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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 December 19, 2025 has been entered.
This action is in response to the papers filed December 19, 2025. Currently, claims 1, 3, 5, 19-20, 23-24, 30 are pending. Claims 19-20 have been withdrawn as drawn to non-elected subject matter.
All arguments have been thoroughly reviewed but are deemed non-persuasive for the reasons which follow.
Any objections and rejections not reiterated below are hereby withdrawn.
The new matter rejection over partial nephrectomy and radical nephrectomy has been overcome by the amendment to remove the limitations.
The enablement rejection has been withdrawn in view of the amendments to the claims to provide a mechanism for classification, albeit these new limitations are rejected under new matter.
The 102 and 103 rejections have been withdrawn in view of the extensive classification limitations provided. Neither Wei nor Zhang nor Sun teach which CpG sites are hypo and hypermethylated as required by Claims 1 and 10.
Election/Restrictions
Applicant's election without traverse of Group I, and the combination of ALL 59 methylation markers, Claims 1-18 in the paper filed August 16, 2024 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Priority
This application claims priority:
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Drawings
The drawings are acceptable.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609 A(1) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The specification has a list of references on pages 21-23 which do not appear to be filed in an IDS.
New Matter
Claims 1, 3, 5, 23-24, 30 are rejected under 35 U.S.C. 112, first paragraph, as containing 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(s), at the time the application was filed, had possession of the claimed invention.
In the amended claims, (ii) provides 12 CpG sites that are hypermethylated in malignant clear cell renal cancer. According to the newly incorporated Table 5, these CpG sites are hypomethylated, i.e. they have a negative coef.
In the amended claims, (iii) provides cg14329285 is hypermethylated however the site in the new Table 5 is negative which suggests hypomethylation.
These classifications are not supported in the specification or the priority document. Applicant should verify each of the CpG sites is appropriately denoted hyper or hypo methylated.
Claims 1, 3, 5, 19-20, 23-24, 30 are also rejected under 35 U.S.C. 112, first paragraph- new matter, as containing 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(s), at the time the application was filed, had possession of the claimed invention.
The claims have been amended to require classifying the malignant kidney tumor by fitting DNA methylation data in a L1 penalized “multimodal logistic regression model”. The specification does not provide multimodal logistic regression models. Instead, the specification states “we fit the L1-penalized multinomial logistic regression model” (see para 73). This does not support multimodal logistic regression. The art teaches multimodal and multinomial are distinct terms from statistics and data analysis that describe different characteristics of data or models. Thus, multinomial and multimodal logistic regression models are different and not synonyms. Thus, the newly added claim language constitutes new matter.
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, 5, 23-24, 30 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.
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 an abstract idea.
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 of classifying kidney tumors” by determining the methylation status of the DNA and classifying the kidney tumor as clear cell malignant, papillary malignant, chromophobe malignant, according to the requirements in the claims.
Claims 1, 3, 5, 23-24, 30 are directed to a process that involves the judicial exceptions of an abstract idea (i.e. the abstract steps of “classifying malignant kidney tumors” and mathematical concepts for using logistic regression models) and a law of nature/natural phenomenon (i.e. the natural correlation between the methylation of elected combination of 59 CpG sites and renal cancer classifications).
Claim 1 and 30 are directed to mathematical calculations and falls into the “mathematical concepts” grouping of abstract ideas.
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 classifying the samples as kidney tumors. This classification is a mental assessment that does not require more.
The claims require determining methylation markers are hypomethylated or hypermethylated. Hypomethylated and hypermethylated are compared to a reference or normal sample. Thus, the claims recite a comparison. A comparison between the methylation levels and a normal control that is deemed an abstract idea (see MPEP 2106.04(a)(2)(III)(A); • claims to “comparing BRCA sequences and determining the existence of alterations,” where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014)).
Claim 1 has been amended to require fitting DNA methylation data obtained in (a) in a logistic regression model. This limitation is a calculation to generate a classification which is a “mathematical concept” grouping of abstract ideas.
Furthermore, a correlation that preexists in the human is an unpatentable phenomenon. The association between methylation states and risk of renal cancer/classifying a kidney tumor is a law of nature/natural phenomenon. The classifying step which tells users of the process to predict or classify renal cancer in the sample, amounts to no more than an "instruction to apply the natural law". These steps are no more than mental steps. Even if the steps require 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 intended use in the preamble of classifying which is a natural correlation. The claims do not require doing anything in light of the correlation. The preambles and the classifying steps fail 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. While the claim recites measuring a methylation status of DNA in a sample, this is not an integration of the exception into a practical application. Instead, these elements are data gathering required to perform the method. Thus, the claim is “directed to” the exception.
