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 . 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.
Priority
The instant application is a 371 of PCT/US2021/034773 filed on 05/28/2021, which claims domestic benefit to US provisional application no. 63/198,864 filed on 11/18/2020, US provisional application no. 63/063,892 filed on 08/10/2020, US provisional application no. 63/060,595 filed on 08/03/2020, and US provisional application no. 63/032,675 filed on 05/31/2020.
Status of the Claims
The claim amendments and remarks filed on 11/25/2025 is acknowledged. Claim 1, 27, and 39 are amended. Claims 2-3, 20-22, and 26 are cancelled.
Accordingly, claims 1, 4-19, 23-25, and 27-39 are pending and being examined on the merits herein.
Withdrawn Objections/Rejections
The objection to claim 39 is withdrawn in view of claim 39 now reciting “at least one FLT3 inhibitor”.
The 35 USC 102 rejection over Peled for claims 1, 4-5, 7, 9, 11-14, 16-19, 21, 32-33, and 35 is withdrawn because CXCR4 inhibitors, which was previously relied upon in the rejection, has been removed from instant claim 1 and changed to requiring at least one E-selectin inhibitor.
The 35 USC 103 rejection over Peled for claims 1, 4, 6, 15, and 14, over Peled in view of Singh for claim 8, over Peled in view of Dai for claim 19, over Peled in view of Magnani for claims 20 and 22-27, and over Peled in view of Magnani and Papadopoulos for claims 10, 28-31, and 36-39 are withdrawn in view of claim 1 now reciting administering “at least one E-selectin inhibitor”, which has changed the scope of the claims.
The nonstatutory double patenting rejections over ‘884, ‘614, ‘598, ‘399, ‘086, ‘910, and ‘474 are withdrawn in view of ‘399 being abandoned and claim 1 now reciting administering “at least one E-selectin inhibitor”, which has changed the scope of the claims.
The following grounds of rejection are new as necessitated by Applicant’s amendments.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claim(s) 1, 4-5, 7, 9, 11-14, 16-18, 23, and 33-34 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Blood, 2015 in IDS filed 09/05/2023).
Zhang discloses that the dual E-selectin / CXCR4 inhibitor, GMI-1359, enhances efficacy of anti-leukemia chemotherapy in FLT3-ITD mutated acute myeloid leukemia (AML) (see Abstract).
Zhang discloses that aberrant activation of the FMS-like tyrosine kinase-3 (FLT3) is driven by internal tandem duplication (ITD) mutations in the FLT3 gene, which are commonly observed in patients with acute myeloid leukemia (AML) (first paragraph in Abstract). Hence, Zhang discloses that FLT3 represents an attractive therapeutic target in AML, and that several small molecule FLT3 inhibitors including sorafenib have showed encouraging efficacy in reducing leukemia blasts in the peripheral blood in FLT3 mutated AML patients (first paragraph in Abstract). However, these agents have little effect on leukemic stem cells in the bone marrow (BM) microenvironment (first paragraph in Abstract).
Zhang discloses that the BM microenvironment is enriched with cytokines and adhesion molecules, such as CXCR4 and E-selectin, which are believed to provide AML cells protection against chemotherapeutic agents, and further discloses that treatment with sorafenib markedly upregulated CXCR4 levels in FLT3-mutated cells (second paragraph in Abstract). Zhang discloses that leukemia cells can activate endothelial cells (EC) that induce adhesion of a sub-set of the leukemia cells through E-selectin (second paragraph Abstract). Therefore, Zhang discloses that blocking CXCR4 and E-selectin in parallel could theoretically eliminate the protection provided by interaction of leukemic cells with their BM microenvironment and enhance effectiveness of chemotherapy in FLT3-mutant AML patients (second paragraph Abstract).
Zhang discloses the effectiveness of a dual CXCR4 and E-selectin antagonist, GMI-1359, in targeting FLT3-ITD mutant AML in vitro and in vivo (second paragraph Abstract).
Zhang discloses that GMI-1359 markedly abrogated the protection provided by the BM microenvironment (i.e., hypoxia and/or MSC and EC) of Baf3-FLT3 -ITD leukemic cells treated with the FLT3 inhibitor sorafenib. Zhang discloses that apoptosis was induced in 48.9% of leukemic cells cultured with GMI-1359 and sorafenib compared to 36.6% apoptosis when treated with sorafenib alone. (second paragraph Abstract).
