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.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/24/2026 has been entered.
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 07/24/2026 are acknowledged. Claims 1, 24-25, 27-29, and 36-37 are amended. Claims 2-3, 20-23, and 26 are cancelled.
Accordingly, claims 1, 4-19, 24-25, and 27-39 are pending and being examined on the merits herein.
Withdrawn Rejections
The cancellation of claim 23 renders the prior art rejections over this claim moot.
The 35 USC 103 rejection over Zhang for claims 1, 4-5, 7, 9, 11-14, 16-18, and 33-34, over Zhang in view of Peled for claims 6, 15, 32, and 35, over Zhang in view of Singh for claim 8, over Zhang in view of Papadopoulos and Magnani for claim 10, and over Zhang in view of Dai for claim 19 are withdrawn because claim 1 now requires that the at least one E-selectin inhibitor is chosen from one of the two recited compounds, which was not previously considered in these rejections.
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, 24-25, 28-29 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) in view of Magnani et al. (WO2018031445A1 in IDS filed on 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).
While Zhang teaches the combination of a FLT-3 inhibitor (sorafenib) and a E-selectin / CXCR4 inhibitor (GMI-1359) for anti-leukemia chemotherapy in FLT3-ITD mutated AML, Zhang does not teach administering a recited E-selectin compound as recited in instant claim 1.
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).
Magnani et al. discloses a structure of their E-selectin inhibitor shown below (see paragraph 069):
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Wherein, n is chosen from 4, 8, 12, 16, 20, 24, and 28 (see paragraph 70). This above compound reads on the claimed compound recited in claims 1 and 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 before the effective filing date of the claimed invention to have substituted the E-selectin / CXCR4 inhibitor (GMI-1359) of Zhang with the E-selectin inhibitor and CXCR4 inhibitor disclosed in Magnani to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element for another to obtain predictable results and would have a reasonable expectation of success in doing so because Zhang demonstrates the effectiveness of the combined administration of a FLT-3 inhibitor (sorafenib) and a E-selectin / CXCR4 inhibitor (GMI-1359) against FLT3-ITD mutated AML, and Magnani also teaches the combined administration of a E-selectin and CXCR4 inhibitor to treat cancers which includes AML.
Alternatively, it would have been prima facie obvious before the effective filing date of the claimed invention to have further included the T-cell checkpoint inhibitor and E-selectin inhibitor and CXCR4 inhibitor treatment regimen of Magnani to the treatment method of Zhang to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to further include the treatment regimen 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 by using these pathways, 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.
One of ordinary skill in the art would have a reasonable expectation of success because both Zhang and Magnani teach the use of E-selectin and CXCR4 inhibitors to disrupt protective mechanisms within the tumor microenvironment, and Magnani further discloses that their treatment method can be combined with other chemotherapy treatments.
In regards to instant claim 28, Magnani teaches that any of their compounds including the E-selectin and/or CXCR4 inhibitors can be administered at 1 mg/kg to 50 mg/kg bodyweight once a day, which overlaps and renders obvious the recited mg/kg dosage range in instant claim 28. See MPEP 2144.05 I.
In regards to instant claim 29, an ordinary skilled artisan would have performed routine optimization to arrive at the recited fixed dosage range per day for the E-selectin inhibitor because Magnani teaches that any of their compounds including the E-selectin and/or CXCR4 inhibitors can be administered at 1 mg/kg to 50 mg/kg bodyweight once a day, which would have a fixed dosage amount per day of 60 mg to 3000 mg given an average bodyweight of an adult human (60 kg). See MPEP 2144.05 II.
Claim(s) 6, 15, 30-32, 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) in view of Magnani et al. (WO2018031445A1 in IDS filed on 09/05/2023), as applied to claims 1, 24, and 29-30 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 combined teachings of Zhang and Magnani are as described above and teach the method of instant claims 1, 24, and 29-30 as discussed above.
The combined references, however, do not teach a relapsed AML patient as well as administering a FLT3 inhibitor that is quizartinib or a first-generation multi-kinase inhibitor or next generation inhibitor. Furthermore, the combined references do not teach the dosage amounts for the FLT3 inhibitor in instant claims 30-31.
