Use of inhaled nitric oxide for the treatment of pulmonary hypertension associated with lung disease

Description

1 / 34 “USE OF INHALED NITRIC OXIDE FOR TREATMENT OF Pulmonary hypertension associated with pulmonary disease. Split order BR112020004205-6. CROSS-REFERENCE TO RELATED REQUESTS

[0001] This request claims priority for the Request Provisional US 62 / 552.022 filed on August 30, 2017 and Application Provisional US 62 / 611.325 filed on December 28, 2017, which are incorporated by reference herein in their entirety. FIELD OF TECHNIQUE

[0002] The principles and embodiments of the present invention generally relate to the field of inhaled nitric oxide administration. FUNDAMENTALS

[0003] Inhaled nitric oxide (iNO) has been well established as an effective vasodilator for use in pediatric pulmonary hypertension, such as persistent pulmonary hypertension of the newborn (PPHN). It has been proposed that iNO could be an effective vasodilator for the treatment of several types of pulmonary hypertension (PH), including pulmonary arterial hypertension (PAH) (WHO Group 1), PH associated with left heart disease (WHO Group 2), PH associated with lung disease and / or chronic hypoxemia (WHO Group 3), chronic thromboembolic pulmonary hypertension (WHO Group 4), or PH with unclear multifactorial mechanisms (WHO Group 5).

[0004] Consequently, new therapies using iNO are needed for the treatment of PH associated with lung disease. SUMMARY

[0005] Several aspects of the present invention relate to iNO dosage regimens for the treatment of PH associated with pulmonary disease.

[0006] One aspect of the present invention relates to Petition 870260080243, dated 10 / 08 / 2026, pp. 134 / 188 2 / 34 a method to improve oxygen saturation in a patient with PH and a ventilation-perfusion (V / Q) mismatch.

[0007] Another aspect of the present invention relates to a method for improving oxygen saturation in a patient with PH associated with lung disease.

[0008] Another aspect of the present invention relates to a method of treating PH in a patient with a V / Q mismatch.

[0009] Another aspect of the present invention relates to a method of treating PH associated with pulmonary disease.

[0010] Another aspect of the present invention relates to a method of treating pH, improving oxygen saturation.

[0011] In one or more embodiments, the patient is administered an effective amount of iNO at a dose of about 5 to about 70 micrograms of NO per kilogram of ideal body weight per hour (mcg / kg IBW / h). In one or more embodiments, the effective amount of iNO is in the range of about 5 to about 60 mcg / kg IBW / hour, such as about 20 to about 40 mcg / kg IBW / hour.

[0012] In one or more modalities, iNO is administered to the patient during the first half of inspiration.

[0013] In one or more modalities, the patient receives an effective amount of iNO in combination with an effective amount of long-term oxygen therapy (LTOT).

[0014] In one or more modalities, iNO is administered for a certain minimum treatment time, such as approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6 or approximately 7 days, or approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7 or approximately 8 weeks, or approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, approximately 12, approximately 18 or approximately 24 months. Petition 870260080243, dated 10 / 08 / 2026, pp. 135 / 188 3 / 34

[0015] In one or more embodiments, iNO is administered for a certain period of time every day, such as at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 16, about 18 or about 24 hours a day.

[0016] In one or more modalities, the patient has a low, intermediate, or high probability of PH.

[0017] In one or more modalities, the patient has PH associated with pulmonary disease and / or chronic hypoxemia (WHO Group 3).

[0018] In one or more modalities, the patient has WHO Group 3 PH associated with interstitial lung disease (PH-ILD).

[0019] In one or more modalities, the patient has WHO Group 3 PH associated with idiopathic pulmonary fibrosis (PH-IPF).

[0020] In one or more modalities, the patient has WHO Group 3 PH associated with chronic obstructive pulmonary disease (CHCOPD).

[0021] In one or more modalities, the patient has PH associated with pulmonary edema due to high altitude illness.

[0022] In one or more modalities, the patient has a V / Q mismatch.

[0023] In one or more modalities, a plurality of pulses of a gas comprising NO is administered to the patient during a plurality of breaths.

[0024] In one or more embodiments, the gas comprising NO is not administered to the patient in at least one breath out of the plurality of breaths.

[0025] In one or more embodiments, the maximum time period between successive pulses of the gas comprising NO does not exceed about 30, about 25, about 20, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8.5, about Petition 870260080243, dated 10 / 08 / 2026, pp. 136 / 188 4 / 34 of 8, approximately 7.5, approximately 7, approximately 6.5, or approximately 6 seconds.

[0026] In one or more modalities, the maximum number of consecutive skipped breaths does not exceed three, two, or one breath.

[0027] In one or more embodiments, the average period between successive pulses of the gas comprising NO does not exceed about 25, about 20, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8.5, about 8, about 7.5, about 7, about 6.5 or about 6 seconds.

[0028] In one or more embodiments, the average time period between successive pulses of the gas comprising NO does not exceed about 3, about 2.5, about 2, about 1.5 or about 1 breaths.

[0029] In one or more embodiments, at least about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400, about 410, about 420, about 430, about 440, about 450, about 460, about 470, about 480, about 490, about 500, about 510, about 520, about 530, about 540, about 550, about 560, about 570, about 580, 590, about 600, about 625, about 650, about Approximately 700, 750, 800, 850, 900, 950, or 1,000 pulses of the gas comprising NO are administered to the patient every hour.

[0030] In one or more embodiments, iNO administration provides an increase in nadir SpO2 during exercise after 4 weeks of iNO administration, such as at least about 1, about 2, about 3, about 4, about 5, or about 6.

[0031] In one or more modalities, iNO administration provides an increase in mean SpO2 during exercise after 4 weeks of iNO administration, such as at least about Petition 870260080243, dated 10 / 08 / 2026, pp. 137 / 188 5 / 34 of 1, approximately 2, approximately 3, approximately 4, approximately 5, or approximately 6. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] This patent or patent application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the office upon request and payment of the required fee.

[0033] Other features of the present invention will be evident from the following written description and the accompanying figures, in which:

[0034] FIG. 1 shows the treatment visit schedule for Part 2a of a three-part clinical trial evaluating the use of iNO;

[0035] FIG. 2 shows the treatment visit schedule for Part 2b of a three-part clinical trial evaluating the use of iNO;

[0036] FIG. 3 shows the details of the dose titration from the treatment visit for Part 3a of a three-part clinical trial evaluating the use of iNO;

[0037] FIG. 4 shows the treatment visit schedule for Part 3b of a three-part clinical trial evaluating the use of iNO;

[0038] FIG. 5 shows regional vasodilation in the lungs of a first patient with PH-IPF receiving an iNO dose of 75 mcg / kg IBW / h;

[0039] FIG. 6 shows regional vasodilation in the lungs of a second patient with PH-IPF receiving an iNO dose of 75 mcg / kg IBW / h;

[0040] FIG. 7 shows regional vasodilation in the lungs of a third patient with PH-IPF receiving an iNO dose of 30 mcg / kg IBW / h; Petition 870260080243, dated 10 / 08 / 2026, pages 138 / 188 6 / 34

[0041] FIG. 8 shows regional vasodilation in the lungs of a fourth patient with PH-IPF receiving an iNO dose of 30 mcg / kg IBW / h;

[0042] FIG. 9 shows ventilation vs vasodilation for patients with PH-COPD during an acute iNO assessment;

[0043] FIG. 10 shows the change in six-minute walk distance (6MWD) in subjects with PH-COPD at baseline and during chronic iNO therapy;

[0044] FIG. 11 shows the systolic pulmonary arterial pressure (sPAP) in subjects with PH-COPD at baseline, during chronic iNO therapy, and after discontinuation of chronic iNO therapy; and

[0045] FIG. 12 shows TAPSE in patients with PH-COPD at baseline, during chronic iNO therapy, and after discontinuation of chronic iNO therapy. DETAILED DESCRIPTION

[0046] Before describing the various exemplary embodiments of the invention, it should be understood that the invention is not limited to the construction details or process steps set forth in the following description. The invention is capable of other embodiments and of being practiced or carried out in various ways.

