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 .
Status of the Claims
Claims 22-45 are pending in the instant application and subject to examination herein.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/EP2021/073429, filed on 08/24/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/04/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Interpretation
Claim 43 is drawn to a method of treating a subject “in need thereof” comprising administering an effective amount of an NHE-1 inhibitor in a prophylactic manner to (1) prevent effects and complications of SARS-CoV-2 infection in a subject at risk for complications of SARS-CoV-2 infection and/or (2) to stabilize and/or reduce progression of other disease and pathological states in a patient infected with SARS-CoV-2. The instant disclosure does not specifically define the population of patients who are “at risk for complications of SARS-CoV-2 infection”; however, the disclosure does mention factors that identify risk complications from SARS-CoV-2 infection:
“Elevated D-Dimer in patients with COVID-19 at the time of hospital admission, is a predictor of the risk of development of [acute respiratory distress syndrome (ARDS)], [pulmonary embolism (PE)], and death” (page 7);
“Increased mean platelet volume has been identified as a risk factor in patients with metabolic syndrome, myocardial infarction, ischemic stroke” (page 7);
“patients with preexisting cardiac diseases are at greater risk for severe cardiovascular and respiratory complications.” (page 9);
“Guo et al. . . . reported that triage of patients with COVID-19 according to the presence of underlying cardiovascular disease or risks and the presence of elevated plasma cardiac biomarkers (N-terminal pro-brain natriuretic peptide and Troponin T levels) is needed to prioritize treatments and propose more aggressive treatment strategies in view of the increased risk for a fatal outcome and/or irreversible myocardial injury in these patients” (page 9);
In view of the references to “risk” found within the instant disclosure, the term “at risk for complications of SARS-CoV-2 infection” is understood to represent the following Markush group of conditions that consists of the following: elevated D-dimer, increased mean platelet volume, preexisting cardiac disease(s), and elevated plasma cardiac biomarkers (N-terminal pro-brain natriuretic peptide and Troponin T levels).
Claim Rejections - 35 USC § 112(b) – Withdrawn
The prior rejection of claims 31 and 43 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in response to Applicant’s amendment of claims 41 and 43.
Claim Rejections - 35 USC § 112(a) – New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
THIS IS A NEW MATTER REJECTION.
Claims 22-34 and 37-45 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. As currently amended, claims 22, 37, 39, 42-43 and 45 are drawn to a further limitation of “NHE-1 inhibitors”, namely “a NHE-1 inhibitor containing a sulfone substituent”. The Specification does not provide a basis for the further limitation of “NHE-1 inhibitor” to “a NHE-1 inhibitor containing a sulfone substituent” for use in any of the methods of treatment disclosed in the instant application. The Specification does disclose, on paragraph [00145], page 49 (second and third paragraphs), that methyl sulfone substituents at the C5 and C6 positions on the periphery of Rimeporide have electrostatic potentials that open possibilities for intermolecular electrostatic interactions at the binding site inside the ion channel lumen; however, this disclosure of the value of a methyl sulfone at the C5 or C6 position of Rimeporide does not support the broader limitation of “a NHE-1 inhibitor containing a sulfone substituent”, because the latter limitation allows for any sulfone substituent at any position on Rimeporide or any other NHE-1 inhibitor, which need not even be of the same scaffold class as Rimeporide (i.e., an acylguanidine) to meet the limitation.
Claims 23-34 and 44-45 depend directly or indirectly from claim 22 and include the same limitation of “a NHE-1 inhibitor containing a sulfone substituent” that is not supported by the instant disclosure. Claim 38 depends from claim 37 and includes the same limitation of “a NHE-1 inhibitor containing a sulfone substituent” that is not supported by the instant disclosure. Claims 40-42 depend directly or indirectly from claim 39 and include the same limitation of “a NHE-1 inhibitor containing a sulfone substituent” that is not supported by the instant disclosure.
Claim Rejections - 35 USC § 112(d) - Withdrawn
The prior rejection of claims 31 and 34 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is withdrawn in response to Applicant’s amendment of claims 31 and 34.
Claim Rejections - 35 USC § 102 – Withdrawn
The prior rejection of claims 22-25, 31 and 33-35 under 35 U.S.C. 102(a)(2) as being anticipated by Asirvatham (U.S. PGPub 2022/0047686 A1)1 is withdrawn in response to Applicant’s amendment of claims 22, 31 and 33-35.
The prior rejection of claims 22-24 and 31-34 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Gage (U.S. PGPub 2007/0099968 A1) is withdrawn in response to Applicant’s amendment of claims 22 and 31-34.
The prior rejection of claims 22-26, 30-31 and 34-35 under 35 U.S.C. 102(a)(1) as being anticipated by Cure (Cure, et al.; Clinical and Applied Thrombosis/Hemostasis, v26; 2020) is withdrawn in response to Applicant’s amendment of claims 22, 31 and 34-35.
Claim Rejections - 35 USC § 103 – Withdrawn
The prior rejection of claims 22-26 and 31-34 under 35 U.S.C. 103 as being unpatentable over Gage (U.S. PGPub 2007/0099968 A1) in view of Chernyshev (Chernyshev, A.; ChemRxiv; 2020; doi:10.26434/chemrxiv.12286421.v1) is withdrawn in response to Applicant’s amendment of claims 22, 26 and 31-34.
The prior rejection of claims 22-27 and 31-34 under 35 U.S.C. 103 as being unpatentable over Lambert (US PGPub 2002/0082274 A1) in view of Marshall (Marshall, J.C., The Lancet Infectious Diseases, v20, ppe195-e197; 2020) is withdrawn in response to Applicant’s amendment of claims 22, 26-27 and 31-34.
The prior rejection of claims 22-27 and 29-38 under 35 U.S.C. 103 as being unpatentable over Lambert in view of Marshall and further in view of Pedersen (Pedersen, S.F. and Counillon, L.; Physiological Reviews, v99, pp2015-2113; 2019) is withdrawn in response to Applicant’s amendment of claims 22, 26-27, 29 and 31-38.
The prior rejection of claims 22-26, 31-34 and 37-38 under 35 U.S.C. 103 as being unpatentable over Lambert in view of Kashani (Kashani, K.B.; Mayo Clinic Proceedings, v95, pp1094-1096; 2020) and Pedersen is withdrawn in response to Applicant’s amendment of claims 22, 31-34 and 37-38.
The prior rejection of claims 22-26, 30-32 and 34-35 under 35 U.S.C. 103 as being unpatentable over Cure (Cure, et al.; Clinical and Applied Thrombosis/Hemostasis, v26; 2020) in view of Mayo Clinic (Mayo Clinic, https://www.mayoclinic.org/drugs-supplements/amiloride-oral-route/description/drg-20071527, retrieved on 24Sep2025 from Wayback Internet Archive, dated 07Oct2017) and Wikipedia (Wikipedia, https://en.wikipedia.org/wiki/Amiloride, retrieved on 24Sep2025 from Wayback Internet Archive, dated 13Aug2020) is withdrawn in response to Applicant’s amendment of claims 22, 26, 31-32 and 34-35.
The prior rejection of claims 22-26, 30-31 and 33-35 under 35 U.S.C. 103 as being unpatentable over Cure in view of Boston Children’s Hospital (Boston Children’s Hospital, Clinical Trial NCT00547053, “Amiloride Solution and Tobramycin Solution for Inhalation for the Eradication of Burkholderia Dolosa in Patients With Cystic Fibrosis”, ClinicalTrials.gov, Record History 13May2011, Accessed 24Sep2025) is withdrawn in response to Applicant’s amendment of claims 22, 26, 30-31 and 33-35.
The prior rejection of claims 22-27, 30-31 and 34-35 under 35 U.S.C. 103 as being unpatentable over Cure in view of Marshall is withdrawn in response to Applicant’s amendment of claims 22, 26-27, 31 and 34-35.
The prior rejection of claims 22-26, and 29-31 and 34-38 under 35 U.S.C. 103 as being unpatentable over Cure in view of Pedersen is withdrawn in response to Applicant’s amendment of claims 22, 26, 31 and 34-38.
The prior rejection of claims 39-40 under 35 U.S.C. 103 as being unpatentable over Cure in view of Kowarz (Kowarz, et al.; “Vaccine-Induced Covid-19 Mimicry” Syndrome:Splice reactions within the SARS-CoV-2 Spike open reading frame result in Spike protein variants that may cause thromboembolic events in patients immunized with vector-based vaccines, 26 May 2021, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-558954/v1]) is withdrawn in view of Applicant’s amendment of claims 22, 26, 31, 34-35 and 39-42 and in view of Applicant’s argument in regard to the validity of Kowarz as timely prior art. While no claims presented in the priority filing application (EP20192749.8) regard the administration of an NHE-1 inhibitor to a patient who has received a SARS-CoV-2 vaccine, the disclosure of the priority application does provide support for the use of the invention with patients who have received a SARS-CoV-2 vaccination, including wherein the subject who has received the vaccination related exacerbation of the infection wherein the exacerbation is antibody-enhanced or antibody-mediated (paragraph [0072]).
