DETAILED ACTION
This Office Action is in response to the amendment, filed March 3, 2026. Primary Examiner acknowledges Claims 1, 3, 5, 10, 15, 17, 25, 27, 31, 35, 43, 46-52, and 56-60 are pending in this application, with Claims 1, 17, and 46 having been currently amended, Claims 58-60 having been newly added, and Claims 2, 4, 6-9, 11-14, 16, 18-24, 26, 28-30, 32-34, 36-42, 44, 45, and 53-55 having been cancelled.
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 .
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3, 10, 15, 17, 25, 27, 46-49, 56-60 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Higenbottam (5,839,433).
As to Claim 17, Higenbottam discloses a method of treating a viral, bacterial, and/or protozoal infection in a patient (“The effects of nitric oxide have already been used, or proposed for use, in the treatment of lung disease and conditions such as asthma, pulmonary hypertension, especially of the neonatal variety, acute lung injury, and even chronic bronchitis and emphysema, where there is a need to dilate the small arteries or airways.” Column 2, Lines 50-65), the method comprising: administering a dose of a therapeutically effective amount of inhaled nitric oxide (“nitric oxide/nitrogen mixture (NO/N.sub.2)” via 15, “The apparatus shown in use in FIG. 1 is very simple. It comprises a face mask (11) to which an oxygen-enriched air mixture is fed along a first tube (12: from a source not shown) and a nitric oxide/nitrogen mixture (NO/N.sub.2) is fed along a second tube (13) from a cylinder (15) thereof.” Column 8, Lines 10-30; “The normal maximum flow rate for the nitric oxide (or, preferably, for the nitrogen-diluted nitric oxide)--that is, the flow rate from the source obtained when the regulator valve is in its normal open position--is chosen to provide a pulse of the required very short duration (as is explained further hereinafter) that nevertheless contains a therapeutically-suitable amount of the nitric oxide.” Column 5, Lines 50-70) to said patient (as shown in Figure 1 via mask 11) in a pulsatile manner over a portion of a total inspiratory time (“pulse … inhalation”— “a controller to cause the regulator to permit the egress of a very short pulse of nitric oxide of a known, predetermined volume at a predetermined time during the patient's inhalation.” Abstract; “More specifically, the invention proposes a method of treatment in which the nitric oxide is administered to the Patient not continuously (either in admixture with, or separately but side by side with a supply of, air, oxygen or oxygen-enriched air) but intermittently and in short pulses of known, pre-determined volume at one or more suitable time during each inhalation. In the treatment of the constriction of the small pulmonary arteries the very short pulse of nitric oxide is provided at the start of the inhalation, such that the resultant bolus of nitric oxide mixture inhaled by the Patient has a nitric oxide concentration high enough to have the desired therapeutic effect” Column 3, Line 45 thru Column 4, Line 15; “In the invention the nitric oxide is fed to the Patient intermittently and in very short pulses of known, pre-determined volume either at the beginning or towards the end of each inhalation.” Column 6, Line 40 thru Column 7, Line 10; “The nitric oxide pulse is delivered either at the beginning or towards the end of each inhalation.” Column 7, Lines 10-25; “To trigger the nitric oxide pulse (at the beginning or near the end of each inhalation), the invention incorporates means to detect this start (or, alternatively, to detect the end of the immediately-preceding exhalation), and then to cause the regulator means to permit the egress of the desired very short pulse at the appropriate time.” Column 7, Lines 25-50; “FIG. 3 shows graphically the Patient's respiration, and the timing of the nitric oxide pulses at the start of an inhalation” Column 7, Lines 60-70; “In this particular case the system is arranged to note the end of an exhalation, and to trigger the operation of the regulator 16 so as to have the pulse of nitric oxide fed into the mask ready for the beginning of the next inhalation.” Column 8, Lines 10-30; “The timing of the bolus delivery is shown graphically in FIG. 3. Airflow in and out of the lungs takes place at regular intervals, as the Patient breathes, and just as the flow starts a pulse of nitric oxide