DETAILED ACTION
This action is in reply to papers filed 9/17/2025.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Examiner’s Note
All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20230226158A1, Published 7/20/2023.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1(a),4,9,14,18,23,27-28,30-31,33,36 and 41) in the reply filed on 9/17/2025 is acknowledged. Claims 1(b),4, 9, 14, 18, 23, 27-28, 30,31, 36, 41, Claims 1(c),4, 9, 14, 18, 23, 27-28, 30, 31, 36, 41 and 44-57 are cancelled. Election was made without traverse in the reply filed on 9/17/2025. Note that the inclusion of claims 44-57 in Groups I, II and III was an error.
Accordingly, claims 1(a),4,9,14,18,23,27-28,30-31,33,36, 41 and 44-57 are pending with claims 1(a),4,9,14,18,23,27-28,30-31,33,36 and 41 examined herein.
Claim Objections
Claims 1, 9, 14 and 28 are objected to because of the following informalities: Independent claim 1 contains an uncommon acronym (NET) that should be fully defined on its first occurrence. Appropriate correction is required.
Claims 1, 9 and 14 each recite an amino acid sequence and a sequence id number enclosed within parenthesis. Applicant should remove the amino acid sequences within parenthesis.
Claim 28 recites “also known as” twice. Recitation of this phrase is unnecessary.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1 (in-part),4,9,14,18,23,27-28,30-31,33,36 and 41 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. Note that the instant rejection is solely based on Applicant’s claiming of ‘preventing inefficient NET hydrolysis in a subject afflicted with a bacterial or viral infection’.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that “Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue.’ Not ‘experimentation;” (Wands, 8 USPQ2d 104). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighting many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” include, but are not limited to:
• (A) The breadth of the claims;
• (B) The nature of the invention;
• (C) The state of the prior art;
• (D) The level of one of ordinary skill;
• (E) The level of predictability in the art;
• (F) The amount of direction provided by the inventor;
• (G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Amount of Direction Provided by Inventor/Working Examples: Relevant to the instant rejection, in describing the present disclosure, para. 31 of the PgPub teaches the DNase I constructs contemplated within the disclosure are useful in preventing immune mediated pathology driven by inefficient NET degradation in bacterial and/or viral infection. Examiner has interpreted this teaching to mean the administration of the DNase I construct prevents immune mediated pathologies caused by incomplete neutrophil extracellular trap (NET) degradation. Stated another way, the claim claims administration of the DNAse I construct prevents immune mediated pathologies by removing NETs. It is within this context that the rejection below is made.
Starting at para. 252, the specification teaches FIG. 1 illustrates NET formation. FIG. 2, at para. 253, illustrates a non-limiting DNAse1-Fc construct of the disclosure, with certain contemplated point mutations highlighted. FIG. 4 , at para. 254, illustrates a non-limiting DNAse1L3-Fc construct of the disclosure, with certain contemplated point mutations highlighted. FIG. 5, at para. 255, illustrates a non-limiting DNAse1-Fc construct of the disclosure, with certain contemplated point mutations highlighted. FIG. 5, at para. 255, illustrates non-limiting constructs of the disclosure, with certain contemplated point mutations highlighted. FIG. 6, at para. 257, illustrates non-limiting constructs of the disclosure, with certain contemplated point mutations highlighted. In certain embodiments, the construct lacks at least a portion of the DNAse1L3 nuclear localization domain. FIG. 7, at para. 258, illustrates a gel indicating that certain DNAse1L3 clones cleave chromatin, but that is not the case for certain DNAse1 clones. FIG. 8, at para. 259, illustrates a non-limiting construct of the disclosure. In certain embodiments, the DNAse1 polypeptide is fused with the C-terminus tail of DNAse1L3. FIGS. 9A-9D, at para. 260, illustrate certain aspects of production and purification of DNAse-Fc constructs. FIG. 10, at para. 261, illustrates a non-limiting enzyme optimization pathway to be applied to NET degrading enzymes, as illustrated with an exemplary protein and/or polypeptide. FIGS. 11A-11D, starting at para. 262, illustrate selected results for optimization of NET degrading enzymes. Specifically, FIG. 11A illustrates free (or plasmid) DNA in the blood was degraded by DNAse1. Histone associated DNA was degraded by DNAse1L3. FIG. 11B illustrates PK Assay of optimized DNAse1 and DNAse1L3 constructs. Mice were injected with 1 mg/kg biologic; blood was withdrawn at various time points; exogenous plasmid or histone associated DNA is added; samples were incubated for 15 min.; degradation of DNA determined by agarose gels. FIGS. 11C-11D illustrates PK of enzyme biologics determined in mice. Lanes 1-2: construct 1171; Lanes 3-4: construct 1671; Lanes 5-6: construct 1687; Lanes 7-8: Mock Injection. Constructs 1671 and 1687 readily degraded both plasmid (top) and chromatin DNA at 91 hours (FIG. 11C), and the activity persisted for 257 hours (FIG. 11D). And FIG. 12 illustrates certain aspects of production and purification of DNAse-Fc constructs.
