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 .
Priority
The present application claimed priority to the following applications: 63/142,566 and PCT/IL2022/050120, with effective filing dates of 28 January 2021 and 27 January 2022, respectively.
Claim Status
This Office Action is in response to Applicant’s Amendment filed, 18 May 2026, wherein the Applicant amended claims 1-2, 4-5, 9, 23, 26, 30, and 32, canceled claim 39, and added new claim 43. Claims 9-10, 12-13, 17, 29, and 31 were previously withdrawn.
Claims 1-2, 4-5, 19, 23-26, 30, 32-33, and 43 are pending.
Information Disclosure Statement
The Information Disclosure Statement filed on 18 May 2026 and the references cited therein have been considered, unless indicated otherwise.
Claim Interpretation
For purposes of clarity, the Examiner notes that claims 1 and 43 (two of the three independent claims) are subject matter eligible. The subject matter eligibility analysis is as follows:
-Claims 1 and 43 recite methods of determining suitability of a subject in need thereof to be treated with a microtubule targeting agent, the method comprising receiving a sample from said subject, measuring SETDB1 expression, and determining suitability based on said SETDB1 expression and possibly administering a microtubule targeting agent (Step 1: Yes),
-Claims 1 and 43 step of determining suitability of a patient for treatment with a microtubule targeting agent (a mental step and thus an abstract idea) based on the natural law correlating expression of SETDB1 in a subject with suitability for treatment. Accordingly, claims 1 and 43 qualify as judicial exceptions (Step 2A Prong 1: Yes),
-Claim 1 and 43 recite steps in addition to the judicial exception: receiving a sample and measuring SETDB1 expression (data-gathering steps, which do not apply the judicial exception and thus do not integrate the judicial exception into a practical application either alone or together) and administer a microtubule targeting agent (applies the judicial exception under MPEP § 2106.04(d)(2)) (Step 2A Prong 2: Yes), and
-Claim 1 and 43 recite an additional element (administration of a microtubule targeting agent) that requires the application of the data-gathering steps and has more than a nominal relationship to the judicial exception (Step 2B: Yes).
Additionally, the instances wherein the subject is suitable for treatment is not enough to render the claim as a whole subject matter ineligible. Accordingly, claims 1 and 43 are subject matter eligible. The Examiner notes that final independent claim, claim 32, recites a method of treating and is thus subject matter eligible.
Further, for purposes of clarity, the Examiner interprets a subject in need thereof to be treated with a microtubule target agent in claims 1 and 43 to be a SETDB1-associated disease or condition.
Additionally, it is noted that in the Response to Restriction Requirement filed 1/11/2026 that Applicant elected a taxane as the compound and breast cancer as the disease.
Rejections Withdrawn
Claim Rejections – 35 U.S.C. § 112
1. Claims 1-2 were rejected for failing to comply with the written description requirement. Claim 1 was amended to recite the predetermined threshold is an expression level of SETDB1 in a healthy control sample. Claim 2 was amended to recite the predetermined threshold is an expression level of SETDB1 in a sample comprising cells that do not comprise a duplication of the SETDB1 locus. Applicant’s amendment, see page 2, with respect to claims 1-2 has been fully considered. The rejection of claim 1-2 has been withdrawn.
2. Claim 32 was rejected for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention, in particular limitation (i) and (ii) recited a microtubule stabilizing agent that would both reduce microtubule stability by increasing SETDB1 expression and increase microtubule stability by decreasing SETDB1 expression. Applicant’s amendment, see page 5, with respect to claim 32, has been fully considered. The rejection of claim 32 has been withdrawn.
Claim Rejections – 35 U.S.C. § 102
3. Claims 1-2, 4-5, 24-25, and 30 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Emran (Oncotarget, 2018, 9(9), 8206-8222; of record, see PTO-892 mailed 23 Feb 2026) as evidenced by Wikipedia 1 (“Small Molecule,” Wikipedia, 2020, <web.archive.org/web/20200112030154/https://en.wikipedia.org/wiki/Small_molecule>,
accessed 12 February 2026; of record; see PTO-892 mailed 23 Feb 2026) and Wikipedia 2 (“Taxane,” Wikipedia, 2020, < <web.archive.org/web/20200301173544/https://en.wikipedia.org/wiki/Taxane>, accessed
12 February 2026; of record, see PTO-892 mailed 23 Feb 2026).
Applicant amended claim 1 (the independent claim) to specify the method receives a sample from the subject before treatment with the microtubule targeting agent, wherein Emran teaches measuring SETDB1 expression post-docetaxel administration (page 8212, column 2, paragraph 1). Applicant’s amendment, see page 2, with respect to claims 1-2, 4-5, 24-25, and 30 has been fully considered. The 102(a)(1) rejection of claims 1-2, 4-5, 24-25, and 30 has been withdrawn.
