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 .
Application Status and Election
Claims 1-3, 5, 9, 10, 13, 15, 17-22, 26-29, 33, and 35 are pending. Claims 1, 9, 26, 27, 33, and 35 have been amended. 35 USC §§§102, 103, and 112 Written Description rejections of record are maintained.
Applicant’s species election in the remarks filed 3/31/25 remains acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Applicant elected the species of:
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Claims 3, 5, 13, 15, and 26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Examination on the merits commences on claims 1, 2, 9, 10, 17-22, 27-29, 33, and 35.
Applicants are informed that the rejections and/or objections of the previous Office action not stated below have been withdrawn from consideration in view of the Applicant' s arguments and/or amendments. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 112(a) – Written Description – MODIFIED MAINTAINTEDThe 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.
Claims 33 and 35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A3.(a).(i) states, “whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
For claims drawn to a genus, MPEP 2163.II.A3.(a).(ii) states, “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species” where “representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.”
The claims are drawn to a method of preventing or treating a disease or disorder associated with increased ten-eleven translocation protein (TET) level, the method comprising administering a treatment to a subject in need thereof, wherein the treatment comprises a reduction of TET level, i.e. the treatment comprises a TET inhibitor and optionally may provide at least one FOXA2 inhibitor and at least one let-7 promoter. These claims 33 and 35 are not limited to any definition FOXA2 inhibitor or Let-7 promoter” provided in the disclosure and Examiner is interpreting the FOXA2 inhibitor and Let-7 promoter described in claim 33 and 35 as not limited to the species described in claim 33 and 35. The specification has not adequately described the entire genus of these gene modulators for the following reasons.Size and Breadth of Genus
According to claims 33 and 35, a composition that decreases FOXA2 levels and well as Let-7 promoters are described only by its function. The claimed language does not limit the structure of the FOXA2 inhibitor or Let-7 promoter, and therefore could encompass any means, directly or indirectly, for treating the claimed disease in a subject. The specification teaches working examples of therapeutic oligonucleotides within the genus of “inhibitors” and “promoters”. However, in the art, non-nucleic acid agents are known to contribute to the binding and regulation of RNA transcripts as well as regulation at the DNA and transcriptional level which can affect gene expression (See e.g., Cheung, Vivian G., and Richard S. Spielman. "The genetics of variation in gene expression." Nature genetics 32.4 (2002): 522-525.). Additionally, small organic molecules other than small nucleic acids are also known in the art to be able to bind to and regulate RNA transcripts (See e.g., Warner et al., Nature Reviews Drug Discovery (2018), 17: 547-558). As such, the genus of inhibitors and promoters is extensive and diverse and includes chemical and biological molecules in variable combinations with variable size, structure, and folding patterns such as nucleic acids including shRNA, miRNA, siRNA, dsDNA, short hairpin RNA, or other agents such as proteins, small organic molecules, enzymatic nucleic acid molecules, allozymes, antisense nucleic acids, 2-5A antisense chimeras, radiation phototherapy, kinase enzymes, chemical inhibitors, fusion proteins, and monoclonal antibodies, and chromatin modifiers like histone acetyl transferases and deacetylases, as well as epigenetic modifiers like DNA methyltransferases, among others.
Species disclosed in the Specification
The Specification teaches (pg 121) Let-7 binding Sites prediction with The RNA hybrid program (Kruger et al., 2006, Nucleic Acids Res 34:W451-454) used to predict let-7 binding sites in TET1 mRNA. The Specification (pg 10) also teaches FOXA2 inhibitor is a nucleic acid, a peptide, a small molecule chemical compound, an siRNA, a ribozyme, an antisense nucleic acid, an aptamer, a peptidomimetic, an antibody, an antibody fragment, an induced protein degradation, or any combination thereof; and in another aspect of the invention, the method of treatment comprises administering a therapeutically effective amount of at least one let-7 promoter. In various embodiments, the let-7 promoter is a nucleic acid, a peptide, a small molecule chemical compound, an siRNA, a ribozyme, an antisense nucleic acid, an aptamer, a peptidomimetic, an antibody, an antibody fragment, or any combination thereof.