[0047] Surprisingly, it has been discovered that long-term iNO therapy at doses below 75 mcg / kg IBW / hour provides improved oxygen saturation in patients with pulmonary hypertension (PH) associated with lung disease. Previously, a clinical study demonstrated that an iNO dose of 75 mcg / kg IBW / hour was effective for the treatment of pulmonary arterial hypertension (PAH), while the same study found an iNO dose of 25 mcg / kg IBW / hour to be ineffective. Consequently, several aspects of the present invention relate to the use of iNO doses below 75 mcg / kg IBW / hour for the treatment of PH and / or improvement of oxygenation in patients. Petition 870260080243, dated 10 / 08 / 2026, pp. 139 / 188 7 / 34 with lung disease and / or V / Q mismatch.

[0048] The maintenance and / or improvement of oxygen saturation can be assessed by several measures. Oxygen saturation is an indication of how much hemoglobin in the blood is bound to oxygen and is usually given as a percentage of oxyhemoglobin to total hemoglobin. SpO2 is an indication of oxygen saturation in the peripheral capillaries. Exemplary methods for measuring SpO2 include, but are not limited to, pulse oximetry. Other parameters can also be used to assess oxygenation, such as arterial oxygen saturation (SaO2) and / or partial pressure of oxygen in arterial blood (PaO2). Oxygen desaturation refers to a drop in oxygen saturation, such as a drop in oxygen saturation after the patient performs a test to assess exercise capacity.

[0049] Oxygen saturation can be measured before, during, or after tests that assess exercise capacity. One approach to assessing exercise capacity is the six-minute walk test, which provides the 6MWD. Other measures that can be used to assess exercise capacity include, but are not limited to, walking test, activity level, strenuous exercise, maximal exercise test, treadmill, bicycle, and cardiopulmonary exercise test.

[0050] Therefore, in one or more modalities, iNO therapy maintains or improves one or more parameters related to oxygen saturation. In some modalities, maintaining a parameter corresponds to no change in that parameter over a given period of time. In some modalities, if a parameter is expected to worsen in an untreated patient over time (e.g., oxygen saturation is expected to decrease in untreated PH patients), maintaining a parameter also includes a clinical worsening of the parameter that is of lesser magnitude than the clinical worsening expected for an untreated patient. Petition 870260080243, dated 10 / 08 / 2026, pages 140 / 188 8 / 34

[0051] In one or more modalities, iNO therapy maintains or increases oxygen saturation (e.g., SpO2) over a period of time, such as after iNO administration for 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 weeks or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18 or 24 months or at least 1, 2, 3, 4 or 5 years.

[0052] In one or more modalities, the patient's oxygen saturation does not change during iNO therapy, even though oxygen saturation is expected to decrease in an untreated patient. In other modalities, a patient's oxygen saturation increases over a certain period of time. Examples of increases in oxygen saturation include increases of approximately 0.1, approximately 0.2, approximately 0.3, approximately 0.4, approximately 0.5, approximately 0.6, approximately 0.7, approximately 0.8, approximately 0.9, approximately 1, approximately 1.5, approximately 2, approximately 2.5, approximately 3, approximately 3.5, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, or approximately 10.

[0053] In one or more modalities, oxygen saturation is provided as an average oxygen saturation during the exercise test, such as an average SpO2 during the 6MWT. In one or more modalities, oxygen saturation is provided as a minimum oxygen saturation during the exercise test, such as a nadir of SpO2 during the 6MWT. Oxygen saturation can be monitored continuously or at specific intervals, such as every minute, every 30 seconds, every 15 seconds, every second, etc.

[0054] In one or more modalities, 4 weeks of iNO therapy provides an average increase in SpO2 during exercise in a patient group of at least 1. In multiple modalities, the average increase in SpO2 during exercise in the patient group after 4 weeks of iNO therapy is at least about 1, 2, 3, 4, 5, or 6.

[0055] In one or more modalities, 4 weeks of iNO therapy provides an average increase in nadir SpO2 during the Petition 870260080243, dated 10 / 08 / 2026, pp. 141 / 188 9 / 34 exercise in a patient group of at least about 1. In various modalities, the mean increase in nadir SpO2 during exercise in the patient group after 4 weeks of iNO therapy is at least about 1, 2, 3, 4, 5, or 6.

[0056] In one or more modalities, 4 weeks of iNO therapy provides a mean increase in mean SpO2 during exercise in a patient group of at least 1. In multiple modalities, the mean increase in SpO2 during exercise in the patient group after 4 weeks of iNO therapy is at least about 1, 2, 3, 4, 5, or 6.

[0057] One or more embodiments of the present invention also relate to the maintenance and / or improvement of right ventricular (RV) function using long-term iNO therapy. Maintenance and / or improvements in RV function can be assessed by many echocardiographic measures. One such quantitative approach to assessing RV function is the measurement of tricuspid annular plane systolic excursion (TAPSE). TAPSE estimates RV systolic function by measuring the level of systolic excursion of the lateral tricuspid valve annulus toward the apex. An excellent correlation between TAPSE and RV ejection fraction, assessed by radionuclide angiography, has been previously established, and the approach appears reproducible and has proven to be a strong predictor of prognosis in heart failure. [Reference: Heart. 2006 Apr; 92(Suppl 1): i19-i26.]

[0058] Other echocardiographic measures that can be used to assess maintenance and / or improvements in RV function include, but are not limited to, RV fractional area change (RVFAC), sPAP, tricuspid annular systolic velocity (TASV), and Tei index.

[0059] Therefore, in one or more modalities, iNO therapy maintains or improves one or more of the following parameters: TAPSE, RVFAC, sPAP, tricuspid annular motion, TAPSE, TASV, and Tei index. In some modalities, maintaining a parameter corresponds to no change in that parameter during a Petition 870260080243, dated 10 / 08 / 2026, pages 142 / 188 10 / 34 a given period of time. In some modalities, if a parameter is expected to worsen in an untreated patient over time (for example, TAPSE is expected to decrease in patients with untreated PH), maintaining a parameter also includes a clinical worsening of the parameter that is of lesser magnitude than the clinical worsening expected for an untreated patient.

[0060] In one or more modalities, iNO therapy maintains or increases TAPSE over a certain period of time, such as after iNO administration for 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 days, 1, 2, 3, 4, 5, 6, 7 or 8 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18 or 24 months, or at least 1, 2, 3, 4 or 5 years.

