DETAILED ACTION
Status of the Application
Claims 57-59, 61-64, 66-69, 71-73 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment of claims 57-58, 64, 66-68, 71, cancellation of claims 1, 60, 65, 70, 74-75, and amendments to the specification as submitted in a communication filed on 3/30/2026 are acknowledged.
As previously indicated, in view of the amendment filed on 3/28/2023 which cancelled claims directed to the elected invention, it was assumed that Applicant elected a method of treating, ameliorating or preventing diseases or disorders associated with inefficient NET hydrolysis in a subject, wherein the method requires the administration of a construct that comprises a human DNase I, a linker and an Fc domain, wherein the Fc domain is an Fc domain from a human IgG1 or a variant of an Fc domain from a human IgG1, wherein the linker comprises SEQ ID NO: 5, the human DNase I comprises the substitutions Q31R, N96K and A136F, and the variant of the Fc domain of the human IgG1 comprises the substitutions M32Y, S34T and T36E. Claims 59, 71 and 72 do not require the elected combination of substitutions in the Fc region. Claim 72 requires all of C6S, C9S, M32Y, S34T and T36E. Claims 69 and 73 encompass a method where the construct comprises a DNase I domain that does not have the elected combination of substitutions and/or the elected linker. Claim 62 requires a linker that comprises at least one of GS and GSC, whereas the elected linker (SEQ ID NO: 5) does not comprise GSC. Claims 67-68 as amended no longer comprise the elected combination of substitutions in the polypeptide of SEQ ID NO: 1 and the polypeptide of SEQ ID NO: 4, respectively. Claims 59, 62, 67-69, 71-72 and 73 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/10/2025.
Claims 57-58, 61, 63 (in part), 64, 66 are at issue and will be examined only to the extent they encompass the elected invention.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Specification
The previous objection to the title of the invention as being not descriptive is hereby withdrawn by virtue of Applicant’s amendment.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/15/2025, 1/14/2026 and 3/30/2026 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claim 57 is objected to due to the recitation of “domain comprises a variant of a polypeptide of SEQ ID NO: 1”. The term “a polypeptide of SEQ ID NO: 1” implies a genus of polypeptides of SEQ ID NO: 1. Since there is only one polypeptide of SEQ ID NO: 1, the claim should be amended to recite “domain comprises a variant of the polypeptide of SEQ ID NO: 1”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
Claims 58 and 66 remain 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 pre-AIA the applicant regards as the invention. New grounds of rejection are necessitated by amendment.
Claim 58 is indefinite in the recitation of “…X1 is a peptide of amino acid sequence …(SEQ ID NO: 3) or a fragment thereof; and….X2 is a peptide of amino acid sequence SEQ ID NO: 3…” for the following reasons. The term “X1/X2 is the peptide of amino acid sequence SEQ ID NO: 3” is unclear because one cannot determine if the peptide is required to comprise SEQ ID NO: 3 or consists of SEQ ID NO: 3. For examination purposes, it will be assumed that the claim recites “…X1 is a peptide that has SEQ ID NO: 3 …and X2 is a peptide that has SEQ ID NO: 3..”. Correction is required.
Claim 66 is indefinite in the recitation of “…wherein the variant of the polypeptide of SEQ ID NO: 1 does not comprise residues 1-22 corresponding to SEQ ID NO: 1” for the following reasons. It is unclear if the claim is requiring the variant to lack the amino acid sequence of residues 1-22 of SEQ ID NO: 1, or if the variant is required to simply lack a signal peptide. For examination purposes, it will be assumed that the variant does not comprise amino acids 1-22 of the protein of SEQ ID NO: 1. Correction is required.
When amending the claims, applicant is advised to carefully review all examined claims and make the necessary changes to ensure proper antecedent basis and dependency.
