DETAILED ACTION
Notice of 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 .
Election/Restrictions
Applicant’s election without traverse of Group V, claim 112 in the reply filed on 10 August 2026 is acknowledged. The requirement is deemed proper and therefore made Final.
Status of Application
Claims 1-4, 13, 19, 26, 33, 40, 46, 49-50, 53-54, 63, 65-67 and 111 are cancelled; claims 142-160 are new and dependent upon elected claim 112. Thus, claims 112 and 142-160 are subject to examination on the merits.
Priority
The instant application is a CON of US 17/732,927 (now ABN) which is a CON of US application 17/509,991 (now US Patent 11352613) which is a CIP of US 17/427,974 filed 03 August 2021, which is a 371 of PCT/US2020/016490 filed 04 February 2020 which claims benefit of US Provisional application 62/800,790 filed 04 February 2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08 August 2024 has been considered by the examiner. See initialed and signed PTO/SB/08.
Compliance with Sequence Rules (Objection Specification)
The sequence listing, filed in computer readable form (.xml) on 13 January 2025, has been received and entered. This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.831(b). However, this application fails to fully comply with the requirements of 37 C.F.R. 1.831-1.839.
The following Figures/parts of the specification contain sequences that contain four or more specifically defined amino acids or ten or more specifically defined nucleotides without any corresponding SEQ ID NO: and/or no reference to any SEQ ID NO: in the Brief Description of the Drawings.
In Figures 6A and 6B there are numerous peptide sequences (e.g. the examiner lost track after about 50) having four or more amino acids, each of which needs its own sequence identifier.
The sequence(s) in Figure 10 requires sequence identifiers, or reference to specific sequence and the corresponding positions therein (e.g. amino acids 283-305 of SEQ ID NO: 4).
* If the noted sequences are in the sequence listing as filed, Applicants must amend the specification to identify the sequences appropriately by SEQ ID NO:. If the noted sequences are not in the sequence listing as filed, Applicants must provide (1) an updated copy of the sequence listing containing the requisite sequences in computer readable form (.xml), (2) an amendment directing its entry into the specification, (3) a statement that no new matter has been added and (4) an amendment to the specification to identify the identified sequences by SEQ ID NO:, which can be in the Brief Description of the Drawings section of the specification and (5) an updated incorporation by reference statement with the new date of creation, sequence file name and size. – See also MPEP 2422.
Claim/Sequences Interpretation
The claims comprise a DNASE enzyme having at least 90% sequence identity to SEQ ID NO: 4 and having one or more substitutions or deletions of the C-terminal tail of said enzyme as defined by SEQ ID NO: 10; and conjugation to one or more PEG molecule/chain.
It is noted, SEQ ID NO: 4 is 305 amino acids in length and is a human D1L3 DNASE. SEQ ID NO: 10 is 23 amino acids in length and is identical to the C-terminal amino acids 283-305 of SEQ ID NO: 4. Thus, effectively, the DNASE used in the methods is a human D1L3 DNASE comprising SEQ ID NO: 4 or those sequences having 90% identity thereto and having one or more substitutions or deletions of SEQ ID NO: 4 at the C-terminus amino acid positions 283-305; and further being conjugated to at least one PEG molecule/chain.
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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 112 and 142-160 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Fuchs et al. (US 10696956 – cited herein).
Fuchs et al. teach:
Regarding claims 112, 151, 152 a method for treating a subject in need of extracellular chromatin degradation, the method comprising administering a therapeutically effective amount of a DNASE enzyme comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 2, and having one or more amino acid substitutions or deletions of the C-terminal tail defined by SEQ ID NO: 33 – See Claim 1. It is noted, SEQ ID NO: 2 of the ‘956 patent has 100% identity to instant SEQ ID NO: 4 (See Supplemental Content, Result #1, Duplicates thereof in the file ending in .rai) and SEQ ID NO: 33 of the ‘956 patent has 100% identity to instant SEQ ID NO: 10. The DNASE furthermore may comprise a half-life extending moiety, which for example, PEG molecule is linked to the D1L3 variant (e.g. SEQ ID NO: 4) – See col. 20, line 59 to Col. 21, line 6.
Regarding claims 148-150, the PEG chain(s) have a molecular weight in the range of about 500 to about 40,000 Daltons; or about 500 to about 5,000 Daltons; or about 10,000 to about 20,000 Daltons - See col. 20, line 59 to Col. 21, line 6.
Regarding claims 142-144, the D1L3 variant of SEQ ID NO: 2 has one or more, such as at least 3, at least 5, or the entire NLS2 domain (e.g. SEQ ID NO: 33) deleted – See Claim 1, and See Col. 16, line 47 to Col. 17, line 3.
Regarding claims 145-147, the entire C-terminal tail is deleted (e.g. SEQ ID NO: 33), and thus, one or more basic C-terminal amino acids are deleted including the lysines listed in claim 147 (e.g. SSRAFTNSKKSVTLRKKTKSKRS is deleted and these are amino acids 283-305). The deletion of said amino acids results in decreased/no proteolysis.
Additional treatments for subjects in need thereof are those in need of neutrophil extracellular trap (NET) degradation – See col. 3, lines 39-47.
Regarding claims 153 and 154, the method includes administration by topical, parenteral, or pulmonary administration (claims 7-8) and is formulated for intravenous of subcutaneous administration (claim 8).
Regarding claim 155, the subject comprises one having chronic or acute inflammatory disorder or an acute or chronic infection (See claim 12).
Regarding claim 156, the subject comprises one having autoimmune disease (See claim 17).
Regarding claim 157, the subject comprises one having systemic lupus erythematosus, vasculitis, rheumatoid arthritis, or systemic sclerosis (See claim 18).
Regarding claim 158, the subject has an inflammatory disease of the respiratory tract (See claim 19).
Regarding claim 159, the subject has a renal inflammatory disease or renal injury (See claim 21).
Regarding claim 160, the subject has or is at risk of a vascular occlusion comprising neutrophil extracellular traps (NETs), including ductal occlusion in a ductal system – See claims 13 and 22-24.
The applied reference has a common inventor and assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Applicants should note, each and every 102(b)(2)(C) statement filed by Applicant’s MUST adhere to the following criteria. Per MPEP 717.02(a)(I) - “The statement(s) should either be on or begin on a separate sheet and must not be directed to other matters (37 CFR 1.4(c)). The statement must be signed in accordance with 37 CFR 1.33(b)” Failure to follow this criteria will result in a deficient statement and maintenance of the rejection of record.
Claim 112 and 142-160 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Fuchs et al. (US 10801019 – cited herein).