[0061] In one or more modalities, the patient's TAPSE does not change during iNO therapy, even though TAPSE is expected to decrease in an untreated patient. In other modalities, a patient's TAPSE increases over a certain period of time. Exemplary increases in TAPSE include increases of approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, or approximately 10 mm. Exemplary increases in TAPSE may also be expressed as percentages, such as increases of approximately 5, approximately 10, approximately 15, approximately 20, approximately 25, approximately 30, approximately 35, approximately 40, approximately 45, approximately 50, approximately 55, approximately 60, approximately 65, or approximately 70%.

[0062] In one or more modalities, 1 week of iNO therapy provides an average increase in TAPSE in a patient group of at least 1 mm. In multiple modalities, the average increase in TAPSE in the patient group after 1 week of iNO therapy is at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 mm.

[0063] In one or more modalities, 1 week of iNO therapy provides an average increase in TAPSE in a group of Petition 870260080243, dated 10 / 08 / 2026, pp. 143 / 188 11 / 34 patients showed at least a 5% increase. Across various modalities, the average increase in TAPSE in the patient group after 1 week of iNO therapy is at least approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, or approximately 70%.

[0064] In one or more modalities, 2 weeks of iNO therapy provides an average increase in TAPSE in a patient group of at least 1 mm. In multiple modalities, the average increase in TAPSE in the patient group after 2 weeks of iNO therapy is at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 mm.

[0065] In one or more modalities, 2 weeks of iNO therapy provides an average increase in TAPSE in a patient group of at least 5%. In multiple modalities, the average increase in TAPSE in the patient group after 2 weeks of iNO therapy is at least about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, or about 70%.

[0066] In one or more modalities, 2 weeks of iNO therapy provides an average increase in TAPSE in a patient group of at least 1 mm. In multiple modalities, the average increase in TAPSE in the patient group after 2 weeks of iNO therapy is at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about or about 10 mm.

[0067] In one or more modalities, 4 weeks of iNO therapy provides an average increase in TAPSE in a patient group of at least 5%. In multiple modalities, the average increase in TAPSE in the patient group after 4 weeks of iNO therapy is at least about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about Petition 870260080243, dated 10 / 08 / 2026, pp. 144 / 188 12 / 34 of 60, approximately 65 or about 70%.

[0068] Furthermore, due to the interdependencies between RV function and left ventricular (LV) function, improving RV function may also improve LV function. Thus, iNO therapy may also be used to maintain and / or improve LV function in a patient.

[0069] Maintenance and / or improvements to the function of LVs can be assessed by many echocardiographic measures. Echocardiographic measures that can be used to assess maintenance and / or improvements in LV function include, among others, LVEF, LV size, and early diastolic relaxation velocity of the LV.

[0070] Therefore, in one or more modalities, iNO therapy maintains or improves one or more of the following parameters: LVEF, LV size, and early diastolic relaxation velocity of the LV. As described above, in some modalities, maintenance of a parameter corresponds to no change in that parameter over a given period of time. In some modalities, if a parameter is expected to worsen in an untreated patient over time, maintenance of a parameter also includes a clinical worsening of the parameter that is of lesser magnitude than the clinical worsening expected for an untreated patient.

[0071] In one or more modalities, the patient or group of patients is diagnosed with PH. The patient(s) may be diagnosed by a cardiologist, pulmonologist, or other physician according to appropriate criteria, using techniques such as echocardiography, right heart catheterization (RHC), etc. Examples of such criteria include, but are not limited to, patients who have a mean pulmonary arterial pressure (mPAP) at rest of at least 25 mm Hg or a tricuspid regurgitation velocity greater than 2.9 m / s or other combinations of factors, as determined by an appropriate physician. The World Health Organization (WHO) has defined Petition 870260080243, dated 10 / 08 / 2026, pp. 145 / 188 13 / 34 five categories of PH:PAH (WHO Group 1); PH associated with left heart disease (WHO Group 2), PH associated with lung disease and / or chronic hypoxemia (WHO Group 3), chronic thromboembolic pulmonary hypertension (WHO Group 4) or PH with unclear multifactorial mechanisms (WHO Group 5).

[0072] Examples of WHO Group 3 patients include patients with PH-COPD and those with interstitial lung disease (ILD), such as patients with PH-IPF. Other examples of WHO Group 3 patients include those with combined pulmonary fibrosis and emphysema (CPFE), chronic exposure to high altitudes, or other lung diseases such as sleep-disordered breathing or developmental diseases. COPD, ILD, and other lung diseases can be diagnosed according to any appropriate factor or combination of factors, such as those established in the American Thoracic Society guidelines. An exemplary set of criteria for the diagnosis of COPD is the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) criteria. In at least one modality, the patient has PH-COPD. In at least one modality, the patient has PH and ILD, such as a patient with PH-IPF. In at least one modality, the patient has PH associated with pulmonary edema due to high-altitude illness.

[0073] In one or more modalities, the patient has a V / Q mismatch.

[0074] In one or more modalities, the patient or group of patients has a low, intermediate, or high probability of PH, as determined by echocardiography or other appropriate technique. An illustrative set of criteria for assessing the probability of PH is set forth in the 2015 ESC / ERS Guidelines for Diagnosis and Treatment of Pulmonary Hypertension. In at least one modality, the patient has a low echocardiographic probability of PH. In at least one modality, the patient has an intermediate echocardiographic probability of PH. In at least one modality, the patient has a high Petition 870260080243, dated 10 / 08 / 2026, pages 146 / 188 14 / 34 echocardiographic probability of PH.

[0075] In one or more modalities, the patient has been placed on a lung transplant waiting list and iNO therapy is used to maintain or improve RV and / or LV function prior to lung transplantation. In other modalities, the patient has already received a lung transplant.

[0076] Patients in need of a lung transplant are assessed and given a Lung Allocation Score (LAS), which estimates the severity of each candidate's disease and their chance of success after a lung transplant. Those with a higher LAS receive a higher priority for a lung offer when a compatible lung becomes available. Improving or maintaining cardiac function (e.g., RV and / or LV function) increases the likelihood of a patient surviving long enough to receive a lung transplant. Furthermore, improving or maintaining cardiac function (e.g., RV and / or LV function) improves the patient's prognosis after lung transplantation. Therefore, in one or more modalities, iNO therapy can be provided to patients on a lung transplant list, particularly patients on a lung transplant list with PH.Furthermore, in one or more modalities, iNO therapy may influence one or more factors used to determine the patient's LAS, and therefore, iNO therapy may alter the patient's LAS.

[0077] iNO can be administered continuously, or by a series of pulses, or any other technique suitable for delivering iNO to the patient's lungs. Exemplary devices for the administration of iNO are described in U.S. Patent 5,558,083; U.S. Patent 7,523,752; U.S. Patent 8,757,148; U.S. Patent 8,770,199; U.S. Patent 8,893,717; U.S. Patent 8,944,051; U.S. Patent Application Publication 2013 / 0239963; U.S. Patent Application Publication 2014 / 0000596; and U.S. Patent Application Publication 2016 / 0106949, the disclosures of which are Petition 870260080243, dated 10 / 08 / 2026, pages 147 / 188 15 / 34 incorporated herein by reference in their entirety.