Claim Rejections – 35 U.S.C. § 103
4. Claims 19, 23, 26, and 32-33 were rejected under 35 U.S.C. 103 as being unpatentable over Emran (Oncotarget, 2018, 9(9), 8206-8222; of record, see PTO-892 mailed 23 Feb 2026) as evidenced by Wikipedia 1 (“Small Molecule,” Wikipedia, 2020, <web.archive.org/web/20200112030154/https://en.wikipedia.org/wiki/Small_molecule>,
accessed 12 February 2026; of record; see PTO-892 mailed 23 Feb 2026) and Wikipedia 2 (“Taxane,” Wikipedia, 2020, < <web.archive.org/web/20200301173544/https://en.wikipedia.org/wiki/Taxane>, accessed
12 February 2026; of record, see PTO-892 mailed 23 Feb 2026) in view of Batham (Cancers, 2019, 11(1143), 1-20; of record, see PTO-892 mailed 23 Feb 2026).
Applicant amended claims 1 and 32 (the independent claims) to specify the method receives a sample from the subject before treatment with the microtubule targeting agent (claim 1) and the subject is naïve to treatment with an agent that reduces microtubule stability or increases microtubule stability (claim 32). Applicant’s amendment, see pages 2 and 5, with respect to claims 19, 23, 26, and 32-33 has been fully considered. The 103 rejection of claims 19, 23, 26, and 32-33 over Emran in view of Batham has been withdrawn.
Rejections New/Modified and Maintained
Claim Rejections – 35 U.S.C. § 112
5. (Maintained) Claim 30 was rejected for failing to further limit the subject matter of the claim upon which it depends.
Applicant’s amendment and arguments, see page 5 and 8, with respect to the rejection of claim 30 have been fully considered but they are not persuasive.
Applicant amended claim 30 to recite “said method further comprises.” Applicant asserts that claim 30 requires in addition to administering a microtubule stabilizing agent the method requires also decreasing HDAC6 expression, function, or both, which is not an inherent characteristic of the stabilizing agent. Applicant asserts the amendment recites an additional step.
The Examiner notes that Figure 7A-C describes the relationship between SETDB1 and HDAC6 (see the specification, [058]). Additionally, the specification describes that there is an interaction between SETDB1 and the tubulin deacetylase, HDAC6, wherein knockdown of SETDB1 increased tubulin acetylation levels, which suggests that SETDB1 affects microtubule dynamics and supports HDAC6 activity (see the specification, [059]). The specification further teaches that there is an in vivo interaction between SETDB1 and HDAC6 and that SETDB1 serves as a co-factor of HDAC6 in the cytoplasm to support tubulin deacetylation to regulate microtubule dynamic (see the specification, Example 5; [0141]; Figures 7A-C). Accordingly, administering a microtubule stabilizing agent, such as a taxane, would also decrease HDAC6 expression, and thus, claim 30 does not recite an additional step.
Thus, the rejection of claim 30 as being unpatentable under 35 U.S.C. § 112(d) is maintained.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
6. (New as necessitated by amendments) Claim 1-2, 4-5, 19, 23-26, 30, 32-33, and 43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of determining suitability of in need thereof to be treated with a microtubule targeting agent and treating a subject suffering from acute myeloid leukemia (AML), the specification does not reasonably provide enablement for treating any and all SETDB1-associated diseases (e.g. breast cancer, melanoma, colon cancer, lung cancer, ovarian cancer, schizophrenia, Huntington’s, and autism spectrum disorder). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The criteria for enablement set out in the In re Wands, MPEP § 2164.01(a), considers the following factors:
Breadth of the Claims
The instant claims are directed to a method of determining suitability of a subject in need thereof to be treated with a microtubule targeting agent (a subject suffering from a SETDB1-associated condition or disease) and treating a subject suffering from a SETDB1-associated cancer. Thus, encompassing all SETDB1-associated diseases and all SETDB1-associated cancers.