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
Claims 57-58, 61, 63-64, 66 remain 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
This rejection has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant argues that the claims 1, 60, 65, 70, 74-75 have been cancelled. Applicant states that the BRI must be considered in light of the specification and as it would be interpreted by one of ordinary skill in the art. Applicant states that background publications provide guidance as to a relationship for structural guiding principles for DNase I enzyme function. Applicant cites Pan et al. (J. Biol. Chem. 273(29):18374-18381, 1998; cited in the IDS) as disclosing the effect of amino acid residue modifications in enzymatic activity and actin binding. Applicant also states that Posada et al. (WO 2018/005954 published 1/4/2018; previously cited) disclose a nuclease domain and provide an in vitro assay to determine enzymatic activity. Applicant states that Pan et al. provide in Figure 1 a structural model of the DNase I-actin interface and that Posada et al. provide a mutation to reduce sensitivity to actin. Applicant states that one of skill in the art would have contemplated in view of the teachings of Minter et al. (U.S. Publication No. 2015/0104450 published 4/16/2015; previously cited) related to Fc modifications, that the present disclosure provides adequate written description. Applicant refers to specific modifications to a human IgG1 Fc associated with half-life extension. Applicant refers to specific Figures in the specification as disclosing structural and functional information regarding DNase and Fc domains variants consonant with the scope of the claimed subject matter. Applicant states that the alignment shown in Figure 5 is informative of conserved residues. Applicant is of the opinion that one of skill in the art having considered the background publications and the guidance of specification, would appreciate that the inventors were in possession of the claimed subject matter.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejection. The Examiner acknowledges the amendments made to the claims, MPEP § 2111, the teachings of the prior art and the teachings of the specification. However, the Examiner disagrees with Applicant’s contention that the entire genus of variants required by the claims is adequately described.
With regard to the argument that the BRI must be considered in light of the specification and as it would be interpreted by one of ordinary skill in the art, it is noted that the claims as amended require domains having any structure which are variants of the human DNase1 protein of SEQ ID NO: 1 and the Fc domain of SEQ ID NO: 4. When given the broadest reasonable interpretation to the claims without importing claim limitations from the specification, the amended claims still require a genus of constructs having essentially any structure because there is no structural limitation with regard to the DNase domain and Fc domain required by the constructs of the claimed method. The only structural limitations recited are three substitutions in the DNase domain and three substitutions in the Fc domain. Therefore, there are only 3 amino acids defined in the DNase I domain and three amino acids defined in the Fc domain. The term human DNase1 domain does not by itself convey any particular structure because it is abundantly clear that the recited DNase1 domain is not limited to a naturally-occurring human DNase1 domain but rather a variant of the polypeptide of SEQ ID NO: 1. There is absolutely no indication as to how much structural variation within the polypeptide of SEQ ID NO: 1 is required for a domain to be considered “a human DNase1 domain”. How many modifications anywhere within the polypeptide of SEQ ID NO: 1 are the most one could have in the polypeptide of SEQ ID NO: 1 before a variant of the polypeptide of SEQ ID NO: 1 is no longer considered encompassed by the term “human DNase1 domain”? With regard to the Fc domain, the claim specifically states that the Fc domain is a variant of the polypeptide of SEQ ID NO: 4, without reciting any additional structural features beyond 3 substitutions. Therefore, contrary to Applicant’s assertions, the Examiner has considered the BRI in light of the specification and as it would be interpreted by one of ordinary skill in the art.
The teachings of Pan et al. and Posada et al. are acknowledged. However, the Examiner disagrees with Applicant’s contention that the prior art provides adequate support to the entire genus of variants of the polypeptide of SEQ ID NO: 1 encompassed by the claims. The Examiner acknowledges that Pan et al. provide some functional characterization of the DNase1 protein of SEQ ID NO: 1 including the effect of certain amino acid modifications on enzymatic activity and actin binding. The Examiner also acknowledges Figure 1 of Pan et al. and the enzymatic assay to determine DNase activity. However, it is noted that the polypeptide of SEQ ID NO: 1 is 282 amino acids long and Pan et al. as well as Posada et al. only provide the functional characterization of approximately 8 substitutions, which is a very small percentage of the entire structure of the polypeptide of SEQ ID NO: 1 (2.8% = 8x100/282). Figure 1 is a mere generic 3D model of the interaction between DNase1 and G-actin and its caption provides 6 positions in the polypeptide of SEQ ID NO: 1 that are associated with hyperactivity upon substitution with a basic residue. Neither Pan et al., Posada et al. or the specification disclose or teach additional modifications, or how additional modifications could alter the 3D structure such that the hyperactivity effect associated with the substitutions disclosed could be altered by these additional modifications. Similarly, the specification of the instant application also discloses a limited number of modifications to increase DNase1 activity, and is completely silent with regard to a structure/function correlation that would allow one of skill in the art to determine which variants of the polypeptide of SEQ ID NO: 1 could be used in the claimed construct. While Applicant argues that Figure 5 provides an alignment that provides conserved regions, it is noted that conserved regions are not necessarily associated with enzymatic activity. Because conserved regions can be associated with how closely related the sources (i.e., organisms) of the proteins in the alignment are, one cannot reasonably conclude that every protein having DNase1 activity would have those conserved regions found in Figure 5.