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). 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. 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 FLT3, E-selectin, and CXCR4 inhibitor treatment method as disclosed by the combined teachings of Zhang and Magnani described above by treating a patient with relapsed AML as disclosed in Peled and to further substitute the sorafenib of Zhang with the 10 mg/kg 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.
One of ordinary skill in the art would have substituted one known element (sorafenib) for another (quizartinib) to obtain predictable results and would have a reasonable expectation of success in doing so because both the combined teachings of Zhang and Magnani described above 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.
In regards to instant claim 31, an ordinary skilled artisan would have performed routine optimization to prepare the recited fixed dosage amounts per day for the FLT3 inhibitor because Peled provides guidance of administering 10 mg/kg quizartinib (FLT3 inhibitor) 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) 8 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Blood, 2015 in IDS filed 09/05/2023) in view of Magnani et al. (WO2018031445A1 in IDS filed on 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).
The combined teachings of Zhang and Magnani are as described above and teach the method of instant claim 1 as discussed above.
The combined references, however, do 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 as disclosed by the combined teachings of Zhang and Magnani 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 been motivated to further include NSAIDs because Singh discloses that NSAIDs may be suitable to improve anti-proliferative treatment modalities for AML patients and have proven to possess significant anti-proliferative potential in various cancer cells in vitro and in vivo.
One of ordinary skill in the art would have a reasonable expectation of success because both the combined teachings of Zhang and Magnani described above and Singh teach treatment methods for AML patients as well as combining different cancer therapeutics together to increase efficacy.
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) in view of Magnani et al. (WO2018031445A1 in IDS filed on 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).
The combined teachings of Zhang and Magnani are as described above and teach the method of instant claim 1 as discussed above.
Furthermore, Magnani teaches that their treatment method, which include E-selectin inhibitors, can be used to treat solid cancers (paragraph 075).
The combined references, however, do not disclose the combination of a FLT3 and E-selectin inhibitor can be used to treat 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).
It would have been prima facie obvious before the effective filing date of the claimed invention that the FLT3, E-selectin, and CXCR4 inhibitor treatment method as disclosed by the combined teachings of Zhang and Magnani described above can also be used to treat a solid cancer as disclosed in Magnani and Papadopoulos to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because both Magnani and Papadopoulos provide guidance that E-selectin and/or CXCR4 inhibitors and FLT3 inhibitors such as quizartinib can be used to treat 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) in view of Magnani et al. (WO2018031445A1 in IDS filed on 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).
The combined teachings of Zhang and Magnani are as described above and teach the method of instant claim 1 as discussed above.
The combined references, however, do 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 modified the FLT3, E-selectin, and CXCR4 inhibitor treatment method as disclosed by the combined teachings of Zhang and Magnani described above by treating an AML patient having high expression level of FUT7 as disclosed in Dai to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to make this modification because Dai 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 teachings of Zhang and Magnani described above provide a method of treating AML patients, and further provides a method to enhance the effectiveness of standard chemotherapy alone.
Claim(s) 1 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Blood, 2015 in IDS filed 09/05/2023) in view of WO2018068010A1 (in IDS filed 09/05/2023) and of Peled et al. (WO2015063768A1 in IDS filed on 09/05/2023)
The teachings of Zhang are as described above.
While Zhang teaches the combination of a FLT-3 inhibitor (sorafenib) and a E-selectin / CXCR4 inhibitor (GMI-1359) for anti-leukemia chemotherapy in FLT3-ITD mutated AML, Zhang does not teach administering a recited E-selectin compound as recited in instant claim 27.
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). WO’010 discloses that determining and adjusting the appropriate doing amount and frequency of dosing can be readily performed by a person of ordinary skill in the relevant art (paragraph 00191) and that an effective amount is an amount in which their compound provides at least one therapeutic effect (paragraph 00194).
The teachings of Peled are as described above. In particular, 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 substituted the E-selectin / CXCR4 inhibitor (GMI-1359) of Zhang with the E-selectin inhibitor of WO’010 and the CXCR4 inhibitor of Peled to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (E-selectin / CXCR4 inhibitor) for another (E-selectin inhibitor of WO’010 and CXCR4 inhibitor of Peled) to obtain predictable results and would have a reasonable expectation of success in doing so because Zhang demonstrates the effectiveness of the combined administration of a FLT-3 inhibitor (sorafenib) and a E-selectin / CXCR4 inhibitor (GMI-1359) against FLT3-ITD mutated AML, WO’010 teaches that their E-selectin inhibitor compounds can treat cancers which includes AML, and Peled demonstrates the synergistic effect of their CXCR4 inhibitor with a FLT3 inhibitor against FLT3-ITD AML.