The prior rejection of claims 22-26 and 28-34 under 35 U.S.C. 103 as being unpatentable over Dhakal (Dhakal, et al.; Heart, Lung and Circulation, v29, pp973–987; 2020) and Cure is withdrawn in view of Applicant’s amendment of claims 22, 28-29 and 31-34. Applicant has traversed this rejection on the grounds that it could only be made via hindsight reasoning, as a person of ordinary skill in the art would not have been motivated to combine Dhakal and Cure. Applicant’s traverse has been considered, but is not found persuasive, because no content from the claims or instant disclosure was used as a basis to combine the teachings of Dhakal and Cure into the rejection. Both of these references discuss in detail the relation between SARS-CoV-2 and intravascular coagulation. Cure discusses the importance of NHE-1 and its inhibition in this context whereas Dhakal does not, and Dhakal discusses the downstream effects of SARS-CoV-2-altered intravascular coagulation at the organ level, which Cure does not. The nexus of their teachings is in the relation of the virus to intravascular coagulation, and the differences in the teachings are the motivation to combine them and understand the relation between NHE-1 inhibition and mitigation of the organ-level effect(s) of SARS-CoV-2 mediated intravascular coagulation. Thus, no hindsight was utilized in this rejection. Nevertheless, Applicant is herein directed to MPEP § 2145(X): "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971).
Claim Rejections - 35 USC § 103 – Necessitated by Amendment
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or -nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 22-25, 31, 33, 35-36 and 43-44 are unpatentable over Asirvatham in view of Pedersen.
Claims 22-25, 29, 31, 33, 35-36 and 43-44 are rejected under 35 U.S.C. 103 as being unpatentable over Asirvatham (U.S. PGPub 2022/0047686 A1)2 in view of Pedersen (Pedersen, S.F. and Counillon, L.; Physiological Reviews, v99, pp2015-2113; 2019).
Claim 22 is drawn to a method of treating a coronavirus infected human subject in need thereof, comprising administering an effective amount of an NHE-1 inhibitor containing a sulfone substituent, or a pharmaceutically acceptable salt thereof, to the subject. Asirvatham discloses a method of treating an infectious disease, including administering a therapeutic agent to the subject and electroporating a tissue of the individual to enhance the absorption or uptake of the therapeutic agent, wherein the therapeutic agent is inhalable (paragraph [0007]). Asirvatham further discloses that the method is applicable to specific treatment of “coronavirus disease 2019 (COVID-19)” and that in some embodiments the therapeutic agent is an ion channel blocker (paragraph [0008]). Asirvatham additionally discloses that in certain aspects the ion channel blocker is a non-voltage gated ion channel blocker, and in some embodiments, the non-voltage gated ion channel blocker is at least one of Amiloride or tetrodotoxin (paragraph [0031]). Asirvatham discloses that such ion blockers can affect the receptivity of the ACE2 receptor, and therefore can block or reduce the binding affinity or the number of binding events of a pathogen (e.g., SARS-CoV-2) to an angiotensin-converting enzyme 2 (ACE2) receptor (paragraph [0030]). Asirvatham further discloses that evidence has suggested that both SARS-CoV and SARS-CoV-2 employ ACE2 as the entry receptor and that the receptor-binding doman of the viral S-protein directly binds to ACE2, triggering endocytosis of the virus particles (paragraph [0028]) and that the treatment with ion blockers can reduce the viral load of a pathogen, including of SARS-CoV-2 (paragraph [0033]).
Asirvatham does not provide an exhaustive list of additional non-voltage gated ion channel blockers for use in the invention disclosed therein, and does not specifically disclose an NHE-1 inhibitor containing a sulfone substituent for use in the invention disclosed therein. However, a person of ordinary skill in the art would have a reasonable expectation of success in using the invention of Asirvatham while substituting Rimeporide, a NHE-1 inhibitor containing two sulfone substituents, for Amiloride, because it was known in the art that Rimeporide is an inhibitor of NHE-1, a non-voltage gated ion channel, in the same family of NHE-1 inhibitors as Amiloride, namely acylguanidines, per the teaching of Pedersen.
Pedersen teaches a review on the SLC9A-C Mammalian Na+/H+ Exchanger family, including gene organization over protein structure and regulation to physiological and pathophysiological roles (page 2015, Abstract). Pedersen teaches a group of structurally-related NHE-1 inhibitors, known as “Acylguanidine-type NHE inhibitors”, which includes Rimeporide (page 2031, Box 6). While Pedersen does not display the structure of Rimeporide, a person of ordinary skill in the art would at once recognize that Rimeporide is an acylguanidine that contains not only one but two sulfone groups, as this aspect of Rimeporide is inherent to the compound and was well known in the art at the effective time of filing – see, for example, PubChem-Rimeporide3. Additionally, while Pedersen does not explicitly use the term “non-voltage gated ion channel” as a descriptor for NHE-1, a person of ordinary skill in the art would at once recognize NHE-1 as a non-voltage gated ion channel because this is an inherent aspect of NHE-1 and was known in the art – see, for example, Demaurex (Demaurex, et al., Journal of General Physiology, v106, pp85-111; 1995), who teaches a study on NHE-1, NHE-2 and NHE-3 ion channels and confirms via whole-cell patch clamp technique and microfluidic measurements that the reputation of these antiporters as being electroneutral and voltage independent is correct (Abstract, page 85).
Applicant’s invention is unpatentable over the disclosure of Asirvatham in view of the teaching of Pedersen, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of modifying and using the invention of Asirvatham to treat a human subject having a coronavirus infection, including of SARS-CoV-2 coronavirus, comprising administering Rimeporide as a substitute for Amiloride disclosed by Asirvatham, as both are inhibitors (i.e., blockers) of NHE-1, a non-voltage gated ion channel, because it was known in the art that Rimeporide is an NHE-1 inhibitor in the same family of acylguanidine NHE-1 inhibitors as Amiloride, per the teaching of Pedersen.
Thus, the invention was prima facie obvious at the time of filing.
Claim 23 further limits claim 22 to wherein the coronavirus causes a SARS or MERS infection, and is met by the rejection above.
Claim 24 further limits claim 23 to wherein the coronavirus causes a SARS-CoV-1 or SARS-CoV-2 or MERS-CoV infection and is met by the rejection above.
Claim 25 further limits claim 24 to wherein the coronavirus causes a SARS-CoV-2 infection and is met by the rejection above.
Claim 29 further limits claim 22 to wherein the subject has COVID-19 and a diagnosed or undiagnosed cardiac disease.
Claim 43 is drawn to a method of treating a human subject in need thereof comprising administering an effective amount of a NHE-1 inhibitor containing a sulfone substituent or a pharmaceutically acceptable salt thereof, to the subject wherein the treatment is in a prophylactic manner to prevent effects and complications of SARS-CoV-2 infection in a subject at risk for complications of SARS-CoV-2 infection, and/or to stabilize and/or reduce progression of other existing disease and pathological states in a patient infected with SARS-CoV-2. As discussed in the “Claim Interpretation” section above, the term “at risk for complications of SARS-CoV-2 infection” is interpreted via the instant disclosure to include patients with pre-existing cardiac disease(s).
Asirvatham teaches that the treatment disclosed therein is applicable to the treatment of renin-angiotensin-aldosterone system, including disorders such as hypertension and cardiac rhythm disturbances (paragraph [0049]). Pedersen discusses the integrated organ physiology and pathophysiology of mammalian NHEs (section VIII), including the role of NHEs, including NHE-1, in hypertension (section VIII.5, page 2065). Pedersen teaches that mice placed in chronic hypoxia develop pulmonary hypertension associated with an increase in intracellular pH (pHi) of pulmonary artery smooth muscle cells and elevated NHE-1 expression and activity (page 2065). Pedersen additionally teaches that pulmonary hypertension solicits the heart’s pumping activity, increases its energetic burden, and induces ventricular hypertrophy, and accordingly, hypertension can be a trigger for cardiac pathology (page 2065).
Claim 31 further limits the method of claim 22 to wherein the human subject is an adult patient. Claim 44 further limits the method of claim 22 to wherein the human subject is a pediatric patient. Asirvatham does not disclose any limitation of patient population by age; accordingly, a person of ordinary skill in the art would have a reasonable expectation of success in treating an adult or pediatric patient.
Claim 33 further limits claim 22 to wherein the NHE-1 inhibitor is administered via parenteral or topical or inhalational routes, and is met by the disclosure of Asirvatham.
Claim 35 further limits claim 22 to wherein the NHE-1 inhibitor containing a sulfone substituent is selected from a Markush group that includes Rimeporide and is met by the rejection above. Claim 36 further limits claim 35 to wherein the NHE-1 inhibitor containing a sulfone substituent is Rimeporide, and is met by the rejection above.
Applicant’s invention is unpatentable over the disclosure of Asirvatham in view of the teaching of Pedersen, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of modifying and using the invention of Asirvatham to treat an adult or pediatric human subject having a SARS-CoV-2 infection, as well as having hypertension or cardiac rhythm disturbances, comprising administering Rimeporide as a substitute for Amiloride, including by topical or parenteral or inhalation administration, as both are inhibitors (i.e., blockers) of NHE-1, a non-voltage gated ion channel, because it was known in the art that Rimeporide is an NHE-1 inhibitor in the same family of acylguanidine NHE-1 inhibitors as Amiloride, per the teaching of Pedersen.
Thus, the invention was prima facie obvious at the time of filing.
