an 80 kg person), without drug-related adverse effects in the host. Accordingly, there is a reasonable expectation of success to escalate the target dose into the claimed range of 12.5 mg/day to about 24 mg/day.
Applicant submits that the highest target dose for which any actual clinical result is reported across Harrison et al, the `584 publication and the `147 publication is 12 mg/day, which falls below the lower bound of the claimed range of 12.5 mg/day to about 24 mg/day. Harrison et al does not refer to any dose above 12 mg, and reports results only up to a 12 mg target dose. The `548 publication expressly caps its target dose at “between 650 μg per day and 12mg per day” (see, e.g., paragraphs [0224] and [0225]). The `147 publication’s Cohorts 2A,2B, and 3, which prospectively refer to target dose “of 12 mg to 18 mg,” are prophetic disclosure for which no clinical results are reported; the only cohort for which the `147 publication reports actual results is Cohort 1, which was administered a target dose of 12 mg (wee [0297]-[0300] and [0322]). The Office’s own concention that Harrison, the `584 publication, and the `147 publication differ from claim 1 in the target dose limitation confirms that these documents do not disclose or suggest the claimed ranges.
This is not found persuasive because the `147 publication teaches the administration of a target dose of 12 mg to 18 mg as a short-term IV infusion (e.g. 60-minute IV infusion) on cycle 1 day 8, 15, and 22 [0300] and Cho et al teach that in an NCI-H929 xenograft model, AMG 701, dose-dependently, blocked tumor growth 5d after the first injection and completely eradicated tumor growth after 3 injections at all dose levels (0.02, 0.2, 2 mg/kg) (1.6, 16, 160 mg for an 80 kg person), without drug-related adverse effects in the host. Accordingly, there is explicit teachings of the claimed range of 12.5 mg/day to about 24 mg/day.
[P]roper analysis under § 103 requires, inter alia, consideration of two factors: (1) whether the prior art would have suggested to those of ordinary skill in the art that they should make the claimed composition or device, or carry out the claimed process; and (2) whether the prior art would also have revealed that in so making or carrying out, those of ordinary skill would have a reasonable expectation of success.
The PTAB held that a showing of obviousness in this case did not require in vivo data as “proof” that an otherwise clear statement in [Reuser] was correct, when it was reasonably based on in vitro studies and other information discussed in the reference. In IPR2013-00535.
It is clear that all doses, intervals of dosing, sequence of administrations, and number of doses of AMG 701 are results effective variables and can be determined by one or ordinary skill in this art with only routine experimentation. Thus, all said values and parameters in the instant claims are obvious.
Applicant argues regarding routine optimization of a result-effective that the cited references stop at a 12 mg target dose and never identify 12.5 mg/day to 24 mg/day as a workable or effective range. Goldstein does not fill this gap. The doses of AMG 701 actually administered in mouse models in Goldstein were 2 mg/kg, 0.2 mg/kg, and 0.02 mg/kg in the subcutaneous flank xenograft model; 0.5 mg/kg, 0.05 mg/kg, and 0.005 mg/kg in the orthotopic model; and 0.25 mg/kg, 0.05 mg/kg, and 0.01 mg/kg in the established-tumor model. See, e.g., p. 4181, column 2, line 34 to p. 4182, column 1, line 10. According to Jackson Laboratory body-weight data for NOD/SCID mice, as used in Goldstein's flank and orthotopic models, mice of that strain have an average body weight ranging from about 10.9 g (female, at 3 weeks of age) to about 28.3 g (male, at 10 weeks of age) (see The Jackson
Laboratory website at https://www.jax.org/jax-mice-and-services/strain-data-sheet-pages/body-
weight-chart-001303). The established-tumor model simply refers to "female SCID mice," but it
is presumed that such mice fall within a similar weight range. Even using the highest charted
mean body weight - approximately 28.3 g (0.0283 kg) - the highest dose administered in
Goldstein et al., 2 mg/kg, corresponds to only about 0.057 mg per administration (i.e.,
approximately 0.057 mg/day on each day of dosing), which is more than 200-fold below the 12.5
mg/day lower bound of the target dose recited by claim 1; the lower doses tested correspond to
still smaller amounts. Because the mice in Goldstein et al. were sublethally irradiated and tumor-
bearing, their actual body weights were, if anything, likely lower than these healthy-animal
reference values, making this estimate conservative. Goldstein et al. thus does not administer,
disclose, or suggest a dose within the claimed range of 12.5 mg/day to 24 mg/day.
