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 .
Status of the Claims
Claims 1 and 3-19 are pending in the application and under consideration. Claims 1, 4, 17, and 19 have been amended. Claim 2 has been cancelled. All previously set forth 112(b) rejections have been overcome and subsequently withdrawn herein.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on June 1st, 2026 has been entered.
Response to Arguments
Applicant's arguments filed June 1st, 2026 have been fully considered but they are not persuasive.
Regarding the rejection of claim 1, while the amended claim limitation is seen to overcome the prior presented rejection, in light of the teachings of Spearman (U.S. Publication 2017/0246375) the newly added limitation is seen to have been obvious to one of ordinary skill in the art (see below rejection of claim 1).
Regarding applicant’s argument that it is not clear that Braun correlates the reduction of cf-DNA as for treatment versus as a predictive element, examiner disagrees in that Braun specifically describes in the objectives that extracorporeal cytokine elimination is a novel promising technique to reduce postoperative inflammation and to improve postoperative recovery which indicates the cytokine elimination as being drawn toward a treatment of a condition of the patient to improve recovery and the conclusion specifically mentions the cf-DNA being eliminated during treatment and usage of such a cf-DNA eliminator reducing the trauma caused by CPB and thus treating. As such this argument is not found to be persuasive.
Regarding applicant’s argument that Braun does not mention the use of a ventilator or ECMO device, this argument is not found to be persuasive as the current rejection does not rely on Braun to teach these elements but rather relies on the teachings of Spearman as seen in the below rejection.
Regarding applicant’s argument that neither reference ties a particular threshold level of total cf-DNA with the treatment of the claims, examiner disagrees in that Braun specifically relates in the conclusion an immediate effect of the CfDNA and NETs elimination being a reduction in release of proinflammatory cytokines and Mitchell specifically teaches on page 20 lines 1-2 “the threshold values can also be used for comparisons to make treatment and/or monitoring decisions” and on Page 1 lines 26-33 that “it has also been found that the levels of Ds cf-DNA and/or total cf-DNA in a subject with a ”normal or desirable course decrease over the first several days post transplant to a baseline level. Thus, the methods and compositions can be used to monitor transplant subjects over time post transplant. Deviations from a “normal” or desirable course may be indicative of one or more transplant complications and/or need for additional monitoring or treatment,” and therefore is seen to suggest utilizing threshold values for determining whether to provide a treatment to the patient, furthermore one would be motivated to provide treatment based on the total cf-DNA threshold suggested by Mitchell as Mitchell has disclosed these levels being indicative of subjects being at risk of complications and Braun has discloses the advantage of eliminating cf-DNA. One cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
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.
Claim(s) 1 and 3-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Braun et al. 2019 (see attached NPL reference “Limitation of Circulating cfDNA Under the Use of a Cytokine Elimination Adsorber (CytoSorbTM) in Cardiac Surgery”) in view of Mitchell et al. (WIPO Publication 2018/237081) and Spearman (U.S. Publication 2017/0246375).
Regarding claim 1, Braun discloses a method of treating a subject in need of mechanical support, the method comprising inhibiting the amount of cf-DNA in the subject (Conclusion: CfDNA elimination using a CytoSorbTM adsorber has an immediate effect of reducing release of proinflammatory cytokines) wherein the subject is treated using mechanical support that comprises a filter that reduces the level of cf-DNA in the subject (objectives patients undergoing cardiac surgery requiring CPB (cardiopulmonary bypass) while using a CytoSorb cytokine adsorber; methods: Patients divided into 3 groups; Conclusion: CfDNA…elimination using a CytoSorb adsorber is feasible and safe).
Braun does not expressly disclose the subject having a total cf-DNA level over 50 ng/mL, or the mechanical support comprising a ventilator and/or ECMO device.
However, regarding the total cf-DNA level, Mitchell, in the same field of endeavor of cf-DNA patient level determination, teaches providing a treatment to a subject exhibiting an amount of total cf-DNA equal to 8 ng/mL or greater as patients with this amount of cf-DNA or greater are seen to have a greater risk of complications including cardiac arrest (Page 20 lines 1-2 the threshold values can also be used for comparisons to make treatment decisions; lines 20-27 an amount equal to or greater than 8 or 9 ng/mL may be indicative of cardiac arrest; Page 1 lines 26-33 that “it has also been found that the levels of Ds cf-DNA and/or total cf-DNA in a subject with a ”normal or desirable course decrease over the first several days post transplant to a baseline level. Thus, the methods and compositions can be used to monitor transplant subjects over time post transplant. Deviations from a “normal” or desirable course may be indicative of one or more transplant complications and/or need for additional monitoring or treatment,”).
