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 April 3, 2026. Currently, claims 1-26 are pending.
Election/Restrictions
Applicant's election without traverse of tumor microenvironment (TME) in the paper filed April 3, 2026 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Priority
This application claims priority to
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Drawings
The drawings are acceptable.
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 1-26 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 predicting a disease outcome in a subject” by identifying epigenetic modifications, identifying an aberrant tissue microenvironment, assigning a tissue of origin, determining cell states and predicting the outcome of a disease”.
Claim 5 states the predicting step is one of diagnosing, predicting remission or recurrence, assessing MRD and predicting response to immunotherapy. Claims 7 and 8, 11-12, 21-22, 25 are similarly directed to predicting and determining steps. Claim 8 is directed to inferring.
Claim 16-20 are directed to providing profiles and generating profiles which is a collection of data or information.
Claim 1 is directed to a process that involves the judicial exceptions of an abstract idea (i.e. the abstract steps of identifying epigenetic modifications, identifying an aberrant tissue microenvironment, assigning a tissue of origin, determining cell states and predicting the outcome of a disease) and a law of nature/natural phenomenon (i.e. the natural correlation between the methylation patterns and disease outcome).
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, claims 1-26 involve the patent-ineligible concept of an abstract process. Claim 1 requires performing the step of “identifying epigenetic modifications in sequence data”, “identifying an aberrant tissue microenvironment” “ assigning a tissue of origin”, “determining cell states…using patterns” and “predicting the outcome of a disease”. Neither the specification nor the claims set forth a limiting definition for "identifying” “determining” or “predicting" and the claims do not set forth how "identifying” “determining” or “predicting" is accomplished. As broadly recited the "identifying” “determining” or “predicting" may be accomplished mentally by thinking about a subject’s methylation state and making identifications, determinations and predictions. Thus, the "identifying” “determining” or “predicting" constitutes an abstract process idea. None of the method steps in Claim 1 are specifically directed to assaying steps.
A correlation that preexists in the human is an unpatentable phenomenon. The association between epigenetic modifications and tissue of origin, cell states and disease outcome is a law of nature/natural phenomenon. The "predicting" step which tells users of the process to predict a disease outcome, amounts to no more than an "instruction to apply the natural law". This assessing step is 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 "assessing" step 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.
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 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.
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-Scope of Enablement
The following is a quotation 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.
Claims 1-26 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 identifying methylation status for predicting a disease outcome, does not reasonably provide enablement for identifying fragment size or end motifs to predict a disease outcome. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to 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 nature of the invention and breadth of claims
Claim 1 is directed to “a method of predicting a disease outcome in a subject” by identifying epigenetic modifications such as fragment size or end motifs, identifying an aberrant tissue microenvironment, assigning a tissue of origin, determining cell states and predicting the outcome of a disease.
Claim 5 states the predicting step is one of diagnosing, predicting remission or recurrence, assessing MRD and predicting response to immunotherapy. Claims 7 and 8, 11-12, 21-22, 25 are similarly directed to predicting and determining steps. Claim 8 is directed to inferring.
Claim 16-20 are directed to providing profiles and generating profiles which is a collection of data or information.
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).
The unpredictability of the art and the state of the prior art
The art fails to teach any fragment size associated with predicting a cancer such as colon cancer, leukemia or glioma. The art fails to any fragment size for predicting response to immunotherapy or toxicity.
Guidance in the Specification.
The specification provides no evidence that the size of fragments or end motifs in cell-free nucleic acid obtained from a liquid biopsy sample may be used to assign a tissue of origin to the cell-free nucleic acid. The specification further provides no guidance for determining cell states using patterns of fragment length or end motifs. Finally, the specification provides no guidance how to predict the outcome of a disease based on the cell states in the tissue microenvironment.
The guidance provided by the specification amounts to an invitation for the skilled artisan to try and follow the disclosed instructions to make and use the claimed invention.
Quantity of Experimentation
The quantity of experimentation in this area is extremely large since there is significant number of parameters which would have to be studied to enable the skilled artisan to practice the claimed invention as broadly as claimed. The claims are broadly directed to identifying epigenetic modifications including fragment size or end motifs to assign a tissue of origin. The specification fails to teach which fragment size is associated with a response to immunotherapy or predicting immunotherapy toxicity or predicting remission, for example. There is no guidance in the specification or the art what size fragments allow for assignment of a tissue of origin or which tissue is associated with which size fragments. Similarly, the specification and art are silent on end motifs in cell-free nucleic acid as a marker for assigning a tissue of origin. The skilled artisan would be required to perform significant inventive effort, with each of the many intervening steps, upon effective reduction to practice, not providing any guarantee of success in the succeeding steps.
Level of Skill in the Art
The level of skill in the art is deemed to be high.
Conclusion
Thus given the broad claims in an art whose nature is identified as 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, the absence of a working example and the negative teachings in the prior art balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of the claim as broadly written.
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.
