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 .
Election/Restrictions
Applicant’s election without traverse of CHRM2 mRNA, LGR5, colorectal cancer and small molecule inhibitors in the reply filed on 10/8/2025 is acknowledged.
Claim Rejections - 35 USC § 112
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 3, 4, and 9 are 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.
Claims 3, 4, and 9 recite that the level of expression of CHRM3 mRNA from “a sample” from “a tumor” (i.e. a single level) is converted into a rating scale. It is unclear how a single observed level can be converted into a scale which is a set of categories or an assessment tool.
Claim 4 as amended recites “using the prognostic rating scale to decide whether the subject is subjected to a treatment by subjecting said subject to …therapy and/or surveillance…based on the rating scale.” It is unclear what it means to “decide” by subjecting the subject to treatment. It is unclear if this claim requires deciding only or if it also requires subjecting a subject to treatment and/or surveillance.
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, 3, 4, 7, 9, 10, 12-18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a natural phenomenon without significantly more.
The claims each recite at least one mental process abstract idea judicial exception which can be precited in the mind by thinking or reviewing data, each claim recites one or more of: “predicting the subject will likely experience a poor outcome of the disease or disorder,” “comparing the level of expression”, that a rating scale “using the prognostic rating scale to decide.”
Claims additionally recite the level of expression “converting the level of expression” into a rating scale, which is a mathematical process judicial exception.
Claims additionally recite that an elevated level of expression compared to the control level indicates that the subject is likely to experience a poor outcome of the disease, which is a law of nature judicial exception because the correlation between elevated expression and disease outcome is a naturally occurring correlation.
This judicial exception is not integrated into a practical application because the steps in claims 1-4 in addition to the judicial exception are extra-solution data gathering steps recited at an extremely high level of generality that do not use or apply the judicial exceptions in anyway.
Claim 4 is indefinite, but even if it does require subjecting the subject to surveillance, this does not integrate the judicial exception because it does not treat the disease. It is more post-solution data gathering.
Claims 7 recites that “when the level of expression is elevated, the subject is subjected to an anti-tumor treatment.” This does not integrate the judicial exception of “comparing” first because it is a conditional step which only occurs for some outcomes of the comparing. Even if the observation were required and thus the step was required, it would not integrate the judicial exception because it recites the treatment at such a high level of generality that it is considered an instruction to “apply it.”
Claim 10 also recites a conditional treatment step, that is the step only occurs “when” the levels meet certain criteria. This does not integrate the judicial exception of “comparing” first because it is a conditional step which only occurs for some outcomes of the comparing.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the steps in addition to the judicial exceptions are data gathering steps recited at an extremely high level of generality merely directing one skilled in the art to gather the data necessary to practice the comparing and subsequent steps. Techniques used to measure expression could include RT-PCR, which was well known routine and conventional (see Van Guilder et al. Biotechniques 2008. BioTechniques 44:619-626).
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 3, 4, 7, 9, and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Masuda et al. INTERNATIONAL JOURNAL OF ONCOLOGY 48: 975-982, 2016, as evidenced by dataset GEO GSE64256, probe set 213880_at.
Masuda teaches obtaining tumor tissue from patients with colorectal cancer (which is inherently a cancer of epithelial origin). The reference teaches gene expression analysis via the human Genome U133plus Array, and teaches that CHRM3 was upregulated with a fold change in >1.5 in patients with recurrence of CRC (p. 967-968). That is, a significantly elevated level of expression of CHRM3 mRNA compared to control level (i.e. patients with no recurrence) indicates that the subject is likely to experience a poor outcome of the disease.
The method taught by Masuda et al. inherently includes measuring LGR5 expression, as illustrated in the graph below where LGR5 is assayed with Affymetrix probe set 213880_at. These data were retrieved from a dataset related to the Masuda paper, see Masuda p. 976 which states that the data were deposited in the GEO under GSE64256. NOTE: the amended claims require determining expression and comparing to a control for LGR5 (consonant with the election) but do not require any further consideration of this data or integration of these data into the prognostic indicator. The “control level” is undefined in the claim and encompasses comparing recurrent patient values to nonrecurrent patient values, a process which is included in the “Extraction of candidate genes” described in the 2nd column of p. 976 of Masuda.
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With regard to claim 3, which requires converting “the level of expression of CHRM3 mRNA” into a “rating scale” the reference teaches assigning a “fold increase” to expression levels and that a 1.5 fold increase indicated a worse prognosis.
Masuda does not teach a step of “predicting” that the subject will “likely” experience a recurrence when the level of expression of CHRM3 mRNA is significantly elevated compared to a control level.
However, Masuda does teach that genes that are overexpressed and have amplified copy number in cases of distant metastasis have the potential to serve as clinical biomarkers (p. 975, 2nd column).
It would have been obvious to have modified the method taught by Masuda so as to have used the expression of CHRM3 as a predictor of recurrence in CRC patients. One would have been motivated to do so because Masuda teaches a need for prognostic indicators (p. 975, 2nd column), suggest that genes that are overexpressed and amplified have potential to act as prognostic markers, and identify CHRM3 as a gene that meets these criteria. Thus, following all of this, it would have been obvious to use CHRM3 to predict recurrence of CRC with a reasonable expectation of success.
