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
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) were submitted on 11/7/2022 and 8/29/20204, before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 22-41 are pending. Claims 22-41 are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Claims 38-41 lack sequence identifiers as required above. Appropriate correction is required.
Claim Objections
Claims 38-41 are objected to because of the following informalities. Claims 38-41 contain peptide sequences with no sequence identifier numbers. Please add the sequence identifiers. Appropriate correction is required.
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 22-26, 29, 33, and 36-39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) as evidenced by Hribar et al. (Hribar et al. European journal of immunology 29.10: 3105-3111 (1999) and Lucas et al. (Lucas, et al. Science 263.5148: 814-817 (1994)).
Regarding claim 1, claim 1 recites “
- obtaining a pharmaceutically acceptable formulation comprising a peptide, wherein the peptide consists of 7-17 amino acids and includes the hexamer TX1EX2X3E, wherein X1, X2 and X3 can be any natural or non-natural amino acid, and wherein the peptide does not exhibit TNF-receptor-binding activity; and
- administering an effective amount of the formulation to a patient having COVID-19 or at risk of developing COVID-19.
Krenn discloses a cyclic synthetic peptide AP301 in a pharmaceutical composition with the sequence: CGQRETPEGAEAKPWYC. This peptide has 17 amino acids and contains the claimed TXEXXE motif highlight in bold. (Krenn, page 2 col. 1, para. 2).
Also, the AP301 peptide (“TIP peptide, amino acid sequence: CGQRETPEGAEAKPWYC), which mimics the lectin-like domain of human tumor necrosis factor (TNF)-α (TIP domain)) does not exhibit TNF-receptor-binding activity (Krenn, page 2 col. 1, para. 2). This is evidenced by Lucas, which establishes the TXEXXE motif as the critical active motif for the activity of the tumor necrosis factor “tip” peptide activity: “Thr105, Glu107, and Glu110 are of critical functional importance.” (Lucas, page 816, col. 2, para. 3) and Hribar: “Importantly, the TNF-derived Ltip peptide did not induce ICAM-1 or VCAM-1 expression in MVEC, as expected, because it lacks a TNF receptor-mediated activity (Table 1)” (Hribar, page 3108, col. 1, para. 1). The peptide of Hribar has the sequence: CGPKDTPEGAELKPWYC, which contains the known critical motif of TXEXXE present in these TNF-derived peptides (Hribar, page 3109, col. 1, para. 4). The shared functional motif of these peptides and the sequence similarity of Hribar and Lucas provides evidence that the peptide of Krenn does not exhibit TNF-receptor-binding activity.
Additionally, the peptide of Krenn is identical to the sequence claimed by Applicant in claim 1. MPEP 2112.01(II) states: “"Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable.” Therefore, the peptide of Krenn would also lack the activity as claimed in claim 1.
For administration to patients, Krenn discloses that AP301 was administered to humans: “Eight patients randomized to the AP301 group and seven randomized to the placebo group had a SOFA score ≤10 at screening (stratum A). Twelve patients randomized to AP301 and 13 patients randomized to placebo had a SOFA score ≥11 at screening (stratum B).” (Krenn, page 3, col. 2, para. 3). Any given human that either has direct contact with society or contact with another person who in turn has contact with society is at risk of developing COVID-19.
Consequently, claim 22 is anticipated by Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) as evidenced by Hribar et al. (Hribar et al. European journal of immunology 29.10: 3105-3111 (1999) and Lucas et al. (Lucas, et al. Science 263.5148: 814-817 (1994)) and rejected.
Regarding claim 23, claim 22 is anticipated as described above. Claim 23 further recites the case the patient is receiving oxygen therapy. Krenn discloses that patients may be on oxygen therapy: “The second most reported reason was technical problems with the measurement, especially in patients on extracorporeal membrane oxygenation (ECMO) therapy.” (Krenn et al., page 3, col. 2, para. 3). Claim 23 is therefore anticipated by Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) as evidenced by Hribar et al. (Hribar et al. European journal of immunology 29.10: 3105-3111 (1999) and Lucas et al. (Lucas, et al. Science 263.5148: 814-817 (1994)) and rejected.
Regarding claim 24, claim 22 is anticipated as described above. Claim 24 further recites the case wherein the patient is ventilated. Krenn discloses that patients may be ventilated: “Mechanically ventilated ICU patients were screened for eligibility during the study period from August 2012 to February 2014.” (Krenn et al., page 3, col. 2, para. 3). Claim 24 is therefore anticipated by Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) as evidenced by Hribar et al. (Hribar et al. European journal of immunology 29.10: 3105-3111 (1999) and Lucas et al. (Lucas, et al. Science 263.5148: 814-817 (1994)) and rejected.
Regarding claim 25, claim 24 is anticipated as described above. Claim 25 further recites the case wherein the patient is ventilated by non-invasive positive pressure ventilation. Krenn et al. discloses the usage of positive pressure ventilation in Table 2 by reciting Peak ventilator pressure statistics (Krenn et al., page 5, Table 2). Claim 25 is therefore anticipated by Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) as evidenced by Hribar et al. (Hribar et al. European journal of immunology 29.10: 3105-3111 (1999) and Lucas et al. (Lucas, et al. Science 263.5148: 814-817 (1994)) and rejected.
