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 response of 02/11/2026, including replacement drawings and a substitute specification, has been received and entered into the application file.
Claims 1, 3, 15, 17, and 21 were amended in the claim set filed 02/11/2026.
Claim 2 was canceled in the claim set filed 02/11/2026.
Claims 1, 3-5, 11, 15, 17, 21, 24-26, 29, 33-36, 38, 41, and 43 are pending, of which claims 4, 5, 26, 29, 33-36, and 38 were previously withdrawn. Election was made without traverse in the reply filed on 08/04/2025
Accordingly, claims 1, 3, 11, 15, 17, 21, 24, 25, 41, and 43 are pending and under consideration.
Information Disclosure Statement
Receipt of an information disclosure statement on 02/11/2026 is acknowledged. The signed and initialed PTO-1449 has been mailed with this action.
Status of Prior Objections/Rejections
RE: Drawings
►The drawings were previously objected to for various informalities.
The amendments to the brief description of the drawings within the substitute specification and the replacement drawing sheets have obviated the basis of the prior objections. Accordingly, the objections of record are hereby withdrawn.
RE: Claim Objections
►Claims 1-3, 11, 15, 21, 24, and 25 were previously objected to for various informalities.
The amendments to the instant claim set have obviated the basis of the prior objections. Accordingly, the objections of record are hereby withdrawn. However, new objections necessitated by amendment are set forth below.
RE: Double Patenting
►Claims 1, 2, 15, 21, 41, and 43 were previously rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 4-8 of U.S. Patent No. 11,773,434 in view of WO 2016/176662 A1 (hereinafter Mitchell; as cited in the IDS filed 05/18/2022).
The cancellation of claim 2 renders the rejection thereof moot.
Applicant has traversed the rejection of record, asserting that the Office has not established that the claims of the instant application are anticipated or rendered obvious by the claims of Patent No. 11,773,434.
In response, the Examiner acknowledges that the rejection of record does not address the amendments to the instant claim set filed 02/11/2026. However, these amendments have necessitated new grounds of rejection. Accordingly, the rejection of record is hereby withdrawn, with new grounds of rejection necessitated by amendment set forth below.
►Claims 1-3, 11, 24-25, 41, and 43 were previously provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 6, 13, 17, 18, 26, and 29 of copending Application No. 17/493,293 (corresponding to US 2022/0267849 A1; as cited in the IDS filed 08/04/2025).
The cancellation of claim 2 renders the rejection thereof moot.
Applicant has traversed the rejection of record, asserting that the Office has not established that the claims of the instant application are anticipated or rendered obvious by the claims of copending Application No. 17/493,293.
In response, the Examiner acknowledges that the rejection of record does not address the amendments to the instant claim set filed 02/11/2026. However, these amendments have necessitated new grounds of rejection. Accordingly, the rejection of record is hereby withdrawn, with new grounds of rejection necessitated by amendment set forth below.
RE: Claim Rejections - 35 USC § 101
►Claims 1-3, 11, 15, 17, 21, 24-25, 41, and 43 were previously rejected under 35 U.S.C. 101 because the claimed invention was directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
The cancellation of claim 2 renders the rejection thereof moot.
Applicant has traversed the rejection of record, asserting that the claims have been amended to be directed to a method of assaying a sample, which is a patent-eligible process.
In response, the amendments to instant claim 1 to recite a method for assaying a sample, rather than a method of assessing a sample from a transplant subject, have not overcome the grounds of rejection previously set forth. While applicant asserts that the present claims are patent-eligible because the recited elements that allegedly constitute a judicial exception to patent eligibility are integrated by patent-eligible steps into a practical application of that alleged exception, the only recited application of the recited elements is comparison of measured values to a threshold value for purposes of determining risk, which is an abstract idea, specifically a mental process, as previously set forth. Furthermore, dependent claims 3, 21, 24, and 25 additionally recite laws of nature, as previously set forth.
Accordingly, while the rejection of record is hereby updated as necessitated by amendment, claims 1, 3, 11, 15, 17, 21, 24-25, 41, and 43 all remain rejected under 35 U.S.C. 101.
RE: Claim Rejections – 35 USC § 112
►Claims 2, 3, 15, 17, 24, and 25 were previously 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.
The cancellation of claim 2 renders the rejection thereof moot.
The amendments to the instant claim set filed 02/11/2026 have obviated the basis of the rejections of record. Accordingly, the rejection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 103
►Claims 1-3, 11, 15, 17, 24, 25, 41, and 43 were previously rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0086477 A1 (hereinafter Wisconsin; as cited in the IDS filed 05/18/2022) in view of WO 2016/176662 A1 (hereinafter Mitchell; as cited in the IDS filed 05/18/2022).
The cancellation of claim 2 renders the rejection thereof moot.
