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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1, 3, 11, 13, 24, 27, and 29 in the reply filed on 07/15/2026 is acknowledged.
Claims 2, 4, 6-7, 9, 15, 17-18, 20-21, 31, 34, and 39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/15/2026.
Claim Rejections - 35 USC § 112
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 13 and 24 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 13 and 24, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For examination purposes, “such as” is interpreted as optional.
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, 13, 24, 27, and 29 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Claim 1 recites the limitations “determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject”.
In accordance with MPEP 2106, the claims are found to recite statutory subject matter (Step 1: YES) and are analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A: Prong 1).
In the instant application, the limitations of “determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject” could be performed mentally or by math. Accordingly, the claims recite abstract ideas (Step 2A: Prong 1: Yes).
This judicial exception is not integrated into a practical application because the claims do not recite any additional elements that reflects an improvement to technology or applies or uses the judicial exception in some other meaningful way (Step 2A, Prong 2: No). In claim 1, the limitation recites “determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject”. Claim 1 further recites “optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA.” However, reporting and/or recording is mere data outputting and is insignificant extra-solution activity, and not a particular practical application. See MPEP 2106.05(g). Additionally, due to the phrase “optionally”, the reporting and/or recording step is not required, and therefore the BRI of claim 1 includes only the step of “determining…”, with no additional steps performed afterwards. Therefore, the claimed limitations do not integrate the abstract idea into a practical application because it does not impose any meaningful limits on practicing the abstract idea. Thus, the claims are directed to an abstract idea that is not integrated into a practical application (Step 2A, Prong 2: No).
The claims 1, 3, 11, 13, 24, 27, 29 do not include additional elements that are sufficient to amount to significantly more than the judicial exception. Claim 1 and dependent claims 3, 11, 13, 24, 27, 29 further recites limitations, however these limitations generally link the judicial exception to a particular field of use (MPEP 2106.05(h)) and are used for data gathering or data outputting, wherein data gathering to be used in the abstract idea is an insignificant extra-solution activity, and not a practical application (see MPEP 2106.05(g)), which alone or in combination do not amount to significantly more. Additionally, the limitations of 1, 3, 11, 13, 24, 27, 29 are well-understood, routine and conventional activities as evidenced by the prior art of Andargie et al. (ANDARGIE et al., Cell-free DNA maps COVID-19 tissue injury and risk of death and can cause tissue injury. JCI Insight. 2021 Apr 8;6(7):e147610. doi: 10.1172/jci.insight.147610; cited in the IDS filed 02/21/2024) and Harrington et al. (Harrington et al., “Circulating Mitochondrial DNA as Predictor of Mortality in Critically Ill Patients: A Systematic Review of Clinical Studies”, August 2019, Original Research: Critical Care, Volume 156, Issue 6, December 2019, Pages 1120-1136). See MPEP 2106.05(d). The additional elements of the claims 1, 3, 11, 13, 24, 27, 29 do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). The claims are not patent eligible.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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, 11, and 29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Andargie et al. (ANDARGIE et al., Cell-free DNA maps COVID-19 tissue injury and risk of death and can cause tissue injury. JCI Insight. 2021 Apr 8;6(7):e147610. doi: 10.1172/jci.insight.147610; cited in the IDS filed 02/21/2024).
Regarding claim 1, Andargie teaches a method of assessing a sample from a subject that has or is suspected of having cellular or tissue injury (abstract teaches methods for analyzing plasma samples from patients that have or is suspected of having tissue injury, i.e. cellular or tissue injury), the method comprising:
(a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject (page 16, section “cfDNA quantification” and Fig. 1 teaches mtcfDNA, i.e. mitochondrial cf-DNA, and ncfDNA, i.e. nuclear cf-DNA, were quantified from isolated cfDNA obtained from patient samples); and
(b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA (page 16, section “cfDNA quantification”, teaches quantification and analysis of mtcfDNA and ncfDNA, i.e. the amount of mtcfDNA and ncfDNA are reported and recorded; Figs. 3-4 teaches reported and recorded levels, i.e. amounts, of mtcfDNA and ncfDNA).
Regarding claim 3, Andargie further teaches wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time (page 4, last paragraph and Fig. 6 teaches amounts of ncfDNA are obtained from patients over multiple days).
Regarding claim 11, Andargie further teaches wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury (abstract, page 1 first paragraph, and page 2, second paragraph teaches COVID-19 can lead to tissue injury, such as damage to the heart; page 4, last paragraph and Fig. 6 teaches amounts of ncfDNA are obtained from COVID-19 patients over multiple days; page 15, paragraphs 1 and 4 teaches cfDNA provides a comprehensive profile of tissue injury in patients with COVID-19; therefore, the amounts of at least ncfDNA is determined at least 12 hours after cellular or tissue injury due to the patient having COVID-19, which is interpreted as the patient including at least some cellular or tissue injury).
Regarding claim 29, Andargie further teaches wherein the subject is one that has or is suspected of having a need for mechanical circulatory support (MCS), or is at increased risk of cardiac arrest, needing MCS, death, or any combination thereof (abstract teaches COVID-19 patients, where the clinical course of COVID-19 ranges from mild to severe multiorgan failure and death; page 12, first paragraph teaches patients with COVID-19 are at risk of severe disease and death; therefore, the subject or patient is interpreted as at increased risk of at least death).
