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 .
Status of Application
Applicants' arguments/remarks filed 07/20/2026 are acknowledged. Claims 1 and 9 are currently amended. Claims 1-2, 4, 9, 39-40, 42-43, 61 and 63-70 are examined on the merits within and are currently pending.
Maintained 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). 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.).
Wanebo teach a combination of C6 (short chain)-ceramide and other anti-cancer agents cytarabine/cytosine arabinoside (AraC) 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). Utilizing AC inhibitors have shown efficacy in resensitizing 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.).
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, 9, 39-40, 42-43, 61 and 63-70:
Applicants argue that the combination of Wanebo in view of Lewis, Wei, and Ogretmen does not support a prima facie case of obviousness of independent claims 1, 9, and 39. Particularly, applicant respectfully submits that a person of skill in the art would not have combined the teachings of the cited art to arrive at the presently claimed subject matter, since each prior art does not teach all limitations of a claim. Applicant lists all points each prior art Wanebo, Lewis, Wei or Ogretment does not each or teaches other things and applicant submits that Wanebo, either alone or in combination with any of the secondary references, does not disclose or suggest present claim 4.”
These arguments have been fully considered but are not found persuasive since 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. Simply adding other components that Wanebo, Lewis, Wei or Ogretment teach that do match applicant’s limitations to a claim do not overcome prior arts’ teachings in the office actions above.
Applicants argue on the same reasons above with Ogretmen that specifically Ogretmen teaches use of short chain ceramides to increase endogenous long chain ceramide levels is misplaced. The cited disclosure relates to the context of promoting cell survival, which applicant submits is the exact opposite of the desired effects of the presently claimed subject matter.
Applicant submits that Ogretmen is not about an effect on viability of A549 cells, the lung cancer cell line employed therein. Rather, Ogretmen focuses purely on the lipid metabolism that takes place to create the increased long chain ceramides. Ogretmen states (pg. 12965, left col., 1st. par.), that trypan blue staining used to follow-up on MTT assay results showed that any perceived change in cell number was explicitly not a result of apoptotic cell death. Based on this, applicant respectfully submits that one of ordinary skill in the art would reasonably conclude that A549 cells, and lung cancer as a whole, can be driven towards a prosurvival state with increased long chain ceramides, as compared to AML, where the presently disclosed subject matter demonstrates that the use of short chain ceramides make cancer cells more sensitive to cell death when exposed to both AraC and venetoclax.
And Ogretmen states that treatment with C6 ceramide resulted mainly in the generation of C16:0 and C24:l ceramides. The present application disclosed subject matter is not to increasing long-chain ceramides generally, but to increasing a ratio in which Cl6 and/or Cl8 ceramide is on one side of the ratio and C24 and/or C24:l ceramide is on the other.
This argument has been fully considered, but is not found persuasive, since Ogretmen teaches the exact biological mechanism the applicant is using short-chain ceramides increasing endogenous long-chain ceramides and similarly to the response above including that one with skill in the art, is known for solving the same problem, is represented with design choices, may modify the teachings of the prior arts until they can achieve better outcome results.
Regarding the argument on (pg. 12965, left col., 1st. par.), the underlying chemical and biological property—using short-chain ceramides to increase endogenous long-chain ceramide levels—is identically taught by the prior art reference. A change in the ultimate intended purpose (promoting cell death instead of cell survival) does not render the underlying mechanism novel or non-obvious.
Regarding arguments that Ogretmen teaches treatment with C6 ceramides resulted mainly increasing endogenous long-chain ceramides in the generation of C16:0 and C24:l ceramides, but not the ratios of C16/C18 and/or C24/C24:1, since Ogrement teaches increasing long-chain ceramides generally, optimizing or selecting a specific ratio of those long-chain ceramides like C16/C18 and or C24/C24:1 to achieve a desired effect is generally prima facie obvious. One with skill in the art would have a reasonable expectation of success in achieving a variation or increase in their ratios depending on the dosage, cell type, or conditions taught.
Applicants argue that since the rejection of claims 2, 9 and 39 is not justified by arguments above, so the rejection of claims 2, 4, 40, 42, 43, 61, and 63-70 should be removed.
This argument has been fully considered, but is not found persuasive, since the rejection of claims 2, 9 and 39 are maintained with responses to arguments above so the rejection of claim 2, 4, 40, 42, 43, 61, and 63-70 is maintained.
Conclusion
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 extension fee 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 date of this final action.
Correspondence
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NGOC-ANH THI NGUYEN whose telephone number is (571)270-0867. The examiner can normally be reached Monday - Friday 8:00 am.
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/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