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 Braun to have treated a subject having a total cf-DNA level over 50 ng/mL, as Mitchell teaches that subjects with 8 ng/mL or greater have a greater risk of complications including cardiac arrest, and since it has been held that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art' a prima facie case of obviousness exists”. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). In the instant case, Braun in view of Mitchell would not operate differently with the claimed range as Mitchell is disclosed to operate with subjects having 8 ng/mL or greater which would include any levels over 50 ng/mL and the ability of the device to reduce cf-DNA is not limited by the level of cf-DNA present. Furthermore, applicant places no criticality on the ranged claimed, indicating simply that 50 ng/mL indicates an increased likelihood of death, cardiac arrest, or mechanical circulatory support with 25 ng/mL indicating longer hospital length of stay, and levels over 10 ng/mL predicted presence of infections (Page 7 lines 1-14 of applicant’s specification), showing that a subject is treated to other thresholds below the greater than 50 ng/mL threshold, and as such not shown to be critical to the treatment of the patient. As such it would have been obvious to one of ordinary skill in the art before the effective filing date to have treated a subject having a total cf-DNA level of over 50 ng/mL as this lies inside the range disclosed by the prior art and one would have treated a patient with 50 ng/mL total cf-DNA utilizing.
Regarding the mechanical support comprising a ventilator and/or ECMO device, Spearman, in the same field of endeavor of extracorporeal circuits for patient treatment (Abstract treat blood outside the body of a patient) discloses a method (Fig. 10) of treating a subject in need of mechanical support (abstract treat blood outside the body of a patient, patient in need of treatment, mechanical support includes extracorporeal circuit and support system 103) wherein the subject is treated using a mechanical support (system of Fig. 8) comprising a ventilator (¶0078 support system can be used to sedate the patient and can include a ventilator and an ECMO device (step 1008 blood is oxygenated to add oxygen from the blood; ¶0069 oxygenator can be implemented using a microporous membrane made of hollow fibers that are permeable to gas but impermeable to blood) for the purpose of providing a patient with oxygen (¶00669 oxygen…administered by a ventilator) such that damage due to pulmonary complications, cardiac decompensation or other conditions is reduced (¶0069 the use of oxygenator can be useful due to, pulmonary complications, cardiac decompensation, a patient’s need for oxygen to reduce the risk of damage above the amount that can be administered by a ventilator).
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 cardiopulmonary bypass mechanical support of Braun including a CytoSorb filter for filtering cf-DNA to have included the ventilator and oxygenator, as taught by Spearman, since it has been held that a particular known technique was recognized as part of the ordinary capabilities of one skilled in the art. One of ordinary skill in the art would have been capable of applying this known technique to a known device (method, or product) that was ready for improvement and the results would have been predictable to one of ordinary skill in the art. This known technique of providing an oxygenator and ventilator with an extracorporeal mechanical support would have yielded predictable results of allowing both the filtration of the desired components from the blood and providing sufficient oxygen to a patient. This would result in reducing the risk of damage to the patient during the cardiopulmonary bypass procedure due to hypoxia as taught by Spearman (¶0069 the use of oxygenator can be useful due to, pulmonary complications, cardiac decompensation, a patient’s need for oxygen to reduce the risk of damage). See MPEP 2143.
Regarding claim 3, Braun in view of Mitchell and Spearman suggest the method of claim 2. Braun further discloses the mechanical support further comprises a cardiopulmonary bypass device (Objectives: using cardiopulmonary bypass).
Regarding claim 4, Braun in view of Mitchell and Spearman suggest the method of claim 2. Braun further discloses the filter comprising an extracorporeal cytokine adsorber (Objectives: extracorporeal cytokine elimination…using a CytoSorb cytokine adsorber).
Regarding claim 5, Braun in view of Mitchell and Spearman suggest the method of claim 1. Braun further discloses the subject being treated by administration of a cf-DNA inhibitor to the subject (Methods: CytoSorbTM adsorber administered to on-pump group, Conclusion: cfDNA eliminated using CytoSorbTM adsorber and thus inhibited from further action within the patients’ blood streams).
Regarding claim 6, Braun in view of Mitchell and Spearman suggest the method of claim 1. Braun further discloses the method further comprises administering an additional therapy or treatment to the subject (Administration of Cardiopulmonary bypass to patient).
