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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/18/2025 has been entered.
Applicant’s election without traverse of Group I and the combination of Septin9, BCAT1 and IKZf1 in the reply filed on 6/25/2024 is acknowledged.
Claims 1,4,6-8,12-15,18,22,28,37,45,47,51,54,56,57,59,71,73, 79-81 are pending. Claims 2-3,5,9-11,16-17,19-21,23-27,29-36,38-44,46,48-50,52-53,55,58,60-70,72,74-78 have been cancelled.
Claims 7,54,56,57,59,71,73, 79-80 are withdrawn as being drawn to a nonelected invention or species.
The following rejections are modified or newly applied. Response to arguetmsn follows where applicable.
This action for claims 1,4,6,8,12-15,18,22,28,37,45,47,51, 81 is NONFINAL.
CFR 1.132
The declaration under 37 CFR 1.132 filed 7/07/2025 is insufficient to overcome the rejection of claims 1,4,6,8,12-15,18,22,28,37,45,47,51, 81 based upon 35 USC 112a as set forth in the last Office action because: is not commensurate in scope with the claims. See detailed response below.
Modified 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 1,4,6,8,12-15,18,22,28,37,45,47,51, 81 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of detecting methylation level of Septin9, BCAT1 and IKZF1, does not reasonably provide enablement for correlation to diagnosis of colorectal neoplasm, onset or risk of onset, increased probably of developing, poor prognosis or risk to poor prognosis. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The breadth of the claims and nature of the invention
The claims are broadly drawn to quantifying the higher methylation of subregions of Septin9, BCAT1, IKZF1 as compared to a reference to determine that the subject has colorectal neoplasm, onset or at a risk to the onset of colorectal neoplasm, develops or with an increased probability of developing colorectal neoplasm, or poor prognosis or risk to poor prognosis of colorectal neoplasm in a subject.
The specification has not provided any guidance for such determine that the subject has colorectal neoplasm, onset or at a risk to the onset of colorectal neoplasm, develops or with an increased probability of developing colorectal neoplasm, or poor prognosis or risk to poor prognosis of colorectal neoplasm in a subject based on increased level of methylation.
Nature of the Invention
The invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
Guidance in the Specification and Working Examples
The specification combined 28 target markers wherein the markers mixtures of fully methylated DNA at all CpG sites into fully unmethylated DNA (p. 99-100). The specification tested 28 markers in colorectal cancer tissue, advanced adenoma tissue, paracancerous tissues from colorectal cancer patients and white blood cells from colonoscopy negated humans (p. 104). The specification states that these markers were lower in normal patients as compared to tissues from colon cancer patients (p. 105 and figure 2). The specification teaches that the methylation abundances of the target markers were lower in paracancerous tissues than in advanced adenoma tissues and colorectal cancer tissues (p. 105-106). The specification asserts that preamplification increased sensitivity (p. 109-110, 113-114).
However, the specification does not provide that individual assessment of the group of markers have correlations. The specification does not provide guidance for this analysis and correlation to diagnosing colorectal neoplasm, onset of neoplasm, risk of colorectal neoplasm, increased probability of developing colorectal neoplasm, poor prognosis or risk of poor prognosis of colorectal neoplasm. Further, the specification has not provided guidance to the multitude of different correlations. For example the claims are drawn to both diagnosing colorectal neoplasm and poor prognosis of colorectal neoplasm based upon the increased methylation level of combination of genes however, the specification has not provided such correlations.
Although the specification teaches that there is a correlation of increased methylation in colorectal cancer tissues versus paracancerous tissues and normal patients, the specification does not provide guidance to diagnosis colorectal cancer or any prognosis.
Quantity of Experimentation and Conclusion
The quantity of experimentation in this area is extremely large as it requires the analysis methylation expression level of multiple genes and association of colorectal diagnosis, prognosis or onset.
As neither the art nor the specification provides guidance as to the breadth of these associations, the claims require trial and error experimentation, with the outcome of colorectal diagnosis, prognosis or onset being unpredictable. The skilled artisan would have to test each sample type for correlation to diagnosing, risk, development by detection methylation in the recited subregions, with any higher methylation of any of the subregions. Further this appears to be contradicting as a higher level is both supposed to be correlative to diagnosis of colorectal neoplasms and screening for onset or risk (e.g. not presently with colorectal neoplasm). This correlation would take many intervening steps without providing any guarantee of success.
