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 Claims 38-41, 44, 56-59, 62 have been withdrawn as drawn to non-elected subject matter.
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Claims 38-41, 44, 56-59, 62 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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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Drawings
MPEP 608.02, part VIII states:
Color drawings and color photographs are not accepted in utility applications filed under 35 U.S.C. 111 unless a petition filed under 37 CFR 1.84(a)(2) or (b)(2) is granted. Color drawings and color photographs are not permitted in international applications (see PCT Rule 11.13 ).
Unless a petition is filed and granted, color drawings or color photographs will not be accepted in a utility patent application filed under 35 U.S.C. 111. The examiner must object to the color drawings or color photographs as being improper and require applicant either to cancel the drawings or to provide substitute black and white drawings.
The description of at least Figure 1 is directed to blue and yellow colors. No petition for color drawings has been filed; therefore, the color drawings or color photographs are being objected to as being improper. The specification is also objected to for not reciting the requisite color petition language as the first paragraph of the brief description of the drawings.
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.
Page 132-136 contains a list of references.
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 21 involves the patent-ineligible concept of an abstract process. Claim 21 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.
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 1-4, 13, 16-17, 24-25, 29 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.
Claim 1 and claims dependent thereon are indefinite because it is unclear how step (d) relates back to the method of determining cell type or cell states. Claim 1 requires determining cell type or cell states. Step (c) assigns DNA to a cell type or cell states based on reference values. Then step (d) further counts DNA molecules assigned to reference CpG value or MHB values. It is unclear how this counting step achieves the claimed method. Clarification is required.
Claim 2 provides five alternative additional steps. However, it is unclear how counting known single CpG methylation profiles increases sensitivity. Does the mere act of counting improve or increase sensitivity? What is required to increase sensitivity.
For the second determining cell state-specific signatures, it is unclear how cell state-specific signatures are determined based on the counting performed. Clarification is required.
Claim 3 provides the sample is blood, plasma, tissue or biopsy, and comprises a bodily fluid. The claim appears to internally narrow the claim such that tissue is no longer permitted. Even more, the claim states “does not comprise a solid tissue biopsy” so it is again narrows the tissue requirement. Similarly, the claim appears to broaden the claim to include urine, saliva. Further the last two recitations appear to be in conflict with each other because it requires a mixture of DNA and RNA but then the cfDNA requires DNA. The “or” from the claim has been deleted, such that each and every limitation is required. The claim is not clear what is required. Claim 4 also appears to require a list of unrelated conflicting limitations. There is no clarity as to what is required by the claim.
Claim 29 depends on Claim 24. Claim 29 requires “if cfDNA analysis detects” however neither Claim 24 nor Claim 1 from which claim 24 depends is directed to cfDNA analysis. The claims do not require cfDNA analysis and thus, Claim 29 lacks proper antecedent basis.
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).
Claim(s) 1-4, 13, 16-17 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by 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.
With respect to Claim 2, Jeschke teaches improved prediction of survival and response to chemotherapy with the MeTIL score. Jeschke teaches the MeTIL score may predict outcomes for TN tumors and tumors with low TILs infiltration (Lum). Figure 3 illustrates the MeTIL score improves the prediction of survival and response to anthracycline treatment.
With respect to Claim 3, Jeschke teaches using FFPE tumor samples or blood samples.
With respect to Claim 4, Jeschke teaches MeTIL signatures were analyzed through bisulfite pyrosequencing and Infinium arrays.
With respect to Claim 13, Jeschke teaches total leukocytes were assessed.
With respect to Claim 16-17, Jeschke teaches the MeTIL score is specific to TILs and does not measure other cell types typically found in the breast tumor microenvironment.
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.
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.
Conclusion
No claims allowable over the art.
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
March 6, 2024