Claims 22-25, 27, 29, 31-38, 43 and 45 are unpatentable over Lambert in view of Marshall and Pedersen.
Claims 22-25, 27, 29, 31-38, 43 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Lambert (US PGPub 2002/0082274 A1) in view of Marshall (Marshall, J.C., The Lancet Infectious Diseases, v20, ppe195-e197; 2020) and Pedersen.
Applicant has traversed the prior rejection with the following arguments:
Marshall’s criteria for oxygen administration to SARS-CoV-2 infected patients should not be interpreted as an indication that such patients are experiencing hypoxia, since oxygen may be administered to patients for a variety of conditions including pneumonia, bronchitis, asthma, pulmonary embolism, severe anemia, and others (pages 15-16, bridging paragraph);
“Marshall does not teach that administration of oxygen is a treatment for Covid-19, just that it is typically provided in an intensive care unit, and, thus, can be used to rate patient data from a broad range of studies” (page 16);
Pedersen teaches that the field of art is unpredictable, as evidenced by a lack of positive results in human clinical trials for NHE-1 inhibition therapies that followed positive results in corresponding in vitro and animal model studies, therefore a person of ordinary skill in the art would not trust in the applicability of NHE-1 inhibition in a method of treating a coronavirus infected subject having a diagnosed or undiagnosed cardiac disease “in view of the collective failures of NHE-1 inhibitors in various human trials” (pages 16-17, bridging paragraph).
Applicant’s traverse has been considered, but is not found persuasive, for the following reasons:
Marshall’s criteria for severity of viral progression is specifically curated for subjects infected with SARS-CoV-2, as indicated therein: see, for example Marshall’s Panel 2 and accompanying Figure (“WHO clinical progression scale”) wherein the score of 0 on the scale of 0-10 represents uninfected patients (page 4).
The alternate conditions listed by Applicant (pneumonia, asthma, anemia, etc.) that may result in oxygen provision to a patient suffering from such condition(s) are not directly treated by oxygen provision, any more than oxygen provision is expected to impact the viral load of a patient infected with SARS-CoV-2; rather, oxygen provision treats the deficiency of oxygen – hypoxia – that can result from any of the conditions provided in Applicant’s traverse; therefore, a patient burdened with infection by SARS-CoV-2 who may also experience, for example, pulmonary embolism, and is judged by a healthcare provider to be oxygen deficient and therefore in need of oxygen provision would be rated accordingly by the scale taught by Marshall and merit the treatment disclosed by Lambert, modified by the teaching of Pedersen as discussed in the prior rejection, independently of whether the evident hypoxia is due directly to the SARS-CoV-2 infection or the pulmonary embolism, or both underlying conditions simultaneously; in this manner, oxygen provision treats the subject (for hypoxia) rather than the viral infection itself, just as the claimed methods of the instant invention are all drawn to the treatment of subject(s), and are not drawn to “treatment of Covid-19”;
Pedersen acknowledges the challenges of the clinical trials cited by Applicant as follows: “Besides differences in drug bioavailability and obvious physiological dissimilarities between humans and animal models requiring additional fine-tuning of the dosing regimen, this [lack of positive outcomes in clinical trials] may in part reflect that patients enrolled in clinical trials for cardiac pathology often have long standing comorbidities (high BMI, dyslipidemia, hypertension, atherosclerosis, etc.) lacking in standard laboratory animals in which the cardiac condition is provoked by a controlled surgical procedure.” Thus, Pedersen teaches that disappointing results in clinical trial(s) are not inherently indicative of a lack of biological effect of the intended treatment, but rather are an indication of the physiological complexity of the patient population available for human clinical trials. A person of ordinary skill in the art, reviewing Pedersen’s review of clinical trial results and evaluation thereof, would at once notice that the researchers of each of those clinical trials would have been aware of the trials that had come before, as persons of skill in the art would be conversant in the field of art prior to initiating a human clinical trial, and yet each of those researchers/teams had a reasonable expectation of success sufficient to embark on the next clinical trial. Thus, knowledge of the biological action of NHE-1 inhibitors in regard to hypoxia and knowledge that patients having moderate to severe SARS-CoV-2 infections experience hypoxia would provide a reasonable expectation of success in treating such patients with NHE-1 inhibitor(s), including inhibitors disclosed by Pederson, for example Rimeporide.
New Rejection:
The limitations of claims 22-25, 29, 31, 33, 35-36 and 43 and the teaching of Pedersen are discussed in the rejection above and hereby incorporated into the instant rejection.
Lambert discloses compounds as inhibitors of NHE-1 (paragraph [0001]), and further discloses a method of reducing tissue damage resulting from ischemia or hypoxia comprising administering a compound disclosed therein4 or a pharmaceutically acceptable composition thereof (paragraph [0063]). Lambert further discloses that compounds disclosed therein can be administered by oral or parenteral routes, in single or multiple doses or via constant infusion (paragraph [0086]).
Lambert does not disclose that the method of reducing tissue damage from hypoxia is applicable to a patient infected with a coronavirus, and does not disclose an NHE-1 inhibitor containing a sulfone substituent. However, a person of ordinary skill in the art would have a reasonable expectation of success in modifying and applying the method of Lambert to the treatment of a subject infected with SARS-CoV-2 having moderate to severe COVID-19 comprising administering Rimeporide, because it was known in the art that patients having moderate to severe COVID-19 suffer from hypoxia, per the teaching of Marshall, and it was known in the art that Rimeporide, a compound that inherently contains a sulfone substituent, is an NHE-1 inhibitor in the same class as Amiloride, and per the teaching of Pedersen, and that NHE-1 activity mediates downstream effects of hypoxia, including pulmonary hypertension, per the teaching of Pedersen.
Marshall presents an editorial regarding critical data required for outcome measures of clinical research, and includes a need to track patient progression through the health-care system by use of the World Health Organization (WHO) Clinical Progression Scale, which reflects patient trajectory and resource use over the course of clinical illness (page 1, Abstract). Marshall provides the WHO Clinical Progression Scale for COVID-19, with scores from 0-10, wherein a score of 5 corresponds to moderate disease wherein the patient is hospitalized and receiving oxygen by mask or nasal prongs, and scores 5-9 correspond to severe disease states wherein the patient is hospitalized and receiving oxygen by increasingly aggressive means, including mechanical ventilation. Thus, Marshall teaches that patients having moderate to severe COVID-19 disease are suffering from inadequate oxygen, known as hypoxia5.
Pedersen teaches a review on the SLC9A-C Mammalian Na+/H+ Exchanger family, including gene organization over protein structure and regulation to physiological and pathophysiological roles (page 2015, Abstract). Pedersen discusses the integrated organ physiology and pathophysiology of mammalian NHEs (section VIII), including the role of NHEs, including NHE-1, in hypertension (section VIII.5, page 2065). Pedersen teaches that mice placed in chronic hypoxia develop pulmonary hypertension associated with an increase in intracellular pH (pHi) of pulmonary artery smooth muscle cells and elevated NHE-1 expression and activity (page 2065). Pedersen additionally teaches that pulmonary hypertension solicits the heart’s pumping activity, increases its energetic burden, and induces ventricular hypertrophy, and accordingly, hypertension can be a trigger for cardiac pathology (page 2065). Pedersen further teaches that NHE-1 knockout abolished high pressure and right ventricular hypertrophy induced by hypoxia (page 2065). In the evaluation of pulmonary hypertension, Pedersen observes that NHE-1 activation is downstream of initiating events, yet aggravates the condition (page 2065). Pedersen teaches a group of structurally-related NHE-1 inhibitors, known as “Acylguanidine-type NHE inhibitors”, which includes Rimeporide (page 2031, Box 6). While Pedersen does not display the structure of Rimeporide, a person of ordinary skill in the art would at once recognize that Rimeporide is an acylguanidine that contains not only one but two sulfone groups, as this aspect of Rimeporide is inherent to the compound and was well known in the art at the effective time of filing – see, for example, PubChem-Rimeporide6.
Applicant’s invention is unpatentable over the disclosure of Lambert in view of the teachings of Marshall and Pedersen, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in modifying and applying the method of Lambert of treating a patient infected with SARS-CoV-2 having moderate to severe COVID-19 comprising administering Rimeporide for hypoxia, because it was known in the art that patients having moderate to severe COVID-19 suffer from hypoxia, per the teaching of Marshall, and it was known in the art that Rimeporide is an NHE-1 inhibitor, per the teaching of Pedersen, and the property of having a sulfone substituent is inherent to Rimeporide.
Thus, the invention was prima facie obvious at the time of filing.
Claim 23 further limits claim 22 to wherein the coronavirus causes a SARS or MERS infection, and is met by the rejection above.
Claim 24 further limits claim 23 to wherein the coronavirus causes a SARS-CoV-1 or SARS-CoV-2 or MERS-CoV infection and is met by the rejection above.
Claim 25 further limits claim 24 to wherein the coronavirus causes a SARS-CoV-2 infection and is met by the rejection above.
Claim 27 further limits claim 25 to wherein the subject has a moderate to severe SARS-CoV-2 infection which requires medical intervention, and is met by the rejection above.