Fuchs et al. teach:
Regarding claims 112, 151 and 152, a method for treating a human subject having an intravascular accumulation of neutrophil extracellular traps (NETs), the method comprising systemically administering an effective amount of a DNase1-like 3 (D1L3) enzyme comprising an amino acid sequence having at least 90% sequence identity to amino acids 21 to 305 of SEQ ID NO: 2 to said subject, wherein the subject has a condition selected from: a severe inflammatory disease selected from acute respiratory distress syndrome (ARDS), sepsis, and a viral infection; partially or fully occluded blood vessels; thrombotic microangiopathy (TMA); disseminated intravascular coagulation (DIC); venous thromboembolism; leukemia; and
tumor metastasis – See Claim 1. It is noted, instant SEQ ID NO: 4 is identical to SEQ ID NO: 2 of the ‘019 patent (See Result #1, .rai file, result under duplicates). Additional aspects of the treatment are for those subjects, such as those recited in claim 1, which are in need of neutrophil extracellular trap (NET) degradation - See col. 3, lines 39-47
Dependent claim recite 4 recites deletion of all of a part of the C-terminal domain as defined by SEQ ID NO: 33 (identical to instant SEQ ID NO: 10); claim 5 recites the D1L3 DNASE comprises a fusion with a carrier protein. It is further taught the fusion carrier protein can be located at either the N- or C-terminus (See Col. 20, lines 52-54).
The DNASE furthermore may comprise a half-life extending moiety, which for example, PEG molecule is linked to the D1L3 variant (e.g. SEQ ID NO: 4) – See col. 20, line 59 to Col. 21, line 6.
Regarding claims 148-150, the PEG chain(s) have a molecular weight in the range of about 500 to about 40,000 Daltons; or about 500 to about 5,000 Daltons; or about 10,000 to about 20,000 Daltons - See col. 21, lines 4-18.
Regarding claims 142-144, the D1L3 variant of SEQ ID NO: 2 has one or more, such as at least 3, at least 5, or the entire NLS2 domain (e.g. SEQ ID NO: 33) deleted – See Claim 4, and See Col. 16, line 51 to Col. 17, line 7.
Regarding claims 145-147, the entire C-terminal tail is deleted (e.g. SEQ ID NO: 33), and thus, one or more basic C-terminal amino acids are deleted including the lysines listed in claim 147 (e.g. SSRAFTNSKKSVTLRKKTKSKRS is deleted and these are amino acids 283-305) – See claim 4. The deletion of said amino acids results in decreased/no proteolysis.
Additional treatments for subjects in need thereof are those in need of neutrophil extracellular trap (NET) degradation – See col. 3, lines 39-47.
Regarding claims 153 and 154, the method includes administration by topical, parenteral, or pulmonary administration and is formulated for intravenous of subcutaneous administration (See Claim 7 and Col. 28, lines 43-49).
Regarding claims 155-160, the subjects comprise those having any or the following: chronic neutrophilia (e.g., an increase in the number of neutrophils), neutrophil aggregation and leukostasis, thrombosis and vascular occlusion (e.g. sickle cell disease), ischemia-reperfusion injury (e.g. midgut volvulus, testicular torsion, limb ischemia reperfusion, vital organ ischemia-reperfusion, organ transplantation), surgical and traumatic tissue injury, an acute or chronic inflammatory reaction or disease, an autoimmune disease (e.g. systemic lupus erythematosus (SLE), lupus nephritis, rheumatoid arthritis, vasculitis, systemic sclerosis), cardiovascular disease (e.g., myocardial infarction, stroke, atherosclerosis, venous thromboembolism, including thrombolytic therapy), metabolic disease (e.g., diabetes), systemic inflammation (e.g., systemic inflammatory response syndrome (SIRS), sepsis, septic shock, disseminated intravascular coagulation (DIC), and thrombotic microangiopathy (TMA)), inflammatory diseases of the respiratory tract (e.g. cystic fibrosis, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), smoke induced lung injury, transfusion induced lung injury (TRALI), acute respiratory distress syndrome (ARDS), and asthma, atelectasis, bronchitis, empyema), renal inflammatory diseases (acute and chronic kidney diseases, including acute kidney injury (AM) and chronic kidney disease (CKD), inflammatory diseases related to transplanted tissue (e.g. graft-versus-host disease) and cancer (e.g. leukemia, tumor metastasis, and solid tumors) – See Col. 3 , line 50 to Col. 4, line 12.
The applied reference has a common inventor and assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Applicants should note, each and every 102(b)(2)(C) statement filed by Applicant’s MUST adhere to the following criteria. Per MPEP 717.02(a)(I) - “The statement(s) should either be on or begin on a separate sheet and must not be directed to other matters (37 CFR 1.4(c)). The statement must be signed in accordance with 37 CFR 1.33(b)” Failure to follow this criteria will result in a deficient statement and maintenance of the rejection of record.
Claim 112 and 142-106 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Fuchs et al. (US 10988746 – cited herein).
Fuchs et al. teach:
Regarding claims 112, 151 and 152 methods of treating a subject in need extracellular DNA degradation, extracellular chromatin degradation, extracellular trap (ET) degradation and/or neutrophil extracellular trap (NET) degradation (Col. 4, lines 36-42) by administering a DNASE N1L3 protein, wherein said DNASE has at least 95% sequence identity to amino acids 21 to 282 of SEQ ID NO: 4 and comprises a C-terminal deletion of amino acids 301-305 and fused N-terminally to an albumin, wherein the modified protein may also have an attached PEG molecule (See col. 19, lines 1-15). Said SEQ ID NO: 4 and instant SEQ ID NO: have 100% sequence identity to one another. (See Supplemental Content, Result #1, Duplicates thereof, in the file ending in .rai).
Regarding claims 148-150, the PEG chain(s) have a molecular weight in the range of about 500 to about 40,000 Daltons; or about 500 to about 5,000 Daltons; or about 10,000 to about 20,000 Daltons - See col. 19, lines 1-15.
Regarding claims 142-144, the D1L3 variant of SEQ ID NO: 2 has one or more, such as at least 3, at least 5, or the entire NLS2 domain (e.g. SEQ ID NO: 33) deleted – See Claim 4, and See Col. 16, line 51 to Col. 17, line 7.
Regarding claims 145-147, the entire C-terminal tail is deleted (e.g. SEQ ID NO: 33), and thus, one or more basic C-terminal amino acids are deleted including the lysines listed in claim 147 (e.g. SSRAFTNSKKSVTLRKKTKSKRS is deleted and these are amino acids 283-305) – See claim 1. The deletion of said amino acids results in decreased/no proteolysis. In addition, it is taught to mutations in K291, K292, K297, K298, K299, K303 and/or K304 - See Col. 19, lines 41-46.
Regarding claims 153 and 154, the method includes administration by topical, parenteral, or pulmonary administration and is formulated for intravenous of subcutaneous administration (See Col. 22, lines 51-58).
Regarding claims 155-160, the subjects comprise those having any or the following: diseases or conditions characterized by the presence or accumulation of NETs. Such diseases or conditions include, but are not limited to, diseases associated with chronic neutrophilia, neutrophil aggregation and leukostasis, thrombosis and vascular occlusion, ischemia-reperfusion injury, surgical and traumatic tissue injury, an acute or chronic inflammatory reaction or disease, an autoimmune disease, cardiovascular disease, metabolic disease, systemic inflammation, inflammatory diseases of the respiratory tract, renal inflammatory diseases, inflammatory diseases related to transplanted tissue (e.g. graft-versus-host disease) and cancer (including leukemia) – See Col. 22, lines 12-25.
