DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims 1-14 are pending in this application.
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 18 Jun. 2026 has been entered.
Status of Claims
Claims 11-13 are amended.
Response to Amendment
The amendments filed on 18 Jun. 2026 have been entered.
Response to Arguments
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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) 1-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over NCT03867682 (ClinicalTrials.gov; published 8 Mar. 2019), in view of Cicic et al. (WO 2018/200841 A1; published 1 Nov. 2018) for the reasons cited in the Office action filed on 17 Feb. 2026.
NCT03867682 teaches venetoclax and lintuzumab-Ac225 in AML patients (see title). NCT03867682 teaches that lintzumab-Ac225 is administered on day 1 of each cycle for four cycles (unless in the 0.5 µgCi/Kg or 0.25 µCi/kg corhorts wherein the is potential for an additional four cycles. Venetoclax is taken on days 1-21 of each cycle for up to 12 cycles. Each cycle is 28 d. Patients will be enrolled into the following dose escalation cohorts 0.5 µCi/kg, 1.0 µCi/kg and 1.5 µCi/kg. 400 mg of venetoclax daily will be taken on days 1-21 of a 28-d cycle. There will be a ramp up of venetoclax dosing in the first cycle. With 100 mg administered on day 1, 200 mg on day 2 and 400 mg on day 2 and day 4 and later. Inclusion criteria include a blast count ≤200/µL (pg. 9). (Reads on a method of treating a human afflicted with AML comprising administering to the subject a regimen of venetoclax and lintuzumab-Ac225 wherein the (a) the regimen comprises a plurality of cycles (4 or 8 cycles), each cycle lasting 28 d, (b) the regimen comprises orally administering venetoclax on days 1 and 2 of the first and second cycles as ramp up dosages of 100 mg and 200 mg, respectively, and thereafter orally administering 400 mg of venetoclax daily on days 3-21 of the first cycle and days 1-21 of each subsequent cycle and (ii) intravenously administering lintuzumab-Ac2256 on day 1 of each cycle at doses of 5 µCi/kg, 1.0 µCi/kg and 1.5 µCi/kg and wherein the subject has a peripheral blast count ≤200/µL).
NCT03867682 does not teach intravenously administering lintuzumab-AC225 on day 4, 5, or 6 of each cycle
Cicic et al. teach a method for treating cancer using a BCL-2 inhibitor in conjunction with an alpha-emitting therapeutic (see title). Cicic et al. teach venetoclax as a BLC-2 inhibitor (pg. 1) and 225Ac-Lintuzumab as 225Ac-HuM195 (pg. 6). Cicic et al. teach a method for inducing the death of an acute myeloid leukemic cell comprising contacting the cell with (i) venetoclax in conjunction with (ii) 225Ac-labeled HuM195 wherein the amounts of venetoclax and 225Ac-labeeld HuM195 when concurrently contacted with the cell are effective to induce the cell’s death (pgs. 5,15). In case of AML, examples of low peripheral blast burden are those yielding blood blast burdens at or below 1,000 blast cells/µl (pg. 10). Cicic et al. teach the scenario: (i) BCL-2 inhibitor is administered first and labeling agent is administered second (single dose or plurality of doses of weeks). Cicic et al. teach sub-saturating doses including doses below 400 mg/day (pg. 12). Cicic et al. teach human dosing regimens in the case of 225Ac-HuM195 for treating AML including the following without limitation such as <0.5 µCi/kg or from 0.5 µCi/kg to 10 µCi/kg (see pg. 13). Cicic et al. teach venetoclax and its normal dosing regimen where therapy is to be initiated at 20 mg followed by weekly ramp up dosing schedule to the recommended dose of 400 mg (example 5). Cicic et al. teach 225Ac-HuM195 and its normal dosing regimen that include the following: (i) 2×2.0 µCi/kg, fractions administered once per week, and (ii) 4.0 µCi/kg in a single administration (pg. 20). The first does of 225Ac is administered on the same day or one day following the last dose of venetoclax (example 7) Cicic et al. teach dosing scenarios I, II, II, IV, V, VI, VII, and VIII where the single dose of 225Ac-HuM195 may be administered on days 4, 5, or 6 (examples 7-14). Cicic et al. teach 28 d cycles (Fig. 6).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the method of NCT03867682 so that the method administers 225Ac-HuM195 on days 4, 5, or 6 optionally day 5 as taught by Cicic et al. because the administering on one of those days would have been expected to provide an equivalent method of treating AML in human subjects wherein the day for administration of 225Ac-HuM195 has been optimized in so that 225Ac-HuM195 gets administered on a day immediately following ramp up of venetoclax whereby achieving concurrent optimal therapeutic doses of venetoclax and 225Ac-HuM195. MPEP 2144.05.II. The day for administration of lintuzumab-Ac225 is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. A person of ordinary skill in the art would have arrived one of days 4, 5, and 6 for the administration of lintuzumab-Ac225 in order to achieve optimal therapeutic efficacy for the combined administration of venetoclax and 225Ac-HuM195. The number of cycles is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. A person of ordinary skill in the art would have arrived at 8 cycles through routine experimentation in order to provide optimal therapeutic treatments since NCT03867682 teaches that there is a potential for an additional 4 cycles.