Claim 6 is 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 6 is indefinite over the recitation “low measured mutational burden” because “low” is a relative term. The term “low” in claim 6 is a relative term which renders the claim indefinite. The term “low” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
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) 1-5, 7-9, 13-16,18-20 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 methods of detecting death of a cell type or tissue in a subject by determining whether cell-free DNA contains methylation patterns characteristic of the cell type or tissue (abstract). In particular Example 3, Dor teaches identification of oligodendrocyte-derived cfDNA in multiple sclerosis and Example 5 is directed to identification of exocrine pancreas-derived cfDNA in pancreatic cancer and pancreatitis. Dor teaches identifying epigenetic modifications in methylation status using Illumina 450K arrays. Analysis of the data reveled multiple CpGs that were unmethylated in the exocrine pancreas and methylated in most other tissues. Two sites were selected for further analysis . Figure 4B illustrates healthy subjects had very low levels of unmethylated exocrine pancreas markers in their cfDNA and pancreatic cancer patients had exocrine pancreas derived cfDNA above background level. This analysis generated a profile of the TME.
With respect to Claim 3, Dor teaches lymphocytes may be analyzed (Figure 24A-B; Example 13).
With respect to Claims 4-5, the analysis may be used to diagnose the subject with cancer, such as pancreatic cancer.
With respect to Claim 7, Figure 4C illustrates different stages of pancreatic cancer.
With respect to Claim 8, Dor teaches combining all CpGs at the MBP3 and WM1 loci greatly increased the discrimination between DNA enriched for oligodendrocytes and DNA from other sources including blood (FIGS. 7A-E and 8A-E). Thus, DNA from the MBP3 (comprised in SEQ ID NO: 1248) or WM1 (comprised in SEQ ID NO: 1247) loci unmethylated in all adjacent CpG sites can serve as an exclusive marker of oligodendrocytes (para 372).
With respect to Claim 13-16, Dor teaches analysis of unmethylated insulin gene promoter in the circulation of T1D patients (Example 2). Dor teaches a 160bp fragment of the insulin gene promoter was amplified from bisulfite-treated DNA obtained from multiple tissues and the product was sequenced to determine the methylation status of each CpG in each tissue (Para 367, Figure 1B). A stretch of 6 adjacent unmethylated CpG sites in the insulin gene promoter (comprised in SEQ ID NO: 1241) robustly distinguishes beta-cells from other tissues with a signal to noise ratio close to 10,000:1.
Claim(s) 1-5, 8, 9, 11-15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chaudhuri et al. (WO 2021/077063, April 22, 2021).
Chaudhuri teaches methods for measuring cell states. Chaudhuri teaches a TME liquid biopsy to detect ctilDNA by tracking highly specific epigenomic markers on DNA (page 66). Chaudhuri teaches each cell type has a unique epigenomic signature (page 66). Chaudhuri teaches TILs differ from their normal peripheral blood leukocyte counterparts.
Chaudhuri teaches the ctilDNA monitoring will provide clinicians with a real-time window into the inner workings of the tumor microenvironment and enable them to goggle their treatments accordingly (i.e. pivot early in alternative treatment if the patient is unlikely to respond or is likely to experience a severe toxicity and track immune-related toxicity from immunotherapy)(page 67-69). Chaudhuri teaches performing LiquidTME experiments and determined that methylation signatures differed between individual TIL subsets and their normal counterparts by sorting CD8 T cell subsets from CRC patients’ tumors as well as peripheral blood CD8 T cells from the same patients (page 70). Chaudhuri teaches whole genome bisulfite sequencing followed by sequence alignment was performed and compared to publicly available healthy donor CD8 T cells (page 70). Figure 16 illustrates differential methylation of the PDCD1 gene in CD8T cells for healthy and CRC patient. Chaudhuri teaches each sample demonstrates a distinct methylation profile for epithelial cells, tissue lymphocytes and PBLs suggesting they can be used to distinguish the cells. (Page 127).
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. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); 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); 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) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 13, 16-17, 24-25, 29 of copending Application No. 17/769,864 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Although the conflicting claims are not identical, they are not patentable distinct from each other because Claims 1-26 of the instant application is generic to all that is recited in Claims 1-4, 13, 16-17, 24-25, 29 of copending Application No. 17/769,864. That is, Claims 1-4, 13, 16-17, 24-25, 29 of copending Application No. 17/769,864 falls entirely within the scope of Claims 1-26, or in other words, Claims 1-26 are anticipated by claims 1-4, 13, 16-17, 24-25, 29 of copending Application No. 17/769,864. The claims of ‘864 are similarly drawn to methods for determining cell type or cell states by analyzing methylation profiles and assigning DNA molecules to a cell type or cell state followed by administering a cancer treatment to the subject and determining the treatment response. Claim 4 of ‘864 is directed to ctilDNA levels compared to responder immunotherapy to determine risk of responding/non-responding. Therefore, the methods of the instant application and ‘864 are not patentably distinct.
Conclusion
No claims allowable.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Wellstein et al. (US 2024/0360508, provisional July 23, 2021) teaches analysis of circulating cell-free methylated DNA to detect tissue damage. The figures are directed to methylation patterns directed to particular cell types.
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 10, 2026
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