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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/20/2026 has been entered.
Application Status
This action is written in response to applicant’s correspondence received on 4/20/2026. Claims 1-3, 6-9, 13, and 17-26 are pending. Claims 1-3, 6-9, 13, and 17-21 have been amended. Claims 4-5. 10-12, 14-16, and 27-28 have been cancelled. Note that claim 29 has been removed from the claim set, but has not been designated “cancelled” in the claims. The removal of claim 29 from the present claim set is being interpreted to mean that it has been cancelled. In the response, applicants are required to confirm the cancelled status of claim 29. All pending claims are currently under examination.
Claim Objections
Claim 7 is objected to because of the following informalities:
Claim 7 recites “comparing the the product” in step “e.” Claim 7 should be amended to read “comparing the product.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112 – New Rejection
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.
Claims 17-21 are 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.
Regarding claims 17-18, these claims recite an increased or decreased risk, respectively. Claim 17 and 18 are indefinite because no specific risk is recited. It is therefore unclear what the subjects are at risk for, and furthermore the metes and bounds of the claims are unclear, as it is unclear how “risk” would be determined without reciting what the subjects are at risk of. It is noted that claim 1 on which claims 17 and 18 depend does not recite any risk.
Regarding claim 19, claim 19 recites that “the determining a monitoring regimen comprises determining the amount…or suggesting such monitoring to the subject.” Claim 19 is therefore directed to determining a monitoring regimen. It is unclear how “suggesting such monitoring to the subject” would constitute “determining a monitoring regimen.” Claim 19 is written in the alternative form, where determining of the monitoring regimen comprises taking measurements of amounts of DNA “or” suggesting monitoring. It is unclear how suggesting monitoring would be an embodiment of “determining” a monitoring regimen.
Regarding claims 20-21, these samples recite “time between samples for monitoring,” and therefore recites plural “samples.” Recitation of “samples,” plural, lacks proper antecedent basis because claims 20-21 depend from claim 7 which only recites that one sample is taken.
Response to Arguments
The Applicant’s arguments filed 4/20/2026 have been considered but are not persuasive. The Applicant argues that their amendments obviate the 112(b) issue. This argument is not persuasive because claims 20-21 still contain antecedent basis issues as they recite plural “samples” but depend from a claim only drawn to one sample.
Claim Rejections - 35 USC § 101 – Maintained/Updated in Response to 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 1-3, 6-9, 13, and 17-26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to naturally occurring phenomenon without significantly more.
Regarding claim 1, claim 1 recites a method of assaying cell-free DNA (cf-DNA) in a sample from a transplant subject, the method comprising a) extracting cell-free DNA from the sample, b) preparing a preparation of amplified DNA by performing PCR amplification on the cf-DNA obtained in a), c) quantifying an amount of donor-specific cell-free DNA (DS cfDNA) and an amount of total cell-free DNA in the preparation, d) determining a product of the amount of DS cf- DNA and the amount of total cf-DNA; and e) comparing the product, the amount of DS-cfDNA, and the amount of total cf-DNA in the sample each to a respective threshold or value from a sample taken from the subject at a prior time point. Thus, claim 1 recites steps of data manipulation and analysis, where such steps are judicial exceptions because they recite an abstract concept (i.e., a mathematical relationships in the form of a product of two numbers, where the values in the method are compared to other numbers). With regards to Step 1 of the Subject Matter Eligibility Test (MPEP 2106), claim 1 recites a process. Regarding Step 2A, prong I, claim 1 recites the abstract concept of a mathematical relationship (MPEP 2106.04(a)(2)). Regarding Step 2A, prong II, claim 1 recites the additional elements of extracting, preparing, and quantifying DNA in a sample. However, with regards to Step 2A, prong II, the action of determining the level of a biomarker in blood is mere data gathering and amounts to insignificant extra-solution activity per MPEP 2106.05(g). Furthermore, MPEP 2106.05(g) states that performing clinical tests to obtain input for an equation, as recited in claim 1, is also mere data gathering and amounts to insignificant extra-solution activity Thus, the additional elements recited in claim 1 do not integrate the subject matter into a practical application because no specific, non-general, actionable step is recited in the method claim of claim 1.