Zhang further demonstrates in an in vivo mice study that 40 mg/kg of GMI-1359 in combination of a standard chemotherapy (cytarabine plus daunorubicin) had a profound survival benefit compared to controls or standard chemotherapy alone at day 135 after leukemia cell injection (third paragraph Abstract and Fig. 1 on page 3). Zhang shows that 67% of mice survived from combination therapy compared to 11% or 30% survival rate in controls and chemotherapy alone, respectively (third paragraph Abstract). Zhang discloses that these findings were consistent with GMI-1359 disrupting the protective effects of tumor microenvironment and mobilizing MV4-11 cells from the BM niche, and their findings provide the pre-clinical basis for evaluation of GMI-1359 in patients with FLT-3 mutant AML (third paragraph Abstract).
Even though Zhang only demonstrates the combination of a FLT-3 inhibitor (sorafenib) and a E-selectin / CXCR4 inhibitor (GMI-1359) in vitro, it would have been prima facie obvious before the effective filing date of the claimed invention to have treated a human patient with FLT-3-ITD AML by administering a combination of standard chemotherapy, FLT3 inhibitor sorafenib, and E-selectin / CXCR4 inhibitor GMI-1359 as disclosed in Zhang to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to make this modification because Zhang demonstrates that the combination of sorafenib and GMI-1359 markedly abrogated the protection provided by the BM microenvironment (i.e., hypoxia and/or MSC and EC) of Baf3-FLT3 -ITD leukemic cells, and further shows a significant increase in apoptosis with the combination in comparison to sorafenib administered alone. One of ordinary skill in the art would have a reasonable expectation of success because Zhang demonstrates that the combination of standard chemotherapy with GMI-1359 was also effective in treating FLT-3 mutant AML in a mouse study.
Claim(s) 6, 15, 32, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Blood, 2015 in IDS filed 09/05/2023), as applied to claim 1 above, and further in view of Peled et al. (WO2015063768A1 in IDS filed on 09/05/2023) and as evidenced by Cortes et al. (Lancet Oncol., 2018 in PTO-892 dated 06/27/25).
The teachings of Zhang are as described above and teach the method of claim 1 as discussed above.
Zhang, however, does not teach a relapsed AML patient as well as administering a FLT inhibitor that is quizartinib or a first-generation multi-kinase inhibitor or next generation inhibitor.
Peled et al. discloses methods of treating acute myeloid leukemia (AML) (see Abstract).
Peled et al. discloses that while many patients with AML are able to achieve a complete remission (CR) with traditional chemotherapy, the majority of AML patients eventually relapse. Peled et al. discloses that rates of relapse are particularly high for patients with a FLT3 (FMS-like tyrosine kinase 3) internal tandem duplication (ITD) mutation (see page 1 lines 9-19).
Peled et al. discloses a method of treating a patient with AML with a FMS-like tyrosine kinase 3 (FLT3)-mutation by administering a therapeutically effective amount of a CXCR4 antagonistic peptide (claim 1) as well as further administering the chemotherapeutic agent quizartinib (claim 14). Here, quizartinib meets the limitation of a next generation FLT3 inhibitor as evidenced by Cortes et al. (see Abstract in Cortes et al.) Peled discloses that the FMS-like tyrosine kinase 3 (FLT3) mutation is a FLT3 internal tandem duplication (ITD) mutation (claim 7). Peled et al. discloses that the FLT3 mutation results in activation of the protein, and in other embodiments, the FLT3 mutation is a missense mutation at aspartic acid residue 835 (D835) (see page 7 lines 29-30 and page 8 lines 1-2). Peled et al. discloses that the term “subject” includes mammals, preferably human beings at any age which suffer from the pathology (see page 13, lines 27-28). Peled et al. discloses that their CXCR4 antagonistic peptide can be administered to the subject either alone or in combination with one or more chemotherapeutic agents (see page 13, lines 29-30). Peled et al. discloses that the chemotherapeutic agent can be cytarabine, quizartinib, sorafenib, … 6-thioguanine, or any combination thereof (see page 14, lines 13-24). Peled et al. discloses that their CXCR4 inhibitor can be co-formulated with a chemotherapy such as cytarabine, which meets the limitations of a subject who will receive chemotherapy (see page 18 lines 12-14).