The applied reference has a common inventor and assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Applicants should note, each and every 102(b)(2)(C) statement filed by Applicant’s MUST adhere to the following criteria. Per MPEP 717.02(a)(I) - “The statement(s) should either be on or begin on a separate sheet and must not be directed to other matters (37 CFR 1.4(c)). The statement must be signed in accordance with 37 CFR 1.33(b)” Failure to follow this criteria will result in a deficient statement and maintenance of the rejection of record.
Claim 112 and 142-160 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Fuchs et al. (US 11046942 – cited herein).
Fuchs et al. teach:
Regarding claims 112, 151 and 152, 155, 159-160, a method for treating a human having an intravascular accumulation of neutrophil extracellular traps (NETs, the method comprising administering to a subject an effective amount of a DNase1-like 3 (D1L3) enzyme (col. 3, lines 42-50), wherein the DNASE D1L3 comprises an amino acid sequence having at least 90% sequence identity to amino acids 21-305 of SEQ ID NO: 2, wherein said sequence further comprises a deletion of the NLS2 domain comprising SEQ ID NO: 33 (which has 100% identity to instant SEQ ID NO: 10, See Result #1, .rai file, result under duplicates) and the subject has a severe inflammatory disease selected from acute respiratory distress syndrome (ARDS), sepsis, and a viral infection; partially or fully occluded blood vessels; thrombotic microangiopathy (TMA); disseminated intravascular coagulation (DIC); venous thromboembolism; leukemia; and
tumor metastasis – See Claim 1. It is noted, instant SEQ ID NO: 4 is identical to SEQ ID NO: 2 of the ‘942 patent (See Result #1, .rai file, result under duplicates), wherein the modified protein may also have an attached PEG molecule (See col. 21, lines 3-18).
Regarding claims 148-150, the PEG chain(s) have a molecular weight in the range of about 500 to about 40,000 Daltons; or about 500 to about 5,000 Daltons; or about 10,000 to about 20,000 Daltons - See col. col. 21, lines 3-18.
Regarding claims 142-144, the D1L3 variant of SEQ ID NO: 2 has one or more, such as at least 3, at least 5, or the entire NLS2 domain (e.g. SEQ ID NO: 33) deleted – See Claim 4.
Regarding claims 145-147, the entire C-terminal tail is deleted (e.g. SEQ ID NO: 33), and thus, one or more basic C-terminal amino acids are deleted including the lysines listed in claim 147 (e.g. SSRAFTNSKKSVTLRKKTKSKRS is deleted and these are amino acids 283-305) – See claim 4. The deletion of said amino acids results in decreased/no proteolysis.
Regarding claims 153 and 154, the method includes administration by topical, parenteral, or pulmonary administration and is formulated for intravenous of subcutaneous administration (See Col. 28, lines 46-52).
Regarding claims 155-160, the subjects comprise those having diseases associated with chronic neutrophilia (e.g., an increase in the number of neutrophils), neutrophil aggregation and leukostasis, thrombosis and vascular occlusion (e.g. sickle cell disease), ischemia-reperfusion injury (e.g. midgut volvulus, testicular torsion, limb ischemia reperfusion, vital organ ischemia-reperfusion, organ transplantation), surgical and traumatic tissue injury, an acute or chronic inflammatory reaction or disease, an autoimmune disease (e.g. systemic lupus erythematosus (SLE), lupus nephritis, rheumatoid arthritis, vasculitis, systemic sclerosis), cardiovascular disease (e.g., myocardial infarction, stroke, atherosclerosis, venous thromboembolism, including thrombolytic therapy), metabolic disease (e.g., diabetes), systemic inflammation (e.g., systemic inflammatory response syndrome (SIRS), sepsis, septic shock, disseminated intravascular coagulation (DIC), and thrombotic microangiopathy (TMA)), inflammatory diseases of the respiratory tract (e.g. cystic fibrosis, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), smoke induced lung injury, transfusion induced lung injury (TRALI), acute respiratory distress syndrome (ARDS), and asthma, atelectasis, bronchitis, empyema), renal inflammatory diseases (acute and chronic kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), inflammatory diseases related to transplanted tissue (e.g. graft-versus-host disease) and cancer (e.g. leukemia, tumor metastasis, and solid tumors) – See Col. 29, lines 33-62.
The applied reference has a common inventor and assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Applicants should note, each and every 102(b)(2)(C) statement filed by Applicant’s MUST adhere to the following criteria. Per MPEP 717.02(a)(I) - “The statement(s) should either be on or begin on a separate sheet and must not be directed to other matters (37 CFR 1.4(c)). The statement must be signed in accordance with 37 CFR 1.33(b)” Failure to follow this criteria will result in a deficient statement and maintenance of the rejection of record.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 112 and 142-160 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 10696956 in view of Molineux (Cancer Treatments Reviews, 2002: 28(SUPPL. A) 13-16 – cited herein), Roberts et al. (Adv. Drug Delivery Rev., 2002, 54:459-476 – cited herein) and Bentley et al. (US 5,990,237 – cited herein). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘956 patent combined with render obvious the instant claim.
The instant claim is drawn to a method for treating a subject in need of extracellular DNA degradation, extracellular chromatin degradation, extracellular trap (ET) degradation and/or neutrophil extracellular trap (NET) degradation, the method comprising administering a therapeutically effective amount of a DNASE enzyme comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 4, and having one or more amino acid substitutions or deletions of the C-terminal tail defined by SEQ ID NO: 10, and conjugation to one or more polyethylene glycol (PEG) chains/molecules.
The claims to the ‘956 patent in their broadest are drawn to a method for treating a subject in need of extracellular chromatin degradation, the method comprising administering a therapeutically effective amount of a DNASE-like 3 (D1L3) enzyme comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 2, and having the deletion of the C-terminal tail defined by SEQ ID NO: 33.
Thus, the difference between the claims is the ‘956 patent claims do not teach adding a PEG molecule to the DNASE-like 3 (D1L3) enzyme comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 2, and having the deletion of the C-terminal tail defined by SEQ ID NO: 33.
It is noted, SQ ID NO: 2 of the ‘956 patent has 100% identity to instant SEQ ID NO: 4 (See Supplemental Content, Result #1, under duplicates of said result #1, in the .rai file) and SEQ ID NO: 33 of the ‘956 patent has 100% identity to instant SEQ ID NO: 10.
Molineux teaches that conjugating PEG molecules (pegylation) to biomolecules, such as proteins, inhibitors and small peptides is a well established method for increasing the circulating half-life of proteins and liposomal pharmaceuticals. It is taught that small peptides and even large proteins are usually quickly degraded by proteolytic enzymes or are quickly and efficiently filtered from the circulatory system through renal clearance. However, by attaching PEG molecules which are nontoxic water-soluble polymers to these same pharmaceutical small peptides or molecules, this increases the hydrodynamic volume of the peptide and creates a shield around the pegylated peptide/drug thereby protecting it from renal clearance, enzymatic degradation or recognition by various cells of the immune system. In essence, the pegylation of pharmaceutical proteins or peptides has been shown to significantly increase the efficiency of administration of pegylated protein/peptide drugs since the half-life of the drug in the circulatory system is increased and said proteins are also less immunogenic. Thus the need for repeated or chronic administration of pharmaceuticals is significantly decreased and the immune reaction of the body to a foreign protein is decreased.
