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 .
Election/Restrictions
Applicant’s election without traverse of Group I and species which is acute myeloid leukemia as myeloid malignancy and azacitinde as hypermethylating agent in the reply filed on 01/05/2026 is acknowledged.
Alternative Names
According to the specification on p. 26, lines 20-22, AML, acute myeloid leukemia, is also called acute myelocytic leukemia, acute myelogenous leukemia, acute granulocytic leukemia, and acute non-lymphocytic leukemia. Also (paragraph bridging pp. 26-27), monocytic AML is also called acute monocytic leukemia, AMoL, AML-M5 and monoblastic AML (having >20% blasts in bone marrow and >80% of those must be of the monocytic lineage).
Antibody cusatuzumab is also known as ARGX-110 and JNJ-74494550 (p. 17, line 8, and Clinicaltrials.gov ID NCT04150887, infra).
BCL-2 inhibitor venetoclax is also known as Venclexta®, ABT-199 and GDC-0199 (p. 21, line 7 and 11).
Information Disclosure Statement
References G and H of the information disclosure statement filed 01/05/2026 fail to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because they do not list the date of publication as required by 37 CDR 1.98 (see MPEP 609.01(B)(1)(e)(v). Without this it is impossible to know which version of the documents are being cited. These references have been lined through. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: METHOD OF TREATMENT OF PATIENTS HAVING REDUCED SENSITIVITY TO A BCL-2 INHIBITOR WITH A CD70 ANTIBODY
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see p. 16, lines 24 and 26). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 1 is objected to because of the following informalities: The first occurrence of an abbreviation should be accompanied by its full name. In this case, “BCL-2” should include the name “B-cell lymphoma 2” as set forth in the specification on p. 15, lines 19-20.
Appropriate correction is required.
Drawings
Figures 1A, 1B, 1C, 1D, 2A, 2B, 2C, 3A and 3B should be designated by a legend such as --Prior Art-- because only that which is old is illustrated. See MPEP § 608.02(g). Corrected drawings in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. The replacement sheet(s) should be labeled “Replacement Sheet” in the page header (as per 37 CFR 1.84(c)) so as not to obstruct any portion of the drawing figures. If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Even though these figures are black and white, that is the only difference from the figures of Pei et al. (2020). As a result, in this application the figures must identify themselves as prior art, regardless of related indication in the Brief Description of the Drawings.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 51-58 and 61-66 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are drawn to treatment of myeloid malignancy by administering an effective amount of an antibody or antigen-binding fragment thereof that binds CD70. The specification teaches that anti-CD70 antibody cusatuzumab is effective to kill malignant myeloid cells resistant to BCL-2 inhibitor treatment. This is an afucosylated IgG antibody with ADCC, CDC and ADCP effector function (p. 17, lines 8-21). Example 9 shows that in vitro when venetoclax (VEN) and azacitidine (AZA) resistant CD70 positive monocytic AML cells were treated with cusatuzumab, the monocytic cells “were significantly targeted by causatumumab-mediated NK cell-dependent ADCC (Fig. 7B and 7C, respectively). Blocking anti-CD70 41D12 FcDead antibody with reduced effector functions was used as a negative control with no significant anti-specific effect in targeting CD70 positive monocytic cells was detected for the blocking antibody (Fig. 7B and 7C). This supports the specificity of cusatuzumab-mediated effects in targeting of CD70-positive VEN+AZA resistant monocytic AML cells.” This is supported by Example 11 showing in xenograft mouse models with patient-derived samples of bone marrow from VEN+AZA resistant monocytic AML, only those treated with cusatuzumab and NK cells from PBMCs of a healthy donor showed a significant reduction in presence of malignant cells. “Therefore, cusatuzumab is effective in depleting VEN+AZA resistant CD70 positive monocytic AML cells via NK-dependent ADCC in vivo in NSGS mice.” (p. 72, end of first paragraph) It does not reasonably appear the inventors were in possession of the method of treatment with an anti-CD70 antibody other than cusatuzumab. It is noted that ADCC activity is dependent on an antibody Fc domain.