Regarding claim 4, Masuda further teaches that patients determined to be at risk for CRC recurrence are good candidates for adjuvant chemotherapy (p. 981).
Therefore, it would have further been obvious to have considered the risk of recurrence of CRC, based on the prognostic CHRM3 marker and decided whether or not to deliver adjuvant chemotherapy to patients, and with regard to claim 7, administering the treatment when expression is high.
Further, with regard to claims 7 and 10, as CHRM3 was measured in the patients whose cancer did not recur, these patients had the level measured that was lower than the “control” group whose cancer did recur. Therefore, for these patients, the treatment is not required since treatment is required only “when” certain conditions are met.
Claim(s) 10, 12, 14, 15, 16, 17, and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Spindel et al. (WO 2007/109142 A2) in view of Hering (Cancers 2021, 13, 3220.; 17 pages).
Spindel et al. teaches a method that includes collecting a sample from a tumor of a subject having a cancer of epithelial cell origin (p. 6, line 30 and following), determining the level of expression of CHRM3 mRNA or CHRM3 protein, and comparing the level to a control (p. 3, line 16, p. 22, line 10 and following; CHRM3 referred to therein as M3 mAChR). The reference further teaches if the CHRM3 mRNA is significantly elevated compared to the control, the subject is subjected to an anti-tumor treatment (p. 2, line 26 and following; p. 3, lines 10-11). One of the cancers that Spindel teaches for treatment is colon cancer.
The reference teaches determining the relative or absolute quantity of the M3 mACHR, thereby assigning a numeric value (i.e. quantity) to the expression level. The quantity can be used as a score against a rating scale. Here the reference teaches that a level greater than a control indicates expression (p. 23, line 16).
Spindel et al. does not teach determining activity of CHRM3 protein.
Hering teaches that M3R is involved in the development and progression of CRC. The reference teaches that binding of ACh to M3R activates pathways that lead to enhanced tumor cell growth, proliferation, survival, MMP-dependent membrane invasion and tumor cell migration (p. 2). Hering teaches measuring M3R activity in colorectal cancer cells, both in vitro and in vivo in response to darifenacin and in control cells or animals (p. 4). Hering et al teaches measuring M3R post receptor signaling (p. 4, section 2.3) and MMP-1 expression, which, with regard to claim 10 is a CHRM3 response gene to the CHRM3 protein activity (p. 4, section 2.4). Hering teaches measuring M3R expression in vivo and also measuring downstream activity of M3R, namely proliferation in treated and untreated animals (p. 4, 2.5).
With regard to claim 12, the Hering measuring M3R expression and activity using techniques where an observed signal is converted into a numeric value to quantify the expression and activity (sections 4.6, 4.8, and 4.9).
With regard to claim 14, Hering teaches treating primary tumors in mouse models, as well as metastases (Abstract and throughout).
With regard to claim 15, Hering teaches colorectal carcinoma (Abstract and throughout).
With regard to claim 16, Spindel teaches treating humans, and Hering suggests adding darifenacin to standard postoperative chemotherapy in CRC patients with PNI (simple summary and p. 11).
With regard to claim 17 and 18, the inhibitor is darifenacin.
It would have been prima facie obvious to have modified the method taught by Spindel so as to have additionally determined the level of CHRM3 activity in the tumors taught by Spindel in order to provide additional and more complete information about the status of the tumors. It would have been evident based on the teachings of Spindel et al. and Hering et al. together that a tumor that had increased expression and activity of CHRM3 relative to a control would have been more likely to develop and progress, as it was known that M3R is involved in the development and progression of colon cancer (Hering, abstract and introduction). It would have been obvious that in order to do so, the numerical data related to levels of activity and expression would be converted into some metric to determine increased expression or activity, which is a rating scale. One would have been motivated to do so by the teachings of Hering et al. that M3R is involved in the development and progression of M3R post receptor signaling leads to progression of invasion and metastasis in colorectal cancer. Furthermore, with regard to the administering step in claim 10, it would have been obvious to deliver darifenacin to the patients having tumors with elevated CHRM3 expression and activity. Darifenacin is an agent that inhibits CHRM3 activity, as taught by both Spindel et al. and Hering et al., and Hering et al. teaches that increased activity of CHRM3 leads to enhanced tumor cell growth, proliferation, survival, MMP-dependent membrane invasion and tumor cell migration (p. 2).
Claim(s) 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Spindel et al. in view of Hering et al. as applied to claims 10, 12, 14, 15, 16, 17, and 18 above, and further in view of Said et al. (Biochemical Journal (2017) 474 647–665).
The teachings of Spindel in view of Hering as they address claim 9, from which claim 13 depends are given previously in this Office action and are fully incorporated here. These do not teach administering an effective amount of an EGFR inhibitor.
Said teaches studies that uncover novel functional interactions between post-muscarinic receptor signaling pathways that augment MMP1 expression and drive colon cancer cell invasion, and that targeting these has therapeutic potential (Abstract). In particular, the reference suggests that combination and EGFR inhibitor with an agent that blocks M3R activity may have therapeutic promise for preventing or retarding colon cancer cell metastasis or blocking cancer cell escape (p. 662).