is delivered, and "washed down" with the remaining inhaled air.” Column 8, Lines 35-45), wherein the dose (“nitric oxide/nitrogen mixture (NO/N.sub.2)” via 15) is delivered at a concentration of nL nitric oxide per mL tidal volume of a patient (“The regulator, which may be of any conventional design, drops the pressure of the 100 ppm nitric oxide/nitrogen mixture so that with a valve-open flow rate of 12 litres per minute opening the valve for 0.5 seconds causes a volume of 100 cc to be delivered.” Column 8, Lines 40-60), and wherein the inhaled nitric oxide is delivered at a constant rate (“12 litres per minute”— “The regulator, which may be of any conventional design, drops the pressure of the 100 ppm nitric oxide/nitrogen mixture so that with a valve-open flow rate of 12 litres per minute opening the valve for 0.5 seconds causes a volume of 100 cc to be delivered.” Column 8, Lines 40-60; “What has been determined by experiment is that for nitric oxide flow rates of the sort discussed hereinbefore--actual nitric oxide rates of a few millilitres (from 1 to 4, say) per minute, or 100 ppm nitric oxide/nitrogen mixture rates of the low tens of litres per minute (typically 12 l/min)--very satisfactory results are obtained using pulse durations of a few tens of milliseconds, and typically 20 to 30 msec.” Column 6, Line 40 thru Column 7, Line 10; “The normal maximum flow rate for the nitric oxide (or, preferably, for the nitrogen-diluted nitric oxide)--that is, the flow rate from the source obtained when the regulator valve is in its normal open position--is chosen to provide a pulse of the required very short duration (as is explained further hereinafter) that nevertheless contains a therapeutically-suitable amount of the nitric oxide. In general, a suitable nitric oxide flow rate can be chosen from a wide range of values, but typically the real nitric oxide flow rate will be around a few millilitres (at NTP, normal temperature and pressure) per minute. Thus, for a nitric oxide source in the form of a 100 ppm nitric oxide/nitrogen mixture the mixture flow rate will be in the units or low tens of litres a minute--say, in the range 5 to 50 l/min, typically 12 l/min.” Column 5, Lines 50-70) forming a square pulse (“The results of this study are shown in FIGS. 6A/B, and are discussed below (the actual volumes obtained are there compared with the volumes expected on the basis of the valve having a "square wave" opening form).” Column 8, Lines 40-60) during the portion of the total inspiratory time.
Regarding the recitation of “treating a viral, bacterial, and/or protozoal infection”, by conventional medical practice, the condition of bronchitis is a function of a viral or bacterial infection. Thus, Higenbottam meets the limitations of the claims.
As to Claims 3, 25 and 47, Higenbottam discloses the delivery of the dose of nitric oxide (“nitric oxide/nitrogen mixture (NO/N.sub.2)” via 15) occurs within a first half of the total inspiratory time (“If the nitric oxide is administered at the beginning of the inhalation, the resultant bolus of inhaled nitric oxide mixture reaches the deeper parts of the lungs to act before being absorbed therein, and before any significant amount of nitrogen dioxide occurs...” Column 5, Lines 35-45; “The nitric oxide pulse is delivered either at the beginning or towards the end of each inhalation. For the treatment of constriction of the small pulmonary blood vessels the pulse of nitric oxide is timed to occur at the beginning of the inhalation.” Column 7, Lines 10-25).
As to Claims 27, 48, and 49, Higenbottam discloses the nitric oxide (“nitric oxide/nitrogen mixture (NO/N.sub.2)” via 15) is administered in combination with at least one additional gas (“oxygen-enriched air mixture” via 12, “an oxygen-enriched air mixture is fed along a first tube (12: from a source not shown)” Column 8, Lines 10-30), and wherein the at least one additional gas includes oxygen (“oxygen-enriched air mixture”).
As to Claims 15, 56 and 57, Higenbottam discloses the portion of the inspiratory time is about 0.4 seconds to about 0.6 seconds (“0.5 seconds” – “The regulator, which may be of any conventional design, drops the pressure of the 100 ppm nitric oxide/nitrogen mixture so that with a valve-open flow rate of 12 litres per minute opening the valve for 0.5 seconds causes a volume of 100 cc to be delivered.” Column 8, Lines 40-60).