With regard to the argument that the teachings of Minter et al. disclose Fc modifications, and that the present disclosure provides adequate written description of the genus of Fc variants required, it is noted that the protein of SEQ ID NO: 4 is 227 amino acids long and Minter et al. as well as the specification disclose a minimal number of substitutions that would extent the half-life of the Fc domain. Neither Minter et al. nor the specification disclose a structure/function correlation that would allow one of skill in the art to envision the structure of any Fc domain that could be used in the claimed construct. Therefore, for the reasons of record and those set forth above, one cannot reasonably conclude that the entire genus of constructs claimed are adequately described by the teachings of the specification and/or the prior art.
Claims 57-58, 61, 63-64, 66 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method that requires administering a construct that comprises (i) a DNase I polypeptide that comprises SEQ ID NO: 1 or a DNase I polypeptide that comprises all of SEQ ID NO: 1 except for one or more substitutions that correspond to substitutions in the protein of SEQ ID NO: 1 selected from Q31R, N96K and A136F, and (ii) an Fc domain that comprises SEQ ID NO: 4 or an Fc domain that comprises all of SEQ ID NO: 4 except for one or more substitutions that correspond to substitutions in the protein of SEQ ID NO: 4 selected from M32Y, S34T and T36E, does not reasonably provide enablement for a method that requires administering a construct that comprises (a) a DNase 1 protein having any structure and one or more substitutions that correspond to substitutions in the protein of SEQ ID NO: 1 selected from Q31R, N96K and A136F, and (b) an Fc domain having any structure and one or more substitutions that correspond to substitutions in the protein of SEQ ID NO: 4 selected from M32Y, S34T and T36E. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
This rejection has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant argues that enablement does not require disclosure of every step required to make the invention. Applicant states that MPEP § 2111 states that the scope of the claims is determined upon giving the claims their broadest reasonable construction in light of the specification as it would be interpreted by one of ordinary skill in the art. Applicant submits that the ample structure function analysis of background publications such as Posada et al., Pan et al. and Minter et al. and the detailed structure function relationships and extensive experimental data guided by structural models detailed in the present application demonstrates that the evidence here exceeds what is needed to satisfy the enablement requirement. Applicant states that the amount of experimentation for confirmation as to whether a variant is within the scope of the claims is not undue. Applicant submits that the assays utilized by background publications and/or in the present application to confirm activity for variants within the scope of the claims are inexpensive and rapid, thus being within the guideposts provided to examiners in United States v. Telectronics for determining whether experimentation is undue.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejection. The Examiner acknowledges the amendments made to the claims, the teachings of the prior art and those of the specification. However, the Examiner disagrees with Applicant’s contention that the claimed invention is fully enabled by the teachings of the specification and/or the prior art.
In its broadest reasonable interpretation, the amended claims still require constructs having essentially any structure because there is no structural limitation with regard to the DNase domain and the Fc domain. The only structural limitations recited are three substitutions in the DNase I domain and three substitutions in the Fc domain. There are only 3 amino acids defined in the DNase I domain and three amino acids defined in the Fc domain. The remaining structures of the DNase domain and Fc domain required by the construct are completely undefined.
As stated above, while Applicant states that Pan et al., Posada et al. and Minter et al. provide ample structure function analysis and the specification provides detailed structure function relationships and extensive experimental data guided by structural models, it is reiterated herein that Pan et al. and Posada et al. specifically disclose a limited number of substitutions in the polypeptide of SEQ ID NO: 1 and their effect on DNase activity and actin binding. These substitutions represent approximately 2.8% of the entire structure of the polypeptide of SEQ ID NO: 1. In the case of the Fc domain, the substitutions represent 1.3% of the entire structure of the polypeptide of SEQ ID NO: 4 (1.3% = 3x100/227; SEQ ID NO: 4 has 227 amino acids). There is no disclosure of a structure/function correlation to determine which additional modifications beyond those substitutions disclosed can be made to the proteins of SEQ ID NO: 1 and 4 to obtain variants that can be used to produce the claimed construct. As explained above, there is no disclosure of how additional modifications could alter the hyperactivity effect nor half-life extension effect found with the substitutions provided.
