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.
Claim Status
Claims 22-41 are pending. Claims 22-41 are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 8, para 2, filed 4/22/2026, with respect to sequence disclosures have been fully considered and are persuasive. The objection to sequence disclosures has been withdrawn.
Claim Objections
Claims 38-41 were 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.
Response to Arguments
Applicant’s arguments, see Applicant Reply, filed 4/22/2026, page 8, para 2, with respect to sequence disclosures have been fully considered and are persuasive. The objection to sequence disclosures has been withdrawn.
Response to Amendment
The affidavit under 37 CFR 1.132 filed 4/22/2026 is insufficient to overcome the rejection of claims 22-41 based upon U.S.C. 103 as set forth in the last Office action because it includes statements which amount to an affirmation that the claimed subject matter functions as it was intended to function.
Specifically, Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017)) discloses the usage of AP301 for ARDS:
“This randomized placebo-controlled phase IIa trial is the first clinical trial reporting the use of inhaled AP301 in mechanically ventilated patients with ARDS. The total number of adverse events was no different between the treatment groups. In addition, all adverse events could be explained by the course of the underlying diseases and the severity of the critical illness.” (Krenn et al., page 7, col. 2, para. 2).
Krenn also discloses that the efficacy of AP301 is higher when the symptoms as categorized by SOFA score are more severe”
“We observed a reduction in EVLWI and ventilation pressures over 7 days together with a trend of more ventilator-free days in patients with initial SOFA scores ≥11 who received AP301. No treatment effect of AP301 was observed in patients with SOFA scores ≤10 at screening. These differences between the patients stratified according to severity of illness (SOFA score strata) may have several explanations.” (Krenn et al., page 7, col. 2, para. 5).
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(Krenn et al, page 7, Fig. 2)
Based off the data of Krenn, a person of ordinary skill in the art would expect an improvement in symptoms and therefore survival rate in COVID-19 patients suffering from ARDS symptoms with a SOFA score of 11 or more.
A person of ordinary skill in the art before the effective filing date of this application would not have had access to the data of Tzotzos et al. mentioned in the affidavit. Even if such information had been available, the difference in survival rate cannot be fairly considered as unexpected when Krenn already demonstrated efficacy of AP301 in severe ARDS cases with SOFA scores of 11 or greater.
For these reasons, the affidavit is not effective.
Previous Claim Rejections - 35 USC § 102
Claims 22-26, 29, 33, and 36-39 were previously 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)).
Applicant’s arguments, see filed 4/22/2026, page 9, para 4, with respect to the rejection of claims 22-26, 29, 33, and 36-39 under U.S.C. 102(a)(1) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made below.
Previous Claim Rejections - 35 USC § 103
Applicant’s arguments, see Applicant Reply, page 10, para. 2, filed 4/22/2026, with respect to the rejections of claims 22-41 under U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made below.
New 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 22-29, 33, 34, 36, 37, and 39-41 are rejected under 35 U.S.C. 103 as being unpatentable over Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) and Gattinoni et al., (Gattinoni, et al. Critical care 24.1: 154. (2020)).
Regarding claim 22, 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 is known as “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).
Krenn does not disclose the treatment of COVID-19 specifically with AP301.
However, Gattinoni discloses that some COVID-19 cases result in ARDS and that these cases have severe phenotypes:
“In 20–30% of these COVID-19 patients admitted to the intensive care unit (ICU), severe hypoxemia is associated with compliance values < 40 ml/cmH2O, indicating severe ARDS. (Gattinoni et al., page 1, 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 use the AP301 peptide as disclosed by Krenn to treat COVID-19 that results in ARDS as disclosed by Gattinoni because Kreen discloses relief to symptoms of severe ARDS: ““We observed a reduction in EVLWI and ventilation pressures over 7 days together with a trend of more ventilator-free days in patients with initial SOFA scores ≥11 who received AP301. No treatment effect of AP301 was observed in patients with SOFA scores ≤10 at screening. These differences between the patients stratified according to severity of illness (SOFA score strata) may have several explanations.” (Krenn et al., page 7, col. 2, para. 5).
A person of ordinary skill in the art would be motivated to use the peptide of Krenn to reduce the symptoms of ARDS in COVID-19 patients to improve patient outcomes and would have a reasonable expectation of success because in both cases AP301 is treating ARDS.
Consequently, clam 22 is obvious over Krenn et al. in view of Gattinoni 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).
Consequently, clam 23 is obvious over Krenn et al. in view of Gattinoni 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).
Consequently, clam 24 is obvious over Krenn et al. in view of Gattinoni 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).
Consequently, clam 25 is obvious over Krenn et al. in view of Gattinoni 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).