Peled et al. demonstrates that quizartinib (AC220) had a synergistic effect with the CXCR4 antagonistic peptide, in which the combination increased the apoptotic death of human FLT3-ITD AML cells as well in an in vivo AML mice model where the mice were administered 10 mg/kg quizartinib daily for seven days (see page 24, lines 5-16 and page 25, lines 1-30).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the treatment of Zhang described above by treating a patient with relapsed AML as disclosed in Peled and further substituting the sorafenib of Zhang with the 10 mg/kg per day quizartinib of Peled to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to treat a relapsed AML patient because Zhang discloses that the rates of relapse are particularly high for FLT3-ITD mutated AML patients. One of ordinary skill in the art would have a reasonable expectation of success both Zhang and Peled demonstrate that FTL3 inhibitors are enhanced when combined with CXCR4 inhibitors in treating FLT3-ITD AML. Furthermore, one of ordinary skill in the art would have made the substitution of sorafenib to quizartinib with a reasonable expectation of success because Zhang and Peled demonstrate that both of these FLT3 inhibitors are enhanced when combined with a CXCR4 / E-selectin or CXCR4 inhibitor to treat FLT3-ITD AML.
Claim(s) 8 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Blood, 2015 in IDS filed 09/05/2023), as applied to claim 1 above, and further in view of Singh et al. (Apoptosis, 2011 in PTO-892 dated 06/27/2025).
Zhang teaches the method of claim 1 as discussed above.
Zhang, however, does not disclose a subject who is receiving, has received, or will receive one of the listed compound types recited in instant claim 8.
Singh et al. discloses that NSAIDs have proven to possess significant anti-proliferative potential in various cancer cells in vitro and in vivo (see Abstract). Singh et al. demonstrate that NSAIDs induce apoptosis in AML through a novel pathway involving increased expression of AP-1 heterodimers, which by itself is sufficient to induce GADD45a expression with consecutive activation of JNK and induction of apoptosis (see Abstract and Fig. 1 on page 893). Singh et al. discloses that NSAIDs may be suitable to improve anti-proliferative treatment modalities for patients with AML (see right column page 899).
It would have been prima facie obvious before the effective filing date of the claimed invention to have further treated the patient disclosed in Zhang described above with NSAIDs as disclosed in Singh et al. to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Singh et al. provides guidance that NSAIDs are suitable for improving anti-proliferative treatment modalities for patients with AML.
Claim(s) 10 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Blood, 2015 in IDS filed 09/05/2023), as applied to claim 1 above, and further in view of Papadopoulos et al. (BMC Cancer, 2018 in PTO-892 dated 06/27/2025) and Magnani et al. (WO2018031445A1 in IDS filed on 09/05/2023).
Zhang teaches the method of claim 1 as discussed above.
Zhang, however, does not disclose wherein the cancer is a solid cancer.
Papadopoulos et al. discloses the use of quizartinib in solid tumors (see Abstract). Papadopoulos et al. discloses that oral administration of quizartinib as a monotherapy stabilized several types of solid tumors such as gastrointestinal (GI) stromal tumors, colorectal, sarcoma, and thyroid (see “Efficacy and PK/KD results” section on pages 4-5 and Fig.1 on page 5).
Magnani et al. discloses compositions and methods for the treatment of diseases, disorders, and/or conditions associated with the increased regulatory T lymphocyte cell (Treg cell) function, comprising the administration of T-cell checkpoint inhibitors in combination with E-selectin inhibitors, CXCR4 receptor inhibitors, and/or heterobifunctional inhibitors that comprise at least one E-selectin inhibitor linked to at least one CXCR4 receptor inhibitor (see Abstract).
Magnani et al. discloses that Treg cells down-regulate other immune cells, thereby playing an important role in, for example, preventing autoimmunity (see paragraph 004). Magnani et al. discloses that Treg cells respond to homing signals within the inflamed tumor microenvironment that include the endothelial cell surface protein, E-selection, and the CXCR4 ligand, SDF-1 (see paragraph 004). Magnani et al. discloses that by using these pathways, the cancer cells use Treg cells to prevent other immune cells from attacking the cancer, and thus, although the immune system is often able to produce a response against the malignancy, due at least in part to the influence of T cells, this response is often insufficient to eliminate the tumor (see paragraph 004). Magnani et al. discloses that the disease, disorder, and/or condition for treatment can be chosen from liquid cancers such as AML and solid cancers such as prostate cancer (see paragraph 075). Magnani discloses that the subject has received or will receive chemotherapy and discloses chemotherapy treatments such as doxorubicin and among others (paragraph 077-078).
It would have been prima facie obvious before the effective filing date of the claimed invention to modify the treatment method of Zhang as described above by treating a patient with a solid cancer as disclosed in Papadopoulos and Magnani. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Papadopoulos et al. discloses that FLT3 inhibitors such as quizartinib also have therapeutic effects on solid cancers, and Magnani et al. discloses that E-selection and/or CXCR4-inhibitors combined with T cell checkpoint inhibitors and chemotherapy can be used for solid cancers.