It is stated in AbbVie Deustschland GmbH v. Janssen Biotechnology, Ltd., 111 USPQ 1780, 1789 (759 F.3d 1285, 1298), (Fed. Cir. 2014) discussing Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005) that, “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed results and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Again in AbbVie at 1788, reiterating Enzo Biochem., Inc., 323 F.3d at 964, “It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date…” However, for the instant claims which require treatment in a human subject resistant to BCL-2 inhibitor treatment, there is no genus of antibodies disclosed either in the specification or the prior art. Therefore, there is no reasonable structure-function correlation established for an antibody with the necessary functional characteristics other than cusatuzumab.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description' inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
With the exception of cusatuzumab, the skilled artisan cannot envision the detailed chemical structure of the encompassed antibody or antigen binding fragment thereof that binds CD70, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Therefore, only the CD70 antibody cusatuzumab, but not the full breadth of the claim meets the written description provision of 35 U.S.C. § 112(a). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
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 § 102/103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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) 51-53, 56, 59-62 and 67-68 is/are rejected under 35 U.S.C. 102(a)(2) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over US Patent 11,712,468 B2 (De Haard).
De Haard teaches treatment of acute myeloid leukemia (AML) by administration of anti-CD70 antibody cusatuzumab, having the variable heavy and light chain antibody regions respectively of SEQ ID NO:7 and 8, with BCL-2 inhibitor venetoclax (claim 1 and 36). Claim 10 includes the addition of azacidine. Claim 13 indicates the combination of the anti-CD70 antibody and venetoclax are synergistic under certain administration conditions. Claim 30 limits the myeloid malignancy to one that is relapsed/refractory. While the claims do not refer to the myeloid malignancy being refractory to venetoclax, it is stated in col. 31, lines 14-25, “The BCL-2 antagonist, venetoclax, targets and eliminates leukemic stem cells (LSCs) by suppression of oxidative phosphorylation and demonstrated very promising activity in older AML patients in clinical phase I and II studies in combination with standard of care (Pollyea et al., Nature Medicine (2018) 24; 1859-1866). However, even with novel agents such as venetoclax, there are still patients that become refractory or relapse. It was hypothesized that combining venetoclax and cusatuzumab with distinct but complementary mechanisms of action could successfully eliminate LSCs.” De Haard to not directly teach that the patient treated with cusatuzumab and venetoclax was resistant to venetoclax or another BCL-2 inhibitor, although it appears to be implied.
Alternatively, it would have been obvious to have treated a patient who had previously been treated with venetoclax, which targets LSCs in AML but who became resistant to venetoclax due to remaining LSCs, with a combination of anti-CD70 antibody cusatuzumab and venetoclax because De Haard showed that the combination synergistically eliminated AML cells in vitro in a CD70-expressing AML cell line (col. 32, 55-60) and primary human AML LSC (col. 33, lines 19-55, and Figs. 6A-B and 7A-B). Additionally, it was shown that venetoclax increased CD70 expression on primary human AML LCSs, thereby presumably making them more susceptible to elimination by cusatuzumab (col. 33, lines 63-67, and col. 34, lines 13-18). Cusatuzumab (ARGX-110) had been demonstrated to deplete CD70-expressing tumor cells by antibody-dependent cell cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), and to increase antibody-dependent cellular phagocytosis (ADCP) of CD70-expressing cells (col. 15, lines 9-30). Therefore, there would have been a reasonable expectation of treatment as in claim 1, wherein said patient was resistant to BCL-2 inhibitor venetoclax, due to remaining LCSs because venetoclax was shown to increase CD70 expression on LCSs from AML patients, which would have reasonably been expected to make the malignant stem cells more susceptible to anti-CD70 antibody-induced cell death, such as ADCC. It reasonably appears that the CD70 expression level would have been upregulated with the combination of cusatuzumab+venetoclax compared to before the combination treatment.
The applied reference has a common a common inventor and applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Claim Rejections - 35 USC § 103
Claim(s) 51-68 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0106498 A1 (‘498, cited in the IDS filed 8/9/2024), Riether et al. J. Exp. Med. 214(2):359-380, 2017), and Pei et al. (Canc. Discov. 10:536-551, Apr. 2020, cited in the IDS filed 8/9/2024) in view of Clinicaltrials.gov ID NCT04150887, version 1, (https://clinicaltrials.gov/study/NCT04150887?term=
Nct04150887%20OR%20nct04023526%20OR%20NCT03030612&viewType=Table&rank=1&tab=history&a=1#version-content-panel, 11/01/2019) and as evidenced by the instant application in Table 1.