Regarding claim 7, Braun in view of Mitchell and Spearman suggest the method of claim 6. Braun further discloses the additional therapy or treatment is any one of the therapies or treatments provided herein (Cardiopulmonary bypass treatment).
Regarding claim 8, Braun in view of Mitchell and Spearman suggest the method of claim 1. Braun further discloses the subject is any one of the subjects described herein (subject in need of Cardiopulmonary bypass treatment).
Regarding claim 9, Braun in view of Mitchell and Spearman suggest the method of claim 1. Braun further discloses the method further comprises determining an amount of cf-DNA in one or more samples from the subject (Results: both on-pump groups had significant 1.5-fold increase of cfDNA, levels of cfDNA quantified using Pico Green Staining).
Regarding claim 10, Braun in view of Mitchell and Spearman suggest the method of claim 1. Braun further discloses the method further comprises comparing the amount of cf-DNA to a threshold (Results: compares to normal cfDNA levels, showed a significant earlier normalization of cfDNA levels) and at least one prior amount of cf-DNA (Results 1.5-fold increase of cfDNA compared with baseline).
Regarding claim 11, Braun in view of Mitchell and Spearman suggest the method of claim 10. Braun further discloses the threshold is any one of the thresholds provided herein (Results compares to normal cfDNA levels).
Regarding claim 12, Braun in view of Mitchell and Spearman suggest the method of claim 1. Braun further discloses the subject is one with, such as one who was determined to have, a level of cf-DNA greater than any one of the thresholds provided herein (Results: both on-pump groups had a significant 1.5 fold increase and on-pump CytosorbTM group showed a significant earlier normalization of cfDNA levels).
Regarding claims 13 and 14, Braun in view of Mitchell and Spearman suggest the method of claim 9. Braun does not expressly disclose the amount of cf-DNA being determined or obtained using an amplification-based quantification assay wherein the amplification-based quantification assay is quantitative real-time PCR (qRT-PCR) or digital PCR, as Braun discloses obtaining the amount of cf-DNA through Pico-green fluorescence.
However, Mitchell, in the same field of endeavor of cf-DNA patient level determination, further teaches the amount of cf-DNA being determined or obtained using an amplification-based quantification assay wherein the amplification-based quantification assay is quantitative real-time PCR (qRT-PCR) (Page 23 lines 12-31 amplification-based quantification assay, such as quantitative PCR; Page 27 lines 27-33 Quantitative PCR including real-time PCR).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the Pico-green assay of Braun that performs the function of quantifying the amount of cf-DNA of a patient for the quantitative real-time PCR assay of Mitchell since these elements perform the same function of quantifying the concentration of plasma free-cell DNA of a patient sample. Simply substituting one cell-free DNA quantifying means for another would yield the predictable result of allowing a(n) amount of cell-free DNA of a patient to be quantified for analysis. See MPEP 2143.
Regarding claim 15, Braun in view of Mitchell and Spearman suggests the method of claim 9. Braun further discloses the level of cf-DNA is determined in the subject daily (Methods: collected at 1 hour and 24 hours resulting in a daily determination).
Regarding claim 16, Braun in view of Mitchell and Spearman suggests the method of claim 1. Braun further discloses the mechanical support and filter are part of a system that is used on the subject (Objectives: patients undergoing cardiac surgery requiring CPB while using a CytoSorbTM cytokine adsorber).
Regarding claim 17, Braun discloses a mechanical support system or circuit that comprises a mechanical support device comprising a filter that reduces the level of cf-DNA in the subject (objectives patients undergoing cardiac surgery requiring CPB (cardiopulmonary bypass) while using a CytoSorb cytokine adsorber; methods: Patients divided into 3 groups; Conclusion: CfDNA…elimination using a CytoSorb adsorber is feasible and safe) connected to a subject (objectives: CPB while using a CytoSorb cytokine adsorber and on-pump disclose connection to subject).
Braun does not expressly disclose the subject having a total cf-DNA level over 50 ng/mL, or the mechanical support comprising a ventilator and/or ECMO device.
However, regarding the total cf-DNA level, Mitchell, in the same field of endeavor of cf-DNA patient level determination, teaches providing a treatment to a subject exhibiting an amount of total cf-DNA equal to 8 ng/mL or greater as patients with this amount of cf-DNA or greater are seen to have a greater risk of complications including cardiac arrest (Page 20 lines 20-27 an amount equal to or greater than 8 or 9 ng/mL may be indicative of cardiac arrest; Page 1 lines 26-33 that “it has also been found that the levels of Ds cf-DNA and/or total cf-DNA in a subject with a ”normal or desirable course decrease over the first several days post transplant to a baseline level. Thus, the methods and compositions can be used to monitor transplant subjects over time post transplant. Deviations from a “normal” or desirable course may be indicative of one or more transplant complications and/or need for additional monitoring or treatment,”).