Regarding Step 2B, the limitations of extracting, preparing, and quantifying cell-free DNA from a sample and determining the amount of DS cf-DNA and total cf-DNA amounts to “determining the level of a biomarker in blood by any means,” which MPEP 2106.05(d) section II states is an example of well-understood, routine, conventional activity. Furthermore, detecting DNA in a sample using PCR is also offered as an example of well-understood, routine, conventional activity per MPEP 2106.05(d) section II. Thus, with regards to Step 2B, the additional elements recited in claim 1 do not amount to significantly more than the judicial exception recited, as the additional steps are well-understood, routine, and conventional per MPEP 2106.05(d). Claim 1 is therefore directed to a judicial exception without significantly more and is rejected under 35 USC 101.
Regarding claims 2-3, these claims recite the judicial exceptions of claim 1. Claim 2 further recites that additional products are calculated from a sample taken from the subject at different time points, and claim 3 recites that samples are taken monthly or bi-monthly. Claims 2-3 therefore recite the abstract mental process of performing a mathematical operation (Step 2A, prong I). Claims 2-3 recite the additional element that the products are calculated from sample derived from a subject at different timepoints. However, recitation of the limitation that the sample is taken over time does not integrate the judicial exception into a practical application because determining the level of a biomarker in blood is mere extra-solution activity (Step 2A, prong II, MPEP 2106.05(g)). Claims 2-3 furthermore do not recite limitations which transform the claim into significantly more because such a steps as collecting a patient sample to measure a biomarker/using PCR to detect DNA are simply a routine data gathering step that is well-understood and known in the art per MPEP 2106.05(d) (Step 2B). Claims 2-3 are therefore drawn to patent ineligible subject matter and are rejected under 35 USC 101.
Regarding claim 6, claim 6 recites the additional judicial exception of “determining and/or assigning a risk to the subject based on the comparisons.” Thus, claim 6 is drawn to the abstract mental process of “determining/assigning” and “comparing,” (Step 2A, prong I). Claim 6 does not recite any additional elements (Step 2A, prong II, and Step 2B). Claim 6 is therefore rejected under 35 USC 101.
Regarding claim 7, claim 7 recites the judicial exceptions of “determining” and “comparing” values/products (i.e., mathematical calculations and relationships) and “determining a treatment or monitoring regimen for a subject.” These are judicial exceptions because they are drawn to mental processes (Step 2A, prong I). Claim 7 recites the additional elements of extracting, preparing using PCR, and quantifying cell-free DNA in a sample from the transplant subject and performing an assay to determine the amount of DS cf-DNA and total cf-DNA. However, these limitations do not integrate the subject matter into a practical application nor transform the claim into significantly more than the recited judicial exception because the remaining elements of the claim amount to mere routine data-gathering steps which are merely extra-solution activity (i.e., determining a biomarker present in blood, performing clinical test to obtain input for an equation, Step 2A, prong II, MPEP 2106.05(g)) that is well-understood in the art (Step 2B, 2106.05(d) section II, which states that determining a biomarker in blood is routine by any means, and measuring DNA using PCR is also routine). Furthermore, recitation of “determining a treatment” lacks specificity and is overly general and therefore does not amount to significantly more than the judicial exception, and furthermore does not recite any actionable steps of a specific treatment (MPEP 2106). Claim 7 is therefore rejected under 35 USC 101.
Regarding claims 8 and 9, these claims simply recite obtaining a sample from a subject to measure a biomarker, with the judicial exceptions of determining a product (i.e., a mathematical relationship). These claims are therefore drawn to the judicial exceptions of claim 7 (Step 2A, prong I). Claims 8 and 9 recite the additional element of obtaining DNA from a subject at timepoints, which is simple extra-solution activity in the form of data gathering (Step 2A, prong II, see claim 7 rejection). Thus, claims 8 and 9 do not recite additional elements which integrate the judicial exceptions into a practical application. Claims 8-9 do not recite additional elements which transform the claims into significantly more than the judicial exceptions, as such data gathering to measure a biomarker in blood is routine, well-understood, and conventions per MPEP 2106.05(d) section II (Step 2B). Claims 8 and 9 are therefore rejected under 35 USC 101.