The specification does not provide clear guidance for the breadth of the claims, and the art teaches that these types of associations are unpredictable.
Thus given the broad claims in an art whose nature is unpredictable, the unpredictability of that art, the large quantity of research required to define these unpredictable variables, the lack of guidance provided in the specification, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the methods of the claims as broadly written.
Response to Arguments and 36 CFR 1.132
The reply and the 35 USC 1.132 declaration traverses the rejection. A summary of the arguments is provided below with response to arguments following.
The declaration provides post filing data to demonstrate the unexpected effects in evaluating development or prognosis of colorectal neoplasm with the combination of Septin9, BCAT1, and IKZF1 (p. 2). The declaration asserts that supplementary data for particular subregions recited in Table VI (p. 2). The declaration asserts that these are particular primer pairs for detection of these regions (p 3). The declaration asserts that post evidence of blood samples collected from patients before and after surgery (p. 3). The declaration provides post filing survival curves (p. 4). The declaration asserts that the combination of SEPTIN9, BCAT1, IKZF1, BCAN and VAV3 indicated effectiveness for post-surgery recurrence of colorectal neoplasm (p. 5). On pages 6-7 the declaration asserts that data post filing indicate that Septin9, BCAT1, and IKZF1 were effective for assessing post-surgery recurrence. These statements have been reviewed but have not been found persuasive. It is noted that the data provided in the declaration is post filing data. Further, the data is not commensurate in scope with the claimed method. The method does not require the same gene combination of SEPTIN9, BCAT1, IKZF1, BCAN and VAV3 nor the primers to amplify the particular subregions. Furthermore the data provided is based upon analysis of blood or plasma from human patients pre and post-surgery who have colorectal neoplasm. The instant claims are drawn to analysis of any sample from any human subject. Further the correlations are different, the data in the declaration is based upon poor prognosis, whereas the claims are drawn to diagnosing, screening onset or risk of onset, development or any prognosis. The declaration has not provided any analysis for these multitude correlations.
The reply asserts that the claims require the combination of methylation level of a particular subregion of 3 target makers (p. 16-17). The reply points to example 6 for diagnosis and onset of risks (p. 17-18).
These arguments have been reviewed but have not been found persuasive.
The claims are drawn to a correlation with diagnosis of colorectal neoplasm, onset or risk of onset of colorectal neoplasm, increased development of neoplasm, poor prognosis of colorectal neoplasm based upon increase methylation level of the subregions recited. Guidance for this correlation has not been fully set forth in the specification because the specification does not provide that individual assessment of the group of markers have correlations. The specification does not provide guidance for this analysis and correlation to diagnosing colorectal neoplasm, onset of neoplasm, risk of colorectal neoplasm, increased probability of developing colorectal neoplasm, poor prognosis or risk of poor prognosis of colorectal neoplasm. Further, the specification has not provided guidance to the multitude of different correlations. For example the claims are drawn to both diagnosing colorectal neoplasm and poor prognosis of colorectal neoplasm based upon the increased methylation level the combination of genes however, the specification has not provided such correlations.
Newly Applied 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 1,4,6,8,12-15,18,22,28,37,45,47,51, 81 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 1,4,8,12-15,18,22,28,45,51, 81 are indefinite over “comparing the methylation level of a subregion” in step iii of claim 1. In particular this phrase and the step is unclear as it is not clear if the claim in intending to compare only the methylation level of the subregion (e.g. consisting language) or if the claims would encompass when the entire gene marker has an increased methylation (e.g. comprising language).
Claim 4 is indefinite over “at least one target marker”. This phrase recitation is unclear as claim 1 requires all the target markers and not the recited “at least one target marker”.
Claim 18 is indefinite. Regarding claim 18, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 6, 37 and 47 are indefinite over “comparing the methylation level of a subregion” in step iii of claim 1. In particular this phrase and the step is unclear as it is not clear if the claim in intending to compare only the methylation level of the subregion (e.g. consisting language) or if the claims would encompass when the entire gene marker has an increased methylation (e.g. comprising language).
Maintained 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 1,4,6,8,12-15,18,22,28,37,45,47,51, 81 are rejected under 35 U.S.C. 101 are rejected under 35 U.S.C. 101 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Note that the unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., No. 10-1150 (March 20, 2012).