Claim 29 further limits claim 22 to wherein the human subject has COVID-19 and a diagnosed or undiagnosed cardiac disease and is met by the rejection above. Additionally, Lambert discloses wherein the NHE-1 inhibitor is disclosed just prior (e.g., within 24 hours) of a cardiac surgery, indicating the treatment of a patient with cardiac disease (paragraph [0090]).
Claim 31 further limits the method of claim 22 to wherein the human subject is an adult patient. Lambert does not disclose any limitation of patient population by age; accordingly, a person of ordinary skill in the art would have a reasonable expectation of success in treating an adult patient.
Claim 32 further limits claim 22 to wherein the NHE-1 inhibitor containing a sulfone substituent is administered via oral route. Claim 33 further limits claim 22 to wherein the NHE-1 inhibitor containing a sulfone substituent is administered via parenteral or topical or inhalation routes. Lambert discloses administration by oral and parenteral routes (paragraph [0086]).
Claim 34 further limits claim 22 to wherein the NHE-1 inhibitor containing a sulfone substituent is administered acutely. Claim 45 further limits claim 22 to wherein the NHE-1 inhibitor containing a sulfone substituent is administered chronically. Lambert discloses administering NHE-1 inhibitors just prior to surgery (e.g., within 24 hours of surgery for example cardiac surgery), or during or subsequent to surgery, each of which constitutes an acute administration, and Lambert further discloses chronic daily administration (paragraph [0090]).
Claim 35 further limits claim 22 to wherein the NHE-1 inhibitor containing a sulfone substituent is selected from a Markush group that includes Rimeporide and is met by the rejection above. Claim 36 further limits claim 35 to wherein the NHE-1 inhibitor containing a sulfone substituent is Rimeporide, and is met by the rejection above.
Claim 43 is drawn to a method of treating a human subject in need thereof comprising administering an effective amount of a NHE-1 inhibitor containing a sulfone substituent or a pharmaceutically acceptable salt thereof, to the subject wherein the treatment is in a prophylactic manner to prevent effects and complications of SARS-CoV-2 infection in a subject at risk for complications of SARS-CoV-2 infection, and/or to stabilize and/or reduce progression of other existing disease and pathological states in a patient infected with SARS-CoV-2. As discussed in the “Claim Interpretation” section above, the term “at risk for complications of SARS-CoV-2 infection” is interpreted via the instant disclosure to include patients with pre-existing cardiac disease(s), and is therefore met by the rejection above.
Applicant’s invention is unpatentable over the disclosure of Lambert in view of the teachings of Marshall and Pedersen, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in applying the method of Lambert of treating a patient with a NHE-1 inhibitor for hypoxia to the treatment of a subject infected with SARS-CoV-2 having moderate to severe COVID-19, by administering Rimeporide, an NHE-1 inhibitor containing a sulfone substituent, including by oral or parenteral administration, including as acute or chronic treatment, including for patients having pre-existing cardiac disease(s), because it was known in the art that patients having moderate to severe COVID-19 suffer from hypoxia, per the teaching of Marshall, and it was known in the art that Rimeporide is an NHE-1 inhibitor, per the teaching of Pedersen, and the property of having a sulfone substituent is inherent to Rimeporide.
Thus, the invention was prima facie obvious at the time of filing.
Claim 37 is drawn to a method of treating a subject suffering from long COVID, presenting with long COVID, having clinical manifestations, organ effects of long COVID or displaying pathological changes or long-term complications associated with long COVID, comprising administering an effective amount of an NHE-1 inhibitor, or a pharmaceutically acceptable salt thereof, to the subject.
Claim 38 further limits claim 37 to wherein the condition of long COVID in the subject in need of treatment is selected from a Markush group that includes new-onset pulmonary arterial hypertension as a consequence of SARS-CoV-2 infection.
Lambert does not specifically disclose the suitability of NHE-1 inhibitors disclosed therein for treatment of pulmonary arterial hypertension; however, a person of ordinary skill in the art would have a reasonable expectation of success in applying the method of Lambert to treating pulmonary arterial hypertension with an NHE-1 inhibitor, because it was known in the art, per the teaching of Marshall discussed above, that patients having moderate to severe COVID-19 suffer from hypoxia, and it was known in the art that hypoxia can contribute to elevated expression of NHE-1 and to pulmonary hypertension, a condition that can be ameliorated with the administration of an NHE-1 inhibitor, per the teaching of Pedersen.
As discussed above, Pedersen teaches that hypoxia leads to pulmonary hypertension, which elevates NHE-1 expression and activity and leads to ventricular hypertrophy, and that suppression of NHE-1 can ameliorate the effects of hypoxia even when NHE-1 activation is downstream of the initiating event(s).
Applicant’s invention is unpatentable over the disclosure of Lambert in view of the teaching of Marshall and further in view of the teaching of Pedersen, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in treating a SARS-CoV-2 infected subject having a pulmonary arterial hypertension using the method of Lambert, because Lambert teaches that NHE-1 inhibitors are useful for reducing tissue damage resulting from hypoxia, and because Marshall teaches that patients with moderate to severe COVID-19 suffer from hypoxia and Pedersen teaches the availability of various alternate NHE-1 inhibitors including Rimeporide, which inherently contains a sulfone substituent, and Pedersen further teaches that hypoxia leads to pulmonary hypertension, which elevates NHE-1 expression and activity and leads to ventricular hypertrophy, and that suppression of NHE-1 can ameliorate the effects of hypoxia even when NHE-1 activation is downstream of the initiating event(s).
Thus, the invention was prima facie obvious at the time of filing.
Claims 22-25, 29, 31-38, 43 and 45 are unpatentable over Lambert in view of Kashani and Pedersen.
Claims 22-25, 29, 31-38, 43 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Lambert in view of Kashani (Kashani, K.B.; Mayo Clinic Proceedings, v95, pp1094-1096; 2020) and Pedersen.
Applicant has traversed the prior rejection that included the teaching of Kashani, on the following grounds:
Kashani presents unresolved questions relating to hypoxia and dyspnea as markers of lung involvement, and reports a high variability of arterial oxygen saturation as a marker of lung capacity for gas exchange, and different acute lung distress syndrome phenotypes wherein inspired oxygen does or does not lead to an increase in partial pressure of oxygen in arterial blood and capillary saturation;
Kashani’s teachings add to the evidence of unpredictability of Covid-19 disease parameters and potential treatments, thus a person of ordinary skill in the art would not combine Kashani with Lambert and Pedersen, and even if they did, they would not have had a reasonable expectation of success in arriving at a method of treating a coronavirus infected subject.
Applicant’s arguments have been considered but are not found persuasive, for the following reasons:
Kashani’s “unresolved questions that should be addressed in future investigations” are specifically listed and do not, as alleged by Applicant, add to the unpredictability of parameters and potential treatments (page 1095):
Accuracy of different measures of oxygen saturation in arterial blood, as different measures may vary by up to 4% in value;
Accuracy of Fraction of Inspired Oxygen (FIO2) measurements are important to help classify patients by known ARDS phenotype (L vs H);
Objective assessment for "dyspnea" is needed to disambiguate from tachypnea, hyperpnea and hyperventilation;
Regarding different ARDS phenotypes, Kashani’s teaching of the distinction between the L phenotype, wherein ventilation to perfusion ratio mismatch drives hypoxia (page 1095), and the H phenotype, wherein hypoxia can be imposed by shunt physiology (hypoventilated areas of the lung are hyperemic – page 1094)) shows that no matter which ARDS phenotype is presented, hypoxia is present. Thus, Kashani does not add to evidence of unpredictability, but rather shows consistently that ARDS, a condition experienced in some patients infected with SARS-CoV-2, includes the condition of hypoxia.
A person of ordinary skill in the art would have a reasonable expectation of success in combining a method of treating hypoxia comprising administering a NHE-1 inhibitor (Lambert) to a patient population suffering from hypoxia (COVID-19 patients with ARDS – Kashani) in the context of known NHE-1 inhibitors and their known biological effects and alternate/additional use cases (Pedersen).
New Rejection:
The limitations of claims 22-25, 29, 31-38, 43 and 45 and the disclosure of Lambert and the teaching of Pedersen are discussed in the rejection above and hereby incorporated into the instant rejection.
As discussed above, Lambert discloses compounds as inhibitors of NHE-1 (paragraph [0001]), and further discloses a method of reducing tissue damage resulting from ischemia or hypoxia comprising administering a compound disclosed therein7 or a pharmaceutically acceptable composition thereof (paragraph [0063]). Lambert further discloses that compounds disclosed therein can be administered by oral or parenteral routes, in single or multiple doses or via constant infusion (paragraph [0086]).
Lambert does not disclose that the method of reducing tissue damage from hypoxia is applicable to patient infected with a coronavirus, particularly SARS-CoV-2. However, a person of ordinary skill in the art would have a reasonable expectation of success in modifying and applying the method of Lambert for the treatment of hypoxia to the treatment of a subject infected with SARS-CoV-2 and suffering from acute respiratory distress syndrome (ARDS) comprising administering Rimeporide, because it was known in the art that COVID patients having ARDS suffer from hypoxia, per the teaching of Kashani, and it was known in the art that hypoxia can contribute to elevated expression of NHE-1 and to pulmonary hypertension, a condition that can be ameliorated with the administration of an NHE-1 inhibitor, per the teaching of Pedersen, and it was known in the art that Rimeporide, which inherently contains a sulfone substituent, is an NHE-1 inhibitor, per the teaching of Pedersen, and that NHE-1 activity mediates downstream effects of hypoxia, including pulmonary hypertension, per the teaching of Pedersen.