Claim(s) 19 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Blood, 2015 in IDS filed 09/05/2023), as applied to claim 1 above, and further in view of Dai et al. (Cancer Gene Therapy, 2019 in PTO-892 dated 06/27/2025).
Zhang teaches the method of claim 1 as discussed above.
Zhang, however, does not disclose wherein the blast cells in the subject have an increased gene expression level of FUT7.
Dai et al. discloses that genetic abnormalities are more frequently viewed as prognostic markers in acute myeloid leukemia (AML) in recent years (see Abstract). Dai et al. discloses that the expression and clinical implication of the FUT family (FUT1-11) in AML has not been investigated (see Abstract). Dai et al. demonstrates that AML patients, who received chemotherapy alone and showed high expression levels of FUT3, FUT6, and FUT7, had adverse effects on event-free survival (EFS) and overall survival (OS) in comparison to AML patients who had low expression of FUT3, FUT6, and FUT7 (see Abstract and Fig.1). Dai et al. concludes that high expressions of FUT3/6/7 predict poor prognosis for AML patients (see Abstract).
It would have been prima facie obvious before the effective filing date of the claimed invention to have used the treatment method of Zhang described above for an AML patient having high expression level of FUT7 as disclosed in Dai et al. One of ordinary skill in the art would have been motivated to make this modification because Dai et al. provides guidance that AML patients undergoing chemotherapy and who also have high expression of FUT7 have poor prognosis. One of ordinary skill in the art would have a reasonable expectation of success because Zhang provides a method of treating AML patients, and further provides a method to enhance the effectiveness of standard chemotherapy alone.
Claim(s) 24-25 and 28-31 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Blood, 2015 in IDS filed 09/05/2023), as applied to claim 1 above, and further in view of Peled et al. (WO2015063768A1 in IDS filed on 09/05/2023) and Magnani et al. (WO2018031445A1 in IDS filed on 09/05/2023).
The teachings of Zhang are as described above and teach the method of claim 1 as discussed above.
Zhang, however, does not teach the recited inhibitor compound in instant claims 24-25 and the recited dosages in instant claims 28-29.
The independent teachings of Peled and Magnani are as described above. Furthermore, Peled et al. demonstrates that quizartinib (AC220) had a synergistic effect with the CXCR4 antagonistic peptide, in which the combination increased the apoptotic death of human FLT3-ITD AML cells as well in an in vivo AML mice model where the mice were administered 10 mg/kg quizartinib daily for seven days (see page 24, lines 5-16 and page 25, lines 1-30).
Magnani et al. discloses a structure of their E-selectin inhibitor shown below (see paragraph 069):
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929
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Wherein, n is chosen from 4, 8, 12, 16, 20, 24, and 28 (see paragraph 70). Here, this above compound reads on the claimed compound recited in claims 24-25 when n is 12. Magnani et al. discloses that their compounds can be administered in an amount ranging from 1 mg/kg to 50 mg/kg bodyweight once a day (see paragraph 099).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the E-selectin / CXCR4 inhibitor (GMI-1359) as disclosed in the combined teachings of Zhang and Peled described above with the CXCR4 inhibitor of Peled and the E-selectin inhibitor of Magnani and further prepare the E-selectin inhibitor at a dosage of 1-50 mg/kg as disclosed in Magnani to arrive at the claimed invention. One of ordinary skill in the art could would have been motivated to make these substitutions with a reasonable expectation of success because Zhang, Peled, and Magnani all disclose the use of E-selectin and/or CXCR4 inhibitors combined with anti-cancer agents for the same purpose of treating cancers by disrupting protective mechanisms within the tumor microenvironment. See MPEP 2144.06 II. Furthermore, one of ordinary skill in the art would have made the modification of the E-selectin dosage with a reasonable expectation of success because Magnani provides guidance that any of their compounds, including the E-selectin inhibitor compounds, can be administered at 1-50 mg/kg bodyweight per day, which overlaps with the recited dosages in instant claims 28-29. See MPEP 2144.05 I.