[0078] In one or more embodiments, iNO is delivered by an NO dispensing device using cylinders containing NO and a carrier gas, such as nitrogen (N2). Exemplary cylinder concentrations of NO include, but are not limited to, concentrations in the range of about 100 ppm to about 15,000 ppm, such as about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1,000, about 1,500, about 2,000, about 2,500, about 3,000, about 3,500, about 4,000, about 4,500, about 5,000, about 6,000, about 7,000, about 8,000, about 9,000, about 10,000 or about 15,000 ppm. In one or more configurations, the NO cylinder concentration is approximately 4,880 ppm.

[0079] In one or more embodiments, NO is generated at the bedside or at the point of delivery. For example, various chemical reactions can be used to generate NO, such as reacting N2 and oxygen (O2) in the presence of an electrode or reacting nitrogen dioxide (NO2) with a reducing agent.

[0080] In one or more modalities, iNO is delivered as a series of pulses. iNO may have a specific pulse volume, such as approximately 0.1, approximately 0.2, approximately 0.3, approximately 0.4, approximately 0.5, approximately 0.6, approximately 0.7, approximately 0.8, approximately 0.9, approximately 1, approximately 1.5, approximately 2, approximately 3, approximately 4, or approximately 5 mL. The pulse volume may be the same from one breath to the next, or the pulse volume may vary according to the patient's respiratory rate and / or the amount of iNO already delivered to the patient.

[0081] In one or more modalities, the effective amount of iNO is in the range of about 5 to about 70 mcg / kg IBW / h. A patient's ideal body weight correlates with the patient's estimated lung size and is a function of the patient's sex and height. In several Petition 870260080243, dated 10 / 08 / 2026, pp. 148 / 188 16 / 34 embodiments, the dose of iNO is about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65 or about 70 mcg / kg IBW / h.

[0082] In one or more embodiments, a constant dose of iNO is delivered to the patient with each breath, as a constant dose in nmol / breath, ng / breath, or mL / breath. Exemplary doses include about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 150, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1,000, or about 1,500 nmol of NO per breath.

[0083] In one or more embodiments, iNO is delivered continuously at a constant concentration. For example, iNO can be administered at a constant concentration from about 1 ppm to about 100 ppm. In various embodiments, the iNO dose is about 1, about 2, about 3, about 4, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95 or about 100 ppm.

[0084] In one or more embodiments, a desired amount of gas is administered to the patient through a plurality of breaths in a manner that is independent of the patient's breathing pattern. For example, a patient's iNO dose may be prescribed in terms of mcg / kg IBW / hour, so that a desired amount is delivered to the patient each hour, regardless of the patient's breathing pattern or respiratory rate. The iNO delivery device may have an input such as a display, screen, touchscreen, or other user interface to receive the patient's prescription. An amount of NO per breath (e.g., nmol NO, ng NO, mL of gas comprising NO, etc.) may be calculated based on the Petition 870260080243, dated 10 / 08 / 2026, pp. 149 / 188 17 / 34 The patient's current respiratory pattern, and this amount of NO can be delivered to the patient in the next breath or over several breaths. The NO delivery device can monitor the patient's respiratory pattern or respiratory rate (or changes in respiratory pattern or respiratory rate) and recalculate and / or adjust the amount of NO-containing gas that is delivered in the current breath or subsequent breaths. The NO delivery device may have a control system with appropriate software and / or hardware (e.g., flow sensors, pressure sensors, processors, memory, etc.) to monitor respiration, calculate or determine the amount of NO to be delivered, and be in communication with other components of the NO delivery device (e.g., flow sensors, pressure sensors, valves, gas lines, etc.) to deliver the NO-containing gas.The amount of NO per breath can be calculated and / or adjusted after each breath, or it can be calculated and / or adjusted at specific intervals, such as every minute, every 10 minutes, every 10 breaths, every 100 breaths, etc.

[0085] In one or more modalities, iNO is not delivered to the patient with each breath, and at least one breath is skipped during iNO therapy. The time period between individual pulses of gas comprising NO may vary or may be constant. In several modalities, a maximum time period between pulses, a maximum average time period between pulses, and / or a minimum pulse frequency may be provided.

[0086] Several situations can result in iNO being skipped on a specific breath. For example, an intermittent dosing regimen can be used in which iNO is administered on each breath, with n being greater than 1. In various modalities, n is approximately 1.01, approximately 1.1, approximately 1.2, approximately 1.3, approximately 1.4, approximately 1.5, approximately 1.6, approximately 1.7, approximately 1.8, approximately 1.9, approximately 2, approximately 2.5, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9 or Petition 870260080243, dated 10 / 08 / 2026, pp. 150 / 188 18 / 34 approximately 10. When n is not a whole number (for example, 1.1 or 2.5), n can represent an average over several breaths. As an example, administering iNO every 2.5 breaths indicates that iNO is administered on average 2 times every 5 breaths (i.e., 5 / 2 = 2.5). Similarly, administering iNO every 1.1 breaths indicates that iNO receives an average of 10 breaths every 11 breaths (i.e., 11 / 10 = 1.1). Similar calculations can be performed for other intermittent dosing schedules, where iNO is administered with each breath, with n being greater than 1.

[0087] In one or more embodiments, an intermittent dosing regimen may be used in which predetermined breaths are skipped. The skipping of predetermined breaths may be based on predetermined patterns, such as skipping all other breaths, skipping every third breath, skipping two consecutive breaths and delivering on the third breath, etc. The predetermined pattern may include delivering gas comprising NO at every nth breath, such as n being greater than 1, for example, about 1.01, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.5, about 2.5, about 3, about 4, about 5, about 6, about 7, about 8, about 9 or about 10.

[0088] In one or more modalities, one or more breaths are skipped within a given time period. For example, 1, 2, 3, 4, 5, etc. breaths may be skipped every hour, every 30 minutes, every 15 minutes, every 10 minutes, every minute, every 30 seconds, etc. In some modalities, as little as one breath is skipped during the entire iNO therapy. In other modalities, multiple breaths are skipped during iNO therapy.

[0089] In one or more modalities, an intermittent dosing regimen may be used in which random breaths are skipped. The skipping of random breaths may be determined according to a random number generator and / or may be based on the conditions. Petition 870260080243, dated 10 / 08 / 2026, pp. 151 / 188 19 / 34 current clinical factors, such as the patient's respiratory pattern, the patient's respiratory rate, the amount of iNO that was delivered to the patient, the patient's prescribed iNO, etc., and / or may be based on the settings of the NO delivery device, such as a minimum pulse volume.

[0090] In one or more embodiments, the NO delivery device may have a minimum amount of gas that can be delivered in a breath, such as a minimum pulse volume. This minimum amount of gas may be user-defined or a minimum threshold value defined by the NO delivery device specifications. In one or more embodiments, when the amount of gas comprising NO to be delivered to the patient in a given breath is less than the minimum amount of gas per breath (e.g., minimum pulse volume), gas delivery is skipped for that breath. In one or more embodiments, when a breath is skipped, a new amount of gas per breath is calculated and / or the amount of gas is carried over and added to the amount of gas to be delivered in one or more subsequent breaths.