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 13, 24, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Andargie as applied to claim 1 above, and further in view of Harrington et al. (Harrington et al., “Circulating Mitochondrial DNA as Predictor of Mortality in Critically Ill Patients: A Systematic Review of Clinical Studies”, August 2019, Original Research: Critical Care, Volume 156, Issue 6, December 2019, Pages 1120-1136).
Regarding claim 13, Andargie fails to teach: wherein the cellular or tissue injury is surgery, such as cardiac surgery, or cardiopulmonary bypass.
Andargie teaches analyzing cfDNA as a biomarker of injury to define sources of tissue injury (abstract). Andargie teaches sources of tissue injury, such as the heart, that contribute to different clinical trajectories remain poorly defined (page 1, first paragraph).
Harrington teaches assessing circulating mitochondrial cell-free DNA (mtDNA) as a biomarker for mortality in critically ill patients (abstract). Harrington teaches patients included in the study includes patients that were admitted to surgery (page 1122, section “Results”, third paragraph; Table 1), the surgery including cardiac or cardiopulmonary bypass (Table 1 teaches various studies involving cardiothoracic surgery and cardiopulmonary bypass). Harrington teaches there is a statistically significant association between mtDNA levels and the mortality of critically ill patients (page 1134, section “Conclusion”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Andargie to incorporate Andargie’s teachings of analyzing cfDNA as a biomarker of tissue injury (abstract; page 1, first paragraph) and Harrington’s teachings of assessing circulating mitochondrial cell-free DNA in patients, such as patients that have had cardiothoracic surgery and cardiopulmonary bypass (page 1122, section “Results”, third paragraph; Table 1) to provide: wherein the cellular or tissue injury is surgery, such as cardiac surgery, or cardiopulmonary bypass. Doing so would have a reasonable expectation of successfully improving analysis of cellular or tissue injury in patients having various conditions, such as tissue injury from cardiac surgery, or cardiopulmonary bypass, and therefore improving assessment of mortality in critically ill patients as taught by Harrington.
Regarding claim 24, Andargie fails to teach: wherein the subject is a subject that has undergone surgery, such as cardiac surgery, or cardiopulmonary bypass or is one with or suspected to have myocardial injury.
Andargie teaches analyzing cfDNA as a biomarker of injury to define sources of tissue injury (abstract). Andargie teaches sources of tissue injury, such as the heart, that contribute to different clinical trajectories remain poorly defined (page 1, first paragraph).
Harrington teaches assessing circulating mitochondrial cell-free DNA (mtDNA) as a biomarker for mortality in critically ill patients (abstract). Harrington teaches patients included in the study includes patients that were admitted to surgery (page 1122, section “Results”, third paragraph; Table 1), the surgery including cardiac or cardiopulmonary bypass (Table 1 teaches various studies involving cardiothoracic surgery and cardiopulmonary bypass). Harrington teaches patients includes patients with myocardial infarction (Table 1). Harrington teaches there is a statistically significant association between mtDNA levels and the mortality of critically ill patients (page 1134, section “Conclusion”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Andargie to incorporate Andargie’s teachings of analyzing cfDNA as a biomarker of tissue injury (abstract; page 1, first paragraph) and Harrington’s teachings of assessing circulating mitochondrial cell-free DNA in patients, such as patients that have had cardiothoracic surgery, cardiopulmonary bypass, or myocardial infarction (page 1122, section “Results”, third paragraph; Table 1) to provide: wherein the subject is a subject that has undergone surgery, such as cardiac surgery, or cardiopulmonary bypass or is one with or suspected to have myocardial injury. Doing so would have a reasonable expectation of successfully improving analysis of cellular or tissue injury in patients having various conditions, such as tissue injury from cardiac surgery, cardiopulmonary bypass, or myocardial injury, and therefore improving assessment of mortality in critically ill patients as taught by Harrington.
Regarding claim 27, Andargie fails to teach: wherein the subject is a pediatric subject.
Andargie teaches analyzing cfDNA as a biomarker of injury to define sources of tissue injury (abstract). Andargie teaches sources of tissue injury, such as the heart, that contribute to different clinical trajectories remain poorly defined (page 1, first paragraph).
Harrington teaches assessing circulating mitochondrial cell-free DNA (mtDNA) as a biomarker for mortality in critically ill patients (abstract). Harrington teaches patients included in the study includes patients that were admitted to surgery (page 1122, section “Results”, third paragraph; Table 1), the surgery including cardiac or cardiopulmonary bypass (Table 1 teaches various studies involving cardiothoracic surgery and cardiopulmonary bypass). Harrington teaches patients includes patients with myocardial infarction (Table 1). Harrington teaches there is a statistically significant association between mtDNA levels and the mortality of critically ill patients (page 1134, section “Conclusion”). Harrington teaches measuring circulating cell-free mtDNA in critically ill patients including adults or pediatric (page 1122, section “selection of studies”; page 1122, section “Characteristics of selected studies”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Andargie to incorporate Andargie’s teachings of analyzing cfDNA as a biomarker of tissue injury (abstract; page 1, first paragraph) and Harrington’s teachings of assessing circulating mitochondrial cell-free DNA in patients, such as adults or pediatric patients (page 1122, section “selection of studies”; page 1122, section “Characteristics of selected studies”; page 1122, section “Results”, third paragraph; Table 1) to provide: wherein the subject is a pediatric subject. Doing so would have a reasonable expectation of successfully improving analysis of cellular or tissue injury in patients of different ages, such as pediatric patients, and therefore improving assessment of mortality in critically ill patients as taught by Harrington.
