DETAILED CORRESPONDENCE
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 .
This action is in response to the papers filed August 22, 2025. Currently, claims 1-2, 4, 6, 12-14, 18-25 are pending.
This action is FINAL.
Election/Restrictions
Applicant's election without traverse of Group I, and cg07319626, claims 1-6, 12-14 in the paper filed December 26, 2024 is acknowledged. Applicant elected a single CpG site, thus claims directed to two or more markers have been withdrawn. In the event the CpG site becomes allowable, additional combinations comprising the allowable subcombination will be considered. MPEP § 821.04(a).
Applicant further elected 241758901 on Chromosome 2 and chromosome 2 region 241758282-241760510.
The requirement is still deemed proper and is therefore made FINAL.
Priority
This application claims priority as a continuation of PCT/JP2020/021173, filed May 28, 2020 and Japan 2019-103299, filed May 31, 2019.
It is noted that a translation of the foreign document has not been received.
Drawings
The drawings are acceptable.
Claim Interpretation
The claims recite particular positions for the CpG sites. The specification provides a list of a few of the sites and the corresponding CpG number.
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Improper Markush Rejection
Claims 1-2, 4, 6, 12-14, 18-25 are rejected under the judicially approved “improper Markush grouping” doctrine. (See Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, page 7166). This rejection is appropriate when the claim contains an improper grouping of alternatively useable species. See In re Harnisch,631 F.2d 716, 719-20 (CCPA 1980). A Markush claim contains an “improper Markush grouping” if:
(1) the species of the Markush group do not share a “single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the specification or known in the art to be functionally equivalent. See MPEP § 2117.
Here each species is considered to each of the CpG sites in the different regions.
The recited alternative species in the groups set forth here do not share a single structural similarity, as each different gene that could be detected is itself located in a separate region of the genome and has its own structure. The genes recited in the instant claims, do not share a single structural similarity since each consists of a different nucleotide sequences with different methylation patterns. The only structural similarity present is that all detected positions are part of nucleic acid molecules. The fact that the markers comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being correlated with sensitivity of chemotherapy against colorectal cancer. Accordingly, while the different markers are asserted to have the property of being sensitivity of chemotherapy against colorectal cancer, they do not share a single structural similarity.
MPEP 2117 (II)(A) provides the following guidance as to what constitutes a physical, chemical, or art recognized class:
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved”
The recited genes do not belong to a recognized chemical class because there is no expectation from the knowledge in the art that the genes will behave in the same manner and can be substituted for one another with the same intended result achieved. In other words, there is no expectation from the knowledge in the art that each of the recited genes would function in the same way in the claimed method; it is only in the context of this specification that it was disclosed that all members of this group may behave in the same way in the context of the claimed invention. Further there is no evidence of record to establish that it is clear from their very nature that each of the recited genes possess the common property of being associated with sensitivity of chemotherapy against colorectal cancer.
MPEP 2117 (II) further states the following:
Where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the compounds do not appear to be members of a recognized physical or chemical class or members of an art-recognized class, the members are considered to share a "single structural similarity" and common use when the alternatively usable compounds share a substantial structural feature that is essential to a common use. Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
The recited alternative species do not share a substantial common structure just because they all have a sugar phosphate backbone. The sugar phosphate backbone of a nucleic acid chain is not considered to be a substantial common structural feature to the group of genes being claimed because it is shared by ALL nucleic acids. Further, the fact that the genes all have a sugar phosphate backbone does not support a conclusion that they have a common single structural similarity because the structure of comprising a sugar phosphate backbone alone is not essential to the asserted common use of being associated with sensitivity of chemotherapy against colorectal cancer.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
Response to Arguments
The response traverses the rejection. The response asserts the common structural characteristic is methylation at a CpG dinucleotide. This argument has been considered but is not convincing. The members of the Markush grouping are considered to share a “single structural similarity” and common use when the alternatively usable compounds share a substantial structural feature that is essential to a common use. Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). See also subsection II.B, below. A dinucleotide embedded in a different larger nucleotide sequence is not considered a substantial structural feature. It is the context of the CpG dinucleotide in a larger sequence that is essential to a particular use such as sensitivity of chemotherapy against colorectal cancer and not the CpG alone. Thus, for the reasons above and those already of record, the rejection is 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 1-2, 4, 6, 12-14, 18-25 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Question 1
The claimed invention is directed to a process that involves a natural principle and a judicial exception.
