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 .
Response to Amendment
The amendment filed November 18th, 2025 is acknowledged. Regarding the Office Action mailed August 19th, 2025:
The objections to the specification are withdrawn in view of the amendments.
The rejection set forth under 35 U.S.C. 112(b) is withdrawn in view of the amendments.
Maintained or modified rejections are set forth below. Responses to arguments, if necessary, follow their respective rejection sections.
Claim Summary
Claims 17, 27, and 31 have been amended. Claims 32 and 39-46 have been canceled. Claims 1-31 and 33-38 are pending. Claims 1-16, 18-19, and 21-25 are withdrawn from consideration as being drawn to a non-elected invention/species. Claims 17, 20, 26-31, and 33-38 are under examination and discussed in this Office action.
Claim Rejections - 35 USC § 101 – Modified – Necessitated by 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 17, 20, 26-31, and 33-38 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and also natural phenomena without significantly more. While the claims are directed to a process, and therefore meet step 1 of the subject matter eligibility test (see MPEP 2106.03), claims 17 and 20 recite the mental process of determining a B-cell fraction with an equation, with claims 26-31 and 33 having inconsequential steps to integrate the judicial exception of the mental process into a practical application. Dependent claims 34-38 further recite the natural correlation between B-cell fraction and disease, which also does not integrate the judicial exception of the mental process into a practical application. The mental process is an abstract idea because the equation can reasonably be performed in the human mind. The natural correlation is a natural phenomenon because it describes a consequence of natural processes in the human body (e.g. B cell fraction as it relates to disease).
Step 2A of the subject matter eligibility test requires a two-pronged analysis. Prong One asks: does the claim recite an abstract idea, law of nature or natural phenomenon? As discussed in MPEP 2106.04(II)(A)(1), the meaning of “recites” is “set forth” or “describes”. That is, a claim recites a judicial exception when the judicial exception is “set forth” or “described” in the claim. In the instant case, the claims describe an abstract idea and a natural phenomenon: the mental process of determining a B-cell fraction with an equation and the natural correlation between B-cell fraction and disease.
Prong Two of the analysis under step 2A asks: does the claim recite additional elements that integrate the judicial exception into a practical application of the judicial exception? As discussed in MPEP 2106.04(II)(A)(2), “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"); Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself."). For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B.” The considerations to be used are set forth at MPEP 2106.05(a) through (c) and (e) through (h). Turning to those sections of the MPEP:
MPEP 2106.05(a) has to do with improvements to the functioning of a computer or to any other technology or technical field. The claims at issue do not improve the functioning of a computer or other technology. While the instant claims recite steps of quantifying a diploid reference markers and a B-cell DNA marker with digital PCR; determining a VDJ rearranged human B-cell fraction via the equation B-cell fraction = 1-([B-cell DNA marker]/[diploid reference DNA marker]); quantifying a class-switched B-cell DNA marker, and determining a fraction of class-switched VDJ rearranged human B-cell fraction; the VDJ rearranged human B-cells expressing a B-cell receptor or an antibody; specific options for the diploid reference; the sample originating from or comprising malignant cells or cells with DNA copy number instability; the sample comprising DNA with chromosome 14q copy number alterations; specific sample options; specific assays; and the method being for monitoring disease, determining medicament, disease prognosis, or diagnosing a disease, with options of the disease, the claims do not improve upon PCR techniques or general mathematics. The claims merely use existing methods for these steps. Note that MPEP 2106.05(a) indicates that “[u]sing well-known standard laboratory techniques to detect enzyme levels in a bodily sample” is an example that the courts have indicated may not be sufficient to show an improvement to technology.
MPEP 2106.05(b) has to do with whether the claims involve the use of a particular machine. In this case, the claims do not involve the use of a particular machine. While the instant claims recite steps of quantifying a diploid reference markers and a B-cell DNA marker with digital PCR; determining a VDJ rearranged human B-cell fraction via the equation B-cell fraction = 1-([B-cell DNA marker]/[diploid reference DNA marker]); quantifying a class-switched B-cell DNA marker, and determining a fraction of class-switched VDJ rearranged human B-cell fraction; the VDJ rearranged human B-cells expressing a B-cell receptor or an antibody; specific options for the diploid reference; the sample originating from or comprising malignant cells or cells with DNA copy number instability; the sample comprising DNA with chromosome 14q copy number alterations; specific sample options; specific assays; and the method being for monitoring disease, determining medicament, disease prognosis, or diagnosing a disease, with options of the disease, no such machines are required by the claim, and certainly no particular machines. Even if some conventional machine were recited in the claims, like a specific PCR machine, further considerations such as the particularity or generality of the recited machine must be taken into account, as well as whether the involvement of the machine is merely extra-solution activity. MPEP 2106.05(g) describes “extra-solution activity”, noting that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra-solution activity.