As to Claims 58, 59 and 60, Higenbottam discloses prior to administration of the dose of the therapeutically effective amount of inhaled nitric oxide (“nitric oxide/nitrogen mixture (NO/N.sub.2)” via 15), detecting a breath pattern of the patient (“To trigger the nitric oxide pulse (at the beginning or near the end of each inhalation), the invention incorporates means to detect this start (or, alternatively, to detect the end of the immediately-preceding exhalation), and then to cause the regulator means to permit the egress of the desired very short pulse at the appropriate time. Actually detecting the start of an inhalation is comparatively simple, and could be effected by a conventional mechanical pressure-drop responsive arrangement such as the demand valve employed in an aqualung or other underwater breathing apparatus. However, to control not merely the opening of the regulator but also its subsequent closing after a predetermined time requires a little more, and conveniently there is used an electronic system that includes a pressure or other appropriate sensor operatively connected to a small computing device that can be programmed to output to the regulator the appropriate control signals as needed. The sensor can be carried in the Patient's mask, or in the tube into his airways (if his breathing is being mechanically assisted), or in the exhalation port; it can be arranged to detect air flow, using a conventional thermistor arrangement, or--and preferably--to detect directly an actual pressure change (a rise or drop, as appropriate).” Column 7, Lines 25-50; “The nitric oxide supply is controlled by a regulator (16) which itself is controlled by a suitably programmed box of electronics (17) driven by signals obtained from a sensor (18) in the mask 11 (the sensor is a thermistor that is cooled by, and so detects, airflow). In this particular case the system is arranged to note the end of an exhalation, and to trigger the operation of the regulator 16 so as to have the pulse of nitric oxide fed into the mask ready for the beginning of the next inhalation.” Column 8, Lines 10-30; “In its automatic mode the apparatus includes an automatic trigger that is fed a suitable trigger stimulus derived from the repeated airway pressure output of the physiological pressure monitoring system. The repeated output is an amplified and stabilised version of the sensor signal. However, to ensure reliable detection of a respiratory event (in the Tests described hereinafter, this is the onset of expiration) some further signal conditioning is required. This latter takes the form of a second-order low pass filter (to remove mains interference), zero-offset cancellation, and amplification.” Column 9, Lines 35-55), wherein the breath pattern includes the total inspiratory time, and wherein the total inspiratory time includes a time of a single inspiration of the patient (a function of the “signal conditioning” to ensure the detection of the single breath).
As to Claim 46, Higenbottam discloses a method for improving the oxygenation or oxygen saturation (“Another well-known and effective dilating agent for treating both lung problems of the blood-vessel-constriction type and of the asthma airway type is the gas nitric oxide.” Column 2, Lines 1-20; “Nitric oxide is rapidly absorbed by the lung tissue and then into the blood stream, but it is not carried along therein because it reacts very rapidly with the haemoglobin, the oxygen-carrying pigment in red blood cells to form the stable product methaemoglobin (and nitrite and nitrate), by which route the nitric oxide is effectively inactivated.” Column 2, Lines 15-35; “The obvious way to deliver nitric oxide to the sites in the lungs where it is needed is by inhalation. The problem, however, is that the concentration of nitric oxide thus delivered must be high enough to have the required vasodilatory or bronchodilatory effect (at concentrations of 40 ppm, nitric oxide is as effective as prostacyclin, and amounts in the range of from 10 to 120 ppm seem generally satisfactory) and yet low enough to minimize its rapid conversion to the harmful nitrogen dioxide (for which even as much as 5 ppm is considered a dangerous and toxic quantity)” Column 2, Line 60 thru Column 3, Line 10; whereby the act of vasodilation increases the transport of oxygen through the blood stream) of a patient suffering from a viral, bacterial, and/or protozoal infection in a patient (“The effects of nitric oxide have already been used, or proposed for use, in the treatment of lung disease and conditions such as asthma, pulmonary hypertension, especially of the neonatal variety, acute lung injury, and even chronic bronchitis and emphysema, where there is a need to dilate the small arteries or airways.” Column 2, Lines 50-65), the method comprising: administering a dose of a therapeutically effective amount of inhaled nitric oxide (“nitric oxide/nitrogen mixture (NO/N.sub.2)” via 15, “The apparatus shown in use in FIG. 1 is very simple. It comprises a face mask (11) to which an oxygen-enriched air mixture is fed along a first tube (12: from a source not shown) and a nitric oxide/nitrogen mixture (NO/N.sub.2) is fed along a second tube (13) from a cylinder (15) thereof.” Column 8, Lines 10-30; “The normal maximum flow rate for the nitric oxide (or, preferably, for the nitrogen-diluted nitric oxide)--that is, the flow rate from the source obtained when the regulator valve is in its normal open position--is chosen to provide a pulse of the required very short duration (as is explained further hereinafter) that nevertheless contains a therapeutically-suitable