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 .
Claims 6, 20-31 are pending in the application.
This office action is in response to the amendment filed on 12/2/2025.
All previous rejection not reiterated in this office action are withdrawn.
Specification
The amendment filed on 12/2/2025 is objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows:
In paragraph [0044]: “If the presence of a suppressed levels of phosphorylation of Ser2 on the CTD of RNA Pol II is found within the tumor tissue, then a CDK9 inhibitor is not efficacious.”
The amendment deleted “not” in front of “found,” which is opposite from the teaching as originally filed specification. Moreover, the amendment paragraph [0044] now reads “If the presence of suppressed levels of phosphorylation of Ser2 on the CTD of RNA Pol II is found within the tumor tissue sample from the patient, greater efficacy may be predicted if a regimen of CDK9 inhibitors is prescribed for the patient. If the presence of a suppressed levels of Ser2 on the CTD of RNA Pol II is found within the tumor tissue, then a CDK9 inhibitor is not efficacious.” As such, under the same condition “suppressed levels of phosphorylation of Ser2 on the CTD of RNA Pol II is found within the tumor tissue,” two complete opposite statement regarding CDK9 inhibitor is stated “greater efficacy” vs. “not efficacious.” This amendment not only make paragraph [0044] confusing, but also is opposite to the teaching of the specification as originally filed. Such amendment thus constitutes new matter.
Applicant is required to cancel the new matter in the reply to this Office Action.
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.
Claims 6 and 20-31 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. This is a new matter rejection.
Claim 6 is amended to recite in step b) “identifying in the patient increased levels of phosphorylation of Ser2 on the CTD of RNA Pol II relative to a control sample.” Applicant states that support for this amendment may be found throughout the claims and specification, including at paragraphs [0005], [0094], [0098] and [0100]. However, the original claim 6 recites detecting in a biological sample from a patient, a suppressed level of CTD or RNA Pol II relative to a control (see deleted text in step a), which is opposite to the amendment. Paragraph [0005] teaches the summary of the invention being detecting overexpression of MYC in a biological sample from a patient, which indicates sensitivity to a treatment by a CDK9 inhibitor. Paragraph [0094] does not mention identifying increased level of phosphorylation of Ser2 on CTD of RNA Pol II either, it only summarizes the result and states “taken together, these results indicate that CDK9 might be crucial for the maintenance of MYC-overexpressing tumors, and identify a potential patient population that might be sensitive to CDK9 inhibition. Paragraph [0098] summarizes the results of MYC overexpression and indicates a key role for transcription elongation in mediating MYC action in tumor maintenance, but fails to mention identifying increased level of phosphorylation of Ser2 on CTD of RNA Pol II. Paragraph [0100] summarizes the results of CDK9 inhibition in xenografts and concludes that CDK9 is required for the maintenance of MYC-overexpressing HCC, implicating transcriptional elongation as important for MYC dependency in vivo. None of the cited paragraphs from the specification supports the amendment for identifying increased level of phosphorylation of Ser2 on CTD of RNA Pol II prior to the administration of a CDK9 inhibitor. Since this amendment is not supported by the as filed original specification, it constitutes new matter.
Dependent claims 20-31 are rejected for same reason because they depend on claim 6.
Response to Arguments
Applicant argues that the instant application inherently discloses the use of increased levels of phosphorylation of Ser2 on the CTD of RNA Pol II relative to a control sample as a marker for treatment of MYC-overexpressing tumors with CDK inhibitors. Applicant uses Figure 6C and 6F of the instant specification to show that MYC overexpression in low MYC Alexander cells dramatically increased Ser2 phosphorylation of RNA Pol II relative to control unmodified Alexander cells and MYC overexpressing cells became more sensitive to CDK9 inhibition. Applicant asserts the specification also explicitly states that CDK9 is “required for initiation and maintenance of MYC-overexpressing liver tumors” and “CDK9 inhibition leads to a decrease in the levels of phosphorylation of Ser2 of RNA pol II” citing paragraph [0016] and Figure 7. Applicant asserts that the specification repeatedly and explicitly describes RNA Pol II Ser2 phosphorylation as a biomarker in cancer treatment, CDK9 inhibitor assays are described “using Ser2 phosphorylation of RNA Pol II as a biomarker” to demonstrate CDK9 inhibition, citing paragraph [0081], “a patient selection criteria (high MYC) and a pharmacodynamics marker (Ser2 phosphorylation of RNA Pol II), which can greatly facilitate preclinical and clinical development of [CDK9 inhibition] in both hematological and solid cancers” (paragraph [0083]). Applicant assert that the specification teaches “for productive transcription, P-TEFb is recruited, and CDK9 phosphorylation Ser2 in the CTD of RNA Pol II, inducing pause-release and subsequent transcription elongation” and that “pharmacological or RNAi-mediated suppression of CDK9 led to a decrease in Ser2 phosphorylation” in MYC overexpressing carcinoma cell lines. Applicant states that post filing art Huang et al. states high MYC expression levels are required to establish sensitivity to CDK9 inhibition” and that the administration of CDK9 inhibitor (PHA) actually decreases Ser2 phosphorylation on the CTD of Pol II. Applicant concludes that all of the teaching above means the teaching of the present specification teaches use of Ser2 phosphorylation on the CTD of RNA Pol II as a marker for CDK9 activity in cancers and contemplates the use of elevated levels of Ser2 phosphorylation as a predictor of efficacy of CDK9 inhibitor treatment in cancer.
