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 .
DETAILED ACTION
This Office Action is non-final because it contains new grounds of rejection, to which Applicant has not previously has the opportunity to respond.
Pursuant to the amendment dated 08/06/2025, claims 1, 3, 4, 12, 13, and 15 are amended. Claims 1-20 are pending in the instant application and are examined on the merits herein.
Priority
The instant application is a National State Application of PCT/US2020/059644, filed on 11/09/2020 and claims benefit of 62/933,138 filed on 11/08/2019.
Withdrawn Objections
Applicant’s response, filed on 08/26/2025, with respect to the objection of claim 11 due to informalities has been considered and is persuasive. The phrase “glasdegib” was not misspelled. The objection is withdrawn.
Withdrawn Rejections
Applicant’s amendment, filed on 08/26/2025, with respect to the rejection of claims 1-12 and 26 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement, has been fully considered and is persuasive. Applicant has amended claim 1 to remove the phrase “preventing”. The rejection is hereby withdrawn.
Applicant’s amendment, filed on 08/26/2025, with respect to the rejection of claim 12 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre- AIA 35 U.S.C. 112, the applicant), regards as the invention, has been fully considered and is persuasive. Applicant has amended claim 12 to replace “further comprises” with “is”. The rejection is hereby withdrawn.
Applicant’s amendment, filed on 08/26/2025, with respect to the rejection of claims 1-5, 13, 14, 25, 26, and 35 under 35 U.S.C. 103 as being unpatentable over Loughran (WO 2018/200931 A1, published 11/01/2018, see PTO-892 dated 02/26/2025) in view of Watters (Leukemia & Lymphoma, published 12/31/2012, see PTO-892 dated 02/26/2025) has been fully considered and is persuasive. Loughran does not teach that the liposomes are ceramide nanoliposomes. The rejection is hereby withdrawn.
Applicant’s amendment, filed on 08/26/2025, with respect to the rejection of claims 1-6, 13, 14, 16, 17, and 24-26 under 35 U.S.C. 103 as being unpatentable over Lewis (Cell Death Discovery, published 06/28/2018, see PTO-892 dated 02/26/2025) in view of Loughran (WO 2018/200931 A1, published 11/01/2018, see PTO-892 dated 02/26/2025) has been fully considered and is not persuasive. The rejection has been withdrawn in favor of the modified/new rejection below. The rejection is hereby withdrawn.
Applicant’s amendment, filed on 08/26/2025, with respect to the rejection of claims 1-4, 6-9, 13, 16, and 17 under 35 U.S.C. 103 as being unpatentable over Lewis (Cell Death Discovery, published 06/28/2018, see PTO-892 dated 02/26/2025) in view of Loughran (WO 2018/200931 A1, published 11/01/2018, see PTO-892 dated 02/26/2025), further in view of Wei (J. Clin Oncol, published 03/20/2019, see PTO-892 dated 02/26/2025) has been fully considered and is not persuasive. The rejection has been withdrawn in favor of the modified/new rejection below. The rejection is hereby withdrawn.
Applicant’s amendment, filed on 08/26/2025, with respect to the rejection of claims 1-4, 10-14, 25, and 26 under 35 U.S.C. 103 as being unpatentable over Tiong (Genes Chromosomes Cancer, published 03/01/2019, see PTO-892 dated 02/26/2025) in view of Wei (J. Clin Oncol, published 03/20/2019, see PTO-892 dated 02/26/2025) and Loughran (WO 2018/200931 A1, published 11/01/2018, see PTO-892 dated 02/26/2025) has been fully considered and is not persuasive. The rejection has been withdrawn in favor of the modified/new rejection below. The rejection is hereby withdrawn.
Applicant’s response with respect to the rejection of claims 1-3 and 13-14 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 11, 14, 15, and 17 of US 11426371 B2, in view of Loughran (WO 2018/200931 A1, published 11/01/2018, see PTO-892 dated 02/26/2025) has been fully considered and is persuasive. Neither Loughran ‘371 or Loughran ‘931 teach the composition comprising a specific additional active ingredient such as a ceramide nanoliposome (CNL). The rejection is hereby withdrawn.