The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, No. 08-964, 2010 WL 2555192 (June 28, 2010) and in Alice Corp. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014).
Applicant’s attention is directed to the USPTO January 7, 2019 Revised Patent Subject Matter Eligibility Guidance (i.e., “PEG”) available at URL:
<https://www.govinfo.gov/content/pkg/FR-2019-01-07/pdf/2018-28282.pdf>.
Regarding Step 1 of the PEG, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature / natural phenomenon. The claims recite relationship between analyzing colorectal cancer and pattern of DNA methylation. As in Mayo Collaborative Services v. Prometheus, the recited relationship to the disease is a natural phenomenon that exists apart from any human action.
Further, the claims are drawn to comparing methylation levels, which can be interpreted as an abstract step of visually looking at data.
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). The steps of quantifying, is not considered an integration as rather, it is using any routine and conventional methods of methylation analysis. Further, the dependent steps merely limit the types of conventional assay techniques and methylation detected but do not limit the steps themselves to integrate the method and the judicial exception.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. The additionally recited steps are routine in the prior art. The claims are using a known method of analysis. The claims are not limited to a specific region using a specific reagent, rather the claims encompass a region comprising the recited subregions. As such the claims encompass naturally occurring genes (Spetin9, BCAT1, and IKZF1) as the recited subregions would be encompassed by the entirety of the gene. Further, the prior art of Mingming et al. (WO/2019/144277 Publication date 1/08/2019) teaches a method of treating DNA with a reagent capable of distinguishing a methylated and unmethylated site withing the target markers are Spetin9, BCAT1, and IKZF1 (para 10-12). Mingming teaches preamplfying using a primer pool as compared to a reference (para 105-106). Mingming et al. teaches a method of using preamplification primer pairs with a methylation specific primer that comprises a forward and reverse primer to the encompassed region (para 48, 50). Mingming et al teaches that these markers increased as compared to a control indicates risk of colorectal cancer (243-246 figure 3). With regard to the newly present claim 81, the claim is interpreted as a generic recitation of “apply it”. The claim does not require any specific integration of the judicial exception and encompasses any “treating”. This treatment could include a general recitation of a drug that treats any cancer type such as chemotherapy. As such the claim does not integrate the judication exception.
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
Response to Arguments
The reply traverses the rejection. A summary of the arguments is provided below with response to arguments following.
The reply asserts that the claims are not routine and conventional as the specific subregions of the markers have not been taught or disclosed by Mingming et al. (p. 18). The reply asserts that claim 81 requires treatment with a therapeutic agent (p. 19).
These arguments have been reviewed but have not been found persuasive.
With regard to claim 1 steps, the claims do not require any particular primers, rather the steps set forth encompass routine steps of PCR methylation that is well known and conventional in the prior art (see paragraphs 24 and 144). Furthermore, the reply asserts that the combination requires specific subregions, however, the claims are not limited to using particular primers to amplify. The claims do require the subregions, but the claims are “comprising”. As such the claims can be interpreted as regions that include the entirety of the gene as this would encompass these subregions. With regard to the newly present claim 81, the claim is interpreted as a generic recitation of “apply it”. The claim does not require any specific integration of the judicial exception and encompasses any “treating”. This treatment could include a general recitation of a drug that treats any cancer type such as chemotherapy.
Newly Applied Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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) 1,4,6,8,12-14,18,22,28,37,45,47,51, 81 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mingming et al. (WO/2019/144277 Publication date 1/08/2019 previously cited).
With regard to claim 1, Mingming et al. teaches a method of treating DNA with a reagent capable of distinguishing a methylated and unmethylated site within the target markers are Septin9, BCAT1, and IKZF1 (para 10-12). Mingming et al teaches that these markers increased as compared to a control indicates risk of colorectal cancer (243-246 figure 3). However, Mingming et al. does not teach the recited subregions. It would be prima facie obvious to one of ordinary skill at the time of the effective filing date to modify Mingming et al. to measure the entire of the recited markers with a reasonable expectation of measuring an increased level of methylation. The claims as amended would encompass the measurement of the entire marker and therefore a measurement of the subregions. The ordinary artisan would have a reasonable expectation of success as Mingming et al. teaches measurement of increased expression in the recited markers associated with colorectal cancer.
With regard to Claim 4, Mingming teaches preamplfying using a primer pool as compared to a reference (para 105-106).