[0091] In addition to the illustrative situations described above, other situations that may result in one or more breaths being skipped during iNO therapy are also covered by this disclosure. Such situations include, but are not limited to, skipped breaths or a pause in iNO therapy due to: alteration or replacement of the drug cylinder or cartridge; purging of the NO delivery device; engagement with other delivery devices or systems, such as LTOT, continuous positive airway pressure (CPAP), bilevel positive airway pressure (BPAP), etc. NO delivery device alarm conditions, such as apnea, empty drug cylinder / cartridge, empty battery, etc.; or NO delivery device failure condition(s).

[0092] In one or more embodiments, there is a maximum time period between successive gas pulses comprising Petition 870260080243, dated 10 / 08 / 2026, pp. 152 / 188 20 / 34 NO. For example, the time period between successive pulses may vary or may be constant, but an upper limit may be provided to prevent a very long period between successive gas pulses. In exemplary embodiments, the maximum time period between successive gas pulses comprising NO does not exceed about 30, about 25, about 20, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8.5, about 8, about 7.5, about 7, about 6.5 or about 6 seconds.

[0093] In one or more embodiments, the maximum time period between successive pulses of the gas comprising NO is given as a maximum number of breaths. In exemplary embodiments, the maximum number of consecutive skipped breaths does not exceed four, three, two, or one breath.

[0094] In one or more embodiments, the average period between successive pulses of the gas comprising NO does not exceed a certain period, such as does not exceed about 30, about 25, about 20, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8.5, about 8, about 7.5, about 7, about 6.5 or about 6 seconds. Again, the time period between individual pulses may vary or may be the same.

[0095] In one or more modes, the average number of consecutive skipped breaths does not exceed about 3, about 2.5, about 2, about 1.5, about 1 or about 0.5 breaths.

[0096] In one or more modalities, the frequency of pulse administration is given as a number of pulses in a given period of time, such as pulses per hour. For example, in one or more modalities, the patient is administered at least approximately 300, approximately 310, approximately 320, approximately 330, approximately 340, approximately 350, approximately 360, approximately 370, approximately 380, approximately 390, approximately 400, approximately 410, approximately 420, approximately 430, approximately 440, approximately 450, approximately 460, approximately Petition 870260080243, dated 10 / 08 / 2026, pages 153 / 188 21 / 34 of 470, approximately 480, approximately 490, approximately 500, approximately 510, approximately 520, approximately 530, approximately 540, approximately 550, approximately 560, approximately 570, approximately 580, approximately 590, approximately 600, approximately 625, approximately 650, approximately 700, approximately 750, approximately 800, approximately 850, approximately 900, approximately 950, or approximately 1,000 pulses of the gas comprising NO per hour.

[0097] Shorter durations can also be used, and these pulse frequencies can also be expressed in terms of pulses per minute or another time period.In one or more modalities, the patient is administered at least approximately 5, approximately 5.1, approximately 5.2, approximately 5.3, approximately 5.4, approximately 5.5, approximately 5.6, approximately 5.7, approximately 5.8, approximately 5.9, approximately 6, approximately 6.1, approximately 6.2, approximately 6.3, approximately 6.4, approximately 6.5, approximately 6.6, approximately 6.7, approximately 6.8, approximately 6.9, approximately 7, approximately 7.1, approximately 7.2, approximately 7.3, approximately 7.4, approximately 7.5, approximately 7.6, approximately 7.7, approximately 7.8, approximately 7.9, approximately 8, approximately 8.1, approximately 8.2, approximately 8.3, approximately 8.4, approximately 8.5, approximately 8.6, approximately 8.7, approximately 8.8, approximately 8.9, approximately 9, approximately 9.5, approximately 10, approximately 10.5, approximately 11, approximately 11.5, approximately 12, approximately 12.5, approximately 13, approximately 13.5, approximately 14, approximately 14.5, approximately 15, approximately 16, approximately 17, approximately 18, approximately 19, or approximately 20 pulses per minute.

[0098] In one or more modes, iNO is administered for a specific period of time each day. For example, iNO may be administered for at least 1 hour per day. In multiple modes, iNO is administered for at least approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, approximately 10, approximately 11, approximately 12, approximately 16, approximately 18, or approximately 24 hours per day.

[0099] In one or more modalities, iNO is administered for a certain treatment time. For example, iNO may be administered for at least 2 days. In several modalities, iNO is administered for at least about 2, about 3, about 4, about 5, Petition 870260080243, dated 10 / 08 / 2026, pp. 154 / 188 22 / 34 approximately 6 or approximately 7 days, or approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7 or approximately 8 days weeks, or approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, approximately 10, approximately 11, approximately 12, approximately 18 or approximately 24 months or 1, 2, 3, 4 or 5 years.

[00100] In one or more modalities, the patient is also receiving long-term oxygen therapy (LTOT). In several modalities, LTOT is administered for at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 16, about 18, or about 24 hours per day. In several modalities, LTOT is administered at a dose of about 0.5 L / min to about 10 L / min, such as about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 L / min. LTOT can be administered continuously or in pulses. EXAMPLES Example 1 - Effect of iNO therapy on vasodilation and hemodynamics in patients with PH-IPF Study Project

[00101] This study was a three-part exploratory clinical trial to evaluate the effect of pulsed iNO on functional parameters of lung imaging in subjects with PH-COPD in LTOT (Part 1) PH-IPF in LTOT (Part 2 and Part 3) (IK-7002-COPD-006; NCT02267655). The aim of this exploratory study was to examine the utility of high-resolution computed tomography (HRCT) to measure changes in functional parameters of respiratory imaging as a function of short-term iNO administration using a pulsed NO delivery device in subjects with PH-IPF (Part 2 and Part 3) in LTOT. The primary objective of this exploratory study is the change from baseline in lobar blood volume to total lung capacity (TLC) after administration of Petition 870260080243, dated 10 / 08 / 2026, pages 155 / 188 23 / 34 pulsed iNO (Part 1), iNO or Placebo (Part 2a) and after 4 weeks of treatment with iNO (Part 3b) as measured by HRCT.

[00102] The secondary outcomes of Part 2a (acute; placebo vs. iNO 75 mcg / kg IBW / h) were changes in the Borg CR10 leg fatigue and dyspnea scale, changes in the breathing questionnaire, and changes in right and left ventricular function.

[00103] The secondary outcomes of Part 2b (chronic dosing) were altered in the 6MWT with Borg CR10 leg fatigue and dyspnea scale and SpO2, at baseline and at the end of the 6MWT and symptoms assessed using a questionnaire after 4 weeks of iNO use at a dose of 75 mcg / kg IBW / he 2 weeks after iNO discontinuation.

[00104] The secondary outcomes of Part 3b (chronic dosing) were changes in the 6MWT with Borg CR10 leg fatigue and dyspnea scale and SpO2, at baseline and at the end of the 6MWT, and symptoms assessed using a questionnaire after 4 weeks of iNO use at a dose of 30 mcg / kg IBW / h.

[00105] The safety outcomes in this study were: 1. Incidence and severity of treatment-emergent adverse events (AEs), including those related to device failure; 2. Incidence of MetHb levels > 7.0%; 3. New symptoms that may be due to the repercussions of PH associated with a temporary acute withdrawal of the investigational drug (i.e., symptoms occurring within 20 minutes of acute withdrawal and including those associated with malfunction or failure of the medical device under investigation): systemic arterial oxygen desaturation, hypoxemia, bradycardia, tachycardia, systemic hypotension, near-syncope, syncope, ventricular fibrillation and / or cardiac arrest; 4. New or worsening symptoms of insufficiency Petition 870260080243, dated 10 / 08 / 2026, pages 156 / 188 24 / 34 left heart or pulmonary edema; and 5. Any reduction in systemic oxygenation as measured by arterial blood oxygen saturation by pulse oximetry (SpO2), i.e., a decrease in hypoxia or oxygen saturation, considered by the Investigator to be clinically significant.