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, 3, 11, 13, 24, 27, and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/493,230 (herein, “App ‘230”) in view of Andargie et al. (ANDARGIE et al., Cell-free DNA maps COVID-19 tissue injury and risk of death and can cause tissue injury. JCI Insight. 2021 Apr 8;6(7):e147610. doi: 10.1172/jci.insight.147610; cited in the IDS filed 02/21/2024).
Regarding claim 1, App ‘230 recites a method of assessing a sample from a subject (claim 1) that has or is suspected of having cellular or tissue injury (claim 1 teaches the transplant subject has or is suspected of having cellular rejection, i.e. cellular or tissue injury), the method comprising:
(a) determining an amount of donor-specific cell-free DNA in a sample taken from the subject (claim 1); and
(b) optionally, reporting and/or recording the amount of cf-DNA (interpreted as not required).
App ‘230 fails to recite: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject; and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA.
Andargie teaches a method of assessing a sample from a subject that has or is suspected of having cellular or tissue injury (abstract teaches methods for analyzing plasma samples from patients that have or is suspected of having tissue injury, i.e. cellular or tissue injury), the method comprising: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject (page 16, section “cfDNA quantification” and Fig. 1 teaches mtcfDNA, i.e. mitochondrial cf-DNA, and ncfDNA, i.e. nuclear cf-DNA, were quantified from isolated cfDNA obtained from patient samples); and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA (page 16, section “cfDNA quantification”, teaches quantification and analysis of mtcfDNA and ncfDNA, i.e. the amount of mtcfDNA and ncfDNA reported and recorded; Figs. 3-4 teaches reported and recorded levels, i.e. amounts, of mtcfDNA and ncfDNA). Andargie teaches analyzing cfDNA as a biomarker of injury to define sources of tissue injury (abstract). Andargie teaches sources of tissue injury, such as the heart, that contribute to different clinical trajectories remain poorly defined (page 1, first paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of App ‘230 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA for analyzing tissue injury to provide: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject; and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 3, App ‘230 fails to recite: wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time.
Andargie further teaches wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time (page 4, last paragraph and Fig. 6 teaches amounts of ncfDNA are obtained from patients over multiple days).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of App ‘230 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA over multiple days to provide wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 11, App ‘230 fails to recite: wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury.
Andargie further teaches wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury (abstract, page 1 first paragraph, and page 2, second paragraph teaches COVID-19 can lead to tissue injury, such as damage to the heart; page 4, last paragraph and Fig. 6 teaches amounts of ncfDNA are obtained from COVID-19 patients over multiple days; page 15, paragraphs 1 and 4 teaches cfDNA provides a comprehensive profile of tissue injury in patients with COVID-19; therefore, the amounts of at least ncfDNA is determined at least 12 hours after cellular or tissue injury due to the patient having COVID-19, which is interpreted as the patient including at least some cellular or tissue injury).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of App ‘230 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA over multiple days to provide wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 13, App ‘230 further recites wherein the cellular or tissue injury is surgery (claim 1 recites a transplant subject and assessing the grade of cellular rejection, therefore the subject’s cellular or tissue injury is from transplant surgery), such as cardiac surgery, or cardiopulmonary bypass (interpreted as not required).
Regarding claim 24, App ‘230 further recites wherein the subject is a subject that has undergone surgery (claim 1 recites a transplant subject and assessing the grade of cellular rejection, therefore the subject’s cellular or tissue injury is from transplant surgery), such as cardiac surgery, or cardiopulmonary bypass or is one with or suspected to have myocardial injury (interpreted as not required).
Regarding claim 27, App ‘230 fails to recite: wherein the subject is a pediatric subject.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the subject of App ‘230 to provide wherein the subject is a pediatric subject. Doing so would have a reasonable expectation of successfully improving assessing various ages of subjects known in the art, such as pediatric or adult subjects.
Regarding claim 29, App ‘230 fails to recite: wherein the subject is one that has or is suspected of having a need for mechanical circulatory support (MCS), or is at increased risk of cardiac arrest, needing MCS, death, or any combination thereof.
Andargie further teaches wherein the subject is one that has or is suspected of having a need for mechanical circulatory support (MCS), or is at increased risk of cardiac arrest, needing MCS, death, or any combination thereof (abstract teaches COVID-19 patients, where the clinical course of COVID-19 ranges from mild to severe multiorgan failure and death; page 12, first paragraph teaches patients with COVID-19 are at risk of severe disease and death; therefore, the subject or patient is interpreted as at increased risk of at least death).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the subject of App ‘230 to incorporate Andargie’s teachings of assessing organs for failure and patient death to provide: wherein the subject is one that has or is suspected of is at increased risk of death. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3, 11, 13, 24, 27, and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 16/623,719 (herein, “App ‘719”) in view of Andargie et al. (ANDARGIE et al., Cell-free DNA maps COVID-19 tissue injury and risk of death and can cause tissue injury. JCI Insight. 2021 Apr 8;6(7):e147610. doi: 10.1172/jci.insight.147610; cited in the IDS filed 02/21/2024).
