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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/02/2026 has been entered.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/02/2026 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner. See attached copy of PTO-1449.
Status of Application
Applicants' arguments/remarks filed 02/02/2026 are acknowledged. Claims 1, 9, 39, 42, 61 and 64 are currently amended. Claims 41 and 64 are newly canceled. Claims 1-2, 4, 9, 39-40, 42-43, 61 and 63-70 are examined on the merits within and are currently pending.
Withdrawn Rejections
With applicants' amendment, filed 02/02/2026 and with respect to application’s arguments/remarks:
The objection of claim 39 is withdrawn in view of the amendment of the claim.
The rejection under 35 U.S.C. 103 of Claims 41 and 62 is withdrawn in view of the cancelation of the claims.
The rejection under 35 U.S.C. 103 of claims 1, 2, 4, 43, 61-64, 67-68 and 70, over Wanebo, Lewis et al., Wei et al., is withdrawn in view of the amendments of the claims.
Modified 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 non-obviousness.
Claims 1, 2, 4, 9, 39-40, 42-43, 61 and 63-70 are rejected under 35 U.S.C. 103 as being obvious over Wanebo (US 9,968,570 B2) in view of Lewis et al., (Lewis et al., Targeting sphingolipid metabolism as an approach for combination therapies in haematological malignancies. Cell Death Discovery (2018) 4:72) and Wei et al., (Wei et al.,Venetoclax Combined With Low-Dose Cytarabine For Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study. J Clin Oncol Vol. 37, Iss. 15, 1277-1284, Feb 13, 2019) and Ogretmen et al. (Ogretmen et al., Biochemical Mechanisms of the Generation of Endogenous Long Chain Ceramide in Response to Exogenous Short Chain Ceramide in the A549 Human Lung Adenocarcinoma Cell Line. JBC, Vol. 277, No. 15, Issue of April 12, pp. 12960–12969, 2002)..
Claims 1, 2, 9, 39, 42-43, 61 and 70,
Wanebo teaches compositions and methods for treating cancer using a combination of C6 (short chain)-ceramide and other anti-cancer agents (Abs), e.g., a chemotherapeutic agent (col. 2, lines 40-43). The method is to deliver ceramide (e.g., C6-ceramide) in combination with one or more anti-cancer agents, e.g., chemotherapeutic agent, for the treatment of cancer. (Col. 6, lines 42-45). Cancer is a disease that condition associated with undesirable cellular proliferation. The combination can be administered to cancer cells, directly or indirectly, using local, regional or systemic means. (col. 11, line 40-42). The methods are delivery of an effective amount ceramide (e.g., C6-ceramide ), in combination with one or more anti-cancer agents, e.g., a chemotherapeutic agent to contact with cancer cells are for the treatment of cancer. (Col. 2, lines 40-50).
In certain embodiments, the subject is a human. (col. 7, lines 1-2). The anti-cancer agent is selected from the group consisting of cytosine arabinoside (AraC). (Col. 3, line 17-20), which is cytarabine,. C6 - Ceramide Dramatically Enhances Paclitaxel (Taxol) Induced Cell Death in L3.6 Pancreatic Cancer Cells In Vitro. (Col. 40, lines 42-43). C6-ceramide also synergized with Taxol, and Gemcitabine in enhancing cytotoxicity of 3 pancreatic cancer cell lines. None of Gemcitabine (3 µg/ml), Taxol (15 µg/ml) or C6-Ceramide (10 µg/ml) alone had a significant effect in inducing cell death whereas combination of either chemo agent with C6-Ceramide caused a dramatic increase in cell death in pancreatic cancer cell lines L3.6 (6A), Pane-I (6B), and MIA cells (6C). (Col. 41, lines 23-30).
Wanebo teach a combination of C6 (short chain)-ceramide and other anti-cancer agents cytarabine, but does not teach the composition includes venetoclax.
