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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/20/2025 has been entered.
Status of Claims
Claims 11, 14, and 23-86 are cancelled.
Claims 1-10, 12-13, 15-22 and 87-97 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 63/594,781 filed 10/31/2023 is acknowledged.
Withdrawn Rejections/Objections
The claim rejections to claims 1-10, 12-13 and 15-22 under 35 USC § 112(a) in the Office Action mailed 20 May 2025 are withdrawn in view of claim amendments filed 20 August 2025.
The claim rejections to claims 1-10, 12-13 and 15-22 under 35 USC § 112(b) in the Office Action mailed 20 May 2025 are withdrawn in view of claim amendments filed 20 August 2025.
Claim Objections
Claim 95 is objected to because of the following informalities: newly added claim 95 recites “to provide the provide the basis for maintaining” in step ii), which should read as “to provide the basis for maintaining”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
This is a new rejection, necessitated by claim amendments.
Claim 95 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 95 recites “acquiring a computed tomographic image of a tumor in the subject; and ii) using the computed tomographic image in conjunction with the final tumor fractional estimate to provide the provide the basis for maintaining, modifying, or adjusting the subject's cancer treatment regimen.” However, “computed tomographic image” has never been mentioned in the specification.
Claim 95 hence recites new matter.
Claim Rejections - 35 USC § 112
This is a new rejection, necessitated by claim amendments.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 95 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 95 recites “ii) using the computed tomographic image in conjunction with the final tumor fractional estimate to provide the provide the basis for maintaining, modifying, or adjusting the subject's cancer treatment regimen”, which attempts to claim a process without setting forth any steps involved in the process. Claim 95 hence raises an issue of indefiniteness.
Claim Rejections - 35 USC § 101
This rejection is maintained from a previous Office Action. Modification is necessitated by claim amendment.
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 1-10, 12-13, 15-22 and 87-97 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 1-10, 12-13, 15-22 and 87-97 are directed to a machine or manufacturer, here a "computer system" for determining whether a subject that is or has been afflicted with a cancer is responsive to a cancer drug, has a relapse with the cancer, or has incurred progression of the cancer, with structural components comprising a memory, a processor, coupled to the memory.
Step 2A Prong One: Identification of judicial exceptions
Claim 1 recites:
B) using the plurality of sequences to determine coverage by (i) binning the plurality of sequences into a plurality of bins, wherein each bin in the plurality of bins represents a portion of a genome, (ii) segmenting the bins into a plurality of segments, and (iii) determining a segment coverage value for each segment in the plurality of segments, thereby forming a plurality of segment coverage values, wherein the first subset of the plurality of sequences map to a first subset of the bins and the second subset of the plurality of sequences map to a second subset of the plurality of bins, and wherein the first subset of bins is other than the second subset of bins;
----this step recites sequence mapping to the genome and analyzing coverage. Under a BRI and at the simplest embodiment, the data analyzing and decision-making process can be achieved in human mind with the help of a pen and paper. Therefore the step equates to an abstract idea of mental processes.
C) modeling a first estimate of circulating tumor fraction (ctFE) based on an error between corresponding values in (i) the plurality of segment coverage values and (ii) a set of integer copy states that includes an integer copy state for each segment in the plurality of segments, by fitting each respective segment in the plurality of segments and a first simulated fraction estimate to a respective integer copy state, in a plurality of integer copy states, best matching the segment coverage value of the respective segment;
----“modeling” is interpreted as mathematical operations including the fitting of two set of values according to the disclosure at [par. 522-530]. Therefore this step equates to an abstract idea of mathematical concepts.
D) determining, for each germline variant in a set of germline variants represented in the liquid sample, a frequency difference (BAFdelta), wherein the frequency difference is determined from a comparison of (i) a frequency of the germline variant in the plurality of sequence reads and (ii) a reference frequency for the germline variant, to identify a second estimate of ctFE based on a corresponding frequency difference for a germline variant;
----this step recites the frequency difference (BAFdelta), which is interpreted as a mathematical relationship. The step therefore equates to an abstract idea of mathematical concepts.
E) determining, for each somatic variant in a set of somatic variants, a variant allele frequency (VAF) for the somatic variant, wherein the VAF is determined from a frequency of the variant in the plurality of sequences, to identify a third estimate of ctFE based on a corresponding VAF for a variant in the set of somatic variants having a maximum VAF value;
----this step recites determining VAF and ctFE, which requires mathematic calculations. The step hence equates to an abstract idea of mathematical concepts.