[00106] This was an exploratory clinical study to evaluate the utility of HRCT for measuring the pharmacodynamic effects of short-term pulsed iNO administration using a pulsed NO delivery device in individuals with PH-IPF (Part 2 and Part 3) in LTOT.

[00107] In Part 2b and Part 3b, the change in A 6MWT with Borg CR10 leg fatigue and dyspnea scale and SpO2 at baseline and end of the 6MWT, and a symptom questionnaire were used to assess the effects of long-term pulsed iNO administered using a pulsed NO distribution in subjects with PH associated with IPF in LTOT.

[00108] In Part 2 of the study, individuals needed to have severe PH, therefore PH in Part 2 was defined as sPAP > 50 mm Hg by 2-D echocardiogram. In Part 3, PH was defined as sPAP > 35 mm Hg by echocardiogram (Part 3).

[00109] The initial protocol intended for 4 subjects to be enrolled in Part 2. However, during the conduct of Part 2 of the study, after the enrollment of 2 subjects, it was noted that the two IPF patients included experienced a sudden increase in PAP after discontinuation of iNO use at a dose of 75 mcg / kg IBW / h. It was decided to temporarily halt recruitment. One of the 2 subjects completed 4 weeks of chronic use in Part 2b.

[00110] In the alteration, a total of 2 subjects participated in Part 3. The dose in Part 3 was lower than in Part 2, and each individual was titrated to the optimal dose as determined by the investigator. The iNO dose was reduced to avoid sudden fluctuations in Petition 870260080243, dated 10 / 08 / 2026, pages 157 / 188 25 / 34 PAP. The dose was monitored with an RHC in place. The investigator found that the next 2 subjects could safely titrate to iNO at a dose of 30 mcg / kg IBW / hour. This dose was used on these 2 subjects in Part 3.

[00111] The 2 subjects enrolled in Part 2 were randomly assigned to Part 2a to 1 of 2 sequences to receive iNO using NO cylinder concentration (4,880 ppm) at a dose of 75 mcg / kg IBW / h or placebo at a dose of 75 mcg / kg IBW / h. FIG. 1 shows the treatment visit schedule for Part 2a.

[00112] A patient from Part 2a entered Part 2b. During Part 2b, the patient receives iNO using the NO cylinder concentration (4,880 ppm) at a dose of 75 mcg / kg IBW / h for 4 weeks for at least 12 hours / day. The treatment visit schedule for Part 2b is summarized in FIG. 2.

[00113] The 2 subjects enrolled in Part 3a received three different doses of iNO using the NO cylinder concentration (4,880 ppm) at doses of 5 mcg / kg IBW / hour, 10 mcg / kg IBW / hour, and 30 mcg / kg IBW / hour, all with LTOT. For each dose, the change in PAP pressure and the change in cardiac output were assessed by RHC. The investigator could decide after each dose whether to continue with the next dose or not. FIG. 3 shows the details of the dose titration from the treatment visit for Part 3a.

[00114] The 2 patients from Part 3a entered the Part 3b. During Part 3b, patients received iNO using the NO cylinder concentration (4,880 ppm) at a dose of 30 mcg / kg IBW / h. One subject did not tolerate the device and discontinued treatment after 2 weeks. FIG. 4 shows the treatment visit schedule for Part 3b.

[00115] The study population consisted of subjects aged > 40 years, < 80 years, with a confirmed diagnosis of IPF (Part 2 and Part 3) who are receiving LTOT and have PH. A total of 4 subjects were enrolled.

[00116] The study had the following criteria of Petition 870260080243, dated 10 / 08 / 2026, pages 158 / 188 26 / 34 inclusion for Parts 2 and 3: 1. Patients will receive a diagnosis of IPF as determined by a responsible and experienced respiratory physician and based on; i. HRCT: usual interstitial pneumonia ii. FVC: 50-90% predicted FVC 2. PH defined as sPAP > 50 mm Hg by echocardiogram (Part 2) and sPAP > 35 mm Hg by echocardiogram or right heart catheterization (Part 3). If, in Part 3a, the Screening Visit and the Treatment Visit are performed on the same day, results documented by echocardiogram or RHC from 12 months prior to the Screening Visit must be available to assess eligibility. 3. Age > 40 years 4. Receiving LTOT for > 3 months 5. Women of childbearing potential must have a negative pre-treatment urine pregnancy test. 6. Informed consent signed before the start of any procedure or assessment required by the study. 7. BMI < 35 (Part 3 only)

[00117] The study had the following key exclusion criteria for Part 2 and Part 3. Subjects who met one of the following criteria were not eligible for enrollment: 1. Patients with an exacerbation or current exacerbation of IPF within the last 30 days. 2. Clinically significant valvular heart disease that may contribute to PH, including mild or major aortic valve disease (aortic stenosis or regurgitation) and / or moderate or major mitral valve disease (mitral stenosis or regurgitation) or post-mitral valve replacement status. 3. Use within 30 days of screening or current use. Petition 870260080243, dated 10 / 08 / 2026, pages 159 / 188 27 / 34 of specific approved medications for PH (ERA or PDE-5 inhibitor or oral, inhaled, subcutaneous or intravenous prostacyclin or a prostacyclin analogue) 4. Use of investigational medications or devices within 30 days prior to study enrollment. 5. Any underlying medical or psychiatric condition that, in the Investigator's opinion, renders the subject an unsuitable candidate for the study. Results

[00118] As can be seen in the description above, patients with PH-IPF underwent acute and chronic treatment with iNO. During the chronic phase, vasodilation and hemodynamics were evaluated. During the chronic phase, the focus was on exercise capacity. Oxygen saturation during exercise was assessed both at baseline and after 4 weeks of chronic treatment with iNO. The acute and chronic phases evaluated iNO doses of 30 and 75 mcg / kg IBW / h.

[00119] Table 1 below shows the acute effect of iNO on blood vessel volume and sPAP. Table 1: Changes in blood vessel volume and sPAP in subjects with PH-IPF Patient 1 Patient 2 Patient 3 Patient 4 iNO Dose (mcg / kg IBW / h) 75 75 30 30 Acute change in blood vessel volume (%) 14.0 ± 4.7 34.2 ± 7.6 2.8 ± 3.0 10.1 ± 3.4 Acute change in sPAP (%) -9.3 -9.7 -14.3 -23.3

[00120] As can be seen in Table 1, the increase Petition 870260080243, dated 10 / 08 / 2026, pages 160 / 188 28 / 34 in blood vessel volume is much greater for the iNO dose of 75 mcg / kg IBW / hour compared to the iNO dose of 30 mcg / kg IBW / hour. However, the effect on sPAP is similar or skewed towards the lower iNO dose of 30 mcg / kg IBW / hour.

