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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on October 4th, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The listing of references in the specification (starting on page 30) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: “anti-BTG2 therapeutic” is not mentioned in the specification, nor is it explained what the term entails.
Status of the Claims
Claims 1-7 are pending in this application.
Claim Objections
Claims 5-6 are objected to because of the following informalities:
Claims 5-6 read: “(…) by chemotherapeutic drug (…)” Claims should read: “(…) by a chemotherapeutic drug (…)” or “(…) by chemotherapeutic drugs (…)”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 7 is 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.
Claim 7 speaks to “anti-BTG2 therapeutics” however, this term is not mentioned in the specification. The art does not seem to disclose direct anti-BTG2 therapeutics, but rather inhibitors of pathways upstream or downstream of BTG2. Thus, the instant claim is directed to a large group of chemical species defined only in terms of what they do, not what they are. Furthermore, the spec. lacks any sort of structural guidance that would allow one to establish a structure-activity relationship. Therefore, “anti-BTG2 therapeutics” requires more structural definition.
In sum, the instant claims lack sufficient of written description pursuant to 35 USC § 112(a) because Applicant has not shown that they had possession of the full scope of a claim to “anti-BTG2 therapeutics”.
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 1-7 is 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.
The terms “optimizing” and “optimal” in claim 1 are relative terms which render the claim indefinite. The terms “optimizing” and “optimal” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 1 recites the limitations: "the treatment"; “the optimal course”. There is insufficient antecedent basis for these limitations in the claim.
Claim 1 is also unclear because step (b) recites: “determining the transcriptional response … across four or more … drugs …”. Then, step (c) recites: “determining the gene signature to determine the optimal course of treatment …” If, in step (c), the determining of the gene signature is done “to determine the optimal course of treatment”, then it is unclear why step (b) is necessary.
Claims 2-7 are rejected for depending upon the limitations of claim 1.
Claim 2 is rejected because it is unclear if 5-fluorouracil, irinotecan, or oxaliplatin are part of “the optimal course of treatment” or if they are administered in combination with “the optimal course of treatment” of claim 1.
Claim 7 is rejected because it is unclear if the “anti-BTG2 therapeutic” is part of “the optimal course of treatment” or if it is administered in combination with “the optimal course of treatment” of claim 1.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 and 3-6 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
Claims 1 and 3-6 do not fall within at least one of the four categories of patent eligible subject matter because the claims are drawn to abstract ideas, such as obtaining human tissues for testing and determining different parameters/collecting data without significantly more to overcome the judicial exception. Specifically, obtaining a cell sample and determining the transcriptional response and gene signature after a chemotherapy are routine operations to a skilled artisan (see art cited in this office action). Furthermore, it is well established that the mere physical or tangible nature of additional elements such as the obtaining and detecting steps does not automatically confer eligibility on a claim directed to an abstract idea (see, e.g., Alice Corp. v. CLS Bank Int’l, 134 S.Ct. 2347, 2358-59 (2014)). See MPEP 2106.05.
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 1-4 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Del Rio et al. (J. Clin Oncol., 2007; 25: 773–780) (“Del Rio”); in view of Toscano et al. (Biochem. Pharmacol., 7, 2007, 392–406) (“Toscano”); further in view of Mao et al. (Int. J. Oncol., 2015, 46: 459-464) (“Mao”); and Tae-Hyoung (Anti-Cancer Drugs, 24 2013, 555-565) (“Tae”).
Regarding claims 1-4 and 7, Del Rio teaches that in patients with advanced colorectal cancer (CRC), FOLFRI (leucovorin, 5-fluorouracil (5-FU), and irinotecan (CPT-11)) is considered first-line of treatment; however, only half of patients respond to this therapy (abstract – purpose). Del Rio also teaches FOLFOX (leucovorin, 5-FU, and oxaliplatin (Ox)), which also displays a response rate of about 50% (page 3, para. 1). Del Rio teaches that a major clinical challenge is to identify the subset of patients who could benefit from this chemotherapy (page 3, para. 2), and discloses that gene expression profiling has become a strategy to predict clinical outcome or to classify molecular tumor subtypes (page 3, para. 3). Del Rio set out to build a predictor classifier for response to FOLFIRI treatment in patients with advanced CRC using microarray gene expression profiles of primary CRC tissue collected from human subjects who received treatment (reading on claim 1-a and 2-3) (page 4). Del Rio discloses a method of determining gene signature expressed by responders and non-responders of treatment, with specific signatures shown in Table 3 (reading on claim 1-c) (pages 11-13). Del Rio further discloses that more recently, two monoclonal antibodies targeting the vascular endothelial growth factor (bevacizumab) and the epidermal growth factor receptor (cetuximab) have been approved for treatment of metastatic CRC in combination with standard regimens (reading on 4 or more chemotherapeutic agents) (page 3, para. 1).
While Del Rio does not specifically teach: determination of transcriptional response in gastrointestinal cells across 4 or more chemotherapeutic drugs in terms of gene identity, magnitude of change, and p53 dependence; the teachings of Toscano, Mao, and Tae have been relied upon for these disclosures.
