DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
This office action is in response to the amendment filed on 04/23/2026. As directed by the amendment, claims 2, 8, 11 and 27-29 have been cancelled, claims 1, 12 and 15-17 have been amended and claims 30-31 have been added. As such, claims 1, 4, 9-10, 12-20, 26 and 30-31 are pending in the instant application.
Applicant has amended claim 15 to address a minor informality; the objection to the claim has been withdrawn.
Applicant has cancelled claims 2, 8, 11 and 27-29; the 112(b)/(d) rejections to the claims have been withdrawn.
Response to Arguments
Applicant's arguments, see pages 7-10 of Remarks, filed 04/23/2026, pertaining to the
newly amended limitations have been noted. However, a new ground(s) of rejection has been
provided below to address the newly added limitations.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 4, 12-14, 26 and 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over Jafri (WO 2016207227 A1) in view of Kohlmann (US 20160106949 A1), Liu (US 20210093816 A1), Collins (US 9555201 B2) and Jafari (US 20020053345 A1; hereinafter known as Kimm).
Regarding claim 1, Jafri teaches a method for delivery of a dose of nitric oxide to a patient being administered oxygen in need thereof (“Although the application of oxygen alleviates the patient's condition by providing improved oxygen intake and gas exchange, thereby also reducing the patient's sensation of insufficient breathing and accompanying distress, this does not treat the underlying cause of impaired respiration. An alternative approach therefore includes the application of nitric oxide, potentially in combination with the application under positive airway pressure.” See page 3, lines 22-26), the method comprising:
a) detecting a breath pattern in the patient, the breath pattern including a total inspiratory time of a single inspiration (“A similar mechanism may allow to check whether the gaseous mixture to be applied is properly applied and inhaled, e.g., by providing feedback of a flow rate sensor and/or an exhaled breathing gas concentration.” See page 21, lines 34-35 to page 22, line 1; “Preferably, the at least one flow rate sensor and/or the controller may be in communication with the processing means to provide input to the algorithm. Using this input, the algorithm may determine, e.g., breathing patterns, breathing intervals, breathing volumes, breathing deficiencies, etc., over time and may accordingly adjust the application of the gaseous mixture and/or the application pattern during a period of time, e.g. 24 hours, to provide an optimal patient-specific application of the target cumulative dose.” See page 14, lines 31-35, to page 15, lines 1-2; Jafri further teaches controller 8 to cause the gaseous mixture 2 to be provided continuously, intermittently, and/or at a predetermined time interval as seen on page 26, lines 27-28);
b) correlating the breath pattern with an algorithm to determine the timing of administration of the dose of nitric oxide (“The algorithm may therefore be programmed to evaluate different variables such as, e.g., a pre-set patient-specific (total daily) dose of the gaseous mixture to be applied, a desired dose to be gradually applied and limits at which the gaseous mixture is to be applied, the actual applied dose and/or the actual cumulative dose applied, the duration of the application of the gaseous mixture, the time of day, etc.” See page 11, lines 28-33; The flow rate sensor and controller will be in communication to determine a breathing pattern and application pattern during a period of time (to calculate the timing) as seen on page 14, lines 31-35, to page 15, lines 1-2);
c) targeting a portion of the total inspiratory time (Jafri teaches controlling the application of the gaseous mixture throughout the inhalation cycle, and further teaches the application of the gaseous mixture may be more beneficial at the beginning of the inspiratory phase (and therefore targets a portion of the total inspiratory time to deliver the gaseous mixture) as seen on page 28, lines 11-28); and
d) delivering, using a delivery device (application device 4, see Fig. 1), the dose of nitric oxide to the patient in a pulsatile manner over the targeted portion of the total inspiratory time (“…the controller may be programmed to control the application of the gaseous mixture in a constant concentration throughout the inhalation cycle, in at least a pulse throughout an inhalation cycle…” see page 15, lines 19-21; Jafri teaches an application device 4 used to deliver the gaseous mixture as seen on page 22, lines 30-32 and Fig. 1)
but does not teach a) detecting a breath pattern in the patient via at least two separate triggers;
e) arming the delivery device for a subsequent dose of nitric oxide when an arming pressure threshold is reached,
wherein the at least two separate triggers comprise a breath level trigger for detecting a breath when a threshold level of pressure is reached upon inspiration and a breath slope trigger for detecting when a slope of a pressure waveform indicates inspiration,
wherein the targeted portion is a first two-thirds of the total inspiratory time,
wherein delivery of at least ninety-nine percent of the dose of nitric oxide occurs in a first third of the total inspiratory time, and
wherein the at least two separate triggers are set at different relative sensitivity levels.