Consequently, clam 26 is obvious over Krenn et al. in view of Gattinoni et al. and rejected.
Regarding claim 27, claim 22 is obvious as described above. Claim 27 further recites the case wherein the patient is hospitalized for management of COVID-19.
Gattinoni discloses that patients are hospitalized for COVID-19: “When presenting at the hospital, type 1 and type 2 patients are clearly distinguishable by CT scan (Fig. 1). If the CT scan is not available, the respiratory system compliance and possibly the response to PEEP are the only imperfect surrogates we may suggest.” (Gattinoni et al., page 1, col. 1, para. 1).
Consequently, clam 27 is obvious over Krenn et al. in view of Gattinoni et al. and rejected.
Regarding claim 28, claim 27 obvious as described above. Gattinoni discloses patients in the ICU: “In 20–30% of these COVID-19 patients admitted to the intensive care unit (ICU), severe hypoxemia is associated with compliance values < 40 ml/cmH2O, indicating severe ARDS. (Gattinoni et al., page 1, col. 2, para. 2).
Consequently, clam 28 is obvious over Krenn et al. in view of Gattinoni 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).
Consequently, clam 29 is obvious over Krenn et al. in view of Gattinoni 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).
Consequently, clam 33 is obvious over Krenn et al. in view of Gattinoni et al. and rejected.
Regarding claim 34, claim 22 is obvious as described above. Gattinoni discloses that severe cases have a compliance value of less than 40 ml/cmH2O: “In 20–30% of these COVID-19 patients admitted to the intensive care unit (ICU), severe hypoxemia is associated with compliance values < 40 ml/cmH2O, indicating severe ARDS. (Gattinoni et al., page 1, col. 2, para. 2).
This range is necessarily at most 40 ml/cmH2O, which substantially overlaps with at most 50 ml/cmH2O and also cannot go above 50 because it is capped at 40.
Consequently, clam 34 is obvious over Krenn et al. in view of Gattinoni 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).
Consequently, clam 36 is obvious over Krenn et al. in view of Gattinoni 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).
Consequently, clam 37 is obvious over Krenn et al. in view of Gattinoni 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).
Consequently, clam 39 is obvious over Krenn et al. in view of Gattinoni et al. and rejected.
Regarding claim 40, claim 40 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- 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 lung compliance of at most 50 mL/cmH2O.
Regarding claim 22, 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 is known as “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).
Krenn discloses inhalation: “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).
Krenn does not disclose the treatment of COVID-19 specifically with AP301.
However, Gattinoni discloses that some COVID-19 cases result in ARDS and that these cases have severe phenotypes:
“In 20–30% of these COVID-19 patients admitted to the intensive care unit (ICU), severe hypoxemia is associated with compliance values < 40 ml/cmH2O, indicating severe ARDS. (Gattinoni et al., page 1, col. 2, para. 2).
The compliance range disclosed above is necessarily at most 40 ml/cmH2O, which substantially overlaps with at most 50 ml/cmH2O and also cannot go above 50 because it is capped at 40.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the AP301 peptide as disclosed by Krenn to treat COVID-19 that results in ARDS as disclosed by Gattinoni because Kreen discloses relief to symptoms of severe ARDS: ““We observed a reduction in EVLWI and ventilation pressures over 7 days together with a trend of more ventilator-free days in patients with initial SOFA scores ≥11 who received AP301. No treatment effect of AP301 was observed in patients with SOFA scores ≤10 at screening. These differences between the patients stratified according to severity of illness (SOFA score strata) may have several explanations.” (Krenn et al., page 7, col. 2, para. 5).
A person of ordinary skill in the art would be motivated to use the peptide of Krenn to reduce the symptoms of ARDS in COVID-19 patients to improve patient outcomes and would have a reasonable expectation of success because in both cases AP301 is treating ARDS.
Consequently, clam 40 is obvious over Krenn et al. in view of Gattinoni 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).
Krenn does not disclose the treatment of COVID-19 specifically with AP301.
However, Gattinoni discloses that some COVID-19 cases result in ARDS and that these cases have severe phenotypes:
“In 20–30% of these COVID-19 patients admitted to the intensive care unit (ICU), severe hypoxemia is associated with compliance values < 40 ml/cmH2O, indicating severe ARDS. (Gattinoni et al., page 1, 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 use the AP301 peptide as disclosed by Krenn to treat COVID-19 that results in ARDS as disclosed by Gattinoni because Kreen discloses relief to symptoms of severe ARDS: ““We observed a reduction in EVLWI and ventilation pressures over 7 days together with a trend of more ventilator-free days in patients with initial SOFA scores ≥11 who received AP301. No treatment effect of AP301 was observed in patients with SOFA scores ≤10 at screening. These differences between the patients stratified according to severity of illness (SOFA score strata) may have several explanations.” (Krenn et al., page 7, col. 2, para. 5).