Although the specification discloses potential embodiments of FOXA2 inhibitors and Let-7 promoters, the specification fails to sufficiently describe representative species, i.e. structure or secondary structures, for the skilled artisan to predict what other molecules for example can function in FOXA2, or Let-7 inhibition/promotion as presently claimed in claim 33 or 35, or how the structures relate to the function of inhibiting or promoting gene expression.
Species Disclosed in the Art
The genus of “gene inhibitor” and “gene promoter” is diverse in the art and includes biological molecules described in the specification as well as genome editing compositions that knock down or knock out the a gene, including CRISPR-Cas reagents, transcription activator-like effector nuclease (TALEN) reagents, or zinc finger nucleases (ZFN) reagents. Such inhibitors can be used by themselves or in combination for gene inhibition.
Regarding FOXA2 inhibitors, Lehner of record (Lehner, Frank, et al. "Inhibition of the liver enriched protein FOXA2 recovers HNF6 activity in human colon carcinoma and liver hepatoma cells." PLoS One 5.10 (2010): e13344. (Year: 2010).) teaches administering a therapeutically effective amount of at least one FOXA2 inhibitor such as the FOXA2 siRNA Probe 3 which causes a significant reduction in FOXA2 and a minor reduction in HNF4-alpha expression and where cancer proliferation was reduced by 80% and 50% in Caco-2 and HepG2 cells, (abstract and Pg. 8, col1 para 1 and Figure 3). This resulted in a statistically significant 6-, 3-, 4-, and 8-fold increase in mRNA expression of HNF6 and of genes targeted by this transcription factor, e.g., HSP105B, CYP51, and C/EBPα, as determined by qRT-PCR. Thus, functional knockdown of FOXA2 recovered HNF6 activity and caused a reduction in tumor proliferation (abstract).
Regarding Let-7 promoters, Sun of record (Sun, Xin, et al. "Possible carcinogenesis of tumor suppressor let-7." Medical Hypotheses 81.3 (2013): 410-413. (Year: 2013)) teaches over expression of let-7 blocks tumor formation and progression, diminish self-renewal and increase apoptosis rates by directly influence its targeted genes. Conversely, knocking down endogenous let-7 with antagonists enhanced self-renewal, tumor regeneration, and metastasis of cancer cells, as would the effects of repressing let-7 in CSCs (pg 410 col 2 para 1). Sun teaches manipulations of let-7 miRNAs are effective and valuable strategies to treat with cancer cells (pg 410 col 2 para 1).
Further regarding nucleic acids gene modulators, Wang teaches that the ability to predict nucleic acid hybridization (i.e., via “rational design”) is generally limited to the use of unmodified nucleic acids, and that many broadly employed chemical modifications to DNA and RNA have not been included in predictive models (pg. 2, para. 1 and pg. 14, para. 1; Wang et al., 2022, PLOS ONE, 17(5), e0268575). Wang teaches thermodynamic models of hybridization for nucleic acid molecules with phosphorothioate linkages, where each linkage modification decreases duplex stability (pg. 13, para. 4) Wang teaches that backbone and sugar ring modifications, in conjunctions with nucleotide sequence, would likely require a combinatorially large (and synthetically intractable) set of duplexes to fully characterize (pg. 13, para. 3). Therefore, it is unpredictable that nucleic acid hybridization without a rational design incorporating thermodynamics, phosphorothioate linkages or backbone/sugar ring modifications would successfully promote nucleic acid binding.