However, Kohlmann teaches wherein the targeted portion is a first two-thirds of the total inspiratory time, and
wherein delivery of at least ninety-nine percent of the dose of nitric oxide occurs in the first third of the total inspiratory time (Kohlmann teaches providing pulse doses of a pharmaceuticals gas with a desired flow profile to maximize therapeutic benefits (see [0035]) and nitric oxide to be provided as a therapeutic pharmaceutical drug as seen in [0003]. Kohlmann further teaches delivering a dose of a pharmaceutical gas into the patient's inspiratory gas flow, preferably during the first ½ of the inspiratory cycle as seen in [0071]. Wherein the dose per breath is delivered within the volume of source (V.sub.d) per breath (see [0072]), such that the time taken to deliver V.sub.d is 0.28 seconds of a 1.66 second inspiratory time (which is within the first 17% of inspiratory time) as seen in [0076]-[0079]. As such, Kohlmann teaches the delivery of the whole (100%) dose of nitric oxide within the first third portion of the total inspiratory time).
Jafri recites “…application of the gaseous mixture may be more beneficial during a specific breathing phase, e.g. at the beginning of the inspiratory breath for optimal spreading throughout the respiratory system… (see page 28, second paragraph)” and adjusting the application of the gaseous mixture to provide an optimal patient specific application (see page 14, last paragraph to page 15, first paragraph). It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the method by Jafri to deliver the entire dose of nitric oxide within the first third of the total inspiratory time as taught by Kohlmann to time the delivery pharmaceutical gas at various points during inspiration to provide benefits to patients (see [0005]), such as within the first third of inspiratory time.
However, Liu teaches a) detecting a breath pattern in the patient via at least two separate triggers,
wherein the at least two separate triggers comprise a breath level trigger for detecting a breath when a threshold level of pressure is reached upon inspiration and a breath slope trigger for detecting when a slope of a pressure waveform indicates inspiration (Liu teaches processor 40 identifying an inspiratory trigger moment of the patient according to the measured pressure change that reflects the self-respiratory effort of the patient wherein the inspiratory trigger moment can be a trend (taken as breath slope trigger) and amplitude (taken as breath level trigger) as seen in Figs. 2 and 7-8 and [0064]-[0065], [0075] and [0115]-[0117]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the method by Jafri in view of Kohlmann to include the processor identifying multiple triggers as taught by Liu to reduce delay and avoid ineffective trigger (see [0007] and [0038]).
However, Collins teaches e) arming the delivery device for a subsequent dose when an arming pressure threshold is reached (Collins teaches a patient exhaling into a mouthpiece and out of the aperture for a predetermined period of time at a threshold level of positive pressure to achieve a qualifying breath as seen in Col. 14, lines 13-20, which can be measured by a pressure sensor (see Col. 9, lines 47-60). When the qualifying breath is reached, medication is dispensed into a chamber as seen in Col. 14, lines 13-20, arming the inhaler device).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the method by modified Jafri to include an arming pressure threshold to arm the delivery device for a subsequent dose as taught by Collins for a mechanism to reload the delivery device after an exhalation and prior to an inhalation for maximum inhalation of dose/medicine (see Col. 9, line 65 to Col. 10, line 4).
However, Kimm teaches wherein the at least two separate triggers are set at different relative sensitivity levels (Kimm teaches using different types of trigger mechanisms, including Trigger #1 which is a pressure trigger that tests the patient pressure against a threshold pressure with a relatively high sensitivity level as seen in Fig. 3 and [0074] and [0094]. Kimm further teaches at least three other triggers with different sensitivity levels, compared to each other and Trigger #1, as seen in Fig. 3 and [0074] and [0095]-[0097]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the method by modified Jafri to have the multiple triggers set at different relative sensitivity levels as taught by Kimm to increase the system’s sensitivity to the patient initiating inspiratory effort (see [0042]).
Regarding claim 4, modified Jafri teaches a method of claim 1, and Kohlmann further teaches wherein delivery of the dose of nitric oxide occurs within a first half of the total inspiratory time (Kohlmann teaches the delivery dose to be within the third of the total inspiratory time as seen in [0076]-[0079] which is within the first half of total inspiratory time).