A person of ordinary skill in the art would be motivated to use the peptide of Krenn to reduce the symptoms of ARDS in COVID-19 patients to improve patient outcomes and would have a reasonable expectation of success because in both cases AP301 is treating ARDS.
Consequently, clam 41 is obvious over Krenn et al. in view of Gattinoni 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) in view of Gattinoni et al., (Gattinoni, et al. Critical care 24.1: 154. (2020)) as applied to claim 29 above, and further in view of Hartmann, et al. (Hartmann, et al. BMC Pulmonary Medicine 15.1: 7 (2015)).
Regarding claim 30, claim 29 is obvious 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 and 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.
Therefore, claim 30 is obvious over Krenn et al. in view of Gattinoni et al. as applied to claim 29., further in view of Hartmann et al. and rejected.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) in view of Gattinoni et al., (Gattinoni, et al. Critical care 24.1: 154. (2020)) as applied to claim 22 above, and further in view of Stebbing et al. (Stebbing, et al. The Lancet Infectious Diseases 20.4: 400-402 (2020)).
Claim 22 is obvious as described above. Krenn and Gattinoni do not disclose the compounds of claim 31.
However, Stebbing et al. discloses that: “To take this work further in a short timescale, a
necessity when dealing with a new human pathogen, we re-examined the affinity and selectivity of all the approved drugs in our knowledge graph to identify those with both antiviral and anti-inflammatory properties. Such drugs are predicted to be of particular importance in the treatment of severe cases of COVID-19, when the host inflammatory response becomes a major cause of lung damage and subsequent mortality.” (Stebbing et al., page 400, col. 1, para. 2). Stebbing further discloses example antiviral drugs (Stebbing et al., page 401, Table 1).
It would have been obvious to a person of ordinary skill in the art to combine the treatment method of Krenn and Gattinoni with the antiviral drugs disclosed by Stebbing et al. A person of ordinary skill in the art would be motivated to combine these treatment methods to gain the additive effects of such treatments on a given patient.
Therefore, claim 31 is obvious over Krenn et al. in view of Gattinoni et al. as applied to claim 22 above, further in view of Stebbing et al. and rejected.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) in view of Gattinoni et al., (Gattinoni, et al. Critical care 24.1: 154. (2020)) as applied to claim 22 above, and further in view of WHO (https://www.who.int/docs/default-source/blue-print/covid-19-therapeutic-trial-synopsis.pdf, accessed 10/18/2025 (Feb 18, 2020)).
Regarding claim 32, claim 22 is obvious as described above. Claim 32 further recites the case wherein the patient has a WHO severity score of 5-7.
Krenn and Gattinoni do not disclose a WHO score.
However, the WHO document discloses that a score of 5-7 corresponds to the case where a patient is hospitalized for severe disease.
It would have been obvious to a person of ordinary skill in the art to use the treatment method of Krenn and Gattinoni in a severe case of COVID-19 as described by the WHO document (WHO document, page 6). A person of ordinary skill in the art would be motivated to use this treatment because Krenn discloses that AP301 is more efficacious in severe cases of ARDS.
Therefore, claim 32 is obvious over Krenn et al. in view of Gattinoni et al. as applied to claim 22 above, further in view of WHO and rejected.
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) in view of Gattinoni et al., (Gattinoni, et al. Critical care 24.1: 154. (2020)) as applied to claim 22 above, further in view of Ogoina (Ogoina, Dimie. Journal of infection and public health 4.3: 108-124 (2011)).
Claim 22 is obvious as described above. Krenn and Gattinoni do not disclose the case wherein the patient has a body temperature more than 37.5°C.
However, Ogoina discloses that a body temperature more than 37.5°C is considered a fever state: “Based on guidelines for management of febrile illnesses provided by authorities such as World Health Organization (WHO) [11,12] and the Society of Critical Care Medicine and the Infectious Disease Society of America (IDSA) [13], among others [14,15], equivalent rectal temperature of ≥38 ◦C (100.4 ◦F) or axillary temperatures of ≥37.5 ◦C (99.5 ◦F) are indicative of fever in both adults and children.” (Ogoina, page 110, 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 use the method of Krenn and Gattinoni in the situation where a patient has a fever as shown by Ogoina. A person of ordinary skill in the art would be motivated to employ the method of Krenn and Gattinoni in response to the temperature described by Ogoina because as Ogoina discloses, “Fever often occurs in response to infection, inflammation and trauma.” (Ogoina, page 109, Introduction). T
Consequently, claim 35 is obvious over Krenn et al. in view of Gattinoni et al. as applied to claim 22 above, further in view of Ogoina et al. and rejected.
