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 15, 2025. Currently, claims 1-4, 13, 16-17, 24-25, 29, 38-41, 44, 56-59, 62 are pending. Claims 38-41, 44, 56-59, 62 have been withdrawn as drawn to non-elected subject matter.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. This action is made FINAL.
Any objections and rejections not reiterated below are hereby withdrawn.
Election/Restrictions
Applicant's election of Group I in the paper filed August 15, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)).
Claims 38-41, 44, 56-59, 62 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
The requirement is still deemed proper and is therefore made FINAL.
Priority
This application claims priority to
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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, 13, 16-17, 24-25, 29 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 of determining cell type or cell states by…generating a methylation profile…counting CpG methylation patterns”, “assigning the DNA to a cell type” and “counting DNA molecules assigned to each reference CpG value or reference MHB” “wherein each reference CpG value or reference MHB value corresponds to a cell type or cell state”.
Claim 1 is directed to a process that involves the judicial exceptions of an abstract idea (i.e. the abstract steps of “counting CpG methylation patterns”, “assigning the DNA to a cell type based on reference values”, “counting DNA molecules” “determining cell type or cell states”) and a law of nature/natural phenomenon (i.e. the natural correlation between the methylation profiles and cell type or cell states).
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 performing the step of “assigning DNA to a cell type or cell state based on a reference CpG value or MHBs”. Neither the specification nor the claims set forth a limiting definition for "assigning" and the claims do not set forth how “assigning” is accomplished. As broadly recited the assigning step may be accomplished mentally by thinking about a subject’s methylation state and assessing whether the subject has the same methylation pattern. Thus, the determining step constitutes an abstract process idea.
Claim 1 further recites a comparison between the methylation profiles and reference CpG values or reference MHB values 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)).
Furthermore, the counting of CpG methylation patterns is a mathematical process that may be performed mentally. Counting is an arithmetic calculation to add values together, which is a “mathematical calculation” so falls into the “mathematical concepts” grouping of abstract ideas.
A correlation that preexists in the human is an unpatentable phenomenon. The association between methylation states such as CpG methylation patterns or methylation haplotype blocks and cell type/cell states is a law of nature/natural phenomenon. The "assigning" step and the preamble for determining cell type or cell states which tells users of the process to predict cell types and cell states, amounts to no more than an "instruction to apply the natural law". These recitations are no more than a mental step. Even if the step 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 "assigning" step and the preamble for determining cell type or cell states does not require the process user to do anything in light of the correlation. The "assigning" step and the preamble for determining cell type or cell states 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 providing a sample and generating a methylation profile for the DNA, 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 2 requires an administering a cancer treatment step and measuring cell type and cell state in a sample as an indication of treatment response. This is not an integration of the exceptions (see MPEP 2106.04(d)(2)(c)). The administration of a cancer treatment in order to gather data for the mental analysis step is extra-solution activity and does not integrate the judicial exception into a practical application.
Accordingly, the claims are directed to judicial exceptions.
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 the biomarkers 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 markers through whatever known processes they wish to use.
The determining the methylation status was well known in the art at the time the invention was made. The prior art teaches that determining methylation haplotypes was known. 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 bisulfite/methylation sequences with any type of next-generation sequencing or microarray technology known in the art may be used (see page 15-16).
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 each of the claim process steps requires physical manipulation of tangible materials. This argument has been reviewed but is not convincing. Step b is a method of counting. This step is not a physical manipulation of tangible materials. This merely requires mentally thinking about how many patterns or MHBs are in the DNA. Further “assigning” is a mental process that does not require any physical manipulation. Thus, the method is not solely directed to physical manipulation of tangible materials as argued by the response.
As discussed above, the claims are directed to numerous judicial exceptions.
This argument has been considered but is not convincing because the counting steps are merely mathematical calculations or mental processes. The assignment of molecules based on the patterns to a cell type is an association step which is also performed mentally. Thus, the claims are directed to more than one judicial exception.
The response argues Claim 1 of the Julitis Example 29 is patent eligible because it was focused on a process of detecting. This argument has been reviewed but is not persuasive. Example 29, Claim 1 did not recite a judicial exception. The instant claims are more closely directed to Claim 2 of Example 29 that recites a judicial exception. The example provides correlations are a consequence of natural processes and can be performed by a human using mental steps or basic critical thinking which are types of activities that have been found by the courts to represent abstract ideas.
Thus for the reasons above and those already of record, the rejection is maintained.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed 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) 1-4, 13, 16, 24-25, 29 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Dor et al. (US 11,203,784, December 21, 2021, priority April 14, 2014).
Claim(s) 1-4, 13, 16, 24-25, 29 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dor et al. (US 2017/0121767, May 4, 2017).
Dor teaches a method of determining cell type or tissue in a tissue by determining the methylation status of at least four methylation sites on a continuous sequence of the DNA characteristic of the cell type or tissue (abstract). Dor teaches quantifying the amount of cell-free DNA and when the amount of cell free DNA derived from the cell type or tissue is above a predetermined level, it is indicative or assigned to the cell type (para 312, and Claims 45-46 of ‘767).
