DETAILED ACTION
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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 5/20/2026 has been entered.
Information Disclosure Statement
The IDS filed 9/10/2026 has been considered by the Examiner.
Status of Claims
Claims 31-43 and 57 are cancelled.
Claims 1-30, 44-56 and 58-59 are pending and are examined on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Priority of US application 62/666,574 filed 05/03/2018 is acknowledged.
Claim Rejections - 35 USC § 101
The instant rejection is maintained the 12/11/2025 Office action. Modification is necessitated by Applicant’s claim amendments filed 5/20/2026.
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 1-30, 44-46 and 58-59 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
Step 1: Process, Machine, Manufacture or Composition
Claims 1-17 and 58-59 are to a "method", for analyzing a mixture of cell-free DNA molecules from a plurality of tissue types in a biological sample, with a series of functional steps. So a process.
Claims 18-30 are to another "method", for analyzing a mixture of cell-free DNA molecules from a plurality of tissue types in a biological sample, with a series of functional steps. So a process.
Claims 44-50 are to a "computer product," with structural limitations including “a non-transitory computer readable medium.” So a machine or manufacture,
Claims 51-56 are to another "computer product," with structural limitations including “a non-transitory computer readable medium.” So a machine or manufacture,
Step 2A Prong One: Identification of an Abstract Idea
The claims recite:
Determining a genomic position in a reference genome corresponding to at least one end of the cell-free DNA molecule, wherein the genomic position is determined by aligning the one or more sequence reads to the reference (claims 1 and 44 2.1 step).
This step recites a judging/decision-making activity (determining) based on data observation (a genomic position in a reference genome corresponding to at least one end of the cell-free DNA molecule), which can be achieved in human mind and hence equates to an abstract idea of mental processes.
Based on the analyzing of the enriched first plurality of cell-free DNA molecules, determining that a first number of the first plurality of cell-free DNA molecules end within one of a plurality of windows (claims 1 and 44 the 3rd step).
This step recites a judging/decision-making activity (determining) based on data analysis (based on analyzing …), which can be achieved in human mind and hence equates to an abstract idea of mental processes. A mental activity repeats 10,000 times is still a mental process.
Computing a relative abundance of the first plurality of cell-free DNA molecules ending within one of the plurality of windows by normalizing the first number of the first plurality of cell-free DNA molecules using a second number of cell-free DNA molecules, wherein the second number of cell-free DNA molecules includes cell-free DNA molecules ending at a second set of genomic positions outside of the plurality of windows including the first set of genomic positions (claims 1 and 44 the 4th step).
This step recites a simple calculation (first number denominated by a second number), which can be achieved in human mind. Therefore this step equates to an abstract idea of mental processes.
Determining the classification of the proportional contribution of the first tissue type by comparing the relative abundance to one or more calibration values determined from one or more calibration samples whose proportional contributions of the first tissue type are known (claims 1 and 44 the 5th step).
This step recites a judging/decision-making activity (determining) based on data analysis (comparing the relative abundance to one or more calibration values determined from one or more calibration samples whose proportional contributions of the first tissue type are known), which equates to an abstract idea of mental processes.
Determining a value of the group of cell-free DNA molecules (claims 18 and 51 the 4th step).
This step recites a decision-making activity (determining a value), which equates to an abstract idea of mental processes.
Determining a classification of whether the sequence imbalance exists in the first tissue type in the chromosomal region of the subject based on a comparison of the value of the group of cell-free DNA molecules to a reference value (claims 18 and 51 the 5th step).
This step recites a judging/decision-making activity (determining a classification) based on data observation (based on a comparison of the value of the group of cell-free DNA molecules to a reference value), which equates to an abstract idea of mental processes.
Hence, claims recite elements constitute the mental process grouping and the mathematical concept grouping of abstract ideas. because the recited elements involve data analysis, data observations, data manipulations, data calculations and judgements/decision makings.
Step 2A Prong Two: Consideration of Practical Application
The claims result in determining the classification of the proportional contribution of the first tissue type by comparing the relative abundance to one or more calibration values determined from one or more calibration samples whose proportional contributions of the first tissue type are known, which is new data and new information. The claims also recite “based on the clinical report, providing a therapeutic treatment to the subject and/or imaging the subject” (claim 59), which are mere instructions to apply an exception (MPEP 2106.05(f)). The claims do not recite any additional elements that integrate the abstract idea/judicial exception into a practical application.
This judicial exception is not integrated into a practical application because the claims do not meet any of the following criteria:
An improvement in the functioning of a computer, or an improvement to other technology or technical field, as discussed in MPEP §§ 2106.04(d)(1) and 2106.05(a);
Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, as discussed in MPEP § 2106.04(d)(2);
Implementing a judicial exception with, or using a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, as discussed in MPEP § 2106.05(b);
Effecting a transformation or reduction of a particular article to a different state or thing, as discussed in MPEP § 2106.05(c); and
Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception, as discussed in MPEP § 2106.05(e).