Regarding such non-nucleic acid based inhibitors, given the lack of structure-function relationship in proteins, the skilled artisan could not predictably design a protein that would bind to a particular RNA transcript for RNA mediated gene expression inhibition. This is evidenced by Hentz of record (Hentz et al., Nature Reviews Molecular Biology (2018), 19: 327-341) and Warner, cited above. Hentz teaches RNA-binding proteins (RBP) can interact with RNA through defined RNA-binding domains to regulate RNA metabolism and function, establishing a functional crosstalk between proteins and RNA (Fig. 1 pg 328). However, Hentz teaches that binding of RBPs to RNA constantly changes, where the composition of RNA interactomes is context-dependent, responds to stimuli, and has regulation of binding activity by multiple agents (pg 331 co 2 para 2). Hentz teaches long non-coding RNAs lncRNAs are currently assumed to participate in the recruitment of transcription factors or chromatin-modifying complexes ---or inhibit protein complexes, however, these functions break with convention by indicating that RNAs may regulate RBP function rather than be regulated by RBPs (Fig. 1b pg 328). Given this dynamic regulation of functional crosstalk between proteins and RNA with context dependent response to stimuli, it is not predictable that a person of ordinary skill in the art could design a protein to bind a particular RNA transcript for the purpose of gene expression inhibition without knowledge of that structure function relationship.
As the prior art establishes, there is substantial variation within the genus FOXA2 inhibitors and Let-7 promoters. Applicant fails to adequately describe a sufficient variety of species to reflect the variation within the genus. Furthermore, the description of a representative number of species from the specification is not representative of the entire genus. Given the lack of guidance in the art and specification regarding common structural characteristics shared by members of the genus and lack of predictability of undefined nucleic acids, proteins, and small molecules as sufficiently inhibiting gene expression, the FOXA2 inhibitors and Let-7 promoters in the specification disclosure are not sufficient to show that the Applicant was in possession of all such at the time the invention was filed.
Claim Rejections - 35 USC § 102 - MAINTAINED
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 2, 9, 10, 17, 20-22, and 27-29 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fraietta of record (Fraietta, J., WO2018175733A1) as evidenced by Good of record (Good, Charly Ryan, et al. "TET1-mediated hypomethylation activates oncogenic signaling in triple-negative breast cancer." Cancer research 78.15 (2018): 4126-4137.), claim 28 as evidenced by Wang of record (Wang, Zhanyu, and Chenfang Dong. "Gluconeogenesis in cancer: function and regulation of PEPCK, FBPase, and G6Pase." Trends in cancer 5.1 (January 2019): 30-45, printed as pages 1/2 to 2/2), claim 29 as evidenced by Cox of record (Cox, Thomas R., and Janine T. Erler. "Molecular pathways: connecting fibrosis and solid tumor metastasis." Clinical Cancer Research 20.14 (2014): 3637-3643.).
Examiner notes new amendments to claim 1, particularly the addition of claim 1(f) FoxA2 inhibitor and claim 1(g) let-7 promoter. However, according to the Markush grouping, neither claim 1(f) FoxA2 inhibitor or claim 1(g) let-7 promoter are necessary limitations within the treatment method which requires merely at least one selected from the group consisting of claim 1(a)-(h), and furthermore from which the species elected without traverse was treating a disorder with increased TET level by administering an siRNA Tet inhibitor.