F) accessing a first trained sigmoid weighting function, a second trained sigmoid
weighting function, and a third trained sigmoid weighting function, wherein the first trained sigmoid weighting function, the second trained sigmoid weighting
function and the third trained sigmoid weighting function are generated by training on a dataset comprising tumor fractions, corresponding segment coverage values across the plurality of bins, corresponding B-allele frequency difference values of the set of germline variants, and corresponding variant allele frequencies of the set of somatic variants to identify a first weight for the first estimate of ctFE, a second weight for the second estimate of ctFE, and a third weight for the third estimate of ctFE based on a value for the first estimate of the ctFE;
----this step recites the processes of how the three sigmoid weighting functions are trained and generated, which reads on mathematical operations (under a Broadest Reasonable Interpretation, such as regressions). Hence, this step equates to an abstract idea of mathematical concepts.
G) modifying the first estimate of ctFE by applying the first weight to the first estimate of ctFE thereby obtaining an adjusted first estimate of ctFE;
----this step is interpreted as calculating the weighted first estimate of ctFE using
the sigmoid function defined in paragraph [697], which is a mathematical formula. Hence, this step reads on mathematical calculations and equates to an abstract idea of mathematical concepts.
H) modifying the second estimate of ctFE by applying the second weight to the second estimate of ctFE thereby obtaining an adjusted second estimate of ctFE;
----this step is interpreted as calculating the weighted second estimate of ctFE using the sigmoid function defined in paragraph [697], which is a mathematical formula. Hence, this step reads on mathematical calculations and equates to an abstract idea of mathematical concepts.
I) modifying the third estimate of ctFE by applying the third weight to the third
estimate of ctFE thereby obtaining an adjusted third estimate of ctFE; and
----this step is interpreted as calculating the weighted third estimate of ctFE using
the sigmoid function defined in paragraph [697], which is a mathematical formula. Hence, this step reads on mathematical calculations and equates to an abstract idea of mathematical concepts.
J) aggregating the adjusted first estimate of ctFE, the adjusted second estimate of ctFE, and the adjusted third estimate of ctFE to provide a final tumor fractional estimate for the subject, wherein the final tumor fractional estimate provides a basis for maintaining, modifying, or adjusting the subject's cancer treatment regimen.
----this step explicitly recites mathematical calculation (sum of three numbers). Hence, this step equates to an abstract idea of mathematical concepts.
Additional claims further limit the data and mathematical calculations around ctFE (claims 2-10, 12-13, 15-20), the subject (claim 20), cancer (claims 20-22), sample (claims 89 and 90), cancer drug (claims 91-94), cancer treatment regimen (claims 87-95). Since claim 1 is constructed in the framework of a computer system with structural computing components, the subject, cancer, sample, cancer drug, cancer treatment regimen are all interpreted as data and data observations, hence they read on abstract ideas of mental processes. Therefore, claims do recite abstract ideas of mental processes and mathematical concepts. Because the steps are directed to judicial exceptions, the claims must therefore be examined further to determine whether the claims integrate the above-identified JEs into a practical application (MPEP 2106.04(d)).
Additional claims also recite the following elements:
“to recommend initiating radiation therapy” (claim 91);
“to facilitate initiating radiation therapy” (claim 93);
“to recommend discontinuing radiation therapy or therapy with the cancer drug” (claim 92);
“to facilitate discontinuing radiation therapy or therapy with the cancer drug” (claim 94); and
“to provide the basis for maintaining, modifying, or adjusting the subject's cancer treatment regimen” (claim 95).
These are all intended use. They read on mental activities of intentions because nothing physical happens. Therefore none of these elements are additional elements and none of these elements contribute to the integration of a practical application.
Step 2A Prong Two: Consideration of Practical Application
The claims result in a process of providing a final tumor fractional estimate for the subject (claim 1), or using the computed tomographic image in conjunction with the final tumor fractional estimate to provide the provide the basis for maintaining, modifying, or adjusting the subject's cancer treatment regimen which reads on generating new information (claim 95). 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:
A computer system, comprising a memory, a processor, coupled to the memory (claim 1).
