DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This instant application is a 371 filing of PCT/US22/13744, filed on 01/25/2022, and claims domestic benefit to US provisional application 63/143,479 filed 01/29/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/05/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 7 and 9 are objected to because of the following informalities: a space is missing between the words “of” and “claim 1”. Appropriate correction is required.
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 6, 8, 9, 12, 14, and 15 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 6 recites the limitation “SNAP-23 is a nucleic acid encoding the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:4”. There is insufficient antecedent basis for this limitation in the claim because SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:4 are as defined in the specification as amino acid sequences of SNAP-23 polypeptide that includes 78, 40, 60, and 24 amino acids respectively. Claim 1 recites the limitation “TAT-fusion protein comprising an 11 amino acid cell penetrating peptide TAT operably linked to an N-terminal SNARE domain of SNAP-23 (TAT- SNAP-23)”. Therefore, the SNAP-23 claimed is a peptide. Claim 6 depends from claim 1. However, claim 6 recites the “SNAP-23 is a nucleic acid encoding the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.” It is unclear what the limitation “SNAP-23 is a nucleic acid” of claim 6 is referencing because it is claimed to be a peptide in claim 1 which is specified as SEQ ID NO:1 is an amino acid sequence of a SNAP-23 polypeptide that includes 78 amino acids from the N-terminus of the full-length human SNAP-23 protein, SEQ ID NO:2 is an amino acid sequence of a SNAP-23 polypeptide that includes 40 amino acids from the N-terminus of the full-length human SNAP-23 protein, SEQ ID NO:3 is an amino acid sequence of a SNAP-23 polypeptide that includes 60 amino acids from the C-terminus of the full-length human SNAP-23 protein, or SEQ ID NO: 4 is an amino acid sequence of a SNAP-23 polypeptide that includes 24 amino acids from the C-terminus of the full-length human SNAP-23 protein. Claim 6 is indefinite because the metes and bounds of the claim with regard to the composition are not clearly and precisely defined.
Claim 8 recites the limitation “TAT-STX-4 is a nucleic acid encoding the amino acid sequence of SEQ ID NO:14”. There is insufficient antecedent basis for this limitation in the claim because SEQ ID NO: 14 is an amino acid sequence defined as syntaxin 4 (STX-4) polypeptide fragment in the specification. Claim 1 recites the limitation “TAT-fusion protein comprising an 11 amino acid cell penetrating peptide TAT operably linked to a SNARE domain of syntaxin-4 (TAT-STX-4)”. Therefore, the syntaxin-4 claimed is a peptide. Claim 8 depends from claim 1. However, claim 8 recites the “TAT-STX-4 is a nucleic acid encoding the amino acid sequence of SEQ ID NO: 14”. It is unclear what the limitation “TAT-STX-4 is a nucleic acid” of claim 8 is referencing because it is claimed to be syntaxin-4 polypeptide fragment in claim 1 which is specified as an amino acid sequence of a syntaxin4 polypeptide aptamer. Claim 8 is indefinite because the metes and bounds of the claim with regard to the composition are not clearly and precisely defined.
Claim 9 recites the limitation “TAT is a nucleic acid encoding the amino acid sequence of SEQ ID NO: 5”. There is insufficient antecedent basis for this limitation in the claim because SEQ ID NO: 5 is an amino acid sequence defined as YGRKKRRQRRR in the specification. Claim 1 recites the limitation “TAT-fusion protein comprising an 11 amino acid cell penetrating peptide TAT”. Therefore, the TAT claimed is a peptide of 11 amino acids. Claim 9 depends from claim 1. However, claim 9 recites the TAT is a nucleic acid encoding the amino acid sequence of SEQ ID NO: 5. It is unclear what the limitation “TAT is a nucleic acid” of claim 9 is referencing because it is claimed to be a peptide in claim 1. Claim 9 is indefinite because the metes and bounds of the claim with regard to the composition are not clearly and precisely defined.
