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 July 1, 2026. Currently, claims 3, 5, 8, 20-21, 28, 30-42 are pending.
Election/Restrictions
Applicant's election without traverse of a single combination of ALL of the methylation sites in Table 2 in the paper filed July 1, 2026 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Priority
This application claims priority to
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The instant claims are not entitled to the earliest priority date because the 63/224,873 provisional does not describe analysis of the quantity of cfDNA. The instant claims are entitled to the benefit of March 27, 2022.
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.
Pages 126-127 provide 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 3, 5, 8, 18, 20-21, 28, 30-42 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 3 is directed to “a method for treating a subject who as suffered tissue damage from exposure to a toxic agent”. The method requires a comparing steps and recites “an increased in measured quantity of the cfDNA….is indicative that the subject has suffered tissue damage”. Claims 5 and 18 similarly are directed to comparing steps and wherein clauses reciting a natural correlation.
The claims are directed to a process that involves the judicial exceptions of an abstract idea (i.e. the abstract steps of “comparing measured quantity of cfDNA with normal quantity of cfDNA”) and a law of nature/natural phenomenon (i.e. the natural correlation between the measured quantity of the cfDNA and tissue damage).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Claims 3, 5, and 18 recite a comparison between the quantity of cfDNA 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)).
A correlation that preexists in the human is an unpatentable phenomenon. The association between measured quantity of the cfDNA and tissue damage is a law of nature/natural phenomenon. The wherein clause which tells users of the process to predict tissue damage in the sample, amounts to no more than an "instruction to apply the natural law". The wherein clause is no more than a mental step. Even if the wherein clause 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 wherein clause does not require the process user to do anything in light of the correlation. The wherein clause 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. While the claim recites administering a treatment for the tissue damage to the subject, this is not an integration of the exception into a practical application. This treatment is entirely generic and does not integrate the judicial exception. Further, it is unclear whether the treatment is required to be administered since the claim does not require the subject has tissue damage. The active step of comparing does not require a increased in the measured cfDNA is determined or detected. Thus, if the increase is not detected, there is no tissue damage and no treatment would be required.
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 determining cellular origin of cfDNA and methylation patters and quantifying cfDNA are 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 cfDNA 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 step of determining cellular origin, measuring the quantity was well known in the art at the time the invention was made. The prior art teaches each of these steps (see Roth, for example). The steps are recited at a high level of generality. 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.
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 3, 5, 8, 18, 20-21, 28, 30-42 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.
Claims 3, 5, 18 are directed to “one or more portions is the same as a known cell-type specific methylation pattern. However, it is unclear what a known cell-type specific methylation pattern encompasses. It is unclear who the pattern was known by, when it was known and what was known. The metes and bounds of the claimed invention are unclear. Claims 20-21, 28, 30-42 are dependent on the rejected claims and are similarly indefinite.
Claims 3, 8, 21, 28-31 are indefinite because it is unclear whether the claim requires administering treatment for all the subjects because the final step in the methods for determining if the subject has suffered from tissue damage is a method of comparing. The claim does not require determining an increased in measured quantity. The claim merely states an intended purpose or inherent property. Thus it is unclear whether the claim only requires administering treatment for some patients or whether the claim encompasses treating all subjects. Clarification is required.
The claims 31, 36, 42 refer to tables. MPEP 2173.05(s) states:
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
Claims 31, 36, and 42 recite Table 2. Appropriate correction is required.
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) 18, 37-41 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Roth et al. (Gastrointestional Disorder, Vol. 3, pages 100-112, July 30, 2021).
Roth teaches a method of monitoring radiation therapy changes in cardiomyocyte-specific cell free DNA (cfDNA). Roth teaches performing an amplicon sequencing method on cell-free DNA extracted from patient serum (page 102). Figure 1 illustrates deep sequencing and quantitation of methylation patterns (page 103). Roth teaches analysis of FAM101A which was found to be cardiomyocyte specific. Roth teaches cfDNA levels were measured (page 104). Roth teaches the study was used to detect cardiac damage as a result of chemotherapy and radiation treatment in cancer patients. The cardiomyocyte-specific cfDNA is a biomarker of detecting and monitoring cardiotoxicity in cancer patients (page 109).
With respect to Claim 37, Roth teaches analysis of chemotherapy and radiation treatment in cancer patients.
With respect to Claim 38, the claim is conditional and does not require adjusting if the treatment is not causing tissue damage.