Applicant has traversed the rejection of record, asserting that the rejection of record does not render the subject matter of amended claim 1 obvious. In response, this is found persuasive. Accordingly, the rejection of record is hereby withdrawn.
However, the amendments to the instant claim set have necessitated new grounds of rejection. Accordingly, new grounds of rejection necessitated by amendment are set forth below.
►Claim 21 was previously rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0086477 A1 (hereinafter Wisconsin; as cited in the IDS filed 05/18/2022) in view of WO 2016/176662 A1 (hereinafter Mitchell; as cited in the IDS filed 05/18/2022) as applied to claim 1 above, and further in view of Moreira et al., 2009, as evidenced by Dan Brudzewsky et al., 2019.
Applicant has traversed the rejection of record, asserting that the rejection of record does not render the subject matter of amended claim 21 obvious. Applicant further asserts that Moreira does not teach or suggest using cell-free DNA values as threshold values for the risk of infection or death, and that the Examiner relied on impermissible hindsight to pick and choose the features of the methods of the claims and combine them from the different references cited.
In response, this is not found persuasive. Moreira is explicitly drawn to utilization of cell-free DNA as a noninvasive marker of transplant complications such as acute rejection, as reflected in the title. As set forth in the rejection of record and in Applicant’s response, Moreira discloses a cutoff value for acute rejection, which is approximately 79 ng/mL (as calculated by the methods of Dan Brudzewsky). Additionally, as set forth in the rejection of record, Moreira discloses that plasma total cell-free DNA concentrations largely increase during infectious episodes, wherein patients with systemic infections had significantly higher concentrations (about 135 ng/mL) of total cell-free DNA. While this value is not the claimed threshold of 20 ng/mL, the instant claim language recites “an amount of total cf-DNA of 20 ng/mL or greater represents the presence of an infection or an increased risk of infection.” Under broadest reasonable interpretation, this claim language embraces any amount of total cf-DNA equal to or greater than 20 ng/mL, wherein said amount of total cf-DNA represents the presence of an infection or an increased risk of infection. As set forth above, Moreira discloses that total cell-free DNA values of about 135 ng/mL, which is greater than 20 ng/mL as instantly claimed, are associated with systemic infections in transplant patients. Thus, it is not found persuasive that one of ordinary skill in the art would only arrive at the instantly claimed subject matter via impermissible hindsight reasoning in view of the disclosure of Moreira.
However, claim 21 depends from amended instant claim 1, which stands rejected under new grounds of rejection necessitated by amendment, as set forth above. Accordingly, the rejection of record regarding amended instant claim 21 is hereby withdrawn, with new grounds of rejection necessitated by amendment set forth below.
New/Maintained Grounds of Objection/Rejection
Claim Objections
Claim 3 is objected to because of the following informalities:
Amended instant claim 3 recites an additional step of the method of amended instant claim 1. Amended instant claim 1 recites steps (a)-(d). However, amended instant claim 3 also recites step (d). It appears that this is a simple typographical oversight meant to recite step (e) as an additional step to the method of claim 1 rather than a substitution of step (d) of claim 1. It would be remedial to amend instant claim 3 such that it recites step (e) rather than step (d).
Appropriate correction is required.
Claim Rejections - 35 USC § 101
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, 11, 15, 17, 21, 24-25, 41, and 43 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a law of nature without significantly more. The claims recite a method for assaying a cell-free DNA (cf-DNA) sample from a transplant subject, wherein the quantified amount of cf-DNA is compared to a threshold value for purposes of determining risk of a transplant subject having a transplant complication, such as infection or death. The broadest reasonable interpretation of the claimed invention is that it reads on an abstract idea (i.e. a mental process) and a law of nature. Accordingly, the claims recite an abstract idea and a law of nature.
This judicial exception is not integrated into a practical application. Amended independent claim 1 recites a method for assaying a cell-free DNA (cf-DNA sample from a transplant subject, said method comprising extraction cf-DNA, performing an amplification-based quantification assay or sequencing of the obtained cf-DNA, quantifying the amount of total cf-DNA in the sample, and determining whether the amount of total cf-DNA is equal to or exceeds a threshold total value of 15 ng/mL. There is no recitation of treatments to be applied or other practical applications. The active steps of measuring total cf-DNA levels are directed to insignificant extra-solution activity that does not constitute a practical application. Furthermore, the active step of determining whether the amount of total cf-DNA is equal to or exceeds a threshold total value of 15 ng/mL can easily be performed in the mind, as there is nothing in the claim precluding such comparison from practically being performed in the mind. Accordingly, the claim recites an abstract idea and is directed to the judicial exception.
