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
The Response of 12 March 2026 has been entered.
Claims 1-19 are currently pending.
Election/Restrictions
Applicant’s election without traverse of the species of: a KDSR inhibitor as the agent, an agent that inhibits KDSR expression as the KDSR inhibitor, guide RNA as the expression inhibitor, palmitate as the 3KDS precursor, colorectal as the cancer and chemotherapy as the additional therapy, in the reply filed on 12 March 2026 is acknowledged. Applicant requests that siRNA also be considered as a species of expression inhibitor, but siRNA is a distinct agent relative to the elected species of guide RNA and would require different search terms and prior art references. Thus, the examination is limited herein to guide RNA.
In the interest of compact prosecution, the species election requirement for species of cancers is hereby withdrawn.
Claims 3, 9, 18 and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12 March 2026.
Claims 1, 2, 4-8 and 10-17 are considered here with respect to the elected species.
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, 2, 4-8, 10 and 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Liu et al., Leukemia 36.1 (2022): 100-110 (published online 9 Aug. 2021) in view of US20180298392 to Cotta-Ramusino.
Regarding claims 1, 2 and 4-8, Liu teaches that inhibition of KDSR by a guide RNA (gRNA) in a CRISPR/Cas9 system leads to apoptosis and cell cycle arrest in cancer cells (blood cancer) (p. 102-105, under Results; Fig. 2). Liu teaches that inhibition of KDSR expression results in the accumulation of KDS, and that KDS causes significant cytotoxicity (p. 103, 1st full ¶; Fig. 4). Liu teaches that KDSR plays a crucial role in cancer cell survival by maintaining the unfolded protein response (UPR) which plays a vital role in cancer progression, and that the anticancer effects of KDSR inhibition act by inducing ER stress and disrupting the UPR (p. 105, 1st ¶ to p. 107, last full ¶). Liu concludes that KDSR is a candidate therapeutic target for cancer treatment (p. 105, 1st ¶).
Regarding claim 12, Liu teaches anticancer effects against human cancer cell lines (p. 101, under Cell lines and culture conditions) and it would have thus been obvious to carry out such treatment in a human patient.
Regarding claims 13 and 14, Liu teaches that a compound that induces ER stress/UPR disruption (tunicamycin) have a synergistic effect with KDSR disruption on cancer cell cytotoxicity (p. 103, last ¶ to p. 105, 1st ¶; Fig. 5). Liu further teaches that effects of KDSR disruption (which disrupts to conversion of KDS to DHS, leading to KDS accumulation) on cytotoxicity and UPR disruption can be mimicked with exogenous KDS (p. 103, 1st full ¶; Fig. 4). Liu further teaches that KDS "exerted a faster cytotoxic effect (within 48 h of treatment) compared to the genetic suppression of the KDSR gene (takes a longer period to accumulate an excessive KDS)", and that "the amphiphilic nature of KDS (contains a hydrophilic head and a hydrophobic tail) may provide unique opportunities for future combinational therapy. For example, KDS can be formulated as “liposomes” to increase its stability in the aqueous phase, and the inner space of the engineered liposomes is eligible for carrying tunicamycin or other ER stress inducers" (p. 107, 2nd ¶). It would have thus been obvious in view of Liu to combine KDSR inhibition via CRISPR with exogenous KDS and/or an ER stress inducer (i.e. chemotherapy) to synergistically enhance the anticancer effects and/or provide therapeutic effects over different time frames.
Claims 1, 2, 4-8 , 10 and 12-14 differ from Liu in that: the method comprises treating cancer by administering the KDSR expression inhibitor/gRNA to a subject (as opposed to in vitro inhibition in cancer cell lines as taught by Liu) (claim 1); the method comprising administering a nucleic acid encoding Cas9 in a vector (claims 4-6); the vector is a viral vector (claim 7) selected from those in claim 8; the gRNA is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier (claim 10); and the patient is a human (claim 12).
Cotta teaches pharmaceutical compositions for inhibiting the expression of a target gene via CRISPR technology in a human subject, comprising a vector encoding a gRNA and Cas9 and a pharmaceutically acceptable carrier ([0090]; [0103]; [0239]; [0649]; [1231]-[1256]; [1477]; claims 97-100). The vector can be an AAV viral vector ([0103]; [1231]-[1256]). The compositions are useful for treating cancer, e.g. by inhibiting growth of cancer cells ([1479]).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to use CRISPR/Cas9 to inhibit KDSR and thereby inhibit cancer cell growth as taught by Liu, wherein the method is used to treat cancer (e.g., leukemia or another hematopoietic cancer) in a human patient as taught by Cotta because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to use the approach of Liu to treat cancer in a human patient in order to attain a therapeutic benefit from the findings of Liu. Using the approach of Liu to treat cancer in a human patient would have led to predictable results with a reasonable expectation of success because Cotta teaches methods and pharmaceutical compositions (including vectors encoding gRNA and Cas9 endonuclease) useful for inhibiting expression of target genes for the treatment of cancer in human subjects.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of Liu in view of Cotta-Ramusino, as applied to claims 1, 2, 4-8, 10 and 12-14, further in view of Huang et al., Cancer letters 360.2 (2015): 257-268.
Claim 11 differs from the combination of Liu in view of Cotta-Ramusino, as applied to claims 1, 2, 4-8, 10 and 12-14, in that: the cancer is colorectal cancer, fibrosarcoma, lung cancer, brain cancer, breast cancer, or prostate cancer.