This is not found persuasive because Applicant’s argument assumes that the instant claims administered the doses to mouse not to human. Goldstein provides the teachings that at all doses tested, AMG 701 completely inhibited tumor formation (P < .001), as well as inhibited growth of established tumors (P ≤ .001) and extended survival in an orthotopic MM model (P ≤ .01). That is the claimed dosing regimen is an obvious variation of the prior art regimen taught by Harrison et al, US 20210139584 and US 20230398147 since all the doses tested in the animal provide tumor growth inhibition without drug-related adverse effects in the host. Further, arriving to the claimed dose regimen would be routine optimization of a result-effective variable. The experimentation needed to arrive at the subject matter claimed was "nothing more than routine" application of a well-known problem-solving strategy, we must conclude it is not invention. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1368 (Fed. Cir. 2007).
I. OBVIOUSNESS REQUIRES A REASONABLE EXPECTATION OF SUCCESS
Applicant argues because the prior art teaches dose-dependent cytokine release syndrome (CRS) toxicity, one of ordinary skill in the art would not have had a reasonable expectation of success in escalating the AMG 701 target dose into the claimed range. For example, Harrison et al. reports that "[a] 0.8-mg step dose was added prior to target doses ≥1.2 mg to prevent severe cytokine release syndrome (CRS)." See "Methods" section of Harrison. The '584 publication likewise reports "a grade 3 dose-limiting toxicity (DLT) of cytokine release syndrome (CRS) at 1600 µg" leading to the addition of "an initial run-in dose of 800 µg" for target doses >1200 µg. See paragraph [0517]. The '147 publication attributes "Grade 2 and higher CRS" to "rapid increases in serum concentrations of free AMG 701." See paragraph [0294]. In view of this known dose-limiting toxicity for BCMA X CD3 HLE bispecific T cell engagers, the skilled worker could not have had any reasonable expectation of success in achieving a safe and effective dose regimen from simply pushing the target dose higher than tht exemplified in the cited documents, into the presently claimed range.
Applicant argument that the skilled worker could not have had any reasonable expectation of success in achieving a safe and effective dose regimen from simply pushing the target dose higher than tht exemplified in the cited documents, into the presently claimed range is not persuasive because it is merely attorney argument, unsupported by evidence of how those of skill in the art would have considered the efficacy and efficiency of escalating the target dose into the claimed range. See Meitznerv. Mindick, 549 F.2d 775, 782 (CCPA 1977) ("Argument of counsel cannot take the place of evidence lacking in the record."). Applicants do not explain why one skilled in the art reading the relied upon references would have been have discouraged from in escalating the target dose into the claimed range when the prior art suggests that high dose up to 18 mg/day would treat MM. Further, the Cho et al suggest that AMG 701, dose-dependently, blocked tumor growth 5d after the first injection and completely eradicated tumor growth after 3 injections at all dose levels (0.02, 0.2, 2 mg/kg), without drug-related adverse effects in the host.
Applicant points that even if a prima facie case of obviousness had been established, which Applicant submits it has not, it would be rebutted by unexpected results. Claim 1 as amended recites a step-dosing regimen comprising a first dose on day 1, a second dose exceeding the first dose administered before day 8, an optional third dose exceeding the second dose, and a target dose of from 12.5 mg/day to 24 mg/day. The subject application provides clinical data from the AMG 701 first-in- human study showing that this step-dosing regimen, with a target dose of 18 mg/day, achieves efficacy together with a manageable safety profile. For example, the application data discloses that out of 10 patients in cohort 15B (first dose of 800 pg, second dose of 6 mg, and target dose of 18 mg), 1 (10%) had a stringent complete response (sCR), 3 (30%) had very good partial responses (VGPR), and 1 (10%) had a partial response (PR). Out of 7 patients in cohort 15C (first dose of 800 pg, second dose of 4.5 mg, third dose of 9 mg, and target dose of 18 mg), 1 (14.3%) had a complete response (CR) and 1 (14.3%) had a partial response. See, e.g., Table 2 (pp. 66-67). The overall study, including these cohorts, was noted to demonstrate a manageable safety profile (p. 67, 1st full paragraph). Further, the application notes at p. 67, 3rd full paragraph that for these two cohorts:
... the safety profile appears to be consistent with previously reported data. The
CRS (cytokine release syndrome) incidence has improved, especially within
cohort 15C (still enrolling): No grade 3 or higher has been reported for the last
two cohorts (15B and 15C).
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This is not found persuasive because item 15B and 15C reported in the specification cannot be clearly equated with the claimed invention. The showing of unexpected results is not commensurate in scope with the invention as claimed. The claims are directed to a genus of BCMA-positive neoplasm subjects, a genus of genus of priming doses, a genus of one or two intermediate doses and a genus of target doses administered at any time during the undefined cycles, while the showings of unexpected results are limited to Multiple Myeloma and a first dose of 800 μg/day is administered on day 1, the second dose of 4.5 mg/day is administered on day 3, the third dose of 9 mg/day is administered on day 5, and the target dose of 18 mg/day is administered on day 8, day 15 and day 22 (item 15 C). Applicants fail to compare the claimed target doses with closest prior art taught in Harrison, US20210139584A1 and/or US 20230398147. Also, In Daikin v. Chemours, the Federal Circuit held that any claimed “unexpected” improvement must be supported by data covering the full scope of the claims; otherwise, the result is not sufficient to overcome an obviousness rejection. MPEP §716.02(d). Not all the dose combination would result in the unexpected 83% ORR in MM treated with AMG 701.