Regarding claim 13, claim 13 recites the judicial exceptions of claim 7 (Step 2A, prong I). Claim 13 recites the additional element of recording the products in a database or a report. However, recitation of this claim limitation amounts to mere extra-solution activity and does not integrate the judicial exception into a practical application or transform the claim into significantly more than the judicial exception (Steps 2A, prong II, Step 2B). Claim 13 is therefore rejected under 35 USC 101.
Regarding claims 17 and 18, these claims recite the judicial exceptions of relating a product value to another mathematical value (“thresholds”) as well as the relationship of such values. Claims 17 and 18 are therefore drawn to the judicial exception of abstract mathematical relationships and relating such relationships (a mental process) to risk characteristics (Step 2A, prong I). Claims 17 and 18 do not recite any additional elements (Steps 2A prong II and Step 2B). Claims 17 and 18 are therefore drawn to judicial exceptions without additional claim limitations and are rejected under 35 USC 101.
Regarding claim 19, claim 19 recites the judicial exception of “determining” a monitoring regimen based on the product of two values, or simply suggesting such monitoring. Claim 19 is therefore broadly drawn to the abstract mental process of “determining” (Step 2A, prong I). Claim 19 further recites determining the product of two values, which is an additional judicial exception because it relates to an abstract mental process/mathematical relationship (Step 2A, prong I). Claim 19 recites the additional element of suggesting monitoring in a subject; however, such claim language is recited broadly without specificity and therefore neither integrates the judicial exceptions into a practical application nor transforms the claim into significantly more than the judicial exceptions recited (Steps 2A prong II and Step 2B). Claim 19 is therefore rejected under 35 USC 101.
Regarding claims 20-21, these claims recite the judicial exceptions of claim 7 (Step 2A, prong I). Furthermore, these claims merely recite extra-solution activity in the form of routine data gathering (Steps 2A prong II and Step 2B). These claims therefore do not integrate the judicial exceptions into a practical application or transform the claim into patent eligible subject matter under 35 USC 101.
Regarding claim 22, claim 22 recites the judicial exceptions of claim 7 (Step 2A, prong I). Claim 22 is further most broadly interpreted to simply recite “suggesting” the use of an additional test. Recitation of “suggesting the use” of an additional test does not amount to a practical application of the judicial exceptions recited, as no actionable step is required by the claim (Steps 2A prong II). Furthermore, no specific “use” of an additional test is recited; the claim language is therefore lacking in specificity and does not transform the judicial exception into significantly more (Step 2B). Thus, claim 22 is simply drawn to the judicial exceptions of claim 1 and is not patentable subject matter under 35 USC 101.
Regarding claim 23, claim 23 recites the judicial exceptions of claim 7. Claim 23 is further most broadly interpreted to simply comprise “suggesting” a treatment. Recitation of “suggesting a treatment for the subject” does not amount to a practical application of the judicial exceptions because no actionable step is required by the claimed method (Step 2A, prong II). Furthermore, no specific “suggestion” of a treatment is recited; the claim language is therefore lacking in specificity and does not transform the judicial exception into significantly more (Step 2B). Thus, claim 23 is simply drawn to the judicial exceptions of claim 1 and is not patentable subject matter under 35 USC 101.
