Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/18/2025 has been entered.
DETAILED ACTION
Claims 2-12 and 14-19 are cancelled.
Claims 1, 13, and 20-25 are pending and under examination.
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 1, 13, and 20-25 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.
Claim 1 recites the limitation "the acute tissue injury" in line 10. There is insufficient antecedent basis for this limitation in the claim.
Claim 20 recites the limitation "the acute tissue injury" in line 11. There is insufficient antecedent basis for this limitation in the claim.
Claims 13 and 21-25 are rejected for depending from a rejected base claim and not rectifying the source of indefiniteness discussed above.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 1, 13, 20, 22, 23, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al. (Basic research in cardiology 110.2 (2015): 3) in view of Timmermans et al. (Intensive Care Med (2016) 42:551–561; cited in the Final Action mailed on 7/21/2025) and Vogel et al. (Basic Res Cardiol (2015) 110:15) as evidenced by Riley et al. (EMBO Rep. 2020 Apr 3;21(4):e49799), Bae et al. (Cells 8.4 (2019): 328), Schmid et al. (Vasc Cell. 2012 Sep 3;4(1):14), Millipore Sigma (2025 website), and Roche (1993 website).
Yang teaches that mtDNA serum levels rise in patients with acute myocardial infarction (page 3, right column, paragraph 3). Yang teaches that circulating (i.e. cell-free) mtDNA contributes to the systemic involvement associated with traumatic shock (page 3, right column, paragraph 4). mtDNA is a double-stranded DNA as evidenced by Riley (right column, top of first full paragraph). Yang teaches that mtDNA is released from the ischemic myocardium (page 7, right column, second paragraph, lines 1-3).
Yang hypothesizes that mtDNA may trigger inflammatory cytokine release that attacks and kills injured but otherwise viable cells (page 5, right column, paragraph 1). Yang suggests that DNase I could prevent accumulation of the mtDNA fragments by simply degrading them as they are released (page 5, right column, paragraph 1).
Yang teaches administering DNase I intravenously at reperfusion (page 1, middle of right column). Reperfusion is restoration of blood flow to tissues deprived of oxygen (i.e. ischemic tissues).
Circulating cell-free mtDNA induces activation of the AIM2-inflammasome in macrophages as evidenced by Bae (paragraph 3 on page 2). Macrophages are a type of myeloid cell as evidenced by Schmid (page 1, left column, Macrophages in normal and tumor biology, line 1). Thus, administering DNase I in any amount necessarily reduces activation of the AIM-2 inflammasome to at least some degree by degrading mtDNA.
Yang does not teach that DNase I is administered before immunosuppression occurs in the subject.
Timmermans teaches that trauma results in the release of DAMPs (danger‑associated molecular patterns), which are associated with a suppressed state of the immune system (final paragraph on page 560). DAMPs include mitochondrial DNA (mtDNA) and nuclear DNA (page 552; left column, bottom paragraph). Timmermans suggests that trauma at first initiates an early anti-inflammatory response (increase in IL-10) prior to immune suppression (Figure 4, Pre-hospital and Figures 1-2). Timmermans detects cytokine IL-10 in plasma from human subjects (page 553, right column, “Plasma cytokine concentrations”).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer the DNase I of Yang immediately after the traumatic event of myocardial infarction in order to decrease the risk of immunosuppression associated with mtDNA. The person of ordinary skill in the art would have had a reasonable expectation of success in administering the DNase I before immunosuppression occurs.
Yang does not teach that the DNase I is human recombinant DNase I. Rather, Yang’s DNase I is Sigma Aldrich catalogue # D5025 (Yang page 4, right column, bottom paragraph), which is bovine pancreatic DNase I, as evidenced by Millipore Sigma (Title).
Vogel teaches administering Pulmozyme® to mice with experimentally-induced myocardial infarction (page 2, right column, Experimental myocardial infarction and acute application of rhDNase 1). Purozyme® is human recombinant DNase I as evidenced by Roche (page 8, Mechanism of Action, paragraph 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to replace Yang’s bovine pancreatic DNase I with Vogel’s human recombinant DNase I. The person of ordinary skill in the art would have been motivated to improve Yang’s method by substituting a human enzyme in the rat model to better predict the outcome of administering DNase I to human subjects. The person of ordinary skill in the art would have had a reasonable expectation of success in the replacement of bovine pancreatic DNase I with human recombinant DNase I.
Regarding claims 13 and 23, Yang administers DNase I in a rat model of myocardial ischemia/reperfusion (Abstract, middle of left column and middle of right column on page 2).
Regarding claim 20, “immunoactivation” is defined within the specification as “an increase in the number and/or function of immune system cells, such as lymphocytes or myeloid cells, and/or an increase in humoral function of the immune system, involved in plasma cell and antibody production along with cytokine production” (0054]). Therefore, the broadest reasonable interpretation of “immunoactivation” in light of the definition provided in the specification includes increased cytokine production.
