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, filed 6/26/2026, has been entered and fully considered.
The IDS filed 06/26/2026 has been considered and fully entered.
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 62/642,480 filed 03/13/2018 is acknowledged.
Claim Status
Claim 1 is cancelled;
Claim 2-21 are pending and are examined on the merits.
Withdrawn Rejections/Objections
The rejection to claim 21 under 35 U.S.C. 112(b) in the Office action posted 28 January 2026 is withdrawn in view of claim amendments filed 26 June 2026.
Claim Rejections - 35 USC § 101
This rejection is maintained from a previous Office action. Modifications are necessitated by claim amendments.
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 2-21 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 2-11 are directed to a process, here a “method” for detecting cancer in a test subject from a cell-free deoxyribonucleic acid (cfDNA) sample, with a series functional steps.
Claims 12-21 is directed to a machine or manufacturer, here a “non-transitory computer-readable storage medium” storing instructions for detecting cancer in a test subject from a cell-free deoxyribonucleic acid (cfDNA) sample fragment, with a well-known structural component.
Step 2A Prong One: Identification of an Abstract Idea
The claims recite:
Generating a list of possibilities of a methylation state vector from the sample genomic location that are of a same length as the sample state vector, wherein each possibility of the methylation state vector is distinct from other possibilities of the methylation state vector (claims 2 and 12);
This step recites generating a list of possibilities of a methylation state vector from the sample genomic location that are of a same length as the sample state vector. The step is interpreted as initializing a methylation state vector with control possibility for CpG sites in the vector (of a fragment). According to the disclosure at paragraph [0005], this step encompasses a control group data and a Markov chain probability analysis. The step hence recites mathematical calculations implicitly and hence it equates to an abstract idea of mathematical concepts.
For each possibility of the methylation state vector, calculating a probability by accessing the counts stored in the data structure aligned to a starting CpG site of the sample state vector (claims 2 and 12);
This step recites calculation a probability by accessing the counts stored in the data structure. The step recites a mathematical calculation explicitly and hence it equates to an abstract idea of mathematical concepts.
Identifying the possibility of the methylation state vector that matches the sample state vector and the calculated probability associated with the identified possibility (claims 2 and 12);
This step recites identifying the possibilities of the methylation state vector that matches the sample state vector and the calculated probability associated with the identified possibility. Under a BRI, this step encompasses the processes of comparing two vectors and identifying associated values from one vector. This processes can be achieved in human mind. Hence this step equates to an abstract idea of mental processes.
Generating a score for the sample fragment of the sample state vector based at least in part on the calculated probability for the identified possibility (claims 2 and 12);
This step recites calculating a score for the sample fragment of the sample state vector based at least in part on the calculated probability for the identified possibility. The step recites mathematical calculations explicitly and hence it equates to an abstract idea of mathematical concepts.
Determining whether the sample fragment has an anomalous methylation pattern based on the generated score (claims 2 and 12);
This step recites a decision making/judgement activity, which equates to an abstract idea of mental process.
Generating a feature vector from one or more sample state vectors for sample fragments determined to have an anomalous methylation pattern (claims 2 and 12);
This step recites generation new data (a feature vector) from existing data (one or more sample state vectors for sample fragments determined to have an anomalous methylation pattern), which is a data manipulation and equates to an abstract idea of mental process.
Applying a cancer classifier to the feature vector to determine a cancer prediction for the test subject (claims 2 and 12);
Although recited as determined by a cancer classifier, nothing stop human mind from determining the cancer or cancer status in the test subject. Therefore, this step equates to an abstract idea of mental processes.
Step 2A Prong Two: Consideration of Practical Application
The claims result in a process of predicting cancer using the feature vector as input, which reads on generating new data (aka information) from existing data. 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 additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
an additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
an additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
an additional element effects a transformation or reduction of a particular article to a different state or thing; and
an additional element applies or uses 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.
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:
Accessing a data structure comprising counts of strings of a plurality of CpG sites within a reference genome wherein the counts of strings are stored according to starting CpG site and length, and wherein strings are subdivided from methylation state vectors representing methylation states of DNA fragments from subjects in a healthy control group (claims 2 and 12);
A non-transitory computer-readable storage medium (claim 12).