Toscano discloses that sensitivity to oxaliplatin (Ox) was a characteristic of p53 wild-type (WT) colon cancer cells (HCT116); in contrast, all p53-mutated cell lines had a high IC50 to oxaliplatin, with the exception of the V9P cell line (see Fig. 1B). Exposure to oxaliplatin resulted in G0/G1 arrest in p53 wildtype cell lines, and in S phase in p53-mutated cell lines (abstract). The tumor suppressor protein p53 has been shown to exert a pivotal role in determining the cellular sensitivity to a number of therapeutic agents, including 5-FU and Ox; and the expression and stability of the p53 protein, modified after chemotherapy-induced DNA damage, leads to a transcriptional activation of its target genes, including the main mediator of cell cycle arrest p21 and the p53 homologue p73 protein; furthermore, the p53 gene is altered in more than 50% of colorectal cancers, and mutations of p53 are usually associated with drug resistance, as some p53 mutants do not completely lose their function, a mutant p53 ‘‘gain of function’’ phenotype has been demonstrated in tumor cells, and consists in increased proliferation, tumorigenicity and chemoresistance (page 393, col. 1, para. 2). Toscano teaches that cells with WT p53 were sensitive to Ox treatment, and that targeted inactivation of p53 leads to resistance to Ox; however, p53 status alone is not sufficient to predict response, and that several molecular markers such as an increased level of the pro-apoptotic proteins Bax and Bak, or the expression of nucleotide excision repair genes could be valuable candidates (page 393, col. 1, para. 3). Thus, Toscano teaches Ox and 5-FU sensitivity is p53-dependent.
Mao teaches BTG2 as a tumor suppressor, whose expression is downregulated in many human cancers; it is an instantaneous early response gene and plays important roles in cell differentiation, proliferation, DNA damage repair, and apoptosis in cancer cells (abstract). Mao teaches BTG2 is highly expressed in the large intestine (para. bridging pages 459-460). Mao discloses overexpression of miRNA-21 has been observed in gastric and colon cancer; and that miRNA-21 promotes cell growth and proliferation; and that miRNA-21 promotes proliferation through downregulation of BTG2 (page 462, para. bridging col. 1-2). Mao discloses that following DNA damage, BTG2 expression is stimulated by p53 and the expression of cyclin D1 is downregulated, inhibiting G1/S transition via the pRB pathway. This pathway is a classical pathway and the activation of BTG2 is p53-dependent. BTG2 expression is also upregulated
by oxidative stress via reactive oxygen species-protein kinase C-NF-kB pathway, which is independent of p53 status (page 460, col. 2, para. 3).
Tae teaches lipoic acid prevents p53 degradation in colon cancer by blocking NF-kB signaling (title and end of abstract).
Therefore, regarding claims 1-4, and 7, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to optimize treatment of CRC in a subject by: (i) obtaining cancer cells from the subject; (ii) determining transcriptional response across 4 drugs in terms of gene identity, magnitude of change, and p53 dependence; (iii) and determine gene signature to determine optimal course of treatment in view of Del Rio, Toscano, Mao, and Tae.
One of ordinary skill would have been motivated to do so because Del Rio teaches that current standard of care treatments (FOLFRI and FOLFOX) have response rates of about 50% and that a major clinical challenge in CRC is to identify the subset of patients who could benefit from standard chemotherapy, disclosing that gene expression profiling has become a strategy to predict clinical outcome or to classify molecular tumor subtypes; also because Toscano discloses that Ox and 5-FU sensitivities (main agents in standard of care therapies) are p53-dependent and that the p53 protein can be modified after chemotherapy-induced DNA damage, leading to chemoresistance; further because Toscano teaches p53 status alone is not sufficient to predict response, and that several molecular markers such as an increased level of the pro-apoptotic proteins and genes could be valuable targets. One would have been further motivated because Mao discloses BTG2 as a tumor suppressor, whose expression is upregulated by oxidative stress via reactive oxygen species-protein kinase C-NF-kB pathway, which is independent of p53 status; and further because Tae teaches lipoic acid prevents p53 degradation in colon cancer by blocking NF-kB signaling (thus blocking oxidative-stress-induced BTG2 upregulation – p53-independent pathway – and reading on administration of an anti-BTG2 agent).
One of ordinary skill would have had a reasonable expectation of success because Del Rio discloses a predictor classifier for response to FOLFIRI treatment in patients with advanced CRC using microarray gene expression profiles of primary CRC tissue collected from human subjects and a method of determining gene signature expressed by responders and non-responders of treatment (Table 3); further because Mao teaches BTG2 expression can be p53-independent, being upregulated by oxidative stress via C-NF-kB; further because Tae teaches lipoic acid prevents p53 degradation in colon cancer by blocking NF-kB signaling, which would be expected to improve treatment by inhibiting p53 degradation and subsequent loss of sensitivity to treatment.
Further regarding claim 2, Del Rio discloses 5-FU, irinotecan, and oxaliplatin as well as combinations thereof.