Step 2B: Consideration of Additional Elements and Significantly More
The claimed method also recites "additional elements" that are not limitations drawn to an abstract idea. The recited additional elements are drawn to:
Storing in a computer readable memory an identified first set of genomic positions at which ends of short cell-free DNA molecules occur at a first rate above a first threshold for samples containing the plurality of tissue types (claims 1 and 44 the first step).
Obtaining reagents that preferentially hybridize to one or more of the first set of genomic positions (claims 1 and 18).
Contacting a first plurality of cell-free DNA molecules from the biological sample of a subject with the reagents under conditions effective to enrich cell-free DNA molecules of the plurality of cell-free DNA molecules covering or ending on the first set of genomic positions, wherein the first plurality of cell-free DNA molecules comprises at least 100,000 cell-free DNA molecules (claims 1, 18 and 44).
Sequencing the cell-free DNA molecule to obtain one or more sequence reads (claims 1, 18 and 44);
A computer product comprising a non-transitory computer readable medium storing a plurality of instructions (claims 44 and 51).
Generating and outputting a clinical report indicating the proportional contribution of the first tissue type for use in diagnosis or monitoring (claim 58).
Based on the clinical report, providing a therapeutic treatment to the subject and/or imaging the subject (claim 59).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception, because working in the computing environment, and storing data in computer disk are well-known, routine and convention previously known to the pertinent industry. Outputting a clinical report is an insignificant extra-solution activity. “Based on the clinical report, providing a therapeutic treatment” is a mere instruction to apply an exception (MPEP 2106.05(f)). It amount to no more than a recitation of the words “apply it”. Viewed as a whole, these additional claim element(s) do not provide meaningful limitation(s) to transform the abstract idea recited in the instantly presented claims into a patent eligible application of the abstract idea such that the claim(s)
The combination of the recited additional element "A computer product comprising a non-transitory computer readable medium storing a plurality of instructions” and “storing in a computer readable memory an identified first set of genomic positions” are also exemplified by Lo: (“Analysis of Fragmentation Patterns of Cell-Free DNA,” US 20170024513 A1, Date Published 2017-01-26. Previously Cited), and generally it is understood that the examples in the reference are well-known and routine.
Therefore, there is no additional element of non-conventional at Step 2B.
Hence, claims 1-30 and 44-59 are ineligible under 35 U.S.C. 101.
Response to Arguments
Applicant's arguments filed 5/20/2026 have been fully considered but they are not persuasive. Particularly,
In the Remarks, Applicant argues (page 17, paras 1-3) that the claims do not recite mental process as "determining a genomic position in a reference genome corresponding to at least one end" of "at least 100,000 cell-free DNA molecules," and "determining that a first number of the first plurality of cell-free DNA molecules end within one of a plurality of windows, the plurality of windows comprising at least 10,000 windows" are not directed to judicial exceptions of mental processes. Applicant’s argument refers to Step 2A, Prong one, relating to whether claims recite abstract idea of mental processes.
In response, the argument is not persuasive. Under a BRI, the argument requires the mapping of a short read to a reference genome sequence, in order to find the ending position (of the short read) in the genome. The mapped position might need to be compared to another pre-defined position range at the last recited step. Such processes can be achieved in the human mind, with the help of a pen and paper. Such processes performed in a generic computer for 100,000 times are still mental processes (MPEP §2106.04(a)(2)(III)(C)).
In the Remarks, Applicant argues (page 18, 2nd para through page 19, 2nd para) that “the claims are directed to patent-eligible subject matter because they recite a laboratory method that requires obtaining a specific product defined by functional properties, and then using that product in a process that transforms a biological sample.“ Applicant’s argument refers to Step 2A, Prong two, relating to whether claims are integrated into a practical application or not.
In response, the argument is not persuasive. “A laboratory method that requires obtaining a specific product defined by functional properties” refers to the step “obtaining reagent that preferentially hybridize to one or more of the first set of genomic positions” and the next step that follows. These two steps are interpreted as targets enrichment through hybridization to specially designed probes. However, these two steps do not integrate with the judicial exceptions into a practical application, because at least: 1) “a first size” of “the short cell-free DNA molecules” recited in claim 1 first step is not captured in any later steps of claim 1 (neither do claims 18 nor claim 44); 2) what is enriched in these two steps and later analyzed, are “cell-free DNA molecules”, which is not “the short cell-free DNA molecules”. From the first step to later steps in claim 1, there is no integration into a practical application.
As to “transforms a biological sample,“ the argument is not persuasive. Claim 1 as a whole is interpreted as a method to target enrich cell-free DNA molecules, then sequencing the enriched molecules followed by analyzing the sequence. There is no clear physical state transformation that brings the biological sample from one state into another.