Regarding claim 1, App ‘719 recites a method of assessing a sample from a subject (claim 1 recites quantifying a sample from a transplant subject) that has or is suspected of having cellular or tissue injury (claim 1 recites the transplant subject has or is suspected of having cellular rejection, i.e. cellular or tissue injury), the method comprising:
(a) determining an amount of donor-specific cell-free DNA in a sample taken from the subject (claim 1); and
(b) optionally, reporting and/or recording the amount of cf-DNA (interpreted as not required).
App ‘719 fails to recite: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject; and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA.
Andargie teaches a method of assessing a sample from a subject that has or is suspected of having cellular or tissue injury (abstract teaches methods for analyzing plasma samples from patients that have or is suspected of having tissue injury, i.e. cellular or tissue injury), the method comprising: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject (page 16, section “cfDNA quantification” and Fig. 1 teaches mtcfDNA, i.e. mitochondrial cf-DNA, and ncfDNA, i.e. nuclear cf-DNA, were quantified from isolated cfDNA obtained from patient samples); and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA (page 16, section “cfDNA quantification”, teaches quantification and analysis of mtcfDNA and ncfDNA, i.e. the amount of mtcfDNA and ncfDNA reported and recorded; Figs. 3-4 teaches reported and recorded levels, i.e. amounts, of mtcfDNA and ncfDNA). Andargie teaches analyzing cfDNA as a biomarker of injury to define sources of tissue injury (abstract). Andargie teaches sources of tissue injury, such as the heart, that contribute to different clinical trajectories remain poorly defined (page 1, first paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of App ‘719 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA for analyzing tissue injury to provide: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject; and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 3, App ‘719 fails to recite: wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time.
Andargie further teaches wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time (page 4, last paragraph and Fig. 6 teaches amounts of ncfDNA are obtained from patients over multiple days).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of App ‘719 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA over multiple days to provide wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 11, App ‘719 fails to recite: wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury.
Andargie further teaches wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury (abstract, page 1 first paragraph, and page 2, second paragraph teaches COVID-19 can lead to tissue injury, such as damage to the heart; page 4, last paragraph and Fig. 6 teaches amounts of ncfDNA are obtained from COVID-19 patients over multiple days; page 15, paragraphs 1 and 4 teaches cfDNA provides a comprehensive profile of tissue injury in patients with COVID-19; therefore, the amounts of at least ncfDNA is determined at least 12 hours after cellular or tissue injury due to the patient having COVID-19, which is interpreted as the patient including at least some cellular or tissue injury).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of App ‘719 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA over multiple days to provide wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 13, App ‘719 further recites wherein the cellular or tissue injury is surgery (claim 1 recites a transplant subject and assessing the grade of cellular rejection, therefore the subject’s cellular or tissue injury is from transplant surgery), such as cardiac surgery, or cardiopulmonary bypass (interpreted as not required).
Regarding claim 24, App ‘719 further recites wherein the subject is a subject that has undergone surgery (claim 1 recites a transplant subject and assessing the grade of cellular rejection, therefore the subject’s cellular or tissue injury is from transplant surgery), such as cardiac surgery, or cardiopulmonary bypass or is one with or suspected to have myocardial injury (interpreted as not required).
Regarding claim 27, App ‘719 fails to recite: wherein the subject is a pediatric subject.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the subject of App ‘719 to provide wherein the subject is a pediatric subject. Doing so would have a reasonable expectation of successfully improving assessing various ages of subjects known in the art, such as pediatric or adult subjects.
Regarding claim 29, App ‘719 further recites wherein the subject is one that has or is suspected of having a need for mechanical circulatory support (MCS), or is at increased risk of cardiac arrest, needing MCS, death, or any combination thereof (claim 1 recites the subject has, is suspected of having, has had, or is at risk of having cardiac arrest).
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3, 11, 13, 24, 27, and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 51 and 67 of copending Application No. 17/349,041 (herein, “App ‘041”) in view of Andargie et al. (ANDARGIE et al., Cell-free DNA maps COVID-19 tissue injury and risk of death and can cause tissue injury. JCI Insight. 2021 Apr 8;6(7):e147610. doi: 10.1172/jci.insight.147610; cited in the IDS filed 02/21/2024).
Regarding claim 51, App ‘041 recites a method of assessing a sample from a subject (claim 51 recites determining an amount of total cf-DNA in a sample from a surgical subject) that has or is suspected of having cellular or tissue injury (claim 67 recites the surgical subject has or is suspected of having organ injury, i.e. cellular or tissue injury), the method comprising:
(a) determining an amount of cell-free DNA in a sample taken from the subject (claim 1); and
(b) optionally, reporting and/or recording the amount of cf-DNA (interpreted as not required).
App ‘041 fails to recite: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject; and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA.