Regarding claims 24 and 25, these claims recite the judicial exceptions of claim 7 (Step 2A, prong I). Claim 24 recites the additional element of treating the subject in an attempt to integrate the judicial exception into a practical application. Claim 25 recites the additional element of providing information about a treatment to a subject. However, as outlined in MPEP section 2106.04(d)(2), these claim limitations are not sufficiently particular to a degree that would warrant the disclosed invention to be labeled as subject matter eligible. As currently written, claims 24 and 25 recite no specific and particular treatment and/or information provided to a subject which would transform the judicial exceptions into patent eligible subject matter, and therefore lack a practicable, actionable step. Recitation of “treating the subject” (claim 24) and “providing information about a treatment to the subject” (claim 25) is recited with a high level of generality, which does not qualify as integration into a practical application (Step 2A, prong II, see MPEP 2106.04(d)(2)). Furthermore, the additional elements recited are not significantly more because they simply append well-understood, routine, conventional activities previously known in the art (see MPEP 2106.05). Claims 24 and 25 are therefore rejected under 35 USC 101.
Regarding claim 26, claim 26 recites the judicial exceptions of claim 1 (Step 2A, prong I). Claim 26 further specifies that the sample is blood, plasma, or serum. However, recitation of the collection of a blood sample from a surgery patient simply amounts to a routine data-gathering step to determine the level of a biomarker and is therefore not integrated into a practical application because it is mere extra solution activity per MPEP 2106.05(g), “mere data-gathering step.” The additional limitations do not amount to significantly more than the recited judicial exceptions as such routine sample collection is routine in the art (MPEP 2106.05(d), section II, which recites that detection of a biomarker in blood and using PCR to amplify DNA are routine and well-understood).
Response to Arguments
The Applicant’s arguments submitted 4/20/2026 have been considered but are not persuasive. The Applicant argues that the presently amended claims are subject matter eligible, as they recite the steps of extracting DNA, making a preparation of DNA (using PCR, as recited in the claims) and quantifying DNA. This argument is not persuasive because the method claims are drawn to a judicial exception, namely, determining a product and comparing the product to other threshold values. The additional limits of the claim are drawn to mere-extra solution activity as recited in the MPEP, where such limits are furthermore routine and well-understood. In the case of the claims, MPEP 2106.05(g), determining the level of a biomarker in blood amounts to insignificant extra solution activity as it is mere data gathering (Step 2A, prong II). As such, the method is not integrated into a practical application as additional, specific, actionable steps are recited in the claim. Furthermore, MPEP 2106.05(d) makes clear that such steps as measuring a biomarker and detecting DNA using PCR are routine and well-understood (Step 2B); as such, the judicial exceptions recited in the claims are not transformed into significantly more. Thus, per the MPEP, and with respect to the subject matter which is presently recited in the claims, the invention is patent-ineligible.
The Applicant argues that the claims are integrated into a practical application. This argument is not persuasive. As presently recited, the mere fact that tangible steps are present in the claims is not sufficient to integrate the judicial exception into a practical application because the tangible steps, under Step 2A prong II analysis, are insignificant extra-solution activity as the steps of measuring a biomarker in blood is stated in the MPEP, section 2106.05(g), as being a mere data-gathering step. Thus, the mere presence of a tangible step is not sufficient to claim that the method is integrated into a practical application. Additionally, MPEP 2106.04(d) section II states:
“It is notable that mere physicality or tangibility of an additional element or elements is not a relevant consideration in Step 2A Prong Two. As the Supreme Court explained in Alice Corp., mere physical or tangible implementation of an exception does not guarantee eligibility.”
In the present case, assaying a biomarker in blood is considered insignificant extra solution activity (MPEP 2106).
The Applicant argues that the claim has not been considered as a whole, and states that when considered as a whole the claims are eligible. The Applicant argues that, as a whole, the claim is eligible because it is integrated into a practical application by reciting that DNA is assayed. This argument is not persuasive because, as discussed above, the claim has been considered as a whole, where the claim recites judicial exceptions of mental processes and mathematical relationships, where the additional elements of the claim amount to mere data gathering steps and are not integrated into a practical application (Step 2A, prong II) and furthermore such data gathering steps as assaying a biomarker in blood and using PCR to detect DNA are routine and well-understood (Step 2B). Thus, the claim and its elements have been evaluated as a whole and determined to be patent-ineligbile following the MPEP guidelines.
Claim Rejections - 35 USC § 102 – Updated in Response to Amendment
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 6-9, 13, and 17-26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Beck (US 11,155,872 B2, original publication date of US 2018/0346982 A1 12/6/2018).
