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 .
Withdrawal of Rejections
The response and amendments filed on 02/10/2026 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated here for brevity, have been withdrawn necessitated by Applicant’s formality correction and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, and/or maintaining, if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s Response to Arguments section.
Briefly, the previous claims rejections under 35 U.S.C. 112(b) for indefiniteness have been withdrawn necessitated by amendments. The previous claim rejections under 35 U.S.C. 103 have been withdrawn necessitated by Applicant’s amendments; however, new grounds of rejection are set forth below.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/02/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
New Grounds of Rejection Necessitated by Amendments
Claim Rejections - 35 USC § 103, Obviousness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 86-87, 90, and 106 are rejected under 35 U.S.C. 103 as being unpatentable over Wagner (U.S. Patent No. 9,642,822; Date of Publication: May 9, 2017 – previously cited) in view of Baker (US2002/0142437; Date of Publication: October 3, 2002 – previously cited) and Schneider (WO2003/072741; Date of Publication: September 4, 2003 – previously cited).
Wagner’s general disclosure relates to neutrophil extracellular traps (NETs) and their ability to provide a stimulus for thrombus formation (see, e.g., Wagner, abstract). Moreover, Wagner discloses “the discovery that treatment of subjects with DNase or anti-histone antibodies reduces the level of NETs in the bloodstream and can reduce the incidence and severity of stroke, deep vein thrombosis, and pulmonary thromboembolism” (see, e.g., Wagner, “Summary”, col. 1, lines 62-66).
Regarding claims 86 and 87 pertaining to treating a subject in need thereof, Wagner teaches the treatment of subjects with DNase to reduce levels of NETs in the bloodstream, which can reduce the incidence and severity of stroke, deep vein thrombosis, and pulmonary thromboembolism (see, e.g., Wagner, “Summary”, col. 1, lines 62-66).
Regarding claim 90 pertaining to the subject having vascular occlusion, Wagner teaches a method of treating or preventing a cardiovascular condition in a patient by administering a therapeutically effective dose of at least one anti-NET compound. The cardiovascular condition is directed to all disorders characterized by insufficient, undesired, or abnormal cardiac function and any diseases and conditions of the blood vessels which result in insufficient, undesired, or abnormal cardiac function, such as but not limited to ischemic heart disease, hypertensive heart disease and pulmonary hypertensive heart disease, valvular disease, congenital heart disease, any condition that leads to congestive heart failure, stroke, thrombosis, ischemia, ischemic reperfusion, vessel occlusion, inflammation, etc. (see, e.g., Wagner, col. 26, lines 47-64). Moreover, Wagner teaches that the anti-NET compound can be DNase I or DNase II; therefore, teaching administering a therapeutically effective amount of D1.
Regarding claim 106 pertaining to the patient sample, Wagner teaches assessing a thrombotic condition in a patient comprising determining the level of NETs in a sample obtained from a patient (see, e.g., Wagner, col. 3, lines 64-67), and teaches assessing the efficacy of the administration of an effective dose of at least one anti-NET compound comprising determining the level of NETs obtained from a patient before and after treatment with the anti-NET compound (see, e.g., Wagner, col. 4, lines 3-10). Therefore, based on these teachings, Wager teaches monitoring the NET-degrading activity of blood, plasma, or serum from subjects.
However, Wagner does not teach: administering a therapeutically effective amount of a DNase 1-like 3 (D1L3) variant comprising an amino acid sequence that is at least 90% identical to the enzyme defined by SEQ ID NO: 2, with a full or partial deletion of a C-terminal tail defined by SEQ ID NO: 33, where the deletion of the C-terminal tail includes deletion of Nuclear Localization Signal 2 (NLS2) (claim 86).