While Fig. 11 evidences DNA degrading activity of DNAse1, none of the cited examples teach preventing inefficient NET hydrolysis in a subject afflicted with a bacterial or viral infection, as claimed. This is problematic.
Given the high level of required effect, a high level of evidence showing prevention is also required. Examiner notes that one skilled in the art could not practice the claimed method to achieve the results of preventing inefficient NET hydrolysis in a subject afflicted with a bacterial or viral infection, because the specification lacks the critical steps necessary in presenting some type of predictable response in a population of hosts deemed necessary to prevent inefficient NET hydrolysis. Reasonable guidance with respect to preventing inefficient NET hydrolysis relies on quantitative analysis from defined populations which have been successfully pre-screened and are predisposed to inefficient NET hydrolysis or have had inefficient NET hydrolysis. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of the onset of inefficient NET hydrolysis in a subject afflicted with a bacterial or viral infection and link those results with subsequent histological confirmation of the presence of an inefficient NET hydrolysis. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. Such is not provided in the instant specification.
The State of the Prior Art: On background, Hosseinnejad et al. (Biomater. Sci., 2022, 10, 85-99) teach neutrophil extracellular traps (NETs) are web-like chromatin structures produced and liberated by neutrophils under inflammatory conditions which also promote the activation of the coagulation cascade and thrombus formation. The formation of NETs is quite prominent when blood comes in contact with artificial surfaces like extracorporeal circuits, oxygenator membranes, or intravascular grafts. DNase I as a factor of the host defense system, digests the DNA backbone of NETs, which points out its treatment potential for NET-mediated thrombosis (Pg. 85, Abstract). However, Leppkes et al. (Nature Communications volume 7, Article number: 10973 (2016)) notes that, in an acute pancreatitis model, while DNase easily digested small extracellular chromatin fibres of bicarbonate- and CaCO3-induced aggNETs, the core of aggNETs was more resistant(Pg. 7, Col. 2, para. 2). Concurring, Kolaczkowska et al. (Nature Communications volume 6, Article number: 6673 (2015)) adds that during a bloodstream infection with methicillin-resistant Staphylococcus aureus, the majority of bacteria are sequestered immediately by hepatic Kupffer cells, resulting in transient increases in liver enzymes, focal ischaemic areas and a robust neutrophil infiltration into the liver. The neutrophils release NETs into the liver vasculature, which remain anchored to the vascular wall via von Willebrand factor and reveal significant neutrophil elastase (NE) proteolytic activity. Importantly, Kolaczkowska teaches DNase although very effective at DNA removal, and somewhat effective at inhibiting NE proteolytic activity, fails to remove the majority of histones from the vessel wall and only partly reduces injury (Pg. 1, Abstract; Pg. 4). Adrover et al. (JCI Insight. 2022 Mar 8;7(5):e157342) points out that DNase I targets NETs that have already formed and have already been released, but does not prevent the formation of NETs from the beginning.