It would have been obvious to have modified the treatment method taught by Spindel in view of Hering so as to have provided a combination treatment of darifenacin along with an agent that blocks EGFR activity. One would have been motivated to do so by the express teaching of Said that combination therapy simultaneously targeting several pathways is needed to incapacitate redundant post-receptor signal transduction mechanisms that retulate MMP1 expression in colon cancer (p. 662).
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 10 and 12-18 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.
Claims 10 and 12-18 require measuring the expression of one or more “response genes.” The specification teaches that the expression of response genes and CHRM3 form a treatment signature that is characteristic for the sensitivity of a subject to tumor treatment. The specification teaches that the correlated genes and response genes are selected from a group of genes but are not necessarily identical (para 39).
The specification provides guidance as to how response genes can be derived from experiments (para 40-41) but it does not provide any guidance as to common structural features of these genes nor any way to identify the genes other than through experimentation. There is no art-recognized correlation between any structure and the activity of being a response gene.
It is well known that gene expression varies by tissue and tumor type, and there is no way to predict “generally” which genes, out of the tens of thousands of possible genes which may be correlated with CHRM3 expression in any type of tumor. Likewise, it is highly unpredictable which genes will function as “response” genes, particularly in that they could predict the efficacy of any treatment. Ali teaches “The physiological activity of muscarinic receptors depends on tissue expression, G protein coupling, and the downstream signal transdu ction pathway (Ali, p. 3).”
Thus, having carefully considered all of this, it is concluded that the specification fails to satisfy the written description requirement with respect to the rejected claims.
Response to Remarks
With respect to the 112b, applicant argues that the specification describes that the measured expression levels are placed on a pre-established rating scale that categorizes subjects based on expression thresholds. Applicant argues that “a measured expression level is compared against a pre-established scale to determine a risk category.” However, the claim language, which remains indefinite, states “converting the level of expression of CHRM3 mRNA…into a prognostic rating scale.” In claim 3, the antecedent basis for “the level of expression” is found in claim 1 where the level of expression in a sample from a tumor is determined. Which is a single sample. Even based on the cited specification passages, it is unclear how this value is converted “into a scale.” Applicant argues a feature not claimed, that is comparing this value to a scale to determine risk category. The rejection is maintained.
Applicant argues that the claims as amended require physical, technical steps that cannot be performed in the mind. However, the rejection addresses why these steps fail to integrate the judicial exception or amount to significantly more. Further, it is noted that “additional” steps identified by applicant as “comparing” and “predicting” are not additional steps but are themselves mental process judicial exceptions.
Applicant argues that the step of gathering data for an additional gene provides a non-routine combination approach to forming a prognostic signature. First, it is noted that no claim requires incorporating the data from the second gene into any prognostic signature. Further, gathering data about the expression of marker genes was well established as routine activity before the invention. Forming a “prognostic signature” or calculating such a signature is itself a judicial exception.
Applicant further argues that claims 7 and 10 recite active treatment steps. The treatment steps in these claims only occur when certain conditions are met, and therefore do not integrate the judicial exception. Furthermore, the treatment recited in claim 7 is highly general and would not integrate the judicial exception even if it were required. See MPEP 2106.04(d)(2).
Amendment of claim 10 to make a positive statement to require detecting levels that are significantly elevated compared to control levels, and then administering the agent recited would overcome this rejection.
With regard to Masuda, applicant argues that the assertion that Masuda inherently measures LGR4 is insufficient since inherently recognizes that the missing element must be present and recognized. The data to support that Masuda detected LGR5 is provided in the Office action; the fact that Masuda provides the data evidences that they method practiced detected the level of expression of the gene. The claims do not require “using LGR5 levels to predict disease outcome.” This is a feature not claimed.
With regard to the obviousness rejection in view of Spindel, the response argues that neither Spindel nor Hering suggest using LGR5 (consonant with the election) to form a prognostic signature. No claim rejected with this combination of references requires this. The response further argues that neither reference alone nor in combination suggests using CHRM3 activity measurement for patient selection or as a “prerequisite” for treatment. Insofar as this argument is referring to the “administering” step (d) in claim 10, this newly amended step is addressed in the revised rejection of record. The rejection is updated and maintained.
Regarding the rejection for written description, applicant argues that response genes are genes controlled by CHRM3 protein activity, and describes how to identify the response genes. However, this is merely an invitation to screen for an identify genes which may be markers of response to a particular drug or treatment regime. There is no written description of what these genes are, and the function of the genes does not suggest any particular structure or identity of the genes. The rejection is maintained for amended claim 10 and those that depend from it.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Calaf teaches muscarinic acetylcholine receptors regulate biological processes by the activation of the EGFR pathway. The ability of muscarinic agonists to stimulate growth and the M3 receptor antagonists to inhibit tumor growth has been demonstrated for breast, melanoma, lung, gastric, colon, pancreatic, ovarian, prostate, and brain cancer. Calaf et al. Cancers 2022, 14, 2322. 32 pages.
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 Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at (571)-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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