Lewis et al. teach conventional chemotherapy-based drug combinations have, until recently, been the backbone of most therapeutic strategies for cancer. In a time of emerging rationale drug development, targeted therapies are beginning to be added to traditional chemotherapeutics to synergistically enhance clinical responses. Of note, the importance of proapoptotic ceramide in mediating the anti-cancer effects of these therapies is becoming more apparent. Agents that manipulate sphingolipid metabolism have been explored as potential anti-cancer agents and have recently demonstrated exciting potential to augment the efficacy of anti-cancer therapeutics. (Abs). Efficacy of many chemotherapeutics and targeted therapies is dictated by cellular ceramide levels. Oncogene activation skews sphingolipid metabolism to favor the production of pro-survival sphingolipids. Inhibitors of enzymes involved in ceramide metabolism exhibit promise in the relapsed-refractory setting. Anti-cancer activity of sphingosine kinase inhibitors provides several options for new drug combinations. (Facts, pg. 1). Utilising AC inhibitors have shown efficacy in resensitising cells to chemotherapeutics. (pg. 3, right col., 3rd par.).
The addition of the Bcl-2 inhibitor, Venetoclax has been a paradigm shift for p53 null CLL patients with 79% of relapsed/refractory patients in a phase II clinical trial responding, 20% of whom exhibited undetectable disease by flow cytometry. As always, resistance to drugs remains a problem with other Bcl-2 family members such as MCL-1, identified as a marker of
resistance to Venetoclax. Although still effective in CLL patients, identifying other drugs to use alongside Venetoclax and prevent the emergence of resistance is crucial.(pg. 5, left col., 3rd par.).
Furthermore, the findings that clinically used small molecule inhibitors of FLT339, BCR-ABL17 and Bcl-267 increase ceramide levels. In particular, the combining of two separate drugs such as the FLT3 inhibitor, Quizartinib and the Bcl-2 inhibitor Venetoclax which have demonstrated synergistic cell death in AML, could be partially attributed to the increases in ceramide levels that are produced by each drug. Thus this could provide an opportunity for targeted combinational therapies under the premise of synergistic increases in ceramide levels. (pg. 9, left col., 1st par.). In certain embodiments of the above-described methods and composition, the ceramide may be a C2-ceramide, C6-ceramide, C8-ceramide, C16-ceramide, or a higher order of ceramide. (Col. 14, right col., 1st par.).
The targeting of MCL-1 through AC inhibition in combination with Bcl-2 inhibitor, Venetoclax. Chemoresistant AML cells were also susceptible to cell death induced by AC inhibition which was correlated with the increase in cellular ceramide levels. (pg. 6, right col., 1st par.). Chemotherapy resistant AML cell lines exhibited a lack of ceramide generation upon drug treatment suggesting an involvement of SPHK1 as a mediator of drug resistance. Overexpression of SPHK1 in chemo-sensitive AML cell lines imparted resistance to chemotherapeutics confirming SPHK1 as a marker of drug resistance in AML. Genetic and chemical inhibition of SPHK1 in AML cell lines and primary patient samples induced cell death and synergized with chemotherapeutic agents. SPHK1 inhibition-induced synergistic cell death with cytarabine in the refractory leukemic initiating cell (LIC) population. (pg. 6, right col., last par.). (SPHK1 (Sphingosine Kinase 1) is an enzyme that metabolizes ceramide-derived sphingosine. SPHK1 converts sphingosine into sphingosine-1-phosphate (S1P). While ceramides promote cell death, SPHK1 promotes survival, reducing ceramide accumulation).
Lewis et al. teach the combining of two separate drugs such as the FLT3 inhibitor, Quizartinib and the Bcl-2 inhibitor Venetoclax, but do not teach the composition combining two drugs venetoclax, and cytosine arabinoside (AraC).
Wei et al. teach Venetoclax Combined With Low-Dose Cytarabine (LDAC) For Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study. (Title). Effective amounts of Venetoclax and LDAC are administered and evaluated to reach efficacy. (pg. 1, Purpose, Methods).