Alternatively, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further included the T-cell checkpoint inhibitor and E-selectin inhibitor treatment regimen of Magnani to the treatment method as disclosed in the combined teachings of Zhang and Peled described above and further prepare the E-selectin inhibitor at a dosage of 1-50 mg/kg as disclosed in Magnani to arrive at the claimed invention. One of ordinary skill in the art could would have been motivated to include the treatment method of Magnani because Magnani discloses that T-cells respond to homing signals within the inflamed tumor microenvironment which include endothelial cell surface protein (E-selectin) and SDF-1 (CXCR4 ligand) to prevent other immune cells from attacking. One of ordinary skill in the art would have a reasonable expectation of success because both Magnani and the combined teachings of Zhang and Peled disclose the use of E-selectin / CXCR4 inhibitors to disrupt protective mechanisms within the tumor microenvironment, and Magnani further discloses that their treatment method can be combined with other chemotherapy treatment. Furthermore, one of ordinary skill in the art would have made the modification of the E-selectin dosage with a reasonable expectation of success because Magnani provides guidance that any of their compounds can be administered at 1-50 mg/kg bodyweight per day, which overlaps with the recited dosages in instant claims 28-29. See MPEP 2144.05 I.
In regards to instant claim 31, it would require only routine optimization to prepare the recited fixed dosages for the FLT3 inhibitor because Peled provides guidance of administering 10 mg/kg quizartinib daily, which would result in a 600 mg fixed dose per day for an average bodyweight of an adult human (60 kg). See MPEP 2144.05 II.
Claim(s) 27 and 36-39 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Blood, 2015 in IDS filed 09/05/2023), as applied to claim 1 above, and further in view of Peled et al. (WO2015063768A1 in IDS filed on 09/05/2023), WO2018068010A1 (in IDS filed 09/05/2023), and Magnani et al. (WO2018031445A1 in IDS filed on 09/05/2023).
The teachings of Zhang are as described above and teach the method of claim 1 as discussed above.
Zhang, however, does not teach the recited inhibitor compound in instant claim 27 and the recited dosages in instant claims 36-37.
The independent teachings of Peled and Magnani are as described above. Furthermore, Peled et al. demonstrates that quizartinib (AC220) had a synergistic effect with the CXCR4 antagonistic peptide, in which the combination increased the apoptotic death of human FLT3-ITD AML cells as well in an in vivo AML mice model where the mice were administered 10 mg/kg quizartinib daily for seven days (see page 24, lines 5-16 and page 25, lines 1-30).
WO’010 teaches multimeric e-selectin antagonist compounds (see Abstract).
WO’010 teaches although selectin-mediated cell adhesion is required for fighting infection and destroying foreign material, there are situations in which such cell adhesion is undesirable or excessive, resulting in tissue damage instead of repair (paragraph 0006). WO’010 discloses some circulating cancer cells can take advantage of the inflammatory mechanism to bind activated endothelium and therefore modulation of selectin-mediated intercellular adhesion may be desirable (paragraph 0006).
WO’010 teaches that their multimeric e-selectin antagonist compounds have been found to be highly potent with the potency being many times greater than the monomer (paragraph 0031). WO’010 teaches that their compounds may improve at least physicochemical, pharmacological, and/or pharmacokinetic property (paragraph 0031).
WO’010 demonstrate their multimeric e-selectin antagonist compound having a structure shown in Example 30 (Compound 45) and shown below:
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This compound shown above is the compound recited in instant claim 27. Furthermore, WO’010 discloses that their compounds can be used in the treatment of cancers including leukemia (eg. AML, ALL, CLL, and CML) and among others (paragraph 00165-00166), and further discloses that their compounds can be combined with a chemotherapy including chemotherapeutic agents (paragraph 00169). WO’010 discloses that their compounds can prevent cancer cells from metastasizing, from adhering to an endothelial cell, or from infiltrating bone marrow including cells of solid and liquid tumors (paragraph 00172).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the E-selectin / CXCR4 inhibitor (GMI-1359) as disclosed in the combined teachings of Zhang and Peled described above with the CXCR4 inhibitor of Peled and the multimeric E-selectin antagonist compound of WO’010 and further prepare the E-selectin inhibitor at a dosage of 1-50 mg/kg as disclosed in Magnani to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to make this substitution because WO’010 discloses that circulating cancer cells can take advantage of the inflammatory mechanism to bind activated endothelium, and that their multimeric E-selectin antagonist compounds can prevent cancer cells from metastasizing, from adhering to an endothelial cell, or from infiltrating bone marrow including cells of solid and liquid tumors. Furthermore, WO’010 discloses that their multimeric E-selectin antagonist compounds are many times greater in potency than the monomer, and Peled demonstrates a synergistic effect for the combination of quizartinib (AC220) and a CXCR4 antagonistic peptide, in which the combination increased the apoptotic death of human FLT3-ITD AML cells as well in an in vivo AML mice model. One of ordinary skill in the art would have a reasonable expectation of success because both WO’010 and the combined teachings of Zhang and Peled disclose the use of E-selectin and/or CXCR4 inhibitors to disrupt protective mechanisms within the tumor microenvironment, and WO’010 further discloses that their treatment method can be combined with other chemotherapy treatment. Furthermore, one of ordinary skill in the art would have made the modification of the E-selectin dosage with a reasonable expectation of success because Magnani provides guidance that E-selectin compounds can be administered at 1-50 mg/kg bodyweight per day, which overlaps with the recited dosages in instant claims 28-29. See MPEP 2144.05 I.