In sum, the art makes clear that while the administration of DNAse I in in vitro and in vivo settings can reduce NET parts (~ DNA backbone of NETs), said administration does not eliminate NETs. The art makes clear that this inefficient NET degradation only partly reduces injury. The art further makes clear that administration of DNAse I does not prevent the formation of NETs. Therefore, it is reasonable to conclude that the administration of DNAse I for the purposes of preventing inefficient NET hydrolysis in a subject afflicted with a bacterial or viral infection was not enabled by the specification or the art.
The level of Predictability in the Art/Conclusion: The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. Due to the lack of guidance or evidence in the specification or in the art regarding the administration of DNAse I for the purposes of preventing inefficient NET hydrolysis in a subject afflicted with a bacterial or viral infection, it would have required undue experimentation for one skilled in the art at the time of the invention to practice the invention, as claimed.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4, 31 and 36 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation “X1 is the peptide of amino acid sequence…” and “X2 is the peptide sequence of amino acid of….” In lines 9 and 12, respectively. There is insufficient antecedent basis for this limitation in the claim. Note there is no earlier recitation (i.e. prior to line 9) of an amino acid sequence in claim 1. Moreover, claim 1 recites, inter alia, “…X2 is null”. When taken with the ordinary and customary meaning of the term (~having or associated with the value zero), it is wholly unclear what Applicant intends with the phrase “X2 is null.”
Claim 4 recites, inter alia, “…the amino acid sequence of SEQ ID NO: 4”. There is no antecedent basis for an amino acid sequence of SEQ ID NO: 4.
Claim 31 recites, inter alia, “…wherein the virus is a coronavirus…”. There is no antecedent basis for the term “virus”.
Claim 36 at step (c) recites, inter alia, “…the vector encodes the construct or precursor construct”. The metes and bounds of the phrase “precursor construct” are wholly unclear. That is, it is unclear what the term ‘precursor’ means in the context of the claimed invention.
Appropriate correction is requested.
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Prior Art Rejection 1
Claim(s) 1, 9, 14, 27, 30, 33, 36, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Ledbetter et al. (PgPub US20140044711A1, Published 2/13/2014; Ref. 2 in IDS filed 10/2/2023) and Garcia-Romo et al. (Sci Transl Med. 2011;3:73ra20).
Regarding claim 1, Ledbetter et al. teach a hybrid nuclease molecule (i.e. a construct) comprising a human DNAseI (Pg. 3, para. 23) of DNAseIL3 polypeptide (Pg. 11, para. 128) and a Fc domain of human IgG1 (Pg. 12, para. 138), wherein the first nuclease domain is operatively coupled to the Fc domain (as in claim 14a). Ledbetter teaches the hybrid nuclease molecule further includes a first linker domain, and the human DNAseIL3 polypeptide is operatively coupled to the Fc domain of human IgG1 by the first linker domain (Pg. 1, para. 5). Ledbetter teaches the linker domains comprises 18 more amino acids in length (as in claim 9b) (Pg. 32, para. 313). In fact, Ledbetter teaches the linker includes an N-linked glycosylation site, which can be sensitive to protease cleavage in vivo. In some embodiments, an N-linked glycosylation site can protect the hybrid nuclease molecules from cleavage in the linker domain. Moreover, Ledbetter teaches an N-linked glycosylation site can assist in separating the folding of independent functional domains separated by the linker domain. (Pg. 10, para. 119).
Ledbetter teaches the invention also includes a vector capable of expressing the peptides in an appropriate host, such as a mammalian cell (as in claim 27) (Pg. 18, para. 189-191). Ledbetter teaches the hybrid nuclease can be delivered by implanting certain cells that have been genetically engineered, using methods such as those described herein, to express and secrete the polypeptides (Pg. 21, para. 219). Ledbetter teaches the DNAseIL3 hybrid nuclease molecules can be active towards extracellular immune complexes containing DNA, e.g., either in soluble form (as in claim 30) or deposited as insoluble complexes (Pg. 10, para. 117). Ledbetter teaches the construct is administered orally (as further in claim 1 and as in claim 36) (Pg. 19, para. 208).Ledbetter teaches a human subject in need of treatment (as in claim 42) is selected or identified. The subject can be in need of, e.g., reducing a cause or symptom of systemic lupus erythematosus (SLE) (Pg. 4, para. 32; Pg. 33, para. 322).