Dependent claim 3 recites the additional limitation of determining whether the assayed transplant subject has, or is at increased risk of having, a transplant complication based on the previously-determined amount of total cf-DNA compared to the threshold total cf-DNA value set forth above. This recitation is drawn to a natural correlative relationship between cf-DNA levels in a transplant subject and the risk of an adverse health outcome, which is well-known in the art, as evidenced by De Vlaminck et al., 2014 (as cited in the IDS filed 05/18/2022; of record), Daly et al., 2015 (as cited in the IDS filed 05/18/2022; of record), and Gielis et al., 2015 (as cited in the IDS filed 05/18/2022; of record), among others. Accordingly, the claim recites a law of nature and a mental process and does not add an additional element or combination of additional elements that apply, reply on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that the claim is more than a drafting effort designed to monopolize the exception. Thus, the claim is directed to the judicial exception.
Dependent claim 11 recites the additional limitation of providing the measured total cf-DNA amount in a report or recording the same in a database. This recitation is drawn to insignificant extra-solution activity that does not constitute a practical application. Thus, the claim is directed to the judicial exception.
Dependent claim 15 recites the additional limitation of quantifying the amount of total cf-DNA by performing an amplification-based quantification assay on the sample, wherein the sample comprises donor and subject cf-DNA, said method comprising PCR analysis of single nucleotide variant (SNV) targets, such that different primer pairs specifically amplify different SNV alleles. However, these active steps are all drawn to techniques that are well-understood, routine, and conventional. As applicants themselves disclosed in a prior patent application (WO 2016/176662 A1; as cited in the IDS filed 05/18/2022; of record), methods for designing primers for use in a multiplex PCR assay are established in the art (page 18, lines 29-30), methods for quantifying DNA using PCR are established in the art (page 20, lines 31-32), and methods for determining total cell-free DNA are established in the art (page 25, lines 28-29). The well-understood, routine, and conventional nature of these methods is emphasized in the disclosure of Celec et al., 2018 (as cited in the IDS filed 08/04/2025; of record), which reviews the role of cf-DNA as a biomarker in kidney disease. Federal Circuit case law has settled that the use of conventional techniques in a standard way to observe genetic material in a biological sample is not eligible for patentability under 35 U.S.C. § 101 (see CareDx, Inc. v. Natera, Inc., 40 F.4th 1371, 1377 (Fed. Cir. 2022)). Thus, the claim is directed to the judicial exception.
Dependent claim 17 recites the additional limitation of the genotype of the donor of the transplant being unknown. However, this recitation does not constitute an active step and does not add any limitations that constitute a practical application. Thus, the claim is directed to the judicial exception.
Dependent claim 21 recites the additional limitation of a 20 ng/mL threshold value of total cf-DNA for indication of presence or increased risk of infection. As set forth above regarding dependent claim 3, this recitation is drawn to a natural correlative relationship between cf-DNA levels in a transplant subject and the risk of an adverse health outcome, which is well-known in the art, as evidenced by De Vlaminck et al., 2014 (as cited in the IDS filed 05/18/2022; of record), Daly et al., 2015 (as cited in the IDS filed 05/18/2022; of record), and Gielis et al., 2015 (as cited in the IDS filed 05/18/2022; of record), among others. Accordingly, the claim recites a law of nature and a mental process and does not add an additional element or combination of additional elements that apply, reply on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that the claim is more than a drafting effort designed to monopolize the exception. Thus, the claim is directed to the judicial exception.
Dependent claims 24 and 25 respectively recite that total cf-DNA amounts greater than the threshold value represent increased or increasing risk, while total cf-DNA amounts lower than the threshold value represent decreased or decreasing risk. As set forth above regarding dependent claim 3, this recitation is drawn to a natural correlative relationship between cf-DNA levels in a transplant subject and the risk of an adverse health outcome, which is well-known in the art, as evidenced by De Vlaminck et al., 2014 (as cited in the IDS filed 05/18/2022; of record), Daly et al., 2015 (as cited in the IDS filed 05/18/2022; of record), and Gielis et al., 2015 (as cited in the IDS filed 05/18/2022; of record), among others. Accordingly, the claims recite a law of nature and a mental process and does not add an additional element or combination of additional elements that apply, reply on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that the claim is more than a drafting effort designed to monopolize the exception. Thus, the claims are directed to the judicial exception.
Dependent claim 41 additionally recites that the assayed sample is a blood, plasma, or serum sample, which neither constitutes a practical application of the judicial exception nor adds an additional element or combination of additional elements that apply, reply on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. Thus, the claim is directed to the judicial exception.
Dependent claim 43 additionally recites that the transplant subject is a heart transplant subject, which neither constitutes a practical application of the judicial exception nor adds an additional element or combination of additional elements that apply, reply on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. Thus, the claim is directed to the judicial exception.
As set forth above, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. Therefore, viewed as a whole, the additional claim elements do not provide meaningful limitations to transform the judicial exception such that the claims amount to significantly more than the judicial exception itself.