Claim 38 is rejected under 35 U.S.C. 103 as being unpatentable over Krenn et al. (Krenn, et al. Critical Care 21.1:194 (2017) in view of Gattinoni et al., (Gattinoni, et al. Critical care 24.1: 154. (2020)) as applied to claim 22 above, and further in view of Fischer et al. (WO2015140125A2, published 9/24/2015).
Regarding claim 38, 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).
Krenn does not explicitly disclose the sequences QRETPEGAEAKPWY, PKDTPEGAELKPWY, or CGPKDTPEGAELKPWTC.
However, Fischer et al., discloses all four of these peptides in claim 6. Furthermore, Fischer discloses why these peptide would have a similar activity to AP301:
“TIP peptides are peptides comprising the human tumour necrosis factor (TNF) lectin-like domain (TIP domain) . The TIP domain is covered for instance by van der Goot et al, 1999, PubMed unique identifier (PMID) 10571070. As used herein, TIP peptides consist of 7-17 amino acids including the hexamer TXiEX2X3E (SEQ ID NO: 6), wherein Xlr X2 and X3 can be any natural or non-natural amino acid, wherein the peptide does not exhibit TNF-specific inflammatory activity (Hribar et al, 1999, PMID 10540321; Elia et al, 2003, PMID 12842853) and may be cyclised. The biological activity of TIP peptides such as AP301 (cyclo- CGQRETPEGAEAKPWYC; CGQRETPEGAEAKPWYC is SEQ ID NO: 1) comprises activation of the amiloride-sensitive epithelial sodium channel (ENaC) , as reported by Tzotzos et al, 2013, PMID 23313096.” (Fischer et al, page 1, 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 use the method of Krenn and Gattinoni utilizing the peptides of Fischer because Fischer discloses the similar activities of the recited peptides.
A person of ordinary skill in the art would have had a reasonable expectation of success because one of the peptides is the same as the same sequence as disclosed by Krenn (Krenn, page 2 col. 1, para. 2). The TXEXXE motif is known to be critical for this effect, and this motif is shared by all four peptides (Fischer et al, page 1, para. 2).
Therefore, claim 38 is obvious over Krenn et al. in view of Gattinoni et al. as applied to claim 22 above, further in view of Fischer et al. and rejected.
Response to Arguments
Because of the similarity of the new rejections, arguments will be addressed here.
Regarding the hindsight reasoning argument, in Applicant Reply, page 12, section I, that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Also, 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).
Also, reference combinations have been changed in this office action.
Regarding the no reasonable expectation of success section, Applicant Reply, page 14, section II, the supplied reference, Romero et al., would not have been available to a person of ordinary skill in the art before the effective filing date. Consequently, such findings could not have informed a person of ordinary skill in the art of the potential differences in ARDS.
Even if this were to be considered, the mechanism of action of AP301 is dependent upon ENaCs, not oxidative stress or vasculopathy as disclosed by Romero. This does not constitute a teaching away. A person of ordinary skill in the art would reasonably expect AP301 to have the same mechanistic effect in COVID-19. Recall that obviousness does not require absolute certainty of effect as stated in MPEP 2144.08(II)(A)(4)(e): “However, obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). “
Regarding the unexpected results section, Applicant Reply, page 15, section III, Applicant again references Romero. Romero et al. would not have been available to a person of ordinary skill in the art before the effective filing date.
Even if this reference were considered, Krenn discloses that AP301 is expected to modulate ENaC: “AFC strongly depends on the function of amiloridesensitive epithelial sodium channels (ENaCs) on the apical surface and Na+/K+-ATPase on the basolateral surface of
alveolar epithelial cells [10, 11]. Recently, the cyclic synthetic peptide AP301 (TIP peptide, amino acid sequence: CGQRETPEGAEAKPWYC), which mimics the lectin-like domain of human tumor necrosis factor (TNF)-α (TIP domain), was synthesized, and it was demonstrated to enhance sodium transport by the ENaC [12–15].” (Krenn et al., page 2, col. 1., para. 2).
Applicants also reference Tzotzos et al., which would also not have been available to a person of ordinary skill in the art.
Even if considered, it is not clear as to why it is unexpected for a treatment for ARDS administered to a condition known to result in ARDS to increase survival rates. In contrast, a person of ordinary skill in the art would expect administration of AP301 to positively affect survival rates. The unexpected result would be if administration of AP301 reduced survival rates.
Conclusion
Claims 22-41 are rejected.
No claim is allowed.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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