Regarding claim 1, Beck is a patent document that teaches a method of evaluating cell-free DNA in transplant patients (Title, Abstract, and see document). Beck teaches a method of assaying a sample from a transplant subject, the method comprising extracting cell-free DNA from a sample and amplifying the cell-free DNA using PCR (column 19, final paragraph “Extraction of cfDNA” and column 20, “For the quantification of total cfDNA, two non- SNP specific assays of single copy genes were used in ddPCR”). Beck teaches quantifying an amount of donor-specific cfDNA and total cfDNA (column 20, third paragraph). Beck teaches determining a product of an amount of donor-specific cell-free DNA (called “GcfDNA” in Beck) and an amount of total cf-DNA in the sample (column 20, third paragraph). Beck teaches: “the GcfDNA was the[sic] calculated by multiplying the GcfDNA [ % ] with the cfDNA [cp/mL] divided by the extraction efficiency of the internal standard,” (column 20, third paragraph). Beck therefore teaches “determining a product” of an amount of donor-specific cell free DNA and an amount of total cell-free DNA because the calculation taught by Beck involves multiplying DS cf-DNA and cell-free DNA, which is broadly encompassed by the claim. Beck teaches comparing the product (in the case of Beck, the product yields whole-value copy number of DS cfDNA) and the amount of DS-cfDNA (as a percentage) to a value taken from a subject from prior time points (see figure 9, where GcfDNA as copy number and as a percentage are graphed over a time course study, which compares the values taken from a subject from a prior time point). Furthermore, the calculation to determine the copy/mL amount of GcfDNA requires first calculating the total cfDNA (column 20, third paragraph); thus, the method taught by Beck inherently requires calculating total cfDNA and comparing it over time to previous values in order to generate, for instance, the graph of Figure 9.
Regarding claim 2, Beck teaches determining GcfDNA products at different points in time (column 4, second paragraph).
Regarding claim 3, Beck teaches determining one or more further products (i.e., GcfDNA measurements, per Beck) from samples taken from the subject monthly or bimonthly (column 11, third paragraph).
Regarding claim 6, Beck teaches that the percentage of GcfDNA can indicate complications/organ rejection (i.e., risks) when compared to a threshold (“the mean, typically 2SD,” column 11, third paragraph). Thus, Beck teaches that comparing the values that they calculate can be used to assess risk.
Regarding claim 7, limitations a) to e) of claim 7 are identical to claim 1 and are discussed in the rejection of claim 1. Beck teaches that GcfDNA analysis can be used to adjust treatment regimens, where determining such treatment is accomplished by monitoring multiple cfDNA samples taken over time (e.g., column 12, second paragraph). Beck also teaches that the calculation of graft cf-DNA is used in their methods to analysis the status of transplant patients (e..g, Example 4). A practitioner could therefore immediately envision using the values calculated by Beck to determine a treatment or monitoring regimen.
Regarding claim 8, Beck teaches obtaining samples from multiple timepoints (column 12, second paragraph).
Regarding claim 9, Beck teaches that sampling can be performed every two weeks (i.e., bimonthly, column 12, second paragraph).
Regarding claim 13, Beck teaches recording results because the document itself is a record of the experiments conducted (e.g., see Figure 9). Furthermore, Beck teaches long-term monitoring of patients as well as results from patient samples; a practitioner of ordinary skill could therefore at once envision that such results – which deal with critical patient medical information – could be formulated into a report (column 12, second and third paragraphs). Furthermore, Beck teaches that information obtained from biomarker analysis can be stored in a computer, which reasonably can be interpreted to be a database (column 12, fourth paragraph).
Regarding claim 17, Beck teaches that a product value (“GcfDNA,” per Beck) is associated with an increased risk when over a threshold (column 11, third paragraph). A practitioner could therefore immediately envision that the calculations made by Beck can be used to assess an increased risk, as Beck teaches the association between increased GcfDNA and risk, where values such as the total cfDNA, GcfDNA, and a product of cfDNA and GcfDNA are all taught by Beck.