amount of the nitric oxide.” Column 5, Lines 50-70) to said patient (as shown in Figure 1 via mask 11) in a pulsatile manner over a portion of a total inspiratory time (“pulse … inhalation”— “a controller to cause the regulator to permit the egress of a very short pulse of nitric oxide of a known, predetermined volume at a predetermined time during the patient's inhalation.” Abstract; “More specifically, the invention proposes a method of treatment in which the nitric oxide is administered to the Patient not continuously (either in admixture with, or separately but side by side with a supply of, air, oxygen or oxygen-enriched air) but intermittently and in short pulses of known, pre-determined volume at one or more suitable time during each inhalation. In the treatment of the constriction of the small pulmonary arteries the very short pulse of nitric oxide is provided at the start of the inhalation, such that the resultant bolus of nitric oxide mixture inhaled by the Patient has a nitric oxide concentration high enough to have the desired therapeutic effect” Column 3, Line 45 thru Column 4, Line 15; “In the invention the nitric oxide is fed to the Patient intermittently and in very short pulses of known, pre-determined volume either at the beginning or towards the end of each inhalation.” Column 6, Line 40 thru Column 7, Line 10; “The nitric oxide pulse is delivered either at the beginning or towards the end of each inhalation.” Column 7, Lines 10-25; “To trigger the nitric oxide pulse (at the beginning or near the end of each inhalation), the invention incorporates means to detect this start (or, alternatively, to detect the end of the immediately-preceding exhalation), and then to cause the regulator means to permit the egress of the desired very short pulse at the appropriate time.” Column 7, Lines 25-50; “FIG. 3 shows graphically the Patient's respiration, and the timing of the nitric oxide pulses at the start of an inhalation” Column 7, Lines 60-70; “In this particular case the system is arranged to note the end of an exhalation, and to trigger the operation of the regulator 16 so as to have the pulse of nitric oxide fed into the mask ready for the beginning of the next inhalation.” Column 8, Lines 10-30; “The timing of the bolus delivery is shown graphically in FIG. 3. Airflow in and out of the lungs takes place at regular intervals, as the Patient breathes, and just as the flow starts a pulse of nitric oxide is delivered, and "washed down" with the remaining inhaled air.” Column 8, Lines 35-45), wherein the dose (“nitric oxide/nitrogen mixture (NO/N.sub.2)” via 15) is delivered at a concentration of nL nitric oxide per mL tidal volume of a patient (“The regulator, which may be of any conventional design, drops the pressure of the 100 ppm nitric oxide/nitrogen mixture so that with a valve-open flow rate of 12 litres per minute opening the valve for 0.5 seconds causes a volume of 100 cc to be delivered.” Column 8, Lines 40-60), wherein at least one of oxygenation or oxygen saturation is improved (a function of the act of vasodilation to increase the transport of oxygen through the blood stream); and wherein the inhaled nitric oxide is delivered at a constant rate (“12 litres per minute”— “The regulator, which may be of any conventional design, drops the pressure of the 100 ppm nitric oxide/nitrogen mixture so that with a valve-open flow rate of 12 litres per minute opening the valve for 0.5 seconds causes a volume of 100 cc to be delivered.” Column 8, Lines 40-60; “What has been determined by experiment is that for nitric oxide flow rates of the sort discussed hereinbefore--actual nitric oxide rates of a few millilitres (from 1 to 4, say) per minute, or 100 ppm nitric oxide/nitrogen mixture rates of the low tens of litres per minute (typically 12 l/min)--very satisfactory results are obtained using pulse durations of a few tens of milliseconds, and typically 20 to 30 msec.” Column 6, Line 40 thru Column 7, Line 10; “The normal maximum flow rate for the nitric oxide (or, preferably, for the nitrogen-diluted nitric oxide)--that is, the flow rate from the source obtained when the regulator valve is in its normal open position--is chosen to provide a pulse of the required very short duration (as is explained further hereinafter) that nevertheless contains a therapeutically-suitable amount of the nitric oxide. In general, a suitable nitric oxide flow rate can be chosen from a wide range of values, but typically the real nitric oxide flow rate will be around a few millilitres (at NTP, normal temperature and pressure) per minute. Thus, for a nitric oxide source in the form of a 100 ppm nitric oxide/nitrogen mixture the mixture flow rate will be in the units or low tens of litres a minute--say, in the range 5 to 50 l/min, typically 12 l/min.” Column 5, Lines 50-70) forming a square pulse (“The results of this study are shown in FIGS. 6A/B, and are discussed below (the actual volumes obtained are there compared with the volumes expected on the basis of the valve having a "square wave" opening form).” Column 8, Lines 40-60) during the portion of the total inspiratory time.
Regarding the recitation of “treating a viral, bacterial, and/or protozoal infection”, by conventional medical practice, the condition of bronchitis is a function of a viral or bacterial infection. Further, regarding the terms “improving oxygenation or oxygen saturation”, by conventional medical practice, nitric oxide operates as a vasodilator which in turn the act of vasodilation to increase the transport of oxygen through the blood stream. Thus, Higenbottam meets the limitations of the claims.