MPEP 2106.05(c) has to do with whether the claims involve a particular transformation. Here, none of the limitations of the claims involve a particular transformation. For example, the quantifying of DNA markers does not turn those DNA markers into something else during the quantification process.
MPEP 2106.05(e) has to do with “other meaningful limitations”. The additional limitations imposed upon the mental process of determining a B-cell fraction with an equation and the natural correlation between B-cell fraction and disease in the instant case have to do with quantifying a diploid reference markers and a B-cell DNA marker with digital PCR; determining a VDJ rearranged human B-cell fraction via the equation B-cell fraction = 1-([B-cell DNA marker]/[diploid reference DNA marker]); quantifying a class-switched B-cell DNA marker, and determining a fraction of class-switched VDJ rearranged human B-cell fraction; the VDJ rearranged human B-cells expressing a B-cell receptor or an antibody; specific options for the diploid reference; the sample originating from or comprising malignant cells or cells with DNA copy number instability; the sample comprising DNA with chromosome 14q copy number alterations; specific sample options; specific assays; and the method being for monitoring disease, determining medicament, disease prognosis, or diagnosing a disease, with options of the disease. These limitations are not considered “meaningful limitations”. MPEP 2106.05(e) states: “The phrase "meaningful limitations" has been used by the courts even before Alice and Mayo in various contexts to describe additional elements that provide an inventive concept to the claim as a whole.” However, as has been discussed, they represent insignificant extra-solution activity, i.e. “data gathering”.
MPEP 2106.05(f) raises the question as to whether the additional elements recited in the claim represent “mere instructions to apply an exception”. Here, the judicial exceptions are the mental process of determining a B-cell fraction with an equation and the natural correlation between B-cell fraction and disease. The additional elements recited in the claims (i.e. quantifying a diploid reference markers and a B-cell DNA marker with digital PCR; determining a VDJ rearranged human B-cell fraction via the equation B-cell fraction = 1-([B-cell DNA marker]/[diploid reference DNA marker]); quantifying a class-switched B-cell DNA marker, and determining a fraction of class-switched VDJ rearranged human B-cell fraction; the VDJ rearranged human B-cells expressing a B-cell receptor or an antibody; specific options for the diploid reference; the sample originating from or comprising malignant cells or cells with DNA copy number instability; the sample comprising DNA with chromosome 14q copy number alterations; specific sample options; specific assays; and the method being for monitoring disease, determining medicament, disease prognosis, or diagnosing a disease, with options of the disease) do amount to mere instructions to apply the correlation, since the process of these claims serve as mere conventional steps taken for the purpose of gathering data related to the B-cell fraction, which any practical use of the natural correlation would require.
MPEP 2106.05(g) has to do with whether the additional elements of the claim amount to insignificant extra-solution activity. MPEP 2106.05(g) notes that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra - solution activity. Likewise, MPEP 2106.05(g) notes that “[p]erforming clinical tests on individuals to obtain input for an equation” also represents insignificant extra-solution activity. This aligns closely with the instant claims, where the additional elements of the claims amount to quantifying DNA markers with digital PCR, using those markers in an equation to determine B-cell fraction, and further using the fraction to determine an aspect of disease.
MPEP 2106.05(h) has to do with whether the additional elements amount to more than generally linking the use of a judicial exception to a particular technological environment or field of use. Here, the recitation of the method being used to quantify a B-cell fraction is considered a “field of use”. However, as MPEP 2106.05(h) indications, such limiting to a particular “field of use” does not confer patentability on otherwise ineligible subject matter.
Having considered the factors discussed in MPEP 2106.05 (a)-(c) and (e)-(h), it is clear that the additional elements recited in the claims, whether considered individually or as a combination, do not integrate the judicial exceptions into a practical application of those exceptions in such a way as to provide meaningful limits on the use of the judicial exceptions. Therefore, claims 17, 20, 26-31, and 33-38 are rejected here under 35 U.S.C. 101.
Response to Arguments
Applicant's arguments filed November 18th, 2025 have been fully considered but they are not persuasive.