With regard to the argument that the amount of experimentation required to enable the entire genus of variants required is not undue because the prior art and the specification provides inexpensive and fast assays to confirm activity for variants within the scope of the claims, it is noted that the argument in the instant case is not the availability of enzymatic assays or the cost associated with an enzymatic assay. Instead, the issue is the essentially infinite number of variants one of skill in the art would have to test to determine which variants can be used in the claimed construct. Contrary to Applicant’s assertions, the amount of experimentation is immense because (i) neither the specification nor the prior art disclose the structural features required in any variant of the polypeptide of SEQ ID NO: 1 so that it can have DNase1 activity, and the structural features required in any variant of the polypeptide of SEQ ID NO: 4 so that it can impart the recited construct with increased half-life, and (ii) neither the specification nor the prior art provide the structural features required in any variant of the polypeptide of SEQ ID NO: 1 having the recited 3 substitutions and any variant of the polypeptide of SEQ ID NO: 4 having the 3 recited substitutions so that they can be used in the construct required by the claimed method. Variants of the polypeptides of SEQ ID NO: 1 and 4 having 3 defined amino acids via the specific substitutions recited in claim 57 allow for any combination of 279 amino acid modifications in the polypeptide of SEQ ID NO: 1 (279 = 282-3; SEQ ID NO: 1 has 282 amino acids), and any combination of 224 amino acid modifications in the polypeptide of SEQ ID NO: 4 (224 – 227-3; SEQ ID NO: 4 has 227 amino acids). The total number of variants of a polypeptide having a specific number of amino acid substitutions can be calculated from the formula N!x19A/(N-A)!/A!, where N is the length in amino acids of the reference polypeptide and A is the number of allowed substitutions. Thus, the total number of variants of the polypeptide of SEQ ID NO: 1 that result from having up to 279 substitutions is 282!x19279/(282-279)!/279! or 2.18x10363 variants, while the total number of variants of the polypeptide of SEQ ID NO: 4 that result from having up to 224 substitutions is 227!x19224/(227-224)!/224! or 5.3x10292 variants. Therefore, while it is agreed that assays are available to test the desired functionality, it was not routine in the art to test by a trial and error process for an essentially infinite number of proteins to find those with the desired functional characteristics. Since there is no indication that the three substitutions recited are all that is required to have a DNase domain and an Fc domain having the desired functional characteristics, and in the absence of some knowledge or guidance as to the structural features required for the desired cleavage activity and increased half-life, one of skill in the art would have to test an infinite number of proteins to enable the entire scope of the claims. This is not deemed routine experimentation. Therefore, for the reasons of record and those set forth above, one cannot reasonably conclude that the entire scope of the claims is fully enabled by the teachings of the specification and/or the prior art.
Claim Rejections - 35 USC § 102 (AIA )
Claims 1, 57-58, 61, 63-67, 70, 74-75 were rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Posada et al. (WO 2018/005954 published 1/4/2018; cited in the IDS).
In view of Applicant’s cancellation of claims 1, 65, 70, 74-75 and the amendment of claims 57-58, 64, 67-68, this rejection is hereby withdrawn.
Claims 1, 57-58, 61, 63-68, 74-75 were rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Ledbetter et al. (U.S. Publication No. 2014/0044711 published 2/13/2014; cited in the IDS).
In view of Applicant’s cancellation of claims 1, 65, 74-75 and the amendment of claims 57-58, 64, 67-68, this rejection is hereby withdrawn.
Claim Rejections - 35 USC § 103 (AIA )
Claims 60, 68 were rejected under 35 U.S.C. 103 as being unpatentable over Posada et al. (WO 2018/005954 published 1/4/2018 in view of Minter et al. (U.S. Publication No. 2015/0104450 published 4/16/2015; cited in the IDS).
In view of the cancellation of claim 60 and the amendments made to claim 68 which no longer encompasses the elected combination, this rejection is hereby withdrawn.