In regards to instant claim 39, it would require only routine optimization to prepare the recited fixed dosages for the FLT3 inhibitor because Peled provides guidance of administering 10 mg/kg quizartinib daily, which would result in a 600 mg fixed dose per day for an average bodyweight of an adult human (60 kg). See MPEP 2144.05 II.
Response to Arguments
Applicant’s arguments filed on 11/25/2025 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
Applicant states the teachings of Peled and Magnani do not teach or suggest anything about the treatment of cancer in a subject with the claimed combination of an E-selectin and FLT3 inhibitor with a reasonable expectation of success.
Applicant’s argument above was not found persuasive because the new rejection over Zhang described above provide guidance of a method to treat FLT3-ITD mutated AML using a combination of an E-selectin / CXCR4 inhibitor, a FLT3 inhibitor, and standard chemotherapy.
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 1, 4-7, 9-18, 23-25, 27-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of copending Application No. 18/291,884 (‘884) in view of Zhang et al. (Blood, 2015 in IDS filed 09/05/2023), Peled et al. (WO2015063768A1 in IDS filed on 09/05/2023), Magnani et al. (WO2018031445A1 in IDS filed on 09/05/2023), WO2018068010A1 (in IDS filed 09/05/2023), and as evidenced by Cortes et al. (Lancet Oncol., 2018 in PTO-892 dated 06/27/2025).
Claim 1 of ‘884 recites a method of treating a cancer in a subject comprising administering at least one E-selectin antagonist, wherein the subject is further administered at least one antineoplastic agent, and wherein the at least one E-selectin antagonist is chosen from the recited structure, which reads on instant claims 26-27. Claim 11 of ‘884 recites a fixed dose of 20 mg to 4000 mg per day of the at least one E-selectin antagonist. Claims 12-16 of ‘884 recite the cancer is chosen from liquid and solid cancers as well as FLT3-ITD mutated cancers. Claims 30-31 of ‘884 recite selecting the subject for treatment when at least 10% of the blast cells from the subject expressed one or more genes including FUT7.
The reference application, however, does not recite administering a FLT3 inhibitor such as sorafenib or quizartinib in the recited dosage and the inhibitor shown in instant claims 24-25 and 27 in the recited dosages.
The independent teachings of Zhang, Peled, Magnani, WO’010, and Cortes are as described above.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the reference application by including the standard chemotherapy of Zhang and either the sorafenib of Zhang or the quizartinib of Peled at 10 mg/kg per day as disclosed in Peled and further substituting the recited E-selectin inhibitors in the reference application with a combination of the CXCR4 inhibitor of Peled and the E-selection inhibitors of either Magnani or WO’010 with further guidance from Zhang and preparing the E-selectin inhibitors at 1-50 mg/kg per day as disclosed in Magnani to arrive at the claimed invention. One of ordinary skill in the could have included the standard chemotherapy and either the sorafenib or quizartinib as well as substitute the recited E-selectin inhibitors with a combination of E-selectin and CXCR4 inhibitors with a reasonable expectation of success because both the reference application and the teachings of Zhang, Peled, Magnani, and WO’010 recite the use of a combination of E-selectin or E-selectin / CXCR4 inhibitor compounds and anti-cancer agents for treating FLT3-ITD AML by disrupting protective mechanisms within the tumor microenvironment, and Zhang further disclose that dual E-selectin / CXCR4 inhibition can enhance the effectiveness of FLT-3 inhibitors and/or standard chemotherapy treatment over E-selectin inhibition alone for treating FLT3-ITD AML. Furthermore, one of ordinary skill in the art would have made the modification of the dosages because Peled discloses that 10 mg / kg per day is an effective FTL3 inhibitor dosage for a combination cancer treatment, and Magnani discloses that 1-50 mg/kg per day is an effective E-selectin inhibitor dosage in combination cancer treatment, which overlaps with the recited dosages. See MPEP 2144.05 I.