‘498 teaches treatment of a patient with AML with a combination of anti-CD70 antibody cusatuzumab and nucleoside metabolic inhibitor (NMI) hypomethylating agent (HMA) azacitidine (aza, [0030],[0032]). It was found that 10/11 patients responded to anti-CD70 treatment ([0223] and Table 4). Further, as proclaimed in [0225], “A response level of greater than 90% is in stark contrast to the response rate of approximately 25% seen with aza alone (Dombret et al., Blood 2015 (Blood. 2015; 126(3):291-299, incorporated herein by reference).” In culture it was shown that lymphocyte stem cell (LSC) number as well as proliferative potential was reduced by treatment with the anti-CD70 antibody and further reduced when aza was included in the treatment ([0245]-[0248]). HMA treatment induced CD70 expression in primary AML stem/progenitor cells ([0057]), It is explained that, “The persistence of leukemic stem cells (LSCs) in AML represents a significant hurdle for the successful treatment of AML patients. LSCs are responsible for disease relapse in AML, and their number is maintained through a process of symmetric cell division—that is, each LSC divides symmetrically to generate two daughter LSCs. Such symmetric division is a driving factor in AML aggressiveness and patient relapse.” Further, expression level of CD117 and CD11b was assessed ([0221]). ‘498 does not teach wherein the patient being treated is resistant to BCL-2 inhibitor treatment or expression levels of proteins related to AML cells.
Reither et al. teach that (paragraph bridging pp. 359-360), “AML is hierarchically organized and maintained by self-renewing leukemia stem cells (LSCs) that sustain a pool of disease-inducing cells… [H]igh LSC numbers as well as stem cell gene signatures in blasts are negative predictors for survival…. Therefore, targeting signals that induce LSC expansion, either by blocking proliferation or by forcing differentiation via asymmetric cell division may lead to resolution of the disease (Horton and Huntly, 2012; Bajaj et al. 2015).” The ligand for receptor CD27 is CD70, both of which were found to be coexpressed on AML blasts and AML stem/progenitor cells. (p. 360) “CD70/CD27 signaling in AML cells induces stem cell gene signature pathways and promotes an undifferentiated and malignant state by increasing symmetric cell divisions. Blocking CD70/CD27 signaling promoted asymmetric cell divisions and differentiation of AML blasts, decreased growth and colony formation, and induced differentiation of AML stem/progenitor cells in vitro. In contrast, HSPCs from healthy BM donors were not affected by this treatment. Blocking CD70/CD27 signaling by mAb [monoclonal antibody] in murine AML xenografts delayed disease progression, reduced the number of AML stem/progenitor cells and prolonged survival.” (paragraph bridging pp. 360 and 362) It is noted that blocking CD70/CD27 signaling increased intracellular Numb and cell surface CD11b protein, which indicates cell differentiation (p. 368, end of first paragraph). It is concluded that (p. 374, col. 1, end of second paragraph), “Importantly, the CD70/CD27 interaction can be blocked using mAb, leading to prolonged survival in primary and secondary xenotransplantation models. Because αCD70 treatment is specific for malignant cells and does not affect healthy HSPCs, blocking the CD70/CD27 interaction may represent a promising therapeutic strategy for AML.”
Pei et al. teaches (p. 537, col. 1) that one treatment for AML has been administration of HMAs, but these have limited effectiveness, especially on overall survival (OS). BCL-2 inhibitor venetoclax (VEN) added to HMA (e.g., azacidine, AZA) has shown greatly increased response rates in untreated patients who cannot have conventional chemotherapy and has been approved by the FDA for this indication. “However, a significant minority of patients do not achieve a remission and are refractory. In addition, the majority of patients who do achieve a remission ultimately relapse (6, 7).” (p. 537, col. 2, first paragraph). It was found that 62% of patients with FAB-M5 (most advanced) AML were refractory to VEN+AZA, while no FAB-M4 were and only 8% of non-FAB-M5 were (Suppl Fig. S1B, and p. 538, end of col. 1) It had previously been shown that FAB-M5 subtype patients lose expression of CD117, a primitive cell marker, and upregulate expression of monocytic markers CD11b, CD68 and CD64 (p. 538, col. 2, first paragraph). It was found that monocytic AML cells and cells from FAB-M5 AML patients relative to FAB-M0/M1/M2 lose expression of BCL-2, the target of VEN (p. 539, col. 2, first paragraph). The level of expression of BCL-2 is opposite that of MCL1, which was shown in vitro and in vivo to indicate that monocytic AML cells rely more on MCL1 than BCL-2 for energy production, stem/progenitor potential, and survival (p. 545, col. 1 and first two paragraphs of col. 2).