Yang does not teach detecting immunoactivation in the subject after acute ischemic injury to the heart before immunosuppression occurs in the subject.
Timmermans teaches that trauma results in the release of DAMPs (danger‑associated molecular patterns), which are associated with a suppressed state of the immune system (final paragraph on page 560). DAMPs include mitochondrial DNA (mtDNA) and nuclear DNA (page 552; left column, bottom paragraph). Timmermans suggests that trauma at first initiates an early anti-inflammatory response (increase in IL-10) prior to immune suppression (Figure 4, Pre-hospital and Figures 1-2). Timmermans detects cytokine IL-10 in plasma from human subjects (page 553, right column, “Plasma cytokine concentrations”).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add a step of detecting IL-10 (“immunoactivation”) in mice prior to the administration of DNase I in the method of Yang modified by Timmermans and Vogel. The person of ordinary skill in the art would have been motivated to monitor the effect of administering the DNase I in the subject in reducing the risk of immunosuppression associated with mtDNA. The person of ordinary skill in the art would have had a reasonable expectation of success in measuring the cytokine IL-10.
Regarding claims 22 and 25, Yang teaches that mtDNA serum levels rise in patients with acute myocardial infarction (page 3, right column, paragraph 3) and Yang administers DNase I intravenously at reperfusion (page 1, middle of right column), which is the restoration of blood flow to ischemic tissues.
Claims 1, 13, 20, 21, 23 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Wagner et al. (US 9,642,822 B2; cited in the Non-Final Action mailed on 1/27/2025) in view of Tsai et al. (Clinica Chimica Acta 412.5-6 (2011): 476-479) and Timmermans et al. (Intensive Care Med (2016) 42:551–561) and as evidenced by Bae et al. (Cells 8.4 (2019): 328), Schmid et al. (Vasc Cell. 2012 Sep 3;4(1):14) and Riley et al. (EMBO Rep. 2020 Apr 3;21(4):e49799)
Wagner teaches a method for treating or decreasing the likelihood of occurrence of a condition associated with neutrophil extracellular traps (NETs) comprising administering a DNase (claim 12, column 95). Wagner administers the DNase I intravenously (column 56, line 62). Wagner also teaches that treatment of subjects with DNase reduces the levels of NETs in the bloodstream and can reduce the incidence and severity of stroke (column 1, claims 61-64). Wagner administers recombinant human DNase I to animals (column 56, lines 55-56).
Wagner administers DNase I to mice following stroke induced by transient middle cerebral artery occlusion (column 54, lines 20-22, and column 56 lines 55-58). Transient middle cerebral artery occlusion (inserting a suture temporarily to block blood flow to a portion of the brain) is a physical noxious stimulus used to induce the acute tissue injury (stroke). Wagner measures the levels of circulating DNA in the plasma samples before the surgical procedure (column 54, lines 41 and 44-46). The circulating DNA is cell-free because Wagner first removes blood cells prior to detecting the DNA by fluorescence (column 54 lines 49-52 and 55-59). Wagner teaches that stroke releases cell-free DNA (compare Figures 7C and 7D).
Wagner does not teach that the DNase I is administered before immunosuppression occurs. Wagner does not teach that the circulating (cell-free) DNA is mtDNA (a specific type of double stranded DNA) or that the circulating DNA is released from the acute ischemic injury.
Tsai teaches that levels of circulating cell-free nuclear and mitochondrial DNA in patients with acute ischemic stroke are elevated relative to controls (Abstract Background and Results). Tsai teaches that the elevated plasma levels of free DNA are released from the damaged cells in the cerebral infarction occurring after ischemic stroke due to the disruption of the blood brain barrier (page 479, left column, paragraph 2).
Timmermans teaches that trauma results in the release of DAMPs (danger‑associated molecular patterns), which are associated with a suppressed state of the immune system (final paragraph on page 560). DAMPs include mitochondrial DNA (mtDNA) and nuclear DNA (page 552; left column, bottom paragraph). Timmermans suggests that trauma at first initiates an early anti-inflammatory response (increase in IL-10) prior to immune suppression (Figure 4, Pre-hospital and Figures 1-2). Timmermans detects cytokine IL-10 in plasma from human subjects (page 553, right column, “Plasma cytokine concentrations”). Timmermans teaches that cell-free nuclear DNA in particular correlates with HLA-DRA, which is an immunosuppression marker (page 555, right column, Immune-suppressed state, bottom paragraph and page 554, right column, top paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer the DNase I of Wagner immediately after the traumatic event (stroke) in order to decrease the risk of immunosuppression associated with cell-free nuclear and mitochondrial DNA. The person of ordinary skill in the art would have had a reasonable expectation of success in administering the DNase I before immunosuppression occurs.