In regards to instant claim 6 and 15, it would have also been prima facie obvious before the effective filing date of the claimed invention to have modified the combined method described above by treating a relapsed AML patient as disclosed in Peled. One of ordinary skill would have been motivated to make this modification Peled et al. provides guidance that a majority of AML patients eventually relapse with a particularly high rate of relapse for FLT3-ITD mutated AML. One of ordinary skill in the art would have a reasonable expectation of success both Zhang and Peled demonstrate that FTL3 inhibitors are enhanced when combined with CXCR4 inhibitors in treating FLT3-ITD AML.
In regards to instant claims 31 and 39, it would require only routine optimization to prepare the recited fixed dosages for the FLT3 inhibitor because Peled provides guidance of administering 10 mg/kg quizartinib daily, which would result in a 600 mg fixed dose per day for an average bodyweight of an adult human (60 kg). See MPEP 2144.05 II.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of copending Application No. 18/291,884 (‘884) in view of Zhang et al. (Blood, 2015 in IDS filed 09/05/2023), Peled et al. (WO2015063768A1 in IDS filed on 09/05/2023), Magnani et al. (WO2018031445A1 in IDS filed on 09/05/2023), WO2018068010A1 (in IDS filed 09/05/2023), and Singh et al. (Apoptosis, 2011 in PTO-892 dated 06/27/2025).
The combination described above meets the limitations of instant claim 1.
The combination, however, does not disclose a subject who is receiving, has received, or will receive one of the listed compound types recited in instant claim 8.
The teachings of Singh are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have further modified the combined method described above by further administering NSAIDs as disclosed in Singh to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Singh et al. provides guidance that NSAIDs are suitable for improving anti-proliferative treatment modalities for patients with AML.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of copending Application No. 18/291,884 (‘884) in view of Zhang et al. (Blood, 2015 in IDS filed 09/05/2023), Peled et al. (WO2015063768A1 in IDS filed on 09/05/2023), Magnani et al. (WO2018031445A1 in IDS filed on 09/05/2023), WO2018068010A1 (in IDS filed 09/05/2023), and Dai et al. (Cancer Gene Therapy, 2019 in PTO-892 dated 06/27/2025).
The combination described above meets the limitations of instant claim 1.
The combination, however, does not recite a subject having an increased expression level of FUT7.
The independent teachings of Peled and Dai are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the combined method described above by treating AML patients having high expression level of FUT7 as disclosed in Dai. One of ordinary skill in the art would have been motivated to make this modification because Dai et al. provides guidance that AML patients undergoing chemotherapy and who also have high expression of FUT7 have poor prognosis. One of ordinary skill in the art would have a reasonable expectation of success because the combined method described above provides a method of treating AML patients, and further provides a method to enhance the effectiveness of standard chemotherapy alone.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 4-7, 9-18, 23-25, 27-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-45 of copending Application No. 18/001,614 (‘614) in view of Zhang et al. (Blood, 2015 in IDS filed 09/05/2023), Peled et al. (WO2015063768A1 in IDS filed on 09/05/2023), Magnani et al. (WO2018031445A1 in IDS filed on 09/05/2023), WO2018068010A1 (in IDS filed 09/05/2023), and as evidenced by Cortes et al. (Lancet Oncol., 2018 in PTO-892 dated 06/27/2025).
Claim 1 of ‘614 recites a method of treating a cancer in a subject comprising administering at least one E-selectin antagonist, wherein the subject is further administered at least one antineoplastic agent. Claim 12 of ‘614 recites wherein the E-selectin antagonist is chosen from the recited structured, which reads on instant claims 24-25. Claim 13 of ‘614 recites a fixed dose of 20 mg to 4000 mg per day of the at least one E-selectin antagonist. Claims 14-18 of ‘614 recite the cancer is chosen from liquid and solid cancers as well as FLT3-ITD mutated cancers. Claims 31-32 of ‘614 recite selecting the subject for treatment when at least 10% of the blast cells from the subject expressed one or more genes including FUT7.
The reference application, however, does not recite administering a FLT3 inhibitor such as sorafenib or quizartinib in the recited dosage and the inhibitor shown in instant claims 24-25 and 27 in the recited dosages.