Roberts et al. teach various strategies and methods of how to efficiently pegylate proteins and peptides. Specifically, first generation methods and second generation methods are taught and discussed. The reasons for pegylating a pharmaceutical are explained in line 3 of the abstract and on p. 460 in the introduction. For simplicity sake, the teachings are substantially identical to that taught by Molineux in the preceding paragraph. On p. 461, section 3. Chemistry of pegylation, it is taught that the most common route for PEG conjugation has been to activate PEG with functional groups so that they can react with an primary amine which can be found on the N-terminal amino acid groups of proteins and peptides, and also on the side-chains of lysine residues. This activation method step is the method of choice by most skilled artisans because lysine’s often constitute up 10% of the total amino acid composition of proteins and peptides (see p. 461, 2nd column, last paragraph through to p. 462 1st column first paragraph). It is also taught that when there are multiple lysine residues it is sometimes difficult to produce homogeneous pegylated products when using first generation pegylation methods. However, it is also taught that with second generation pegylation methods (e.g. the recent new advances to the technique) that it is possible to eliminate heterogeneity in substitutions by using mPEG-propionaldehyde and an appropriate pH to control the reaction. (see p. 464, 2nd column, first paragraph under Section 3.2.1). Finally, it is taught also that many of the important benefits of pegylation (e.g. increased half-life, less immunogenic pharmaceuticals etc.)….”can be controlled by proper conjugation of various molecular weight PEGs to the protein at specific locations..” (see p. 462, 1st column, 12th line from the bottom). Thus, one must vary the PEG size, which can range from 1 kDa to 20 kDa, in order to see if there is significant variance in the benefits elicited by pegylating a selected protein or peptide pharmaceutical.
Bentley et al. teach step-by-step procedures for pegylating a protein, beginning with how to prepare the PEG molecules to pegylating lysozyme (used as an exemplary protein/enzyme) (see Examples 1-6).
Therefore it would have been obvious to one of ordinary skill prior to the effective filing date of the claimed invention to pegylate the therapeutically effective DNASE-like 3 (D1L3) enzyme comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 2, and having the deletion of the C-terminal tail defined by SEQ ID NO: 33, used to treat a subject in need of extracellular chromatin degradation, the method comprising administering because it affords the following attributes: by attaching PEG molecules which are nontoxic water-soluble polymers to these same pharmaceutical small peptides or molecules, this increases the hydrodynamic volume of the peptide and creates a shield around the pegylated peptide/drug thereby protecting it from renal clearance, enzymatic degradation and reduced immunogenicity as taught by Molineux and Roberts. This would motivation in and of itself because increasing the therapeutic half-life while also reducing potential immunogenic effects for the patient are both very desirable outcomes. In addition, there would be a reasonable expectation of success in pegylating the DNase-like 3 enzyme as in the claims of the ‘956 patent because Molineux, Roberts et al. and Bentley teach precisely how to achieve this and also demonstrate many successful outcomes in the prior art.
Claim 112 and 142-160 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11352613 in view of Molineux (Cancer Treatments Reviews, 2002: 28(SUPPL. A) 13-16 – cited herein), Roberts et al. (Adv. Drug Delivery Rev., 2002, 54:459-476 – cited herein) and Bentley et al. (US 5,990,237 – cited herein). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘613 patent anticipate the instant claim.
The instant claim is drawn to a method for treating a subject in need of extracellular DNA degradation, extracellular chromatin degradation, extracellular trap (ET) degradation and/or neutrophil extracellular trap (NET) degradation, the method comprising administering a therapeutically effective amount of a DNASE enzyme comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 4, and having one or more amino acid substitutions or deletions of the C-terminal tail defined by SEQ ID NO: 10, and conjugation to one or more polyethylene glycol (PEG) chains/molecules.
The claims to the ‘613 patent in their broadest are drawn to a method for treating a subject in need of extracellular DNA degradation, extracellular chromatin degradation, extracellular trap (ET) degradation and/or neutrophil extracellular trap (NET) degradation, the method comprising administering a therapeutically effective amount of a DNASE enzyme comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 4, and having one or more amino acid substitutions of the C-terminal tail defined by SEQ ID NO: 10, and a C-terminal fusion to a carrier protein optionally through a linking sequence.
Thus, the difference between the claims is the ‘613 patent claims do not teach adding a PEG molecule to the DNASE-like 3 (D1L3) enzyme comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 4, and having the deletion of the C-terminal tail defined by SEQ ID NO: 10 and a C-terminal fusion to a carrier protein.
It is noted, instant SEQ ID NO: 4 and 10 are identical to SEQ ID NO: 4 and 10 of the ‘613 patent (See Supplemental Content, the .rai file, Duplicates of Result #1).
Molineux teaches that conjugating PEG molecules (pegylation) to biomolecules, such as proteins, inhibitors and small peptides is a well established method for increasing the circulating half-life of proteins and liposomal pharmaceuticals. It is taught that small peptides and even large proteins are usually quickly degraded by proteolytic enzymes or are quickly and efficiently filtered from the circulatory system through renal clearance. However, by attaching PEG molecules which are nontoxic water-soluble polymers to these same pharmaceutical small peptides or molecules, this increases the hydrodynamic volume of the peptide and creates a shield around the pegylated peptide/drug thereby protecting it from renal clearance, enzymatic degradation or recognition by various cells of the immune system. In essence, the pegylation of pharmaceutical proteins or peptides has been shown to significantly increase the efficiency of administration of pegylated protein/peptide drugs since the half-life of the drug in the circulatory system is increased and said proteins are also less immunogenic. Thus the need for repeated or chronic administration of pharmaceuticals is significantly decreased and the immune reaction of the body to a foreign protein is decreased.
Roberts et al. teach various strategies and methods of how to efficiently pegylate proteins and peptides. Specifically, first generation methods and second generation methods are taught and discussed. The reasons for pegylating a pharmaceutical are explained in line 3 of the abstract and on p. 460 in the introduction. For simplicity sake, the teachings are substantially identical to that taught by Molineux in the preceding paragraph. On p. 461, section 3. Chemistry of pegylation, it is taught that the most common route for PEG conjugation has been to activate PEG with functional groups so that they can react with an primary amine which can be found on the N-terminal amino acid groups of proteins and peptides, and also on the side-chains of lysine residues. This activation method step is the method of choice by most skilled artisans because lysine’s often constitute up 10% of the total amino acid composition of proteins and peptides (see p. 461, 2nd column, last paragraph through to p. 462 1st column first paragraph). It is also taught that when there are multiple lysine residues it is sometimes difficult to produce homogeneous pegylated products when using first generation pegylation methods. However, it is also taught that with second generation pegylation methods (e.g. the recent new advances to the technique) that it is possible to eliminate heterogeneity in substitutions by using mPEG-propionaldehyde and an appropriate pH to control the reaction. (see p. 464, 2nd column, first paragraph under Section 3.2.1). Finally, it is taught also that many of the important benefits of pegylation (e.g. increased half-life, less immunogenic pharmaceuticals etc.)….”can be controlled by proper conjugation of various molecular weight PEGs to the protein at specific locations..” (see p. 462, 1st column, 12th line from the bottom). Thus, one must vary the PEG size, which can range from 1 kDa to 20 kDa, in order to see if there is significant variance in the benefits elicited by pegylating a selected protein or peptide pharmaceutical.