The above argument has been fully considered but deemed unpersuasive. The specification describes Figure 6C as “immunoblots showing MYC overexpression effect on Ser2 phosphorylation of RNA Pol II in low MYC expressing SNU475 and Alexander cells,” and 6F “proliferation rates of PHA-767491 treated cells in Figure 6C.” Further explaining the data in Figure 6C and 6F, paragraph [0098] states “to directly determine whether modulation of MYC activity could influence cellular dependence on CDK9 activity, the experiment tested the ability of enforced MYC expression to influence sensitivity to CDK9 inhibition. Ecotopic expression in the low MYC Alexander cells produced MYC levels ~50% of those measured in sensitive HepG2 cells and an increase in MYC dependent transcription elongation as measured by reduced pausing index at the NPM1 and MCM4 but not BRG1 mRNA genes (Figs 6C and 6D)…Concordantly, MYC-overexpressing Alexander cells became more sensitive to CDK9 inhibition by PHA-767491 or CDK9 shRNAs (Figure 6F).” The above teaching establishes that tumor cells with high expression of MYC is more sensitive to CDK9 inhibitors, however, there is no direct teaching indicates measuring a biological sample with level of phosphorylation of Ser2 on CTD of RNA Pol II identifies a patient being a better candidate that would responding to CDK9 inhibition. The fact that “CDK9 is required for initiation and maintenance of MYC-overexpressing tumors,” and “CDK9 inhibition leads to a decrease in the levels of phosphorylation of Ser2 of RNA pol II” does not mean patient with a high overall phosphorylation of Ser2 on the CTD of RNA Pol II relative to a control indicates the patient would be sensitive to CDK inhibitor treatment. Paragraph [0081] is directed to how to get improved CDK9 inhibitor for the clinical management of MYC-overexpressing tumors. The alleged use of Ser2 phosphorylation of RNA Pol II as a biomarker (and paragraph [0083]) means using phosphorylation of RNA Pol II as a pharmacodynamic marker, which is a measurable indicator of drug’s activity and efficacy on its target body. Such markers are used to confirm whether a drug is engaging its intended target and producing a biological response, such pharmacodynamic biomarker is different from the marker as claimed in claim 6, which serves as a biomarker to identify a subpopulation from cancer patients that will respond to CDK9 inhibitor therapy. The teaching from post filing art Huang et al. exhibit A states “we predict that HCCs with high MYC levels will be most likely to respond to improved CDK9 inhibitors. Thus, our study identifies a drug target (CDK9), tool compounds, a patient selection criteria (high MYC), and a pharmacodynamic marker (Ser2 phosphorylation on the CTD of Pol II).” Again, the phosphorylation of Ser2 on the CTD of Pol II is a pharmacodynamic marker for evaluating improved CDK9 inhibitors, not a patient selection criteria, in the instant case, it is high MYC expression in tumor cells. None of the above teaching indicates that increased level of phosphorylation of Ser2 on the CTD of RNA Pol II compared to a control indicates a patient would respond better to CDK inhibitor therapy. Therefore, the above rejection is still considered proper and thus maintained.
Claims 6 and 20-31 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to: (a) the nature of the invention; (b) the breadth of the claims; (c) the state of the prior art; (d) the amount of direction provided by the inventor; (e) the existence of working examples; (f) the relative skill of those in the art; (g) whether the quantity of experimentation needed to make or use the invention based on the content of the disclosure is "undue"; and (h) the level of predictability in the art (MPEP 2164.01 (a)).