Claims 57-58, 61, 63-64, 66 are rejected under 35 U.S.C. 103 as being unpatentable over Posada et al. (WO 2018/005954 published 1/4/2018 in view of Minter et al. (U.S. Publication No. 2015/0104450 published 4/16/2015; cited in the IDS). This rejection is necessitated by amendment.
As previously stated, Posada et al. teach a method of treating or preventing a condition associated with an abnormal immune response by administering a fusion protein (Abstract), wherein the condition is systemic lupus erythematosus (SLE), and the fusion protein degrades DNA (page 9, third full paragraph). As known in the art and also asserted in the specification of the instant application, SLE is a condition associated with inefficient NET hydrolysis. Posada et al. teach binuclease fusion proteins that comprise a human DNase I, an RNase I and an Fc domain, wherein the DNase I is operably linked with or without a linker to the N- or C-terminus of an Fc region (page 2, second full paragraph; page 7, last 10 lines). Posada et al. teach that the linkers have 1-50 amino acids in length or 1-61 amino acids in length (page 42, first and second full paragraphs) and disclose a linker that comprises SEQ ID NO: 5 (SEQ ID NO: 30, page 79). See alignment previously provided. Posada et al. teach that the Fc domain is a human IgG1 Fc that can comprise SEQ ID NO: 45 or can be a variant of this Fc domain (page 32, last 11 lines). Posada et al. teach that the human DNase I can be the human DNase I of SEQ ID NO: 20 (page 29) or a variant of this DNase I that comprises substitutions that correspond to substitutions in the protein of SEQ ID NO: 20 such as Q9R, E13R, HN74K, and A114F (page 30, first and second paragraphs). The human DNase I of SEQ ID NO: 20 is a fragment of the protein of SEQ ID NO: 1 of the instant application and lacks amino acids 1-22 of the protein of SEQ ID NO: 1. The substitutions Q9R, N74K, and A114F in the protein of SEQ ID NO: 20 correspond to substitutions Q31R, N96K and A136F in the protein of SEQ ID NO: 1 of the instant application. See alignment previously provided (residues in italics/bold/underlined). Posada et al. do not teach an Fc domain that comprises a Y at the position corresponding to position 32 of the protein of SEQ ID NO: 4, a T at the position corresponding to position 34 of the protein of SEQ ID NO: 4, or a E at the position corresponding to position 36 of the protein of SEQ ID NO: 4.
Minter et al. teach fusions that comprise a cytotoxic T-lymphocyte antigen 4 (CTLA-4) and an IgG Fc having improved stability and longer in vivo half-life (Abstract). Minter et al. teach that the YTE mutation in the Fc region of an IgG provides an extended in vivo half-life that may improve therapeutic efficacy and/or may allow therapeutic benefits to be achieved at reduced or less frequent dosage. Minter et al. teach an Fc that comprises Y at residue 38, T at residue 40 and E at residue 42 and that this represents mutations M38Y, S40T and T42E in the human IgG1 Fc (page 11, paragraph [0191]). Minter et al. teach a CTLA-4 polypeptide conjugated to the Fc domain of SEQ ID NO: 59 (page 11, paragraph [0193]; page 20, paragraph [0302]). Minter et al. teach that the Fc domain of SEQ ID NO: 59 (Fc variant-3) was the optimal fusion partner based on the lowest rates of purity loss (page 21, paragraph [0306]). The Fc domain of SEQ ID NO: 59 comprises substitutions that correspond to substitutions M32Y, S34T and T36E in the protein of SEQ ID NO: 4 of the instant application as shown in the alignment previously provided (residues in italics/bold/underlined). Minter et al. do not tech a human DNase I polypeptide.