Claim 12 recites the limitation “SNAP-23 is a nucleic acid encoding the amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:4”. There is insufficient antecedent basis for this limitation in the claim because SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:4 are as defined in the specification as amino acid sequences of SNAP-23 polypeptide that includes 78, 40, 60, and 24 amino acids respectively. Claim 2 recites the limitation “TAT-fusion protein comprising an 11 amino acid cell penetrating peptide TAT operably linked to an N-terminal SNARE domain of SNAP-23 (TAT- SNAP-23)”. Therefore, the SNAP-23 claimed is a peptide. Claim 12 depends from claim 2. However, claim 12 recites the “SNAP-23 is a nucleic acid encoding the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.” It is unclear what the limitation “SNAP-23 is a nucleic acid” of claim 12 is referencing because it is claimed to be a peptide in claim 2 which is specified as SEQ ID NO:1 is an amino acid sequence of a SNAP-23 polypeptide that includes 78 amino acids from the N-terminus of the full-length human SNAP-23 protein, SEQ ID NO:2 is an amino acid sequence of a SNAP-23 polypeptide that includes 40 amino acids from the N-terminus of the full-length human SNAP-23 protein, SEQ ID NO:3 is an amino acid sequence of a SNAP-23 polypeptide that includes 60 amino acids from the C-terminus of the full-length human SNAP-23 protein, or SEQ ID NO: 4 is an amino acid sequence of a SNAP-23 polypeptide that includes 24 amino acids from the C-terminus of the full-length human SNAP-23 protein. Claim 12 is indefinite because the metes and bounds of the claim with regard to the composition are not clearly and precisely defined.
Claim 14 recites the limitation “TAT-STX-4 is a nucleic acid encoding the amino acid sequence of SEQ ID NO:14”. There is insufficient antecedent basis for this limitation in the claim because SEQ ID NO: 14 is an amino acid sequence defined as syntaxin 4 (STX-4) polypeptide fragment in the specification. Claim 2 recites the limitation “TAT-fusion protein comprising an 11 amino acid cell penetrating peptide TAT operably linked to a SNARE domain of syntaxin-4 (TAT-STX-4)”. Therefore, the syntaxin-4 claimed is a peptide. Claim 14 depends from claim 2. However, claim 14 recites the “TAT-STX-4 is a nucleic acid encoding the amino acid sequence of SEQ ID NO: 14”. It is unclear what the limitation “TAT-STX-4 is a nucleic acid” of claim 14 is referencing because it is claimed to be syntaxin-4 polypeptide fragment in claim 2 which is specified as an amino acid sequence of a syntaxin4 polypeptide aptamer. Claim 14 is indefinite because the metes and bounds of the claim with regard to the composition are not clearly and precisely defined.
Claim 15 recites the limitation “TAT is a nucleic acid encoding the amino acid sequence of SEQ ID NO: 5”. There is insufficient antecedent basis for this limitation in the claim because SEQ ID NO: 5 is an amino acid sequence defined as YGRKKRRQRRR in the specification. Claim 2 recites the limitation “TAT-fusion protein comprising an 11 amino acid cell penetrating peptide TAT”. Therefore, the TAT claimed is a peptide of 11 amino acids. Claim 15 depends from claim 2. However, claim 15 recites the TAT is a nucleic acid encoding the amino acid sequence of SEQ ID NO: 5. It is unclear what the limitation “TAT is a nucleic acid” of claim 15 is referencing because it is claimed to be a peptide in claim 2. Claim 15 is indefinite because the metes and bounds of the claim with regard to the composition are not clearly and precisely defined.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.
Claims 1 - 20 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent No. 8,709,758 B2 (Date of Patent April 29, 2014, IDS 06/05/2024) in view of Cavalcante-Silva et al. “Neutrophils and COVID-19: The road so far”, International Immunopharmacology 90 (2021) 107233 (available online 30 November 2020).
US’758 teaches methods for inhibiting neutrophil granule exocytosis that comprise contacting a neutrophil with a fusion polypeptide including a cell-penetrating polypeptide and a SNARE polypeptide aptamer such that the fusion polypeptide enters the neutrophil and inhibits neutrophil granule exocytosis (Abstract). They disclose compositions and methods of using the same for inhibiting neutrophil exocytosis. In particular, the disclosed subject matter relates to fusion polypeptides comprising a cell-penetrating polypeptide, which facilitates entry of the fusion polypeptide into a neutrophil, and a SNARE polypeptide aptamer, which inhibits SNARE-associated exocytosis in a neutrophil (See col 1, line 20-26). US ‘758 disclosed an isolated fusion polypeptide is provided that inhibits soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-associated exocytosis in neutrophils. In some embodiments, the fusion polypeptide comprises a cell-penetrating polypeptide and a SNARE polypeptide aptamer selected from the polypeptides provided in SEQ ID NOS: 1 and 18. In some embodiments, the cell-penetrating polypeptide comprises a human immunodeficiency virus transactivator of transcription (TAT), or a transportan polypeptide. In some embodiments, the cell-penetrating polypeptide is a TAT polypeptide of SEQ ID NO: 5 (See col 2, line 54-65). In some embodiments, the SNARE polypeptide aptamer comprises a syntaxin 4 polypeptide fragment, such as the one provided in SEQ ID NO: 18. In other embodiments, the SNARE polypeptide aptamer comprises a (SNAP)-23 polypeptide, such as the one provided in SEQ ID NO: 1. In some embodiments, the SNARE polypeptide aptamer comprises a polypeptide of SEQ ID NO: 1 and the cell-penetrating polypeptide comprises a polypeptide of SEQ ID NO: 5 (col 2, line 66-67; col 3, line 1-8). US’768 discloses the methods for inhibiting neutrophil granule exocytosis, the neutrophil is contacted with a concentration of the fusion polypeptide of above about 0.5 mu. g/ml to thereby inhibit neutrophil granule exocytosis (See col 3, line 38-41). US’758 teaches that the fusion polypeptide inhibits exocytosis of a secretory vesicle, a specific granule, or a gelatinase granule (See col 3, line 42-43). More specifically, US’758 disclosure relates to a therapeutic method that comprises administering to a subject an effective amount of a fusion polypeptide such that the fusion polypeptide inhibits SNARE-associated exocytosis in neutrophils to thereby treat the neutrophil-mediated inflammatory disorder (See col 3, line 51-56).