Kashani teaches an editorial on the characteristics of SARS-CoV-2 associated acute respiratory distress syndrome (ARDS) and studies of patient mortality in relation to treatments, with particular care to the importance of distinguishing between dyspnea (shortness of breath) and hypoxia (inadequate absorption of oxygen by the lungs) (page 1095). Importantly, Kashani teaches that some patients with SARS-CoV-2 associated ARDS do suffer from hypoxia, both when the ARDS phenotype is H-type (page 1094) and when the phenotype is L-type (1095).
Pedersen teaches a review on the SLC9A-C Mammalian Na+/H+ Exchanger family, including gene organization over protein structure and regulation to physiological and pathophysiological roles (page 2015, Abstract). Pedersen discusses the integrated organ physiology and pathophysiology of mammalian NHEs (section VIII), including the role of NHEs, including NHE-1, in hypertension (section VIII.5, page 2065). Pedersen teaches that mice placed in chronic hypoxia develop pulmonary hypertension associated with an increase in intracellular pH (pHi) of pulmonary artery smooth muscle cells and elevated NHE-1 expression and activity (page 2065). Pedersen additionally teaches that pulmonary hypertension solicits the heart’s pumping activity, increases its energetic burden, and induces ventricular hypertrophy, and accordingly, hypertension can be a trigger for cardiac pathology (page 2065). Pedersen further teaches that NHE-1 knockout abolished high pressure and right ventricular hypertrophy induced by hypoxia (page 2065). In the evaluation of pulmonary hypertension, Pedersen observes that NHE-1 activation is downstream of initiating events, yet aggravates the condition (page 2065). Pedersen teaches a group of structurally-related NHE-1 inhibitors, known as “Acylguanidine-type NHE inhibitors”, which includes Rimeporide (page 2031, Box 6). While Pedersen does not display the structure of Rimeporide, a person of ordinary skill in the art would at once recognize that Rimeporide is an acylguanidine that contains not only one but two sulfone groups, as this aspect of Rimeporide is inherent to the compound and was well known in the art at the effective time of filing – see, for example, PubChem-Rimeporide8.
Applicant’s invention is unpatentable over the disclosure of Lambert in view of the teachings of Kashani’s and Pedersen, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in modifying and applying the method of Lambert of treating a patient with for hypoxia as a treatment of a subject infected with SARS-CoV-2 having ARDS (acute respiratory distress syndrome) comprising administering Rimeporide, because it was known in the art that COVID-19 patients having ARDS suffer from hypoxia, per the teaching of Marshall, and it was known in the art that Rimeporide is an NHE-1 inhibitor, per the teaching of Pedersen, and the property of having a sulfone substituent is inherent to Rimeporide.
Thus, the invention was prima facie obvious at the time of filing.
Claim 37 is drawn to a method of treating a subject suffering from long COVID, presenting with long COVID, having clinical manifestations, organ effects of long COVID or displaying pathological changes or long-term complications associated with long COVID, comprising administering an effective amount of an NHE-1 inhibitor, or a pharmaceutically acceptable salt thereof, to the subject.
Claim 38 further limits claim 37 to wherein the condition of long COVID in the subject in need of treatment is selected from a Markush group that includes new-onset pulmonary arterial hypertension as a consequence of SARS-CoV-2 infection.
Lambert does not specifically disclose the suitability of NHE-1 inhibitors disclosed therein for treatment of pulmonary arterial hypertension; however, a person of ordinary skill in the art would have a reasonable expectation of success in applying the method of Lambert to treating pulmonary arterial hypertension with an NHE-1 inhibitor, because it was known in the art, per the teaching of Kashani discussed above, that COVID-19 patients having ARDS suffer from hypoxia, and it was known in the art that hypoxia can contribute to elevated expression of NHE-1 and to pulmonary hypertension, a condition that can be ameliorated with the administration of an NHE-1 inhibitor, per the teaching of Pedersen.
As discussed above, Pedersen teaches that hypoxia leads to pulmonary hypertension, which elevates NHE-1 expression and activity and leads to ventricular hypertrophy, and that suppression of NHE-1 can ameliorate the effects of hypoxia even when NHE-1 activation is downstream of the initiating event(s).
Applicant’s invention is unpatentable over the disclosure of Lambert in view of the teaching of Kashani and further in view of the teaching of Pedersen, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in treating a SARS-CoV-2 infected subject having a pulmonary arterial hypertension using the method of Lambert, because Lambert teaches that NHE-1 inhibitors are useful for reducing tissue damage resulting from hypoxia, and because Kashani teaches that COVID-19 patients with ARDS suffer from hypoxia and Pedersen teaches the availability of various alternate NHE-1 inhibitors including Rimeporide, which inherently contains a sulfone substituent, and Pedersen further teaches that hypoxia leads to pulmonary hypertension, which elevates NHE-1 expression and activity and leads to ventricular hypertrophy, and that suppression of NHE-1 can ameliorate the effects of hypoxia even when NHE-1 activation is downstream of the initiating event(s).
Thus, the invention was prima facie obvious at the time of filing.
Claims 22-26, 29-38, 43 and 45 are unpatentable over Lang in view of Cure and Pedersen.
Claims 22-26, 29-38, 43 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Lang (CA2476446A1) in view of Cure (Cure, et al.; Clinical and Applied Thrombosis/Hemostasis, v26; 2020) and Pedersen.
The limitations of claims 22-25, 29, 31-38, 43 and 45 and the teaching of Pedersen are discussed in the rejections above and hereby incorporated into the instant rejection.
Claim 22 is drawn to a method of treating a coronavirus infected human subject in need thereof, comprising administering an effective amount of an NHE-1 inhibitor containing a sulfone substituent, or a pharmaceutically acceptable salt thereof, to the subject.
Lang discloses that inhibitors of cellular sodium/hydrogen exchangers (NHE) display an inhibiting effect on the secretion of von-Willebrand factor, and that such inhibitors can thus be used for the treatment of thrombotic and inflammatory diseases (Abstract). Lang discloses that certain disorders are caused by elevated concentrations of von Willebrand Factor (vWF), inducing, for example, an increased tendency to blood coagulation and inflammatory processes, that there is a significant association between elevated vWF levels in the blood and an increased rate of thrombotic disorders, that Factor VIII forms with vWF a complex as necessary precondition for blood coagulation, and that it has been possible to establish that high levels of vWF and of vWF-bound factor VIII in the blood represent a clear thrombosis risk factor (pages 3-4, bridging paragraph). Lang further discloses that vWF secretion takes place normally and constitutively at the normal pH of blood which is known to be about 7.4 and part of the vWF is stored in Weibel-Palade bodies (cytoplasmic granules), and there is a delay and reduction in the release as pH falls, for example in the condition of tissue ischemia wherein significant pH reductions below 7 occur, whereas at the instant of realkalinization and endothelial stimulation, which corresponds to the reperfusion state, within seconds exocytosis takes place and thus emptying of the Weibel-Palade bodies, leading to massive release of the prothrombotic risk factor (page 4, lines 19-30). Lang further discloses exemplary compounds as sodium/hydrogen exchanger inhibitors (pages 6-8), and specifically includes the compound Rimeporide, presented by its structure (page 6, lines 6-7):
PNG
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228
418
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Greyscale
(Rimeporide)
Lang does not disclose that Rimeporide specifically inhibits NHE-1 among the family of NHE ion channels, and Lang does not disclose that the treatment disclosed therein, comprising administering an NHE inhibitor, for example Rimeporide, would be applicable to the treatment of a human patient having a coronavirus infection. However, a person of ordinary skill in the art would have a reasonable expectation of success in applying the treatment disclosed by Lang, comprising administering an NHE inhibitor, including comprising Rimeporide, to a method of treating a coronavirus infected human subject, because it was known in the art that activation of vascular endothelial NHE, via elevated lactate levels and hypoxia that occurs as a result of SARS-CoV-2 infection, plays a key role in the development of thrombosis and that teaches that treatment with an NHE inhibitor is a strategy to interrupt the link between ACE2 activation and thrombosis in SARS-CoV-2 infections, per the teaching of Cure, and it was known in the art that Rimeporide is specifically a NHE-1 inhibitor and that NHE-1 activity is particularly relevant to conditions that stem from hypoxia, per the teaching of Pedersen.
Cure provides a letter to the Editor, explaining a link between SARS-CoV-2 spike protein binding to angiotensin-converting enzyme 2 (ACE2) and thrombosis attacks known to occur during SARS-CoV-2 infections9. Cure teaches that Angiotensin II is one of the strongest stimulants of NHE, and that its local level is increased upon removal of ACE2 receptors as a consequence of spike protein/ACE2 binding in vascular endothelial cells. Cure also teaches that NHE-1 is found in vascular endothelium and platelets, and that activation of vascular endothelial NHE, via elevated lactate levels and hypoxia that occurs as a result of SARS-CoV-2 infection, plays a key role in the development of thrombosis. Cure teaches that activation of NHE in the vascular endothelium alkalizes intracellular pH and results in release of the von Willebrand Factor (vWF), and that NHE pumping H+ out of the cell causes Ca2+ accumulation within the cell and leads to endothelial dysfunction. Cure further teaches that in endothelial dysfunction, adhesion of platelets to endothelium increases via the released vWF, and that platelets also have NHE-1 that can be activated by the increased local level of angiotensin II, resulting in a procoagulant effect, as NHE activation causes Na+ migration into platelets, leading to the deterioration of platelet membrane structure and activation of fibrinogen receptors. Cure teaches that inhibition of NHE with Amiloride prevents endothelial dysfunction. Accordingly, Cure teaches that treatment with the known NHE inhibitor Amiloride is a strategy to interrupt the link between ACE2 activation and thrombosis in SARS-CoV-2 infections.