Regarding claim 1, Fraietta teaches compositions of matter and methods of use for the treatment of a disease such as cancer using immune effector cells (e.g., T cells, NK cells) engineered with CARs of the invention (pg 149 line 15). Fraietta teaches compositions comprising, e.g., modulators of a Tet-associated genes and inhibitors of a Tet (Tetl, Tet2, and/or Tet3, e.g., Tet2), and methods for enhancing immune effector cell functions, e.g., CAR-expressing cell function (pg 81 line 10), and in particular, the invention provides CAR-expressing T cells comprising inhibitors and use of the one or more genes in connection with CAR T cells (pg 81 line 29). Fraietta teaches expression and/or function of the Tet-associated gene is altered when expression and/or function of a Tet (e.g., Tetl, Tet2 and/or Tet3) is inhibited(pg 76 line 13). In some embodiments, expression and/or function of the Tet-associated gene is reduced or eliminated when expression and/or function of a Tet (e.g., Tetl, Tet2 and/or Tet3) is inhibited and in other embodiments, expression and/or function of the Tet-associated gene is increased or activated when expression and/or function of a Tet (e.g., Tetl, Tet2 and/or Tet3) is inhibited (pg 76 line 13). Fraietta teaches administration of the CAR compositions to treat hyperproliferative disorders such as metastatic melanoma, thymoma, lymphoma, sarcoma, lung cancer, liver cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, leukemias, uterine cancer, cervical cancer, bladder cancer, kidney cancer and adenocarcinomas such as breast cancer, prostate cancer, ovarian cancer, pancreatic cancer (pg 40 line 30) and dermatofibrosarcoma (pg 238 line 19). Fraietta further teaches the method comprises introducing into said cell nucleic acid encoding an inhibitory dsRNA, e.g., a shRNA or siRNA, which inhibits Tet-associated gene and/or a Tet (e.g., Tetl, Tet2, and/or Tet3, e.g., Tet2) levels in a method of a vector encoding a CAR (pg 149 line 6).
Fraietta is silent as to whether the treated hyperproliferative diseases are conditions of increases TET expressions, however, Good teaches TET1, TET2, and TET3 is upregulated in all subtypes of Triple-negative breast cancer (Supplementary Fig. S1A and S1B). Good further teaches the TET enzymes (TET1, TET2, and TET3) are DNA demethylases that convert 5 methyl-cytosine (5mC) into 5 hydroxymethylcytosine (5hmC), which can then be further oxidized or converted to unmethylated cytosine (pg 4126 col 1 para 1).
Therefore, Fraietta and Good teach the elected limitations of claim 1, i.e. a method of method of preventing or treating a disease or disorder associated with increased ten-eleven translocation protein (TET) level, the method comprising administering a treatment to a subject in need thereof, wherein the treatment comprises a reduction of TET level.
Regarding claim 2, 9, 10, and 17, Fraietta teaches inhibition of TET3 levels, as described in the teachings above with siRNA TET3 inhibition (pg 149 line 6).
Regarding claim 20-22, Fraietta teaches the method comprises introducing into said cell nucleic acid encoding an inhibitory dsRNA, e.g., a shRNA or siRNA, which inhibits Tet-associated gene and/or a Tet (e.g., Tet1, Tet2, and/or Tet3, e.g., Tet2) levels in a method of a vector encoding a CAR (pg 149 line 6). Fraietta teaches Examples of viral transfer vectors include, but are not limited to, adenoviral vectors, adeno-associated virus vectors, retroviral vectors, lentiviral vectors, and the like (pg 34 line 30).
Regarding claim 27, Fraietta teaches compositions of matter and methods of use for the treatment of a disease such as cancer using immune effector cells (e.g., T cells, NK cells) engineered with CARs of the invention (pg 149 line 15). Fraietta teaches compositions comprising, e.g., modulators of a Tet-associated genes and inhibitors of a Tet (Tet1, Tet2, and/or Tet3, e.g., Tet2), and methods for enhancing immune effector cell functions, e.g., CAR-expressing cell function (pg 81 line 10), and in particular, the invention provides CAR-expressing T cells comprising inhibitors and use of the one or more genes in connection with CAR T cells (pg 81 line 29).
Regarding claim 28, Fraietta is silent as to whether the treated hyperproliferative diseases are conditions associated with gluconeogenesis regulation, however, Wang teaches gluconeogenesis plays an essential role in cancers (abstract). Therefore, Examiner is interpreting Fraietta’s method of treating cancers including breast cancer to also treat a disease or disorder also associated with gluconeogenesis.
