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 .
Claim Status
The amendment of 10/28/2025 has been entered. Claims 1, 19, and 21 are pending (claim set as filed on 10/28/2025).
Claims 1, 19, and 21 are currently under examination and were examined on their merits.
Declaration under 37 CFR 1.132
Applicant’s declaration under 37 CFR 1.132 filed on 10/28/2025 has been received and considered.
Withdrawn Objections/Rejections
The rejections under 35 U.S.C. 112(a), under 102(a)(1), and the double patenting rejections, as set forth in the previous Office action, are withdrawn in light of the amendment filed on 10/28/2025.
Claim Rejections - 35 USC § 112 (b)
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, 19, and 21 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 a “DNASE1-LIKE3 (D1L3) enzyme comprising amino acids 21 to 282 of SEQ ID NO: 4", and “wherein the D1L3 enzyme has a truncation consisting of 20 amino acids from a C-terminus of SEQ ID NO:4”, which renders the claim indefinite, since the consisting language makes it unclear, what other additional unrecited elements may be encompassed by the comprising language. For example, it is unclear if the truncation of the enzyme is limited to the recited 20 amino acids from the C-terminus (amino acids 286-305), or if in addition to the 20aa truncation, amino acids 283-285 of the enzyme could be deleted as well, due to the comprising language in the claim. One of ordinary skill in the art would not be able to determine the metes and bounds of claim 1, and thus, could not clearly determine how to avoid infringement of claim .
Dependent claims 19 and 21 are rejected because they do no not remedy the deficiency of claim 1.
In the interest of compact prosecution, claim 1 is interpreted to the broadest embodiment claimed.
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.
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 factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 19, and 21 are newly rejected as necessitated by amendment under 35 U.S.C. 103 as being unpatentable over Sisirak et al. (“Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity”, published on 06/30/2016, Cell, Vol. 166, pages 88-101, supplemental Figures S1-S7, and supplemental information, pages 1-6), hereinafter ‘Sisirak’, in view of Posada et al. (US 2016/0251638 A1, published on 09/01/2016), hereinafter ‘Posada’.
Sisirak’s general disclosure relates to extracellular microparticle-associated chromatin as a potential self-antigen normally digested by circulating DNASE1L3 (see entire document, including abstract).
Regarding claim 1, please note the rejection under Claim Rejections - 35 USC § 112 (b) above.
Pertaining to DNASE1-LIKE3 enzyme, Sisirak teaches a DNASE1-LIKE3 (D1L3) enzyme comprising amino acids 21 to 281 of instant SEQ ID NO: 4, wherein the D1L3 enzyme has a truncation consisting of 20 amino acids from the C-terminus of SEQ ID NO: 4 ((“DNASE1L3 (NCBI:NP_004935.1)”, “DNASE1L3 variants … C-terminal truncation (amino acids [aa] 282-305)”; page 99, right column, paragraph 4; see Figure 5A). It is noted, that Sisirak and Applicant are both citing full-length NP_004935.1, which is designated as SEQ ID NO: 4 by Applicant (instant specification, page 52, lines 1-2), and that Sisirak’s D1L3 variant has an additional deletion of positions 282-285.
Further, Sisirak teaches that the D1L3 enzyme comprising the C-terminal truncation has increased DNase activity for genomic DNA (gDNA) in comparison to non-truncated D1L3 enzyme and DNase 1, while still retaining some DNase activity toward nucleosome DNA (nDNA) and microparticle DNA (MP DNA) (see percentage of input gDNA, nDNA, and MP DNA in the presence of truncated D1L3, non-truncated D1L3, and DNase1 in Fig. 5C and 5D).
Sisirak discloses wherein “the observed delay of anti-DNA reactivity by DNASE1L3 re-expression warrants the exploration of DNASE1L3 protein delivery as a therapeutic tool in SLE and other systemic autoimmune diseases” (page 99, left column, paragraph 3).
Sisirak does not teach wherein the Dnase1Like3 (D1L3) comprises the amino acid in position 282 of SEQ ID NO: 4 (instant claim 1), wherein the D1L3 enzyme is fused or conjugated to a carrier selected from a fusion partner or a polyethylene glycol (PEG) (instant claim 19), or wherein the DlL3 enzyme further comprises an albumin amino acid sequence fused at the N-terminal side, via a linking amino acid sequence (instant claim 21).
Posada’s general disclosure relates to hybrid nuclease-albumin molecules (see entire document, including abstract).
Regarding claim 19, pertaining to the D1L3 enzyme fused to a carrier, Posada teaches wherein a D1L3 is fused to a fusion partner (“The hybrid nuclease-albumin molecules of the invention have one or more nuclease domains (e.g., an RNase and/or DNase domain) operably coupled to an albumin, or a variant or fragment thereof”, “In some embodiments, the hybrid nuclease-albumin molecule is a polypeptide comprising an amino acid sequence of a nuclease domain and an amino acid sequence of an albumin”, “the hybrid nuclease-albumin molecule includes DNase 1L3-albumin. In some embodiments, the DNase 1L3 is constructed from a human”; paragraphs [0004], [0124]; see abstract).
Regarding claim 21, pertaining to the D1L3 enzyme fused to a carrier, Posada teaches wherein the D1L3 enzyme comprises an albumin amino acid sequence fused at the N-terminal (“In some embodiments, the hybrid nuclease-albumin molecule is a polypeptide comprising an amino acid sequence of a nuclease domain and an amino acid sequence of an albumin”, “Such fusions include albumin N-terminal fusions, albumin C-terminal fusions”, “the hybrid nuclease-albumin molecule includes DNase 1L3-albumin. In some embodiments, the DNase 1L3 is constructed from a human (SEQ ID NO: 70); paragraphs [0004], [0124], [0142]; see SEQ ID NO:70 in Table 1 on page 51), via a linking amino acid sequence (“polypeptide linkers may be used to connect a nuclease domain to an albumin, or a variant or fragment thereof”; paragraph [0065]).
