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 .
DETAILED ACTION
Claims 1, 13, 20, and 23 are pending and under examination. Claims 2-12, 14-19, 21-22, and 24-25 are cancelled.
Response to Arguments
Applicant's arguments filed 5/4/2026 do not pertain to the rejections made in this action and are thus not addressed.
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.
(New Rejection Necessitated by Amendment) Claims 20 and 23 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 20 recites a method of treating a subject after a stroke in the subject to prevent consecutive lymphopenia comprising: a) detecting immunoactivation by IL-1β-mediated induction of Fas ligand expression on monocytes in the subject after a stroke in the subject and before lymphopenia occurs in the subject, and b) administering intravenously a composition comprising a human recombinant DNase to the subject, before lymphopenia occurs in the subject in an amount effective to reduce the activation of a cell-free double stranded DNA sensing AIM2-inflammasome in monocytes, wherein the reduction of the AIM2-inflammasome activation reduces IL-1β-mediated induction of Fas ligand expression on said monocytes, thereby preventing consecutive lymphopenia. Claim 20 is indefinite because the method preamble recites both a method of treating a subject after a stroke as well as “to prevent consecutive lymphopenia,” leading to ambiguity in the claim scope since it is unclear whether the claim is to a method of treatment, a method of prevention, or a method of treatment and prevention. In addition, there are at least two different reasonable interpretations of consecutive lymphopenia. In one interpretation, consecutive lymphopenia is the lymphopenia that occurs after the stroke. In a second interpretation, consecutive lymphopenia is an absolute lymphocyte count below the normal range on two or more back-to-back tests.
Claim 20 is further indefinite because the claim recites “detecting immunoactivation by IL-1β-mediated induction of Fas ligand expression on monocytes.” It is unclear if the claim requires detecting IL-1β, detecting Fas ligand expression on monocytes, detecting both IL-1β and Fas ligand expression on monocytes, detecting induction of expression, or detecting any form of immunoactivation (e.g. quantifying immune cells).
Claim 23 is rejected for depending from a rejected base claim and not rectifying the source of indefiniteness discussed above.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
(New Rejection Necessitated by the Amendment) Claims 20 and 23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Claim 20 is drawn to a method of treating a subject after a stroke in the subject to prevent consecutive lymphopenia comprising: a) detecting immunoactivation by IL-1β-mediated induction of Fas ligand expression on monocytes in the subject after a stroke in the subject and before lymphopenia occurs in the subject, and b) administering intravenously a composition comprising a human recombinant DNase to the subject, before lymphopenia occurs in the subject in an amount effective to reduce the activation of a cell-free double stranded DNA sensing AIM2-inflammasome in monocytes, wherein the reduction of the AIM2-inflammasome activation reduces IL-1β-mediated induction of Fas ligand expression on said monocytes, thereby preventing consecutive lymphopenia.
The specification does not provide any special definition for consecutive lymphopenia. Consecutive lymphopenia can either be interpreted as lymphopenia that occurs after stroke or an absolute lymphocyte count below the normal range on two or more back-to-back tests. Under either interpretation, claims 20 and 23 introduce new matter. The term “consecutive lymphopenia” is mentioned exactly once in the specification: “The induction of FasL-expressing monocytes and preferably consecutive lymphopenia is in a more detailed embodiment of the invention driven by inflammasome-dependent IL-1 secretion” ([008]). The specification does not provide any working examples or embodiments that describe administering human recombinant DNase or DNase I to prevent consecutive lymphopenia.
(New Rejection Necessitated by the Amendment) Claims 20 and 23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Per MPEP 2164.01(a), the following eight factors should be considered when determining whether the person of ordinary skill in the art would face undue experimentation to make and/or use the invention: (1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. While it is not essential that every factor be examined in detail, those factors deemed most relevant should be considered.
Nature of the invention. Claim 20 is drawn to a method of treating a subject after a stroke in the subject to prevent consecutive lymphopenia. The method has two active steps: a) detecting immunoactivation by IL-1β-mediated induction of Fas ligand expression on monocytes in the subject after a stroke in the subject and before lymphopenia occurs in the subject, and b) administering intravenously a composition comprising a human recombinant DNase to the subject, before lymphopenia occurs in the subject in an amount effective to reduce the activation of a cell-free double stranded DNA sensing AIM2-inflammasome in monocytes, wherein the reduction of the AIM2-inflammasome activation reduces IL-1β-mediated induction of Fas ligand expression on said monocytes, thereby preventing consecutive lymphopenia.