Double Patenting
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 1, 15, 21, 41, and 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, and 8 of U.S. Patent No. 11,773,434 in view of Gielis et al., 2015 (hereinafter Gielis; as cited in the IDS filed 05/18/2022) and WO 2016/176662 A1 (hereinafter Mitchell; as cited in the IDS filed 05/18/2022; of record).
Patent ‘434 discloses methods and compositions for assessing an amount of total cell-free DNA, such as from a transplant subject, for the purpose of determining risk of complications following transplantation, including infection, cardiac arrest, and death, in a subject (abstract). Claim 1 of patent ‘434 recites a method for preparing a preparation of amplified DNA from a sample from a heart transplant recipient (the sample being blood, plasma, or serum, as in instant claim 41) for determining whether an amount of total cf-DNA is equal to or exceeds a threshold, said method comprising PCR amplification and quantification of the amount of total cf-DNA in the sample to determine whether the amount of total cf-DNA is equal to or exceeds a threshold of 20 ng/mL (recited at claim 8 of patent ‘434). Thus, claims 1 and 8 of patent ‘434 disclose the limitations of instant claims 1, 21, and 41, with the exception of the amended limitation of a threshold value of 15 ng/mL recited at amended instant claim 1. However, this deficiency is cured by Gielis.
Gielis discloses that cell-free DNA is a useful biomarker in transplantation for monitoring transplant subjects, as both acute rejection and systemic infections increase total cfDNA levels (abstract; page 2548, column 2, paragraph 6). Gielis further discloses that healthy individuals have low concentrations of total cf-DNA, wherein the threshold low concentration in healthy individuals is 15 ng/mL (Table 1). Thus, one of ordinary skill in the art would reasonably conclude that cf-DNA values exceeding 15 ng/mL, as instantly claimed, would be indicative of transplant recipients at risk for acute rejection and systemic infections, as set forth above. Thus, claims 1 and 8 of patent ‘434 are not patentably distinct from instant claims 1, 21, and 41 in view of Gielis.
Instant claim 1 recites a method of assessing a sample from a transplant subject, said method comprising determining an amount of total cf-DNA in a sample from the subject, wherein the subject is suspected of having, has had, or is at risk of having a transplant complication and reporting and/or recording the amount of total cf-DNA. While claim 1 of patent ‘434 does not recite that the claimed transplant subject is suspected of having, has had, or is at risk of having a transplant complication, nor does it recite reporting and/or recording of the amount of total cf-DNA, this deficiency is remedied by the disclosure of Wisconsin, as set forth in greater detail below. Regarding instant claims 21, and 41, claim 8 of patent ‘434 recites determining whether the amount of total cf-DNA is equal to or exceeds a threshold of 20 ng/mL, as in instant claim 21, which clearly involves comparison of the determined total cf-DNA value and the threshold value of 20 ng/mL. While instant claim 21 recites that a threshold value of 20 ng/mL is indicative of being at a risk of infection, this subject matter is recited in patent ‘434 at claims 4 and 8, which recite that the assessed transplant complication is cardiac arrest, infection or death, wherein a total cf-DNA amount of 20 ng/mL or greater represents the presence of an infection or an increased risk of an infection. Additionally, as set forth above, claim 1 of patent ‘434 recites that the queried sample is blood, plasma, or serum, as in instant claim 41. Finally, claim 1 of patent ‘434 specifically recites a heart transplant recipient, which is also recited at instant claim 43.
To address the deficiencies of claim 1 of patent ‘434, which does not recite that the claimed transplant subject is suspected of having, has had, or is at risk of having a transplant complication, nor does it recite reporting and/or recording of the amount of total cf-DNA, Mitchell discloses methods and compositions for assessing an amount of non-native nucleic acids, including obtaining the level of total cf-DNA (such as in ng/mL), to determine the risk of a condition, such as transplant rejection, in a transplant recipient (abstract; page 6, lines 33-34; page 25, lines 21-31). Mitchell defines “risk” as the presence or absence of any undesirable condition in a subject (page 24, lines 5-6), which establishes that any transplant recipient must be at risk per the definition taught therein. Additionally, Mitchell discloses reporting and/or recording of the amount of total cf-DNA (page 5, lines 15-19). Thus, instant claims 1, 21, and 41 recite identical subject matter of claim 1 of patent ‘434 with the exception of the subject matter taught in Mitchell.
Claim 5 of patent ‘434 recites the methods of a polymerase chain reaction (PCR) quantification assay in which primer pairs are designed for performing multiplex PCR capable of detecting individual alleles, the output of which is used to assess the amount of total cf-DNA in the sample. This methodology is identical to that which is recited in instant claim 15.
Claim 6 of patent ‘434 recites that the amount of total cf-DNA is determined or obtained using an amplification-based quantification assay, as is recited in instant claims 1 and 15.