New and Maintained Rejections
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3, 5, 6, 8-11, 24, and 25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 3, 5, 8-11, 24, and 25, the phrase "optionally" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claims 6, 8, 10, and 11, the phrase "and/or" renders the claim indefinite because it is unclear whether the limitations are required to be in combination or in the alternatives. For the purposes of applying prior art, the examiner will interpret the “and/or” in the alternative as “or”.
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.
Claims 1-5, 10, 13, 14, 24, 26, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Loughran (WO 2018/200931 A1, published 11/01/2018, see PTO-892 dated 02/26/2025) and Tan et al. (Expert Opinion on Therapeutic Targets, published 04/19/2017, see PTO-892) as evidenced by Zhang et al. (Blood, published 12/03/2015, see PTO-892).
Loughran drawn to the use of SACLAC as an acid ceramidase (AC) inhibitor for the treatment of acute myeloid leukemia (AML) (abstract). Loughran teaches a pharmaceutical composition comprising a therapeutically effective amount of at least one AC inhibitor and the AC inhibitor may be SACLAC (page 4, lines 24-26). Loughran teaches that the compounds may be administered to a mammalian host (page 27, line 25). Loughran further teaches the composition of SACLAC encapsulated in liposomes which can be comprised of a polyol such as polyethylene glycols (page 29, lines 1-8). Loughran teaches that the SACLAC blocks a common mechanism of ceramide detoxification in AML and is likely to provide therapeutic benefit by facilitating ceramide accumulation and apoptotic death of the proliferative cells (page 35, lines 16-18. Loughran teaches that an additional therapeutic agent may be administered along with SACLAC (page 4, lines 29-30). Loughran teaches the pharmaceutical composition may further comprise one or more additional therapeutic agents (page 25, lines 10-11).
Regarding instant claim 24, Loughran teaches that SACLAC exhibited efficacy in all cell lines testing including drug resistant variants HL60/ABTR, HL60/VCR, KGlA-R and KG1-R. As evidenced by Zhang, KG1-R is a venetoclax-resistant AML cell line.
Loughran does not specify the additional therapeutic agents as recited in instant claim 1.
Tan is drawn to the study of the emergence of acid ceramidase as a therapeutic target for acute myeloid leukemia (title). Tan teaches that AC has emerged as a promising therapeutic target due to its role in neutralizing the pro-death effects of ceramide. Tan teaches that AC inhibitors may prove more effective when combined with other sphingolipid modulators such as exogenous short chain ceramide nanoliposomes (CNL) and that additional studies of AC inhibitors are needed in combination with existing AML therapies (page 588). Tan teaches that DNA hypomethylating agents such as azacitidine and decitabine can increase survival in a fraction of older AML patients (page 583).
Regarding instant claims 1-5, 13 and 14, it would have been prima facie obvious to combine the teachings of Loughran and Tan before the effective filing date of the claimed invention by selecting CNL as the additional therapeutic agent as taught by Tan in the method of treating AML with SACLAC as taught by Loughran to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to combine SACLAC with an additional therapeutic agent such as CNL because Tan teaches that AC inhibitors may be more effective when combined with CNL and Laughran teaches that SACLAC is an AC inhibitor that may be combined with other therapeutic agents. One of ordinary skill in the art would have a reasonable expectation of success because Tan teaches that AC inhibitors may be more effective when combined with CNL and Laughran teaches that SACLAC is an AC inhibitor that may be combined with other therapeutic agents.
Regarding instant claim 10, it would have been prima facie obvious to combine the teachings of Loughran and Tan before the effective filing date of the claimed invention by selecting either decitabine or azacitidine as the additional therapeutic agent as taught by Tan in the method of treating AML with SACLAC as taught by Loughran to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to combine SACLAC with an additional therapeutic agent such as CNL because Tan teaches that studies with AC inhibitors are needed in combination with existing AML therapies and that azacitidine and decitabine are existing AML therapies and Laughran teaches that SACLAC is an AC inhibitor that may be combined with other therapeutic agents. One of ordinary skill in the art would have a reasonable expectation of success because Tan teaches that studies with AC inhibitors are needed in combination with existing AML therapies and that azacitidine and decitabine are existing AML therapies and Laughran teaches that SACLAC is an AC inhibitor that may be combined with other therapeutic agents.