Claim 1 has been amended to treating the human subject for the kidney tumor by surgical removal, and/or in situ ablation. The claim requires treating “a human subject”. This treatment is administered regardless of tumor classification; thus, this is not an integration of the judicial exception. The claim does not specify which patients are treated or only treat a specific patient population based upon their genetic composition. Thus, claims are directed to the relationship and is not a practical application of the judicial exception.
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. That is, the step of determining the presence of the methylation status of each of the claimed 59 CpG sites was well known in the art at the time the invention was made. The specification teaches the Illumina 450K chip was used to determine the methylation status of the CpG sites. The prior art teaches that genotyping analysis with the commercially available Illumina's 450K BeadChip allows over 450,000 CpG sites to be analyzed. It is an inherent property that the chip comprises the claimed SNPs. The specification further teaches the Illumina 450K chip is used (see page 8). Further, the Cancer Genome Atlas data is publicly available (see provisional application page, 15).
The art teaches methylation analysis of kidney biopsies (see Chen et al. PLOS, Vol. 8, NO. 11, e79856, 2013).
The steps which are set forth in the claims must be taken or used by others to apply the disclosed law of nature, and they encompass using any of a variety of well-understood techniques in the prior art for detection.
The claims are set forth at a high level of generality such that all methods for measuring of the natural products are encompassed. The “measuring” steps are insufficient to make the claims patent eligible.
The measuring step is a mere data gathering step that amounts to extra solution activity to the judicial exception. It merely tells the users of the method to determine the genotype 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 determining step essentially tells users to determine the methylation status through whatever known processes they wish to use.
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 reviews the framework for patent eligibility thoroughly.
The response argues that the claims require treating a human subject identified with a malignant renal cancer and provides a treatment for all of the subjects. This argument has been reviewed but is not persuasive. The claim does not require the treatment is for a human subject identified with a malignant renal cancer. Instead, the claim requires obtaining a sample from a subject with malignant renal cancer. The claim does not require identification of a malignant renal cancer. The claim does not require the treatment following a classification. The claim does not require using a classification to make any treatment decisions. The treatment is administered regardless of disease classification; thus, this is not an integration of the judicial exception. MPEP 2106.04(d)(2)(b) provides the treatment limitation must have more than a nominal or insignificant relation to the exception. Thus, the surgical removal or in situ ablation of the kidney tumor is not an integration of the classification of different kidney tumors.
The response argues the classifier detected malignancy in 426 out of 429 cancers and the results were highly reproducible. This argument has been reviewed but is not persuasive because the claimed step of classifying is a judicial exception that may be performed in the mind and is a correlation of nature. Thus, this judicial exception cannot overcome the rejection.
The response the claimed methods provide a clear improvement over existing methods and provide a solution to the unmet need in the field of kidney tumor classification. The newly issued 101 Examples (July 2024), Example 49, claim 1 discusses improvements. Example 49, claim 1 state there is no improvement to the functioning of a computer nor to any other technology. At best, the claimed combination amounts to an improvement to the abstract idea of determining patient risk rather than to any technology. See MPEP 2106.05(a). Thus, there is no integration of the recited exception into a practical application.
Thus, for the reasons above and those already of record, the rejection is maintained.
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.
Claims 1, 3, 5, 23-24, 30 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.
Claim 1 recites classifying the malignant kidney tumor as malignant chromophobe renal cancer when each of the 10 CpG sites are hypomethylated. This provides a very clear requirement that each of the 10 CpG sites are hypomethylated. The claim has been amended to add a limitation of fitting DNA methylation data in a L1 penalized multimodal logistic regression model and outputting probability of the sample being in a kidney tumor subgroup. It is unclear whether classifying is completed by detecting hypomethylation of 10CpG sites or whether data from (a) is fitted in a model. It is unclear how the same sample can be classified two different ways. It is unclear if samples are classified using both methods or whether the claim is redundant. The dependent claims are similarly indefinite. Clarification is required.
Conclusion
No claims allowable.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Chen et al. teaches DNA methylation-based classification and identification of renal cell carcinoma prognosis-subgroups (Chen et al. Cancer Cell Int. Vol. 19, No. 185, 2019). Chen uses the 450K Illumina array comprising CpGs and using a risk regression model to classify samples.
Chen et al. (Cell Reports, Vol. 14, pages 2476-2489, March 15, 2016) teaches multilevel genomics-based taxonomy of renal cell carcinoma. Chen teaches collecting 894 primary RCC specimens from KIRC, KICH, chromophobe RCC and KIRP and analyzing using methylation analysis. Chen used ConsensusClusteringPlus to define molecular subgroups.
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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682 January 14, 2026