Regarding claim 18, Beck teaches that a rise in GcfDNA in a sample is indicative of rejection as compared with “uncomplicated courses,” (column 11, third paragraph). Thus, Beck teaches that lower GcfDNA values are associated with less risk (i.e., “uncomplicated courses”). A practitioner could therefore immediately envision that the calculations made by Beck can be used to assess a decreased risk, as Beck teaches the association between increased GcfDNA and risk, where values such as the total cfDNA, GcfDNA, and a product of cfDNA and GcfDNA are all taught by Beck to be used to assess risk.
Regarding claim 19, Beck teaches that monitoring regimens can be varied over a desired period of time depending on cfDNA counts (column 12, second paragraph).
Regarding claims 20 and 21, Beck teaches that monitoring can be performed “at desired intervals,” (paragraph 12, second paragraph). Given that Beck also teaches that an increase in GcfDNA is associated with negative outcomes, a practitioner could immediately envision that sample monitoring inerval times could be decreased if an increased medical risk is present in a patient (column 11, third paragraph). Similarly, regarding claim 21, a practitioner could at once envision increased time between sample monitoring if a decreased risk is present (column 11, third paragraph through column 12).
Regarding claim 22, Beck teaches additional testing to be conducted during monitoring in conjunction with GcfDNA monitoring (e.g., bilirubin and AST biomarker testing, Figure 5).
Regarding claim 23, Beck teaches that their methods are used to adjust treatment of a patient (column 3, fourth paragraph, column 12, second paragraph).
Regarding claim 24, Beck teaches treating a subject (column 12, third paragraph, column 4, fourth paragraph).
Regarding claim 25, Beck teaches adjusting an administrative schedule or dosage or one or more drugs (column 4, fourth paragraph). Given that Beck teaches that the administrative schedule of a drug is changed, it is reasonable to say that Beck teaches providing information about a treatment to a subject, who would be made aware of the administrative schedule change of the drug (column 4, fourth paragraph).
Regarding claim 26, Beck teaches that the sample can be a blood sample (column 11, third paragraph).
Response to Arguments
The Applicant’s arguments filed 4/20/2026 have been considered but are not persuasive. The Applicant argues that the amendments are sufficient to obviate the 102 rejection based on Beck, stating that Beck “does not teach all of the steps of the methods of the claims, let alone how to do so.” This argument is not found to be persuasive because Beck does teach each of the method steps (e.g., Beck does teach extracting total cfDNA, PCR-amplifying the cfDNA preparation, and calculating donor specific-cfDNA and also total cfDNA, and furthermore teaches that their method involves a calculation involving a product between the total cfDNA and donor-specific cfDNA (see Example 2 of Beck). Furthermore, Beck teaches that such samples and calculations are made over time and compared to each other by teaching a time course monitoring study using such calculations (see Figure 9). Thus, Beck anticipates the claims.
Claim Rejections - 35 USC § 103 – New Rejection
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 6-9, 13, and 17-26 are rejected under 35 U.S.C. 103 as being unpatentable over Beck (US 11,155,872 B2, original publication date of US 2018/0346982 A1 12/6/2018), as applied to claims 1-3, 6-9, 13, and 17-26 in the 102 rejection, above, and further in view of Zhong (Zhong XY et al. Ann N Y Acad Sci. 2001 Sep;945:250-7).
This 103 rejection is given in addition to the 102 rejection above. This rejection is given with regards to the interpretation that Beck does not inherently teach calculating the total amount of cfDNA in the sample and comparing it to a value taken from a previous timepoint. Thus, this 103 rejection is given in the interest of compact prosecution, as it was also already known in the art as taught by Zhong that calculating the total cell-free DNA and comparing it to values over time after transplantation is a known and useful measurement/technique (see below).