Claims 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Loughran (WO 2018/200931 A1, published 11/01/2018, see PTO-892 dated 02/26/2025) and Tan et al. (Expert Opinion on Therapeutic Targets, published 04/19/2017, see PTO-892) as applied to claim 1 above, and further in view of Pereg et al. (US 2019/0046602, published 02/14/2019, see PTO-892).
Claim 1 is rejected as discussed above.
The combined teachings of Loughran and Tan are discussed above.
The combined teachings of Loughran and Tan do not teach that the additional therapeutic agents may be gemtuzumab ozogamicin or midostaurin.
Pereg is drawn to methods of treating AML (title). Pereg teaches a method of treating AML that includes administering to a subject a therapeutically effective amount of a CXCR4 antagonist and a therapeutically effective amount of a chemotherapeutic agent (abstract).Pereg teaches that the chemotherapeutic acgent may be cytarabine (cytosine arabinoside, Ara-C, Cytosar-U), quizartinib (AC220), sorafenib (BAY 43-9006), lestaurtinib (CEP-701), midostaurin (PKC412), carboplatin, carmustine, chlorambucil, dacarbazine, ifosfamide, lomustine, mechlorethamine, procarbazine, pentostatin, (2′deoxycoformycin), etoposide, teniposide, topotecan, vinblastine, vincristine, paclitaxel, dexamethasone, methylprednisolone, prednisone, all-trans retinoic acid, arsenic trioxide, interferon-alpha, rituximab (Rituxan®), gemtuzumab ozogamicin, imatinib mesylate, Cytosar-U), melphalan, busulfan (Myleran®), thiotepa, bleomycin, platinum (cisplatin), cyclophosphamide, Cytoxan®), daunorubicin, doxorubicin, idarubicin, mitoxantrone, 5-azacytidine, cladribine, fludarabine, hydroxyurea, 6-mercaptopurine, methotrexate, 6-thioguanine, or any combination thereof (paragraph 0152).
Regarding instant claims 11 and 12, it would have been prima facie obvious to combine the combined teachings of Loughran and Tan with the teachings of Pereg before the effective filing date of the claimed invention by selecting either gemtuzumab ozogamicin or midostaurin as the additional therapeutic agent as taught by Pereg in the method of treating AML with a with SACLAC as taught by Loughran to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to combine SACLAC with an additional therapeutic agent such as gemtuzumab ozogamicin or midostaurin because Tan teaches that studies should be done with existing AML therapies in combination with AC inhibitors, Loughran teaches the use of the AC inhibitor, SACLAC, for treating AML, and Pereg teaches that gemtuzumab ozogamicin or midostaurin may be used as chemotherapeutics in the treatment of AML. One of ordinary skill in the art would have a reasonable expectation of success because because Tan teaches that studies should be done with existing AML therapies in combination with AC inhibitors, Loughran teaches the use of the AC inhibitor, SACLAC, for treating AML, and Pereg teaches that gemtuzumab ozogamicin or midostaurin may be used as chemotherapeutics in the treatment of AML.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Loughran (WO 2018/200931 A1, published 11/01/2018, see PTO-892 dated 02/26/2025) and Tan et al. (Expert Opinion on Therapeutic Targets, published 04/19/2017, see PTO-892) as applied to claim 13 above, and further in view of Gunderson (The production and characterization of drug-loaded liposomal and PLGA nanocarriers for targeted treatment of acute myeloid leukemia, published 06/2016, see PTO-892).
Claim 13 is rejected as discussed above.
The combined teachings of Loughran and Tan are discussed above.
Loughran further teaches that SACLAC exhibits low solubility in vehicles for IV drug delivery and suboptimal uptake following i.p. injections (page 36, lines17-19). Drug delivery must be further enhanced in order to achieve additional reduction in leukemic burden and induce remission or cure (page 37, lines 3-5).
The combined teachings of Loughran and Tan do not teach that the AC inhibitor and/or the one or more additional active agents is encapsulated in a polymer nanoparticle, wherein the polymer nanoparticle comprises a biodegradable and biocompatible polymer.