Further regarding claim 4, for a transcriptional response indicating both p53 dependent and independent signatures, one of ordinary skill would have had a reasonable expectation of success, in view the disclosures above, by targeting BTG2 with a NF-kB inhibitor which can also prevent p53 degradation, as taught by Mao and Tae.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Del Rio et al. (J. Clin Oncol., 2007; 25: 773–780) (“Del Rio”); in view of Toscano et al. (Biochem. Pharmacol., 7, 2007, 392–406) (“Toscano”); further in view of Mao et al. (Int. J. Oncol., 2015, 46: 459-464) (“Mao”); and Tae-Hyoung (Anti-Cancer Drugs, 24 2013, 555-565) (“Tae”); as applied to claims 1-4 and 7; further in view of Chung et al. (Cancer Biology & Therapy, 2010, 10, 1147-1156) (“Chung”).
The teachings of Del Rio, Toscano, Mao, and Tae are disclosed above and incorporated herein.
While Del Rio, Toscano, Mao, and Tae don’t specifically teach wherein the transcriptional response produces a measurement of the regulation of histone genes by a chemotherapeutic drug (claim 5); the teachings of Chung are relied upon for these disclosures.
Chung teaches that 5-FU treatment of MMR-proficient SW480 cells (colorectal cancer cell lines) downregulated histones H2A, H2B and H3 (page 1148, col. 2, para. 3, 6th line from bottom; and Table 1) and upregulated p53. Chung further summarizes that 5-FU reduction of histone H3 levels could be related to DNA access by repair proteins and/or triggering cell death; and that 5-FU may trigger downstream events that contribute to CRC patient survival (page 1154, col. 2, top).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to expect that downregulation of histone genes would correlate with improvement of CRC patient survival, as taught by Del Rio, Toscano, Mao, and Tae, further in view of Chung. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Del Rio, Toscano, Mao, and Tae disclose a process for optimizing treatment efficiency of CRC patients, and teach that standard of care treatments for CRC comprise 5-FU; further because Chung teaches treatment of CRC cell lines with 5-FU downregulated histones H2A, H2B and H3, and that reduction of histone H3 levels could be related to DNA access by repair proteins and/or triggering cell death, thus improving CRC patient survival.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Del Rio et al. (J. Clin Oncol., 2007; 25: 773–780) (“Del Rio”); in view of Toscano et al. (Biochem. Pharmacol., 7, 2007, 392–406) (“Toscano”); further in view of Mao et al. (Int. J. Oncol., 2015, 46: 459-464) (“Mao”); and Tae-Hyoung (Anti-Cancer Drugs, 24 2013, 555-565) (“Tae”); as applied to claims 1-4 and 7; further in view of Park et al. (Cell Reports, 2020, 32, 108077, 19 pages) (“Park”).
The teachings of Del Rio, Toscano, Mao, and Tae are disclosed above and incorporated herein.
Del Rio teaches that in patients with CRC, standard treatments comprise leucovorin, 5-FU, CPT-11, and/or Ox; displaying response rates of about 50% (abstract – purpose; and page 3, para. 1).
Toscano further teaches oxaliplatin induces fewer complications, restricted to peripheral sensory neuropathy, as compared to other platinum derivates such as cisplatin and carboplatin that induce nephrotoxicity and myelosuppression, respectively (page 392, col. 2).
While Del Rio, Toscano, Mao, and Tae don’t specifically teach wherein the transcriptional response produces a measurement of the regulation of FOS and ATF3 by chemotherapy drug (claim 6); the teachings of Park are relied upon for these disclosures.
Park studied the cell-fate responses after 5-FU treatment (apoptosis, cell-cycle checkpoint, and stress resistance) (abstract). Park characterized the individual cell response to 5-FU in CRC cells RKO (colon p53 WT), HCT116 (p53 WT), and SW480 (p53 mutated) (page 3, col. 1). Park teaches that the stress group of treated cells expressed high levels of stress responsive transcription factors, including ATF3 and FOS, as well as their targets; and that ATF3 and FOS, which are among the top stress-group-specific markers (page 10, col. 1). Park teaches that the number of cells in the stress group were not reduced at the high 5-FU dose (Figures S2B–S2D), indicating that the cells in these groups were relatively resistant to the genotoxic stress induced by 5-FU (page 4, col. 2, para. 3, end).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to expect that upregulation of FOS and ATF3 would correlate with peripheral neuropathy in subjects, in view of Del Rio, Toscano, Mao, Tae, and Park. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Del Rio teaches different treatment regimens for CRC, which comprise leucovorin, 5-FU, CPT-11, and/or Ox; Toscano teaches that Ox induces peripheral neuropathy; and Park teaches that cells wherein 5-FU treatment results in upregulation of FOS and ATF3 were resistant to the genotoxic stress induced by 5-FU. In view of these teachings, one of ordinary skill, upon finding upregulation of FOS and ATF3 in 5-FU treated CRC cells, would be motivated to switch chemotherapeutic agents and treat with Ox instead, which has the known side effect of peripheral neuropathy. One of ordinary skill would have had a reasonable expectation of success in view of the disclosures above.
Conclusion
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627