As to Claims 1 and 10, Higenbottam discloses a method for delivery of a dose of gaseous drug to a patient (“nitric oxide/nitrogen mixture (NO/N.sub.2)” via 15, “The apparatus shown in use in FIG. 1 is very simple. It comprises a face mask (11) to which an oxygen-enriched air mixture is fed along a first tube (12: from a source not shown) and a nitric oxide/nitrogen mixture (NO/N.sub.2) is fed along a second tube (13) from a cylinder (15) thereof.” Column 8, Lines 10-30; “The normal maximum flow rate for the nitric oxide (or, preferably, for the nitrogen-diluted nitric oxide)--that is, the flow rate from the source obtained when the regulator valve is in its normal open position--is chosen to provide a pulse of the required very short duration (as is explained further hereinafter) that nevertheless contains a therapeutically-suitable amount of the nitric oxide.” Column 5, Lines 50-70), said method comprising delivering the dose of the gaseous drug (“nitric oxide/nitrogen mixture (NO/N.sub.2)” via 15) to the patient in a pulsatile manner over a portion of a total inspiratory time (“pulse … inhalation”— “a controller to cause the regulator to permit the egress of a very short pulse of nitric oxide of a known, predetermined volume at a predetermined time during the patient's inhalation.” Abstract; “More specifically, the invention proposes a method of treatment in which the nitric oxide is administered to the Patient not continuously (either in admixture with, or separately but side by side with a supply of, air, oxygen or oxygen-enriched air) but intermittently and in short pulses of known, pre-determined volume at one or more suitable time during each inhalation. In the treatment of the constriction of the small pulmonary arteries the very short pulse of nitric oxide is provided at the start of the inhalation, such that the resultant bolus of nitric oxide mixture inhaled by the Patient has a nitric oxide concentration high enough to have the desired therapeutic effect” Column 3, Line 45 thru Column 4, Line 15; “In the invention the nitric oxide is fed to the Patient intermittently and in very short pulses of known, pre-determined volume either at the beginning or towards the end of each inhalation.” Column 6, Line 40 thru Column 7, Line 10; “The nitric oxide pulse is delivered either at the beginning or towards the end of each inhalation.” Column 7, Lines 10-25; “To trigger the nitric oxide pulse (at the beginning or near the end of each inhalation), the invention incorporates means to detect this start (or, alternatively, to detect the end of the immediately-preceding exhalation), and then to cause the regulator means to permit the egress of the desired very short pulse at the appropriate time.” Column 7, Lines 25-50; “FIG. 3 shows graphically the Patient's respiration, and the timing of the nitric oxide pulses at the start of an inhalation” Column 7, Lines 60-70; “In this particular case the system is arranged to note the end of an exhalation, and to trigger the operation of the regulator 16 so as to have the pulse of nitric oxide fed into the mask ready for the beginning of the next inhalation.” Column 8, Lines 10-30; “The timing of the bolus delivery is shown graphically in FIG. 3. Airflow in and out of the lungs takes place at regular intervals, as the Patient breathes, and just as the flow starts a pulse of nitric oxide is delivered, and "washed down" with the remaining inhaled air.” Column 8, Lines 35-45) wherein the dose (“nitric oxide/nitrogen mixture (NO/N.sub.2)” via 15) is delivered at a concentration of nL nitric oxide per mL tidal volume of a patient (“The regulator, which may be of any conventional design, drops the pressure of the 100 ppm nitric oxide/nitrogen mixture so that with a valve-open flow rate of 12 litres per minute opening the valve for 0.5 seconds causes a volume of 100 cc to be delivered.” Column 8, Lines 40-60), wherein the gaseous drug (“nitric oxide/nitrogen mixture (NO/N.sub.2)” via 15) has an antimicrobial effect (“treatment of certain lung diseases or conditions” Column 1, Lines 1-10; “The effects of nitric oxide have already been used, or proposed for use, in the treatment of lung disease and conditions such as asthma, pulmonary hypertension, especially of the neonatal variety, acute lung injury, and even chronic bronchitis and emphysema, where there is a need to dilate the small arteries or airways.” Column 2, Lines 50-65; whereby the effective treatment of conditions such as bronchitis includes disruption of the infection caused by the bacteria and or virus resulting in the claimed antimicrobial effect), and wherein the inhaled nitric oxide is delivered at a constant rate (“12 litres per minute”— “The regulator, which may be of any conventional design, drops the pressure of the 100 ppm nitric oxide/nitrogen mixture so that with a valve-open flow rate of 12 litres per minute opening the valve for 0.5 seconds causes a volume of 100 cc to be delivered.” Column 8, Lines 40-60; “What has been determined by experiment is that for nitric oxide flow rates of the sort discussed hereinbefore--actual nitric oxide rates of a few millilitres (from 1 to 4, say) per minute, or 100 ppm nitric oxide/nitrogen mixture rates of the low tens of litres per minute (typically 12 l/min)--very satisfactory results are obtained using pulse durations of a few tens of milliseconds, and typically 20 to 30 msec.” Column 6, Line 40 thru Column 7, Line 10; “The normal maximum flow rate for the nitric oxide (or, preferably, for the nitrogen-diluted nitric oxide)--that is, the flow rate from the source obtained when the regulator valve is in its normal open position--is chosen to provide a pulse of the required very short duration (as is explained further hereinafter) that nevertheless contains a therapeutically-suitable amount of the nitric oxide. In general, a suitable nitric oxide flow rate can be chosen from a wide range of values, but typically the real nitric oxide flow rate will be around a few millilitres (at NTP, normal temperature and pressure) per minute. Thus, for a nitric oxide source in the form of a 100 ppm nitric oxide/nitrogen mixture the mixture flow rate will be in the units or low tens of litres a minute--say, in the range 5 to 50 l/min, typically 12 l/min.” Column 5, Lines 50-70) forming a square pulse (“The results of this study are shown in FIGS. 6A/B, and are discussed below (the actual volumes obtained are there compared with the volumes expected on the basis of the valve having a "square wave" opening form).” Column 8, Lines 40-60) during the portion of the total inspiratory time.