The teachings of US’758 differ from that of the instantly claimed invention in that US’758 does not teach therapeutic activity against infectious inflammatory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19, but only discloses the elucidation of molecular mechanisms involved in neutrophil granule secretion, which is of pharmaceutical interest for anti-inflammatory therapies.
Cavalcante-Silva et al. teaches that neutrophils enhance antiviral defenses by interaction with other immune cell populations, virus internalization and killing mechanism, cytokines release, degranulation, oxidative burst, and neutrophil extracellular traps (NETs) (See page 2, Neutrophils in COVID-19, paragraph 1). Further teaches that neutrophil activation and degranulation are highly activated processes in the SARS infection (See page 2, Neutrophils in COVID-19, paragraph 2). Cavalcante-Silva et al. teaches in COVID-19, neutrophils accumulation generates toxic molecules that might contribute to acute respiratory distress syndrome (ARDS)’s physiopathology. Respiratory burst from activated neutrophils induces ROS release, such as superoxide radicals and H2O2, leading to oxidative stress that contributes to the cytokine storm and blood clots formation in SARS-CoV-2 infection. Further teaches in addition to ROS formation, neutrophil elastase has been implicated in COVID-19 pathogenesis. This proteolytic enzyme, which is stored in azurophil granules, is secreted to degrade antigens (See page 2, Neutrophils in COVID-19, paragraph 7). The neutrophils are drivers of hyperinflammation by enhanced degranulation of primary granules and pro-inflammatory cytokines release (See page 2, Neutrophils in COVID-19, paragraph 8).
Cavalcante-Silva et al. elucidates viral infection can also induce the release of neutrophils extracellular traps (NETs) by neutrophils, however, NETs can act as a double-edged sword of immunity, having a pro- or anti-inflammatory effect (See page 3, Neutrophils in COVID-19, paragraph 2). An aggregate of NETs can degrade cytokines and chemokines, reducing inflammation. This anti-inflammatory effect has also been demonstrated in the ocular microenvironment. On the other hand, NETs can promote tissue damage, having already been shown that NETs and platelets’ interaction can cause endothelial damage in infections. NETs can also participate in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, where elevated levels of NETs have been seen in serum and synovial fluid, respectively, in patients with these diseases (See page 3, Neutrophils in COVID-19, paragraph 2). Thus, Cavalcante-Silva et al. teaches that an elevated level of NETs in patients with COVID-19, and an increased plasma NETs is correlated with increased COVID-19 severity, besides contributing to lung injury and microvascular thrombosis (See page 3, Neutrophils in COVID-19, paragraph 3).
Cavalcante-Silva et al teaches that despite the immune system modulation needs being tightly controlled to avoid immunosuppression, the different neutrophil mechanisms (e.g., neutrophils enzymes and cytokines, NETs) are potential targets to treat COVID-19 (See page 3, concluding paragraph).
It would have been obvious to combine the teaching of US’758 and Cavalcante-Silva et al. before the effective filing date of the claimed invention by considering neutrophils as an effective and rational therapeutic target for the treatment of patients with severe COVID-19 to arrive at the instantly claimed invention. One of ordinary skill in the art would have been motivated to utilize the fusion protein with high fusogenic activity of US’758 as potent membrane fusion inhibitors against inflammation related to SARS-CoV-2 with a reasonable expectation of success because Cavalcante-Silva et al. teaches that hyperactive and dysregulated neutrophil response represent novel therapeutic targets for treatment approved for COVID-19 symptoms and advance in neutrophil mediated pathology will provide benefit to patients with immunodeficiency due to COVID-19 infection.
It would have been prima facie obvious for one of ordinary skill in the art to optimize the US‘758 disclosure expressing that TAT-SNAP-23 inhibits neutrophil degranulation; to administer TAT-SNAP-23 to a patient with SARS-CoV-2 driven hyperinflammation as taught by Cavalcante-Silva et al.