Level of Skill in the Art
The level of skill in the art is a clinician or an artisan with a PhD.
State of the Art
Emran (Oncotarget, 2018, 9(9), 8206-8222; of record, see PTO-892 mailed 23 Feb 2026) teaches upregulation of SETDB1 in WM1366 (melanoma), WM164 (melanoma), A549 (lung), and HT29 (colon) cancer cell lines (page 8207, column 2, paragraphs 1 and 2; page 8212, column 2, paragraph 1). Thus, SETDB1 is overexpressed in melanoma, lung, and colon cancer cell lines compared to a healthy control.
Ropa (Haematologica, 2020, 105(a), 2273-2285) teaches that SETDB1 expression is lower in AML patient samples compared to normal hematopoietic cells (page 2274, column 2, paragraph 7). Ropa teaches that epigenetic regulators play a critical role in normal and malignant hematopoiesis. Ropa teaches that SETDB1 is an oncogene in melanoma, breast cancer, liver cancer, and lung cancer (page 2274, column 1, paragraph 2). Ropa teaches that SETDB1 is amplified in melanoma, which results in aberrant binding and regulation of the HOXA locus (page 2274, column 1, paragraph 2). Ropa teaches that SETDB1 differs in squamous tumors in that depletion of H3K9 methyltransferase G9a leads to a delayed, more aggressive phenotype due to expanded cancer progenitor pools with increased genomic instability (page 2274, column 1, paragraph 2). Ropa teaches that loss of G9a has no effect on hematopoietic stem cells, and SETDB1 is required for both hematopoietic stem and progenitor cell maintenance and leukemic stem cells (page 2274, column 1, paragraph 2). Ropa further teaches that SETDB1 mediated silencing of endogenous retroviral elements is required for the growth of AML cell lines and that SETDB1 negatively regulates the expression of the pro-leukemic Hoxa9 and Meis1 genes , which implies a more complex role for H3K9 methylation in AML wherein H3K9 methyltransferases display both oncogenic and suppressive roles (page 2274, column 1, paragraph 2). Ropa teaches that AML patients with higher expression of SETDB1 display a better prognosis, consistent with repression of HOXA9 and MEIS1 expression (page 2274, column 1, paragraph 3). Ropa teaches that SETDB1 overexpression induces cellular differentiation and delays disease onset in a mouse model of AML, recapitulating AML patient survival (page 2274, column 1, paragraph 3). Thus, SETDB1 is overexpressed in melanoma, breast cancer, liver cancer, and lung cancer as compared to a healthy control, and SETDB1 is under-expressed in AML as compared to a healthy control.
Johnson (Immunology, 2023, 169, 1-12) teaches that SETDB1 is overexpressed in cancer, particularly that of multiple myeloma, breast cancer, lung adenocarcinoma, stomach adenocarcinoma, colon adenocarcinoma, and glioblastoma (abstract, page 6, column 2, paragraph 2; page 7, column 1, paragraph 1). Johnson teaches that SETDB1 is a significant contributor to cell viability and survival in acute myeloid leukemia (AML; page 8, column 1, paragraph 2). Johnson teaches that patients expressing lower SETDB1 levels have significantly longer progress-free survival compared to higher SETDB1 expressing patients undergoing radiotherapy in non-small-cell lung cancer and skin cutaneous melanoma (page 9, column 1, paragraph 1). Johnson teaches SETDB1 is upregulated in autism (page 10, column 1, paragraph 2; page 10, column 2, paragraph 1). Thus, SETDB1 is overexpressed in multiple myeloma, breast cancer, lung adenocarcinoma, stomach adenocarcinoma, and colon adenocarcinoma as compared to a heathy control, and SETDB1 is under-expressed in AML as compared to a healthy control.
Markouli (Progress in Neurobiology, 2021, 200(101968), 1-11) teaches that SETDB1 is upregulated in brain tumors, schizophrenia (and other mood related and cognition disorders), Huntington’s, and Prader-Willi syndrome (Table 1, page 4). However, Markouli teaches that SETDB1 is downregulated in autism spectrum (Table 1, page 4). Thus, SETDB1 is overexpressed in brain tumors, schizophrenia (among other mood related and cognition disorders), Huntington’s Disease, and Prader-Willi syndrome as compared to healthy control.