Regarding claim 26, claim 24 is anticipated as described above. Claim 26 further recites the case wherein the patient is mechanically ventilated. Krenn discloses that patients may be ventilated: “Mechanically ventilated ICU patients were screened for eligibility during the study period from August 2012 to February 2014.” (Krenn et al., page 3, col. 2, para. 3). Claim 26 is therefore anticipated by Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) as evidenced by Hribar et al. (Hribar et al. European journal of immunology 29.10: 3105-3111 (1999) and Lucas et al. (Lucas, et al. Science 263.5148: 814-817 (1994)) and rejected.
Regarding claim 29, claim 22 is anticipated as described above. Claim 29 further recites the case wherein the peptide is administered to the patient by inhalation. Krenn discloses that “The present study was a single-center, randomized, double-blind, placebo-controlled clinical trial (n = 20 AP301 inhalation, n = 20 placebo 0.9% saline inhalation).” and “Inhalations (AP301 or 0.9% saline) were started in the evening of the day of screening or the next morning if randomization was performed after 12 am.” (Krenn, page 2, col. 2, para. 3). Claim 29 is therefore anticipated by Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) as evidenced by Hribar et al. (Hribar et al. European journal of immunology 29.10: 3105-3111 (1999) and Lucas et al. (Lucas, et al. Science 263.5148: 814-817 (1994)) and rejected.
Regarding claim 33, claim 22 is anticipated as described above. Claim 33 further recites the case wherein the patient has a SOFA score of at least 8. Krenn discloses that: “An exploratory post-hoc subgroup analysis indicated reduced EVLWI in patients with SOFA
scores ≥11 receiving treatment with inhaled AP301.” (Krenn, page 7, col. 2, para. 3). Claim 33 is therefore anticipated by Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) as evidenced by Hribar et al. (Hribar et al. European journal of immunology 29.10: 3105-3111 (1999) and Lucas et al. (Lucas, et al. Science 263.5148: 814-817 (1994)) and rejected.
Regarding claim 36, claim 22 is anticipated as described above. Claim 36 further recites the case wherein the peptide includes the amino acid hexamer TPEGAE. Krenn discloses a cyclic synthetic peptide AP301 with the sequence: CGQRETPEGAEAKPWYC. This peptide has 17 amino acids and contains the claimed TXEXXE motif highlight in bold. (Krenn, page 2 col. 1, para. 2). Claim 36 is therefore anticipated by Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) as evidenced by Hribar et al. (Hribar et al. European journal of immunology 29.10: 3105-3111 (1999) and Lucas et al. (Lucas, et al. Science 263.5148: 814-817 (1994)) and rejected.
Regarding claim 37, claim 22 is anticipated as described above. Krenn discloses a cyclic synthetic peptide AP301 with the sequence: CGQRETPEGAEAKPWYC. (Krenn, page 2 col. 1, para. 2). Claim 37 is therefore anticipated by Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) as evidenced by Hribar et al. (Hribar et al. European journal of immunology 29.10: 3105-3111 (1999) and Lucas et al. (Lucas, et al. Science 263.5148: 814-817 (1994)) and rejected.
Regarding claim 38, claim 22 is anticipated as described above. Krenn discloses a cyclic synthetic peptide AP301 with the sequence: CGQRETPEGAEAKPWYC. (Krenn, page 2 col. 1, para. 2). Claim 38 is therefore anticipated by Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) as evidenced by Hribar et al. (Hribar et al. European journal of immunology 29.10: 3105-3111 (1999) and Lucas et al. (Lucas, et al. Science 263.5148: 814-817 (1994)) and rejected.
Regarding claim 39, claim 22 is anticipated as described above. Krenn discloses a cyclic synthetic peptide AP301 with the sequence: CGQRETPEGAEAKPWYC. (Krenn, page 2 col. 1, para. 2). Claim 39 is therefore anticipated by Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) as evidenced by Hribar et al. (Hribar et al. European journal of immunology 29.10: 3105-3111 (1999) and Lucas et al. (Lucas, et al. Science 263.5148: 814-817 (1994)) and rejected.
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.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) as evidenced by Hribar et al. (Hribar et al. European journal of immunology 29.10: 3105-3111 (1999) and Lucas et al. (Lucas, et al. Science 263.5148: 814-817 (1994)) as applied to claim 22 above, in view of Choi et al. (Choi, et al. Integrative Medicine Research 9.3: 100421 (2020), Vadász, et al. (Vadász, et al. Frontiers in immunology 8: 757 (2017)), Ji, et al. (Ji, et al. American Journal of Physiology-Lung Cellular and Molecular Physiology 296.3: L372-L383 (2009)), and Shabbir et al.( Shabbir, et al. Molecular pharmacology 84.6: 899-910 (2013)), and Wadhera et al. (Wadhera, et al. Jama 323.21: 2192-2195 (2020)) as evidenced by Li et al. (Li, Hua, Zhe Liu, and Junbo Ge. Journal of cellular and molecular medicine 24.12: 6558-6570 (2020)).
Regarding claim 27, claim 22 is anticipated as described above. Krenn does not disclose the case wherein the patient is hospitalized for management of COVID-19.