Gunderson is drawn to the study of the production and characterization of drug-loaded liposomal and PLGA nanocarriers for targeted treatment of acute myeloid leukemia (title). Gunderson teaches that the advantages of the use of nanocarrier formulations is the ability to load/encapsulate or bind drugs and therapeutic agents to nanocarriers. Encapsulation enables the use of insoluble drugs by stably incorporating them into hydrophobic microenvironments of nanocarriers. Gunderson teaches that multiple drugs may be loaded onto the same nanocarrier at certain ideal ratios if necessary, as is the case for the daunorubicin-cytarabine loaded liposomal formulation CPX-351, currently in clinical trials for treatment against AM (page 5). Gunderson exemplifies the use of PLGA-PEG nanoparticles for drug encapsulation and release of chlorpromazine (page 27).
It would have been prima facie obvious to combine the combined teachings of Loughran and Tan with the teachings of Gunderson before the effective filing date by encapsulating the AC inhibitor taught by Loughran into the PEG-PGLA nanoparticle taught by Gunderson to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to encapsulate the AC inhibitor, SACLAC, into the PEG-PGLA nanoparticle taught by Gunderson because Loughran teaches that SACLAC has low solubility and Gunderson teaches that PGLA nanocarriers can enable the use of insoluble drugs by incorporating them into hydrophobic microenvironments of nanocarriers. One of ordinary skill in the art would have a reasonable expectation of success because Loughran teaches that SACLAC delivery must be further enhanced in order to achieve additional reduction in leukemic burden and induce remission and Gunderson teaches that PGLA nanocarriers can enable the use of insoluble drugs by incorporating them into hydrophobic microenvironments of nanocarriers.
Claims 1-4, 6, 7, 9, 13, 14, 16, 17 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Loughran (WO 2018/200931 A1, published 11/01/2018, see PTO-892 dated 02/26/2025) and Lewis (Cell Death Discovery, published 06/28/2018, see PTO-892 dated 02/26/2025).
The teachings of Loughran are discussed above.
Loughran further teaches that sphingolipid metabolism produces bioactive signaling molecules that regulate cell survival and differentiation. Ceramide, sphingosine, and sphingosine 1-phosphate (S1P) represent the bioactive core of the complex sphingolipid synthetic and inter-conversion pathways. Ceramide can be cleaved by a ceramidase to produce sphingosine, which is subsequently phosphorylated by sphingosine kinase (SK) to produce S1P. Ceramide accumulation induces cell death mechanisms while S1P promotes survival through receptor dependent or independent signaling pathways that play a key role in response to therapy. Ceramide and S1P also exert opposing effects on apoptotic regulators of the Bcl-2 family. Ceramide decreases Mcl-1 but S1P promotes Mcl-1 expression. Mcl-1 is a key survival protein and promising therapeutic target that is able to prevent apoptosis and mediate resistance to Bcl-2 targeting agents (page 2, lines 7-17). Treatment with SACLAC reduces S1P in AML cells (page 4, line 5).
Loughran does not specify the additional therapeutic agents may be a Bcl-2 inhibitor or cytarabine (AraC).
Lewis teaches the administration of venetoclax for treatment of AML. Lewis teaches that ceramides are deacylated by ceramidases to form sphingosine and subsequently, through the action of sphingosine kinases (SPHKs), generate sphingosine-2-phosphate (S1P). Notably, considerable evidence implicates important roles for several of these sphingolipid metabolic enzymes in tumorigenesis and resistance to therapy in hematological malignancies (page 2, column 2). Lewis also teaches that overexpression of AC can reduce the effectiveness and suggests that combining a Bcl-2 inhibitor with another compound for AC inhibition for treatment (column 2, page 6). Lewis teaches that treatment with cytarabine has a synergistic effect when combined with SPHK1 inhibition (page 6, column 2). SPHK1 inhibition is linked with Mcl-1 degradation and Mcl-1 is a marker of resistance to venetoclax. Therefore, it can be inferred that inhibition of SPHK1 with cytarabine could work to overcome venetoclax resistance in AML (page 7, column 1). Lewis further teaches that the targeting of Mcl-1 through AC inhibition warrants further investigation in combination with Bcl-2 inhibitor, Venetoclax (page 6, column 2).