The claims do not include additional elements that are sufficient to amount of significantly more than the judicial exception because “accessing a data structure …” (claims 2 and 12) is an insignificant extra-solution activity of data-gathering. Reciting the computer storage medium (claim 12) is a mere application of abstract idea in a computer environment (MPEP § 2106.05(h)). The conventionality of recited additional elements are further evidenced by the following references:
Kang (“CancerLocator: non-invasive cancer diagnosis and tissue-of-origin prediction using methylation profiles of cell-free DNA”. Genome Biol 18, 53 (2017), as cited on the "Notice of References Cited" form 892 0f 4/19/2022. Newly cited);
Shen (“Detect differentially methylated regions using non-homogeneous hidden Markov model for methylation array data”, Bioinformatics, Volume 33, Issue 23, 01 December 2017, Pages 3701–3708. Newly cited); and
Krueger (“Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications”, Bioinformatics, Volume 27, Issue 11, 1 June 2011, Pages 1571–1572, (Year: 2011), Fig 1, page 1572. Newly cited).
Kang discloses a computational method to locate cancer origin (para 2, col 1, pg. 7). Kang further teaches accessing a data structure comprising counts of strings of CpG sites within a reference genome and their respective methylation states from a set of training fragments (Fig. 1, page 3 of 12); and generating of a sample state vector for each CpG cluster (Fig 1 upper part, page 3 of 12; " the numbers of methylated and unmethylated cytosines are counted for each CpG site” (line 3-5, par 3 col 1, page 8 of 12).
Shen discloses the DMRMark, a novel method based on non-homogeneous hidden Markov model (NHMM) to detect DMRs from methylation array data (DMR stands for “Differentially Methylation Regions”, examiner) (page 3702-3704 under section “2 Model”, and Fig 2).
Krueger’s Bismark is employed to align the reads to the reference genome HG19 and call the methylated cytosines (“Bismark is employed to align the reads to the reference genome HG19 and call the methylated cytosines”, first 2 lines under section “WGBS data processing”, col 1, page 8 of 12).
It is emphasized that analysis of what is conventional generally pertains to the above-identified additional elements and not to elements earlier identified as part of a judicial exception.
Other elements of the method include a non-transitory computer-readable storage medium which is a recitation of generic computer structure that serves to perform generic computer functions that are well-understood, routine, and conventional activities 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) amounts to significantly more than the abstract idea itself. Therefore, the claim(s) are rejected under 35 U.S.C. 101 as being directed to non-statutory subject matter.
Response to Applicant’s Argument:
Applicant's arguments filed 26 June 2026 have been fully considered but they are not persuasive. Particularly:
In the Remarks filed 06/26/2026, Applicant argues (page 11, 2nd para) that “under Step 2A, Prong Two, the additional elements integrate any alleged judicial exception into a practical application.”
In response, Applicant’s argument is not persuasive. To integrate any alleged judicial exception into a practical application at Step 2A/Prong Two, additional elements are needed to apply, to capture and to reflect the technical merits rooted in judicial exceptions. However, the claims result in a process of predicting cancer using the feature vector as input, which reads on generating new data (aka information) from existing data. The claims do not recite any additional elements that integrate the abstract idea/judicial exception into a practical application.
In the Remarks, Applicant argues (page 11, 3rd para through page 12, 1st para) that the limitation "accessing a data structure comprising counts of strings of a plurality of CpG sites within a reference genome, wherein the counts of strings are stored according to starting CpG site and length, and wherein strings are subdivided from methylation state vectors representing methylation states of DNA fragments from subjects in a healthy control group" is not an abstract idea, because it is neither a mathematical concept nor a mental process.
In response, Applicant’s argument is not persuasive. A data structure reads on a table, an excel spread sheet or any data structure used to organize information. It is routine to use data structures to hold data, for example any relational database will contain data structures with defined data formats for different data attributes. It is true that a data structure is classified into an additional element in the 101 analysis above. However, data structure is routine and conventional. It is not clear what technical merits rooted in judicial exceptions are captures and reflected in the data structure. Data structure is not significant enough to integrate claims into a practical application at either Step 2A/Prong two or at Step 2B.