Garcia-Romo et al. teach SLE is a chronic inflammatory disease caused by inefficient NETolyisis (Pg. 8, Col. 1) (as in claim 33). Garcia-Romo explains that SLE neutrophils readily release NETs in response to exogenous stimuli, such as bacterial infection (as further in claim 1), and that these NETs can then potently activate pDCs to release high levels of IFN which in turn primes neutrophils for additional NETosis. Garcia-Romo teaches this loop promotes the disease development and progression in SLE) (Pg. 8, Col. 1, last paragraph).
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and G are applicable. Before the effective filing date of the claimed invention, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Ledbetter et al., wherein Ledbetter teaches a hybrid nuclease comprising a DNAse1L3 polypeptide and an Fc domain of human IgG1 for the purposes of treating SLE with the teachings of Garcia-Romo et al. who teaches SLE neutrophils readily release NETs when induced by bacterial infection, with a reasonable expectation of arriving at the claimed invention. That is, one of ordinary skill in the art would have found it prima facie obvious to treat SLE patients afflicted with a bacterial infection with the construct of Ledbetter et al. because Garcia-Romo teaches bacteria induces NETosis in SLE patients. Thus, for the purposes of efficient NET hydrolysis, the skilled artisan would have found the modification prima facie obvious.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Prior Art Rejection 2
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Ledbetter et al. (PgPub US20140044711A1, Published 2/13/2014; Ref. 2 in IDS filed 10/2/2023) and Garcia-Romo et al. (Sci Transl Med. 2011;3:73ra20) as applied to claims 1, 9, 14, 27, 30, 33, 36, and 42 above, and further in view of Karin et al. (PgPub US20100196406A1, Published 9/11/2012).
The teachings of Ledbetter et al. and Garcia-Romo et al. are relied upon as detailed above. And although Ledbetter teach a human Fc of human IgG1, Ledbetter fails to teach said human Fc comprises the amino acid sequence of SEQ ID NO: 4 (as in claim 4).
Before the effective filing date of the claimed invention, Karin et al. taught agent for the treatment of inflammatory diseases and methods of using the same (Title). In one embodiment, Karin teaches said inflammatory disease is systemic lupus erythematosus (Pg. 2, para. 40) and said agent comprises an Fc region of human IgG1 (Pg. 14,para. 201).The alignment between SEQ ID NO: 4 (Qy, query) and the human Fc of human IgG1 taught by Karin et al. (Db, database) is provided below.
RESULT 24
US-12-602-771-4
Sequence 4, US/12602771
Patent No. 8263064
GENERAL INFORMATION
APPLICANT: Rappaport Family Institute for Research in the Medical Sciences
APPLICANT: Karin, Nathan
APPLICANT: Zohar, Yaniv
APPLICANT: Wildbaum, Gizi
TITLE OF INVENTION: AGENTS FOR THE TREATMENT OF INFLAMMATORY DISEASES AND METHODS OF
TITLE OF INVENTION: USING SAME
FILE REFERENCE: 47472
CURRENT APPLICATION NUMBER: US/12/602,771
CURRENT FILING DATE: 2009-12-03
NUMBER OF SEQ ID NOS: 31
SEQ ID NO 4
LENGTH: 238
TYPE: PRT
ORGANISM: Artificial sequence
FEATURE:
OTHER INFORMATION: human Ig derived fragment
Query Match 100.0%; Score 1233; Length 238;
Best Local Similarity 100.0%;
Matches 227; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 8 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD 67
Qy 61 GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 68 GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK 127
Qy 121 GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 128 GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 187
Qy 181 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 227
|||||||||||||||||||||||||||||||||||||||||||||||
Db 188 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 234
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationale B is applicable. Before the effective filing date of the claimed invention, it would have been prima facie obvious to an artisan of ordinary skill to substitute the generic human Fc of human IgG1 of Ledbetter with the human Fc of human IgG1 of Karin et al. The skilled artisan would have found it prima facie obvious to do as the Karin teaches their agent (i.e. construct) is specifically used to treat SLE. Thus, for these purposes, the substitution would have been prima facie obvious.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Prior Art Rejection 3
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Ledbetter et al. (PgPub US20140044711A1, Published 2/13/2014; Ref. 2 in IDS filed 10/2/2023) and Garcia-Romo et al. (Sci Transl Med. 2011;3:73ra20) as applied to claims 1, 9, 14, 27, 30, 33, 36, and 42 above, and further in view of Shaaltiel et al. (PgPub US20150010527A1, Published 1/8/2015).