Claims 57-58, 61, 63-64, 66 as interpreted/amended are directed in part to a method of treating, ameliorating, or preventing diseases or disorders associated with inefficient NET hydrolysis (NETolysis) in a subject, wherein said method requires administering a fusion protein (i.e., construct) that comprises a DNase I domain and a Fc domain wherein said DNase I domain is a variant of the polypeptide of SEQ ID NO: 1 that comprises at least three substitutions that correspond to the substitutions Q31R, N96K and A136F in the polypeptide of SEQ ID NO: 1, wherein said Fc domain is a variant of the polypeptide of SEQ ID NO: 4 that comprises at least three substitutions that correspond to substitutions M32Y, S34T and T36E in the polypeptide of SEQ ID NO: 4, wherein the fusion protein comprises a linker between the DNase I polypeptide and the Fc domain, wherein said linker can have between 1-100 amino acids, wherein said linker can comprise SEQ ID NO: 5, wherein the DNase1 domain does not have amino acids 1-22 of the polypeptide of SEQ ID NO: 1, wherein the Fc domain is at the C-terminus of the DNase1 domain. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the Fc domain of SEQ ID NO: 59 disclosed by Minter et al. in the fusion protein of Posada et al. A person of ordinary skill in the art is motivated to use the Fc domain of Minter et al. in the fusion protein of Posada et al. because Minter et al. teach that an Fc domain that comprises the YTE mutation, such as the Fc domain of SEQ ID NO: 59, provides an extended in vivo half-life that may improve therapeutic efficacy and/or may allow therapeutic benefits to be achieved at reduced or less frequent dosage. One of ordinary skill in the art has a reasonable expectation of success at using the Fc domain of Minter et al. in the fusion protein of Posada et al. because the molecular biology techniques required to produce a fusion protein are well known in the art as evidenced by Posada et al. and Minter et al. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
With regard to the previous rejection of claims 60, 68 over the teachings of Posada et al. and Minter et al., Applicant argues that Posada et al. relates to the development of binuclease fusion proteins and provides no direction to the combination of the recited substitutions. Applicant submits that the Office provides no motivation to arrive to the DNase1 variant comprising the recited substitutions, namely Q31R, N96K and A136F. Applicant states that one of skill in the art would be left to limitless trials and errors to arrive to the recited combination of substitutions recited in claim 1. Applicant states that the Office has not established predictable results citing MPEP 2143(I)(B). Applicant refers to the teachings of Pan et al., which is a reference cited by Posada et al., to indicate that the combinations of substitutions Q9R+E13R+N74K, A114F, and Q9R+E13R+N74K+A114F have been previously characterized. Applicant states that hyperactive variants were characterized by Pan et al. and that the hyperactivity increases progressively with additional positive charges up to 3+, with an additional benefit if the A114F is added. Applicant refers to the combination Q9R+E13R+N74K+A114F as having a 100 fold increase in potency compared to the wild type DNAse1. Applicant states that the combination recited in the claims which corresponds to the combination Q9R+N74K, A114F results in a 2+ charge, which is not an ideal combination according to Pan et al. Applicant states that the teachings of Posada et al. also teach the E13R+N74K+A114F+T205K mutant. According to Applicant, the teachings of Posada et al. are consistent with those of Pan et al. and thus there is no basis for predictable results for a composition having the recited 3 substitutions in claim 1. Applicant states that the teachings of Miner et al. do not cure the deficiencies of Posada et al. and refer to Fc modifications. Applicant refers to a post-filing reference by Stabach et al. (JCI Insight 9(14):e177003, pages 1-21; June 18, 2024) to show that post filing data supports the argument of superior and unexpected results associated with the claimed subject matter. Applicant refers to the findings regarding the construct ID 1833 in support of the argument that it was unexpected, based on the teachings of Pan et al., to find that a DNase1 variant that does not have a 3+ charge yields the benefits disclosed by Stabach et al.
Applicant’s arguments have been fully considered to the extent they are relevant to the current rejection of claims 57-58, 61, 63-64, 66 over the teachings of Posada et al. and Minter et al. The Examiner acknowledges the amendments to the claims, the teachings of Pan et al. and Stabach et al. and MPEP 2143(I)(B). However, the Examiner disagrees with Applicant’s contention that the combined teachings of Posada et al. in combination with those of Minter et al. do not render the claimed invention obvious.