[00121] The assessment of regional vasodilation provides greater insight into the effect of iNO doses of 30 mcg / kg IBW / hour versus 75 mcg / kg IBW / hour. As seen in FIGS. 5 and 6, there is little or no targeted vasodilation for the iNO dose of 75 mcg / kg IBW / h (Patients 1 and 2), where essentially the entire lung is green. However, as shown in FIGS. 7 and 8, there is clear targeting of the drug for the lower iNO dose of 30 mcg / kg IBW / h (Patients 3 and 4), where only portions of the lung are green and others remain unchanged (gray) or show some reduction in blood flow (red / orange). This correlates with overall vasodilation of 14.2-34.2% for the iNO dose of 75 mcg / kg IBW / hour and a more modest 2.8-10.1% for the lower iNO dose of 30 mcg / kg IBW / hour. Table 2: Nadir SpO2 and mean SpO2 in subjects with PH-IPF Patient 1 Patient 3 iNO Dose (mcg / kg IBW / h) 75 30 Time Point Baseline 4 weeks Baseline 4 weeks SpO2 Nadir 76 79 83 89 Mean SpO2 89.4 86.6 88.9 95.7

[00122] As can be seen in Table 2, there is a much greater improvement in SpO2 Nadir with the iNO dose of 30 mcg / kg of Petition 870260080243, dated 10 / 08 / 2026, pp. 161 / 188 29 / 34 IBW / hour compared to the iNO dose of 75 mcg / kg IBW / hour. Furthermore, mean SpO2 actually decreases for the iNO dose of 75 mcg / kg IBW / hour, while mean SpO2 increases for the iNO dose of 30 mcg / kg IBW / hour. These results are consistent with the non-targeted vasodilation observed for the iNO dose of 75 mcg / kg IBW / hour, which results in an inability to maintain V / Q matching and therefore oxygen saturation levels during exercise.

[00123] The results show that, in Group 3 of PH, the iNO dose needs to be lower, as selective vasodilation cannot be maintained with the higher iNO dose of 75 mcg / kg IBW / h.

[00124] Table 3 below shows the results of TAPSE of two subjects with PH-IPF in this experiment. Subject 1 received pulsed iNO at a dose of 75 mcg / kg IBW / hour for 4 weeks, and Subject 3 received pulsed iNO at a dose of 30 mcg / kg IBW / hour for 4 weeks. Table 3: Changes in TAPSE in subjects with PHIPF during chronic iNO therapy TAPSE CRF ID Baseline 4 Week Increase % Change Subject 1 14 17 3 21% Subject 3 25 28 4 12% Average 20 23 3 15%

[00125] As can be seen in Table 3, these results show that long-term pulsed iNO therapy increased TAPSE in both subjects with PH-IPF. This increase in TAPSE indicates an improvement in RV function. However, as explained above, the dose of Petition 870260080243, dated 10 / 08 / 2026, pages 162 / 188 30 / 34 iNO needs to be less than 75 mcg / kg / ibw / h to provide selective vasodilation. Example 2 - Effect of long-term iNO therapy on RV function in subjects with PH-COPD

[00126] This study is an open-label Phase 1 study of iNO therapy in subjects with PH-COPD (PULSE-COPD-007; NCT03135860). The primary outcome of this study is the change in lobar blood volume in total lung capacity with iNO and the change in lobar blood volume with iNO after 4 weeks of iNO treatment, measured by HRCT.

[00127] The subjects had a confirmed diagnosis of COPD by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. The subjects also presented with sPAP > 38 mm Hg, measured by echocardiography, a post-bronchodilator FEV1 / FVC < 0.7, and a predicted FEV1 <60%. All subjects were at least 40 years old and were current smokers or former smokers with at least 10 pack-years of smoking prior to study entry. All subjects were also receiving LTOT for at least 3 months for at least 10 hours per day.

[00128] Subjects with PH-COPD received pulsed iNO therapy for 4 weeks for at least 12 hours / day. The iNO was administered using a cylinder concentration of 4,880 ppm of NO.

[00129] Table 4 below shows the results of TAPSE levels were measured in four subjects with PH-COPD in this experiment. These individuals were diagnosed with PH-COPD and received 4 weeks of treatment with iNO at a dose of 30 mcg / kg IBW / h. The results show an increase in TAPSE levels, which correlates with RV function. Petition 870260080243, dated 10 / 08 / 2026, pages 163 / 188 31 / 34 Table 4: Changes in TAPSE in subjects with PHCOPD during chronic iNO therapy. TAPSE CRF ID Baseline 4 Week Increase % Change Subject 1 11 18 7 67% Subject 6 23 28 5 22% Subject 7 16 18 2 13% Subject 12 14 14 0 0% Average 16 20 4 25%

[00130] As can be seen in Table 4, these results show that long-term pulsed iNO therapy increased TAPSE in three subjects, and TAPSE did not change in the fourth subject. This increase in TAPSE indicates an improvement in RV function for the three subjects and a maintenance of RV function for the fourth subject. Overall, the average increase in TAPSE of 25% in all four subjects shows that iNO therapy improves and / or maintains RV function.

[00131] An acute assessment with iNO of nine individuals with PH-COPD showed a statistically significant increase (mean of 4.2%) in blood vessel volume in iNO. As shown in FIG. 9, the ventilation-vasodilation correlation was significant (p = 0.03), indicating targeted distribution to well-ventilated alveoli.

[00132] Further analysis was performed on seven individuals with PH-COPD who completed 4 weeks of iNO treatment at a dose of 30 mcg / kg IBW / hour. A summary of baseline, acute, and chronic parameters for these patients is shown in Table 5 below. The Petition 870260080243, dated 10 / 08 / 2026, pages 164 / 188 Results 32 / 34 from 6MWD and sPAP are also presented in FIGS. 10 and 11, respectively. Table 5: Acute change in blood vessel volume and chronic changes in sPAP and 6MWD in subjects with PH-COPD #1 #2 #3 #4 #5 #6 #7 Subject Identification Number 001 007 006 012 010 013 014 Age (years) / Sex 52 / M 62 / M 59 / F 60 / M 62 / M 72 / M 79 / M Compliance (hours / day) 19.9 9.9 9 23.2 11.9 16.1 17.2 Acute Change in Blood Vessel Volume % 6.2 ± 1.6 3.3 ± 2.1 6.6 ± 4.5 9.7 ± 3.5 -1.0 ± 4.0 N / A* 2.7 ± 0.4 Chronic Change in sPAP (mm Hg) Baseline 94 47 55 78 40 46 62 4 weeks of iNO 69 37 40 74 30 34 54 Change in sPAP (mm Hg) -25 -10 -15 -4 -10 -12 -8 % change -27% -21% -27% -5% -25% -26% -13% Petition 870260080243, dated 10 / 08 / 2026, pages 165 / 188 33 / 34 Chronic change in 6MWD (meters) Baseline 200 184 478 80 470 343 142 2 weeks of iNO 335 263 493 115 495 400 173 Change from baseline +135 +79 +15 +35 +25 +57 +32 4 weeks of iNO 335 195 480 77 498 423 242 Change from baseline +135 +11 +2 -3 +28 +80 +100 * Method error during testing

[00133] iNO 30 mcg / kg / IBW resulted in a significant increase in 6MWD (FIG. 10) and a decrease in sPAP as measured by echocardiography (FIG. 11). As shown in FIG. 10, the change in 6MWD after 2 weeks of iNO therapy is +53.9 meters (p = 0.02). Similarly, the change in 6MWD after 4 weeks of iNO therapy is +50.7 meters (p = 0.04). In the literature, improvements of 27 to 54 meters in 6MWD are considered clinically significant, as measured by the patient's perception of improvement.