Question 2A Prong I
The claims are taken to be directed to an abstract idea, a law of nature and a natural phenomenon.
Claim 1 is directed to “a method for testing for sensitivity of chemotherapy against colorectal cancer” using methylation. Claim 4 also teaches using the detection result as an indicator of sensitivity of chemotherapy against colorectal cancer.
Claim 1 is directed to a process that involves the judicial exceptions of an abstract idea (i.e. the abstract steps of “determining a patient is sensitive to drug therapy “when” methylation is not detected”) and a law of nature/natural phenomenon (i.e. the natural correlation between the methylation and sensitivity of chemotherapy against colorectal cancer).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Herein, claim 1 involves the patent-ineligible concept of an abstract process. Claim 1 requires determining a patient is sensitive to drug therapy “when” methylation is not detected. Neither the specification nor the claims set forth a limiting definition for "determined" and the claims do not set forth how “determining” is accomplished. As broadly recited the using may be accomplished mentally by thinking about a subject’s methylation state and assessing whether the subject has sensitivity of chemotherapy against colorectal cancer. Thus, the determining step constitutes an abstract process idea.
The claims recite a correlation that preexists in the human and is an unpatentable phenomenon. The association between methylation states such as cg07319626 (position 207308244 of chromosome 2) methylation state and sensitivity of chemotherapy against colorectal cancer is a law of nature/natural phenomenon. The preamble and wherein clause which tells users of the process to predict sensitivity of chemotherapy against colorectal cancer, amounts to no more than an "instruction to apply the natural law". This is no more than a mental step. Even if the claim requires something more such as to verbalize the discovery of the natural law, this mere verbalization is not an application of the law of nature to a new and useful end. The preamble does not require the process user to do anything in light of the correlation. The "assessing" step fails to provide the “practical assurance” sought by the Prometheus Court that the “process is more than a drafting effort designed to monopolize the law of nature itself.”
Question 2A Prong II
The exception is not integrated into a practical application of the exception. The claims do not recite any additional elements that integrate the exception into a practical application of the exception. Thus, the claim is “directed to” the exception.
The claims have been amended to recite administer drug therapy to the patient with the colorectal cancer determined to be sensitive to drug therapy. The administering is only required “when methylation is not detected”. This is a conditional limitation and thus, administering a therapy is not required “when” methylation is detected.
Even if the claim were to be amended to require detecting methylation was not detected, the administration of “therapy” is generical and not particular to the judicial exception. “Therapy” is not a specific therapy.
Question 2B
The second step of Alice involves determining whether the remaining elements, either in isolation or combination with the other non patent ineligible elements, are sufficient to “’transform the nature of the claim’ into a patent eligible application” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
The claims are not sufficiently defined to provide a method which is significantly more from a statement of a natural principle for at least these reasons:
The claims do not include applying the judicial exception, or by use of, a particular machine. The claims do not tie the steps to a “particular machine" and therefore do not meet the machine or transformation test on these grounds. The use of machines generally does not impose a meaningful limit on claim scope.
The claims also do not add a specific limitation other than what is well-understood, routine and conventional in the field. The measuring methylation status is mere data gathering step that amounts to extra solution activity to the judicial exception. It merely tells the users of the method to determine methylation of a sample without further specification as to how the sample should be analyzed. The claim does not recite a new, innovative method for such determination. The “using methylation” essentially tells users to determine the markers through whatever known processes they wish to use.
Using methylation was well known in the art at the time the invention was made. The prior art teaches that methylation analysis using commercially available biochips and arrays that comprise the claimed genes, namely the Illumina 450K beadchip. The steps are recited at a high level of generality. The claim merely instructs a scientist to use any methylation analysis to determine the methylation status. The claim does not require the use of any particular non-conventional reagents. When recited at this high level of generality, there is no meaningful limitation that distinguishes this step from well understood, routine and conventional activities engaged in by scientists prior to applicant’s invention and at the time the application was filed.
Additionally, the teachings in the specification demonstrate the well understood, routine, conventional nature of additional elements because it teaches that the additional elements were well known. Specifically, the specification teaches methylation can be detected using a method using a bead array of Illumina, Inc. Human Methyatlion 450BeadChip or Infinium MethylationEPIC Bead Chip (page 20, para 37).