Claim Rejections - 35 USC § 103
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.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Higenbottam (5,839,433) in view of Murray (WO 2005/110052 A2).
As to Claim 5, Higenbottam discloses the delivery of the dose of nitric oxide (“nitric oxide/nitrogen mixture (NO/N.sub.2)” via 15) occurs within a first half of the total inspiratory time (“If the nitric oxide is administered at the beginning of the inhalation, the resultant bolus of inhaled nitric oxide mixture reaches the deeper parts of the lungs to act before being absorbed therein, and before any significant amount of nitrogen dioxide occurs…” Column 5, Lines 35-45; “The nitric oxide pulse is delivered either at the beginning or towards the end of each inhalation. For the treatment of constriction of the small pulmonary blood vessels the pulse of nitric oxide is timed to occur at the beginning of the inhalation.” Column 7, Lines 10-25).
Although Higenbottam states clearly the timing of the delivery of the dosage is directly related to the location within the lungs the dosage is delivered, Higenbottam, does not expressly disclose “wherein delivery of at least fifty percent of the dose of the gaseous drug occurs within a first third of the total inspiratory time, delivery of at least ninety percent of the dose of the gaseous drug occurs within a first two-thirds of the total inspiratory time, or delivery of at least seventy percent of the dose of the gaseous drug occurs within a first half of the total inspiratory time.”
Murry teaches a method for delivery of a dose of gaseous drug (“USE OF INHALED GASEOUS NITRIC OXIDE AS A MUCOLYTIC AGENT OR EXPECTORANT” Title) to a patient, said method comprising delivering the dose of gaseous drug (“GASEOUS NITRIC OXIDE”) to the patient in a pulsatile manner (“a pulse of about 1 to 1.5 seconds of nitric oxide would deliver 100 to 150 milliliters of nitric oxide into the airway and the lungs.” Para 0061; “In another embodiment, a pulse dose delivery or a bolus injection delivery of the NO containing gas may be used.” Para 0069; also see: Para 0074-0079, 0082, and 0090) over a portion of a total inspiratory time (“A total inspiratory time per treatment may then be calculated multiplying the inspiratory time ratio by the treatment time, or 8.33 min×0.33=2.78 min, in this example.” Para 0062), wherein the dose of the gaseous drug (“GASEOUS NITRIC OXIDE”) is delivered at a concentration of gaseous drug per tidal volume of the patient (“Preferably, the flow rate of gaseous nitric oxide is regulated dependent on the mammal's respiratory tidal volume and the administration is repeated over several breaths. The target concentration of nitric oxide in the mammal's airways preferably ranges from 80 ppm to 400 ppm, and more preferably 160 ppm to 220 ppm.” Para 0010; “These calculations in humans may be recalculated using any concentration of source gas, using the tidal volume of human, which is about 0.5 mL per breath. If a source gas of 10,000 ppm is used and a target therapeutic concentration is 200 ppm, knowing that the tidal volume is 0.5 mL/bth, 1 liter of the gNO may be delivered over 100 breaths. … Calculations may be based on total minute ventilation of a patient, which is respiratory rate multiplied by tidal volume, for example is 0.5 L/bth×12 bth/min=6 L/min.” Para 0062; also see: Para 0013, 0028, 0029, 0050, 0060, 0063-0065, 0099).