In the Remarks, Applicant argues (page 12, 2nd para through page 13, 1st para) that “The additional elements, in combination with the other elements of the claim allegedly directed to the abstract idea judicial exception, embody an improvement to the field of bioinformatics. The data structure is particularly architected to store counts in an efficient manner for retrieval in the data computation steps of the claim. The intermediate steps of the claim involve computation of a probability for "each possibility of the of the methylation state vector."
In response, Applicant’s argument is not persuasive. The argument “embody an improvement to the field of bioinformatics” is too broad. “Bioinformatics” is not claimed in the instant claims.
To integrate any alleged judicial exception into a practical application at Step 2A/Prong Two, additional elements are needed to apply, to capture and to reflect the technical merits rooted in judicial exceptions. However, the claims result in a process of predicting cancer using the feature vector as input, which reads on generating new data (aka information) from existing data. The claims do not recite any additional elements that integrate the abstract idea/judicial exception into a practical application.
The argued data structure, as discussed above, reads on a table, an excel spread sheet or any data structure used to organize information. It is routine to use data structures to hold data, for example any relational database will contain data structures with defined data formats for different data attributes. Hence, data structure is not significant enough to integrate claims into a practical application at either Step 2A/Prong two or at Step 2B.
Therefore, the 101 rejection is maintained.
Double Patenting
This rejection is maintained from a previous Office action. Modifications are necessitated by claim amendments.
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12, 2, 14, 5, 6, 7, 8, 11, 12, 12, 14, 15, 16, 17, 18, 19, 22 of U.S. Patent No. US12027237B2. Although the claims at issue are not identical, they are not patentably distinct from each other because every step of instant claim 2 is claimed in the reference claim 1, sometimes in more details. The order of the instant steps are different comparing the order of the same steps in the reference claim 1 but every steps in the instant claim 2 is anticipated by at least one step in the reference claim 1. Although claims 1 new amendment “wherein the counts of strings are stored according to starting CpG site and length, and wherein strings are subdivided from methylation state vectors representing methylation states of DNA fragments from subjects in a healthy control group” (claims 2 and 12, 1st step), it is obvious over the reference claim 2 (which reads as “The method of claim 1, wherein each of the strings of CpG sites comprises the methylation state for each of the CpG sites at a plurality of genomic locations within the reference genome, wherein each of the methylation states is determined to be methylated or unmethylated”), because the reference genome is from the healthy control.
Instant claim 2 fed “a feature vector” to a cancer classifier to determine a cancer prediction. In the reference claim 1, it is the “sample state vector” that applied by a cancer classifier to determine a cancer prediction. According to instant claim 2 limitation “generating a feature vector from one or more sample state vectors for sample fragments determined to have an anomalous methylation pattern”, Literally, “a feature vector” is “one sample state vector” under a BRI.
In reality, there is only one sample state vector for one sample fragment because there is only one “sample state vector” for one sample fragment according to this limitation:
“generating a sample state vector for the sample fragment comprising a sample genomic location within the reference genome and a methylation state for each of a plurality of CpG sites in the sample fragment” (claim 2 step 2).
Hence, without disclosing any “feature” other than the methylation state and probability/possibility disclosed for the “sample state vector”, a “feature vector” is a “sample state vector” under a BRI, or at least. “one sample state vector” in the reference claim 1 anticipate “a feature vector” in the instant claim 2.
In summary, Claims 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12, 2, 14, 5, 6, 7, 8, 11, 12, 12, 14, 15, 16, 17, 18, 19, 22 of U.S. Patent No. US12027237B2.
A detailed step-by-step mapping between the instant claim 1 (bulleted) and reference claim 1 (following the bulleted items) is outlined here:
A method for detecting cancer in a test subject from a cell-free deoxyribonucleic acid (cfDNA) sample, the method comprising:
A method for detecting cancer in a test subject from a cell-free deoxyribonucleic acid (cfDNA) sample fragment, the method comprising:
accessing a data structure comprising counts of strings of a plurality of CpG sites within a reference genome, wherein the counts of strings are stored according to starting CpG site and length, and wherein strings are subdivided from methylation state vectors representing methylation states of DNA fragments from subjects in a healthy control group;
accessing the data structure comprising the counts of the strings of the plurality of CpG sites within the reference genome and their respective methylation states from the set of training fragments;
(Reference claim 2). The method of claim 1, wherein each of the strings of CpG sites comprises the methylation state for each of the CpG sites at a plurality of genomic locations within the reference genome, wherein each of the methylation states is determined to be methylated or unmethylated.