[00134] As shown in FIG. 11, the baseline sPAP was 60.3 mm Hg. After 4 weeks of iNO therapy, the sPAP was 48.3 mm Hg [decrease of 12.0 mm Hg; decrease of 19.9%] (p = 0.02). 4 weeks after stopping iNO therapy, the sPAP increased to 58.0 mm Hg.

[00135] The decrease in sPAP correlated with a trend toward improvement in RV function as measured by TAPSE, as shown in FIG. 12. The baseline TAPSE was 18.8 (N = 6), the TAPSE Petition 870260080243, dated 10 / 08 / 2026, pages 166 / 188 34 / 34 after chronic iNO therapy was 21.3 (N = 7) and TAPSE after iNO therapy discontinuation was 19.0 (N = 5). These results further confirm that iNO therapy improves and / or maintains RV function.

[00136] Reference throughout this descriptive report to a modality, certain modalities, several modalities, one or more modalities, or a modality means that a particular resource, structure, material, or feature described in connection with the modality is included in at least one modality of the disclosure. Thus, the appearance of phrases such as in one or more modalities, in certain modalities, in several modalities, in a modality, or in a modality in several parts throughout this descriptive report does not necessarily refer to the same modality of the disclosure. Furthermore, specific resources, structures, materials, and features may be combined in any appropriate manner in one or more modalities.

[00137] Although the present disclosure has provided a description with reference to certain embodiments, it is understood that these embodiments are merely illustrative of the principles and applications of the disclosure. It will be evident to those skilled in the art that various modifications and variations can be made to the present disclosure without departing from its spirit and scope. Therefore, this disclosure is intended to include the modifications and variations that are within the scope of the appended claims and their equivalents. Petition 870260080243, dated 10 / 08 / 2026, pp. 167 / 188

Claims

1 / 4 CLAIMS 1. Use of an effective amount of inhaled nitric oxide (iNO), characterized in that it is in the manufacture of a medicament that assists in oxygen saturation in a patient with pulmonary hypertension and a ventilation-perfusion (V / Q) mismatch, wherein the iNO is administered at a dose of about 5 to about 70 mcg / kg IBW / hour for at least 2 weeks.

2. Use of an effective amount of inhaled nitric oxide (iNO), characterized by being in the manufacture of a medicine that assists in oxygen saturation in a patient with pulmonary hypertension associated with lung disease, wherein iNO is administered at a dose of about 5 to about 70 mcg / kg IBW / hour for at least 2 weeks.

3. Use of an effective amount of inhaled nitric oxide (iNO), characterized by being in the manufacture of a medicament that assists in the treatment of pulmonary hypertension in a patient with a ventilation-perfusion (V / Q) mismatch, wherein iNO is administered at a dose of approximately 5 to approximately 70 mcg / kg IBW / hour for at least 2 weeks.

4. Use of an effective amount of inhaled nitric oxide (iNO), characterized by being in the manufacture of a medicine that assists in the treatment of pulmonary hypertension associated with lung disease, wherein iNO is administered at a dose of about 5 to about 70 mcg / kg IBW / hour for at least 2 weeks.

5. Use of an effective amount of inhaled nitric oxide (iNO), characterized by being in the manufacture of a medicine that assists in the treatment of pulmonary hypertension associated with lung disease by improving oxygen saturation, wherein iNO is administered at a dose of approximately 5 to approximately 70 mcg / kg IBW / hour for at least 2 weeks.

6. Use, according to any of claims 1 to 5, characterized in that iNO is administered to the patient during Petition 870260080243, dated 10 / 08 / 2026, page 168 / 188 2 / 4 the first half of inspiration.

7. Use, according to any one of claims 1 to 6, characterized in that iNO is administered in combination with an effective amount of long-term oxygen therapy (LTOT).

8. Use, according to any one of claims 1 to 7, characterized in that iNO is administered for at least 2 hours per day.

9. Use, according to any one of claims 1 to 8, characterized in that iNO is administered for at least 6 hours per day.

10. Use, according to any one of claims 1 to 9, characterized in that iNO is administered for at least 12 hours per day.

11. Use, according to any one of claims 1 to 10, characterized in that the patient has WHO Group 3 pulmonary hypertension associated with interstitial lung disease (PH-ILD).

12. Use, according to any one of claims 1 to 10, characterized in that the patient has WHO Group 3 pulmonary hypertension associated with idiopathic pulmonary fibrosis (PH-IPF).

13. Use, according to any one of claims 1 to 10, characterized in that the patient has WHO Group 3 pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD).

14. Use, according to any one of claims 1 to 13, characterized in that iNO is administered for at least 4 weeks.

15. Use, according to any one of claims 1 to 14, characterized in that iNO is administered for at least 3 months.

16. Use, according to any of claims 1 to 15, characterized in that iNO is administered at a dose of Petition 870260080243, dated 10 / 08 / 2026, page 169 / 188 3 / 4 of approximately 15 mcg / kg IBW / hour to approximately 45 mcg / kg IBW / hour.

17. Use, according to any one of claims 1 to 16, characterized in that iNO is administered at a dose of approximately 30 mcg / kg IBW / h.

18. Use, according to any of claims 1 to 17, characterized in that administration of iNO provides an increase in SpO2 Nadir during a six-minute walk test (6MWT) after 4 weeks of iNO administration.

19. Use, according to any of claims 1 to 18, characterized in that administration of iNO provides an increase in mean SpO2 during a six-minute walk test (6MWT) after 4 weeks of iNO administration.

20. Use of an effective amount of inhaled nitric oxide (iNO), characterized by being in the manufacture of a medicament that assists in the treatment of pulmonary hypertension associated with lung disease, wherein iNO is administered at a dose of approximately 10 to approximately 70 mcg / kg IBW / hour for at least 2 weeks.

21. Use of an effective amount of inhaled nitric oxide (iNO), characterized by being in the manufacture of a medicament that assists in the treatment of WHO Group 3 pulmonary hypertension associated with interstitial lung disease (PH-ILD), wherein iNO is administered at a dose of approximately 30 mcg / kg IBW / hour for at least 2 weeks.

22. Use of an effective amount of inhaled nitric oxide (iNO), characterized by being in the manufacture of a medicine that assists in the treatment of WHO Group 3 pulmonary hypertension associated with idiopathic pulmonary fibrosis (PH-IPF), wherein iNO is administered at a dose of approximately 30 mcg / kg IBW / hour for at least 2 weeks.

23. Use of an effective amount of inhaled nitric oxide (iNO), characterized by being in the manufacture of a medicine that assists in the treatment of pulmonary hypertension WHO Group 3 associated with Petition 870260080243, dated 10 / 08 / 2026, p. 170 / 188 4 / 4 chronic obstructive pulmonary disease (PH-COPD), in which iNO is administered at a dose of approximately 30 mcg / kg IBW / hour for at least 2 weeks.

24. Use, according to any of claims 20 to 23, characterized in that iNO is administered in combination with an effective amount of long-term oxygen therapy (LTOT). Petition 870260080243, dated 10 / 08 / 2026, pp. 171 / 188

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