It would have been prima facie obvious to combine the teachings of Loughran and Lewis before the effective filing date of the claimed invention selecting venetoclax as the additional therapeutic agent as taught by Lewis in the method of treating AML with SACLAC as taught by Loughran to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to select venetoclax as the additional therapeutic agent because Lewis teaches combining a Bcl-2 inhibitor such as venetoclax with another compound for AC inhibition for treatment and Loughran teaches the administration of SACLAC, an AC inhibitor, with additional therapeutic agents for treatment of AML. One of ordinary skill in the art would have a reasonable expectation of success Lewis teaches combining a Bcl-2 inhibitor with an AC inhibitor for treating AML.
It would have been prima facie obvious to combine the teachings of Loughran and Lewis before the effective filing date of the claimed invention by selecting AraC as the additional therapeutic agents as taught by Lewis in the method of treating AML with SACLAC as taught by Loughran to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to select AraC as the additional therapeutic agents because Lewis teaches AraC can work synergistically with SPHK1 inhibition and Loughran teaches the administration of SACLAC, an AC inhibitor, with additional therapeutic agents for treatment of AML. One of ordinary skill in the art would have a reasonable expectation of success Lewis teaches inhibition of SPHK1 with cytarabine could work to overcome venetoclax resistance in AML and Loughran teaches that SACLAC reduces S1P in AML cells.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Loughran (WO 2018/200931 A1, published 11/01/2018, see PTO-892 dated 02/26/2025) and Lewis (Cell Death Discovery, published 06/28/2018, see PTO-892 dated 02/26/2025) as applied to claims 1 and 6 above, and further in view of Wei et al. (J. Clin Oncol, published 03/20/2019, see PTO-892 dated 02/26/2025).
Claims 1 and 6 are rejected as discussed above.
The combined teachings of Loughran and Lewis are discussed above.
The combined teachings of Loughran and Lewis do not teach administration of the combination of the additional active agents venetoclax and cytarabine.
Wei is drawn to the study of venetoclax combined with low-dose cytarabine for patients with AML (title). Wei teaches that cytarabine had demonstrated the ability to down regulate Mcl-1 expression and act synergistically with venetoclax against AML (column 1, page1278).
It would have been prima facie obvious to combine the combine teachings of Loughran and Lewis with the teachings of Wei before the effective filing date of the claimed invention by selecting the combination of cytarabine and venetoclax as taught by Wei as the additional therapeutic agents with SACLAC for the treatment of AML taught by Loughran to arrive at the claimed invention. It would have been prima facie obvious for a person of ordinary skill in the art to select the combination of cytarabine and venetoclax as additional therapeutic agents in combination with SACLAC for the treatment of AML because Wei teaches that cytarabine and venetoclax work synergistically against AML, Lewis a Bcl-2 inhibitor combined with another compound for AC inhibition for treatments, and Loughran teaches that SACLAC is an AC inhibitor that may be used in combination with other therapeutics for the treatment of AML. One of ordinary skill in the art would have a reasonable expectation of success because Wei teaches that cytarabine and venetoclax work synergistically against AML, Lewis a Bcl-2 inhibitor combined with another compound for AC inhibition for treatments, and Loughran teaches that SACLAC is an AC inhibitor that may be used in combination with other therapeutics for the treatment of AML
Response to Arguments
Applicant’s arguments are moot because the previous rejections have all been withdrawn. However, to the extent the arguments are considered applicable to new grounds presented above, applicant argues that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Loughlan teaches the administration of SACLAC as an AC inhibitor for the treatment of AML and teaches that it may be administered with additional active agents. One of ordinary skill in the art would have the predictable result of treating AML when administering SACLAC that Loughran teaches may be used to treat AML and combined with additional active ingredients that are also taught to be used for treatment of AML.
Conclusion
No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA LYNN SCHACHERMEYER whose telephone number is (703)756-5337. The examiner can normally be reached Monday thru Friday, alternate Fridays off, 7:30AM-5PM EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Goon can be reached on (571) 270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format.
For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SAMANTHA LYNN SCHACHERMEYER/Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693