NCT04150887 teaches treatment of patients with AML by administration of cusatuzumab (JNJ-74484550) in combination with other therapies (Brief Title). In the Arms, there are 3 cohorts described: 1) cusatuzmab + azacitidine, 2) cusatuzmab + ventoclax, and 3) cusatuzumab + azacitidine + venetoclax.
Table 1 of the application shows the sequence of cusatuzumab, having the heavy chain CDRs of SEQ ID NO:1-3, light chain CDRs of SEQ ID NO:4-6, variable heavy and light chain region respectively of SEQ ID NO:7 and 8.
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant application to have treated a patient with venetoclax-resistant AML with anti-CD70 antibody cusatuzumab because ‘498 showed that LSC numbers as well as proliferative potential was reduced by treatment with the anti-CD70 antibody and further reduced with azacidine. Also, clinical trial NCT04150887 teaches treatment of AML patients by administration with cusatuzumab, with AZA and/or VEN. Because Pei et al. discuss that more advanced AML and resistant AML corresponds with loss of BCL-2 expression. Also, AZA treatment leads to increased CD70 expression in AML stem/progenitor cells (‘498). These findings suggest first, treatment of advanced and/or VEN-resistant AML patients with the anti-CD70 antibody cusatuzumab, which also reduces the number and proliferation of AML LSCs. Second, treatment with also a HMA such as aza, which was shown to augment cusatuzumab activity on LSCs (‘498). Third, to add/increase treatment with a BCL-2 inhibitor, e.g., venetoclax, that targets AML cells still expressing BCL-2 or more differentiated AML cells expressing BCL-2 that result from cusatuzumab treatment. One of ordinary skill in the art would have reasonably expected the AML cell to express BCL-2, CD117, CD11b, CD68, CD64 and MCL1 as discussed by the prior art. Pei et al. showed that BCL-2 is downregulated with venetoclax treatment and also in advanced FAB-M5 AML along with CD117, a primitive cell marker, and concomitant upregulated expression of monocytic markers CD11b, CD68 and CD64.
Table 1 of the instant application is not necessary for obviousness, but cited only to show the sequence of anti-CD70 antibody cusatuzumab is the same as recited in instant claims 59 and 67.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 51-68 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 and 21-23 and 30-36 of U.S. Patent No. 11,712,468 B2 (‘468) in view of Pei et al. (Canc. Discov. 10:536-551, Apr. 2020, cited in the IDS filed 8/9/2024).
Both the instant application (claim 51 and 61) and patent (claim 1) claim a method of treating a malignancy in a human by administering the same anti-CD70 antibody (variable heavy chain region (VH) and variable light chain region (VL) of SEQ ID NO:4 and 8 of the patent which are identical respectively to SEQ ID NO:7 and 8 of the instant application). The patent claim 1 further requires treatment of venetoclax, which is a BCL-2 inhibitor, and coincides with instant claims 58 and 66. The treatment is of AML (claim 1 of patent and instant claim 53 and 62). The patent does not claim wherein the subject is resistant to BCL-2 inhibitor treatment or expression markers, although it does claim in 30 that the subject has a relapsed/refractory myeloid malignancy.
Pei et al. teaches (p. 537, col. 1) that one treatment for AML has been administration of HMAs, but these have limited effectiveness, especially on overall survival (OS). BCL-2 inhibitor venetoclax (VEN) added to HMA (e.g., azacidine, AZA) has shown greatly increased response rates in untreated patients who cannot have conventional chemotherapy and has been approved by the FDA for this indication. “However, a significant minority of patients do not achieve a remission and are refractory. In addition, the majority of patients who do achieve a remission ultimately relapse (6, 7).” (p. 537, col. 2, first paragraph). It was found that 62% of patients with FAB-M5 (most advanced) AML were refractory to VEN+AZA, while no FAB-M4 were and only 8% of non-FAB-M5 were (Suppl Fig. S1B, and p. 538, end of col. 1) It had previously been shown that FAB-M5 subtype patients lose expression of CD117, a primitive cell marker, and upregulate expression of monocytic markers CD11b, CD68 and CD64 (p. 538, col. 2, first paragraph). It was found that monocytic AML cells and cells from FAB-M5 AML patients relative to FAB-M0/M1/M2 lose expression of BCL-2, the target of VEN (p. 539, col. 2, first paragraph). The level of expression of BCL-2 is opposite that of MCL1, which was shown in vitro and in vivo to indicate that monocytic AML cells rely more on MCL1 than BCL-2 for energy production, stem/progenitor potential, and survival (p. 545, col. 1 and first two paragraphs of col. 2).