Given that patent ‘434 discloses a method of assessing risk in heart transplant patients based on determining total cf-DNA levels in blood, plasma, or serum samples obtained from the subject, in which these levels inform treatment decisions based on thresholds of 20 ng/mL for infection, that Gielis discloses that the upper threshold of low cf-DNA concentration in healthy individuals is 15 ng/mL, and that Mitchell discloses assessing total cf-DNA levels in transplant recipients at risk (per the definition taught therein, any transplant recipient must be at risk, as set forth above) and administering treatment based on the risk assessed by cf-DNA levels, it would have been obvious to someone of ordinary skill in the art to combine the teachings of patent ‘434, Gielis, and Mitchell to arrive at the instantly claimed subject matter. One would have been motivated to make such a modification in order to receive the expected benefit of assessing transplant patient risk and tailoring treatment accordingly.
Claims 1, 3, 11, 24-25, 41, and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 13, 17, 18, 26, and 29 of copending Application No. 17/493,293 (corresponding to US 2022/0267849 A1; as cited in the IDS filed 08/04/2025; of record) in view of Gielis et al., 2015 (hereinafter Gielis; as cited in the IDS filed 05/18/2022).
The examiner notes that the claims of copending application ‘293 were amended as of 06/30/2025. The rejections set forth below reflect the amended claim set.
Copending application ‘293 discloses methods and compositions for assessing an amount of donor-specific fraction of cell-free DNA as well as total cell-free DNA, such as from a transplant subject to determine risk of one or more transplant complications (abstract). Copending claim 1 recites a method of assessing a sample from a transplant subject in which cell-free DNA is obtained from a sample (recited to be blood, plasma, or serum at copending claim 26) and the amount of donor-specific cf-DNA and total cf-DNA in said sample is measured and reported (this is also recited in copending claim 13), as in instant claims 1 and 11. Regarding the biological sample of copending application ‘293, instant claim 41 also recites that the biological sample may be blood, plasma or serum. While instant claim 1 does not recite measurement of donor-specific cf-DNA, copending claim 1 nonetheless recites each and every limitation of instant claim 1 (with the exception of the amended limitation of a threshold value of 15 ng/mL recited at amended instant claim 1), especially in view of the definition of “risk” taught in the instant application. The instant specification defines “risk” as “the presence or absence or progression of any undesirable condition in a subject, or an increased likelihood of the presence or absence or progression of such a condition” (page 8, line 31-page 9, line 2). According to this definition, any transplant recipient must necessarily be at least suspected of being at risk, as instantly claimed. The deficiency of the copending application ‘293 regarding the amended limitation of a threshold value of 15 ng/mL is cured by Gielis.
Gielis discloses that cell-free DNA is a useful biomarker in transplantation for monitoring transplant subjects, as both acute rejection and systemic infections increase total cfDNA levels (abstract; page 2548, column 2, paragraph 6). Gielis further discloses that healthy individuals have low concentrations of total cf-DNA, wherein the threshold low concentration in healthy individuals is 15 ng/mL (Table 1). Thus, one of ordinary skill in the art would reasonably conclude that cf-DNA values exceeding 15 ng/mL, as instantly claimed, would be indicative of transplant recipients at risk for acute rejection and systemic infections, as set forth above. Thus, copending claim 1 is not patentably distinct from instant claim 1 in view of Gielis.
Copending claim 6 recites determining and/or assigning a risk to the subject based on comparing the measured amount of the claimed cf-DNA levels to threshold values or to values obtained from prior time points. Copending claim 17 recites that a value greater than a threshold value or prior value represents an increased or increasing risk. Collectively, these recitations read on the claimed subject matter of instant claims 3 and 24. Additionally, copending claim 18 recites that a value lower than a threshold value or prior value represents a decreased or decreasing risk, as is recited in instant claim 25.
Copending claim 29 recites that the transplant subject assessed by the claimed methods is a heart transplant subject, as is recited in instant claim 43.
Given that copending application ‘293 discloses a method of assessing risk in transplant patients based on determining cf-DNA levels in blood, plasma, or serum samples obtained from the subject and that Gielis discloses that the upper threshold of low cf-DNA concentration in healthy individuals is 15 ng/mL, it would have been obvious to someone of ordinary skill in the art to combine the teachings of copending application ‘293 and Gielis to arrive at the instantly claimed subject matter. One would have been motivated to make such a modification in order to receive the expected benefit of assessing transplant patient risk and tailoring treatment accordingly.
This is a provisional nonstatutory double patenting rejection.
Claim Rejections - 35 USC § 103
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.