Importantly, Applicant’s reliance on unexpected results do not overcome clear and convincing evidence of obviousness. Also see Richardson-Vicks Inc. v. Upjohn Co., 44 USPQ2d 1181 (CAFC 1997). Here, applicants have not provided any objective evidence to support the difference between the prior art and instant method. The record does not contain sufficient objective evidence that the referenced method differs in any significant manner from that claimed. With respect item 15B and 15C unexpected results, Harrison et al provide first dose of 800μg, and escalation dose of less than 6.5 mg/day, less than 9 mg/ day and less than 12 mg/day and target dose of 6.5 mg/day, 9 mg/day and 12 mg, respectively (see Table in Harrison et al and Swimmer plot). Harrison et al provides the same asserted “unexpected” response rate of 36% at doses of 3-12 mg. Further, Harrison et al teaches same asserted “unexpected” response with earlier dose escalation with 9 mg, the response rate was 83% (5/6, 3 PRs, 2 VGPRs) even though the target doses are less than 12.5mg. The prior art teaches same asserted “unexpected results”. Applicant assertion of unexpected results should be genuine, well-supported, and relevant to the scope of what is being claimed.
Applicants have not provided comparative data to show that the claimed dosage regimen provides unexpectedly superior results when compared to the closest prior art. See In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (“[W]hen unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art.”).
12. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
13. Claims 1, 3-5, 14-18, 20-23, 26, 29, 36, 38, 40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-11, 17, 18, 21, and 24-41 of copending Application No. 16869793 (reference application) optionally in view of Goldstein et al (Blood Adv (Sept. 4,2020) 4 (17): 4180–4194) for the same reasons set forth in the previous office action.
Applicant’s arguments, filed 08/04/2026, have been fully considered, but have not been found convincing.
Applicant submits that the claimed range would not have been obvious over the `793 claims in view of Goldstein et al. Applicant submits that the reference claims and Goldstein et al do not disclose or suggest a target does within the claimed range of 12.5 mg/day to 24 mg/day; the highest reported target dose in the `793 claims is 12 mg and the Goldstein et al murine dose are more than 200-fold below the 12 mg/day lower bound of the claimed range.
This not found persuasive because Applicant cannot compare the mouse dose to human dose without calculating the mouse to human dose conversion, Drug Dose Converter (Human vs Mouse). For example, the 2 mg/kg mouse dose is equivalent to 1.6 mg/kg human dose, for an average person with 70 kg, the dose is 112 mg/day.
Applicant submits that the prior art teaches dose-dependent cytokine release syndrome (CRS) toxicity that undercuts any reasonable expectation of success in escalating the target dose into the claimed range. The same routine-optimization and result-effective-variable rationale relied upon by the Office fails here for the reasons given under § 103. The skilled worker with the '793 claims and Goldstein in hand could not have predicted that the claimed dose regimen - with a target dose of 12.5 mg/day to 24 mg/day - would yield the unexpected efficacy and improved CRS safety profile discussed under the § 103 section.
This is not found persuasive because the asserted unexpected efficacy and improved CRS safety profile is not sufficient to overcome the 103 rejection and the NS ODP rejection as addressed above.
14. No claim is allowed.
15. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Cho et al. AMG 701 Potently Induces Anti-Multiple Myeloma (MM) Functions of T Cells and IMiDs Further Enhance Its Efficacy to Prevent MM Relapse In Vivo. Blood, 134(Supp. 1):135, Abstract no. 652 November 2019.
Cho teaches that AMG 701 potently induces anti-multiple Myeloma (MM) functions in vivo. In the human NCI-H929 xenograft model reconstituted with human T effector cells, AMG 701 effectively blocked tumor growth 5d after the first injection, regardless of doses (0.02-2 mg/kg). Tumors were completely eradicated following 3 separate injections in the host without weight loss. Next, sub-optimal doses and treatment schedules for AMG 701 and len were then used to investigate in vivo anti-MM effects by the combination vs monotherapy. Mice receiving MM cells were treated, from d15 until the end of the study, with len once daily, AMG 701 once weekly, or combination of AMG 701 and len. Two days after the first drug administration, all three treatments significantly inhibited MM tumor growth in mice (p<0.001). Most importantly, while AMG 701 or len group showed tumor progress eventually, the combination of AMG 701 with len continuously suppressed tumor growth (p<0.05 after d26; p<0.001 after d40 for combination vs either agent alone).
16. 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 extension fee 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 date of this final action.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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September 15, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644
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