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 .
Applicant's Amendment/Request for Reconsideration-After Non-Final Rejection filing of 29 August 2025, has been entered and fully considered.
Information Disclosure Statement
The IDS filed 7/28/2025 has been considered by the Examiner.
Status of Claims
Claims 31-43 are cancelled.
Claims 57-59 are newly added.
Claims 1-30 and 44-59 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 from the previous Office action. Modification is necessitated by Applicant’s amendments filed 8/29/2025.
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.
For each rejection below, dependent claims are rejected similarly as not remedying the rejection, unless otherwise noted.
Claims 1-30 and 44-59 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 57-59 are directed to a process, here a "method", for analyzing a mixture of cell-free DNA molecules from a plurality of tissue types in a biological sample, with process steps including “storing…,” “analyzing…,” “determining…,” and “computing…”
Claims 18-30 are directed to another process, here another "method" claims, for analyzing a mixture of cell-free DNA molecules from a plurality of tissue types in a biological sample, with process steps including “storing…,” “analyzing…,” “determining…,” and “computing…”
Claims 44-50 are directed to a machine or manufacture, here a "computer product," with structural limitations including “a non-transitory computer readable medium.”
Claims 51-56 are directed to another machine or manufacture, here another "computer product," with structural limitations including “a non-transitory computer readable medium.”
Step 2A Prong One: Identification of an Abstract Idea
The claim(s) recite(s):
Analyzing a first plurality of cell-free DNA molecules from the biological sample of a subject (claims 1 and 44 2nd step);
This step recites data analysis explicitly, which can be achieved in the human mind and hence equates to an abstract idea of mental processes. Although at least 100,000 cell-free DNA molecules seems challenging, it does not preclude human mental activity from analyzing the molecules. A mental activity repeating 100,000 times is still a mental process.
Determining a genomic position in a reference genome corresponding to at least one end of the cell-free DNA molecule (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 a human mind and hence equates to an abstract idea of mental processes.
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 a 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 … (claims 1 and 44 the 4th step);
This step recites an 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. Hence the 101 analysis needs to move to the next step.
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 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:
1. “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).
This step recites storing data (information) in a computer disk, which equates to data output and hence this step is an additional element.
2. "A computer product comprising a non-transitory computer readable medium storing a plurality of instructions" (claims 44 and 51).
This element recites a hardware, which is an additional element.
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 store data in computer disk are well-known, routine and convention previously known to the pertinent industry. 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 8/29/2025 have been fully considered but they are not persuasive.
Applicant argues that claim does not recite mental process as the following cited claim elements “cannot be practically performed by a human mind (page 16, 2nd para through page 18, 2nd para):
“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... wherein the first set of genomic positions comprises at least 10,000 genomic positions,”
“analyzing a first plurality of cell-free DNA molecules from the biological sample of a subject, wherein the first plurality of cell-free DNA molecules comprises at least 100,000 cell-free DNA molecules;”
for each of the at least 100,000 cell-free DNA molecules, “determining a genomic position in a reference genome corresponding to at least one end,” 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.”
Applicant’s argument refers to Step 2A, Prong one, relating to whether claims recite abstract idea of mental processes. The argument is not persuasive. A claim that requires a computer may still recite a mental processes (MPEP §2106.04(a)(2)(III)(C)). Except the first element of using a computer for processing efficiency is now designated to an additional element, the other three elements, under a BRI, require 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 cited step. Such processes can be achieved in human mind, with the help of a pend and paper. Such a process performed in a generic computer repeatedly over 100,000 molecules is still a mental process (MPEP §2106.04(a)(2)(III)(C)).
Applicant argues that claims does not recite mathematical concepts as the following cited claim elements “cannot be practically performed by a human mind (page 18, last para through page 19, 1st para). Applicant’s argument is not supported by evidence.
Applicant argues that the claim does not recite abstract ideas in summary (page 19, 2nd para). Applicant’s argument is not persuasive. As claims are directed to mental processes, the claims are directed to abstract ideas at Step 2A/Prong one.
Applicant argues that claims provide technical improvements and represent a practical application (page 19, last para through page 21, 1st para) under Step 2A/Prong two. Applicant’s argument is not persuasive. Claims are interpreted as analyzing a biological sample, through data analysis. The claims recites no experimental procedures toward sample analysis. The claims as a whole, is directed to computerized data analysis. There is no additional elements that capture and reflect the potential technical improvements rooted in data analysis. Hence the alleged “technical improvement” is an improvement to data analysis. There is no practical application as an improvement to judicial exceptions cannot be a practical application.
Applicant argues that the technical improvements result from additional element that are not extra-solution activities (page 21, 2nd para through page 22, 1st para). Applicant’s argument is not persuasive. The additional element “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) is an extra-solution activity of data recording to a computer disk. This is a routine step in data analytical work-flow. The additional element does not meaningfully limit claim 1 by adding significantly more to the abstract idea. Storing results of a sequence analysis is extra-solution activity that is well known, as described in MPEP 2106.05(g).
Applicant argues “the claims impose meaningful limitations” (page 22, 2nd para through 3rd para). This argument is not persuasive. The identified additional elements do not capture nor reflect the alleged technical improvements rooted in data analysis. There is no meaningful limitations.
Regarding the arguments against Step 2B (page 23, 2nd para through page 25, 1st para), the argued elements:
analyzing at least 100,000 cell-free DNA molecules from a test sample;
mapping the end positions of each molecule to a reference genome;
determining whether each fragment end corresponding to one of at least 10,000 empirically identified windows;
normalizing the count data with respect to molecules ending outside these windows; and
determining the proportional tissue contribution by comparing the resulting measurement to empirically derived calibration values
are all part of judicial exceptions. A judicial exception alone cannot provide the inventive concept or particular combination and the identification of whether the additional elements amount to such an inventive concept requires considering the additional elements individually and in combination to determine if they provide significantly more than the judicial exception. (MPEP 2106.05.A i-vi).
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 of additional elements are required. A nonobvious abstract idea/judicial exception may render claims free from the prior art.. However, 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.
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 GUOZHEN LIU whose telephone number is (571)272-0224. The examiner can normally be reached Monday-Friday 8-5.
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, Larry D Riggs can be reached at (571) 270-3062. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/GL/
Patent Examiner
Art Unit 1686
/Anna Skibinsky/
Primary Examiner, AU 1635