A) Obtaining a plurality of sequences comprising a corresponding sequence for each cell- free DNA fragment in a plurality of cell-free DNA fragments obtained from a panel-enriched sequencing reaction of a first liquid sample from the subject after the subject has initiated or completed a cancer treatment regimen that includes taking the cancer drug, wherein the plurality of sequences comprises 100,000 sequences, and wherein the panel-enrichment nucleic acid sequencing includes a probe for each locus in a plurality of loci, wherein the plurality of loci comprises at least 50 human genomic loci, a first subset of the plurality of sequences are off-target to the plurality of loci, and each sequence in a second subset of the plurality of sequences is on-target to at least one locus in the plurality of loci (claim 1).
i) Acquiring a computed tomographic image of a tumor in the subject (claim 95).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the above identified additional elements can be divided into two groups: Group 1: the model input/output data (claim 1); Group 2: a computer system and components (claim 1). The group 1) additional elements are all insignificant extra-solution activities (MPEP §2106.05(g)) because they are necessary for data analysis. The group 2) additional elements barely provide technical environment for executing the abstract ideas. These two groups are all well-known and are conventional.
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 101 rejection is maintained.
Response to Applicant’s Arguments
In the Remarks filed 8/20/2025, Applicant argues (page 16, 3rd para through page 17, 3rd para) that claim 1 is not directed to a judicial exception. Particularly, Applicants argued for two reasons: 1) like Example 39, claim 1 uses, but does not recite mathematical concepts (page 16, last para through page 17, 1st para); and 2) the claim requires processing 100,000 DNA sequences.(page 18, 3rd line)
To response, the argument is not persuasive. Above all, claim 1 recites mathematical calculations at steps C-J) explicitly or implicitly. Therefore claim 1 is directed to abstract ideas of mathematical concepts.
Particularly, in respect to the first reason that like Example 39, claim 1 uses, but does not recite mathematical concepts. Example 39 was image facial recognition by a NN and in contrast the instant claims are drawn to binning data, mathematics and mental steps. Human mind is not equipped to process binary facial images, but human mind is certainly equipped to process text data of sequences with respect to binning data, and comparing one sequence’s reads against another sequence, and perform the related mathematical calculation, with or without the aid of a pen and paper. Hence Example 39 is not analogous to the instant claims. Instant claim 1 does recite abstract ideas in the mathematical concept grouping.
In respect to the second reasoning that instant claims recite 100,000 DNA sequences are analyzed. It is noted that a lot of data does not augment the steps being performed to analyze the data, which are abstract ideas. Computations on a lot of data performed mentally, or with paper and pencil, would take considerable time and effort, but that is, of course, the singular purpose of computers and computer networks, to perform large numbers of calculations, via algorithms, rapidly, and without error (assuming no error in user input). Although a general purpose computer can perform calculations at a rate and accuracy that can far outstrip the mental performance of a skilled artisan, the nature of the activity is essentially the same, and constitutes an abstract idea. See Bancorp Serves., L.L. C. v. Sun Life Assur. Co. of Canada (U.S.), 687 F.3d 1266,1278 (Fed. Cir. 2012) (holding that “the fact that the required calculations could be performed more efficiently via a computer does not materially alter the patent eligibility of the claimed subject matter”); see also See SiRF Tech., Inc. v. Int’l Trade Comm ’n, 601 F.3d 1319,1333 (Fed. Cir. 2010) (holding that: In order for the addition of a machine to impose a meaningful limit on the scope of a claim, it must play a significant part in permitting the claimed method to be performed, rather than function solely as an obvious mechanism for permitting a solution to be achieved more quickly, i.e., through the utilization of a computer for performing calculations).
In the Remarks, Applicant argues (page 17, 4th para) regarding organized human activity. The argument is not based on fact.
In the Remarks, Applicant argues (page 17, penultimate para through page 19, penultimate para) that claim 1 does not recite mental processes.
To response, the argument is not persuasive. Claim 1 step B) recites only binning, segmenting and segment coverage calculation. These can be achieved easily in human mind, with the help of a pen and paper.
In the Remarks, Applicant argues (page 18, penultimate para through page 21, 1st para) that claim 1 is not directed to a judicial exception because it is similar to Example 37 claim 2. The argument is not persuasive. Example 37 claim 2 is not about rubber molding. Claim 37 is titled “Relocation of Icons on a Graphical User Interface” Applicant probably want to align instant claims to Example 25, which is about rubber molding. However, the USPTO released Example 25 is different from the example provided by Applicant.