However, Choi discloses a relationship between SARS-CoV2 and acute lung injury (ALI) or acute respiratory distress syndrome (ARDS): “It should be noted that the dire consequence of SARS-CoV2 infection is not due to the virus per se but to entailing inflammatory response in the lung.” (Choi et al., page 1, col. 2, para. 1) and “Fortunately, the mortality of SARS-CoV2 infection, which is related to ALI or ARDS, is lower than those of the other two outbreaks. Since ALI can be regulated by suppressing inflammation, various anti-inflammatory regimens had been attempted to treat patients during the last CoV outbreaks, including steroids and antibodies against cytokines. Given the pathologic similarity among three different outbreaks of hCoV, it is highly likely that managing ALI and ARDS attentively and vigorously leads to quick recovery from SARS-CoV2 infection.” (Choi et al., page 1, col. 2, para. 1).
Vadász et al. discloses that: “Disruption of the alveolar–capillary barrier and accumulation of pulmonary edema, if not resolved, result in poor alveolar gas exchange leading to hypoxia and hypercapnia, which are hallmarks of acute lung injury and the acute respiratory distress syndrome (ARDS). Alveolar fluid clearance (AFC) is a major function of the alveolar epithelium and is mediated by the concerted action of apically-located Na+ channels [epithelial Na+ channel (ENaC)] and the basolateral Na,K-ATPase driving vectorial Na+ transport. Importantly, those patients with ARDS who cannot clear alveolar edema efficiently have worse outcomes.” (Vadász, et al , Introduction). This shows the relationship between ENaC function and outcomes for ALI and ARDS.
Ji et al. also discusses this phenomenon in the context of older viruses, stating that sodium (Na+) channels ENaC activity positively correlates to patient outcomes by limiting alveolar edema: “A variety of studies have clearly established that active Na+ transport limits the degree of alveolar edema under pathological conditions in which the alveolar epithelium has been damaged.” (Ji et al. page L372, col. 2, para. 2).
Viruses that impact this transport capability, such as RSV and influenza, have significant morbidity rates: “Acute respiratory viral infections cause significant morbidity and mortality in both adults and children. For example, respiratory syncytial virus (RSV), a member of the pneumovirus genus of the Paramyxoviridae, is the most common cause of lower respiratory tract infections in infants and children worldwide and also causes community-acquired lower respiratory tract infections among adults (39). Influenza viruses (types A and B) account for more than 50% of all viral pneumonias in adults. Influenza has a high morbidity, affecting 10–20% of the U.S. population, accounting for up to 40,000 deaths annually. There is also a continuing risk of more severe influenza pandemics. Both of these viruses have been shown to impair Na_ transport,…” (Ji et al., page L372, col. 2, para. 3).
Ji et al. discloses that SARS-CoV causes lung failure by decreasing epithelial sodium (Na+) channels (ENaC) activity: “As discussed below, numerous studies have shown that viral infections downregulate lung epithelial cell ENaC activity, which leads to pulmonary edema. However, our results demonstrate for the first time that expression of two viral proteins (SARS-CoV S or E) in Xenopus oocytes injected with α-, β-, γ-hENaC decreases amiloride-sensitive whole cell currents and single-channel ENaC activities as well as plasma membrane γ-hENaC levels.” (Ji, page L381, col. 1, para. 3).
Shabbir et al. describes how the synthetic cyclic peptide A301 (Applicant SEQ ID NO: 1) is used to treat this exact condition: “The lectin-like domain of tumor necrosis factor (TIP) and the TIP peptide, a cyclic peptide mimicking this domain (Lucas et al., 1994), effect ALF reabsorption due to their capacity to enhance amiloride-sensitive Na+ current in alveolar epithelial cells (Fukuda et al., 2001; Elia et al., 2003; Braun et al., 2005; Vadász et al., 2008;Hamacher et al., 2010;Hazemi et al., 2010). The edema-reducing effect of the lectin-like domain involves binding to specific oligosaccharides such as N,N-diacetylchitobiose and branched trimannoses (Hribar et al., 1999; Braun et al., 2005).
AP301 [Cyclo(CGQRETPEGAEAKPWYC)], a cyclic peptide comprising the human TIP sequence and currently being developed as a treatment for lung edema (phase II clinical trials), has been shown to reduce extravascular lung water and improve lung function in a pig model of acute lung injury (Hartmann et al., 2013) and to enhance the amiloride-sensitive Na+ current in freshly isolated ATII cells from dog, pig, and rat lungs (Hamacher et al., 2010; Tzotzos et al., 2013). The current-enhancing effect of AP301 is not inhibited by CNG channel blockers, suggesting that AP301 activates Na+ current flowing through ENaC (Tzotzos et al., 2013).” (Shabbir et al., page 900, col. 1, para. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to extend the method of Krenn to treat a patient hospitalized for management of COVID-19, caused by the CoV-SARS2 virus: “A cluster of pneumonia (COVID-19) cases have been found in Wuhan China in late December, 2019, and subsequently, a novel coronavirus with a positive stranded RNA was identified to be the aetiological virus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2), which has a phylogenetic similarity to severe acute respiratory syndrome coronavirus (SARS-CoV)” (Li et al., Introduction).