Regarding claim 1, Beck is a patent document that teaches a method of evaluating cell-free DNA in transplant patients (Title, Abstract, and see document). Beck teaches a method of assaying a sample from a transplant subject, the method comprising extracting cell-free DNA from a sample and amplifying the cell-free DNA using PCR (column 19, final paragraph “Extraction of cfDNA” and column 20, “For the quantification of total cfDNA, two non- SNP specific assays of single copy genes were used in ddPCR”). Beck teaches quantifying an amount of donor-specific cfDNA and total cfDNA (column 20, third paragraph). Beck teaches determining a product of an amount of donor-specific cell-free DNA (called “GcfDNA” in Beck) and an amount of total cf-DNA in the sample (column 20, third paragraph). Beck teaches: “the GcfDNA was the[sic] calculated by multiplying the GcfDNA [ % ] with the cfDNA [cp/mL] divided by the extraction efficiency of the internal standard,” (column 20, third paragraph). Beck therefore teaches “determining a product” of an amount of donor-specific cell free DNA and an amount of total cell-free DNA because the calculation taught by Beck involves multiplying DS cf-DNA and cell-free DNA, which is broadly encompassed by the claim. Beck teaches comparing the product (in the case of Beck, the product yields whole-value copy number of DS cfDNA) and the amount of DS-cfDNA (as a percentage) to a value taken from a subject from prior time points (see figure 9, where GcfDNA as copy number and as a percentage are graphed over a time course study, which compares the values taken from a subject from a prior time point). Furthermore, the calculation to determine the copy/mL amount of GcfDNA requires first calculating the total cfDNA (column 20, third paragraph); thus, the method taught by Beck inherently requires calculating total cfDNA and comparing it over time to previous values in order to generate, for instance, the graph of Figure 9. Beck teaches that the transplant monitoring can be associated with kidney transplants (column 4, fourth paragraph).
While Beck teaches calculating total cfDNA, and the value of cfDNA is used to generate GcfDNA calculations which are compared to values from previous timepoints in Figure 9, where the total cfDNA value is inherently part of the calculation and could be derived from the graph of Figure 9 given the equation provided by Beck in column 20, third paragraph, it could be argued that Beck does not explicitly teach comparing total cfDNA values to values taken from a prior time point.
Nonetheless, Zhong is a research article that focuses on calculating cell-free DNA in transplant patients to assess health risks (Title, Abstract, and throughout). Zhong and Beck therefore directly overlap in subject matter, goal, and design, because they both focus on monitoring cell-free DNA in transplant patients, where both teach monitoring kidney transplant patients. Furthermore, Zhong teaches that total cell-free DNA can be monitored over time and compared to previous values, where useful correlations can be drawn when comparing total cell-free DNA, donor-specific DNA, and drug treatments (e.g., see page 253, final two paragraphs). Thus, Zhong teaches that it is not only a known technique to monitor total cell-free DNA in a transplant patient over time, but also that such measurement and monitoring provides useful post-transplantation information (page 253, final two paragraphs).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the cell-free DNA quantification and measurement methods of Beck to include comparing total cell-free DNA levels to prior samples as taught by Zhong because such a method is the simple combination of known prior art elements with predictable results. Furthermore, in this particular case, the combination is not merely the combination of elements: a practitioner would be motivated to include the total cell-free DNA comparisons over time because Zhong teaches that such total cell-free DNA tracking provides useful medical information in the context of kidney transplantation. Furthermore, the results are predictable because 1) Zhong and Beck are quantifying the same types of materials (i.e., cell-free DNA) and 2) the methods of Beck in fact already require measuring total cell-free DNA. Thus, the practitioner would simply be using data from a calculation which they have already made in the methods of Beck in order to follow the suggestions of Zhong.
Regarding claim 2, Beck teaches determining GcfDNA products at different points in time (column 4, second paragraph). Furthermore, Zhong teaches tracking total cell-free DNA over time to monitor drug treatment (“we also observed a striking elevation in the level of total cell-free DNA to greater than 65,000 copies per mL, which receded rapidly following antirejection treatment,” page 253, final paragraph).
Regarding claim 3, Beck teaches determining one or more further products (i.e., GcfDNA measurements, per Beck) from samples taken from the subject monthly or bimonthly (column 11, third paragraph).
