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.
Status of Claims
The amendments and arguments filed on 07/10/2026 are acknowledged and have been fully considered. Claims 6, 8, 9, 12, 14, and 15 are cancelled.
Claims 1-5, 7, 10, 11, 13, and 16-20 will be examined on the merits herein.
Objections/Rejections Withdrawn
Objections and/or rejections not reiterated from previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied, and constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103 (modified and maintained)
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 1-5, 7, 10, 11, 13, and 16-20 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 that 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 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).
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.
Response to Arguments
Applicant's arguments filed 07/10/2026 have been fully considered but they are not persuasive.
Applicant argues that the examiner must consider the prior art in its entirety; the prior art is good for everything it teaches, not just the invention it describes or claims. US'758 only discloses the elucidation of molecular mechanisms involved in neutrophil granule secretion, which is of pharmaceutical interest for anti-inflammatory therapies. The Examiner cites Cavalcante-Silva to remedy the deficiencies of US'758. Applicant respectfully asserts that the combination of the teachings of the two cited references (US'758 and Cavalcante-Silva) would not have suggested that the administration of the claimed fusion protein would be effective in inhibiting neutrophil degranulation (claim 1), generation of ROS (claim 2) or degranulation (claim 3) in a patient infected with SARS-CoV-2. Cavalcante-Silva in the introduction on page 1 states that "when compared to the influenza virus, SARS-CoV-2 infection presents greater chances of progressing to severe and critical infections, which require oxygen therapy and ventilatory support." This statement indicates that data from other viral infections cannot be obviously extrapolated to SARS-CoV-2. – Examiner would like to remind the applicant In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The instant invention claims inhibition of neutrophil exocytosis with administration of cell-penetrating SNARE-domain fusion proteins. TAT-SNAP-23 and TAT-STX-4 inhibit membrane fusion, thus reducing the release of granule content from neutrophils; which in turn lowers downstream inflammation causing elements like reactive oxygen species and neutrophil extracellular traps (NETs). Therefore, the claimed therapy targets mechanistic step upstream of multiple neutrophil driven cellular injury pathways; which is in direct correlation with targeting hyperactivated neutrophils in severe COVID-19 patients.
Applicants argument Cavalcante-Silva the authors state that "although the evidence is limited, it has been suggested 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)." This statement indicates to one of ordinary skill in the art that neutrophil degranulation and respiratory burst activity provide a protective activity in viral infections, including SARS-CoV-2. One of ordinary skill in the art would interpret this statement to indicate that interruption of degranulation could worsen SARS-CoV-2 infection. Moreover, on page 2, section 3 of Cavalcante-Silva the authors state "although the neutrophils could present a protective role, extensive and prolonged activation of these leukocytes can lead to detrimental effects in the lungs and result in pneumonia and/or ARDS." This statement indicates that the authors are merely speculating about the relative protective versus destructive of neutrophils in the lung injury from SARS-CoV-2 and are uncertain regarding their role in SARS-CoV-2 infection. The Examiner is not permitted to "pick and choose" from a reference only so much of it as will support the Examiner's position, to the exclusion of other parts necessary to the full appreciation of what such reference fairly suggests to one of ordinary skill in the art. Applicant submits that the cited documents fail to teach all the elements of the claimed invention, and therefore, the pending claims are not obvious over the cited art. - However, the therapeutic mechanism on which the instantly claimed invention is based on, is elucidated above. Examiner would like to bring to Applicant’s notice that it is known in the art that neutrophils act as double-edged swords by playing essential roles in clearing infection but also causing tissue damage (see Abstract; Parkos, 2016). Parkos reviews the beneficial and detrimental roles of neutrophils during the host inflammatory response; elaborates that neutrophils are critical for mucosal health while also contributing directly to the pathology of numerous inflammatory diseases; and exemplifies key aspects of neutrophil-epithelial interactions and explains how neutrophils and conditions associated with inflammation affect epithelial barrier integrity and homeostasis (see Conclusion; Parkos, 2016). Further, it is noted that it is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006).
Prior Art of Record
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Parkos (“Neutrophil-Epithelial Interactions: A Double-Edged Sword”; Am J Pathol; 186(6):1404–1416; published June 2016)
Conclusion
No claims are allowed.
Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KOYELI BANERJEE whose telephone number is (571)272-5751. The examiner can normally be reached Monday-Friday 8-4PM.
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/KOYELI BANERJEE/ Examiner, Art Unit 1658 /Melissa L Fisher/ Supervisory Patent Examiner, Art Unit 1658