Claims 1, 3, 11, 15, 17, 24, 25, 41, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0086477 A1 (hereinafter Wisconsin; as cited in the IDS filed 05/18/2022; of record) in view of Gielis et al., 2015 (hereinafter Gielis; as cited in the IDS filed 05/18/2022) and WO 2016/176662 A1 (hereinafter Mitchell; as cited in the IDS filed 05/18/2022; of record).
With regard to amended claim 1, which recites “a method for assaying a cell-free DNA (cf-DNA) sample from a transplant subject, the method comprising:
extracting cf-DNA from the sample;
performing an amplification-based quantification assay or sequencing the cf-DNA obtained in (a);
quantifying the amount of total cf-DNA in the sample from the subject, wherein the subject has, is suspected of having, has had, or is at risk of having a transplant complication, and wherein the transplant complication is infection or death; and
determining whether the amount of total cf-DNA is equal to or exceeds a threshold total cf-DNA value of 15 ng/mL,”
Wisconsin discloses a method of assessing risk in a subject such as a transplant recipient in which the amount of cf-DNA extracted from a biological sample obtained from said transplant recipient is quantified, thereby facilitating determination of risk (i.e. of systemic disease) to the transplant recipient (paragraphs [0002] and [0004]). Wisconsin explicitly discloses that the cf-DNA of any of the methods taught therein may be total cf-DNA (paragraphs [0013], [0064], and [0070]). Total cf-DNA content is disclosed to be evaluated by TaqMan real-time PCR (paragraph [0121]), which reads on the instantly claimed amplification-based quantification assay. Wisconsin further discloses at paragraphs [0074] and [0075] that an increase in total cf-DNA is correlated with an increased risk of a condition such as transplant rejection, transplant injury, infection, and/or systemic disease associated with the transplant, as instantly claimed. Thus, the amount of total cf-DNA can be indicative of the presence or absence of a risk associated with a condition, such as developing an infection after having received a transplant (paragraphs [0074], [0075], and [0080]). The Examiner notes that per the instant specification, “risk” is defined as “the presence or absence or progression of any undesirable condition in a subject, or an increased likelihood of the presence or absence or progression of such a condition” (emphasis added; page 11, lines 8-10). According to this definition, any transplant recipient must necessarily be at least suspected of being at risk, as instantly claimed. Thus, while Wisconsin discloses the subject matter of steps (a)-(c) of the instantly claimed method, they do not disclose the instantly claimed threshold total cf-DNA value of 15 ng/mL.
This deficiency is cured by Gielis. Gielis discloses that cell-free DNA is a useful biomarker in transplantation for monitoring transplant subjects, as both acute rejection and systemic infections increase total cfDNA levels (abstract; page 2548, column 2, paragraph 6). Gielis further discloses that healthy individuals have low concentrations of total cf-DNA, wherein the threshold low concentration in healthy individuals is 15 ng/mL (Table 1). Thus, one of ordinary skill in the art would reasonably conclude that cf-DNA values exceeding 15 ng/mL, as instantly claimed, would be indicative of transplant recipients at risk for acute rejection and systemic infections, as set forth above. Thus, it is considered that Wisconsin and Gielis collectively disclose the method of amended instant claim 1.
With regard to amended claim 3, which recites “the method [of claim 1] further comprises: [(e)] determining that the subject has, or is at increased risk of having, a transplant complication based on the determined amount of total cf-DNA compared to the threshold total cf-DNA value,” as set forth above, Wisconsin discloses comparing levels of total cf-DNA to a threshold value for purposes of determining increased or decreased risk of a condition (paragraph [0074]), while Gielis discloses that 15 ng/mL is the upper threshold for low concentration of total cf-DNA in healthy individuals (Table 1). Total cf-DNA values exceeding this threshold value are disclosed to indicate that the transplant recipient is at increased risk of a condition such as a transplant complication; whereas, total cf-DNA values below this threshold value are disclosed to indicate that the transplant recipient is at decreased risk of a condition such as a transplant complication (i.e. an infection) (paragraphs [0074], [0075], and [0100]). Thus, it is considered that Wisconsin discloses the additional limitations of amended instant claim 3.
With regard to claim 11, which recites “the total cf-DNA amount [of the method of claim 1] is provided in a report or recorded in a database,” while neither Wisconsin nor Gielis disclose providing the measured amount of cf-DNA in a report or database, Mitchell discloses methods and compositions for assessing an amount of non-native nucleic acids, including obtaining the level of total cf-DNA (such as in ng/mL), to determine the risk of a condition, such as transplant rejection, in a transplant recipient (abstract; page 6, lines 33-34; page 25, lines 21-31). These results are disclosed to be provided in a report (page 5, lines 15-19). Thus, it is considered that Mitchell discloses the additional limitations of amended instant claim 3.