The nature of the invention
The claimed invention is a method of treating a patient suffering from cancer, carcinoma, lymphoma and leukemia, wherein the cancer overexpresses MYC. The method comprises the steps of detecting levels of phosphorylation of Ser2 on a CTD of RNA Pol II in a patient sample; identifying in the patient increased levels of phosphorylation of Ser2 on the CTD of RNA Pol II relative to a control; and administering a therapeutically effective amount of CDK9 inhibitor. Dependent claims further limits the method to specific types of cancer (claims 20-24), specific CDK9 inhibitor (claim 25), different types of biological sample being analyzed (claims 26-28), process for obtain protein, and process for determining level of phosphorylation (claim 31).
The breadth of the claim and the teaching from the specification
The claim scope encompasses a method of treating a wide variety of cancer that overexpresses MYC based on the determination of overall phosphorylation level of Ser2 of RNA Pol II being increased compared to a control. However, the teaching from the present specification appears to contradict with the claimed method because the specification teaches methods that are based on the presence of suppressed level of phosphorylation of Ser2 in the CTD of RNA Pol II (see paragraph [0007]). The specification teaches of the presence of suppressed levels of phosphorylation of Ser2 on the CTD of RNA Pol II is found within tumor tissue sample from the patient, greater efficacy may be predicted if a regime of CDK9 inhibitors is prescribed for the patient. If the presence of a suppressed levels of phosphorylation of Ser2 on the CTD of RNA Pol II is not found within the tumor tissue, then a CDK9 inhibitor is not efficacious (see paragraph [0044]). There is no working example that demonstrates that increased Ser2 phosphorylation of RNA Pol II predicts effective CDK9 inhibitor therapy. As such, based on the teaching from the specification, whether identifying a patient with increased level of Ser2 phosphorylation of RNA Pol II indicates said patient would have better outcome with CDK9 inhibitor is unpredictable.
The teaching from the prior art and the level of predictability in the art
Sengupta (IDS) is a relevant prior that teaches CDK9 mediated transcriptional de-regulation of cMYC is a critical determinant of endocrine-therapy resistance in breast cancers (title). Sengupta teaches Ser2 phosphorylation Pol II is recruited to c-MYC promoter in MYC overexpressing cells MCF7:5C compared to parental MCF7 cells (Figure 4A and 4B, legend and page 118, 1st col., line 1-11). Sengupta teaches that no difference was observed in overall total levels of phosphorylated Ser2 RNA Pol II in MCF7:5C compared to MCF7 (page 118, 1st col., line 14-17). Sengupta teaches the increased phosphorylation of Ser2 is associated with CDK9 level and using CDK9 inhibitor selectively inhibited tumor growth that is resistant to endocrine therapy (page 120, 2nd col., 3rd paragraph, line 5-15). The teaching from Sengupta also contradicts with the claimed method in claim 6, which relies on the detection of total Ser2 phosphorylation of Pol II increase as claimed.
The amount of guidance required
In view of the teaching from both the specification and knowledge in the art at the time of filing, whether a skilled artisan would be able to practice the claimed invention would have been unpredictable because both teaches the opposite from the claimed method of claim 6. A skilled artisan would have to engage in undue experimentation to practice the method as claimed.
Therefore, claim 6, and dependent claims thereof, are not enabled by the instant specification.
Response to Arguments
Applicant presented same argument as discussed above. Applicant alleges that Sengupta teaches “the increased phosphorylation of Ser2 is associated with CDK9 level and using CDK9 inhibitor selectively inhibited” growth in an entirely different cancer type, which is entirely consistent with the claimed method of using increased levels of phosphorylation of Ser2 on CTD of RNA Pol II relative to a control sample as a marker for selecting MYC-overexpressing tumors that are predicted to be responsive to inhibitor therapy. Applicant asserts that the teaching in paragraph [0044] is a typographical error in view of the experimental data disclosed in the instant application and described above in both exhibit A and in Sengupta.
The above arguments have been fully considered but unpersuasive. The data presented in the specification and exhibit A does not support the notion that increased phosphorylation of Ser2 on CTD of RNA Pol II indicates a patient is likely to respond to CDK9 inhibitor for reason discussed above. Sengupta teaches that no difference was observed in overall total levels of phosphorylated Ser2 RNA Pol II in MCF7:5C compared to MCF7 (page 118, 1st col., line 14-17). The teaching from paragraph [0044] is not a typographical error for reason discussed in the above objection to the specification. Therefore, the enablement rejection is still considered proper and thus maintained.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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/CELINE X QIAN/ Primary Examiner, Art Unit 1637