Ogretmen et al. teach treatment of A549 cells with C6-ceramide resulted in a significant increase in the endogenous long chain ceramide levels. (Title and pg. 12960, left col., 1st par.). There is a direct relationship between exogenous and endogenous ceramides. It has been shown that treatment of Madin-Darby canine kidney cells with N-octanoyl-sphingosine liposomes caused about 10-fold increase in the total ceramide levels. (pg. 12961, left col., 3rd par.). It would be obvious that administrating of short chain ceramide increase in longer chain of ceramide means administrating of short chain ceramide increase the ratio of longer chain of ceramide comparing to ceramide amount before dosing.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer directly or indirectly to cancer cells one or more chemotherapeutic agents in combination with a short chain C6 ceramide, with the anti-cancer agent arabinoside (AraC), cytarabine,. C6 - Ceramide Dramatically Enhances Paclitaxel (Taxol) Induced Cell Death in L3.6 Pancreatic Cancer Cells and also synergized with chemotherapeutics in enhancing cytotoxicity in cancer cell lines, or increase sensitivity of chemotherapeutics to destroy cancer cells, taught by Wanebo, and to select the second chemotherapeutic venetoclax, which have demonstrated synergistic cell death in AML, could be partially attributed to the increases in ceramide levels and SPHK1 inhibition-induced synergistic cell death with cytarabine in the refractory leukaemic initiating cell (LIC) population taught by Lewis et al., and results in a phase Ib/II study of Venetoclax combined with low-dose Cytarabine for patients with AcuteMyeloid Leukemia: taught by Wei et al., administrating of short chain ceramide increase in longer chain of ceramide means administrating of short chain ceramide increase the ratio of longer chain of ceramide, taught by Ogretmen et al., since they have provided treatment methods and results of cell deaths in relation with increasing short chain ceramide in cancer cells.
With regard to claim 4,
Wanebo teach the anti - cancer agent is selected from the group consisting of daunorubicin, (col. 3, line 20), PTEN (epigenetic inactivation) (col. 18, line 64).
Wei et al. teach azacytidine or decitabine combined with venetoclax, (pg. 1278, left col., 1st par.).
With regard to claims 63-64,
Wei et al. teach Resistance to venetoclax monotherapy may be mediated by other prosurvival
proteins, such as MCL1, that sequester endogenous BCL-2 homology domain 3-only proteins (eg, Bim) released by venetoclax on BCL-2 binding. Several drugs—including anthracyclines, hypomethylating agents (HMAs), and cytarabine—have demonstrated the ability to down-regulate MCL1 expression and act synergistically with venetoclax against AML cells in preclinical studies. As proof of concept, a 61% CR/CRi rate was reported for venetoclax combined with hypomethylating agents (HMAs) (ie, azacitidine or decitabine) in treatment-naive older adults with AML, exceeding previously reported response rates for HMAs alone (pg. 1278, left col, 1st par.).
With regard to claims 67-68,
Wanebo teaches ceramide forms have an anti - cancer effect on many cancer cell lines, including Jurkat leukemia. (Col. 1, lines 39-41), acute myeloblastic leukemia, acute lymphoblastic leukemia, (Col. 7, lines 11-12) or leukemias (Col. 11, line 32).
With regard to claim 69,
Wei et al. teach 61% CR/CRi rate was reported for venetoclax combined with HMAs (ie, azacitidine or decitabine) in treatment-naive older adults with AMLazacitidine, decitabine. (pg. 1278, left col., 1st par.).
With regard to claims 40 and 65,
Wei et al. teach as proof of concept, a 61% CR/CRi rate was reported for venetoclax combined with hypomethylating agents (HMAs) (ie, azacitidine or decitabine) in treatment-naive older adults with AML,21 exceeding previously reported response rates for HMAs alone. (pg. 1278, left col., 1st par.).
With regard to claim 66
Wanebo teaches Paclitaxel - induced apoptosis has been shown to be attributable, in part, to ceramide and sphingoid bases. (Col. 44, lines 48-49). ( F ) % apoptosis rate increase with ceramide comparing without ceramide. (Fig. 16, E and E and Col. 6, lines 16-24).
Response to Arguments
With Regard to Obviousness Rejection of claims 1, 2, 4, 43, 61-64, 67, 68, and 70:
Applicants argue that the combination of Wanebo in view of Lewis and Wei supports a rejection of claims 1, 2, 4, 43, 61-64, 67, 68, and 70 under 35 U.S.C. §103 has not established a prima facie case of obviousness over this combination, and even if it has, applicant has established sufficient evidence of unexpectedly superior results to rebut the Patent Office's prima facie case because Wanebo does not teach venetoclax, and Lewis teaching Quizartinib and venetoclax that would not have motivated one of ordinary skill in the art to have added venetoclax to the compositions of Wanebo with a reasonable expectation of success and similarly for Wei that there is no discussion whatsoever in Wei of ceramides, and thus there would have been no
motivation for one of ordinary skill in the art to have looked to Wei for the purpose of increasing a ratio of Cl6 ceramide and/or Cl8 ceramide to C24 ceramide and/or C24: 1 ceramide in a target cell in order to treat a disease, disorder, and/or condition with venetoclax and AraC. the
combination of Wanebo in view of Lewis and Wei would not have motivated one of ordinary skill in the art to have combined a short chain ceramide, venetoclax, and AraC to treat any diseases.