A person of ordinary skill in the art would have a reasonable expectation of success using the method of Krenn to treat COVID-19 due to the analyses and teachings of Choi, Vadász, Ji, and Shabbir. Specifically, Choi discloses that ARDS and ALI are dangerous aspects of CoV-SARS2 infection, management of which are important for outcomes (Choi et al., page 1, col. 2, para. 1). Vadász discloses that ENaC function is extremely important for overcoming ARDS symptoms (Vadász, et al., Introduction). Ji further supports this finding by disclosing that ENaC function can limit edema damage (Ji et al. page L372, col. 2, para. 2). Finally, Shabbir discloses that the molecule of Krenn can be used to enhance ENaC function, which directly treats one of the most dangerous aspects of COVID-19 infection (Shabbir et al., page 900, col. 1, para. 3). A person of ordinary skill in the art would also be motivated to make this combination in order to reduce symptoms in hospitalized patients as described by Wadhera. Consequently, claim 27 is obvious over Krenn et al. as evidenced by Hribar et al. and Lucas et al. as applied to claim 22 above, in view of Choi et al., Vadász, et al., Ji, et al., Shabbir et al., and Wadhera et al. as evidenced by Li et al. and rejected.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) as evidenced by Hribar et al. (Hribar et al. European journal of immunology 29.10: 3105-3111 (1999) and Lucas et al. (Lucas, et al. Science 263.5148: 814-817 (1994)) as applied to claim 22 above, in view of Choi et al. (Choi, et al. Integrative Medicine Research 9.3: 100421 (2020), Vadász, et al. (Vadász, et al. Frontiers in immunology 8: 757 (2017)), Ji, et al. (Ji, et al. American Journal of Physiology-Lung Cellular and Molecular Physiology 296.3: L372-L383 (2009)), and Shabbir et al.( Shabbir, et al. Molecular pharmacology 84.6: 899-910 (2013)) as evidenced by Li et al. (Li, Hua, Zhe Liu, and Junbo Ge. Journal of cellular and molecular medicine 24.12: 6558-6570 (2020)) as applied to claim 27, and further in view of Shen, et al. (Shen, et al. Critical care 24.1: 200 (2020)).
Regarding claim 28, claim 27 is obvious as described above. Shen et al. describes COVID-19 patients as requiring ICU care: “The Department of Critical Care Medicine, Wuhan Pulmonary Hospital, is the designated hospital for the treatment of severe patients with COVID-19. It has a total of 20 intensive care unit (ICU) beds and 102 nurses from the local hospital and other hospitals in the provinces and cities outside of Wuhan City. The critically ill patients receive mechanical ventilation.” (Shen et al., page 1, col. 1, para. 1). Therefore, claim 28 is obvious over Krenn et al. as evidenced by Hribar et al. and Lucas et al. as applied to claim 22 above, in view of Choi et al., Vadász, et al., Ji, et al., and Shabbir et al. as evidenced by Li et al., further in view of Shen et al. and rejected.
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) as evidenced by Hribar et al. (Hribar et al. European journal of immunology 29.10: 3105-3111 (1999) and Lucas et al. (Lucas, et al. Science 263.5148: 814-817 (1994)) as applied to claim 22 above, further in view of Hartmann, et al. (Hartmann, et al. BMC Pulmonary Medicine 15.1: 7 (2015))
Regarding claim 30, claim 29 is anticipated as described above. Claim 30 further recites the case wherein the peptide is administered via endotracheal inhalation. Hartmann discloses the administration of a similar peptide by way of endotracheal inhalation: “The present study therefore investigates the influence of the inhaled TIP peptide AP318 on intrapulmonary inflammatory response in a porcine model of systemic sepsis.” (Hartmann et al., Introduction) and “During the induction phase a non-participant randomized the animals into two groups and prepared the peptide solution for blinded endotracheal inhalation:…” (Hartmann, et al., page 2, col. 2, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of Krenn with the endotracheal inhalation delivery of Hartmann to arrive at the claimed invention. A person of ordinary skill in the art would have a reasonable expectation of success due to method of Hartmann also being used to deliver peptides. Consequently, claim 30 is obvious over Krenn as evidenced by Hribar and Lucas, further in view of Hartmann and rejected.
Claims 22-26, 29, 33, 36, 37, 39, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) as evidenced by Hribar et al. (Hribar et al. European journal of immunology 29.10: 3105-3111 (1999) and Lucas et al. (Lucas, et al. Science 263.5148: 814-817 (1994)) in view of Choi et al. (Choi, et al. Integrative Medicine Research 9.3: 100421 (2020), Vadász, et al. (Vadász, et al. Frontiers in immunology 8: 757 (2017)), Ji, et al. (Ji, et al. American Journal of Physiology-Lung Cellular and Molecular Physiology 296.3: L372-L383 (2009)), and Shabbir et al.( Shabbir, et al. Molecular pharmacology 84.6: 899-910 (2013)) as evidenced by Li et al. (Li, Hua, Zhe Liu, and Junbo Ge. Journal of cellular and molecular medicine 24.12: 6558-6570 (2020)).
Krenn discloses a cyclic synthetic peptide AP301 in a pharmaceutical composition with the sequence: CGQRETPEGAEAKPWYC. This peptide has 17 amino acids and contains the claimed TXEXXE motif highlight in bold. (Krenn, page 2 col. 1, para. 2).