Regarding claim 6, Beck teaches that the percentage of GcfDNA can indicate complications/organ rejection (i.e., risks) when compared to a threshold (“the mean, typically 2SD,” column 11, third paragraph). Thus, Beck teaches that comparing the values that they calculate can be used to assess risk.
Regarding claim 7, limitations a) to e) of claim 7 are identical to claim 1 and are discussed in the rejection of claim 1. Beck teaches that GcfDNA analysis can be used to adjust treatment regimens, where determining such treatment is accomplished by monitoring multiple cfDNA samples taken over time (e.g., column 12, second paragraph). Beck also teaches that the calculation of graft cf-DNA is used in their methods to analyze the status of transplant patients (e..g, Example 4). A practitioner could therefore immediately envision using the values calculated by Beck to determine a treatment or monitoring regimen.
Regarding claim 8, Beck teaches obtaining samples from multiple timepoints (column 12, second paragraph).
Regarding claim 9, Beck teaches that sampling can be performed every two weeks (i.e., bimonthly, column 12, second paragraph).
Regarding claim 13, Beck teaches recording results because the document itself is a record of the experiments conducted (e.g., see Figure 9). Furthermore, Beck teaches long-term monitoring of patients as well as results from patient samples; a practitioner of ordinary skill could therefore at once envision that such results – which deal with critical patient medical information – could be formulated into a report (column 12, second and third paragraphs). Furthermore, Beck teaches that information obtained from biomarker analysis can be stored in a computer, which reasonably can be interpreted to be a database (column 12, fourth paragraph).
Regarding claim 17, Beck teaches that a product value (“GcfDNA,” per Beck) is associated with an increased risk when over a threshold (column 11, third paragraph). A practitioner could therefore immediately envision that the calculations made by Beck can be used to assess an increased risk, as Beck teaches the association between increased GcfDNA and risk, where values such as the total cfDNA, GcfDNA, and a product of cfDNA and GcfDNA are all taught by Beck.
Regarding claim 18, Beck teaches that a rise in GcfDNA in a sample is indicative of rejection as compared with “uncomplicated courses,” (column 11, third paragraph). Thus, Beck teaches that lower GcfDNA values are associated with less risk (i.e., “uncomplicated courses”). A practitioner could therefore immediately envision that the calculations made by Beck can be used to assess a decreased risk, as Beck teaches the association between increased GcfDNA and risk, where values such as the total cfDNA, GcfDNA, and a product of cfDNA and GcfDNA are all taught by Beck to be used to assess risk.
Regarding claim 19, Beck teaches that monitoring regimens can be varied over a desired period of time depending on cfDNA counts (column 12, second paragraph).
Regarding claims 20 and 21, Beck teaches that monitoring can be performed “at desired intervals,” (paragraph 12, second paragraph). Given that Beck also teaches that an increase in GcfDNA is associated with negative outcomes, a practitioner could immediately envision that sample monitoring inerval times could be decreased if an increased medical risk is present in a patient (column 11, third paragraph). Similarly, regarding claim 21, a practitioner could at once envision increased time between sample monitoring if a decreased risk is present (column 11, third paragraph through column 12).
Regarding claim 22, Beck teaches additional testing to be conducted during monitoring in conjunction with GcfDNA monitoring (e.g., bilirubin and AST biomarker testing, Figure 5).
Regarding claim 23, Beck teaches that their methods are used to adjust treatment of a patient (column 3, fourth paragraph, column 12, second paragraph).
Regarding claim 24, Beck teaches treating a subject (column 12, third paragraph, column 4, fourth paragraph).
Regarding claim 25, Beck teaches adjusting an administrative schedule or dosage or one or more drugs (column 4, fourth paragraph). Given that Beck teaches that the administrative schedule of a drug is changed, it is reasonable to say that Beck teaches providing information about a treatment to a subject, who would be made aware of the administrative schedule change of the drug (column 4, fourth paragraph).
Regarding claim 26, Beck teaches that the sample can be a blood sample (column 11, third paragraph).
Conclusion
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/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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