Andargie teaches a method of assessing a sample from a subject that has or is suspected of having cellular or tissue injury (abstract teaches methods for analyzing plasma samples from patients that have or is suspected of having tissue injury, i.e. cellular or tissue injury), the method comprising: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject (page 16, section “cfDNA quantification” and Fig. 1 teaches mtcfDNA, i.e. mitochondrial cf-DNA, and ncfDNA, i.e. nuclear cf-DNA, were quantified from isolated cfDNA obtained from patient samples); and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA (page 16, section “cfDNA quantification”, teaches quantification and analysis of mtcfDNA and ncfDNA, i.e. the amount of mtcfDNA and ncfDNA reported and recorded; Figs. 3-4 teaches reported and recorded levels, i.e. amounts, of mtcfDNA and ncfDNA). Andargie teaches analyzing cfDNA as a biomarker of injury to define sources of tissue injury (abstract). Andargie teaches sources of tissue injury, such as the heart, that contribute to different clinical trajectories remain poorly defined (page 1, first paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of App ‘041 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA for analyzing tissue injury to provide: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject; and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 3, App ‘041 fails to recite: wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time.
Andargie further teaches wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time (page 4, last paragraph and Fig. 6 teaches amounts of ncfDNA are obtained from patients over multiple days).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of App ‘041 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA over multiple days to provide wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 11, App ‘041 fails to recite: wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury.
Andargie further teaches wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury (abstract, page 1 first paragraph, and page 2, second paragraph teaches COVID-19 can lead to tissue injury, such as damage to the heart; page 4, last paragraph and Fig. 6 teaches amounts of ncfDNA are obtained from COVID-19 patients over multiple days; page 15, paragraphs 1 and 4 teaches cfDNA provides a comprehensive profile of tissue injury in patients with COVID-19; therefore, the amounts of at least ncfDNA is determined at least 12 hours after cellular or tissue injury due to the patient having COVID-19, which is interpreted as the patient including at least some cellular or tissue injury).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of App ‘041 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA over multiple days to provide wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 13, App ‘041 further recites wherein the cellular or tissue injury is surgery (claim 1 recites a surgical subject and claim 67 teaches the subject has or is suspected of organ injury, therefore the subject’s cellular or tissue injury is from surgery), such as cardiac surgery, or cardiopulmonary bypass (interpreted as not required).
Regarding claim 24, App ‘041 further recites wherein the subject is a subject that has undergone surgery (claim 1 recites a surgical subject; therefore the subject has undergone surgery), such as cardiac surgery, or cardiopulmonary bypass or is one with or suspected to have myocardial injury (interpreted as not required).
Regarding claim 27, App ‘041 fails to recite: wherein the subject is a pediatric subject.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the subject of App ‘041 to provide wherein the subject is a pediatric subject. Doing so would have a reasonable expectation of successfully improving assessing various ages of subjects known in the art, such as pediatric or adult subjects.
Regarding claim 29, App ‘041 fails to recite: wherein the subject is one that has or is suspected of having a need for mechanical circulatory support (MCS), or is at increased risk of cardiac arrest, needing MCS, death, or any combination thereof.
Andargie further teaches wherein the subject is one that has or is suspected of having a need for mechanical circulatory support (MCS), or is at increased risk of cardiac arrest, needing MCS, death, or any combination thereof (abstract teaches COVID-19 patients, where the clinical course of COVID-19 ranges from mild to severe multiorgan failure and death; page 12, first paragraph teaches patients with COVID-19 are at risk of severe disease and death; therefore, the subject or patient is interpreted as at increased risk of at least death).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the subject of App ‘041 to incorporate Andargie’s teachings of assessing organs for failure and patient death to provide: wherein the subject is one that has or is suspected of is at increased risk of death. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3, 11, 13, 24, 27, and 29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 9 of U.S. Patent No. 10,385,396 (herein, Patent ‘396) in view of Andargie et al. (ANDARGIE et al., Cell-free DNA maps COVID-19 tissue injury and risk of death and can cause tissue injury. JCI Insight. 2021 Apr 8;6(7):e147610. doi: 10.1172/jci.insight.147610; cited in the IDS filed 02/21/2024).
Regarding claim 51, Patent ‘396 recites a method of assessing a sample from a subject (claim 1 recites determining an amount of cf-DNA in a sample from subject that is a recipient of a transplant) that has or is suspected of having cellular or tissue injury (claim 2 recites the risk associated with the transplant includes injury to the transplant, i.e. cellular or tissue injury), the method comprising:
(a) determining an amount of cell-free DNA in a sample taken from the subject (claim 1); and
(b) optionally, reporting and/or recording the amount of cf-DNA (interpreted as not required).
Patent ‘396 fails to recite: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject; and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA.
Andargie teaches a method of assessing a sample from a subject that has or is suspected of having cellular or tissue injury (abstract teaches methods for analyzing plasma samples from patients that have or is suspected of having tissue injury, i.e. cellular or tissue injury), the method comprising: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject (page 16, section “cfDNA quantification” and Fig. 1 teaches mtcfDNA, i.e. mitochondrial cf-DNA, and ncfDNA, i.e. nuclear cf-DNA, were quantified from isolated cfDNA obtained from patient samples); and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA (page 16, section “cfDNA quantification”, teaches quantification and analysis of mtcfDNA and ncfDNA, i.e. the amount of mtcfDNA and ncfDNA reported and recorded; Figs. 3-4 teaches reported and recorded levels, i.e. amounts, of mtcfDNA and ncfDNA). Andargie teaches analyzing cfDNA as a biomarker of injury to define sources of tissue injury (abstract). Andargie teaches sources of tissue injury, such as the heart, that contribute to different clinical trajectories remain poorly defined (page 1, first paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Patent ‘396 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA for analyzing tissue injury to provide: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject; and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 3, Patent ‘396 fails to recite: wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time.