for each sample fragment in the cfDNA sample:
for each training fragment in the set of training fragments,
generating a sample state vector for the sample fragment comprising a sample genomic location within the reference genome and a methylation state for each of a plurality of CpG sites in the sample fragment;
generating a sample state vector for a sample fragment comprising a sample genomic location within the reference genome and a methylation state for each of a plurality of CpG sites in the sample fragment, each methylation state determined to be methylated or unmethylated;
generating a list of possibilities of a methylation state vector from the sample genomic location that are of a same length as the sample state vector, wherein each possibility of the methylation state vector is distinct from other possibilities of the methylation state vector;
generating a list of possibilities of a methylation state vector from the sample genomic location that are of a same length as the sample state vector, wherein each possibility of the methylation state vector is distinct from other possibilities of the methylation state vector;
for each possibility of the methylation state vector, calculating a probability by accessing the counts stored in the data structure aligned to a starting CpG site of the sample state vector;
for each possibility of the methylation state vector, calculating a probability by accessing the counts stored in the data structure;
identifying the possibility of the methylation state vector that matches the sample state vector and the calculated probability associated with the identified possibility;
identifying the possibility of the methylation state vector that matches the sample state vector and correspondingly the calculated probability as a sample probability;
generating a score for the sample fragment of the sample state vector based at least in part on the calculated probability for the identified possibility;
generating the score for the sample fragment by summing the one or more identified calculated probabilities with the sample probability;
determining whether the sample fragment has an anomalous methylation pattern based on the generated score;
determining whether the sample fragment has an anomalous methylation pattern based on the generated score; and
generating a feature vector from one or more sample state vectors for sample fragments determined to have an anomalous methylation pattern; and applying a cancer classifier to the feature vector to determine a cancer prediction for the test subject.
In response to determining the sample fragment to have an anomalous methylation pattern, applying a cancer classifier to the sample state vector to determine a cancer prediction for the test subject that originated the sample fragment, wherein a cancer treatment is prescribed based on the cancer prediction.
As can be seen, although the claim 2 at issue are not identical to reference claim 1, they are not patentably distinct from each other because every step of instant claim 2 is claimed in the reference claim 1. The newly amended part is obvious over reference claim 2.
Claim 12 is amended similarly to claim 1. All the dependent claims are not amended. Therefore, claims 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12, 2, 14, 5, 6, 7, 8, 11, 12, 12, 14, 15, 16, 17, 18, 19, 22 of U.S. Patent No. US12027237B2.
In summary, the nonstatutory double patenting as being unpatentable over Claims 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21 are maintained.
Response to Applicant’s Argument:
Applicant's arguments filed 26 June 2026 have been fully considered but they are not persuasive. Particularly:
In the Remarks filed 06/26/2026, Applicant argues (page 13, penultimate para) that “Claim 2 as amended is patentably distinct over the claims of U.S. Patent No. 12,027,237 B2. In particular, claim 2 is amended to recite: "accessing a data structure comprising counts of strings of a plurality of CpG sites within a reference genome, wherein the counts of strings are stored according to starting CpG site and length, and wherein strings are subdivided from methylation state vectors representing methylation states of DNA fragments from subjects in a healthy control group," which renders claim 2 patentably distinct over the claims of U.S. Patent No. 12,027,237 B2”.
In response, Applicant’s argument is not persuasive. The newly amended part, when combined with the existing part in instant claim 2, is obvious over reference claim 2. The reference genome is from a healthy control. Otherwise counting CpG in a fragment (marked by starting CpG and length) and store the information in a data structure is taught in reference claims. The concept “methylation state vector” is recited multiple times in reference claim 1.
Therefore the nonstatutory double patenting rejection is 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.
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/GL/
Patent Examiner
Art Unit 1686
/Anna Skibinsky/
Primary Examiner, AU 1635
Prosecution Insights