Bentley et al. teach step-by-step procedures for pegylating a protein, beginning with how to prepare the PEG molecules to pegylating lysozyme (used as an exemplary protein/enzyme) (see Examples 1-6).
Therefore it would have been obvious to one of ordinary skill prior to the effective filing date of the claimed invention to pegylate the therapeutically effective DNASE-like 3 (D1L3) enzyme comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 4, and having the deletion of the C-terminal tail defined by SEQ ID NO: 10 and a carrier protein, used to treat a subject in need of extracellular chromatin degradation, the method comprising administering because it affords the following attributes: by attaching PEG molecules which are nontoxic water-soluble polymers to these same pharmaceutical small peptides or molecules, this increases the hydrodynamic volume of the peptide and creates a shield around the pegylated peptide/drug thereby protecting it from renal clearance, enzymatic degradation and reduced immunogenicity as taught by Molineux and Roberts. This would motivation in and of itself because increasing the therapeutic half-life while also reducing potential immunogenic effects for the patient are both very desirable outcomes. In addition, there would be a reasonable expectation of success in pegylating the DNase-like 3 enzyme as in the claims of the ‘613 patent because Molineux, Roberts et al. and Bentley teach precisely how to achieve this and also demonstrate many successful outcomes in the prior art.
Claim 112 and 142-160 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11840712. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘712 patent render obvious the instant claim.
The instant claims are drawn to a method for treating a subject in need of extracellular DNA degradation, extracellular chromatin degradation, extracellular trap (ET) degradation and/or neutrophil extracellular trap (NET) degradation, the method comprising administering a therapeutically effective amount of a DNASE enzyme comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 4, and having one or more amino acid substitutions or deletions of the C-terminal tail defined by SEQ ID NO: 10, and conjugation to one or more polyethylene glycol (PEG) chains/molecules.
The claims to the ‘712 patent in their broadest are drawn to a
a DNase1-like 3 (D1L3) variant having chromatin and/or NET-degrading activity in vitro, wherein the D1L3 variant comprises: an amino acid sequence that is at least 95% identical to amino acids 21 to 282 of SEQ ID NO: 4 or amino acids 21 to 252 of SEQ ID NO: 5; and a C-terminal deletion of at least 5 contiguous amino acids corresponding to amino acids 301 to 305 of the polypeptide of SEQ ID NO: 4; and
wherein the D1L3 variant is fused or conjugated to a half-life extending moiety
Dependent claim 6 stipulates the DNASE is a comprises a PEG molecule conjugated to the DNase.
Dependent claim 3 stipulates said SEQ ID NO: 4 lacks at least 10 continuous amino acids corresponding to amino acids 296-305 or of the C-terminal domain of SEQ ID NO: 4. It is noted, SEQ ID NO: 4 of the ’712 patent and SEQ ID NO: 4 of the instant claim are identical (See SCORE, Result #1, under duplicates of said result #1, in the .rai file).
Thus, the difference between the claims, when claims 1 and 6 of the ‘712 patent when combined, is the ‘712 patent does not mention method of treatment claims, rather just pharmaceutical compositions thereof. It is noted SEQ ID NO: 4 of the ‘712 patent has 100% identity to instant SEQ ID NO: 4 (See SCORE, Result #1, under duplicates of said result #1, in the .rai file) and thus the D1L3 variant lacking amino acids 301-305, of SEQ ID NO: 4 are identical to the same positions in the instant claims (See claim/sequence interpretation above).
However, it would be obvious to administer/use a product for methods of treatment for which said product was clearly designed (Col. 23, lines 8 to Col. 24, line 21); see also Geneva Pharms. Inc. v. GlaxoSmithKline PLC, 349 F.3d 1373, (Fed. Cir. 2003); Pfizer v. Teva, 518 F.3d 1353 (Fed Cir. 2008) and Sun Pharmaceutical Industries, Ltd. v. Eli Lilly and Company (Fed. Cir. July 28, 2010)).
Claim 112 and 142-160 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 11578314. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘314 patent render obvious the instant claim.
The instant claims are drawn to a method for treating a subject in need of extracellular DNA degradation, extracellular chromatin degradation, extracellular trap (ET) degradation and/or neutrophil extracellular trap (NET) degradation, the method comprising administering a therapeutically effective amount of a DNASE enzyme comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 4, and having one or more amino acid substitutions or deletions of the C-terminal tail defined by SEQ ID NO: 10, and conjugation to one or more polyethylene glycol (PEG) chains/molecules.
The claims to the ‘314 patent in their broadest are drawn to a
a DNASE D1L3 protein, wherein said DNASE has at least 90% sequence identity to amino acids 21 to 282 of SEQ ID NO: 4 or 21-25 of SEQ ID NO: 5. Dependent claims 4-7 stipulate the DNase is pegylated with at least one PEG molecule in the MW range of about 10kDa to about 40 kDa or about 20 kDa to about 30 kDa. It is noted, SEQ ID NO: 4 of the ‘950 application and SEQ ID NO: 4 of the instant claim are identical (See SCORE, Result #1, under duplicates of said result #1, in the .rapbm file)
Dependent claims 21-22 recite deletion of at least five amino acids of C-terminal basic domain comprising the final 23 amino acids of said sequence or the entire C-terminal basic domain (e.g. all 23 amino acids).
Thus, the difference between the claims, when claims 1, 4-7 and 21-22 of the ‘314 patent when combined is the claims are drawn to the product itself rather than the method of treating with said enzyme. As is noted SEQ ID NO: 4 of the ‘124 patent has 100% identity to instant SEQ ID NO: 4 (See SCORE, Result #1, under duplicates of said result #1, in the .rai file).
However, it would be obvious to administer/use a product for methods of treatment for which said product was clearly designed (Col. 22, line 12 to Col. 23, line 21); see also Geneva Pharms. Inc. v. GlaxoSmithKline PLC, 349 F.3d 1373, (Fed. Cir. 2003); Pfizer v. Teva, 518 F.3d 1353 (Fed Cir. 2008) and Sun Pharmaceutical Industries, Ltd. v. Eli Lilly and Company (Fed. Cir. July 28, 2010)).
Claim 112 and 142-160 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10801019 in view of Molineux (Cancer Treatments Reviews, 2002: 28(SUPPL. A) 13-16 – cited herein), Roberts et al. (Adv. Drug Delivery Rev., 2002, 54:459-476 – cited herein) and Bentley et al. (US 5,990,237 – cited herein). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘019 patent anticipate the instant claim.