Also, the AP301 peptide (“TIP peptide, amino acid sequence: CGQRETPEGAEAKPWYC), which mimics the lectin-like domain of human tumor necrosis factor (TNF)-α (TIP domain)) does not exhibit TNF-receptor-binding activity (Krenn, page 2 col. 1, para. 2). This is evidenced by Lucas, which establishes the TXEXXE motif as the critical active motif for the activity of the tumor necrosis factor “tip” peptide activity: “Thr105, Glu107, and Glu110 are of critical functional importance.” (Lucas, page 816, col. 2, para. 3) and Hribar: “Importantly, the TNF-derived Ltip peptide did not induce ICAM-1 or VCAM-1 expression in MVEC, as expected, because it lacks a TNF receptor-mediated activity (Table 1)” (Hribar, page 3108, col. 1, para. 1). The peptide of Hribar has the sequence: CGPKDTPEGAELKPWYC, which contains the known critical motif of TXEXXE present in these TNF-derived peptides (Hribar, page 3109, col. 1, para. 4). The shared functional motif of these peptides and the sequence similarity of Hribar and Lucas provides evidence that the peptide of Krenn does not exhibit TNF-receptor-binding activity.
For administration to patients, Krenn discloses that AP301 was administered to humans: “Eight patients randomized to the AP301 group and seven randomized to the placebo group had a SOFA score ≤10 at screening (stratum A). Twelve patients randomized to AP301 and 13 patients randomized to placebo had a SOFA score ≥11 at screening (stratum B).” (Krenn, page 3, col. 2, para. 3).
Krenn does not disclose the case wherein a patient has COVID-19.
However, Choi discloses a relationship between SARS-CoV2 and acute lung injury (ALI) or acute respiratory distress syndrome (ARDS): “It should be noted that the dire consequence of SARS-CoV2 infection is not due to the virus per se but to entailing inflammatory response in the lung.” (Choi et al., page 1, col. 2, para. 1) and “Fortunately, the mortality of SARS-CoV2 infection, which is related to ALI or ARDS, is lower than those of the other two outbreaks. Since ALI can be regulated by suppressing inflammation, various anti-inflammatory regimens had been attempted to treat patients during the last CoV outbreaks, including steroids and antibodies against cytokines. Given the pathologic similarity among three different outbreaks of hCoV, it is highly likely that managing ALI and ARDS attentively and vigorously leads to quick recovery from SARS-CoV2 infection.” (Choi et al., page 1, col. 2, para. 1).
Vadász et al. discloses that: “Disruption of the alveolar–capillary barrier and accumulation of pulmonary edema, if not resolved, result in poor alveolar gas exchange leading to hypoxia and hypercapnia, which are hallmarks of acute lung injury and the acute respiratory distress syndrome (ARDS). Alveolar fluid clearance (AFC) is a major function of the alveolar epithelium and is mediated by the concerted action of apically-located Na+ channels [epithelial Na+ channel (ENaC)] and the basolateral Na,K-ATPase driving vectorial Na+ transport. Importantly, those patients with ARDS who cannot clear alveolar edema efficiently have worse outcomes.” (Vadász, et al , Introduction). This shows the relationship between ENaC function and outcomes for ALI and ARDS.
Ji et al. also discusses this phenomenon in the context of older viruses, stating that sodium (Na+) channels ENaC activity positively correlates to patient outcomes by limiting alveolar edema: “A variety of studies have clearly established that active Na+ transport limits the degree of alveolar edema under pathological conditions in which the alveolar epithelium has been damaged.” (Ji et al. page L372, col. 2, para. 2).
Viruses that impact this transport capability, such as RSV and influenza, have significant morbidity rates: “Acute respiratory viral infections cause significant morbidity and mortality in both adults and children. For example, respiratory syncytial virus (RSV), a member of the pneumovirus genus of the Paramyxoviridae, is the most common cause of lower respiratory tract infections in infants and children worldwide and also causes community-acquired lower respiratory tract infections among adults (39). Influenza viruses (types A and B) account for more than 50% of all viral pneumonias in adults. Influenza has a high morbidity, affecting 10–20% of the U.S. population, accounting for up to 40,000 deaths annually. There is also a continuing risk of more severe influenza pandemics. Both of these viruses have been shown to impair Na_ transport,…” (Ji et al., page L372, col. 2, para. 3).
Ji et al. discloses that SARS-CoV causes lung failure by decreasing epithelial sodium (Na+) channels (ENaC) activity: “As discussed below, numerous studies have shown that viral infections downregulate lung epithelial cell ENaC activity, which leads to pulmonary edema. However, our results demonstrate for the first time that expression of two viral proteins (SARS-CoV S or E) in Xenopus oocytes injected with α-, β-, γ-hENaC decreases amiloride-sensitive whole cell currents and single-channel ENaC activities as well as plasma membrane γ-hENaC levels.” (Ji, page L381, col. 1, para. 3).
Shabbir et al. describes how the synthetic cyclic peptide A301 (Applicant SEQ ID NO: 1) is used to treat this exact condition: “The lectin-like domain of tumor necrosis factor (TIP) and the TIP peptide, a cyclic peptide mimicking this domain (Lucas et al., 1994), effect ALF reabsorption due to their capacity to enhance amiloride-sensitive Na+ current in alveolar epithelial cells (Fukuda et al., 2001; Elia et al., 2003; Braun et al., 2005; Vadász et al., 2008;Hamacher et al., 2010;Hazemi et al., 2010). The edema-reducing effect of the lectin-like domain involves binding to specific oligosaccharides such as N,N-diacetylchitobiose and branched trimannoses. (Hribar et al., 1999; Braun et al., 2005).