Pedersen teaches a review on the SLC9A-C Mammalian Na+/H+ Exchanger family, including gene organization over protein structure and regulation to physiological and pathophysiological roles (page 2015, Abstract). Pedersen also teaches a group of structurally-related NHE-1 inhibitors, known as “Acylguanidine-type NHE inhibitors”, which includes Rimeporide (page 2031, Box 6).
Applicant’s invention is unpatentable over the disclosure of Lang in view of the teachings of Cure and Pedersen, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in applying the method of Lang to treating a coronavirus infected human subject suffering from thrombotic attacks, because the method of Lang comprises administering a NHE inhibitor, including administering Rimeporide, to suppress the secretion of von Willebrand Factor (vWF) and thereby treat thrombotic and inflammatory conditions, and because it was known in the art that human patients infected with SARS-CoV-2 experience thrombotic attacks as a result of elevated intravascular coagulation mediated by the secretion of vWF that is itself stimulated by activation of NHE, particularly NHE-1, and that the inhibition of NHE prevents endothelial function that drives intravascular coagulation, per the teaching of Cure, and it was known in the art that Rimeporide, a NHE inhibitor disclosed by Lang, is particularly a NHE-1 inhibitor, per the teaching of Pedersen.
Thus, the invention was prima facie obvious at the time of filing.
Claim 23 further limits claim 22 to wherein the coronavirus causes a SARS or MERS infection, and is met by the rejection above.
Claim 24 further limits claim 23 to wherein the coronavirus causes a SARS-CoV-1 or SARS-CoV-2 or MERS-CoV infection and is met by the rejection above.
Claim 25 further limits claim 24 to wherein the coronavirus causes a SARS-CoV-2 infection and is met by the rejection above.
Claim 29 further limits claim 22 to wherein the subject has COVID-19 and a diagnosed or undiagnosed cardiac disease. Lang discloses that the inhibition of NHE channels protects cardiac tissue that is at risk of death from hypoperfusion (inadequate blood flow) (page 1, lines 11-15). Additionally, Pedersen discusses the integrated organ physiology and pathophysiology of mammalian NHEs (section VIII), including the role of NHEs, including NHE-1, in hypertension (section VIII.5, page 2065). Pedersen teaches that mice placed in chronic hypoxia develop pulmonary hypertension associated with an increase in intracellular pH (pHi) of pulmonary artery smooth muscle cells and elevated NHE-1 expression and activity (page 2065). Pedersen additionally teaches that pulmonary hypertension solicits the heart’s pumping activity, increases its energetic burden, and induces ventricular hypertrophy, and accordingly, hypertension can be a trigger for cardiac pathology (page 2065). Thus, a person of ordinary skill in the art would recognize from the disclosure of Lang and the teachings of Cure and Pedersen that the method of treatment of Lang may simultaneously treat a SARS-CoV-2 infected human patient having cardiac disease that is unrelated to the coronavirus infection (cardiac hypoperfusion) and/or a cardiac disease that is a downstream result of the coronavirus infection (ventricular hypertrophy from pulmonary hypertension caused by hypoxia).
Claim 26 further limits claim 22 to wherein the subject is suffering from a hyperinflammatory host immune response to a SARS-CoV-2 infection. Claim 30 further limits claim 26 to wherein the hyperinflammatory host immune response is associated with one or more clinical indications selected from a Markush group, including hypercoagulability. Cure teaches the ameliorative effect of an NHE inhibitor (Amiloride) on hypercoagulability in SARS-CoV-2 patients. Thus, these claims are met by the rejection above.
Claim 31 further limits the method of claim 22 to wherein the human subject is an adult patient. Lang does not disclose any limitation of patient population by age; however, Lang does specifically refer to adult patients in providing exemplary oral dose strengths: “These data relate to an adult weighing about 75 kg” (page 12, lines 14-22). Accordingly, a person of ordinary skill in the art would have a reasonable expectation of success in treating an adult patient.
Claim 32 further limits claim 22 to wherein the NHE-1 inhibitor containing a sulfone substituent is administered via oral route. Claim 33 further limits claim 22 to wherein the NHE-1 inhibitor containing a sulfone substituent is administered via parenteral or topical or inhalation routes. Lang discloses administration by oral, parenteral (intravenous) and inhalation routes (page 11, lines 12-15).
Claim 34 further limits claim 22 to wherein the NHE-1 inhibitor containing a sulfone substituent is administered acutely. Claim 45 further limits claim 22 to wherein the NHE-1 inhibitor containing a sulfone substituent is administered chronically. Lang discloses that the compounds disclosed therein, which include Rimeporide as discussed above, are suitable for the prophylaxis and therapy of acute or chronic diseases which are caused by elevated levels of von Willebrand Factor (vWF) in the blood (page 10, lines 29-32) and provides examples including actue myocardial infarction and thrombotic disorders occurring during or after surgical operations, as well as vasculitis associated with autoimmune disease or connective tissue disease (pages 10-11, bridging paragraph). Lang further provides exemplary dosing for daily dosing (page 12, lines 14-22).
Claim 35 further limits claim 22 to wherein the NHE-1 inhibitor containing a sulfone substituent is selected from a Markush group that includes Rimeporide and is met by the rejection above. Claim 36 further limits claim 35 to wherein the NHE-1 inhibitor containing a sulfone substituent is Rimeporide, and is met by the rejection above.
Claim 37 is drawn to a method of treating a subject suffering from long COVID, presenting with long COVID, having clinical manifestations, organ effects of long COVID or displaying pathological changes or long-term complications associated with long COVID, comprising administering an effective amount of an NHE-1 inhibitor, or a pharmaceutically acceptable salt thereof, to the subject.
Claim 38 further limits claim 37 to wherein the condition of long COVID in the subject in need of treatment is selected from a Markush group that includes new-onset pulmonary arterial hypertension as a consequence of SARS-CoV-2 infection.
While none of Lang, Cure and Pedersen specifically address long COVID as a disease state, a person of ordinary skill in the art would have a reasonable expectation of treating a long COVID patient having newly-onset pulmonary hypertension with the NHE inhibition treatment of Lang, because it was known in the art that the hypoxia is experienced by SARS-CoV-2 patients, per the teaching of Cure, and it was known in the art that chronic hypoxia leads to pulmonary hypertension that is associated with elevated NHE-1 expression and activity, per the teaching of Pedersen, as discussed above.
Claim 43 is drawn to a method of treating a human subject in need thereof comprising administering an effective amount of a NHE-1 inhibitor containing a sulfone substituent or a pharmaceutically acceptable salt thereof, to the subject wherein the treatment is in a prophylactic manner to prevent effects and complications of SARS-CoV-2 infection in a subject at risk for complications of SARS-CoV-2 infection, and/or to stabilize and/or reduce progression of other existing disease and pathological states in a patient infected with SARS-CoV-2. As discussed in the “Claim Interpretation” section above, the term “at risk for complications of SARS-CoV-2 infection” is interpreted via the instant disclosure to include patients with pre-existing cardiac disease(s), and this claim is therefore met by the rejection above.
Applicant’s invention is unpatentable over the disclosure of Lang in view of the teachings of Cure and Pedersen, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in applying the method of Lang, comprising administering the NHE-1 inhibitor Rimeporide as a treatment of thrombosis, to a method of treating a SARS-CoV-2 infected adult human subject, including a patient also experiencing a pre-existing cardiac disease, for example cardiac hypoperfusion, or experiencing newly-onset pulmonary hypertension, including the use of chronic or acute administration, including by oral, parenteral or inhalation route, for the following reasons:
It was known in the art that human patients infected with SARS-CoV-2 experience thrombotic attacks as a result of elevated intravascular coagulation mediated by the secretion of vWF that is itself stimulated by activation of NHE, particularly NHE-1, and that the inhibition of NHE prevents endothelial function that drives intravascular coagulation, per the teaching of Cure,
It was known in the art that Rimeporide, a NHE inhibitor disclosed by Lang, is particularly a NHE-1 inhibitor, per the teaching of Pedersen;
Lang provides for the NHE inhibition treatment of cardiac diseases including cardiac hypoperfusion and acute myocardial infarction as well as chronic conditions, and provides for oral, parenteral and inhalation administration on a daily basis;
It was known in the art that SARS-CoV-2 infection brings hypoxia, and that hypoxia leads to NHE activation, per the teaching of Cure, and it was also known that hypoxia leads to pulmonary hypertension that is associated with elevated NHE-1 expression and activity, per the teaching of Pedersen.
Thus, the invention was prima facie obvious at the time of filing.