The teachings of Ledbetter et al. and Garcia-Romo et al. are relied upon as detailed above. And although Ledbetter teach a human DNAseI, Ledbetter fails to teach said DNAseI lacks residues 1-22 of SEQ ID NO: 1 or a portion thereof (as in claim 18).
Before the effective filing date of the claimed invention, Shaaltiel et al. taught recombinant DNase constructs that can be used for treatment of bacterial or viral infections (Pg. 23, para. 236). Shaaltiel teach a cDNA encoding the human deoxyribonuclease I (DNase I) protein was optimized such that the 22 amino acid leader peptide was removed (as in claim 18). Shaaltiel teaches the nucleotide sequence of the native human DNase I leader peptide was replaced with a nucleotide sequence encoding the 33 amino acid endoplasmic reticulum targeting signal peptide (leader peptide) of the Arabidopsis ABPI as this ER targeting signal peptide provides efficient targeting of DNase I to the secretory pathway and is then cleaved from the polypeptide, by signal peptidase, once the protein has been translocated into the endoplasmic reticulum (Pg. 24, para. 256).
When taken with the teachings of Ledbetter et al. in view of Garcia-Romo et al., wherein the combination teaches a method of treating SLE by expressing a hybrid nuclease comprising a DNAse1L3 polypeptide and an Fc domain of human IgG1 in a mammalian cell, wherein said cell expresses and secretes the nuclease in a subject in need thereof, one of ordinary skill in the art would have found it prima facie obvious to substitute the endogenous leader peptide for a nucleotide sequence encoding the 33 amino acid endoplasmic reticulum targeting signal peptide because Shaaltiel teaches this signal peptide is capable of targeting DNAse I to the secretory pathway.
Thus, for the purposes of efficiently delivering the hybrid nuclease, the combination would have been prima facie obvious.
Prior Art Rejection 4
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Ledbetter et al. (PgPub US20140044711A1, Published 2/13/2014; Ref. 2 in IDS filed 10/2/2023) and Garcia-Romo et al. (Sci Transl Med. 2011;3:73ra20) as applied to claims 1, 9, 14, 27, 30, 33, 36, and 42 above, and further in view of Fuchs. T. (PgPub US20220025343A1, Filed 2/4/2020).
The teachings of Ledbetter et al. and Garcia-Romo et al. are relied upon as detailed above. However, none of Ledbetter et al. nor Garcia-Romo et al. teach the DNAse 1L3 comprises a V254T mutation with respect to SEQ ID NO: 2 (as in claim 23).
Before the effective filing date of the claimed invention, Fuchs teach a library of engineered DNASE proteins (including DNASE1L3) that allows to select drug candidates for developing therapeutics for treating conditions characterized by neutrophil extracellular trap (NET) accumulation and/or release. In accordance with the invention, the selected DNase variant has improved properties, including properties amenable to clinical development, including manufacturing, toxicology, pharmacokinetic, and/or use in therapy (Abstract). In some embodiments, Fuchs teaches the building block substitutions to D1L3 are selected from non-human D1L3 proteins and result in variants of human D1L3 which feature a V254T mutation (Pg. 8, para. 69) (as in claim 23b).