However, Tovo (Int. J. Mol. Sci., 2022, 23, 5964) teaches that SETDB1 is upregulated along with TRIM28 in autism spectrum disorder (abstract; page 11, paragraph 5). Thus, it is unclear if SETDB1 is overexpressed or under-expressed in autism spectrum disorder as the art conflicts as to the expression level of SETDB1 as compared to a healthy control.
Predictability in the Art
Johnson teaches that continued research must be done to fully understand the effect of SETDB1 on the immune system in a wide range of cancers (page 11, column 1, paragraph 1). Johnson further questions if there are differences in the mechanisms altered by SETDB1 overexpression in different cancers and if those differences would affect drug treatments (page 11, column 1, paragraph 1). Johnson teaches that finding the optimal level of decreased SETDB1 expression in cancer cells, without completely diminishing SETDB1 expression in immune cells is critical as well as identifying differences in repressing components that SETDB1 forms in cancer cells versus in immune cells (page 11, column 1, paragraph 1), underscoring the unpredictability in the art.
Ropa further teaches that SETDB1 mediated silencing of endogenous retroviral elements is required for the growth of AML cell lines and that SETDB1 negatively regulates the expression of the pro-leukemic Hoxa9 and Meis1 genes, which implies a more complex role for H3K9 methylation in AML wherein H3K9 methyltransferases display both oncogenic and suppressive roles (page 2274, column 1, paragraph 2), highlighting the unpredictability in the art.
Markouli (Progress in Neurobiology, 2021, 200(101968), 1-11) teaches that SETDB1 is downregulated in autism spectrum (Table 1, page 4). However, Tovo (Int. J. Mol. Sci., 2022, 23, 5964) teaches that SETDB1 is upregulated along with TRIM28 in autism spectrum disorder (abstract; page 11, paragraph 5). Thus, it is unclear if SETDB1 is overexpressed or under-expressed in autism spectrum disorder as the art conflicts as to the expression level of SETDB1 as compared to a healthy control, emphasizing the unpredictability in the art.
Working Examples
While the instant specification teaches a prophetic example of assessing the effect of SETDB1 on cell sensitivity to microtubule-targeting agents, specifically paclitaxel (a microtubule stabilizing agent) and vinblastine (a microtubule disrupting agent) in the breast cancer cell line, MDA-231, with overexpressed and knocked-out SETDB1 levels ([0144]), the instant specification teaches that SETDB1 is overexpressed in various cancer types ([0144]). Accordingly, the instant specification does not teach administration of a microtubule targeting agent in any SETDB1-associated cancer or SETDB1-associated condition/disease wherein SETDB1 is present but under-expressed relative to a healthy sample.
Quantity of Experimentation
The amount of experimentation required to determine which microtubule targeting agent, which disease, in which subject, in what amounts, what order, would be astronomical. A skilled artisan would be required to state with proof-of-concept and proceed through all levels of lead identification and optimization, which is invention and not development; this is an unduly burdensome amount of experimentation.
As such, while the specification is enabling for a method of determining suitability of in need thereof to be treated with a microtubule targeting agent and treating a subject suffering from acute myeloid leukemia (AML), it does not reasonably provide enablement for treating any and all SETDB1-associated diseases (e.g. breast cancer, melanoma, colon cancer, lung cancer, ovarian cancer, schizophrenia, Huntington’s, and autism spectrum disorder).
Claim Rejections – 35 U.S.C. § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
7. (New as necessitated by amendments) Claims 1-2, 4-5, 24-26, 30, and 43 are rejected under 35 U.S.C. § 103 as being unpatentable over Emran (Oncotarget, 2018, 9(9), 8206-8222; of record, see PTO-892 mailed 23 Feb 2026) as evidenced by Wikipedia 1 (“Small Molecule,” Wikipedia, 2020, <web.archive.org/web/20200112030154/https://en.wikipedia.org/wiki/Small_molecule>,
accessed 12 February 2026; of record; see PTO-892 mailed 23 Feb 2026) and Wikipedia 2 (“Taxane,” Wikipedia, 2020, < <web.archive.org/web/20200301173544/https://en.wikipedia.org/wiki/Taxane>, accessed
12 February 2026; of record, see PTO-892 mailed 23 Feb 2026) in view of Ropa (Haematologica, 2020, 105(a), 2273-2285) as evidenced by Wikipedia 3 (“Cytoplasm,” Wikipedia, 2026, < en.wikipedia.org/wiki/Cytoplasm>, accessed 11 June 2026) and Wikipedia 4 (“Eukaryote,” Wikipedia, 2026, < en.wikipedia.org/wiki/Eukaryote>, accessed 11 June 2026).