Regarding claim 29, Fraietta is silent as to whether the treated hyperproliferative cancer diseases treated are associated with fibrosis, however, Cox teaches fibrosis and cancer are known to be inextricably linked (abstract). Therefore, Examiner is interpreting Fraietta’s method of treating cancers including breast cancer to also treat a disease or disorder with fibrosis.
Claim Rejections - 35 USC § 103 - MAINTAINED
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.
Claim(s) 1, 18, and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fraietta of record (Fraietta, J., WO2018175733A1) as evidenced by Good of record (Good, Charly Ryan, et al. "TET1-mediated hypomethylation activates oncogenic signaling in triple-negative breast cancer." Cancer research 78.15 (2018): 4126-4137.) as applied for claim 1, in further view of Finley of record (Finley, L., US2017/0022475A1).
The teachings of Fraietta and Good as applied above for claim 1 are incorporated here.
Briefly, Fraietta teaches compositions comprising, e.g., modulators of a Tet-associated genes and inhibitors of a Tet (Tetl, Tet2, and/or Tet3, e.g., Tet2), and methods for enhancing immune effector cell functions, e.g., CAR-expressing cell function (pg 81 line 10), and applying this method to the treatment of hyperproliferative disorders including breast cancers (pg 40 line 30).
Briefly, Good teaches the TET enzymes (TET1, TET2, and TET3) are DNA demethylases that convert 5 methyl-cytosine (5mC) into 5 hydroxymethylcytosine (5hmC), which can then be further oxidized or converted to unmethylated cytosine (pg 4126 col 1 para 1). Good teaches TET1, TET2, and TET3 is upregulated in all subtypes of Triple-negative breast cancer (Supplementary Fig. S1A and S1B).
Although Fraietta does teach gene editing inhibition of a Tet and/or a Tet-associated gene, e.g., Tet2 and/or a Tet2-associated gene, refers to a group of molecules, e.g., one or more molecules, which together act to effect a desired function (pg 77 line 17), Fraietta does not disclose specific TET associated genes such that the reduction of TET level comprises a reduction of at least one TET co-factor such as the TET co-factor a-ketoglutarate.
However, Finley teaches DNA methylation plays an integral role in carcinogenesis [0122]. Finley teaches a method of controlling cell proliferation by manipulating metabolism through decreasing levels of α-ketoglutarate [0005]. Finley teaches modulating epigenetic changes in cells by administering an agent that decreases intracellular levels of α-ketoglutarate to regulate Ten eleven translocation (Tet)-dependent DNA demethylation [0120]
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified the method of Fraietta to also include inhibition of a-ketoglutarate such as in the epigenetic influencing method of Finley. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation that inhibiting α-ketoglutarate would influence methylation of TET because Finley teaches decreasing intracellular levels of α-ketoglutarate regulates Tet-dependent DNA demethylation. The skilled artisan would therefore be motivated to add compositions which also inhibit α-ketoglutarate in the viral CAR mediated treatment method for the purpose of further modulating epigenetic changes in order to increase regulation of TET in the treatment of hyperproliferative disorders such as breast cancer.
Claim(s) 1 and 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fraietta of record (Fraietta, J., WO2018175733A1) as evidenced by Good of record (Good, Charly Ryan, et al. "TET1-mediated hypomethylation activates oncogenic signaling in triple-negative breast cancer." Cancer research 78.15 (2018): 4126-4137.) and Finley of record (Finley, L., US2017/0022475A1), as applied to claim 1, and in further view of Lehner of record (Lehner, Frank, et al. "Inhibition of the liver enriched protein FOXA2 recovers HNF6 activity in human colon carcinoma and liver hepatoma cells." PLoS One 5.10 (2010): e13344. (Year: 2010).).
The teachings of Fraietta and Good and Finley as applied above for claim 1 and 17-19 are incorporated here.