With regard to the argument that the Office provides no motivation to arrive to the DNase1 variant comprising the recited substitutions, namely Q31R, N96K and A136F and that one of skill in the art would be left to limitless trials and errors to arrive to the recited combination of substitutions recited in claim 1, it is reiterated herein that the substitutions Q9R, N74K, and A114F in the protein of SEQ ID NO: 20 of Posada et al. correspond to substitutions Q31R, N96K and A136F in the protein of SEQ ID NO: 1 of the instant application. See alignment previously provided. On page 30, lines 6-9, Posada et al. state “For example, a mutant human DNase can include one or more of the following substitutions: Q9R, E13R, T14K, H44K, N74K, N110R, T205K. In some embodiments, the mutant human DNase also includes an A114F substitution, which reduces sensitivity to actin (see US 6348343)”. Therefore, contrary to Applicant’s assertions, Posada et al. teach the combination of these three substitutions. There are 63 combinations of the 8 substitutions disclosed by Posada et al. that comprise these three substitutions (63 = 26 -1; 6 = E13R, T14K, H44K, N110R, T205K and Q9R+N74K+A114F). This is not the case of limitless trials and errors as asserted, or a case where the combination of substitutions is suggested. Posada et al. teach the combination of substitutions recited. It is unclear to the Examiner as to how the teachings of Posada et al. do not teach the specific combination of mutations recited in the claims when Posada et al. discloses 63 combinations of substitutions that comprise the substitutions that correspond to substitutions Q31R, N96K and A136F in the polypeptide of SEQ ID NO: 1. In the instant case, a single reference (Posada et al.) provides the combination of all the substitutions recited in claim 1. It should also be noted that as correctly asserted by Applicant, the reference by Pan et al. cited by Posada et al., discloses the mutant Q9R+E13R+N74K+A114F, as a hyperactive variant (same as Q31R+E35R+N96K+A136F in the instant application). Therefore, at the time of the invention, mutants of the polypeptide of SEQ ID NO: 1 that comprise the combination of substitutions recited was already known in the art.
With regard to the argument that the teachings of Pan et al. suggest that the combination Q9R+N74K+A114F results in a 2+ charge, which is not an ideal combination, it is noted that (i) neither Pan et al. nor Posada et al. teach that a mutant that comprises the combination of substitutions Q9R+N74K, A114F does not have increased DNase activity, or that a variant that has a 2+ charge is undesirable, and (ii) the claims are not limited solely to the three substitutions as evidenced by claim 67, which includes the combination Q9R+E13R+N74K+A114F, a combination that has a 3+ charge and has 100-fold increase in potency compared to the wild type DNase 1 according to Pan et al. With regard to the argument that there is no basis for predictable results for a composition having the recited 3 substitutions in claim 1 (Q9R+N74K+A114F), it is noted that as evidenced by Pan et al., all the variants that comprise Q9R+N74K have increased DNase activity according to Table 1 of Pan et al. As taught by Posada et al., the A114F substitution (A136F in the instant application) is only associated to a reduction in sensitivity to actin. Therefore, the teachings of Pan et al. or Posada et al. do not support the argument that it is unpredictable to expect a variant comprising the three substitutions recited to have increased DNase activity compared to the wild type human DNase1 of SEQ ID NO: 1.
With regard to the arguments of unexpected results and the post-filing data of Stabach et al., it is noted that one of skill in the art did not need to know the superior properties of the 1883 construct to find a motivation to combine the teachings of Posada et al. and Minter et al. to arrive to the claimed invention. As previously indicated, a construct comprising a human DNase domain having the recited substitutions was disclosed by Posada et al. and the motivation to replace the Fc domain in the constructs of Posada et al. with an Fc domain having the recited substitutions is found in the fact that Minter et al. teach that an Fc domain that comprises the YTE mutation, such as the Fc domain of SEQ ID NO: 59, provides an extended in vivo half-life that may improve therapeutic efficacy and/or may allow therapeutic benefits to be achieved at reduced or less frequent dosage. Minter et al. specifically teach an Fc domain having substitutions that correspond to substitutions M32Y, S34T and T36E in the protein of SEQ ID NO: 4, namely the Fc domain of SEQ ID NO: 59, which when linked to a therapeutic protein (CTLA-4) increased the stability and in vivo half-life of said therapeutic protein. This finding alone would have strongly motivated one of skill in the art to replace the Fc domain of Posada et al. with the Fc domain of Minter et al., thus arriving to the claimed invention. Therefore, the claimed construct is obvious because it was suggested by the prior art even though the particular benefit asserted by Applicant was not disclosed in the prior art. See MPEP 2144.09 (VII). Moreover, Table 2 of the Stabach reference discloses several constructs having the substitutions corresponding to substitutions Q31R, N96K and A136F in the polypeptide of SEQ ID NO: 1 and not all of these constructs have the same therapeutic effect. In addition, the 1833 construct has more than the three substitutions recited in claim 1. As such, one cannot reasonably conclude that the “unexpected” results obtained from the 1833 construct are solely associated to these three substitutions.