Claim(s) 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) in view of WO2018068010A1 (in IDS filed 09/05/2023) and Peled et al. (WO2015063768A1 in IDS filed on 09/05/2023, as applied to claims 1 and 27 above, and further in view of Magnani et al. (WO2018031445A1 in IDS filed on 09/05/2023).
The combined teachings of Zhang, WO’010, and Peled are as described above and teach the method of instant claims 1 and 27 as discussed above.
Furthermore, Peled teaches that 10 mg/kg dosage of quizartinib daily along with a CXCR4 antagonistic peptide had a synergistic effect against for seven days had a human FLT3-ITD AML cells as described above.
The combined references, however, do not teach the dosage amounts for the E-selectin inhibitor recited in instant claims 36-37 as well as the fixed dosage amounts per day for the FLT3 inhibitor recited in instant claim 39.
The teachings of Magnani are as described above. In particular, Magnani teaches that their compounds, which include E-selectin inhibitor compounds, can be administered in an amount ranging from 1 mg/kg to 50 mg/kg bodyweight once a day (see paragraph 099).
Therefore, an ordinary skilled artisan would have performed routine optimization to arrive at the recited mg/kg dosages in instant claim 36 for the multimeric E-selectin antagonist compound based on Magnani disclosing that 1 mg/kg to 50 mg/kg bodyweight once a day is a suitable dosage amount for using E-selectin inhibitors compounds against cancers, and WO’010 further disclosing that an effective amount of their multimeric E-selectin antagonist compounds are any amount that provides at least a therapeutic effect.
Furthermore, the ordinary skilled artisan would have also performed routine optimization to arrive at the fixed dosages per day recited in instant claim 37 based on the same guidance described above and given an average bodyweight of an adult human (60 kg). See MPEP 2144.05 II.
Lastly, in regards to instant claim 39, an ordinary skilled artisan would have performed routine optimization to prepare the recited fixed dosage amounts per day for the FLT3 inhibitor because Peled provides guidance of administering 10 mg/kg quizartinib (FLT3 inhibitor) 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 07/24/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
Applicant states that Zhang teaches a dual E-selectin/CXCR4 inhibitor GMI-1359 and repeatedly emphasizes the importance of simultaneously inhibiting both pathways. Applicant states that Zhang teaches away from using a combination of sorafenib and E-selectin and omitting the CXCR4 because Zhang demonstrates that the apoptosis percentages for sorafenib + E-selectin compared to sorafenib alone was slightly worse (35.6% vs 36.6%) and that the dual E-selectin / CXCR4 inhibitor produced substantially greater apoptosis (48.9%). Therefore, Applicant states that the ordinary skilled artisan would determine that the therapeutic benefit was associated with the addition of CXCR4 inhibition and not E-selectin inhibition. Applicant states the Office has not articulated why an ordinary skilled artisan would have chosen a claimed E-selectin inhibitor that selectively inhibits E-selectin to combine with a FLT3 inhibitor when the data in Zheng teaches that a compound that selectively inhibits E-selectin did not provide any benefit.
Applicant further points to Peled to reinforce this conclusion as Peled teaches that the combination of FLT-3 and CXCR4 inhibition and not E-selection inhibition had synergistic benefits. Applicant states that neither Magnani nor WO’010 cure this deficiency as these references only disclose specific E-selectin inhibitor and do not provide experimental data for treating AML in combination with a FLT3 inhibitor.
Applicant’s arguments described above were not found persuasive because the previous and current prior art rejections described above do not rely on just a combination of a FLT3 inhibitor and a E-selectin inhibitor to arrive at the claimed invention. Rather, the previous rationale and as described above was made based on either substituting the dual E-selectin/CXCR4 inhibitor GMI-1359 disclosed in Zhang with both a E-selectin of Magnani or WO’010 and a CXCR4 inhibitor as disclosed in Magnani or Peled, or further including the T-cell checkpoint inhibitor and E-selectin inhibitor and CXCR4 inhibitor treatment regimen of Magnani to arrive at the claimed invention. Therefore, Zhang does not teach away from the proposed modifications because these modifications also include both E-selectin and CXCR4 inhibiting compounds.