Briefly, Fraietta teaches compositions comprising, e.g., modulators of a Tet-associated genes and inhibitors of a Tet (Tetl, Tet2, and/or Tet3, e.g., Tet2), and methods for enhancing immune effector cell functions, e.g., CAR-expressing cell function (pg 81 line 10), and applying this method to the treatment of hyperproliferative cancer disorders such as breast cancers (pg 40 line 30).
Briefly, Good teaches the TET enzymes (TET1, TET2, and TET3) are DNA demethylases that convert 5 methyl-cytosine (5mC) into 5 hydroxymethylcytosine (5hmC), which can then be further oxidized or converted to unmethylated cytosine (pg 4126 col 1 para 1). Good teaches TET1, TET2, and TET3 is upregulated in all subtypes of Triple-negative breast cancer (Supplementary Fig. S1A and S1B).
Finley teaches DNA methylation (such as TET3 DNA demethylases taught by Good) plays an integral role in carcinogenesis [0122].
Although Fraietta does teach gene editing inhibition of a Tet3 to treat cancers (pg 77 line 17), Fraietta does not disclose comprising a FOXA2 inhibitor in the method.
However, Lehner is in the field of understanding key regulators in cancer such as colorectal and liver metastases (Abstract). Lehner teaches administering a therapeutically effective amount of at least one FOXA2 inhibitor such as the FOXA2 siRNA Probe 3 which causes a significant reduction in FOXA2 and a minor reduction in HNF4-alpha expression and where cancer proliferation was reduced by 80% and 50% in Caco-2 and HepG2 cells, (abstract and Pg. 8, col1 para 1 and Figure 3). This resulted in a statistically significant 6-, 3-, 4-, and 8-fold increase in mRNA expression of HNF6 and of genes targeted by this transcription factor, e.g., HSP105B, CYP51, and C/EBPα, as determined by qRT-PCR. Thus, functional knockdown of FOXA2 recovered HNF6 activity and caused a reduction in tumor proliferation (abstract).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified the method of Fraietta to also include inhibition of FOXA2 such as in the influencing method of Lehner. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation that inhibiting FOXA2 would further inhibit cancer proliferation because Lehner teaches FOXA2 inhibition plays as an important role in the regulation of cancer such as colorectal and liver metastasis. The skilled artisan would be motivated to add compositions which also inhibit FOXA2 in Fraietta’s viral CAR mediated treatment method for the purpose of further modulating epigenetic changes in order to increase regulation of TET in the treatment of hyperproliferative cancer disorders.
Claim(s) 1 and 35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fraietta of record (Fraietta, J., WO2018175733A1) as evidenced by Good of record (Good, Charly Ryan, et al. "TET1-mediated hypomethylation activates oncogenic signaling in triple-negative breast cancer." Cancer research 78.15 (2018): 4126-4137.) and Finley of record (Finley, L., US2017/0022475A1), as applied to claim 1, and in further view of Sun of record (Sun, Xin, et al. "Possible carcinogenesis of tumor suppressor let-7." Medical Hypotheses 81.3 (2013): 410-413.).
The teachings of Fraietta and Good and Finley as applied above for claim 1 and 17-19 are incorporated here.
Briefly, Fraietta teaches compositions comprising, e.g., modulators of a Tet-associated genes and inhibitors of a Tet (Tetl, Tet2, and/or Tet3, e.g., Tet2), and methods for enhancing immune effector cell functions, e.g., CAR-expressing cell function (pg 81 line 10), and applying this method to the treatment of hyperproliferative cancer disorders such as breast cancers (pg 40 line 30).
Briefly, Good teaches the TET enzymes (TET1, TET2, and TET3) are DNA demethylases that convert 5 methyl-cytosine (5mC) into 5 hydroxymethylcytosine (5hmC), which can then be further oxidized or converted to unmethylated cytosine (pg 4126 col 1 para 1). Good teaches TET1, TET2, and TET3 is upregulated in all subtypes of Triple-negative breast cancer (Supplementary Fig. S1A and S1B).