Emran teaches epigenetic reprogramming can lead to acquired drug resistance and identified early stress-induced multi-drug tolerant cancer cells in multiple cancer lines, such as breast cancer (abstract).
Emran specifically teaches silencing of SETDB1 reverses drug tolerance and higher expression of SETDB1 in drug resistant models of cancer (abstract; page 8212 column 2, paragraph 1). Emran specifies that chronic exposure to docetaxel (a taxane, see the specification, page 4, [013]) at high concentrations led to a similar transition to the IDTC (induced drug-tolerant cells) state which involves SETDB1 up-regulation, which Emran teaches corresponds with higher expression of SETDB1 (page 8212, column 2, paragraph 1). Emran further teaches that SETDB1 up-regulation suggests increased expression of SETDB1, which stabilizes H3K9me3 and is characteristic across different cancer types as a generic response toward stress (page 8212, column 2, paragraph 1). Emran further specifies that silencing of SETDB1 restores drug sensitivity with dabrafenib due to a significant reduction of H3K9me3 and that knockdown inhibited the acquisition of induced drug tolerance (page 8212, column 2, paragraph 2). Emran further teaches that shSETDB1 cells exposed to high concentrations of docetaxel were sensitive to the small molecule (page 8212, column 2, paragraph 2). Emran further teaches upregulation of SETDB1 in WM1366 (melanoma), WM164 (melanoma), A549 (lung), and HT29 (colon) cancer cell lines (page 8207, column 2, paragraphs 1 and 2; page 8212, column 2, paragraph 1).
Regarding claim 1, Emran fails to teach measuring SETDB1 expression and then administering a taxane.
Ropa teaches that SETDB1 expression is lower in AML patient samples compared to normal hematopoietic cells (page 2274, column 2, paragraph 7). Ropa teaches that epigenetic regulators play a critical role in normal and malignant hematopoiesis. Ropa teaches that SETDB1 is an oncogene in melanoma, breast cancer, liver cancer, and lung cancer (page 2274, column 1, paragraph 2). Ropa teaches that SETDB1 is amplified in melanoma, which results in aberrant binding and regulation of the HOXA locus (page 2274, column 1, paragraph 2). Ropa teaches that SETDB1 differs in squamous tumors in that depletion of H3K9 methyltransferase G9a leads to a delayed, more aggressive phenotype due to expanded cancer progenitor pools with increased genomic instability (page 2274, column 1, paragraph 2). Ropa teaches that loss of G9a has no effect on hematopoietic stem cells, and SETDB1 is required for both hematopoietic stem and progenitor cell maintenance and leukemic stem cells (page 2274, column 1, paragraph 2). Ropa further teaches that SETDB1 mediated silencing of endogenous retroviral elements is required for the growth of AML cell lines and that SETDB1 negatively regulates the expression of the pro-leukemic Hoxa9 and Meis1 genes , which implies a more complex role for H3K9 methylation in AML wherein H3K9 methyltransferases display both oncogenic and suppressive roles (page 2274, column 1, paragraph 2). Ropa teaches that AML patients with higher expression of SETDB1 display a better prognosis, consistent with repression of HOXA9 and MEIS1 expression (page 2274, column 1, paragraph 3). Ropa teaches that SETDB1 overexpression induces cellular differentiation and delays disease onset in a mouse model of AML, recapitulating AML patient survival (page 2274, column 1, paragraph 3). Ropa teaches that loss of SETDB1 is detrimental to leukemic cells due to derepression of endogenous retroviral elements and inhibition of HOXA9 transcriptional activity (page 2284, column 2, paragraph 2). Ropa teaches that SETDB1 and H3K9 methylation suppresses AML disease progression in vivo through the repression of pro-leukemic genes including direct MLL-fusion protein targets (page 2284, column 1, paragraph 2). Ropa teaches that overexpression of SETDB1 significantly reduced MLL-AF9 mediated colony formation (page 2275, column 2, paragraph 1). Ropa teaches that bone marrow treated by a H3K9 inhibitor, UNC0638, is more amendable to transformation by MLL-AF9 (abstract).