The Applicant first summarizes the Examiner’s previous rejection (Page 12 of the Remarks filed November 18th, 2025). The Applicant then summarizes aspects of case law related to Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011), arguing that given this case law, pending claims satisfy 35 U.S.C. 101 if they recite a concrete, physical step (Pages 12-13 of the Remarks filed November 18th, 2025). The Applicant argues given this case law, the pending instant claims satisfy 35 U.S.C. 101 (Page 13 of the Remarks filed November 18th, 2025). The Applicant then states the amendment to claim 17 regarding quantification by digital PCR (Page 13 of the Remarks filed November 18th, 2025). The Applicant argues that the method of claim 17 requires technical steps to be performed and therefore include claim elements that render the claim non-abstract, while also arguing that the included element of digital PCR was not considered a well-known standard laboratory technique in the field (Page 13 of the Remarks filed November 18th, 2025). The Applicant argues that this is an improvement in the technical field of quantification of T- or B-cells (Page 13 of the Remarks filed November 18th, 2025). The Applicant then argues that the present claims integrate the judicial exceptions into a practical application of those exceptions because the pending claims improve the general techniques or general mathematics routinely used in the field (Page 13 of the Remarks filed November 18th, 2025). The Applicant finally argues that although the dependent claims are not specifically discussed, they should also be allowable given the allowability of the independent claim (Page 14 of the Remarks filed November 18th, 2025).
In response to these arguments, the Examiner would first like to note for the Applicant that while the case law of Classen indicates that the immunization step integrates the results of an abstract analysis into a specific and tangible method, it did so by adding a specific application of the abstract analysis. In the instant case, while there may be a concrete, physical step now included in claim 17, it does not give a specific application of the mental process previously identified. The addition of the DNA markers being quantified by digital PCR merely adds a more specific data gathering step. As cited above, MPEP 2106.05(g) describes “extra-solution activity”, noting that “[d]etermining the level of a biomarker in blood” and “[p]erforming clinical tests on individuals to obtain input for an equation” are examples of “mere data gathering” which the courts have found to be insignificant extra-solution activity. The claims as currently written amount to similar limitations.
Furthermore, while the Applicant may state that determining B-cell fraction using digital PCR is not considered a well-known technique, it is noted that reference can be found to quantifying relative representation of B-cells using digital PCR in the prior art made of record, but not relied upon, in the last Office Action. Robins (US20130288237A1; previously cited) teaches quantifying T or B cells in a complex mixture of cells that include cells which are not adaptive immune cells (Abstract). Robins teaches amplifying DNA from V-regions that encode a polypeptide for immunoglobulin (Ig) and J-regions that encode a polypeptide for Ig using multiplex dPCR (Pages 3-4, paragraph [0017]). Robins teaches comparing the number of molecules which contain rearranged DNA molecules of Ig identified by dPCR to the number of molecules which contain an internal control product identified by dPCR and quantifying the relative fraction of adaptive immune cells from the comparison (Pages 3-4, paragraph [0017]). This is further reiterated in continuations of this patent document, US20140186848A1 and US20150051089A1.
In addition, using digital PCR to quantify other immune cells is well-known in the prior art, as detailed in the following table:
Reference
Summary
Robins, Digital Genomic Quantification of Tumor-Infiltrating Lymphocytes, Science Translational Medicine, December 2013, 5, 1-7; cited on the IDS filed May 29th, 2024
Developed method called QuanTILfy to measure number of T lymphocytes using droplet digital PCR
de Lange, Digital PCR-based T Cell Quantification Assisted Deconvolution of the Microenvironment Reveals that Activated Macrophages Drive Tumor Inflammation in Uveal Melanoma, Molecular Cancer Research, August 2018, 1-29; cited on the IDS filed May 29th, 2024
Quantifies copy number stable reference gene and T-cell DNA marker using digital PCR to determine absolute T cell counts
Zoutman, Accurate Quantification of T Cells by Measuring Loss of Germline T-Cell Receptor Loci with Generic Single Duplex Droplet Digital PCR Assays, The Journal of Molecular Diagnostics, March 2017, 19, 236-243; cited on the IDS filed July 8th, 2022
Quantifies copy number stable reference gene and T-cell DNA marker using digital PCR to determine a fraction of mature T cells
Apart from these citations, it is very well known and conventional to use digital PCR to quantify DNA, which is ultimately what the method is using digital PCR for. Therefore, the use of digital PCR cannot be considered an improvement in the technical field of quantification of T- or B-cells and still serves as merely a data gathering step needed for any practical use of the judicial exceptions.
Overall, the arguments are not considered persuasive, and therefore claims 17, 20, 26-31, and 33-38 remain rejected under 35 U.S.C. 101.
Conclusion
All claims are rejected.
THIS ACTION IS MADE FINAL. 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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/ALLISON E SCHLOOP/Examiner, Art Unit 1683
/Robert T. Crow/Primary Examiner, Art Unit 1683