Claims 22-26, 28-38, 43 and 45 are unpatentable over Lang in view of Cure and Pedersen, and further in view of Dhakal.
Claims 22-26, 28-38, 43 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Lang in view of Cure and Pedersen, and further in view of Dhakal (Dhakal, et al.; Heart, Lung and Circulation, v29, pp973–987; 2020).
The limitations of claims 22-26, 30-38, 43 and 45 and the disclosure of Lang and the teachings of Cure and Pedersen are discussed in the rejection above and hereby incorporated into the instant rejection.
Claim 28 further limits claim 22 to wherein the subject has COVID-19 myocardial injury.
Lang discloses that the method of anti-thrombotic treatment disclosed therein, of administering a NHE inhibitor to a patient in need thereof, is suitable for the treatment of acute or chronic diseases caused by elevated levels of von Willebrand Factor, including thrombotic disorders caused by ischemic states with subsequent reperfusion, such as acute myocardial thrombosis (page 10, lines 29-35). While Lang does not specifically disclose that NHE-1 inhibitors disclosed therein are useful for the treatment of myocardial injury caused by COVID-19, a person of ordinary skill in the art would have a reasonable expectation of success in treating a subject having myocardial injury caused by SARS-CoV-2 with an NHE-1 inhibitor disclosed by Lambert because it was known in the art that myocardial ischemia and infarction (injury) caused by SARS-CoV-2 may be triggered by thrombosis secondary to hypercoagulability, per the teaching of Dhakal, and it was known in the art that hypercoagulability in SARS-CoV-2 infected patients is a downstream effect of SARS-CoV-2 binding to ACE2 receptor, is mediated by NHE-1 activation, and can be prevented by treatment with an NHE inhibitor, per the teaching of Cure.
Dhakal teaches a review of cardiovascular complications caused by SARS-CoV-2 infection, including myocardial injury (page 973, Abstract). Dhakal reviews the pathophysiology of SARS-CoV-2, and describes how the viral spike protein (S protein) mediates the viral entry into host cells via binding to angiotensin converting enzyme 2 (ACE2) receptors expressed in many organs such as heart, kidneys, intestine, lung, brain and liver, leading to cardiac and renal injury, endothelial and microvascular dysfunction in the lungs, and other symptoms, and that after gaining entry into cells via ACE2 receptors, SARS-CoV-2 down-regulates the ACE2 expression such that the enzyme is unable to exert organ protective effects (page 974). Dhakal additionally teaches that, similar to an influenza outbreak, myocardial injury due to COVID-19 may be related to increased viscosity, heightened coagulation cascade, pro-inflammatory effects or endothelial cell dysfunction caused by SARS-CoV-2 virus. Dhakal observes that autopsy of SARS-CoV-2 patients showed cardiomyocyte necrosis and that pericytes may be infected with SARS-CoV-2 virus and cause capillary endothelial cell or microvascular dysfunction leading to individual cell necrosis (page 974). Dhakal also reviews cardiovascular manifestations of SARS-CoV-2, and reports that myocardial ischemia and infarction could be from thrombosis secondary to hypercoagulability. Thus, Dhakal shows that myocardial injury can be caused by hypercoagulability caused by SARS-CoV-2, and alternatively by dysfunction of the vascular endothelium in the heart, but Dhakal does not provide a link between these two causal factors for myocardial injury.
Cure teaches that Angiotensin II is one of the strongest stimulants of NHE, and that NHE-1 is found in vascular endothelium and platelets, and that activation of NHE, via elevated lactate levels and hypoxia, plays a key role in the development of hypercoagulability and consequent thrombosis. Cure also teaches that activation of NHE in the vascular endothelium alkalizes intracellular pH and results in release of the von Willebrand Factor (VWF), and that NHE pumping H+ out of the cell causes Ca2+ accumulation within the cell and leads to endothelial dysfunction. Cure further teaches that in endothelial dysfunction, adhesion of platelets to endothelium increases, via the released VWF, and that platelets also have NHE-1 and the NHE activation in platelets, due to increased local level of Angiotensin II, shows a procoagulant effect, as NHE activation causes Na+ migration into platelets, leading to the deterioration of platelet membrane structure and activation of fibrinogen receptors. Cure teaches that inhibition of NHE with Amiloride prevents endothelial dysfunction. Accordingly, Cure teaches that treatment with the known NHE inhibitor Amiloride is a strategy to interrupt the link between ACE2 activation and thrombosis in SARS-CoV-2 infections, which are two factors put forward by Dhakal for SARS-CoV-2 incident myocardial injury. Additionally, while Cure reports Amiloride as an inhibitor of NHE, a person of ordinary skill in the art would readily envisage the suitability of a simple substitution of an NHE inhibitor disclosed by Lambert for the Amiloride treatment taught by Cure, because Cure teaches that the primary NHE variant of concern in the biochemical cascade from Spike protein/ACE2 binding through to platelet coagulation is NHE-1.
Applicant’s invention is unpatentable over the disclosure of Lang in view of the teachings of Cure and Pedersen, and further in view of the teaching of Dhakal, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation treating a SARS-CoV-2 infected subject having COVID-19 myocardial injury with a Rimeporide, a NHE inhibitor disclosed by Lang, because Lang discloses that the NHE inhibitors disclosed therein are suitable for the prevention and treatment of myocardial thrombosis (injury), and it was known in the art that SARS-CoV-2 infected patients can suffer from myocardial thrombosis that can be caused by factors including endothelial dysfunction and hypercoagulability, per the teaching of Dhakal, and it was known in the art that SARS-CoV-2 Spike protein binding to ACE2 begins a cascade of biochemical actions culminating in platelet hypercoagulability and this cascade is mediated, in multiple steps, by NHE-1, and that endothelial dysfunction in particular can be prevented by treatment by NHE inhibition, per the teaching of Cure, and it was known in the art that Rimeporide is specifically an inhibitor of NHE-1, per the teaching of Pedersen.
Thus, the invention was prima facie obvious at the time of filing.
Claims 22-26, 29-40, 43 and 45 are unpatentable over Lang in view of Cure and Pedersen and further in view of Schattner.
Claims 22-26, 29-40, 43 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Cure in view of Lang and Pedersen and further in view of Schattner (Schattner, A.; Vaccine, v23, pp3876–3886; 2005).
The limitations of claims 22-26, 30-38, 43 and 45 and the disclosure of Lang and the teachings of Cure and Pedersen are discussed in the rejection above and hereby incorporated into the instant rejection.
Claim 39 is drawn to a method of treating a subject who has received a SARS-CoV-2 vaccination, comprising administering an effective amount of an NHE-1 inhibitor containing a sulfone substituent, or a pharmaceutically acceptable salt thereof, to the subject.
Claim 40 further limits claim 39 to wherein the subject suffers from SARS-CoV-2 vaccination induced complications.
Lang and Pedersen are silent on the treatment of patients who have received vaccination, and while Cure discusses the effects of SARS-CoV-2 infection, Cure is silent on patients who receive a SARS-CoV-2 vaccine, including patients who may have vaccination-induced complications, including myocarditis. However, a person of ordinary skill in the art would have a reasonable expectation of success in treating a SARS-CoV-2 patient having myocarditis or pericarditis that is a vaccination induced complication, for the following reasons:
Lang discloses that the treatment disclosed therein, in addition to suppressing the secretion of vWF, also suppresses the secretion of P-selectin, an initiator of inflammation, and that the treatment is suitable for inflammatory disorders, including during vasculitis associated with autoimmune disease;
It was known in the art that vasculitis (inflammation of blood vessels) and is a known autoimmune complication that can occur upon vaccination for viruses, per the teaching of Schattner.
Lang discloses that the same cytoplasmic granules (Weibel-Palade bodies) that store von Willebrand Factor (vWF) and are released in the secretion of vWF also store P-selectin, a biomarker of and initiator of vascular inflammation (page 4, final paragraph and page 5, initial paragraph). Lang further discloses that the treatment disclosed therein, of administering a NHE inhibitor to a patient in need thereof, is suitable to the treatment of inflammatory disorders as occur during vasculitis associated with autoimmune disorders, because these disorders are caused by increased expression of P-selectin (pages 10-11, bridging paragraph).
Schattner provides a review of autoimmune manifestations after viral vaccines, and teaches that vasculitis is one of the most frequently reported autoimmune manifestations for hepatitis B vaccine and influenza vaccine (Abstract, page 3876) and is also known to occur after vaccination with hepatitis A vaccine (page 3877), MMR vaccine (page 3878) and varicella vaccine (page 3880). Schattner discusses the mechanisms by which vaccines may induce autoimmunity in patients, including that virus infections themselves are known to generate autoantibodies and that viral antigens that mimic host antigens have been shown to trigger self-reactive T cell clones that attack host tissue, and that the effect of viral antigens may be the same whether the antigens are delivered by viral infection or viral vaccination (page 3881).
Applicant’s invention is unpatentable over the disclosure of Lang in view of the teachings of Cure and Pedersen and further in view of the teaching of Schattner, because a person of ordinary skill in the art, engaged in the treatment of a patient experiencing SARS-CoV-2 vaccination-induced of autoimmune vasculitis would have a reasonable expectation of success in employing the treatment method of Lang, because Lang teaches that the inhibition of NHE, including with Rimeporide, an NHE-1 inhibitor containing a sulfone substituent, is a suitable treatment for autoimmune vasculitis.