Regarding claim 1, US'758 teaches that pre-treatment with TAT-SNAP-23 resulted in neutrophils that retained most of their granules. These results thus indicate that TAT-SNAP-23 impairs neutrophil degranulation (See col 22, line 12-15).
Regarding claims 1-4, US’758 discloses the SNARE polypeptide aptamer comprises a syntaxin 4 polypeptide fragment, such as the one provided in SEQ ID NO: 18. In other embodiments, the SNARE polypeptide aptamer comprises a (SNAP)-23 polypeptide, such as the one provided in SEQ ID NO: 1. In some embodiments, the SNARE polypeptide aptamer comprises a polypeptide of SEQ ID NO: 1 and the cell-penetrating polypeptide comprises a polypeptide of SEQ ID NO: 5 (See col 3, line 1-10). SEQ ID NO: 18 of US’758 is identical with SEQ ID NO: 14 for syntaxin-4 in the instant claims. SEQ ID NO: 1 of US’758 is identical with SEQ ID NO: 1 for (SNAP)-23 in the instant claims. SEQ ID NO: 5 of US’758 is identical with SEQ ID NO: 5 for cell-penetrating polypeptide TAT in the instant claims.
Regarding claims 6 and 12, US’758 discloses that SEQ ID NO: 1 is an amino acid sequence of a SNAP-23 polypeptide that includes 78 amino acids from the N-terminus of the full-length human SNAP-23 protein, SEQ ID NO: 2 is an amino acid sequence of a SNAP-23 polypeptide that includes 40 amino acids from the N-terminus of the full-length human SNAP-23 protein, SEQ ID NO: 3 is an amino acid sequence of a SNAP-23 polypeptide that includes 60 amino acids from the C-terminus of the full-length human SNAP-23 protein, SEQ ID NO: 4 is an amino acid sequence of a SNAP-23 polypeptide that includes 24 amino acids from the C-terminus of the full-length human SNAP-23 protein (See col 6, line 15-26).
Regarding claims 5, 11, 17 and 19, US’758 discloses TAT-SNAP-23 fusion protein. (See col. 19, line 46 and SEQ ID NO: 12).
Regarding claims 7, 10, 13, 16, 18, and 20, US’758 teaches TAT-fusion proteins containing the amino terminal SNARE domain (SEQ ID NO: 1) of SNAP-23 (TAT-SNAP-23) and the SNARE domain of syntaxin 4 (SEQ ID NO: 18) (See col 21, line 7-9). The SNARE domain of syntaxin 4 (FIG. 7C; TAT-Syntaxin-4) (See col 4, line 50-51). US’758 teaches the SNARE polypeptide aptamer comprises a SNAP-23 amino-terminus polypeptide fragment or a syntaxin 4 polypeptide fragment. In some embodiments, the SNARE polypeptide aptamer comprises a syntaxin 4 polypeptide fragment, such as the one provided in SEQ ID NO: 18 (See col 12, line 55-60).
Regarding claims 6, 8, 12 and 14, US’758 discloses that the isolated nucleic acids are comprise a nucleotide sequence encoding a fusion polypeptide that inhibits SNARE-associated exocytosis in neutrophils. In some embodiments, an isolated nucleic acid is provided that encodes a fusion polypeptide comprising a cell-penetrating polypeptide and a SNARE polypeptide aptamer, which is selected from a SNAP-23 amino-terminus polypeptide fragment, such as the one provided in SEQ ID NO: 1, or a syntaxin 4 polypeptide fragment, such as the one provided in SEQ ID NO: 18 (See col 12, line 15-25). In some embodiments, a nucleic acid sequence is provided that encodes a SNARE polypeptide aptamer of SEQ ID NO: 1 and a cell-penetrating peptide of SEQ ID NO: 5 (See col 12, line 26-29).
Regarding claims 9 and 15, US’758 teaches SEQ ID NO: 5 is an amino acid sequence of a human immunodeficiency virus transactivator of transcription (TAT) cell-penetrating polypeptide (See col 6, line 27-29) In some embodiments, the cell-penetrating polypeptide is a TAT polypeptide and has the following amino acid sequence: YGRKKRRQRRR (SEQ ID NO: 5) (See col 10, line 37-39). US’758 discloses a nucleic acid sequence is provided that encodes a fusion polypeptide comprising a SNARE polypeptide aptamer of SEQ ID NO: 1 and a cell-penetrating peptide of SEQ ID NO: 5 (See col 3, line 19-22).
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Conclusion
No claims are allowed.
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/KOYELI BANERJEE/ Examiner, Art Unit 1658
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654