When taken with the teachings of Ledbetter et al. in view of Garcia-Romo et al., wherein the combination teaches a method of treating SLE, exacerbated by the production of NETs by SLE neutrophils, by expressing a hybrid nuclease comprising a DNAse1L3 polypeptide and an Fc domain of human IgG1 in a mammalian cell, with the teachings of Fuchs, wherein Fuchs teaches mutating a human D1L3 such that it comprises a V254T mutation, with a reasonable expectation at arriving at the claimed invention. The skilled artisan would have found it prima facie obvious to do so because Fuchs teaches the DNase variant has improved properties in treating diseases characterized by NETosis.
Thus, the modification would have been prima facie obvious.
Prior Art Rejection 5
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Ledbetter et al. (PgPub US20140044711A1, Published 2/13/2014; Ref. 2 in IDS filed 10/2/2023) and Garcia-Romo et al. (Sci Transl Med. 2011;3:73ra20) as applied to claims 1, 9, 14, 27, 30, 33, 36, and 42 above, and further in view of Faridmoayer et al. (PgPub 20210332403, Filed 6/28/2018).
The teachings of Ledbetter et al. and Garcia-Romo et al. are relied upon as detailed above. And although Ledbetter teach the construct is expressed in a mammalian cell, Ledbetter fails to teach the mammalian cell is stably transfected with ST6GAL1 (as further in claim 28a).
Before the effective filing date of the claimed invention, Faridmoayer et al. taught
methods for producing N-glycosylated target proteins. In one embodiment, Faridmoayer teaches a method of producing glycosylated target proteins in vivo, using a host cell described herein. In a specific embodiment, provided herein is a method for producing glycosylated target proteins, said method comprising (i) culturing a host cell provided herein under conditions suitable for protein production and (ii) isolating said target protein. In a specific embodiment, the host cell comprises (a) a recombinant nucleic acid encoding a target protein; and (b) a recombinant nucleic acid encoding a heterologous sialyltransferase (Pg. 28,para. 254-255), such as Beta-galactoside alpha-2,6-sialyltransferase 1 of Homo sapiens (as in claim 28a) (Pg. 25,para. 222).
When taken with the teachings of Ledbetter et al. in view of Garcia-Romo et al., wherein the combination teaches a method a construct comprising a human DNAse1L3 polypeptide, an Fc domain of human IgG1, and an N-linked glycosylation site for the purposes of treating SLE, with the teachings of Faridmoayer, wherein Faridmoayer teaches a method for producing glycosylated target proteins in a host cell comprising a recombinant nucleic acid encoding a target protein and a recombinant nucleic acid encoding a heterologous sialyltransferase, such as Beta-galactoside alpha-2,6-sialyltransferase 1 of Homo sapiens, with a reasonable expectation of arriving at the claimed invention. The skilled artisan would have found it prima facie obvious to modify the teachings of Ledbetter et al. in view of Garcia-Romo et al to include the teachings of Faridmoayer because Faridmoayer teaches inclusion of sialyltransferase aids in producing glycosylated proteins in vivo. Thus, for the purposes of treating SLE in patients, the combination would have been prima facie obvious.
Prior Art Rejection 6
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Ledbetter et al. (PgPub US20140044711A1, Published 2/13/2014, Filed 4/27/2012; Ref. 2 in IDS filed 10/2/2023) and Garcia-Romo et al. (Sci Transl Med. 2011;3:73ra20) as applied to claims 1, 9, 14, 27, 30, 33, 36, and 42 above, and further in view of Posada et al. (PgPub US20160251638A1, Published 9/1/2016).
The teachings of Ledbetter et al. and Garcia-Romo et al. are relied upon as detailed above. And although Ledbetter teach the construct comprises a human DNAse1 or human DNAse1L3, Ledbetter fails to teach a homodimeric construct comprising two independently selected constructs (I), wherein each Y is an independently selected human DNAsel or human DNAselL3 polypeptide (as further in claim 41).