It is noted that the instant method recites a method of treating cancer “comprising” administering the at least FLT3 inhibitor and at least one E-selectin inhibitor. As stated in MPEP 2111.03 I, the term “comprising” is open-ended and does not exclude additional unrecited elements or methods steps.
Therefore, the modification of substituting the dual E-selectin/CXCR4 inhibitor GMI-1359 of Zhang with two separate E-selectin and CXCR4 inhibitor compounds as disclosed in Magnani or further including the T-cell checkpoint inhibitor and E-selectin inhibitor and CXCR4 inhibitor treatment regimen of Magnani is within scope of the instant claims.
Furthermore, as pointed by the Applicant and described above, while Peled may teach a synergy between FLT3 inhibitors and CXCR4 antagonist compounds without a E-selectin inhibitor, Zhang still establishes the importance of blocking both E-selectin and CXCR4 pathways for the treatment of FLT3-mutant AML and also further demonstrates increased efficacy of a FLT3 inhibitor when both pathways are inhibited. Therefore, the ordinary skilled artisan would have predictably considered using treatment options which block both pathways, and Magnani provides a treatment method in which both E-selectin and CXCR4 inhibitor compounds are administered to treat cancers and also teaches AML as an example cancer that can be treated.
Furthermore, in regards to Magnani and WO’010 lacking experimental data for treating the recited AML, MPEP 2143.02 I states that “Conclusive proof of efficacy is not required to show a reasonable expectation of success” … To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success … the expectation of success need only be reasonable, not absolute”.
In this case, the ordinary skilled artisan would have a reasonable expectation of success because Zhang demonstrates the importance of dual E-selectin and CXCR4 inhibition to treat FLT3-mutant AML using FLT3 inhibitors, and Magnani provides guidance of administering both E-selectin and CXCR4 inhibitor compounds for the treatment of cancers which includes AML.
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, 24-25, and 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 art would have been motivated to include 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 because Zhang discloses 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.
One of ordinary skill in the art would have 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 / CXCR4 inhibitor compounds and anti-cancer agents for treating FLT3-ITD AML.
Furthermore, one of ordinary skill in the art would have made the modification of the E-selectin and FLT3 inhibitor 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 and II.
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 been motivated to further include NSAIDs because Singh discloses that NSAIDs may be suitable to improve anti-proliferative treatment modalities for AML patients and have proven to possess significant anti-proliferative potential in various cancer cells in vitro and in vivo.
One of ordinary skill in the art would have a reasonable expectation of success because both the combination of references described above and Singh recite treatment methods for AML patients as well as combining different cancer therapeutics together to increase efficacy.
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, 24-25, and 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 art would have been motivated to include 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 because Zhang discloses 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.
One of ordinary skill in the art would have 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.
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 and II.
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 been motivated to further include NSAIDs because Singh discloses that NSAIDs may be suitable to improve anti-proliferative treatment modalities for AML patients and have proven to possess significant anti-proliferative potential in various cancer cells in vitro and in vivo.
One of ordinary skill in the art would have a reasonable expectation of success because both the combination of references described above and Singh recite treatment methods for AML patients as well as combining different cancer therapeutics together to increase efficacy.
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 recites 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 07/24/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive. Applicant states that the reference ‘884 and ‘614 applications do not teach or suggest anything about the treatment of cancer in a subject with the claimed combination with a reasonable expectation of success.
Applicant’s argument described above was not found persuasive because the provisional nonstatutory obviousness-type double patenting rejections over ‘884 and ‘614 in view of the combination of the references described above do establish obviousness to arrive at the claimed combination of agents as discussed above.
Applicant notes that the provisional nonstatutory obviousness-type double patenting rejections over ‘884 and ‘614 should be withdrawn when they are the only rejection remaining in an application having the earlier patent term filing date.
However, because other rejections remain on record, the provisional nonstatutory obviousness-type double patenting rejections over ‘884 and ‘614 are maintained.
Conclusion
No claim is found allowable.
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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