The instant claims are drawn to a method for treating a subject in need of extracellular DNA degradation, extracellular chromatin degradation, extracellular trap (ET) degradation and/or neutrophil extracellular trap (NET) degradation, the method comprising administering a therapeutically effective amount of a DNASE enzyme comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 4, and having one or more amino acid substitutions or deletions of the C-terminal tail defined by SEQ ID NO: 10, and conjugation to one or more polyethylene glycol (PEG) chains/molecules.
The claims to the ‘019 patent in their broadest are drawn to a method for treating a human subject having an intravascular accumulation of neutrophil extracellular traps (NETs), the method comprising systemically administering an effective amount of a DNase1-like 3 (D1L3) enzyme comprising an amino acid sequence having at least 90% sequence identity to amino acids 21 to 305 of SEQ ID NO: 2 to said subject, wherein the subject has a condition selected from: a severe inflammatory disease selected from acute respiratory distress syndrome (ARDS), sepsis, and a viral infection; partially or fully occluded blood vessels; thrombotic microangiopathy (TMA); disseminated intravascular coagulation (DIC); venous thromboembolism; leukemia; and
tumor metastasis. It is noted, instant SEQ ID NO: 4 is identical to SEQ ID NO: 2 of the ‘019 patent (See Result #1, .rai file, result under duplicates).
Dependent claims recite 4 recites deletion of all of a part of the C-terminal domain as defined by SEQ ID NO: 33 (identical to instant SEQ ID NO: 10).
Thus, the difference between the claims is the ‘019 patent claims do not teach adding a PEG molecule to the DNASE-like 3 (D1L3) enzyme comprising an amino acid sequence that has at least 90% sequence identity to amino acids 21 to 305 of SEQ ID NO: 2, and having the deletion of the C-terminal tail defined by SEQ ID NO: 10 and PEG molecule conjugated.
It is noted, instant SEQ ID NO: 4 and 10 are identical to SEQ ID NO: 4 and 10 of the ‘613 patent (See Supplemental Content, the .rai file, Duplicates of Result #1).
Molineux teaches that conjugating PEG molecules (pegylation) to biomolecules, such as proteins, inhibitors and small peptides is a well established method for increasing the circulating half-life of proteins and liposomal pharmaceuticals. It is taught that small peptides and even large proteins are usually quickly degraded by proteolytic enzymes or are quickly and efficiently filtered from the circulatory system through renal clearance. However, by attaching PEG molecules which are nontoxic water-soluble polymers to these same pharmaceutical small peptides or molecules, this increases the hydrodynamic volume of the peptide and creates a shield around the pegylated peptide/drug thereby protecting it from renal clearance, enzymatic degradation or recognition by various cells of the immune system. In essence, the pegylation of pharmaceutical proteins or peptides has been shown to significantly increase the efficiency of administration of pegylated protein/peptide drugs since the half-life of the drug in the circulatory system is increased and said proteins are also less immunogenic. Thus the need for repeated or chronic administration of pharmaceuticals is significantly decreased and the immune reaction of the body to a foreign protein is decreased.
Roberts et al. teach various strategies and methods of how to efficiently pegylate proteins and peptides. Specifically, first generation methods and second generation methods are taught and discussed. The reasons for pegylating a pharmaceutical are explained in line 3 of the abstract and on p. 460 in the introduction. For simplicity sake, the teachings are substantially identical to that taught by Molineux in the preceding paragraph. On p. 461, section 3. Chemistry of pegylation, it is taught that the most common route for PEG conjugation has been to activate PEG with functional groups so that they can react with an primary amine which can be found on the N-terminal amino acid groups of proteins and peptides, and also on the side-chains of lysine residues. This activation method step is the method of choice by most skilled artisans because lysine’s often constitute up 10% of the total amino acid composition of proteins and peptides (see p. 461, 2nd column, last paragraph through to p. 462 1st column first paragraph). It is also taught that when there are multiple lysine residues it is sometimes difficult to produce homogeneous pegylated products when using first generation pegylation methods. However, it is also taught that with second generation pegylation methods (e.g. the recent new advances to the technique) that it is possible to eliminate heterogeneity in substitutions by using mPEG-propionaldehyde and an appropriate pH to control the reaction. (see p. 464, 2nd column, first paragraph under Section 3.2.1). Finally, it is taught also that many of the important benefits of pegylation (e.g. increased half-life, less immunogenic pharmaceuticals etc.)….”can be controlled by proper conjugation of various molecular weight PEGs to the protein at specific locations..” (see p. 462, 1st column, 12th line from the bottom). Thus, one must vary the PEG size, which can range from 1 kDa to 20 kDa, in order to see if there is significant variance in the benefits elicited by pegylating a selected protein or peptide pharmaceutical.
Bentley et al. teach step-by-step procedures for pegylating a protein, beginning with how to prepare the PEG molecules to pegylating lysozyme (used as an exemplary protein/enzyme) (see Examples 1-6).
Therefore it would have been obvious to one of ordinary skill prior to the effective filing date of the claimed invention to pegylate the therapeutically effective DNASE-like 3 (D1L3) enzyme comprising an amino acid sequence that has at least 90% sequence identity to amino acids 21-305 of SEQ ID NO: 2, and having the deletion of the C-terminal tail defined by SEQ ID NO: 33 in methods of treating a subject in need of extracellular chromatin degradation, the method comprising administering because it affords the following attributes: by attaching PEG molecules which are nontoxic water-soluble polymers to these same pharmaceutical small peptides or molecules, this increases the hydrodynamic volume of the peptide and creates a shield around the pegylated peptide/drug thereby protecting it from renal clearance, enzymatic degradation and reduced immunogenicity as taught by Molineux and Roberts. This would motivation in and of itself because increasing the therapeutic half-life while also reducing potential immunogenic effects for the patient are both very desirable outcomes. In addition, there would be a reasonable expectation of success in pegylating the DNase-like 3 enzyme as in the claims of the ‘019 patent because Molineux, Roberts et al. and Bentley teach precisely how to achieve this and also demonstrate many successful outcomes in the prior art.
Claim 112 and 142-160 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11046942 in view of Molineux (Cancer Treatments Reviews, 2002: 28(SUPPL. A) 13-16 – cited herein), Roberts et al. (Adv. Drug Delivery Rev., 2002, 54:459-476 – cited herein) and Bentley et al. (US 5,990,237 – cited herein). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘942 patent anticipate the instant claim.
The instant claims are drawn to a method for treating a subject in need of extracellular DNA degradation, extracellular chromatin degradation, extracellular trap (ET) degradation and/or neutrophil extracellular trap (NET) degradation, the method comprising administering a therapeutically effective amount of a DNASE enzyme comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 4, and having one or more amino acid substitutions or deletions of the C-terminal tail defined by SEQ ID NO: 10, and conjugation to one or more polyethylene glycol (PEG) chains/molecules.