AP301 [Cyclo(CGQRETPEGAEAKPWYC)], a cyclic peptide comprising the human TIP sequence and currently being developed as a treatment for lung edema (phase II clinical trials), has been shown to reduce extravascular lung water and improve lung function in a pig model of acute lung injury (Hartmann et al., 2013) and to enhance the amiloride-sensitive Na+ current in freshly isolated ATII cells from dog, pig, and rat lungs (Hamacher et al., 2010; Tzotzos et al., 2013). The current-enhancing effect of AP301 is not inhibited by CNG channel blockers, suggesting that AP301 activates Na+ current flowing through ENaC (Tzotzos et al., 2013).” (Shabbir et al., page 900, col. 1, para. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to extend the method of Krenn to treat a patient hospitalized for management of COVID-19, caused by the CoV-SARS2 virus: “A cluster of pneumonia (COVID-19) cases have been found in Wuhan China in late December, 2019, and subsequently, a novel coronavirus with a positive stranded RNA was identified to be the aetiological virus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2), which has a phylogenetic similarity to severe acute respiratory syndrome coronavirus (SARS-CoV)” (Li et al., Introduction).
A person of ordinary skill in the art would have a reasonable expectation of success using the method of Krenn to treat COVID-19 due to the analyses and teachings of Choi, Vadász, Ji, and Shabbir. Specifically, Choi discloses that ARDS and ALI are dangerous aspects of CoV-SARS2 infection, management of which are important for outcomes (Choi et al., page 1, col. 2, para. 1). Vadász discloses that ENaC function is extremely important for overcoming ARDS symptoms (Vadász, et al., Introduction). Ji further supports this finding by disclosing that ENaC function can limit edema damage (Ji et al. page L372, col. 2, para. 2). Finally, Shabbir discloses that the molecule of Krenn can be used to enhance ENaC function, which directly treats one of the most dangerous aspects of COVID-19 infection (Shabbir et al., page 900, col. 1, para. 3).
Consequently, claim 22 is obvious over Krenn et al. as evidenced by Hribar et al. and Lucas et al.in view of Choi et al., Vadász, et al., Ji, et al., and Shabbir et al. as evidenced by Li et al. and rejected.
Regarding claim 23, claim 22 is obvious as described above. Claim 23 further recites the case the patient is receiving oxygen therapy. Krenn discloses that patients may be on oxygen therapy: “The second most reported reason was technical problems with the measurement, especially in patients on extracorporeal membrane oxygenation (ECMO) therapy.” (Krenn et al., page 3, col. 2, para. 3). Claim 23 is therefore obvious over Krenn et al. as evidenced by Hribar et al. and Lucas et al. in view of Choi et al., Vadász, et al., Ji, et al., and Shabbir et al. as evidenced by Li et al. and rejected.
Regarding claim 24, claim 22 is obvious as described above. Claim 24 further recites the case wherein the patient is ventilated. Krenn discloses that patients may be ventilated: “Mechanically ventilated ICU patients were screened for eligibility during the study period from August 2012 to February 2014.” (Krenn et al., page 3, col. 2, para. 3). Claim 24 is therefore obvious over Krenn et al. as evidenced by Hribar et al. and Lucas et al. in view of Choi et al., Vadász, et al., Ji, et al., and Shabbir et al. as evidenced by Li et al. and rejected.
Regarding claim 25, claim 24 is obvious as described above. Claim 25 further recites the case wherein the patient is ventilated by non-invasive positive pressure ventilation. Krenn et al. discloses the usage of positive pressure ventilation in Table 2 by reciting Peak ventilator pressure statistics (Krenn et al., page 5, Table 2). Claim 25 is therefore obvious over Krenn et al. as evidenced by Hribar et al. and Lucas et al. in view of Choi et al., Vadász, et al., Ji, et al., and Shabbir et al. as evidenced by Li et al. and rejected.
Regarding claim 26, claim 24 is obvious as described above. Claim 26 further recites the case wherein the patient is mechanically ventilated. Krenn discloses that patients may be ventilated: “Mechanically ventilated ICU patients were screened for eligibility during the study period from August 2012 to February 2014.” (Krenn et al., page 3, col. 2, para. 3). Claim 26 is therefore obvious over Krenn et al. as evidenced by Hribar et al. and Lucas et al. in view of Choi et al., Vadász, et al., Ji, et al., and Shabbir et al. as evidenced by Li et al. and rejected.
Regarding claim 29, claim 22 is obvious as described above. Claim 29 further recites the case wherein the peptide is administered to the patient by inhalation. Krenn discloses that “The present study was a single-center, randomized, double-blind, placebo-controlled clinical trial (n = 20 AP301 inhalation, n = 20 placebo 0.9% saline inhalation).” and “Inhalations (AP301 or 0.9% saline) were started in the evening of the day of screening or the next morning if randomization was performed after 12 am.” (Krenn, page 2, col. 2, para. 3). Claim 29 is therefore obvious over Krenn et al. as evidenced by Hribar et al. and Lucas et al. in view of Choi et al., Vadász, et al., Ji, et al., and Shabbir et al. as evidenced by Li et al. and rejected.