Baker’s general disclosure relates to “a novel human deoxyribonuclease, referred to as LS-DNase, that is relatively resistant to inhibition by actin, as compared to human DNase I” (see, e.g., Baker, abstract). Moreover, Baker discloses that this novel polypeptide is referred to as LS-DNase, and is of human origin (see, e.g., Baker, [0009]). Furthermore, Baker discloses “methods for reducing the viscoelasticity or viscous consistency of DNA-containing material in a patient, comprising administering a therapeutically effective dose of LS-DNase to the patient. The invention is particularly directed to a method of treating a patient having a disease such as cystic fibrosis, chronic bronchitis, pneumonia, bronchiectasis, emphysema, asthma, or systemic lupus erythematosus, that comprises administering a therapeutically effective amount of LS-DNase to the patient” (see, e.g., Baker, [0012]).
Regarding claim 86 pertaining to the D1L3 variant, Baker teaches administering a therapeutically effective amount of LS-DNase to the patient, wherein the LS-DNase (SEQ ID NO: 2) has 100% sequence identity to instant SEQ ID NO: 2 (see, e.g., Office Action Appendix). Additionally, Baker teaches variants of SEQ ID NO: 2 for LS-DNase possessing at least 80% identity (see, e.g., Baker, [0020]). Baker teaches that the variants of LS-DNase result from amino acid sequence substitutions, insertions, and deletions or in extent or pattern of glycosylation, but substantially retain the biological activity of LS-DNase (see, e.g., Baker, [0019], [0022[). Furthermore, Baker teaches covalent modifications to amino acid side chains or N- or C-terminal residues and covalent coupling of glycosides (see, e.g., Baker, [0044]-[0045]). An ordinary artisan would readily recognize that these modifications can include one or more of the listed modifications: a mutated DNA binding site or a mutated chromatin binding site, a glycosylation site, inactivation of a nuclear localization signal, and/or deletion of all or part of a C-terminal tail.
Schneider’s general disclosure relates to D1L3 and that “differing therapeutic benefits may result from either the upward or downward therapeutic regulation of D1 L3 activity. For example, blocking D1 L3 activity enhances liposomal transfection for gene therapy, while increasing D 1 L3 activity may enhance destruction of pathogenic DNA, whether viral, bacterial or endogenous. Destruction of pathogenic DNA may provide treatment for lupus, or viral and oncogenic diseases” (see, e.g., Schneider, abstract).
Regarding claim 86 pertaining to the C-terminal tail of the D1L3 variant, Schneider teaches a C-terminal tail of D1L3 (SEQ ID NO: 67), which has 100% sequence identity to instant SEQ ID NO: 33 (see, e.g., Office Action Appendix). Schneider teaches production of D3pCT, where “a point mutation was created in the full-length clone, such that a stop codon is substituted for the codon for Ser-289. The amino acids 289 to 310 (289-end) of the murine D1L3 are hence called the D1L3 C-terminus” (see, e.g., Schneider, pg. 35, lines 24-28). Therefore, one of ordinary skill in the art would understand that the D3pCT clone has the entire C-terminal tail deleted since there was a stop codon introduced at the start of the C-terminal tail resulting in no C-terminal tail being expressed, which would inherently include deletion of the Nuclear Localization Signal 2. Furthermore, Schneider teaches that the D3pCT clone has increased nuclease activity relative to wildtype D1L3 (see, e.g., Schneider, pg. 36, lines 6-7 & Figures 6 and 8).
It would have been first obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the LS-DNase or variants thereof, as taught by Baker, in a method of treating a subject in need of NET degradation, wherein the subject is experiencing stroke, as taught by Wagner. One would have been motivated to do so because Baker teaches that DNA-hydrolytic activity of LS-DNase is not inhibited by concentrations of actin that fully inhibit human DNase I (see, e.g., Baker, [0070]). Therefore, LS-DNase shows improved activity even when inhibitors are present, which is a desirable characteristic for treatment in subjects. Moreover, Baker teaches “reducing the viscoelasticity or viscous consistency of DNA-containing material in a patient, comprising administering a therapeutically effective dose of LS-DNase to the patient”; therefore, one of ordinary skill in the art would readily recognize that LS-DNase can be used to reduce the amount DNA in a sample. Furthermore, Wagner teaches that DNase can reduce levels of NETs in the bloodstream, which can reduce the incidence and severity of stroke, deep vein thrombosis, and pulmonary thromboembolism (see, e.g., Wagner, “Summary”, col. 1, lines 62-66).. Therefore, based on the teachings of Wagner and Baker, it would have been obvious to utilize LS-DNase, as taught by Baker, for treatment of a subject in need thereof, as taught by Wagner. One would have expected success because Wagner and Baker both teach therapeutic or pharmaceutical compositions and methods involving DNase, which can be used to reduce the amount of extracellular DNA in a sample.