In the Remarks, Applicant argues (page 19, 3rd para through page 20, 3rd para) that
“the claims are directed to an improvement in a technology or technical field within the meaning of MPEP § 2106.05(a) because they recite a specific, technically driven method that increases the efficiency and accuracy of analyzing cell-free DNA for tissue quantification.” Applicant’s argument refers to Step 2A, Prong two, relating to whether claims are integrated into a practical application or not.
In response, the argument is not persuasive. The claims end at providing data regarding tissue contribution. Even though claim 58 recites “generating and outputting a clinical report indicating the proportional contribution of the first tissue type for use in diagnosis or monitoring”, “diagnosis” is a potential usage for the clinical report. Under a BRI, diagnosis is not necessarily executed. Even if the diagnosis is executed, diagnosis reads on information, or opinion, or decision making, that can be achieved in the human mind. Therefore diagnosis is directed to an abstract idea of mental processes. An abstract idea cannot integrate claims into a practical application.
In the Remarks, Applicant argues (page 20, 3rd para through page 21, 3rd para) that
“The Claims Include Meaningful Limits Beyond Generic Data Gathering”, and “This approach is distinct from conventional, untargeted sequencing or generic nucleic acid capture, because it dictates at the molecular level which fragments are made available for analysis, thereby controlling and limiting the nature of the data acquired.” Applicant’s argument refers to Step 2A, Prong two, relating to whether claims are integrated into a practical application or not.
In response, the argument is not persuasive. The step “obtaining reagents designed to preferentially hybridize to a defined set of genomic positions, followed by using those reagents to contact the sample under conditions effective to enrich for cell-free DNA molecules” is a conventional strategy used in cancer research, when only the hot region or hot gene are profiled. Subsequent sequencing is a routine step in this kind of research. The problem in claim 1 is lack of integration from step to step. For example, “a laboratory method that requires obtaining a specific product defined by functional properties” refers to the step “obtaining reagent that preferentially hybridize to one or more of the first set of genomic positions” and the next step that follows. These two steps are interpreted as targets enrichment through hybridization to specially designed probes. However, these two steps do not integrate with the judicial exceptions into a practical application, because at least: 1) “a first size” of “the short cell-free DNA molecules” recited in claim 1 first step is not captured in any later steps of claim 1 (neither do claims 18 nor claim 44); 2) what is enriched in these two steps and later analyzed, are “cell-free DNA molecules”, which is not “the short cell-free DNA molecules”. From the first step to later steps in claim 1, there is no integration.
In the Remarks, Applicant argues (page 21, last para through page 22, 2nd para) that “the combination of claimed steps of "obtaining reagents that preferentially hybridize to genomic positions" identified according to defined technical criteria (namely, "genomic positions at which ends of short cell-free DNA molecules occur at a first rate above a first threshold"), "contacting a first plurality of cell-free DNA with the reagents under conditions effective to enrich cell-free DNA molecules covering or ending on the genomic positions," and "sequencing" the enriched molecules to quantify the proportional contribution of a tissue type, was well-understood, routine, and conventional as of the effective filing date.”
In response, the argument is not persuasive. As discussed above, the step “obtaining reagents designed to preferentially hybridize to a defined set of genomic positions, followed by using those reagents to contact the sample under conditions effective to enrich for cell-free DNA molecules” is a conventional strategy used in cancer research, when only the hot region or hot gene are profiled. Subsequent sequencing is a routine step in this kind of research. The problem in claim 1 is lack of integration from steps to steps. For example, “a laboratory method that requires obtaining a specific product defined by functional properties” refers to the step “obtaining reagent that preferentially hybridize to one or more of the first set of genomic positions” and the next step that follows. These two steps are interpreted as targets enrichment through hybridization to specially designed probes. However, this two steps do not integrate with the judicial exceptions, because at least: 1) “a first size” of “the short cell-free DNA molecules” recited in claim 1 first step is not captured in any later steps of claim 1 (neither do claims 18 nor claim 44); 2) what is enriched in these two steps and later analyzed, are “cell-free DNA molecules”, which is not “the short cell-free DNA molecules”. From the first step to later steps in claim 1, there is no integration.
The conclusion reached at art examination that independent claims are “free of the analogous art” and therefore nonobvious has no direct connection to Step 2B in the 101 analysis. At Step 2B of the 101 analysis non-conventional combinations in additional elements are required. For art examination nonobvious combination in data analysis is good enough. Applicant’s argument is not persuasive when applying the art examination conclusion to Step 2B.
The 101 rejection is hence maintained.
Conclusion
No claims are allowed.
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/GL/
Patent Examiner
Art Unit 1686
/Anna Skibinsky/
Primary Examiner, AU 1635