It would have been prima facie obvious to one or ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to select the method of Emran with the method of Ropa to develop a method of increasing SETDB1 expression via measuring SETDB1 expression and then administering a taxane to arrive at instant claim 1. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Emran teaches that chronic exposure to docetaxel (a taxane, see the specification, page 4, [013]) at high concentrations led to a similar transition to the IDTC (induced drug-tolerant cells) state which involves SETDB1 up-regulation, which corresponds with higher expression of SETDB1,
-Emran teaches that SETDB1 up-regulation suggests increased expression of SETDB1 stabilizes H3K9me3, which is characteristic across different cancer types as a generic response toward stress,
-Emran teaches that silencing of SETDB1 restores drug sensitivity with dabrafenib due to a significant reduction of H3K9me3 and that knockdown inhibited the acquisition of induced drug tolerance,
-Emran teaches that shSETDB1 cells exposed to high concentrations of docetaxel were sensitive to the small molecule,
- Emran teaches a method of treating a subject via administering a taxane and measuring SETDB1 expression in a sample from the subject,
-Ropa teaches that SETDB1 expression is lower in AML patient samples compared to normal hematopoietic cells,
-Ropa teaches that epigenetic regulators play a critical role in normal and malignant hematopoiesis,
-Ropa teaches that SETDB1 is an oncogene in melanoma, breast cancer, liver cancer, and lung cancer,
-Ropa teaches that SETDB1 is amplified in melanoma, which results in aberrant binding and regulation of the HOXA locus,
-Ropa teaches that SETDB1 differs in squamous tumors in that depletion of H3K9 methyltransferase G9a leads to a delayed, more aggressive phenotype due to expanded cancer progenitor pools with increased genomic instability,
-Ropa teaches that loss of G9a has no effect on hematopoietic stem cells, and SETDB1 is required for both hematopoietic stem and progenitor cell maintenance and leukemic stem cells,
-Ropa further teaches that SETDB1 mediated silencing of endogenous retroviral elements is required for the growth of AML cell lines and that SETDB1 negatively regulates the expression of the pro-leukemic Hoxa9 and Meis1 genes, which implies a more complex role for H3K9 methylation in AML wherein H3K9 methyltransferases display both oncogenic and suppressive roles,
-Ropa teaches that AML patients with higher expression of SETDB1 display a better prognosis, consistent with repression of HOXA9 and MEIS1 expression,
-Ropa teaches that SETDB1 overexpression induces cellular differentiation and delays disease onset in a mouse model of AML, recapitulating AML patient survival,
-Ropa teaches that loss of SETDB1 is detrimental to leukemic cells due to derepression of endogenous retroviral elements and inhibition of HOXA9 transcriptional activity,
-Ropa teaches that SETDB1 and H3K9 methylation suppresses AML disease progression in vivo through the repression of pro-leukemic genes including direct MLL-fusion protein targets,
-Ropa teaches that overexpression of SETDB1 significantly reduced MLL-AF9 mediated colony formation, and
-Ropa teaches that bone marrow treated by a H3K9 inhibitor, UNC0638, is more amendable to transformation by MLL-AF9.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection, to predictably arrive at a method of treating a SETDB1-associated disease via measuring SETDB1 expression and then administering a taxane.
Regarding claim 2, Ropa teaches that SETDB1 expression is lower in AML patient samples compared to normal hematopoietic cells (page 2274, column 2, paragraph 7).
Regarding claim 4, Emran teaches the microtubule stabilizing agent is a taxane, Emran teaches the microtubule stabilizing agent is docetaxel, which is a taxane (see the specification, page 4, [013]). Taxane is a small molecule that are a class of diterpenes as evidenced by Wikipedia 1 (page 2, paragraph 3) and Wikipedia 2 (page 1, paragraph 1).
Regarding claim 5, Emran teaches a microtubule stabilizing agent is docetaxel, which is a taxane (see the specification, page 4, [013]).
Regarding claim 24, , Emran teaches the sample is a tumor sample (page 8212, column 2, paragraphs 1 and 2). Additionally, Ropa teaches that SETDB1 expression is lower in AML patient samples compared to normal hematopoietic cells (page 2274, column 2, paragraph 7).
Regarding claim 25, Emran teaches that the expression is protein expression (abstract). Ropa teaches use of AML patient RNA sequencing (mRNA expression) were mined (page 2274, column 2, paragraph 1).