The claims to the ‘942 patent in their broadest are drawn to a method for treating a human subject having an intravascular accumulation of neutrophil extracellular traps (NETs), the method comprising administering to said subject an effective amount of a polynucleotide encoding a DNase1-like 3 (D1L3) enzyme comprising an amino acid sequence having at least 90% sequence identity to amino acids 21 to 305 of SEQ ID NO: 2, wherein the subject has a condition selected from: a severe inflammatory disease selected from acute respiratory distress syndrome (ARDS), sepsis, and a viral infection; partially or fully occluded blood vessels; thrombotic microangiopathy (TMA); disseminated intravascular coagulation (DIC); venous thromboembolism; leukemia; and
tumor metastasis. It is noted, instant SEQ ID NO: 4 is identical to SEQ ID NO: 2 of the ‘942 patent (See Result #1, .rai file, result under duplicates).
Dependent claims recite 4 recites deletion of all of a part of the C-terminal domain as defined by SEQ ID NO: 33 (identical to instant SEQ ID NO: 10).
Thus, the difference between the claims is the ‘942 patent claims do not teach adding a PEG molecule to the DNASE-like 3 (D1L3) enzyme comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 4, and having the deletion of the C-terminal tail defined by SEQ ID NO: 10 and PEG molecule conjugated thereto.
It is noted, instant SEQ ID NO: 4 and 10 are identical to SEQ ID NO: 2 and 33 of the ‘942 patent (See Supplemental Content, the .rai file, Duplicates of Result #1).
Molineux teaches that conjugating PEG molecules (pegylation) to biomolecules, such as proteins, inhibitors and small peptides is a well established method for increasing the circulating half-life of proteins and liposomal pharmaceuticals. It is taught that small peptides and even large proteins are usually quickly degraded by proteolytic enzymes or are quickly and efficiently filtered from the circulatory system through renal clearance. However, by attaching PEG molecules which are nontoxic water-soluble polymers to these same pharmaceutical small peptides or molecules, this increases the hydrodynamic volume of the peptide and creates a shield around the pegylated peptide/drug thereby protecting it from renal clearance, enzymatic degradation or recognition by various cells of the immune system. In essence, the pegylation of pharmaceutical proteins or peptides has been shown to significantly increase the efficiency of administration of pegylated protein/peptide drugs since the half-life of the drug in the circulatory system is increased and said proteins are also less immunogenic. Thus the need for repeated or chronic administration of pharmaceuticals is significantly decreased and the immune reaction of the body to a foreign protein is decreased.
Roberts et al. teach various strategies and methods of how to efficiently pegylate proteins and peptides. Specifically, first generation methods and second generation methods are taught and discussed. The reasons for pegylating a pharmaceutical are explained in line 3 of the abstract and on p. 460 in the introduction. For simplicity sake, the teachings are substantially identical to that taught by Molineux in the preceding paragraph. On p. 461, section 3. Chemistry of pegylation, it is taught that the most common route for PEG conjugation has been to activate PEG with functional groups so that they can react with an primary amine which can be found on the N-terminal amino acid groups of proteins and peptides, and also on the side-chains of lysine residues. This activation method step is the method of choice by most skilled artisans because lysine’s often constitute up 10% of the total amino acid composition of proteins and peptides (see p. 461, 2nd column, last paragraph through to p. 462 1st column first paragraph). It is also taught that when there are multiple lysine residues it is sometimes difficult to produce homogeneous pegylated products when using first generation pegylation methods. However, it is also taught that with second generation pegylation methods (e.g. the recent new advances to the technique) that it is possible to eliminate heterogeneity in substitutions by using mPEG-propionaldehyde and an appropriate pH to control the reaction. (see p. 464, 2nd column, first paragraph under Section 3.2.1). Finally, it is taught also that many of the important benefits of pegylation (e.g. increased half-life, less immunogenic pharmaceuticals etc.)….”can be controlled by proper conjugation of various molecular weight PEGs to the protein at specific locations..” (see p. 462, 1st column, 12th line from the bottom). Thus, one must vary the PEG size, which can range from 1 kDa to 20 kDa, in order to see if there is significant variance in the benefits elicited by pegylating a selected protein or peptide pharmaceutical.
Bentley et al. teach step-by-step procedures for pegylating a protein, beginning with how to prepare the PEG molecules to pegylating lysozyme (used as an exemplary protein/enzyme) (see Examples 1-6).
Therefore it would have been obvious to one of ordinary skill prior to the effective filing date of the claimed invention to pegylate the therapeutically effective DNASE-like 3 (D1L3) enzyme comprising an amino acid sequence that has at least 90% sequence identity to amino acids 21-305 of SEQ ID NO: 2, and having the deletion of the C-terminal tail defined by SEQ ID NO: 33 in methods of treating a subject in need of extracellular chromatin degradation, the method comprising administering because it affords the following attributes: by attaching PEG molecules which are nontoxic water-soluble polymers to these same pharmaceutical small peptides or molecules, this increases the hydrodynamic volume of the peptide and creates a shield around the pegylated peptide/drug thereby protecting it from renal clearance, enzymatic degradation and reduced immunogenicity as taught by Molineux and Roberts. This would motivation in and of itself because increasing the therapeutic half-life while also reducing potential immunogenic effects for the patient are both very desirable outcomes. In addition, there would be a reasonable expectation of success in pegylating the DNase-like 3 enzyme as in the claims of the ‘942 patent because Molineux, Roberts et al. and Bentley teach precisely how to achieve this and also demonstrate many successful outcomes in the prior art.
Claim 112 and 142-160 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12565642 in view of Molineux (Cancer Treatments Reviews, 2002: 28(SUPPL. A) 13-16 – cited herein), Roberts et al. (Adv. Drug Delivery Rev., 2002, 54:459-476 – cited herein) and Bentley et al. (US 5,990,237 – cited herein). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘642 patent anticipate the instant claim.
The instant claims are drawn to a method for treating a subject in need of extracellular DNA degradation, extracellular chromatin degradation, extracellular trap (ET) degradation and/or neutrophil extracellular trap (NET) degradation, the method comprising administering a therapeutically effective amount of a DNASE enzyme comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 4, and having one or more amino acid substitutions or deletions of the C-terminal tail defined by SEQ ID NO: 10, and conjugation to one or more polyethylene glycol (PEG) chains/molecules.
The claims to the ‘642 patent in their broadest are drawn to method for treating a subject for thrombosis, stroke, myocardial infarction, intrabiliary blood clots or ischemia-reperfusion injury, the method comprising administering a therapeutically effective amount of a DNase1-like 3 (D1L3) variant to a subject in need, wherein the D1L3 variant has chromatin-degrading activity and comprises an amino acid sequence that has at least 95% sequence identity to amino acids 21-282 of SEQ ID NO: 4 or amino acids 21 to 252 of SEQ ID NO: 5, wherein the D1L3 variant comprises a substitution at the amino acid corresponding to position 68 of the polypeptide of SEQ ID NO: 4, and wherein the D1L3 variant has a C-terminal deletion of at least 10 consecutive amino acids corresponding to amino acids 296-305 of the polypeptide of SEQ ID NO: 4
It is noted, instant SEQ ID NO: 4 is identical to SEQ ID NO: 4 and 5 of the ‘942 patent (See Result #1, .rai file, result under duplicates).