Regarding the limitations to the percentage of delivery, Murray teaches the delivery of dose of gaseous drug – in the form of nitric oxide – such that at least fifty percent occurs within a first third of the total inspiratory time, delivery of at least ninety percent of the dose of the gaseous drug occurs within a first two-thirds of the total inspiratory time, or delivery of at least seventy percent of the dose of the gaseous drug occurs within a first half of the total inspiratory time (“A typical respiratory rate of a human is 12 bth/min, resulting in a treatment time of about 8.33 minutes. … An inspiratory ratio of 1:2 may be used with a human patient, resulting in a inspiratory time ratio of 0.33. A total inspiratory time per treatment may then be calculated multiplying the inspiratory time ratio by the treatment time, or 8.33 min×0.33=2.78 min, in this example.” Para 0062). By this citation, it appears the delivery of the dose of gaseous drug – in the form of nitric oxide – occurs within the a first one third (0.33) of the total inspiratory time for the total percentage volume of the dose.
In light of the teachings of Murray with Higenbottam, the resultant effect of ensuring the total percentage volume of the dose is delivered ensures the administration location within the depths of the lungs as desired.
Therefore, it would have been obvious to one having ordinary skill in the art to modify specific timing of the delivery with respect to the percentage of the total volume of the dose of Higenbottam as taught by Murray to ensure the maximum amount of the dosage is delivered to the specific depth within the lungs of the patient.
Claims 31, 35, 43, and 50-52 are rejected under 35 U.S.C. 103 as being unpatentable over Higenbottam (5,839,433) in view of Av-Gay et al. (2015/0034084).
As to Claims 31 and 50, Higenbottam discloses the delivery of the dose of nitric oxide (“nitric oxide/nitrogen mixture (NO/N.sub.2)” via 15) for the treatment of a patient; yet, does not expressly disclose “the inhaled nitric oxide is administered for at least 24 hours per day over a course of a treatment period, at least 18 hours per day over a course of a treatment period, at least 12 hours per day over a course of a treatment period, or at least 8 hours per day over a course of a treatment period.”
Av-Gay teaches a method for delivery of a dose of a gaseous drug to a patient (“INHALATION OF NITRIC OXIDE FOR TREATING RESPIRATORY DISEASES” Title), wherein the gaseous drug is nitric oxide, whereby “animal studies have shown that gNO at 160-200 ppm can exert potent antimicrobial effects against a broad range of microbes in vitro, ex vivo and in animal models … further suggesting its use as an antimicrobial agent in appropriate concentrations.” (Para 0014) and “inhalation of gaseous nitric oxide (gNO) has been shown to be a highly effective broad-spectrum antimicrobial therapy; however, at effective antimicrobial concentration gNO may present serious adverse effects on humans.” (Para 0107).
Regarding the limitations of the specific treatment protocol, Av-Gay teaches the administration of inhaled nitric oxide for a variety of hours per day over a course of a treatment period. Explicitly, Av-Gay teaches continuous 8 hours - (“For the biofilm experiment, a drip flow reactor was used to grow a MRSA biofilm which was then exposed for eight hours to Ringers lactate, 200 ppm gNO (1,600 ppm hours), air or vancomycin (100-times MIC level). A reduction in the population of all five MRSA planktonic strains was observed after exposure to 1,600 ppm hours of gNO. In the biofilm experiment gNO was also shown to reduce MRSA.” Para 0013), discontinuous 8 hours – (“gNO at a high concentration ranging 160-400 ppm with a regime of two 4-hour sessions, interrupted by 1 hour of rest” Para 0020), and a 4 hour treatment period repeated up to 6 times per day – resulting in 24 hour treatment period – (“a cycle of intermittent delivery of gNO, e.g., 160 ppm for 30 minutes followed by 3.5 hours of breathing no gNO, is repeated from 1 to 6 times a day. According to some embodiments, the cycles are repeated 5 times a day.” Para 0137).
Therefore, it would have been obvious to one having ordinary skill in the art to modify the nitric oxide treatment protocol of Higenbottam as taught by Av-Gay in order to achieve the effective treatment of the patient’s respiratory condition.
As to Claims 35 and 51, the modified Higenbottam, specifically Av-Gay teaches the treatment protocol; yet, does not expressly disclose “wherein the treatment period is at least 21 days, at least fourteen days, at least ten days, at least seven days, at least five days, at least three days, or at least two days.”
Av-Gay teaches a method for delivery of a dose of a gaseous drug to a patient (“INHALATION OF NITRIC OXIDE FOR TREATING RESPIRATORY DISEASES” Title), wherein the gaseous drug is nitric oxide, whereby “animal studies have shown that gNO at 160-200 ppm can exert potent antimicrobial effects against a broad range of microbes in vitro, ex vivo and in animal models … further suggesting its use as an antimicrobial agent in appropriate concentrations.” (Para 0014) and “inhalation of gaseous nitric oxide (gNO) has been shown to be a highly effective broad-spectrum antimicrobial therapy; however, at effective antimicrobial concentration gNO may present serious adverse effects on humans.” (Para 0107).