. Claim(s) 1-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over NCT03867682 (ClinicalTrials.gov; published 8 Mar. 2019), in view of Cicic et al. (WO 2018/200841 A1; published 1 Nov. 2018), in further view of Hagemann et al. (Mol. Cancer Ther.; published 2016) for the reasons cited in the Office action filed on 17 Feb. 2026.
NCT03867682 teaches as discussed above.
NCT03867682 do not further teach additionally intravenously administering lintuzumab-Ac225 on day 18, 19, or 20 optionally day of each cycle at a dose from 0.05 µCi/kg to 1.0 µCi/kg
Cicic et al. teach as discussed above.
Hagemann et al. teach in vitro and in vivo efficacy of a novel CD33-targeted thorium-227 conjugate for the treatment of acute myeloid leukemia (see title). Hagemann et al. teach that CD33-TTC demonstrated antitumor activity in subcutaneous xenograft mouse model using HL-60 cells at a single dose regimen. Dose dependent significant survival benefit was further demonstrated in a disseminated mouse tumor model after administration as a fractionated dose (see abstract). At study day 5, animals received a single intravenous injection of CD33-TTC as at doses of 50, 150, or 300 kBq/kg. An additional treatment group received a second intravenous injection of CD33-TTC as a dose of 150 kBq/kg (day 19) (two week interim). Hagemann et al. teach that in animals receiving a fractionated dose of 2 × 150 kBq/kg of CD33-TTC at an interim of two weeks had similar MST as a single dose of 300 kBq/kg of CD33-TTC (see pg. 2426). Hagemann et al. teach Fig. 6A
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. Animals were administered twice with CD33-TTC at a dose of 150 kBq/kg on day 5 and day19 (indicated with dashed lines). Mean survival time was calculated to be 115.5 d (CD33-TTC, 150 kBq/kg) (pg. 2429).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify NCT03867682 so that the lintuzumab-Ac225 is additionally administered on day 18, 19, or 20, optionally day 19 of each cycle at a dose of 0.5 µg/kg as taught by NCT03867682, Cicic et al. and Hagemann et al. because the additional administration on one of those days would have been expected to enable a 2× fractional administration whereby reducing toxicity and optimizing survival times. The days of fractional administration and doses are a result effective variable that a person of ordinary skill in the art would have been motivate to optimize at the time of invention. A person of ordinary skill in the art would have arrived at days 5 and 19 through routine experimentation in order arrive an optimal resting period for each dose.
Applicants Arguments
Applicants assert that NCT03867682 administers the radioimmunoconjugate of day 1 not days 4, 5, or 6. The primary reference does not teach the claimed timing and on its face places the radioimmunoconjugate at a different point in the cycle. Cicic discloses days 4, 5, and 6 only as undifferentiated members of a twenty one day list. Days 4, 5, and 6 appear in that list beside the other eighteen days with nor data, no working example and no statement of preference setting them apart from day 1 or any other day. Cicic gives the skilled artisan no reason to select days 4-6 from its list. Cicic’s worked embodiments teach administration after the last venetoclax dose contrary to the Examiner’s rationale. The cited reason for administration on days 4-6 is not drawn from the references. Cicic points to the end of the venetoclax course, not to days 4-6 near its start. The rationale of selecting days4-6 so that the radioimmunoconjugate coincides with full-dose venetoclax is found nowhere in the art of record and is articulated for the first time in the rejection. That is hindsight. The finite number of identified, predictable solutions rationale does not apply because the result is not predictable. The pairing of an alpha-emitting radioimmunoconjugate with a BCL-2 inhibitor where efficacy turns on the temporal relationship between radiation inducted DNA damage and BCL-2 mediated control of apoptosis is not the small predictable solution set the KSR rationale addresses. Point to a list of twenty-one possible days, in combination the reference describes as unpredictable in humans is hope not a reasonable expectation that days 4-6 will succeed where the art teaches day 1. The specifications clinical data show that the claimed timing neither equivalent to nor predictable from day 1 administration. The specification reports a phase I clinical study that compares the two timings directly. In this case, the patient who received it on day 5 at the same dose achieved a complete remission with incomplete platelet recovery, with normocellular marrow and no increase in blasts. These results rebut the equivalence premise on which the rejection rests and confirms that the timing was not a predictable choice among interchangeable options. The claims define a specific, integrated regimen that no reference teaches. Applicants assert piecemeal reconstruction the obviousness inquiry is meant to prevent. The same reasoning applies for NCT03867682, in view of Cicic, in further view of Hagemann. Cicic’s fractionated regimens administer two doses “one week apart”. Hagemann uses a different radioisotope in a preclinical mouse model. The result effective variable fails because the art does not recognize the day of administration as result effective. Treating days as equivalent is the opposite of recognizing the day as a variable that drives the outcome.