Regarding claim 12, Jafri teaches a method for treating a pulmonary disease in a patient being administered oxygen, (“Especially in the situation where pulmonary infections are associated with respiratory disorders, as described above, a systemic approach to target pulmonary infections…An alternative approach therefore includes the application of nitric oxide, potentially in combination with the application under positive airway pressure.” See page 3, lines 1-26; Jafri teaches application of NO and oxygen to patients as seen on page 6, lines 8-13 and page 7, lines 7-16) the method comprising:
a) detecting a breath pattern in the patient, the breath pattern including a total inspiratory time of a single inspiration (“A similar mechanism may allow to check whether the gaseous mixture to be applied is properly applied and inhaled, e.g., by providing feedback of a flow rate sensor and/or an exhaled breathing gas concentration.” See page 21, lines 34-35 to page 22, line 1; “Preferably, the at least one flow rate sensor and/or the controller may be in communication with the processing means to provide input to the algorithm. Using this input, the algorithm may determine, e.g., breathing patterns, breathing intervals, breathing volumes, breathing deficiencies, etc., over time and may accordingly adjust the application of the gaseous mixture and/or the application pattern during a period of time, e.g. 24 hours, to provide an optimal patient-specific application of the target cumulative dose.” See page 14, lines 31-35, to page 15, lines 1-2; Jafri further teaches controller 8 to cause the gaseous mixture 2 to be provided continuously, intermittently, and/or at a predetermined time interval as seen on page 26, lines 27-28);
b) correlating the breath pattern with an algorithm to determine the timing of administration of the dose of nitric oxide (“The algorithm may therefore be programmed to evaluate different variables such as, e.g., a pre-set patient-specific (total daily) dose of the gaseous mixture to be applied, a desired dose to be gradually applied and limits at which the gaseous mixture is to be applied, the actual applied dose and/or the actual cumulative dose applied, the duration of the application of the gaseous mixture, the time of day, etc.” See page 11, lines 28-33; The flow rate sensor and controller will be in communication to determine a breathing pattern and application pattern during a period of time (to calculate the timing) as seen in page 14, lines 31-35, to page 15, lines 1-2);
c) targeting a portion of the total inspiratory time (Jafri teaches controlling the application of the gaseous mixture throughout the inhalation cycle, and further teaches the application of the gaseous mixture may be more beneficial at the beginning of the inspiratory phase (and therefore targets a portion of the total inspiratory time) as seen on page 28, lines 11-28); and
d) delivering, using a delivery device (application device 4, see Fig. 1), the dose of nitric oxide to the patient in a pulsatile manner over the targeted portion of the total inspiratory time (“…the controller may be programmed to control the application of the gaseous mixture in a constant concentration throughout the inhalation cycle, in at least a pulse throughout an inhalation cycle…” see page 15, lines 19-21; Jafri teaches an application device 4 used to deliver the gaseous mixture as seen on page 22, lines 30-32 and Fig. 1)
but does not teach a) detecting a breath pattern in the patient via at least two separate triggers;
e) arming the delivery device for a subsequent dose of nitric oxide when an arming pressure threshold is reached,
wherein the at least two separate triggers comprise a breath level trigger for detecting a breath when a threshold level of pressure is reached upon inspiration and a breath slope trigger for detecting when a slope of a pressure waveform indicates inspiration,
wherein the targeted portion is a first two-thirds of the total inspiratory time,
wherein delivery of at least ninety-nine percent of the dose of nitric oxide occurs in a first third of the total inspiratory time, and
wherein the at least two separate triggers are set at different relative sensitivity levels.
However, Kohlmann teaches wherein the targeted portion is a first two-thirds of the total inspiratory time,
wherein delivery of at least ninety-nine percent of the dose of nitric oxide occurs in a first third of the total inspiratory time (Kohlmann teaches providing pulse doses of a pharmaceuticals gas with a desired flow profile to maximize therapeutic benefits (see [0035]) and nitric oxide to be provided as a therapeutic pharmaceutical drug as seen in [0003]. Kohlmann further teaches delivering a dose of a pharmaceutical gas into the patient's inspiratory gas flow, preferably during the first ½ of the inspiratory cycle as seen in [0071]. Wherein the dose per breath is delivered within the volume of source (V.sub.d) per breath (see [0072]), such that the time taken to deliver V.sub.d is 0.28 seconds of a 1.66 second inspiratory time (which is within the first 17% of inspiratory time) as seen in [0076]-[0079]. As such, Kohlmann teaches the delivery of the whole (100%) dose of nitric oxide within the first third portion of the total inspiratory time).