With regard to amended claim 15, which recites “the amount of total cf-DNA [of the method of claim 1] is quantified by performing an amplification-based quantification assay on the sample, wherein the sample comprises donor and subject cf-DNA, the method comprising: (a) for a plurality of single nucleotide variant (SNV) targets, performing a polymerase chain reaction (PCR) quantification assay on the sample, or a portion thereof, with at least two primer pairs, wherein each primer pair comprises a forward primer and a reverse primer, wherein one of the at least two primer pairs comprises a 3' penultimate mismatch in a primer relative to one allele of the SNV target, but a 3' double mismatch relative to another allele of the SNV target and specifically amplifies the one allele of the SNV target, and another of the at least two primer pairs specifically amplifies another allele of the SNV target, and (b) assessing the amount of total cf-DNA based on the results,” Mitchell discloses the claimed PCR quantification assay at page 1, lines 25-33 (under “summary of invention”), detailing the methodology of multiplexed optimized mismatch amplification in which primers are designed such that they include a 3’ penultimate mismatch for the amplification of a specific sequence but a double mismatch relative to an alternate sequence, thereby permitting quantitative determination of amounts of non-native nucleic acids in a sample, as well as total cf-DNA levels (such as in ng/mL) in a sample (page 25, lines 21-31). As shown in Figure 1, this assay is capable of distinguishing recipient (i.e. subject) and donor cf-DNA, as instantly claimed. Mitchell discloses that this method can be used to specifically amplify each allele of the SNV target separately (i.e. one allele is specifically amplified by one primer pair, while at least one other primer pair specifically amplifies another allele of the SNV target) (page 2, lines 3-27). Mitchell further discloses that this method is applicable to determining the amount of total cf-DNA in a sample from the subject (page 25, lines 21-31). Thus, it is considered that Mitchell discloses the additional limitations of amended instant claim 15.
With regard to amended claim 17, which recites “the genotype of the donor of the transplant is unknown” in the method of claim 15, Mitchell discloses that in the event that all donor genotypes are unknown, it is possible to bootstrap from the knowledge that any assays exhibiting nearly zero minor allele are donor AA and the highest is donor BB (page 36, lines 5-23). Additionally, figures 6-8 (page 13) are disclosed to demonstrate the use of expectation maximization to predict non-native donor genotypes when unknown. Thus, it is considered that Mitchell discloses the additional limitations of amended instant claim 17.
With regard to claim 24, which recites “an amount of total cf-DNA [of the method of claim 1] that is greater than the threshold value and/or is increased relative to the amount from an earlier time point represents an increased or increasing risk,” as set forth above, Wisconsin discloses comparing levels of total cf-DNA to a threshold value for purposes of determining increased or decreased risk of a condition (paragraph [0074]). Total cf-DNA values exceeding this threshold value are disclosed to indicate that the transplant recipient is at increased risk of a condition such as a transplant complication; whereas, total cf-DNA values below this threshold value are disclosed to indicate that the transplant recipient is at decreased risk of a condition such as a transplant complication (paragraphs [0074] and [0100]). Thus, it is considered that Wisconsin discloses the additional limitations of instant claim 24.
With regard to claim 25, which recites “an amount of total cf-DNA [of the method of claim 1] that is lower than the threshold value and/or is decreased relative to the amount from an earlier time point represents a decreased or decreasing risk,” as set forth above, Wisconsin discloses comparing levels of total cf-DNA to a threshold value for purposes of determining increased or decreased risk of a condition (paragraph [0074]). Total cf-DNA values exceeding this threshold value are disclosed to indicate that the transplant recipient is at increased risk of a condition such as a transplant complication; whereas, total cf-DNA values below this threshold value are disclosed to indicate that the transplant recipient is at decreased risk of a condition such as a transplant complication (paragraphs [0074] and [0100]). Thus, it is considered that Wisconsin discloses the additional limitations of instant claim 25.
With regard to claim 41, which recites “the sample [of the method of claim 1] is a blood, plasma or serum sample,” Wisconsin discloses that the biological sample obtained from the subject (i.e. a transplant recipient such as a heart transplant recipient (paragraph [0036])) for purposes of determining levels of total cf-DNA (paragraph [0074]) may comprise blood, plasma, or serum (paragraphs [0039] and [0064]), as instantly claimed. Thus, it is considered that Wisconsin discloses the additional limitations of instant claim 41.
With regard to claim 43, which recites “the transplant subject [of the method of claim 1] is a heart transplant subject,” Wisconsin discloses that the transplant recipient assessed by the methods taught therein may be a heart transplant recipient (paragraphs [0036]), as instantly claimed. Thus, it is considered that Wisconsin discloses the additional limitations of instant claim 43.