Breadth of the claims. “Consecutive lymphopenia” is interpreted in the context of the claim as lymphocyte count below the normal after stroke. Thus, preventing lymphopenia is interpreted as requiring that the lymphocyte count is normal or above normal after stroke. Lymphocytes encompass T cells, B cells, and natural killer cells. The subject is not limited but in one embodiment encompasses a human (specification [0049]).
State of the prior art and unpredictability. The prior art does not teach administering human recombinant DNase to prevent consecutive lymphopenia after stroke.
Guidance in the specification and working examples. The specification does not provide any working examples of administering a recombinant human DNase to prevent consecutive lymphopenia. In Example 4, mice are treated in vivo with 1000 U of human recombinant DNase, which results in a reduction of cf-dsDNA blood concentrations, substantially reduces inflammasome activation in splenic monocytes, prevents the expansion of FasL+ myeloid cell population and improves T cell survival after experimental stroke ([00162]). Example 8 of the specification discloses that patients with severe tissue injuries after stroke were analyzed for serum concentrations of dsDNA and IL-1β on hospital admission and their blood lymphocyte counts were quantified on the subsequent day ([0172]). The inventors detected a significant association between serum dsDNA and IL-1β concentration as well as a significant negative association between IL-1β concentration on admission and blood lymphocyte counts on the following day ([0172]). The specification does not provide evidence that administering human recombinant DNase to a subject after a stroke prevents consecutive lymphopenia in the subject.
Amount of experimentation necessary. At minimum, the person of ordinary skill in the art would have needed to perform experiments in animal models demonstrating that administering human recombinant DNase to the subject after a stroke results in levels of lymphocytes (including T cells, B cells, and natural killer cells) that are the same as before stroke (i.e. normal or above normal), whereas a control not administered human recombinant DNase exhibits lymphopenia after stroke.
Taking these factors into account, undue experimentation would be required by one of ordinary skill in the art to practice the claimed invention. Thus, the claims are not enabled by the disclosure.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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 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.
The following rejections are necessitated by the amendment.
Claims 1 and 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wagner et al. (US 9,642,822 B2; cited in the Non-Final Action mailed on 1/27/2025) as evidenced by Tsai et al. (Clinica Chimica Acta 412.5-6 (2011): 476-479; cited in the Non-Final Action mailed on 2/2/2026), Riley et al. (EMBO Rep. 2020 Apr 3;21(4):e49799; cited in the Non-Final Action mailed on 2/2/2026), Bortolotti et al. (Frontiers in immunology 9 (2018): 1900; cited in the Final Action mailed on 7/21/2025), and Chamorro et al. (Stroke 38.3 (2007): 1097-1103).
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 used to induce the acute tissue injury (stroke). The DNase I is administered five minutes before reperfusion following 1 h hour transient middle cerebral artery occlusion (column 56, line 62).
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’s circulating (cell-free DNA) necessarily includes mtDNA because elevated plasma levels of free DNA, which includes nuclear and mitochondrial DNA, are released from the damaged cells in the cerebral infarction occurring after ischemic stroke due to the disruption of the blood brain barrier as evidenced by Tsai (Abstract Background and Results; page 479, left column, paragraph 2). mtDNA is a double-stranded DNA as evidenced by Riley (right column, top of first full paragraph).
Double-stranded DNA (dsDNA) is an activator for the AIM2 inflammasome in trauma, as evidenced by Bortolotti (Table 1 on page 3). Inflammasomes are highly expressed in immune cells, especially monocytes and macrophages as evidenced by Bortolotti (page 2, right column, General Description, paragraph 1). Therefore, administering DNase I would have necessarily reduced activation of the AIM2 inflammasome in monocytes by lowering double-stranded circulating free DNA in blood.
The time scale for lymphopenia (a decrease in the number of lymphocytes) following stroke occurs on the order of days, as evidenced by Chamorro (Fig. 3C). Therefore, Wagner administers the DNase I before lymphopenia occurs because Wagner intravenously administers the DNase I five minutes before reperfusion following a 1 h transient middle cerebral artery occlusion (column 56, line 62). In other words, Wagner administers the DNase I immediately following the stroke.
Regarding the limitation “wherein the reduction of the AIM2-inflammasome activation reduces IL-lβ-mediated induction of Fas ligand expression on said monocytes,” this is an inherent outcome of reducing the AIM2-inflammasome activation.
Regarding claim 13, Wagner administers recombinant human DNase I to animals (column 56, lines 55-56).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to 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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Louise Humphrey can be reached at (571)272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/CANDICE LEE SWIFT/Examiner, Art Unit 1657
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