The independent teachings of Zhang, Peled, Magnani, WO’010, and Cortes are as described above.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the reference application by including the standard chemotherapy of Zhang and either the sorafenib of Zhang or the quizartinib of Peled at 10 mg/kg per day as disclosed in Peled and further substituting the recited E-selectin inhibitors in the reference application with a combination of the CXCR4 inhibitor of Peled and the E-selection inhibitors of either Magnani or WO’010 with further guidance from Zhang and preparing the E-selectin inhibitors at 1-50 mg/kg per day as disclosed in Magnani to arrive at the claimed invention. One of ordinary skill in the could have included the standard chemotherapy and either the sorafenib or quizartinib as well as substitute the recited E-selectin inhibitors with a combination of E-selectin and CXCR4 inhibitors with a reasonable expectation of success because both the reference application and the teachings of Zhang, Peled, Magnani, and WO’010 recite the use of a combination of E-selectin or E-selectin / CXCR4 inhibitor compounds and anti-cancer agents for treating FLT3-ITD AML by disrupting protective mechanisms within the tumor microenvironment, and Zhang further disclose that dual E-selectin / CXCR4 inhibition can enhance the effectiveness of FLT-3 inhibitors and/or standard chemotherapy treatment over E-selectin inhibition alone for treating FLT3-ITD AML. Furthermore, one of ordinary skill in the art would have made the modification of the dosages because Peled discloses that 10 mg / kg per day is an effective FTL3 inhibitor dosage for a combination cancer treatment, and Magnani discloses that 1-50 mg/kg per day is an effective E-selectin inhibitor dosage in combination cancer treatment, which overlaps with the recited dosages. See MPEP 2144.05 I.
In regards to instant claim 6 and 15, it would have also been prima facie obvious before the effective filing date of the claimed invention to have modified the combined method described above by treating a relapsed AML patient as disclosed in Peled. One of ordinary skill would have been motivated to make this modification Peled et al. provides guidance that a majority of AML patients eventually relapse with a particularly high rate of relapse for FLT3-ITD mutated AML. One of ordinary skill in the art would have a reasonable expectation of success both Zhang and Peled demonstrate that FTL3 inhibitors are enhanced when combined with CXCR4 inhibitors in treating FLT3-ITD AML.
In regards to instant claims 31 and 39, it would require only routine optimization to prepare the recited fixed dosages for the FLT3 inhibitor because Peled provides guidance of administering 10 mg/kg quizartinib daily, which would result in a 600 mg fixed dose per day for an average bodyweight of an adult human (60 kg). See MPEP 2144.05 II.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-45 of copending Application No. 18/001,614 (‘614) in view of Zhang et al. (Blood, 2015 in IDS filed 09/05/2023), Peled et al. (WO2015063768A1 in IDS filed on 09/05/2023), Magnani et al. (WO2018031445A1 in IDS filed on 09/05/2023), WO2018068010A1 (in IDS filed 09/05/2023), and Singh et al. (Apoptosis, 2011 in PTO-892 dated 06/27/2025).
The combination described above meets the limitations of instant claim 1.
The combination, however, does not disclose a subject who is receiving, has received, or will receive one of the listed compound types recited in instant claim 8.
The teachings of Singh are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have further modified the combined method described above by further administering NSAIDs as disclosed in Singh to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Singh et al. provides guidance that NSAIDs are suitable for improving anti-proliferative treatment modalities for patients with AML.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-45 of copending Application No. 18/001,614 (‘614) in view of Zhang et al. (Blood, 2015 in IDS filed 09/05/2023), Peled et al. (WO2015063768A1 in IDS filed on 09/05/2023), Magnani et al. (WO2018031445A1 in IDS filed on 09/05/2023), WO2018068010A1 (in IDS filed 09/05/2023), and Dai et al. (Cancer Gene Therapy, 2019 in PTO-892 dated 06/27/2025).
The combination described above meets the limitations of instant claim 1.
The combination, however, does not recite a subject having an increased expression level of FUT7.
The independent teachings of Peled and Dai are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the combined method described above by treating AML patients having high expression level of FUT7 as disclosed in Dai. One of ordinary skill in the art would have been motivated to make this modification because Dai et al. provides guidance that AML patients undergoing chemotherapy and who also have high expression of FUT7 have poor prognosis. One of ordinary skill in the art would have a reasonable expectation of success because the combined method described above provides a method of treating AML patients, and further provides a method to enhance the effectiveness of standard chemotherapy alone.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments filed on 11/25/2025 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
Applicant states none of the reference applications recite anything about the treatment of cancer in a subject with the claimed combination of an E-selectin and FLT3 inhibitor with a reasonable expectation of success.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Here, the new nonstatutory double patenting rejections over the reference applications in view of the secondary references described above provide guidance of a method to treat FLT3-ITD mutated AML using a combination of an E-selectin inhibitor, a FLT3 inhibitor, and standard chemotherapy.
Conclusion
No claim is found allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693