With respect to Claim 2, Dor teaches monitoring treatment for a pathological process (para 46, para 309). Dor teaches the methods are used to determine the efficacy of a therapeutic agent or treatment when the amount of the DNA is decreased following administration of the therapeutic agent.
With respect to Claim 3, 16, Dor teaches the sample may be blood, plasma, sperm, urine, saliva, cerebral spinal fluid (see para 23). Dor teaches cell death in tumors should give rise to cDNA carrying the normal methylation patterns of the tumor’s tissue or origin. Dor teaches isolating cells with antibodies to purify duct and acinar cells to identify cells that were unmethylated in exocrine pancreas and methylated in most other tissues, a microenvironment (para 377).
With respect to Claim 4, Dor teaches methylation profiles were generated using bisulfite sequencing and Illumina 450K arrays (para 87-88, 276).
With respect to Claim 13, the tumor microenvironment sampled in Example 5, the pancreas, inherently comprises tumor-infiltrating leukocytes. The claim does not require the DNA analysis is performed on the tumor-infiltrating leukocytes.
With respect to Claims 24-25, Dor teaches the method an be used to detect kidney cell death in various pathologic conditions including acute tubular necrosis in some patients with sepsis (para 396).
With respect to Claim 29, Dor teaches the method can be used for early diagnosis, monitoring disease progress and assessment of response to therapy in a wide variety of pathologies including infections (para 131). More specifically, Dor teaches when the amount of DNA associated with a cell population associated with the disease is decreased following administration of the therapeutic agent, it is indicative that the agent or treatment is therapeutic (para 316).
Response to Arguments
The response traverses the rejection. The response asserts Dor does not disclose CpG or MHB patterns comprises a methylation status at two or more CpG sites on a single molecule. This argument has been reviewed but is not convincing. Figure 7A, 8A, 9A, 10A, and 11A for example are direct to analysis of at least four methylation sites on a continuous sequence of the same molecules of the cell-free DNA (abstract). Dor analyzes continuous sequences. In particular, Dor teaches severity of disease may be determined by quantifying the amount of DNA molecules having the specific methylation pattern of a cell population associated with the disease. Quantifying the amount of DNA molecules having the specific methylation pattern of a target tissue may be achieved using a calibration curve produced by using known and varying numbers of cells from the target tissue (para 130). Even more, Dor state “scoring for DNA molecules in which multiple adjacent CpG sites share the same tissue-specific methylation pattern gave a dramatically higher discriminatory power between the tissue of interest and other tissues, compared with the information content of individual CpG sites. Thus, the present inventors have defined short sequences of DNA, containing 4-9 CpG sites, whose combined methylation status constitutes an epigenetic signature unique to a tissue of interest relative to blood cells and other tissues” (para 366).Thus, the teachings of Dor are directed to a single DNA molecule, counting and assigning to a classification.
Thus for the reasons above and those already of record, the rejection is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the "right to exclude" granted by a patent and to prevent possible harassment by multiple assignees. See In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970);and, In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent is shown to be commonly owned with this application. See 37 CFR 1.130(b).
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims1-4, 13, 16-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-12 of copending Application No. 18/848,052 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The claims of ‘052 are directed to methods of determining a cell state in a biological sample by determining methylation levels and comparing methylation levels to cell and tissue states to assign DNA fragments to methylation levels by counting the number of fragments. The claims are also directed to determining treatment responses; tumor infiltrating leucocyte fractions; cell free DNA and TEM levels.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
The Applicant requests that this rejection be held in abeyance until allowable subject matter is found in the pending application. This request has been noted and is denied. See 804(I)(b)(1) and 37 C.F.R. 1.111(b), which allows that some objections may be held in abeyance but includes no provision for holding rejections in abeyance. Thus, for the reasons above and those already of record, the rejection is maintained.
Claims 1-4, 13, 16-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of copending Application No. 18/484,726 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The claims of ‘726 are directed to identifying epigenetic modifications in microenvironment infiltrating lymphocytes from TME. The cell states are also used for predicting toxicity/response to a treatment.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
The Applicant requests that this rejection be held in abeyance until allowable subject matter is found in the pending application. This request has been noted and is denied. See 804(I)(b)(1) and 37 C.F.R. 1.111(b), which allows that some objections may be held in abeyance but includes no provision for holding rejections in abeyance. Thus, for the reasons above and those already of record, the rejection is maintained.
Conclusion
No claims allowable over the art.
Cited Pertinent Art:
Jeschke et al. (J. Clin. Investigation, vol. 127, No. 8, pages 3090-3102, July 2017). Jeschke teaches methylation based immune response signature improves patient diagnosis in multiple cancers. Specifically, Jeschke teaches profiling DNA methylation markers to identify a methylation of TIL (meTIL) signature that recapitulates TIL evaluations and their prognostic value for long-term outcomes in breast cancer (abstract). Jeschke teaches MeTIL signature scores were correlated with clinical endpoints reflecting overall or disease-free survival and a pathologic complete response to preoperative anthracycline therapy in 3 breast cancer cohorts. Jeschke’s METIL signature comprises five CpGs in five different genes on different chromosomes, not on the same DNA molecule.
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
June 4, 2026
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