Jafri recites “…application of the gaseous mixture may be more beneficial during a specific breathing phase, e.g. at the beginning of the inspiratory breath for optimal spreading throughout the respiratory system… (see page 28, second paragraph)” and adjusting the application of the gaseous mixture to provide an optimal patient specific application (see page 14, last paragraph to page 15, first paragraph). It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the method by Jafri to deliver the entire dose of nitric oxide within the first third of the total inspiratory time as taught by Kohlmann to time the delivery pharmaceutical gas at various points during inspiration to provide benefits to patients (see [0005]), such as within the first third of inspiratory time.
However, Liu teaches a) detecting a breath pattern in the patient via at least two separate triggers,
wherein the at least two separate triggers comprise a breath level trigger for detecting a breath when a threshold level of pressure is reached upon inspiration and a breath slope trigger for detecting when a slope of a pressure waveform indicates inspiration (Liu teaches processor 40 identifying an inspiratory trigger moment of the patient according to the measured pressure change that reflects the self-respiratory effort of the patient wherein the inspiratory trigger moment can be a trend (taken as breath slope trigger) and amplitude (taken as breath level trigger) as seen in Figs. 2 and 7-8 and [0064]-[0065], [0075] and [0115]-[0117]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the method by Jafri in view of Kohlmann to include the processor identifying multiple triggers as taught by Liu to reduce delay and avoid ineffective trigger (see [0007] and [0038]).
However, Collins teaches e) arming the delivery device for a subsequent dose when an arming pressure threshold is reached (Collins teaches a patient exhaling into a mouthpiece and out of the aperture for a predetermined period of time at a threshold level of positive pressure to achieve a qualifying breath as seen in Col. 14, lines 13-20, which can be measured by a pressure sensor (see Col. 9, lines 47-60). When the qualifying breath is reached, medication is dispensed into a chamber as seen in Col. 14, lines 13-20, arming the inhaler device).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the method by modified Jafri to include an arming pressure threshold to arm the delivery device for a subsequent dose as taught by Collins for a mechanism to reload the delivery device after an exhalation and prior to an inhalation for maximum inhalation of dose/medicine (see Col. 9, line 65 to Col. 10, line 4).
However, Kimm teaches wherein the at least two separate triggers are set at different relative sensitivity levels (Kimm teaches using different types of trigger mechanisms, including Trigger #1 which is a pressure trigger that tests the patient pressure against a threshold pressure with a relatively high sensitivity level as seen in Fig. 3 and [0074] and [0094]. Kimm further teaches at least three other triggers with different sensitivity levels, compared to each other and Trigger #1, as seen in Fig. 3 and [0074] and [0095]-[0097]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the method by modified Jafri to have the multiple triggers set at different relative sensitivity levels as taught by Kimm to increase the system’s sensitivity to the patient initiating inspiratory effort (see [0042]).
Regarding claim 13, modified Jafri teaches a method of claim 12, and Jafri further teaches wherein the cardiopulmonary disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), pulmonary hypertension or pulmonary arterial hypertension (PH or PAH), Group I-V pulmonary hypertension, chronic obstructive pulmonary disease (COPD), combined pulmonary fibrosis and emphysema (CPFE), emphysema, interstitial lung disease (ILD), chronic thromboembolic pulmonary hypertension (CTEPH), chronic high altitude sickness, or other lung disease (“The device according to the invention may be applied to a variety of respiratory disorders or complications thereof…acute pulmonary hypertension, acute pulmonary thromboembolism, adult respiratory distress syndrome, an acute pulmonary vasoconstriction…” see page 16, lines 27-32).
Regarding claim 14, modified Jafri teaches a method of claim 12, and Jafri further teaches wherein the cardiopulmonary disease is Group I-V pulmonary hypertension (PH) (“The device according to the invention may be applied to a variety of respiratory disorders or complications thereof… acute pulmonary hypertension, acute pulmonary thromboembolism, adult respiratory distress syndrome, an acute pulmonary vasoconstriction…” see page 16, lines 27-32).
Regarding claim 26, modified Jafri teaches a method of claim 1, and Jafri further teaches wherein the dose of nitric oxide is a therapeutically effective dose (“The intermittent application may be provided by multiple short high dose bursts lasting e.g. for 10 seconds up to 30 minutes, but may also last longer, e.g. be varied on a daily basis, as described above. The duration time of these bursts may be dependent on the therapeutic goal to be achieved, e.g., minimize coughing, respiratory irritation, and other symptoms.” See page 27, lines 13-17).