It would have been secondly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize a D1L3 variant comprising full deletion of the C-terminal tail, as taught by Schneider, wherein the subject is experiencing stroke, as taught by Wagner. One would have been motivated to do so because Schneider teaches that deletion of the C-terminal tail for D1L3 results in increased nuclease activity relative to wildtype D1L3 (see, e.g., Schneider, pg. 36, lines 6-7 & Figures 6 and 8). Moreover, Wagner teaches that DNase’s are capable to reducing NETs in the bloodstream of individuals, which can reduce the severity or incidence of stroke (see, e.g., Wagner, “Summary”, col. 1, lines 62-66). Therefore, based on the teachings of Wagner and Schneider, it would have been obvious to treat a stroke patient with D1L3, wherein the C-terminal tail is deleted, because this D1L3 variant has increased nuclease activity, which can result in enhanced reduction in NETs in the bloodstream. One would have expected success because Wagner and Schneider both teach formulations comprising DNases.
Examiner’s Response to Arguments
Applicant's arguments filed 02/10/2026 have been fully considered but they are not persuasive.
Regarding Applicant’s argument that Baker, Wagner, nor Schneider suggest a C-terminal tail deletion in D1L3 and that this deletion is not obvious (remarks, pages 7-8), this argument is not persuasive because, as discussed in the 103 rejection above, Schneider teaches a C-terminal tail of D1L3 (SEQ ID NO: 67), which has 100% sequence identity to instant SEQ ID NO: 33 (see, e.g., Office Action Appendix). Schneider teaches production of D3pCT, where “a point mutation was created in the full-length clone, such that a stop codon is substituted for the codon for Ser-289. The amino acids 289 to 310 (289-end) of the murine D1L3 are hence called the D1L3 C-terminus” (see, e.g., Schneider, pg. 35, lines 24-28). Therefore, one of ordinary skill in the art would understand that the D3pCT clone has the entire C-terminal tail deleted, which would inherently include deletion of the Nuclear Localization Signal 2. Furthermore, Schneider teaches that the D3pCT clone has increased nuclease activity relative to wildtype D1L3 (see, e.g., Schneider, pg. 36, lines 6-7 & Figures 6 and 8). Applicant states that deletion of the C-terminal tail increases the function of D1L3 to degrade lipid-free and cell-free chromatin (remarks, page 7); however, Schneider also shows that deletion of the C-terminal tail in Figures 6 and 8 result in increased nuclease activity, compared to wildtype. Based on the teachings of Schneider, the C-terminal tail is not required for nuclease activity exhibited by D1L3 because deletion of the C-terminal tail, which inherently includes deletion of NLS2, results in increased nuclease activity (see, e.g., Schneider, pg. 35, lines 24-28 & pg. 36, lines 6-9 & Figures 6 and 8). Therefore, Applicant’s statement that Schneider fails to teach a C-terminal tail deletion is incorrect because this deletion, and the motivation behind this deletion, is taught by Schneider. Based on the teachings of Schneider, one of ordinary skill in the art would be motivated to delete the C-terminal tail from D1L3 in order to increase nuclease activity.
Regarding Applicant’s argument pertaining to Baker not teaching deletion of the C-terminal tail in D1L3 (remarks, page 8), this argument is not persuasive because, as discussed above, Schneider was used to teach deletion of the C-terminal tail in D1L3.
Conclusion
Claims 86-87, 90, and 106 are rejected.
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE IANNUZO whose telephone number is (703)756-5559. The examiner can normally be reached Mon - Fri: 8:30-6:00 EST.
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/NATALIE IANNUZO/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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