Thus, the invention was prima facie obvious at the time of filing.
Claims 22-26, 29-38, 41-43 and 45 are unpatentable over Lang in view of Cure and Pedersen and further in view of Kowarz.
Claims 22-26, 29-38, 41-43 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Cure in view of Lang and Pedersen and further in view of Kowarz (Kowarz, et al.; “Vaccine-Induced Covid-19 Mimicry” Syndrome:Splice reactions within the SARS-CoV-2 Spike open reading frame result in Spike protein variants that may cause thromboembolic events in patients immunized with vector-based vaccines, 26 May 2021, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-558954/v1]).
Applicant has traversed the prior rejection including Kowarz on the grounds that Kowarz is not valid prior art as the reference was first made available 26May2021, whereas the instant application claims priority to foreign application EP20192749.8 with a filing date of 08/25/2020. Applicant’s argument has been considered, but is not found persuasive, because while the disclosure of the priority application does provide support for the use of the invention with patients who have received a SARS-CoV-2 vaccination, including wherein the subject who has received the experiences vaccination related exacerbation of the infection wherein the exacerbation is antibody-enhanced or antibody-mediated (paragraph [0072]), no support is provided in the priority disclosure in regard to the further limitation of treating patients experiencing vaccination induced complications that specifically include pulmonary arterial hypertension, myocarditis, pericarditis or cardiac fibrosis, and/or including wherein the human subject has pre-existing pulmonary arterial hypertension and the treatment (i.e, administering an NHE-1 inhibitor containing a sulfone substituent) is administered to prevent SARS-CoV-2 vaccination-induced worsening of the pulmonary arterial hypertension. The earliest support for claims 41-42 is found in the 371 parent application PCT/EP2021/073429, having a filing date of 24Aug2021, wherein the disclosure provides support for the invention in regards to vaccine-induced complications specifically including pulmonary arterial hypertension, myocarditis or pericarditis or fibrosis, and wherein the subject has pre-existing pulmonary arterial hypertension and the treatment (i.e, administering an NHE-1 inhibitor containing a sulfone substituent) is administered to prevent SARS-CoV-2 vaccination-induced worsening of the pulmonary arterial hypertension (paragraph [0043]). Since the teaching of Kowarz was first made publicly available on 21May2021, Kowarz is valid prior art over the PCT filing date of 24Aug2021, and consequently is valid prior art over claims 41-42
New Rejection:
The limitations of claims 22-26, 30-38, 43 and 45 and the disclosure of Lang and the teachings of Cure and Pedersen are discussed in the rejection above and hereby incorporated into the instant rejection.
Claim 41 further limits the method of treatment of claim 40, regarding the treatment of a human subject who suffers from SARS-CoV-2 vaccination-induced complications comprising administering a NHE-1 inhibitor containing a sulfone substituent, to wherein the complications are selected from a Markush group that includes pulmonary arterial hypertension.
Claim 42 further limits the method of treatment of claim 39, regarding the treatment of a human subject who has received a SARS-CoV-2 vaccine, to wherein the subject has pre-existing pulmonary arterial hypertension and the administration of a NHE-1 inhibitor containing a sulfone substituent is performed to prevent vaccination-induced worsening of the pulmonary arterial hypertension.
Lang discloses that the treatment disclosed therein, of administering an NHE inhibitor, is suitable for the prophylaxis and therapy of acute or chronic disease which are caused by elevated levels of von Willebrand Factor (vWF) in the blood and/or increased expression of P-selectin (page 11, lines 29-32). Lang and Pedersen are silent on the treatment of patients who have received vaccination, and while Cure discusses the effects of SARS-CoV-2 infection, Cure is silent on patients who receive a SARS-CoV-2 vaccine, including patients who may have vaccination-induced complications, including pulmonary arterial hypertension. However, a person of ordinary skill in the art would have a reasonable expectation of success in treating a patient who has received a SARS-CoV-2 vaccination and suffers from SARS-CoV-2 vaccine-induced complication(s), for the following reasons:
It was known in the art that SARS-CoV-2 vaccine encodes the Spike protein, and that vector-based vaccines, such as the adenovirus-based vaccine, can lead to soluble Spike protein that can move through the patient’s body and interact with ACE2 receptors in the vascular endothelium in the same manner as SARS-CoV-2 virus capsids bearing the Spike protein, leading to thrombosis, per the teaching of Kowarz;
It was known in the art that hypoxia-induced thrombosis triggered by Spike protein binding with ACE2 is mediated by NHE activation, particularly NHE-1 activation at platelets, which causes elevated release of von Willebrand Factor (vWF) and that NHE inhibition can alleviate such thrombotic endothelial dysfunction, per the teaching of Cure;
It was known in the art that elevated NHE-1 expression and activity is associated with the onset of pulmonary hypertension as a downstream effect of hypoxia, per the teaching of Pedersen.
As discussed above, Cure teaches that Spike protein of SARS-CoV-2 binds to Angiotensin-converting enzyme II (ACE2), a binding which irreversibly occupies each bound ACE2 receptor and leads to NHE activation in vascular endothelial cells from the subsequent increase in local Angiotensin level, and the NHE activation leads to release of von Willebrand Factor (VWF). This result constitutes endothelial dysfunction, which could be ameliorated by treatment with Amiloride. If left unchecked, the endothelial dysfunction proceeds with platelets binding to the released VWF, and as NHE-1 on the platelets becomes activated by Angiotensin in the environment (increased due to reduction of ACE2), coagulation is promoted, leading to thrombosis.
Pedersen discusses the integrated organ physiology and pathophysiology of mammalian NHEs (section VIII), including the role of NHEs, including NHE-1, in hypertension (section VIII.5, page 2065). Pedersen teaches that mice placed in chronic hypoxia develop pulmonary hypertension associated with an increase in intracellular pH (pHi) of pulmonary artery smooth muscle cells and elevated NHE-1 expression and activity (page 2065). Pedersen additionally teaches that pulmonary hypertension solicits the heart’s pumping activity, increases its energetic burden, and induces ventricular hypertrophy, and accordingly, hypertension can be a trigger for cardiac pathology (page 2065).
Kowarz teaches that both mRNA and adenovirus-based SARS-CoV-2 vaccines encode the Spike protein (page 5, Introduction), and that the adenovirus-based vaccine encodes via DNA rather than RNA and these mechanisms result in different expression modes: mRNA-encoded Spike protein ends up expressed on the membrane surface of the expressing host cells, whereas the adenovirus DNA-encoded Spike is not optimized to be transcribed inside the host cell nucleus, may lead to undesirable splice events during transcription, and results in some portion of soluble Spike proteins (page 5, Introduction). The soluble Spike proteins cause adverse effects, e.g., a strong inflammatory response on endothelial cells, including thromboembolic events (page 11, Discussion). Thus, a person of ordinary skill in the art would understand that certain SARS-CoV-2 vaccines, in producing soluble Spike proteins in the host body, present the same risk and mechanism of thrombosis as caused by the SARS-CoV-2 virus itself.
Applicant’s invention is unpatentable over the disclosure of Lang in view of the teachings of Cure and Pedersent, and further in view of the teaching of Kowarz, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in treating/preventing endothelial dysfunction/thrombosis by administering Rimeporide, a NHE-1 inhibitor containing a sulfone substituent and disclosed by Lang, to a subject who has received a SARS-CoV-2 vaccine, because it was known in the art that NHE inhibition prevents hypoxia-induced endothelial dysfunction that can lead to release of vWF and resultant thrombosis, and that endothelial dysfunction is downstream from SARS-CoV-2 Spike protein binding to ACE2 receptor, per the teaching of Cure, and it was known in the art that elevated expression and activity of NHE-1 results from hypoxia and is associated with pulmonary hypertension, per the teaching of Pedersen, and it was known in the art that SARS-CoV-2 vaccines can cause adverse effects when soluble Spike protein is formed, rather than membrane-bound Spike protein, and the soluble Spike protein can migrate to vascular endothelial cells and bind ACE2 receptor in the same manner as SARS-CoV-2 virus, per the teaching of Kowarz.
Thus, the invention was prima facie obvious at the time of filing.
Conclusion
THIS ACTION IS MADE FINAL. 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 W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Effective Filing Date: Aug. 14, 2020
2 Effective Filing Date: Aug. 14, 2020
3 PubChem CID 9799487: https://pubchem.ncbi.nlm.nih.gov/compound/9799487, captured by Wayback Machine Internet Archive on 28Aug2016, accessed by Examiner on 16Mar2026.
4 N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine monomesylate
5 See for example, Merriam-Webster dictionary definition for hypoxia: https://www.merriam-webster.com/dictionary/hypoxia.
6 PubChem CID 9799487: https://pubchem.ncbi.nlm.nih.gov/compound/9799487, captured by Wayback Machine Internet Archive on 28Aug2016, accessed by Examiner on 16Mar2026.
7 N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine monomesylate
8 PubChem CID 9799487: https://pubchem.ncbi.nlm.nih.gov/compound/9799487, captured by Wayback Machine Internet Archive on 28Aug2016, accessed by Examiner on 16Mar2026.
9 Page number not provided as the letter is one-page and not numbered.