Finley teaches DNA methylation (such as TET3 DNA demethylases taught by Good) plays an integral role in carcinogenesis [0122].
Although Fraietta does teach gene editing inhibition of a Tet3 to treat cancers (pg 77 line 17), Fraietta does not disclose comprises administering a therapeutically effective amount of at least one let-7 promoter.
However, Sun teaches over expression of let-7 blocks tumor formation and progression, diminish self-renewal and increase apoptosis rates by directly influence its targeted genes. Conversely, knocking down endogenous let-7 with antagonists enhanced self-renewal, tumor regeneration, and metastasis of cancer cells, as would the effects of repressing let-7 in CSCs (pg 410 col 2 para 1). Sun teaches manipulations of let-7 miRNAs are effective and valuable strategies to treat with cancer cells (pg 410 col 2 para 1).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified the method of Fraietta to also include an effective amount of at least one let-7 promoter such as in the influencing method of Sun. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation that promoting Let-7 would further inhibit cancer proliferation because Sun teaches Let-7 promotion plays as an important role in the regulation of cancers. The skilled artisan would be motivated to add compositions which also promote Let-7 in Fraietta’s viral CAR mediated treatment method for the purpose of further modulating epigenetic changes in order to increase regulation of TET in the treatment of hyperproliferative cancer disorders.
Related Prior Art
Nakano et. al., (WO-2016031996-A1 ) of record teaches prophylactic / therapeutic agent for arthritis, particularly rheumatoid arthritis (RA), and a screening method for a prophylactic / therapeutic agent for arthritis, particularly rheumatoid arthritis. More specifically, arthritis, particularly a prophylactic and / or therapeutic agent for rheumatoid arthritis, which contains a substance that inhibits the function of Tet 3 (Ten-Eleven translocation 3), and arthritis using Tet 3 function inhibition as an index (pg 2 para 2). Nakano further teaches Rheumatoid arthritis is an intractable autoimmune disease that causes chronic inflammation in joints throughout the body. The synovial tissue in the joint grows and progressively destroys cartilage and bone. Rheumatoid arthritis synovial fibroblasts (FLS) are activated by stimulation (inflammatory cytokines such as TNFα and IL-1β) by macrophages and lymphocytes, and activated synovial fibroblasts While chemokine production and substrate-degrading enzyme secretion cause joint destruction, it also has properties similar to cancer cells, such as increased proliferation and invasion and decreased apoptosis sensitivity (pg 2 para 2).
Response to Arguments
Examiner again notes that Applicants have elected without traverse the following species:
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Applicant’s arguments regarding the §112A Scope of Enablement rejection (pg 7-8) are drawn to a withdrawn rejection. Therefore, those arguments are moot.
Regarding the 112A Written Description rejection, Applicants amendments to claim 1, the addition of claim 1(f) FoxA2 inhibitor and claim 1(g) let-7 promoter, are noted. Applicant’s arguments have been thoroughly reviewed and found unpersuasive because the arguments (Remarks pg 12) are drawn to amendments to claim 1(f-g), however, claims 33 and 35 still lack written description. As the prior art establishes, there is substantial variation within the genus of FOXA2 inhibitors and Let-7 promoters as described in claims 33 and 35. Applicant fails to adequately describe a sufficient variety of species to reflect the variation within the genus. Furthermore, the description of a representative number of species from the specification is not representative of the entire genus. Given the lack of guidance in the art and specification regarding common structural characteristics shared by members of the genus and lack of predictability of undefined nucleic acids, proteins, and small molecules as sufficiently inhibiting gene expression, the FOXA2 inhibitors and Let-7 promoters in the specification disclosure are not sufficient to show that the Applicant was in possession of all such at the time the invention was filed.