Huang teaches that the UPR plays an important role in driving tumor growth, and that a UPR inhibitor compound was effective in inhibiting cell growth and inducing cell cycle arrest and apoptosis against cancer cell lines and tumor xenografts, including human cervical adenocarcinoma cells (HeLa cells and xenografts), human lung cancer cells (A549 and H1299 cells) and human colorectal cancer cells (HCT116) (p. 257-285, under Introduction; p. 258, under Cell lines and culture conditions; p. 259-262, under Results; Figs. 1-3).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to use the method of Liu in view of Cotta to treat cancer via CRISPR inhibition of KDSR wherein the cancer is lung cancer or colorectal cancer as taught by Huang because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to use the method of Liu in view of Cotta to treat lung or colorectal cancer in order to achieve the widest possible range of therapeutic benefits (i.e. one would be motivated to treat any cancer susceptible to treatment, and the teaching in Huang that lung and colorectal cancers can be treated via UPR inhibition indicates that such cancers would be susceptible to treatment). Using the method of Liu in view of Cotta to treat lung or colorectal cancer would have led to predictable results with a reasonable expectation of success because Liu teaches that KDSR plays a crucial role in maintaining the UPR and that the anticancer effects of KDSR inhibition occur via disruption of the UPR, and Huang teaches that the UPR inhibition has anticancer effects on a variety of cancers including lung and colorectal cancer cells. While Liu teaches that KDSR inhibition did not significantly inhibit growth of certain cell lines (including colorectal cancer cell line SW620; see Liu, Fig. 2C), one of ordinary skill would have recognized that various cancer cell lines can have different cancer etiologies and drug susceptibilities. The teachings of Huang showing that the UPR plays an important role in tumorigenesis generally, and that UPR inhibition is effective against different cancer cell types including lung and colorectal cancer cell lines would have given a reasonable expectation of success in using the method of Liu in view of Cotta to treat lung or colorectal cancer.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of Liu in view of Cotta-Ramusino and Huang, as applied to claim 11, further in view of Zhang et al., FEBS Open Bio 9.12 (2019): 2117-2125 and/or Yang et al., Journal of Clinical Oncology 35.26 (2017): 3055-3064.
Claim 15 differs from the combination of Liu in view of Cotta-Ramusino and Huang, as applied to claim 11, in that: the subject consumes a high fat or ketogenic diet.
Zhang teaches that obesity has a significant association with colorectal cancer occurrence, and that adipokines and cytokines induced by a high-fat diet promote the proliferation, migration and invasion of colorectal cancer cells (Abstract).
Yang teaches that dietary fat intake has a significant association with the incidence of lung cancer (Abstract).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to use the method of Liu in view of Cotta and Huang to treat lung or colorectal cancer via inhibition of KDSR wherein the subject consumes a high-fat diet because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to use the method of Liu in view of Cotta and Huang to treat cancer in a subject having a high-fat diet because Zhang and Yang teaches that a high-fat diet has a significant association with the incidence of and/or has causative effects on cancer progression (i.e. it would have been obvious to treat any subject in need of treatment, and Zhang and Yang teach that subjects consuming high-fat diets are at increased cancer risk). Using the method of Liu in view of Cotta and Huang to treat cancer in a subject having a high-fat diet would have led to predictable results with a reasonable expectation of success because such patients could be identified as at risk via routine screening (e.g., intake questioning) and the treating such patients would not require any modification of the treatment method. It is noted that claim 15 requires only that the patient "consumes a high fat or ketogenic diet" and does not recite an affirmative step of administering such a diet as part of the claimed method nor that any particular effect results from the diet.
Claims 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Liu in view of Cotta-Ramusino and Huang, as applied to claim 11, further in view of US20130130966 to Wikman et al.
Claims 16 and 17 differ from the combination of Liu in view of Cotta-Ramusino and Huang, as applied to claim 11, in that: the method further comprises determining expression levels of SPTLC 1 and/or SPTLC2 in the cancer (claim 16); and expression levels of SPTLC1 and/or SPTLC2 in the cancer are predictive of the cancer's sensitivity to inhibition of KDSR (claim 17).
Wikman teaches a method of determining the risk of metastasis and/or of tumor-related death of a patient, comprising measuring the expression of one or more genes that can include SPTLC2 ([0014]-[0035]; claims 1, 8). The tumor can be a colorectal tumor or a lung tumor ([0018]).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to use the method of Liu in view of Cotta and Huang to treat lung or colorectal cancer via inhibition of KDSR wherein the method further comprises measuring expression of SPTLC2 in the tumor because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to use the method of Liu in view of Cotta and Huang to treat lung or colorectal cancer wherein the method further comprises measuring expression of SPTLC2 because Wikman teaches that gene expression profiling including SPTLC2 can measure the risk of metastasis and/or death in the patient. Carrying out the method of Liu in view of Cotta and Huang to treat lung or colorectal cancer wherein the method further comprises measuring expression of SPTLC2 would have led to predictable results with a reasonable expectation of success because Wikman teaches that the method can be used specifically with colorectal or lung tumors, and because gene expression profiling methods are well known in the art (e.g., using methods in [0020]-[0021] of Wikman). It is noted that claim 16 does not require that the step of determining SPTLC1/2 levels is used for any particular purpose or effect in the claimed method. Similarly, claim 17 requires only that "expression levels of SPTLC1 and/or SPTLC2 in the cancer are predictive of the cancer's sensitivity to inhibition of KDSR". The instant specification states that SPTLC1/2 produces KDS which yields anticancer effects, and thus elevated SPTLC1/2 indicates enhanced sensitivity (Published Spec. US20240342255, [0027]-[0029]; Example 6). As such, any level of SPTLC1/2 would inherently be "predictive of the cancer's sensitivity to inhibition of KDSR" (whether elevated or not). Claim 17 does not require that the cancer has any particular level of SPTLC1/2 or that any particular effect is achieved.
Conclusion
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/ROBERT J YAMASAKI/Primary Examiner, Art Unit 1657