Thus, the difference between the claims is the ‘642 patent claims do not teach adding a PEG molecule to the DNASE-like 3 (D1L3) enzyme comprising an amino acid sequence that has 95% sequence identity to amino acids 21-282 of SEQ ID NO: 4 or amino acids 21 to 252 of SEQ ID NO: 5, wherein the D1L3 variant comprises a substitution at the amino acid corresponding to position 68 of the polypeptide of SEQ ID NO: 4, and wherein the D1L3 variant has a C-terminal deletion of at least 10 consecutive amino acids corresponding to amino acids 296-305 of the polypeptide of SEQ ID NO: 4 and a PEG molecule conjugated thereto.
It is noted, instant SEQ ID NO: 4 and 10 are identical to SEQ ID NO: 2 and 33 of the ‘642 patent (See Supplemental Content, the .rai file, Duplicates of Result #1).
Molineux teaches that conjugating PEG molecules (pegylation) to biomolecules, such as proteins, inhibitors and small peptides is a well established method for increasing the circulating half-life of proteins and liposomal pharmaceuticals. It is taught that small peptides and even large proteins are usually quickly degraded by proteolytic enzymes or are quickly and efficiently filtered from the circulatory system through renal clearance. However, by attaching PEG molecules which are nontoxic water-soluble polymers to these same pharmaceutical small peptides or molecules, this increases the hydrodynamic volume of the peptide and creates a shield around the pegylated peptide/drug thereby protecting it from renal clearance, enzymatic degradation or recognition by various cells of the immune system. In essence, the pegylation of pharmaceutical proteins or peptides has been shown to significantly increase the efficiency of administration of pegylated protein/peptide drugs since the half-life of the drug in the circulatory system is increased and said proteins are also less immunogenic. Thus the need for repeated or chronic administration of pharmaceuticals is significantly decreased and the immune reaction of the body to a foreign protein is decreased.
Roberts et al. teach various strategies and methods of how to efficiently pegylate proteins and peptides. Specifically, first generation methods and second generation methods are taught and discussed. The reasons for pegylating a pharmaceutical are explained in line 3 of the abstract and on p. 460 in the introduction. For simplicity sake, the teachings are substantially identical to that taught by Molineux in the preceding paragraph. On p. 461, section 3. Chemistry of pegylation, it is taught that the most common route for PEG conjugation has been to activate PEG with functional groups so that they can react with an primary amine which can be found on the N-terminal amino acid groups of proteins and peptides, and also on the side-chains of lysine residues. This activation method step is the method of choice by most skilled artisans because lysine’s often constitute up 10% of the total amino acid composition of proteins and peptides (see p. 461, 2nd column, last paragraph through to p. 462 1st column first paragraph). It is also taught that when there are multiple lysine residues it is sometimes difficult to produce homogeneous pegylated products when using first generation pegylation methods. However, it is also taught that with second generation pegylation methods (e.g. the recent new advances to the technique) that it is possible to eliminate heterogeneity in substitutions by using mPEG-propionaldehyde and an appropriate pH to control the reaction. (see p. 464, 2nd column, first paragraph under Section 3.2.1). Finally, it is taught also that many of the important benefits of pegylation (e.g. increased half-life, less immunogenic pharmaceuticals etc.)….”can be controlled by proper conjugation of various molecular weight PEGs to the protein at specific locations..” (see p. 462, 1st column, 12th line from the bottom). Thus, one must vary the PEG size, which can range from 1 kDa to 20 kDa, in order to see if there is significant variance in the benefits elicited by pegylating a selected protein or peptide pharmaceutical.
Bentley et al. teach step-by-step procedures for pegylating a protein, beginning with how to prepare the PEG molecules to pegylating lysozyme (used as an exemplary protein/enzyme) (see Examples 1-6).
Therefore it would have been obvious to one of ordinary skill prior to the effective filing date of the claimed invention to pegylate the therapeutically effective 95% sequence identity to amino acids 21-282 of SEQ ID NO: 4 or amino acids 21 to 252 of SEQ ID NO: 5, wherein the D1L3 variant comprises a substitution at the amino acid corresponding to position 68 of the polypeptide of SEQ ID NO: 4, and wherein the D1L3 variant has a C-terminal deletion of at least 10 consecutive amino acids corresponding to amino acids 296-305 of the polypeptide of SEQ ID NO: 4 in methods of treating a subject in need of extracellular chromatin degradation, the method comprising administering because it affords the following attributes: by attaching PEG molecules which are nontoxic water-soluble polymers to these same pharmaceutical small peptides or molecules, this increases the hydrodynamic volume of the peptide and creates a shield around the pegylated peptide/drug thereby protecting it from renal clearance, enzymatic degradation and reduced immunogenicity as taught by Molineux and Roberts. This would be motivation in and of itself because increasing the therapeutic half-life while also reducing potential immunogenic effects for the patient are both very desirable outcomes. In addition, there would be a reasonable expectation of success in pegylating the DNase-like 3 enzyme as in the claims of the ‘642 patent because Molineux, Roberts et al. and Bentley teach precisely how to achieve this and also demonstrate many successful outcomes in the prior art.
Claim 112 and 142-160 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 19 of copending Application No. 17800950 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘950 application render obvious the instant claim.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
T The instant claims are drawn to a method for treating a subject in need of extracellular DNA degradation, extracellular chromatin degradation, extracellular trap (ET) degradation and/or neutrophil extracellular trap (NET) degradation, the method comprising administering a therapeutically effective amount of a DNASE enzyme comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 4, and having one or more amino acid substitutions or deletions of the C-terminal tail defined by SEQ ID NO: 10, and conjugation to one or more polyethylene glycol (PEG) chains/molecules.
The claims to the ‘950 application are drawn to a DNASE D1L3 protein, wherein said DNASE has at least consists of amino acids 21 to 285 of SEQ ID NO: 4, wherein C68 of SEQ ID NO: 4 is optionally substituted or PEGylated. It is noted, SEQ ID NO: 4 of the ‘950 application and SEQ ID NO: 4 of the instant claim are identical (See SCORE, Result #1, under duplicates of said result #1, in the .rapbm file). The DNase of the ’950 claim therefore does not have the C-terminal domain of amino acids 283-305, e.g. it is deleted.
Thus, the difference between the two sets of claims is that application claims do not indicate which terminus the carrier protein is located. However, when construing the scope of the claims as defined in the patent, the fusion protein has only two options for location of the carrier protein, e.g. either at the N- or C-terminus (See paragraph 0011), making said claims of the ‘950 application an obvious overlap in scope with the instant claims.
Thus, the difference between the claims is that the claims of the ‘950 application are drawn to the product itself rather than the method of treating with said enzyme.
However, it would be obvious to administer/use a product for methods of treatment for which said product was clearly designed (p. 35, line 10 to p. 38, line 27); see also Geneva Pharms. Inc. v. GlaxoSmithKline PLC, 349 F.3d 1373, (Fed. Cir. 2003); Pfizer v. Teva, 518 F.3d 1353 (Fed Cir. 2008) and Sun Pharmaceutical Industries, Ltd. v. Eli Lilly and Company (Fed. Cir. July 28, 2010)).
Conclusion
No claim is allowed.
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/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656 29 September 2026
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