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 Braun to have treated a subject having a total cf-DNA level over 50 ng/mL, as Mitchell teaches that subjects with 8 ng/mL or greater have a greater risk of complications including cardiac arrest, and since it has been held that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art' a prima facie case of obviousness exists”. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). In the instant case, Braun in view of Mitchell would not operate differently with the claimed range as Mitchell is disclosed to operate with subjects having 8 ng/mL or greater which would include any levels over 50 ng/mL and the ability of the device to reduce cf-DNA is not limited by the level of cf-DNA present. Furthermore, applicant places no criticality on the ranged claimed, indicating simply that 50 ng/mL indicates an increased likelihood of death, cardiac arrest, or mechanical circulatory support with 25 ng/mL indicating longer hospital length of stay, and levels over 10 ng/mL predicted presence of infections (Page 7 lines 1-14 of applicant’s specification), showing that a subject is treated to other thresholds below the greater than 50 ng/mL threshold, and as such not shown to be critical to the treatment of the patient. As such it would have been obvious to one of ordinary skill in the art before the effective filing date to have treated a subject having a total cf-DNA level of over 50 ng/mL as this lies inside the range disclosed by the prior art and one would have treated a patient with 50 ng/mL total cf-DNA utilizing.
Regarding the mechanical support comprising a ventilator and/or ECMO device, Spearman, in the same field of endeavor of extracorporeal circuits for patient treatment (Abstract treat blood outside the body of a patient) discloses a method (Fig. 10) of treating a subject in need of mechanical support (abstract treat blood outside the body of a patient, patient in need of treatment, mechanical support includes extracorporeal circuit and support system 103) wherein the subject is treated using a mechanical support (system of Fig. 8) comprising a ventilator (¶0078 support system can be used to sedate the patient and can include a ventilator and an ECMO device (step 1008 blood is oxygenated to add oxygen from the blood; ¶0069 oxygenator can be implemented using a microporous membrane made of hollow fibers that are permeable to gas but impermeable to blood) for the purpose of providing a patient with oxygen (¶00669 oxygen…administered by a ventilator) such that damage due to pulmonary complications, cardiac decompensation or other conditions is reduced (¶0069 the use of oxygenator can be useful due to, pulmonary complications, cardiac decompensation, a patient’s need for oxygen to reduce the risk of damage above the amount that can be administered by a ventilator).
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 cardiopulmonary bypass mechanical support of Braun including a CytoSorb filter for filtering cf-DNA to have included the ventilator and oxygenator, as taught by Spearman, since it has been held that a particular known technique was recognized as part of the ordinary capabilities of one skilled in the art. One of ordinary skill in the art would have been capable of applying this known technique to a known device (method, or product) that was ready for improvement and the results would have been predictable to one of ordinary skill in the art. This known technique of providing an oxygenator and ventilator with an extracorporeal mechanical support would have yielded predictable results of allowing both the filtration of the desired components from the blood and providing sufficient oxygen to a patient. This would result in reducing the risk of damage to the patient during the cardiopulmonary bypass procedure due to hypoxia as taught by Spearman (¶0069 the use of oxygenator can be useful due to, pulmonary complications, cardiac decompensation, a patient’s need for oxygen to reduce the risk of damage). See MPEP 2143.
Regarding claim 18, Braun in view of Mitchell and Spearman suggest the mechanical support system of claim 17. Braun further discloses the mechanical support device further comprising a cardiopulmonary bypass device (Objectives: using cardiopulmonary bypass).
Regarding claim 19, Braun in view of Mitchell and Spearman suggest the mechanical support system of claim 17. Braun further discloses the filter comprising an extracorporeal cytokine adsorber (Objectives: extracorporeal cytokine elimination…using a CytoSorb cytokine adsorber).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Chan et al. (U.S. Publication 20240197977) discloses a cytokine adsorber in an extracorporeal circuit (¶0172).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER DANIEL SMITH whose telephone number is (571)272-8564. The examiner can normally be reached Monday - Friday 7:30am-5:00pm.
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/PETER DANIEL SMITH/Examiner, Art Unit 3781
/CATHARINE L ANDERSON/Primary Examiner, Art Unit 3781
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