Regarding claim 26, Emran specifies that chronic exposure to docetaxel (a taxane, see the specification, page 4, [013]) at high concentrations led to a similar transition to the IDTC (induced drug-tolerant cells) state which involves SETDB1 up-regulation, which Emran teaches corresponds with higher expression of SETDB1 (page 8212, column 2, paragraph 1). Emran further teaches that SETDB1 up-regulation suggests increased expression of SETDB1, which stabilizes H3K9me3 and is characteristic across different cancer types as a generic response toward stress (page 8212, column 2, paragraph 1). Emran teaches that the expression is protein expression (abstract). Ropa teaches use of AML patient RNA sequencing (mRNA expression) were mined (page 2274, column 2, paragraph 1). Ropa teaches that SETDB1 expression is lower in AML patient samples compared to normal hematopoietic cells (page 2274, column 2, paragraph 7). Ropa additionally utilized primary MLL0AF9 mouse leukemia cells to measure SETDB1 expression (page 2274, column 2, paragraph 3), which are eukaryotic cells that have a cytoplasm as evidenced by Wikipedia 3 (page 1, paragraph 1) and Wikipedia 4 (page 1, paragraph 1). Ropa teaches that SETDB1 and H3K9 methylation suppresses AML disease progression in vivo through the repression of pro-leukemic genes including direct MLL-fusion protein targets (page 2284, column 1, paragraph 2). Ropa teaches that overexpression of SETDB1 significantly reduced MLL-AF9 mediated colony formation (page 2275, column 2, paragraph 1).
Regarding claim 30, Emran teaches the microtubule stabilizing agent, docetaxel, and its effect relative to SETDB1 expression (page 8212, column 2, paragraphs 1 and 2). As Applicant does not further specify a certain concentration dosage of a taxane for decreasing HDAC6 expression or function, claim 30 does not specify an additional step but does specify an additional effect. Thus, claim 30 merely recites an additional effect of a claimed method. Consequently, Emran teaches the claimed method of treating a subject via administering a taxane and measuring SETDB1 expression in a sample from the subject (page 8212, column 2, paragraphs 1 and 2). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Where Applicant claims a composition in terms of a function, property or characteristic and the composition of the prior art is the same as that of the claim but the function is not explicitly disclosed by the reference, the Examiner may make a rejection under both 35 U.S.C. 102 and 103. This same rationale should also apply to product, apparatus, and process claims claimed in terms of function, property or characteristic. See MPEP § 2112(II) and (III). Thus, Emran teaches the microtubule stabilizing agent, docetaxel, and its effect relative to SETDB1 expression that decreases HDAC6 expression or function.
Regarding claim 43, Emran specifies that chronic exposure to docetaxel (a taxane, see the specification, page 4, [013]) at high concentrations led to a similar transition to the IDTC (induced drug-tolerant cells) state which involves SETDB1 up-regulation, which Emran teaches corresponds with higher expression of SETDB1 (page 8212, column 2, paragraph 1). Emran further teaches that SETDB1 up-regulation suggests increased expression of SETDB1, which stabilizes H3K9me3 and is characteristic across different cancer types as a generic response toward stress (page 8212, column 2, paragraph 1). Emran further specifies that silencing of SETDB1 restores drug sensitivity with dabrafenib due to a significant reduction of H3K9me3 and that knockdown inhibited the acquisition of induced drug tolerance (page 8212, column 2, paragraph 2). Ropa teaches that SETDB1 expression is lower in AML patient samples compared to normal hematopoietic cells (page 2274, column 2, paragraph 7). Ropa additionally utilized primary MLL0AF9 mouse leukemia cells to measure SETDB1 expression (page 2274,column 2, paragraph 3), which are eukaryotic cells that have a cytoplasm as evidenced by Wikipedia 3 (page 1, paragraph 1) and Wikipedia 4 (page 1, paragraph 1). Ropa teaches that SETDB1 and H3K9 methylation suppresses AML disease progression in vivo through the repression of pro-leukemic genes including direct MLL-fusion protein targets (page 2284, column 1, paragraph 2). Ropa teaches that overexpression of SETDB1 significantly reduced MLL-AF9 mediated colony formation (page 2275, column 2, paragraph 1). Ropa teaches that bone marrow treated by a H3K9 inhibitor, UNC0638, is more amendable to transformation by MLL-AF9 (abstract).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Madeline M Dekarske whose telephone number is (571)272-1789. The examiner can normally be reached Monday - Thursday 10am - 4pm.
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, James Alstrum-Acevedo can be reached at 571-272-5548. 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.
/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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