With regard to claim 6, Mingming et al. teaches a method of treating DNA with a reagent capable of distinguishing a methylated and unmethylated site withing the target markers are Spetin9, BCAT1, and IKZF1 (para 10-12). Mingming teaches preamplfying using a primer pool as compared to a reference (para 105-106). Mingming et al teaches that these markers increased as compared to a control indicates risk of colorectal cancer (243-246 figure 3).
With regard to claim 8, Mingming et al. taches a method of treating DNA with a reagent capable of distinguishing a methylated and unmethylated site within the target markers are Spetin9, BCAT1, and IKZF1 (para 10-12). The “preferably” limitations are considered optional and therefore are not required for the breadth of the claims.
With regard to claim 12, Mingming et al. teaches the target markers of Spetin9, BCAT1, and IKZF1 (para 10-12) and as such teaches the marker comprises the regions that are encompassed by the Hg19 coordinates of the claim as each encompass the region of each gene recited.
With regard to claim 13-14, Mingming et al. taches DNA comprising genomic DNA (para 32-35). Further although Mingming et al. does not recite circulating tumor DNA, as Mingming et al. teaches measuring blood samples (para 35) to detect colorectal cancer, this sample would encompass measurement of circulating tumor DNA.
With regard to claim 18, Mingming et al. teaches that the biological sample is a tissue sample or a body fluid (para 35).
With regard to claim 22, Mingming et al. teaches a method of using bisulfite reagent of sodium bisulfite to distinguishing (para 32). As the specification does not limit “does not significantly modify methylated” this phrase does not appear to limit the reagent to any particular reagent more than a regent capable of distinguishing between an unmethylated and methylated site.
With regard to claim 28, Mingming et al. teaches a method of using preamplification primer pairs with a methylation specific primer that comprises a forward and reverse primer to the encompassed region (para 48, 50).
With regard to claim 37, Mingming et al. teaches a method of treating DNA with a reagent capable of distinguishing a methylated and unmethylated site withing the target markers are Spetin9, BCAT1, and IKZF1 (para 10-12). Mingming teaches preamplfying using a primer pool as compared to a reference (para 105-106). Mingming et al. teaches a method of using preamplification primer pairs with a methylation specific primer that comprises a forward and reverse primer to the encompassed region (para 48, 50). Mingming et al teaches that these markers increased as compared to a control indicates risk of colorectal cancer (243-246 figure 3). The “preferably” limitations are considered optional and therefore are not required for the breadth of the claims.
With regard to claim 45, Mingming teaches comparing Ct values of targets with references (para 231-232). As the claim does not require any particular correlation to be detected the claim encompasses comparing steps.
With regard to claim 47, Mingming et al. teaches qualifying methylation level based on the level of CpG (para 4 and para 10-12).
With regard to claim 51, Mingming et al. teaches detection of colorectal cancer (para 5).
With regard to claim 81, Mingming et al. teaches a method wherein a patient is treated with drugs to inhibit colorectal cancer (para 63).
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mingming et al. (WO/2019/144277 Publication date 1/08/2019) in view of Kennedy et al. (US Patent Application Publication 2018/0305738 October 25, 2018 previously recited)
Mingming et al. teaches a method of treating DNA with a reagent capable of distinguishing a methylated and unmethylated site within the target markers are Septin9, BCAT1, and IKZF1 (para 10-12) and as such suggests regions that encompass the subregions. Mingming et al teaches that these markers increased as compared to a control indicates risk of colorectal cancer (243-246 figure 3).
However, Mingming does not teaches the target marker in cfDNA at the level claimed.
With regard to claim 15, Kennedy et al. teaches methods of sample obtaining from a sample of cfDNA that can be used for detection of methylation that is 1 ng (para 137 and 326).
Therefore it would be prima facie obvious to one of ordinary skill in the art at the time of the effective filing date to use a known amount of cfDNA as suggested by Kennedy et al. in the methylation of Mingming et al. with the expectation of methylation detection analysis of the extracted DNA. The ordinary artisan would have a reasonable expectation of success as Kennedy et al. teaches that this amount of sample can be used for methylation detection.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE D SALMON whose telephone number is (571)272-3316. The examiner can normally be reached 9-530.
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/KATHERINE D SALMON/Primary Examiner, Art Unit 1682