In addition, Posada teaches wherein a nuclease can be an enzymatically active fragment of a DNase (paragraph [0113]), and discloses the use of hybrid nuclease-albumin molecules comprising DNases, including DNAse1 and D1L3, for treating diseases characterized by defective clearance or processing of apoptotic cells and cell debris, such as SLE and Sjogren's syndrome (paragraphs [0019]-[0020], [0037], [0114]-[0117]). Posada further teaches wherein “[w]ild-type albumin has a long serum half-life”, “when operably coupled to one or more nucleases, the resulting hybrid nuclease-albumin molecules exhibit altered serum half-life”, and that “[a]nother advantage conferred by albumin is that it does not activate effector Fc receptors, and thus the hybrid nuclease-albumin molecules may avoid toxicity associated with activating these receptors” (paragraph [0038]).
While Sisirak does not teach wherein the D1L3 enzyme comprises the amino acid in position 282 of SEQ ID NO: 4 (instant claim 1), the recited length of the C-terminal truncation and thus of the recited D1L3 amino acid sequence (positions 21-282 of SEQ ID NO: 4) would be within the realm of routine experimentation since Sisirak teaches a D1L3 variant comprising positions 21-281 of SEQ ID NO: 4 (page 99, right column, paragraph 4). It would have been obvious to a skilled artisan to have determined the optimal length of the truncation and thus the length of the D1L3 amino acid sequence, in order to maximize the activity of the truncated D1L3 enzyme towards genomic DNA, nucleosome DNA, and microparticle DNA. One would have been motivated to do so, in order to create a superior DNase for degrading extracellular DNA including DNA in immune complexes, since Posada teaches the use of different DNase activities including DNase1 and D1L3 for degrading circulating DNA and DNA in immune complexes associated with SLE (Posada, paragraphs [0009], [0019], [0037], [0114]-[0117]).
While modified Sisirak does not teach wherein the D1L3 enzyme is fused or conjugated to a carrier selected from a fusion partner or a polyethylene glycol (PEG) (instant claim 19), or wherein the DlL3 enzyme further comprises an albumin amino acid sequence fused at the N-terminal side, via a linking amino acid sequence (instant claim 21), it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have combined modified Sisirak’s D1L3 variant with Posada’s teachings’ on albumin-nuclease fusion proteins comprising a linker, in order to have created a D1L3 enzyme wherein the D1L3 enzyme is fused to an albumin amino acid sequence (instant claims 19 and 21), and wherein the albumin amino acid sequence is fused at the N-terminal side, via a linking amino acid sequence (instant claim 21). One would have been motivated to do so, in order to develop a superior D1L3 enzyme with increased serum half-life, that can be used for the treatment of SLE. A skilled artisan would have reasonably expected success in the combination of Sisirak’s and Posada’s teachings since both references are directed to Dnases for treatment of SLE.
Response to Arguments
Applicant has traversed the prior art previous rejections in the reply filed on 10/29/2025 (remarks, pages 3-4). Applicant's arguments have been fully considered but they are not persuasive.
In Applicant’s reply, Applicant states that the references Sisirak and Posada, whether taken alone or in combination, do not teach or suggest the D1L3 enzyme recited in claim 1 (remarks, page 4).
The Examiner responds that, as discussed above under Claim Rejections - 35 USC § 112 (b), claim 1 recites indefinite claim language. As such, the claim is interpreted to the broadest embodiment claimed, which would allow for additional amino acid deletions of SEQ ID NO: 4 outside of the claimed amino acid sequence from position 21 to position 282 of SEQ ID NO: 4 and outside the claimed C-terminal truncation. In view of the claim interpretation, Sisirak teaches a truncation consisting of 20 amino acids from the C-terminus of SEQ ID NO:4, as discussed above under Claim Rejections - 35 USC § 103.
Applicant describes that “the claims are non-obvious in view of the unexpected result that a truncation of 20 amino acids from the DlL3 C-terminal tail increases chromatin degrading activity, while reducing or eliminating protein heterogeneity observed with a 23 amino acid truncation”, and further states: “The Specification demonstrates that increasing deletions (e.g., truncations) of the C-terminal basic domain of D1L3 substantially increase its chromatin degrading activity. See FIGS. 8B, 9A, and 9B. This increase in activity is maximum at around 20 amino acids deleted.” (remarks, page 4).
The Examiner responds that proper interpretation of the presented results in the specification and in the declaration in regard to claim 1 is not possible since the limitations in claim 1 are unclear, as discussed under Claim Rejections - 35 USC § 112 (b) above. It is further noted that if Applicant intended to claim a D1L3 enzyme consisting of amino acids 21 to 285, or or of amino acids 1 to 285 of SEQ ID NO: 4, corresponding to a D1L3 variant missing the last 20 amino acids from the C-terminus, no results for such a sequence and its chromatin degrading activity are shown in Figures 8B, 9A, and 9B. The Figures show results for D1L3 variants having a C-terminal truncation of 1, 3, 12, 15, 21, and 23 amino acids.
Conclusion
No claims are allowed.
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.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SANDRA ZINGARELLI whose telephone number is (703)756-1799. The examiner can normally be reached M-F 9-5.
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/SANDRA ZINGARELLI/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/ Supervisory Patent Examiner, Art Unit 1653