Regarding the §102 rejection of record, Applicants argue (Remarks pg 14) that Fraietta as evidenced by Good, Wang, and Cox, does not teach the claim limitations as newly amended. Applicant’s arguments have been thoroughly reviewed and found unpersuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., Fraietta teaching the newly amended limitations in claims 1(f-g)) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Examiner again recognizes the new amendments to claim 1, particularly the addition of claim 1(f) FoxA2 inhibitor and claim 1(g) let-7 promoter. However, according to the Markush grouping, neither claim 1(f) FoxA2 inhibitor or claim 1(g) let-7 promoter are necessary limitations within the treatment method which requires merely at least one selected from the group consisting of claim 1(a)-(h), and furthermore from which the species elected without traverse was treating a disorder with increased TET level by administering an siRNA Tet inhibitor.
As described in the above rejections, Fraietta teaches compositions comprising, e.g., modulators of a Tet-associated genes and inhibitors of a Tet (Tetl, Tet2, and/or Tet3, e.g., Tet2), and methods for enhancing immune effector cell functions, e.g., CAR-expressing cell function (pg 81 line 10), and in particular, the invention provides CAR-expressing T cells comprising inhibitors and use of the one or more genes in connection with CAR T cells (pg 81 line 29). Fraietta teaches "Tet" refers to the family of genes, and the proteins encoded by said genes, of the ten-eleven translocation methlcytosine dioxygenase family. Tet includes, for example, Tetl, Tet2 and Tet3 (pg 43 line 35). Fraietta teaches administration of the CAR compositions to treat hyperproliferative disorders such as metastatic melanoma, thymoma, lymphoma, sarcoma, lung cancer, liver cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, leukemias, uterine cancer, cervical cancer, bladder cancer, kidney cancer and adenocarcinomas such as breast cancer, prostate cancer, ovarian cancer, pancreatic cancer (pg 40 line 30) and dermatofibrosarcoma (pg 238 line 19). Fraietta further teaches the method comprises introducing into said cell nucleic acid encoding an inhibitory dsRNA, e.g., a shRNA or siRNA, which inhibits Tet-associated gene and/or a Tet (e.g., Tetl, Tet2, and/or Tet3, e.g., Tet2) levels in a method of a vector encoding a CAR (pg 149 line 6).
Good teaches TET1, TET2, and TET3 is upregulated in all subtypes of Triple-negative breast cancer (Supplementary Fig. S1A and S1B). Good further teaches the TET enzymes (TET1, TET2, and TET3) are DNA demethylases that convert 5 methyl-cytosine (5mC) into 5 hydroxymethylcytosine (5hmC), which can then be further oxidized or converted to unmethylated cytosine (pg 4126 col 1 para 1). Therefore, Fraietta and Good teach the elected limitations of claim 1, i.e. a method of method of preventing or treating a disease or disorder associated with increased ten-eleven translocation protein (TET) level, the method comprising administering a treatment to a subject in need thereof, wherein the treatment comprises a reduction of TET level.
Wang teaches gluconeogenesis plays an essential role in cancers (abstract). Therefore, Examiner is interpreting Fraietta’s method of treating cancers including breast cancer to also treat a disease or disorder also associated with gluconeogenesis.
Cox teaches fibrosis and cancer are known to be inextricably linked (abstract). Therefore, Examiner is interpreting Fraietta’s method of treating cancers including breast cancer to also treat a disease or disorder with fibrosis.
Regarding the §103 rejection of record, Applicants similarly argue as above (Remarks pg 17) that the newly amended claim 1 additions to the Markush grouping undermines Fraietta as a primary reference because Fraietta does not teach “all the words of a claim.” Applicant further argues hindsight bias based on the combination of reference teachings. Applicant’s arguments have been thoroughly reviewed and found unpersuasive for the same reasons above applied to the discussion of the §102 rejection of reference. Furthermore, In response to applicant's argument 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).
Conclusion
No claims are allowable.
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 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.
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/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637