Regarding the limitations of the specific treatment protocol, Av-Gay teaches the administration of inhaled nitric oxide over various numbers of days. Explicitly, Av-Gay teaches (“groups of 10 rats each were exposed to room air or to 80, 200, 300, 400 or 500 ppm gNO for 6 continuous hours per day for up to 7 days.” Para 0010; “rats were exposed continuously to room air, 40, 80, 160, 200 and 250 ppm gNO for 6 hours/day for 28 days.” Para 0011; “intermittent delivery high-low doses of gNO for a period of time which cycles between high and low concentration, with an exemplary cycle regimen of 160-200 ppm for 30 minutes followed by 0-80 ppm 3.5 hours wherein the cycling regimen can span 1-3 days.” Para 0021; “intermittent inhalation is effected during a time period that ranges from 1 to 7 days.” Para 0063). Still further, correlated to the aforementioned 4 hour treatment period repeated up to 6 times per day – resulting in 24 hour treatment period – (“a cycle of intermittent delivery of gNO, e.g., 160 ppm for 30 minutes followed by 3.5 hours of breathing no gNO, is repeated from 1 to 6 times a day. According to some embodiments, the cycles are repeated 5 times a day.” Para 0137) of Claim 31, Av-Gay teaches “the regimen of 1-5 cycles per day is carried out for 1 to 7 days, or from 2 to 7 days, or from 3 to 7 days. According to some embodiments of the present invention, the intermittent inhalation is effected during a time period of 5 days. However, longer time periods of intermittent gNO administration as described herein, are also contemplated.” (Para 0138).
Therefore, it would have been obvious to one having ordinary skill in the art to modify the nitric oxide treatment protocol of the modified Higenbottam as taught by Av-Gay in order to achieve the effective treatment of the patient’s respiratory condition.
As to Claims 43 and 52, Higenbottam discloses the delivery of the dose of nitric oxide (“nitric oxide/nitrogen mixture (NO/N.sub.2)” via 15) for the treatment of a patient; yet, does not expressly disclose the specific grouping of “viral infection”, “bacterial infection”, or “protozoal infection”.
Av-Gay teaches a method for delivery of a dose of a gaseous drug to a patient (“INHALATION OF NITRIC OXIDE FOR TREATING RESPIRATORY DISEASES” Title), wherein the gaseous drug is nitric oxide, whereby “animal studies have shown that gNO at 160-200 ppm can exert potent antimicrobial effects against a broad range of microbes in vitro, ex vivo and in animal models … further suggesting its use as an antimicrobial agent in appropriate concentrations.” (Para 0014) and “inhalation of gaseous nitric oxide (gNO) has been shown to be a highly effective broad-spectrum antimicrobial therapy; however, at effective antimicrobial concentration gNO may present serious adverse effects on humans.” (Para 0107).
Regarding the limitations of the specific groupings of infection, Av-Gay teaches the application of nitric oxide for antibacterial properties and effects against the claimed infections including “S. aureus” (Paras 0097, 0245, 0259, 0261, 0293, 0324-0326, 0330, 0332, 0438, 0448, 0467, 0483), “H. influenzae” (Paras 0245, 0438, 0448, 0467, 0483); “Candida albicans” (Paras 0259, 0330), “S. pneumoniae” (Paras 0259, 0261, 0448, 0467, 0483), “Legionella” (Para 0260), “Moraxella catarrhalis” (Para 0260), and “Neisseria gonorrhoea” (Para 0260), “Corynebacterium haemolyticum” (Para 0261), “Corynebacterium diphtheriae” (Para 0261).
Therefore, it would have been obvious to one having ordinary skill in the art to modify the treatment protocol of Higenbottam to include the specific listing of infection types, as taught by Av-Gay in order to ameliorate the respiratory conditions of the patient.
Response to Arguments
Applicant’s arguments with respect to claim(s) have been considered but are moot.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Stenzler (6,786,217) and Stenzler et al. (7,516,742) each disclose a method and apparatus for the delivery of nitric oxide to a patient over a portion of the total inspiratory time in an intermittent / pulsatile manner by the opening and closing of the valves, whereby the nitric oxide can be delivered at a constant concentration of nitric oxide or a non-constant concentration of nitric oxide as desired with respect to the preset tidal volume, and the rates of delivery over the flow profile of each breath can be in a square shaped waveform (Figure 2a).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANNETTE F DIXON whose telephone number is (571)272-3392. The examiner can normally be reached M-F 9-5 EST with flexible hours.
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ANNETTE FREDRICKA DIXON
Primary Examiner
Art Unit 3782
/Annette Dixon/Primary Examiner, Art Unit 3785