Regarding claim 33, claim 22 is obvious as described above. Claim 33 further recites the case wherein the patient has a SOFA score of at least 8. Krenn discloses that: “An exploratory post-hoc subgroup analysis indicated reduced EVLWI in patients with SOFA scores ≥11 receiving treatment with inhaled AP301.” (Krenn, page 7, col. 2, para. 3). Claim 29 is therefore obvious over Krenn et al. as evidenced by Hribar et al. and Lucas et al. in view of Choi et al., Vadász, et al., Ji, et al., and Shabbir et al. as evidenced by Li et al. and rejected.
Regarding claim 36, claim 22 is obvious as described above. Claim 36 further recites the case wherein the peptide includes the amino acid hexamer TPEGAE. Krenn discloses a cyclic synthetic peptide AP301 with the sequence: CGQRETPEGAEAKPWYC. This peptide has 17 amino acids and contains the claimed TXEXXE motif highlight in bold. (Krenn, page 2 col. 1, para. 2). Claim 36 is therefore obvious over Krenn et al. as evidenced by Hribar et al. and Lucas et al. in view of Choi et al., Vadász, et al., Ji, et al., and Shabbir et al. as evidenced by Li et al. and rejected.
Regarding claim 37, claim 22 is obvious as described above. Krenn discloses a cyclic synthetic peptide AP301 with the sequence: CGQRETPEGAEAKPWYC. (Krenn, page 2 col. 1, para. 2). Claim 37 is therefore obvious over Krenn et al. as evidenced by Hribar et al. and Lucas et al. in view of Choi et al., Vadász, et al., Ji, et al., and Shabbir et al. as evidenced by Li et al. and rejected.
Regarding claim 39, claim 22 is obvious as described above. Krenn discloses a cyclic synthetic peptide AP301 with the sequence: CGQRETPEGAEAKPWYC. (Krenn, page 2 col. 1, para. 2). Claim 37 is therefore obvious over Krenn et al. as evidenced by Hribar et al. and Lucas et al. in view of Choi et al., Vadász, et al., Ji, et al., and Shabbir et al. as evidenced by Li et al. and rejected.
Regarding claim 41, claim 41 recites a method for treating COVID-19 comprising
- obtaining a pharmaceutically acceptable formulation comprising a peptide, wherein the peptide is 17-20 amino acids in length and comprises the amino acid sequence CGQRETPEGAEAKPWYC, wherein the peptide does not TNF-receptor- 5 binding activity, and wherein the peptide is cyclized; and
- administering an effective amount of the formulation by inhalation to a patient having COVID-19, wherein the patient has a sequential organ failure assessment (SOFA) score of at least 8.
sequence: CGQRETPEGAEAKPWYC. This peptide has 17 amino acids and contains the claimed TXEXXE motif highlight in bold. (Krenn, page 2 col. 1, para. 2).
Also, the AP301 peptide (“TIP peptide, amino acid sequence: CGQRETPEGAEAKPWYC), which mimics the lectin-like domain of human tumor necrosis factor (TNF)-α (TIP domain)) does not exhibit TNF-receptor-binding activity (Krenn, page 2 col. 1, para. 2). This is evidenced by Lucas, which establishes the TXEXXE motif as the critical active motif for the activity of the tumor necrosis factor “tip” peptide activity: “Thr105, Glu107, and Glu110 are of critical functional importance.” (Lucas, page 816, col. 2, para. 3) and Hribar: “Importantly, the TNF-derived Ltip peptide did not induce ICAM-1 or VCAM-1 expression in MVEC, as expected, because it lacks a TNF receptor-mediated activity (Table 1)” (Hribar, page 3108, col. 1, para. 1). The peptide of Hribar has the sequence: CGPKDTPEGAELKPWYC, which contains the known critical motif of TXEXXE present in these TNF-derived peptides (Hribar, page 3109, col. 1, para. 4). The shared functional motif of these peptides and the sequence similarity of Hribar and Lucas provides evidence that the peptide of Krenn does not exhibit TNF-receptor-binding activity.
For administration to patients, Krenn discloses that AP301 was administered to humans: “Eight patients randomized to the AP301 group and seven randomized to the placebo group had a SOFA score ≤10 at screening (stratum A). Twelve patients randomized to AP301 and 13 patients randomized to placebo had a SOFA score ≥11 at screening (stratum B).” (Krenn, page 3, col. 2, para. 3).
Krenn does not disclose the case wherein a patient has COVID-19.
However, Choi discloses a relationship between SARS-CoV2 and acute lung injury (ALI) or acute respiratory distress syndrome (ARDS): “It should be noted that the dire consequence of SARS-CoV2 infection is not due to the virus per se but to entailing inflammatory response in the lung.” (Choi et al., page 1, col. 2, para. 1) and “Fortunately, the mortality of SARS-CoV2 infection, which is related to ALI or ARDS, is lower than those of the other two outbreaks. Since ALI can be regulated by suppressing inflammation, various anti-inflammatory regimens had been attempted to treat patients during the last CoV outbreaks, including steroids and antibodies against cytokines. Given the pathologic similarity among three different outbreaks of hCoV, it is highly likely that managing ALI and ARDS attentively and vigorously leads to quick recovery from SARS-CoV2 infection.” (Choi et al., page 1, col. 2, para. 1).