Just to response to provided example, the claim recites a series of acts including determining the temperature of the mold and molding the rubber into a tire component. Thus, the claim is directed to a process, which is one of the statutory categories of invention (Step 1: YES).
The claim is then analyzed to determine whether it is directed to any judicial exception. The claim recites determining that the predicted processing temperature is within a predefined acceptable range. This limitation sets forth a judicial exception, because it is a human mental activity of judgement/decision-making, which are types of activities that have also been found by the courts to represent abstract ideas. Thus, the claim is directed to at least one exception (Step 2A/Prong One: YES).
Next, the claim as a whole is analyzed to determine whether any additional element, or combination of elements, integrated claims into a practical application. The claimed steps taken as a combination effect a transformation of the raw, uncured synthetic rubber into a different state or thing, i.e., a cured and molded rubber product for a tire. Alternatively, the judicial exception is applied by, captured in and reflected in additional elements (Step 2A/Prong Two: YES).
Step 2B analysis is not necessary. Since the example claim is 101 eligible at Step 2A/Prong Two.
Coming back to our instant claim 1, claim 1 does not recite any additional element to apply, to capture, and to reflect the judicial exceptions. Although Applicant listed “wherein the final tumor fractional estimate provides basis for maintaining, modifying or adjusting the subject’s cancer treatment regimen” in parallel to the last step of the example claim, the “wherein…” clause is not an additional element. In fact, it reads on information.
In summary, the provided example is not a good comparison to instant claims. The core issues as discussed above in the 101 rejection (Step 2A/Prong Two), is the claims do not recite any additional elements that integrate the abstract idea/judicial exception into a practical application. There is no additional elements to apply, to capture and to reflect the technical merits rooted in judicial exceptions.
In the Remarks, Applicant argues (page 21, 2nd para through page 23, 3rd para) that claims are patentable at Step 2A/Prong Two, due to technological improvements.
To response, the argument is not persuasive. The argued practical applications, such as:
“An improvement to another technology: determining whether a subject that is or has been afflicted with a cancer is responsive to a cancer drug” (page 21, last para) are merely prognostic information. There is no concrete, particular treatment applied to the cancer patients.
“Targeted-panel sequencing provides higher sequence coverage, it can suffer the detriment of not spanning a large enough portion of the genome to accurately estimate tumor fraction. While whole genome sequencing spans a large enough portion of the genome, it can lack adequate sequence coverage. The instant claims address this problem by using sequence reads that are targeted by probes (and thus have high coverage) as well as sequence reads that are not targeted by probes. In this way, the claimed plurality of sequence reads have the best of both worlds: regions that have ample coverage as well as numerous additional regions albeit at lower coverage” (page 22, 2nd para). This is not a convincing advantage. Inventor has to balance in reading coverage and reading depth due to NGS budget. It is obvious that if instant invention can get extra sequence reads outside the targets, other researchers can too. If Inventor need more coverage in NGS, why not design more probes targeting more targets at the beginning? Doing so can achieve wider coverage in a more controlled way. After all, there is no additional element that applies, captures and reflect this technical merit.
“The claims combines copy number variation, somatic variation allele frequency and difference in B-allele frequency of germline frequency to provide a more accurate and robust tumor fraction” (page 22, last para). First it is the “copy number” not the “copy number variation” recited in instant claim 1. Second including these information in ctFE estimation merely reads on better data analysis. There is no additional element that applies, captures and reflect this technical merit.
“Maintaining, modifying, or adjusting the subject’s cancer treatment regimen” (page 23, 2nd para) are merely implied in the “final tumor fractional estimate for the subject”, or part of the information embedded in a model output. “Maintaining, modifying, or adjusting the subject’s cancer treatment regimen” are not actively performed. . There is no concrete, particular treatment based on the aggregated estimate of ctFE.
In summary, instant claim 1 does not have any additional element to apply, to capture, and to reflect the judicial exceptions. The argued technical improvements, are merely better data analysis, which is still part of the judicial exception. There is integration into a practical application at Step 2A/Prong Two.
Therefore, the 101 rejection is maintained.
Conclusion
No claims are allowed.
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/GL/
Patent Examiner
Art Unit 1686
/Anna Skibinsky/
Primary Examiner, AU 1635