Given that Wisconsin discloses a method of assessing risk in transplant recipients such as heart transplant recipients in which total cf-DNA values are quantified and compared to a threshold value for the purpose of determining whether the recipient is at increased or decreased risk of a complication; that Gielis discloses that the upper threshold of low cf-DNA concentration in healthy individuals is 15 ng/mL; and that Mitchell discloses a multiplexed PCR method for quantifying cf-DNA values (including when the transplant donor genotype is unknown) as well as recording/reporting these quantified values, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to perform the risk assessment method based on total cf-DNA levels disclosed in Wisconsin using the multiplexed PCR method of Mitchell to obtain and record total cf-DNA levels to predictably assess whether the transplant recipient is at increased or decreased risk of a complication as compared to the threshold of 15 ng/mL, as disclosed in Gielis. One would have been motivated to make such a modification in order to receive the expected benefit of non-invasively assessing whether the transplant recipient is at increased or decreased risk of a complication.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0086477 A1 (hereinafter Wisconsin; as cited in the IDS filed 05/18/2022) in view of Gielis et al., 2015 (hereinafter Gielis; as cited in the IDS filed 05/18/2022) and WO 2016/176662 A1 (hereinafter Mitchell; as cited in the IDS filed 05/18/2022) as applied to claim 1 above, and further in view of Moreira et al., 2009 (hereinafter Moreira; of record), as evidenced by Dan Brudzewsky et al., 2019 (of record).
The combined disclosures of Wisconsin, Gielis, and Mitchell are described above and applied as before. However, these disclosures do not teach the cf-DNA risk threshold values of instant claim 21.
The examiner notes that while Dan Brudzewky et al., 2019 was presented at the Proceedings of the American Association for Cancer Research Annual Meeting 2019 (March 29-April 3), it lists a publication date that post-dates the effective filing date of the instant application (07/01/2019). However, the disclosure of Dan Brudzewky et al., 2019 is relied upon only for its teaching of the mathematical conversion of one unit (genome equivalents/mL) to another unit (ng/mL), which is a fundamental and unchanging mathematical concept.
With regard to amended claim 21, which further recites following determining an amount of total cf-DNA in a sample “an amount of 20 ng/mL or greater represents the presence of an infection or an increased risk of infection,” as set forth above, Mitchell discloses that the levels of the non-native nucleic acids disclosed therein (including total cf-DNA (page 25, lines 21-31)) may be compared to a threshold value to identify a subject at increased or decreased risk of a condition such as a transplant rejection (page 25, line 32-page 26, line 9). Additionally, Gielis discloses that the upper threshold of low cf-DNA concentration in healthy individuals is 15 ng/mL (Table 1).
However, neither Wisconsin, Mitchell, nor Gielis disclose the instantly claimed threshold value of 20 ng/mL for establishing relative risk of cardiac arrest or infection. However, this deficiency is cured by Moreira, which discloses that plasma total cell-free DNA concentrations largely increase during infectious episodes (page 1961, column 2, paragraph 3). As shown in figure 3, patients with systemic infections had significantly higher concentrations of total cell-free DNA (median=40,400 genome equivalents (GE)/mL) than those with local infections (median=9,200 GE/mL) (page 1961, column 2, paragraph 3). Furthermore, as shown in figure 3, total cell-free DNA concentration precipitously rose in each patient prior to clinical diagnosis (as indicated by arrows). In view of the mathematical conversion disclosed in Dan Brudzewky et al., 2019, which states that 1-10 ng/mL corresponds to 300-3,000 GE/mL, kidney transplant patients with systemic infections had ~135 ng/mL of total cell-free DNA, while those with local infections had ~31 ng/mL of total cell-free DNA, both of which satisfy the recited claim limitation of an amount of total cf-DNA of 20 ng/mL or greater representing either the presence of an infection or the increased risk of an infection.
Given that Wisconsin, Gielis, and Mitchell disclose methods and compositions for assessing an amount of non-native nucleic acids, including total cf-DNA (such as in ng/mL), to determine the risk of a condition, such as transplant rejection, in a transplant recipient upon comparison to a threshold value, and that Moreira (as evidenced by Dan Brudzewsky et al., 2019) discloses that kidney transplant patients who developed infections had very high concentrations of total cell-free DNA exceeding 20 ng/mL, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to utilize the disclosure of Moreira to interpret an amount of total cf-DNA equal to exceeding 20 ng/mL as predictably representing the presence of an infection or an increased risk of infection, thereby establishing a meaningful cf-DNA threshold value for predicting infection risk in transplant recipients. One would have been motivated to make such a modification in order to receive the expected benefit of establishing a meaningful cf-DNA threshold value for predicting infection risk in transplant recipients.
Conclusion
No claims are allowed.
Claim 3 is objected to.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah E Allen whose telephone number is (571)272-0408. The examiner can normally be reached M-Th 8-5, F 8-12.
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/SARAH E ALLEN/Examiner, Art Unit 1637
/J. E. ANGELL/Primary Examiner, Art Unit 1637