Vadász et al. discloses that: “Disruption of the alveolar–capillary barrier and accumulation of pulmonary edema, if not resolved, result in poor alveolar gas exchange leading to hypoxia and hypercapnia, which are hallmarks of acute lung injury and the acute respiratory distress syndrome (ARDS). Alveolar fluid clearance (AFC) is a major function of the alveolar epithelium and is mediated by the concerted action of apically-located Na+ channels [epithelial Na+ channel (ENaC)] and the basolateral Na,K-ATPase driving vectorial Na+ transport. Importantly, those patients with ARDS who cannot clear alveolar edema efficiently have worse outcomes.” (Vadász, et al , Introduction). This shows the relationship between ENaC function and outcomes for ALI and ARDS.
Ji et al. also discusses this phenomenon in the context of older viruses, stating that sodium (Na+) channels ENaC activity positively correlates to patient outcomes by limiting alveolar edema: “A variety of studies have clearly established that active Na+ transport limits the degree of alveolar edema under pathological conditions in which the alveolar epithelium has been damaged.” (Ji et al. page L372, col. 2, para. 2).
Viruses that impact this transport capability, such as RSV and influenza, have significant morbidity rates: “Acute respiratory viral infections cause significant morbidity and mortality in both adults and children. For example, respiratory syncytial virus (RSV), a member of the pneumovirus genus of the Paramyxoviridae, is the most common cause of lower respiratory tract infections in infants and children worldwide and also causes community-acquired lower respiratory tract infections among adults (39). Influenza viruses (types A and B) account for more than 50% of all viral pneumonias in adults. Influenza has a high morbidity, affecting 10–20% of the U.S. population, accounting for up to 40,000 deaths annually. There is also a continuing risk of more severe influenza pandemics. Both of these viruses have been shown to impair Na_ transport,…” (Ji et al., page L372, col. 2, para. 3).
Ji et al. discloses that SARS-CoV causes lung failure by decreasing epithelial sodium (Na+) channels (ENaC) activity: “As discussed below, numerous studies have shown that viral infections downregulate lung epithelial cell ENaC activity, which leads to pulmonary edema. However, our results demonstrate for the first time that expression of two viral proteins (SARS-CoV S or E) in Xenopus oocytes injected with α-, β-, γ-hENaC decreases amiloride-sensitive whole cell currents and single-channel ENaC activities as well as plasma membrane γ-hENaC levels.” (Ji, page L381, col. 1, para. 3).
Shabbir et al. describes how the synthetic cyclic peptide A301 (Applicant SEQ ID NO: 1) is used to treat this exact condition: “The lectin-like domain of tumor necrosis factor (TIP) and the TIP peptide, a cyclic peptide mimicking this domain (Lucas et al., 1994), effect ALF reabsorption due to their capacity to enhance amiloride-sensitive Na+ current in alveolar epithelial cells (Fukuda et al., 2001; Elia et al., 2003; Braun et al., 2005; Vadász et al., 2008;Hamacher et al., 2010;Hazemi et al., 2010). The edema-reducing effect of the lectin-like domain involves binding to specific oligosaccharides such as N,N-diacetylchitobiose and branched trimannoses. (Hribar et al., 1999; Braun et al., 2005).
AP301 [Cyclo(CGQRETPEGAEAKPWYC)], a cyclic peptide comprising the human TIP sequence and currently being developed as a treatment for lung edema (phase II clinical trials), has been shown to reduce extravascular lung water and improve lung function in a pig model of acute lung injury (Hartmann et al., 2013) and to enhance the amiloride-sensitive Na+ current in freshly isolated ATII cells from dog, pig, and rat lungs (Hamacher et al., 2010; Tzotzos et al., 2013). The current-enhancing effect of AP301 is not inhibited by CNG channel blockers, suggesting that AP301 activates Na+ current flowing through ENaC (Tzotzos et al., 2013).” (Shabbir et al., page 900, col. 1, para. 3).
Krenn discloses that: “An exploratory post-hoc subgroup analysis indicated reduced EVLWI in patients with SOFA scores ≥11 receiving treatment with inhaled AP301.” (Krenn, page 7, col. 2, para. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to extend the method of Krenn to treat a patient hospitalized for management of COVID-19, caused by the CoV-SARS2 virus: “A cluster of pneumonia (COVID-19) cases have been found in Wuhan China in late December, 2019, and subsequently, a novel coronavirus with a positive stranded RNA was identified to be the aetiological virus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2), which has a phylogenetic similarity to severe acute respiratory syndrome coronavirus (SARS-CoV)” (Li et al., Introduction).
A person of ordinary skill in the art would have a reasonable expectation of success using the method of Krenn to treat COVID-19 due to the analyses and teachings of Choi, Vadász, Ji, and Shabbir. Specifically, Choi discloses that ARDS and ALI are dangerous aspects of CoV-SARS2 infection, management of which are important for outcomes (Choi et al., page 1, col. 2, para. 1). Vadász discloses that ENaC function is extremely important for overcoming ARDS symptoms (Vadász, et al., Introduction). Ji further supports this finding by disclosing that ENaC function can limit edema damage (Ji et al. page L372, col. 2, para. 2). Finally, Shabbir discloses that the molecule of Krenn can be used to enhance ENaC function, which directly treats one of the most dangerous aspects of COVID-19 infection (Shabbir et al., page 900, col. 1, para. 3).
Consequently, claim 41 is obvious over Krenn et al. as evidenced by Hribar et al. and Lucas et al.in view of Choi et al., Vadász, et al., Ji, et al., and Shabbir et al. as evidenced by Li et al. and rejected.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Krenn et al.