Further it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For these reasons the claims are rejected under section 101 as being directed to non-statutory subject matter.
Response to Arguments
The response traverses the rejection. The response asserts the claims have been amended to recite administer drug therapy to the patient with the colorectal cancer determined to be sensitive to drug therapy. This argument has been considered but is not convincing because the administering is only required “when methylation is not detected”. This is a conditional limitation and thus, administering a therapy is not required “when” methylation is detected.
Even if the claim were to be amended to require detecting methylation was not detected, the administration of “therapy” is generical and not particular to the judicial exception. “Therapy” is not a specific therapy.
Thus for the reasons above and those already of record, the rejection is maintained.
Claim Rejections - 35 USC § 112- Second Paragraph
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.
Claims 1-6, 12-14 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 pre-AIA the applicant regards as the invention.
A) The claims are indefinite. It is not clear how the recited preamble is intended to breathe life and meaning into the claim. The preamble of Claim 1 is directed to a method for testing for sensitivity of chemotherapy against colorectal cancer. However, the claim requires administering drug therapy to the patient with the colorectal cancer. Thus, it is not clear if applicant intends to cover any method for testing for sensitivity of chemotherapy against colorectal cancer, or if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If the claim requires something more such as administering drug therapy, it is unclear what additional active process step the method requires and it appears that the claims are incomplete. The claims fail to provide any active steps that clearly accomplish the goal set for the by the preamble of the claims. Claims 2-6, 12-14 are similarly indefinite
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
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 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.
Claim(s) 1-6, 12-14 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ishioka et al. (US 2017/0356051, December 14, 2017).
Ishioka teaches a method for predicting sensitivity to anti-cancer therapy for colorectal cancer, using, as an indicator, DNA methylation profiles in a specimen containing a colorectal cancer tissue, colorectal cancer cells, or colorectal cancer cell-derived DNA of a colorectal cancer patient (para 1)(limitations of Claim 1-6, 12). Ishioka teaches the subject is sensitive to cancer drug therapy when the subject is classified into the low-methylated group and the subject is resistant to cancer drug therapy when the subject is classified into the highly methylated group (para 19). Ishioka teaches predicting the therapeutic sensitivity of metastatic colorectal cancer to anti-EGFR antibody drugs, such as cetuximab and panitumumab (para 5, 47)(limitations of Claim 13-14). Isioka teaches using the Illumina 450K bead chip for analysis of the methylation patterns. The 450K beadchip comprises probes for detecting the presence or absence of the cg02610058, or position 241758901 on chromosome 2. Ishioka lists cg07319616 which is position 207308244 on chromosome 2 in Table 7. Table 7 is a list of CpG sites having a significant difference in the beta-value between highly methylated and low methylated groups, i.e. sites that are indicators for sensitivity of chemotherapy against colorectal cancer.
Ishioka teaches administer drug therapy when the cancer is sensitive. Ishioka teaches the therapy is chemotherapy or molecular targeted drug (para 8-10).
Response to Arguments
The response traverses the rejection. The response asserts Ishioka does not recite CpG sites disclosed in Ishioka. This argument has been considered but is not convincing because the claim requires detecting presence or absence of methylation for the CpG sites. Each of the sites recited in the claim are found on the 450K Illumina Bead chip. Ishioka teaches, in at least Examples 1 and 2 using the Infinium 450K bead chips. Thus, the assays performed by Ishioka inherently determining the presence or absence of methylation as required by the claim. The claim as written does not require the administering step “when” the methylation is detected at the CpG sites. However, Ishioka teaches administering therapy when the methylation is not detected, and the cancer is sensitive. Thus, for the reasons above and those already of record, the rejection is maintained.
Conclusion
No claims allowable.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Ouchi et al. (Cancer Science, Vol. 106, No. 12, pages 1722-1729, October 2015) teaches DNA methylation status as a biomarker of anti-epidermal growth factor receptor treatment for metastatic colorectal cancer and identifies markers that are reliable biomarkers to predict the clinical response to anti-EGFR treatment.
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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 JEANINE ANNE GOLDBERG whose telephone number is (571)272-0743. The examiner can normally be reached Monday-Friday 6am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng (Winston) Shen can be reached on (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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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682
September 22, 2025