With respect to Claim 39, Roth teaches the FAM101A was compared to methylomes of human serum from normal healthy donors (page 107).
With respect to Claim 40, Roth teaches analysis of serum (page 102).
With respect to Claim 41, Roth teaches analysis of 6 C’s reads s Ts in contracts to lymphocytes where they read as C’s.
Claim(s) 18, 37, 39-40 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Makranz et al (Neuro-Oncology, Vol. vi198, NCMP-24, November 2018).
Makranz teaches brain-derived circulating DNA is a biomarker for radiotherapy induced brain damage (limitations of Claim 18, 37). Makranz teaches obtaining a blood sample for bncfDNA and observing elevation of cfDNA derived from neurons, oligodfendrocytes and astrocytes following brain radiotherapy (limitation of Claim 40). Makranz teaches comparing the cfDNA with healthy individuals (limitations of Claim 39).
Claim(s) 18, 37, 39-40 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Makranz et al (Neuro-Oncology, Vol. vi147, NCMP-01, November 2021).
Makranz teaches analyzing brain-derived cfDNA biomarkers in plasma samples of patients following brain irradiation. Blood samples were collected for DNA analysis and correlated bncfDNA levels were analyzed. Makranz teaches increase in bncfDNA levels characterizes RIN independent of tumor response and may be a biomarker for brain cells death incurred by radiotherapy.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 3, 5, 8, 20-21, 28, 30, 32-35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Desai et al. (JACC, Vol. 74, No. 7, pages 906-927, August 20, 2019) in view of Roth et al. (Gastrointestional Disorder, Vol. 3, pages 100-112, July 30, 2021).
Desai teaches prevention, diagnosis and management of radiation-associated cardiac disease. Desai teaches management may be individualized for surgery or percutaneous interventions (page 907). Desai further teaches numerous treatments for RACD.
Desai does not teach determining or diagnosing subjects that have suffered from tissue damage using cfDNA analysis.
However, Roth teaches a method of monitoring radiation therapy changes in cardiomyocyte-specific cell free DNA (cfDNA). Roth teaches performing an amplicon sequencing method on cell-free DNA extracted from patient serum (page 102). Figure 1 illustrates deep sequencing and quantitation of methylation patterns (page 103). Roth teaches analysis of FAM101A which was found to be cardiomyocyte specific. Roth teaches cfDNA levels were measured (page 104). Roth teaches the study was used to detect cardiac damage as a result of chemotherapy and radiation treatment in cancer patients. The cardiomyocyte-specific cfDNA is a biomarker of detecting and monitoring cardiotoxicity in cancer patients (page 109).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention to have treated tissue damage in subjects exposed to radiation, as taught by Desai where the subject was diagnosed using the methods of Roth. Roth teaches cardiac damage as a result of radiation treatment in cancer patients may be detected using cfDNA cardiomyocyte methylation markers. The ordinary artisan would have been motivated to have detected cardiac damage as a result of chemotherapy and radiation treatment in cancer patients and treated the tissue damage using known methods of treatment.
With respect to Claim 5, Roth teaches cardiomyocyte-specific cfDNA showed some distinct changes during the course of treatment and recovery. It would be obvious to monitor these changes over time to obtain information about the treatment response.
With respect to Claims 8, 32, Roth teaches analysis of radiation, a synthetic chemical and a pharmaceutical therapy.
With respect to Claims 21 and 33, Roth teaches the FAM101A was compared to methylomes of human serum from normal healthy donors (page 107).
With respect to Claims 28 and 34, Roth teaches analysis of serum (page 102).
With respect to Claims 30 and 35, Roth teaches analysis of 6 C’s reads s Ts in contracts to lymphocytes where they read as C’s.
Conclusion
No claims allowable over the art.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Bahtiyar et al. (Radiation and Environmental Biophysics, Vol. 65, pages 461-472, 2026) teaches assessment of radiotherapy effect and toxicity using tissue-associated DNA methylation markers in cfDNA: a study on prostate cancer. Bahtiyar teaches radiotherapy did not significantly alter the relative DNA levels of these tissue-associated genes.
Makranz et al. (Neuro-Oncology, Vol. iii273, September 2018, P02.07) teaches brain-derived circulating DNA as a biomarker for radiotherapy induced brain damage. bncDNA levels following brain radiotherapy were studied.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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 9, 2026
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