Regarding claim 30, modified Jafri teaches the method of claim 1, but does not teach further comprising determining a total time needed to deliver a therapeutically effective amount of the dose of nitric oxide based on one or more of the breath pattern, a concentration of the nitric oxide, a volume of each pulse, and a duration of each pulse.
However, Kohlmann further teaches comprising determining a total time needed to deliver a therapeutically effective amount of the dose of nitric oxide based on one or more of the breath pattern, a concentration of the nitric oxide, a volume of each pulse, and a duration of each pulse (Kohlmann teaches determining a total time to deliver pharmaceutical gas, such as nitric oxide (see [0003]), is based on a breath pattern. In particular, Kohlmann teaches generating a desired flow profile (taken as breath pattern) for pulse doses of pharmaceutical gas can determine or set a desired duration of pharmaceutical gas therapy as seen in [0041]. Kohlmann further teaches the total dose of pharmaceutical gas to be delivered is calculated by multiplying the dosage/hr by the total time duration, wherein once the desired quantity of gas has been set, the system can determine the quantity delivered in each breath (as determined by breath pattern as seen in [0049] and [0071]) and the amount of time/number of breaths it will take to deliver the total quantity of a drug as seen in [0047]. As such, the total time needed to deliver gas is based on the flow profiles).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the device by modified Jafri to determine a total time needed to deliver a therapeutically effective amount of the dose of nitric oxide based on one or more of the breath pattern, a concentration of the nitric oxide, a volume of each pulse, and a duration of each pulse as taught by Kohlmann to use a desired flow profile for a patient that can maximize therapeutic benefits (see [0035] and [0041]).
Regarding claim 31, modified Jafri teaches the method of claim 12, but does not teach further comprising determining a total time needed to deliver a therapeutically effective amount of the dose of nitric oxide based on one or more of the breath pattern, a concentration of the nitric oxide, a volume of each pulse, and a duration of each pulse.
However, Kohlmann further teaches comprising determining a total time needed to deliver a therapeutically effective amount of the dose of nitric oxide based on one or more of the breath pattern, a concentration of the nitric oxide, a volume of each pulse, and a duration of each pulse (Kohlmann teaches determining a total time to deliver pharmaceutical gas, such as nitric oxide (see [0003]), is based on a breath pattern. In particular, Kohlmann teaches generating a desired flow profile (taken as breath pattern) for pulse doses of pharmaceutical gas can determine or set a desired duration of pharmaceutical gas therapy as seen in [0041]. Kohlmann further teaches the total dose of pharmaceutical gas to be delivered is calculated by multiplying the dosage/hr by the total time duration, wherein once the desired quantity of gas has been set, the system can determine the quantity delivered in each breath (as determined by breath pattern as seen in [0049] and [0071]) and the amount of time/number of breaths it will take to deliver the total quantity of a drug as seen in [0047]. As such, the total time needed to deliver gas is based on the flow profiles).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the device by modified Jafri to determine a total time needed to deliver a therapeutically effective amount of the dose of nitric oxide based on one or more of the breath pattern, a concentration of the nitric oxide, a volume of each pulse, and a duration of each pulse as taught by Kohlmann to use a desired flow profile for a patient that can maximize therapeutic benefits (see [0035] and [0041]).
Claims 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Jafri (WO 2016207227 A1) in view of in view of Kohlmann (US 20160106949 A1), Liu (US 20210093816 A1), Collins (US 9555201 B2) and Jafari (US 20020053345 A1; hereinafter known as Kimm), as applied to claim 1 above, and further in view of Deane (US 7841343 B2).
Regarding claim 9, modified Jafri teaches a method of claim 1, and Jafri further teaches wherein the breath pattern is detected by a device (device 1, see Fig. 1) comprising a breath sensitivity control (“A similar mechanism may allow to check whether the gaseous mixture to be applied is properly applied and inhaled, e.g., by providing feedback of a flow rate sensor and/or an exhaled breathing gas concentration.” See page 21, lines 34-35 to page 22, line 1; “Preferably, the at least one flow rate sensor and/or the controller may be in communication with the processing means to provide input to the algorithm. Using this input, the algorithm may determine, e.g., breathing patterns, breathing intervals, breathing volumes, breathing deficiencies, etc., over time and may accordingly adjust the application of the gaseous mixture and/or the application pattern during a period of time, e.g. 24 hours, to provide an optimal patient-specific application of the target cumulative dose.” See page 14, lines 31-35, to page 15, lines 1-2)
But does not teach wherein the breath sensitivity control is adjustable.