Andargie further teaches wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time (page 4, last paragraph and Fig. 6 teaches amounts of ncfDNA are obtained from patients over multiple days).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Patent ‘396 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA over multiple days to provide wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 11, Patent ‘396 fails to recite: wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury.
Andargie further teaches wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury (abstract, page 1 first paragraph, and page 2, second paragraph teaches COVID-19 can lead to tissue injury, such as damage to the heart; page 4, last paragraph and Fig. 6 teaches amounts of ncfDNA are obtained from COVID-19 patients over multiple days; page 15, paragraphs 1 and 4 teaches cfDNA provides a comprehensive profile of tissue injury in patients with COVID-19; therefore, the amounts of at least ncfDNA is determined at least 12 hours after cellular or tissue injury due to the patient having COVID-19, which is interpreted as the patient including at least some cellular or tissue injury).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Patent ‘396 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA over multiple days to provide wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 13, Patent ‘396 further recites wherein the cellular or tissue injury is surgery (claim 1 recites a subject that is a recipient of a transplant and claim 2 recites the risk of the transplant is injury to the transplant, therefore the subject’s cellular or tissue injury is from surgery, i.e. transplant surgery), such as cardiac surgery, or cardiopulmonary bypass (interpreted as not required).
Regarding claim 24, Patent ‘396 further recites wherein the subject is a subject that has undergone surgery (claim 1 recites the subject is a recipient of a transplant; therefore the subject has undergone surgery), such as cardiac surgery, or cardiopulmonary bypass or is one with or suspected to have myocardial injury (interpreted as not required).
Regarding claim 27, Patent ‘396 recite: wherein the subject is a pediatric subject (claim 9).
Regarding claim 29, Patent ‘396 fails to recite: wherein the subject is one that has or is suspected of having a need for mechanical circulatory support (MCS), or is at increased risk of cardiac arrest, needing MCS, death, or any combination thereof.
Andargie further teaches wherein the subject is one that has or is suspected of having a need for mechanical circulatory support (MCS), or is at increased risk of cardiac arrest, needing MCS, death, or any combination thereof (abstract teaches COVID-19 patients, where the clinical course of COVID-19 ranges from mild to severe multiorgan failure and death; page 12, first paragraph teaches patients with COVID-19 are at risk of severe disease and death; therefore, the subject or patient is interpreted as at increased risk of at least death).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the subject of Patent ‘396 to incorporate Andargie’s teachings of assessing organs for failure and patient death to provide: wherein the subject is one that has or is suspected of is at increased risk of death. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Claims 1, 3, 11, 13, 24, 27, and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of copending Application No. 16/504,469 (herein, “App ‘469”) in view of Andargie et al. (ANDARGIE et al., Cell-free DNA maps COVID-19 tissue injury and risk of death and can cause tissue injury. JCI Insight. 2021 Apr 8;6(7):e147610. doi: 10.1172/jci.insight.147610; cited in the IDS filed 02/21/2024).
Regarding claim 51, App ‘469 recites a method of assessing a sample from a subject (claim 51 recites determining an amount of cf-DNA in a sample from a subject that is a recipient of a transplant) that has or is suspected of having cellular or tissue injury (claim 2 recites the transplant has a risk of injury, i.e. cellular or tissue injury), the method comprising:
(a) determining an amount of cell-free DNA in a sample taken from the subject (claim 1); and
(b) optionally, reporting and/or recording the amount of cf-DNA (interpreted as not required).
App ‘469 fails to recite: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject; and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA.
Andargie teaches a method of assessing a sample from a subject that has or is suspected of having cellular or tissue injury (abstract teaches methods for analyzing plasma samples from patients that have or is suspected of having tissue injury, i.e. cellular or tissue injury), the method comprising: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject (page 16, section “cfDNA quantification” and Fig. 1 teaches mtcfDNA, i.e. mitochondrial cf-DNA, and ncfDNA, i.e. nuclear cf-DNA, were quantified from isolated cfDNA obtained from patient samples); and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA (page 16, section “cfDNA quantification”, teaches quantification and analysis of mtcfDNA and ncfDNA, i.e. the amount of mtcfDNA and ncfDNA reported and recorded; Figs. 3-4 teaches reported and recorded levels, i.e. amounts, of mtcfDNA and ncfDNA). Andargie teaches analyzing cfDNA as a biomarker of injury to define sources of tissue injury (abstract). Andargie teaches sources of tissue injury, such as the heart, that contribute to different clinical trajectories remain poorly defined (page 1, first paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of App ‘469 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA for analyzing tissue injury to provide: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject; and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 3, App ‘469 fails to recite: wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time.
Andargie further teaches wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time (page 4, last paragraph and Fig. 6 teaches amounts of ncfDNA are obtained from patients over multiple days).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of App ‘469 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA over multiple days to provide wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 11, App ‘469 fails to recite: wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury.