Circulating cell-free mtDNA induces activation of the AIM2-inflammasome in macrophages, as evidenced by Bae (paragraph 3 on page 2). Macrophages are a type of myeloid cells, as evidenced by Schmid (page 1, left column, Macrophages in normal and tumor biology line 1). Thus, administering DNase I in any amount necessarily reduces activation of the AIM-2 inflammasome to at least some degree by degrading mtDNA.
mtDNA is a double-stranded DNA as evidenced by Riley (right column, top of first full paragraph).
Regarding claims 13 and 23, Wagner administers recombinant human DNase I to animals (column 56, lines 55-56).
Regarding claim 20, “immunoactivation” is defined within the specification as “an increase in the number and/or function of immune system cells, such as lymphocytes or myeloid cells, and/or an increase in humoral function of the immune system, involved in plasma cell and antibody production along with cytokine production” (specification 0054]). Therefore, the broadest reasonable interpretation of “immunoactivation” in light of the definition provided in the specification includes increased cytokine production.
Wagner does not teach detecting immunoactivation in the subject after acute ischemic injury to the brain before immunosuppression occurs in the subject.
Timmermans suggests that trauma at first initiates an early anti-inflammatory response (increase in IL-10) prior to immune suppression (Figure 4, Pre-hospital and Figures 1-2). Timmermans detects cytokine IL-10 in plasma from human subjects immediately after trauma occurs as well as several days afterwards (page 553, right column, “Plasma cytokine concentrations;” Figure 1F, ER and subsequent days on the y-axis).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add a step of detecting IL-10 (“immunoactivation”) in mice prior to the administration of DNase I in the method of Wagner modified by Tsai and Timmermans. The person of ordinary skill in the art would have been motivated to monitor the effect of administering the DNase I in the subject in reducing the risk of immunosuppression associated with mtDNA. The person of ordinary skill in the art would have had a reasonable expectation of success in measuring the cytokine IL-10.
Regarding claims 21 and 24, Wagner administers DNase I to mice following stroke induced by transient middle cerebral artery occlusion (column 54, lines 20-22, and column 56 lines 55-58). Transient middle cerebral artery occlusion (inserting a suture temporarily to block blood flow to a portion of the brain) is a physical noxious stimulus used to induce the acute tissue injury (stroke).
Response to Arguments
Applicant's arguments filed 12/18/2025 have been fully considered but they are not persuasive.
Applicant argues against the rejection of claims under 35 U.S.C. 103 over Wagner in view of Timmermans on the grounds that neither Wagner nor Timmermans suggest that the specific mechanistic involvement of cf-dsDNA in activating the AIM2 inflammasome in myeloid cells (Arguments, first full paragraph on page 11). Applicant argues further against the rejection of claims under 35 U.S.C. 103 on the grounds that the AIM2 inflammasome is activated by cytosolic ds-DNA rather than cell-free DNA (Arguments, paragraphs 3-4 on page 11).
In response, this argument is unpersuasive because Wagner teaches the active method step of administering a DNase I to a subject in order to treat the subject after acute ischemic injury to the brain (stroke) (Wagner column 54, lines 20-22, and column 56 lines 55-58). Administering a DNase I degrades cell-free mtDNA (double stranded DNA), which necessarily reduces activation of the AIM2-inflammasome because the AIM2 inflammasome in macrophages (a type of myeloid cell) is activated by cell-free mitochondrial DNA, as evidenced by Bae (Cells 8.4 (2019): 328; paragraph 3 on page 2). Mitochondrial DNA is double stranded, as evidenced by Riley (EMBO Rep. 2020 Apr 3;21(4):e49799; right column, top of first full paragraph). To summarize, the active method step (intravenously administering DNase I to a subject after acute ischemic injury to the brain) is taught by the prior art and the result of reducing the activation of a cell-free double stranded DNA sensing AIM2-inflammasome in myeloid cells necessarily results from the administration of DNase I.
Applicant also argues that Timmermans does not mention NETs but rather focuses on DAMPs such as mitochondrial DNA and nuclear DNA (Arguments, paragraph spanning pages 10-11).
In response, this argument is not persuasive because Tsai (Clinica Chimica Acta 412.5-6 (2011): 476-479) teaches that levels of circulating cell-free nuclear and mitochondrial DNA in patients with acute ischemic stroke are elevated relative to controls (Abstract Background and Results). Therefore, the person of ordinary skill in the art would have recognized that acute ischemic stroke results not only in NETs, but also mtDNA, and would have thus inferred that administering DNase I would have had the additional benefit of decreasing the likelihood of immunosuppression by degrading both cell-free nuclear and mtDNA.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CANDICE LEE SWIFT whose telephone number is (571)272-0177. The examiner can normally be reached M-F 8:00 AM-4:30 PM (Eastern).
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/CANDICE LEE SWIFT/Examiner, Art Unit 1657