This argument has been fully considered, but is not found persuasive, because the basis for 103 rejection is that no one reference has to teach all the claim limitations for an obviousness rejection and therefore several references are combined to render the claims obvious. One with ordinary skill in the art can learn from and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results even though some prior arts may teach more and may teach different things. And MPEP 2121.02(I) states "a reference is presumed operable until applicant provides facts rebutting the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980)", MPEP § 716.07. See also In re Antor Media Corp., 689 F.3d 1282, 103 USPQ2d 1555 (Fed. Cir. 2012). And In response to applicant' s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case Wanebo teaches a combination of C6 (short chain)-ceramide and other anti-cancer agents (Abs), e.g., a chemotherapeutic agent, cytosine arabinoside (AraC), cytarabine; Lewis teaches Venetoclax and the ceramide may be a C2-ceramide, C6-ceramide, C8-ceramide, C16-ceramide, or a higher order of ceramide; and Wei teaches Venetoclax Combined With Low-Dose Cytarabine. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine these ideas to achieve better outcome results.
With Regard to Obviousness Rejection of claims 9 and 69
Applicants argue that the combination of Wanebo, Lewis, Wei, and Ogretmen does not supports a prima facie case of obviousness of claims 9 and 69. In particular, applicant respectfully submits that the cited combination fails to disclose or suggest that total ceramide levels are increase in cells, and also fails to suggest that ratios of long chain ceramides to very long chain ceramides are increased. Ogretmen teaches that treating a cell with C6-ceramides results in an increase in endogenous long chain ceramide levels, but it does so by modifying a pre-existing cellular ceramide by "recycling of the sphingosine backbone of C6-ceramide, which involves
deacylation and reacylation of ceramide for the generation of endogenous long chain ceramide
(mainly C16:o- and C24:1 ceramides)". Thus, the disclosure of Ogretmen clearly relates to producing a long chain ceramide from another already present endogenous ceramide. Changing the nature of a ceramide in a cell from one type of ceramide to another does not alter total ceramide levels in the cell, and thus there is no disclosure in the combination of Wanebo in view of Lewis and Wei and Ogretmen that would have led one of ordinary skill in the art to a reasonable expectation that the instantly claimed compositions would increase total ceramide levels.
This argument has been fully considered, but is not found persuasive, because Wanebo already teach administration C6 - Ceramide Dramatically Enhances Paclitaxel (Taxol) Induced Cell Death in L3.6 Pancreatic Cancer Cells and synergized with Taxol, and Gemcitabine in enhancing cytotoxicity of 3 pancreatic cancer cell lines. And Ogretmen et al. teach treatment of A549 cells with C6-ceramide resulted in a significant increase in the endogenous long chain ceramide levels. It would be obvious that administrating of short chain ceramide increase in longer chain of ceramide means administrating of short chain ceramide increase the ratio of longer chain of ceramide comparing to ceramide amount before dosing. C6 can be called short chain and C16, C18 and/or C24 can be called long chain.
With Regard to Obviousness Rejection of claims 39, 40, 41, 42, 65, and 66
Applicants argue that the combination of Wanebo, Lewis, and Wei fail to support the prima facie obviousness of methods for treating any cancer or tumor with a combination of short chain ceramide, AraC, and venetoclax, and Ogretmen does not disclose anything that would lead one of ordinary skill in the art to a reasonable expectation that this combination would have increased sensitivity of any cell to one or more small chain ceramides in combination with venetoclax and AraC by increasing a ratio of Cl6 and/or Cl8 ceramide to C24 ceramide and/or C24:l ceramide in the drug-resistant tumor and/or cancer cell to thereby increase the sensitivity of the cell to the combination of venetoclax and AraC.
This argument has been fully considered, but is not found persuasive, as explain above. Please see the explanation above.
Conclusion
No claim is allowed.
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/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615