Andargie further teaches wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury (abstract, page 1 first paragraph, and page 2, second paragraph teaches COVID-19 can lead to tissue injury, such as damage to the heart; page 4, last paragraph and Fig. 6 teaches amounts of ncfDNA are obtained from COVID-19 patients over multiple days; page 15, paragraphs 1 and 4 teaches cfDNA provides a comprehensive profile of tissue injury in patients with COVID-19; therefore, the amounts of at least ncfDNA is determined at least 12 hours after cellular or tissue injury due to the patient having COVID-19, which is interpreted as the patient including at least some cellular or tissue injury).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of App ‘469 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA over multiple days to provide wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 13, App ‘469 further recites wherein the cellular or tissue injury is surgery (claim 1 recites the subject is a recipient of a transplant, therefore the subject’s cellular or tissue injury is from transplant surgery), such as cardiac surgery, or cardiopulmonary bypass (interpreted as not required).
Regarding claim 24, App ‘469 further recites wherein the subject is a subject that has undergone surgery (claim 1 recites a subject is a recipient of a transplant ; therefore the subject has undergone surgery), such as cardiac surgery, or cardiopulmonary bypass or is one with or suspected to have myocardial injury (interpreted as not required).
Regarding claim 27, App ‘469 fails to recite: wherein the subject is a pediatric subject.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the subject of App ‘469 to provide wherein the subject is a pediatric subject. Doing so would have a reasonable expectation of successfully improving assessing various ages of subjects known in the art, such as pediatric or adult subjects.
Regarding claim 29, App ‘469 fails to recite: wherein the subject is one that has or is suspected of having a need for mechanical circulatory support (MCS), or is at increased risk of cardiac arrest, needing MCS, death, or any combination thereof.
Andargie further teaches wherein the subject is one that has or is suspected of having a need for mechanical circulatory support (MCS), or is at increased risk of cardiac arrest, needing MCS, death, or any combination thereof (abstract teaches COVID-19 patients, where the clinical course of COVID-19 ranges from mild to severe multiorgan failure and death; page 12, first paragraph teaches patients with COVID-19 are at risk of severe disease and death; therefore, the subject or patient is interpreted as at increased risk of at least death).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the subject of App ‘469 to incorporate Andargie’s teachings of assessing organs for failure and patient death to provide: wherein the subject is one that has or is suspected of is at increased risk of death. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3, 11, 13, 24, 27, and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 3 of copending Application No. 16/666,210 (herein, “App ‘210”) in view of Andargie et al. (ANDARGIE et al., Cell-free DNA maps COVID-19 tissue injury and risk of death and can cause tissue injury. JCI Insight. 2021 Apr 8;6(7):e147610. doi: 10.1172/jci.insight.147610; cited in the IDS filed 02/21/2024).
Regarding claim 51, App ‘210 recites a method of assessing a sample from a subject (claim 51 recites determining an amount of cf-DNA in a sample from a subject that is a recipient of a transplant) that has or is suspected of having cellular or tissue injury (claim 3 recites the transplant has a risk of injury, i.e. cellular or tissue injury), the method comprising:
(a) determining an amount of cell-free DNA in a sample taken from the subject (claim 1); and
(b) optionally, reporting and/or recording the amount of cf-DNA (interpreted as not required).
App ‘210 fails to recite: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject; and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA.
Andargie teaches a method of assessing a sample from a subject that has or is suspected of having cellular or tissue injury (abstract teaches methods for analyzing plasma samples from patients that have or is suspected of having tissue injury, i.e. cellular or tissue injury), the method comprising: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject (page 16, section “cfDNA quantification” and Fig. 1 teaches mtcfDNA, i.e. mitochondrial cf-DNA, and ncfDNA, i.e. nuclear cf-DNA, were quantified from isolated cfDNA obtained from patient samples); and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA (page 16, section “cfDNA quantification”, teaches quantification and analysis of mtcfDNA and ncfDNA, i.e. the amount of mtcfDNA and ncfDNA reported and recorded; Figs. 3-4 teaches reported and recorded levels, i.e. amounts, of mtcfDNA and ncfDNA). Andargie teaches analyzing cfDNA as a biomarker of injury to define sources of tissue injury (abstract). Andargie teaches sources of tissue injury, such as the heart, that contribute to different clinical trajectories remain poorly defined (page 1, first paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of App ‘210 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA for analyzing tissue injury to provide: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject; and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 3, App ‘210 fails to recite: wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time.
Andargie further teaches wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time (page 4, last paragraph and Fig. 6 teaches amounts of ncfDNA are obtained from patients over multiple days).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of App ‘210 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA over multiple days to provide wherein one or more further amounts of mitochondrial cf-DNA and/or nuclear cf-DNA are obtained from a sample taken from the subject at a different point in time. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 11, App ‘210 fails to recite: wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury.