It would have been obvious to treat advanced and/or VEN-resistant AML patients with anti-CD70 antibody cusatuzumab, which also reduces the number and proliferation of AML LSCs. Pei et al. discuss that more advanced AML and resistant AML corresponds with loss of BCL-2 expression and patients can become resistant to venetoclax. It would have been reasonably expected that the AML cells had upregulated CD11B, CD68, CD64 and MCL1 and downregulated CD117 and BCL-2 according to Pei et al.
Claims 51-68 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-7, 10-11 and 14-17 of copending Application No. 19/134,675 (‘675, reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both applications claim a method of treating AML by administration of anti-CD70 antibody cusatuzumab (instant claims 51, 56, 59-61, 67-68 and claims 1-4 and 7). The instant claims further require the patient to be resistant to BCL-2 inhibitor treatment, and claims 14-15 of ‘675 specify the subject has previously received at least one AML treatment which is at least one BCL-2 inhibitor and one HMA, with claim 17 specifying the subject is refractory to treatment with the combination and or will suffer a relapse after treatment with the BCL-2 inhibitor + HMA. Further, claims 1-4 of ‘675 require expression of at least one of CD34, CD4, CD11b, CD14 and CD36, wherein a monocytic LSC is CD11b-, CD64+, CD70+, CD117- (see instant claims 54-55 and 63-64).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
WO2018229303 (cited in the IDS filed 8/9/2024) discloses the use of the anti CD70 mAb cusatuzumab for treating AML or MDS, alone or in combination with azacitidine, a hypomethylating agent (Examples 1-3, claims 1-52). Its combined use with a BCL-2 inhibitor is also disclosed (claim 22, page 5, line 12 and page 26, line 25). The reference does not disclose VEN as an inhibitor or resistance thereto.
US Patent 11,820,827 B2 teaches in claim 1 a method of treating a CD70-expressing cancer which may be acute myeloid leukemia (AML) by administration of a nonfucosylated anti-CD70 antibody. Claim 13 specifies the AML is relapsed or refractory. Claim 19 includes administration of azacitidine, while claim 20 includes administration of venetoclax and claim 21 includes both azacitidine and venetoclax. It does not teach where the resistance is to BCL-2 inhibitor treatment. However, it is cumulative with references relied upon above for teaching treatment of AML with an anti-CD70 antibody and its combination with aza and ven.
Campos et al. (Blood, 81(11):3091-3096, June 1, 1993) teaches that high expression of BCL-2 in AML cells is associated with poor response to chemotherapy. Using an anti-BCL-2 antibody to stain cells of patients with AML, it was found that 34% of 82 samples showed at least 20% stained cells, and expression was significantly higher in monoblastic (FAB M4 and M5) subtypes (p. 3093, col.1, first col.). The mean percentage of bcl-2-expressing cells was 11.1% in the samples from patients in whom remission was obtained versus 45.6% when remission was not obtained (P < 10-5) The CR rate decreased as the percentage of bcl-2+ cells increased, as is shown in Table 2, and none of the 16 patients whose percentage of bcl-2-expressing cells exceeded 60% went into remission…. The main cause for not achieving remission was resistant disease….” (p. 3094, col. 1, second paragraph) Further (p. 3093, col. 2, last paragraph), “The survival of blast cells in liquid culture was significantly correlated with the percentage of bcl-2+ cells (Table 2).” This reference is cited to show the state of the art three decades ago and basis for initial treatment of AML with a BCL-2 inhibitor.
Pollyea et al. (Nature Med. 24(12):1859-1866,12 November 2018, cited in the IDS filed 8/9/2024) discloses the beneficial effect of using venetoclax with azicitidine for treating AML and the breakthrough that such a use could represent in the treatment of elderly patients having AML This reference is cumulative with others cited above for the combined treatment.
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
April 13, 2026
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