Applicant's arguments filed 18 Jun. 2026 have been fully considered but they are not persuasive. NCT03867682 describes preliminary first stage phase I/II study of venetoclax and lintuzumab-Ac225 in patients refractory or relapsed AML. In this phase I/II study, human patients received venetoclax on days 1-21 of each cycle for up to 12 cycles. There was a ramp up of venetoclax dosing in the first cycle, with 100 mg administered on day 1, 200 mg on day 2, and 400 mg on day 3 and day 4 and later. Lintuzumab-Ac225 was administered on day 1 of each cycle for up to 4 cycles. Patients were enrolled into the following dose escalation cohorts: 0.5 µCi/kg. 1.0 µCi/kg, and 1.5Ci/kg. Eligible patients were required to have a circulating blast count < 200/µL within 10 days prior to first cycle. The instant claims differ from the instant claims mainly because NCT03867682 does not describe or suggest administering lintuzumab-Ac225 on day 4, 5, or 6 of each cycle. Cicic teaches that has significant myelosuppressive effect on neutrophils, with 40% of patient experiencing grade 3 and/or 4 neutropenia. In addition, person of ordinary skill in the art would have understood that venetoclax is given as a ramp up to allow the body to handle to tumor cell breakdown and metabolic changes. Cicic provides human dosing scenarios and Cicic teaches that lintuzumab-Ac225 may just as well be administered on days 4-6 of treatment cycle. Nothing in Cicic teaches that lintuzumab-Ac225 should be administered only on day 1 or at the end of a treatment cycle. NCT03867682 suggests a preference for administering venetoclax at the beginning of the treatment cycle. Regarding Applicants arguments a provided reason for administering lintuzumab-Ac225 on days 4-6 of a treatment cycle is not supported in the references themselves, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, a person of ordinary skill in the art would have understood that the NCT03867682 phase I/II study can be improved upon because that study administered lintuzumab-Ac225, itself a myelosuppressive agent, at same time as the initial dose of venetoclax having known to have significant myelosuppressive effects whereby inhibiting recovery from tumor cell lysis metabolic change over a significant period of time. Since Cicic teaches that lintuzumab-Ac225 may just as well be administered on days 4-6 of the treatment cycle after an expected adjustment of the venetoclax dosing, a person of ordinary skill in the art would have immediately recognized that an obvious improvement to NCT03867682 would be to administer lintuzumab-Ac225 immediately following ramp up after an adjustment to tumor cell breakdown and metabolic changes. A recognized advantage is the strongest reason to combine. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify NCT03867682 on days 4-6 of each cycle at a dose from 0.1 µCi/kg to 2.0 µCi/kg as taught by Cicic and general knowledge because the administration of lintuzumab-Ac225 on days 4-6 would have expected to provide an improved therapeutic outcome by allowing the patient’s body to adjust and recover from venetoclax administration prior to administration of lintuzumab-Ac225, a radiotherapeutic and myelosuppressive agent expected to have prolonged residence in the patient. Instant example 17 describes the results obtained for only 3 patients possibly selected out of a group of results to support superiority of otherwise comparable regiments wherein patients 2 and 3 exhibited different molecular analysis. It is not clear if the results obtained in example 17 would allow for a superior treatment of any human subject afflicted with AML. In addition, instant example 17 describes expected beneficial results as described above, which are evidence of obviousness.
Regarding claims 8-14, at for example pg. 13, Cicic teaches and motivates fractional dosing regimens where the administration of lintuzumab-Ac225 includes the following without limitation: (i) 2×<0.5 µCi/kg, 2×0.5 µCi/kg, and 2× 1.0 µCi/kg. The dosing method does not cause unacceptable levels of neutropenia. At Fig. 6, Cicic teaches fractional dosing regimen wherein dose 1 gets administered on D-14-17 and dose 2 gets administered on D-18-24. Hagemann teaches and motivates the treatment of AML using lintuzumab-Th227 wherein patients get treated using a fractional dosing regimen that includes administration of lintuzumab-Th227 on days 5 and 19 of the dosing cycle. In this case, the fractional dosing regimen provided an optimal duration of survival in comparison to a single administration of lintuzumab-Th227. Hagemann teaches and motivates in vivo biodistribution experiments of lintuzumab-Th227 and Hagemann teaches and motivates evaluating clinical blood chemistry. As discussed above a person of ordinary skill in the art would have had adequate reasonable and motivation to administer lintuzumab-Ac225 on days 4-6 of a 28 day dosing cycle that combines administration with venetoclax. Using in vivo biodistribution results and blood chemistry from human patients, a person of ordinary skill in the art would have reason and motivation to administer a second dose of lintuzumab-Ac225 on days 18-20 of a dosing cycle in to provide an optimal median duration of survival by allowing the patient’s body to adjust and recover from the first dose of lintuzumab-Ac225.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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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/SEAN R. DONOHUE/
Examiner, Art Unit 1618
/Robert A Wax/
Supervisory Patent Examiner, Art Unit 1615
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