Andargie further teaches wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury (abstract, page 1 first paragraph, and page 2, second paragraph teaches COVID-19 can lead to tissue injury, such as damage to the heart; page 4, last paragraph and Fig. 6 teaches amounts of ncfDNA are obtained from COVID-19 patients over multiple days; page 15, paragraphs 1 and 4 teaches cfDNA provides a comprehensive profile of tissue injury in patients with COVID-19; therefore, the amounts of at least ncfDNA is determined at least 12 hours after cellular or tissue injury due to the patient having COVID-19, which is interpreted as the patient including at least some cellular or tissue injury).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of App ‘210 to incorporate Andargie’s teachings of measuring mtcfDNA and ncfDNA over multiple days to provide wherein at least one amount of mitochondrial cf-DNA and/or nuclear cf-DNA is determined 12 hours or more after the cellular or tissue injury or wherein at least one amount of mitochondrial cf-DNA is determined 12 or more hours after the cellular or tissue injury and at least one amount of nuclear cf-DNA is determined 24 hours or more after the cellular or tissue injury. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
Regarding claim 13, App ‘210 further recites wherein the cellular or tissue injury is surgery (claim 1 recites the subject is a recipient of a transplant, therefore the subject’s cellular or tissue injury is from transplant surgery), such as cardiac surgery, or cardiopulmonary bypass (interpreted as not required).
Regarding claim 24, App ‘210 further recites wherein the subject is a subject that has undergone surgery (claim 1 recites a subject is a recipient of a transplant ; therefore the subject has undergone surgery), such as cardiac surgery, or cardiopulmonary bypass or is one with or suspected to have myocardial injury (interpreted as not required).
Regarding claim 27, App ‘210 fails to recite: wherein the subject is a pediatric subject.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the subject of App ‘210 to provide wherein the subject is a pediatric subject. Doing so would have a reasonable expectation of successfully improving assessing various ages of subjects known in the art, such as pediatric or adult subjects.
Regarding claim 29, App ‘210 fails to recite: wherein the subject is one that has or is suspected of having a need for mechanical circulatory support (MCS), or is at increased risk of cardiac arrest, needing MCS, death, or any combination thereof.
Andargie further teaches wherein the subject is one that has or is suspected of having a need for mechanical circulatory support (MCS), or is at increased risk of cardiac arrest, needing MCS, death, or any combination thereof (abstract teaches COVID-19 patients, where the clinical course of COVID-19 ranges from mild to severe multiorgan failure and death; page 12, first paragraph teaches patients with COVID-19 are at risk of severe disease and death; therefore, the subject or patient is interpreted as at increased risk of at least death).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the subject of App ‘210 to incorporate Andargie’s teachings of assessing organs for failure and patient death to provide: wherein the subject is one that has or is suspected of is at increased risk of death. Doing so would have a reasonable expectation of successfully improving characterization and assessing tissue injury and clinical trajectory of the transplant subject.
This is a provisional nonstatutory double patenting rejection.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Chou et al. (CHOU et al., Plasma nuclear DNA and mitochondrial DNA as prognostic markers in corrosive injury patients. Dig Surg. 2008;25(4):300-4. doi: 10.1159/000152846. Epub 2008 Sep 4; cited in the IDS filed 07/15/2026) teaches a method of assessing a sample from a subject that has or is suspected of having cellular or tissue injury (abstract, “study objectives” and “methods” teaches the study examines patients for corrosive injury), the method comprising:
(a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject (abstract, “methods” teaches nuclear and mtDNA); and
(b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA (abstract, “methods” and “conclusion”).
Gogenur et al. (GOGENUR et al., The role of total cell-free DNA in predicting outcomes among trauma patients in the intensive care unit: a systematic review. Crit Care. 2017 Jan 24;21(1):14. doi: 10.1186/s13054-016-1578-9; cited in the IDS filed 07/15/2026) teaches reviewing whether cell-free DNA is a useful prognostic biomarkers in trauma patients (abstract). Gogenur teaches the value of nDNA and mtDNA should be investigated in patients undergoing major elective surgery (section, “conclusion”).
Lo et al. (US 20160203260 A1) teaches a method of assessing a sample from a subject that has or is suspected of having cellular or tissue injury (abstract and [0155] teaches monitoring conditions, such as tissue damage), the method comprising: (a) determining an amount of mitochondrial cell-free DNA (mitochondrial cf-DNA) and/or nuclear cf-DNA in a sample taken from the subject (abstract teaches measuring mitochondrial and nuclear DNA; [0088] teaches cell-free DNA of the biological sample include mitochondrial DNA and nuclear DNA); and (b) optionally, reporting and/or recording the amount of mitochondrial cf-DNA and/or nuclear cf-DNA ([0051]).
Arnalich et al. (Arnalich et al., “Circulating cell-free mitochondrial DNA: A better early prognostic marker in patients with out-of-hospital cardiac arrest”, Resuscitation 83 (2012) e162– e163) teaches plasma levels of cell-free mtDNA and nDNA can help physicians in the outcome prediction after cardiac arrest (e162, right column, first full paragraph). Arnalich teaches the amount of plasma mtDNA could be a new good marker for the intensity of injury in patients after out of hospital cardiac arrest (e126, left column, second paragraph).
Qin et al. (Qin et al., “Release of mitochondrial DNA correlates with peak inflammatory cytokines in patients with acute myocardial infarction”, Oct 5 2016, Anatol J Cardiol; 17: 224-8) teaches exploration of the dynamic changes of plasma mitochondrial deoxyribonucleic acid (mtDNA) and inflammatory level in patients with acute myocardial infarction (abstract), including collecting blood samples of patients on admission, 12 hour, 24, hour and 28 hour post-percutaneous coronary intervention (abstract).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HENRY H NGUYEN whose telephone number is (571)272-2338. The examiner can normally be reached M-F 7:30A-5:00P.
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/HENRY H NGUYEN/ Primary Examiner, Art Unit 1758
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