Before the effective filing date of the claimed invention, Posada et al. taught a hybrid nuclease- glycosalated protein molecules of the invention have one or more nuclease domains (e.g., an RNase and/or DNase domain) (Abstract) operably coupled to glycosalated protein (Pg. ,para. 38). Posada teaches the hybrid nuclease- glycosalated protein molecules can be used in treating diseases characterized by defective clearance or processing of apoptotic cells and cell debris, such as SLE (Pg. 2, para. 20). Posada teaches the nuclease domains are identical, e.g., RNase and RNase, or DNase1 and DNase1 (as in claim 41a) (Pg. 8, para. 98). Posada teaches the hybrid nuclease glycosalated proteins molecules of the invention have at least one nuclease domain specific for a target molecule which mediates a biological effect (Pg. 8, para. 104). Posada teaches binding of the hybrid nuclease- glycosalated proteins molecules of the invention to a target molecule (e.g. DNA or RNA) results in the reduction or elimination of the target molecule, e.g., from a cell, a tissue, or from circulation.
When taken with the teachings of Ledbetter et al. in view of Garcia-Romo et al., wherein the combination teaches a method of treating SLE, one of ordinary skill in the art would have found it prima facie obvious to modify the construct of Ledbetter et al. in view of Garcia-Romo et al., such that it includes two DNase1 in the construct. The skilled artisan would have found it prima facie obvious to do so because Posada suggests and additive therapeutic effect in treating SLE. Thus, for the purposes of treating SLE in patients, the combination would have been prima facie obvious.
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.
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Claims 1,4,9,14,18,23,27-28,30-31,33,36 and 41 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 57-58, 60-70 and 73-75 of copending Application No. 17792101 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
The claims of instant application are drawn to a method of treating, ameliorating, or preventing inefficient NET hydrolysis ("NETolysis") in a subject afflicted with a bacterial or viral infection, the method comprising administering to the subject a therapeutically effective amount of a construct comprising the amino acid sequence: Y-Xl-LINKER-Fc-X2 (I), wherein: Y is a human DNAsel polypeptide or a human DNAselL3 polypeptide; XI is a covalent bond, or XI is the peptide of amino acid sequence RAFTNNRKSVSLKKRKKGNRS (SEQ ID NO:3) or a fragment thereof; LINKER is a chemical bond or a polypeptide comprising 1-100 amino acids; X2 is null, or X2 is the peptide of amino acid sequence RAFTNNRKSVSLKKRKKGNRS (SEQ ID NO:3) or a fragment thereof; Fc is the Fe domain of human IgGl. Dependent claim 18 claims the DNAse1 lacks at least a portion of residues 1-22 corresponding toe SEQ ID NO: 1.
The claims of the ‘101 application are drawn to a method of treating, ameliorating, or preventing diseases or disorders associated with inefficient NET hydrolysis (NETolysis) in a subject, the method comprising administering to the subject a therapeutically effective amount of a construct comprising the amino acid sequence: DNAse1-X1-LINKER-Fc-X2 (I) wherein in (I):
DNAse 1 is a human DNAse1 polypeptide variant comprising at least one mutation that decreases actin binding as compared to the corresponding human DNAsel polypeptide lacking the at least one mutation; X1 is a covalent bond, or X1 is the peptide of amino acid sequence RAFTNNRKSVSLKKRKKGNRS (SEQ ID NO:3) or a fragment thereof; LINKER is a chemical bond or a polypeptide comprising 1-100 amino acids; X2 is null, or X2 is the peptide of amino acid sequence SEQ ID NO:3 or a fragment thereof; Fc is the Fc domain of human IgG1. Claim 66 limits the human DNAse1 polypeptide variant to a variant that lacks resides 1-22 of corresponding to SEQ ID NO: 1.
The claims of the ‘101 application anticipate the method of instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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Conclusion
No claim is allowed.
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/TITILAYO MOLOYE/ Primary Examiner, Art Unit 1632