Double Patenting
Claims 57-58, 61, 63-64, 66 remain provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 18, 23, 27-28, 30-31, 33, 36, 42, 44-58 of copending Application No. 18/000,957.
This rejection has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant argues that MPEP 804 states that if a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the Examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent. Applicant states that the present application has the earliest priority date and requests reconsideration and withdrawal of the instant application.
Applicant’s arguments have been fully considered. However, it is noted that the instant provisional double patenting rejection is not the only rejection remaining in the instant application.
Claims 57-58, 61, 63-64, 66 as interpreted and amended are directed in part to a method of treating, ameliorating, or preventing diseases or disorders associated with inefficient NET hydrolysis in a subject, wherein said method requires administering a fusion protein (i.e., construct) that comprises a DNase I polypeptide and a Fc domain wherein said Fc domain can be a variant of an Fc domain of a human IgG1, wherein the DNase I polypeptide can be a variant of the human DNase I protein of SEQ ID NO: 1 that comprises one or more substitutions that correspond to substitutions in the protein of SEQ ID NO: 1 selected from Q31R, N96K, and A136F, wherein the Fc domain can be a variant of the protein of SEQ ID NO: 4 that comprises the substitutions that correspond to substitutions M32Y, S34T, and T36E in the protein of SEQ ID NO: 4, wherein the fusion protein comprises a linker between the DNase I polypeptide and the Fc domain, wherein said linker can have between 1-100 amino acids, wherein said linker can comprise SEQ ID NO: 5, wherein the DNase I polypeptide can have an amino acid sequence that lacks amino acids 1-22 of SEQ ID NO: 2, wherein the Fc domain is at the C-terminus of the DNase I polypeptide. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
Claims 1, 18, 23, 27-28, 30-31, 33, 36, 42, 44-58 of copending Application No. 18/000,957 are directed in part to a method of ameliorating or preventing inefficient NET hydrolysis in a subjected afflicted with a bacterial or viral infection, or a method of treating or ameliorating sepsis by administering a construct that comprises a human DNase 1 polypeptide and an Fc domain, wherein the DNase I polypeptide can be a variant of the human DNase I protein of SEQ ID NO: 1 that lacks the fragment consisting of amino acids 1-22 of SEQ ID NO: 1 or a variant that comprises one or more substitutions that correspond to substitutions in the protein of SEQ ID NO: 1 selected from Q31R, N96K, and A136F, wherein the Fc domain can comprise SEQ ID NO: 4 or can be a variant of the protein of SEQ ID NO: 4 that comprises the substitutions that correspond to substitutions M32Y, S34T, and T36E in the protein of SEQ ID NO: 4, wherein the fusion protein comprises a linker between the DNase I polypeptide and the Fc domain, wherein said linker has between 1-100 amino acids, wherein said linker comprises SEQ ID NO: 5, wherein the Fc domain is at the C-terminus of the DNase I polypeptide. As indicated in the specification of copending Application No. 18/000,957, sepsis is associated with inefficient NET hydrolysis. Therefore, the methods of claims 1, 18, 23, 27-28, 30-31, 33, 36, 42, 44-58 of copending Application No. 18/000,957 anticipate the method of claims 57-58, 61, 63-64, 66 as written/interpreted.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Conclusion
No claim is in condition for allowance.
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 extension fee 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 date of this final action.
Applicant is advised that any Internet email communication by the Examiner has to be authorized by Applicant in written form. See MPEP § 502.03 (II). Without a written authorization by Applicant in place, the USPTO will not respond via Internet email to any Internet correspondence which contains information subject to the confidentiality requirement as set forth in 35 U.S.C. 122. Sample written authorization language can be found in MPEP § 502.03 (II). An Authorization for Internet Communications in a Patent Application or Request to Withdraw Authorization for Internet Communications form (SB/439) can be found at https://www.uspto.gov/patent/forms/ forms-patent-applications-filed-or-after-september-16-2012, which can be electronically filed.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to DELIA M RAMIREZ, Ph.D., whose telephone number is (571) 272-0938. The examiner can normally be reached on Monday-Friday from 8:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert B. Mondesi, can be reached at (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/DELIA M RAMIREZ/Primary Examiner, Art Unit 1652
DR
June 23, 2026
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