However, Deane teaches wherein the breath sensitivity control (breath sensor 5 and conserver controller 6, see Fig. 1) is adjustable (“The conserver, many designs of which are known in the art, senses a patient's breath demand, and responds by delivering a volume of oxygen-rich gas (known as a bolus) to the patient.” see Col. 1, lines 33-35; “The sensitivity of the conserver may be different in each mode to allow for different activity levels and breathing characteristics. The sensitivity level for each of the above modes may be either accessed through a simple user interface such that the patient may manually adjust the sensitivity.” see Col. 3, lines 13-18).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the method by modified Jafri to allow the breath sensitivity level to be adjusted manually as taught by Deane to give the patient control of the therapy (see Col. 3, lines 13-18) and allow them the ability to adjust the sensitivity to their comfort.
Regarding claim 10, modified Jafri teaches a method of claim 1, and Jafri further teaches wherein the breath pattern is detected by a device (device 1, see Fig. 1) comprising a breath sensitivity control (“A similar mechanism may allow to check whether the gaseous mixture to be applied is properly applied and inhaled, e.g., by providing feedback of a flow rate sensor and/or an exhaled breathing gas concentration.” See page 21, lines 34-35 to page 22, line 1; “Preferably, the at least one flow rate sensor and/or the controller may be in communication with the processing means to provide input to the algorithm. Using this input, the algorithm may determine, e.g., breathing patterns, breathing intervals, breathing volumes, breathing deficiencies, etc., over time and may accordingly adjust the application of the gaseous mixture and/or the application pattern during a period of time, e.g. 24 hours, to provide an optimal patient-specific application of the target cumulative dose.” See page 14, lines 31-35, to page 15, lines 1-2)
But does not teach wherein the breath sensitivity control is fixed.
However, Deane teaches wherein the breath sensitivity control (breath sensor 5 and conserver controller 6, see Fig. 1) is fixed (“The sensitivity levels may be pre-set discrete values that are pre-selected.” see Col. 3, lines 9-11).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the method by modified Jafri to allow the breath sensitivity level to be fixed as taught by Deane to give control to the patient’s caregiver (see Col. 3, line 18-20) to provide beneficial therapy to the user.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Jafri (WO 2016207227 A1) in view of in view of Kohlmann (US 20160106949 A1), Liu (US 20210093816 A1), Collins (US 9555201 B2) and Jafari (US 20020053345 A1; hereinafter known as Kimm), as applied to claim 1 above, and further in view of “Administration of nitric oxide into open lung regions, delivery and monitoring” by Heinonen et al. (hereinafter “Heinonen”)
Regarding claim 15, modified Jafri teaches a method of claim 1, but does not teach wherein less than 10% of poorly ventilated (a) areas of a lung or (b) alveoli are exposed to the nitric oxide.
However, Heinonen teaches wherein less than 10% of poorly ventilated (a) areas of a lung or (b) alveoli are exposed to the nitric oxide (“With pulsed administration nitric oxide therapy can be directed to well-ventilated lung regions. Avoiding administration to the anatomic dead space eliminates nitric oxide exhalation effectively, which makes the method optimal for nitric oxide therapy in a rebreathing circuit.” see page 338, Conclusion).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the method by modified Jafri to deliver pulsed nitric oxide to the well-ventilated lung regions as taught by Heinonen to eliminate nitric oxide exhalation for an optimal nitric oxide therapy (see page 338, Conclusion).
Claims 16 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Jafri (WO 2016207227 A1) in view of in view of Kohlmann (US 20160106949 A1), Miller (US 20140216452 A1), Liu (US 20210093816 A1), Collins (US 9555201 B2) and Jafari (US 20020053345 A1; hereinafter known as Kimm).
Regarding claim 16, Jafri teaches a programmable device (device 1, see Fig. 1) for delivering a dose of nitric oxide to a patient being administered oxygen in need thereof, (“The controller may further be programmed to apply the gaseous mixture with a breath by breath variability and/or with a predetermined breathing frequency.” see page 15, lines 7-8; “The gaseous mixture 2 enriched with nitric oxide and oxygen is then provided at the downstream patient interface 3 to be inhaled as a medicament by the patient.” see page 24, lines 7-8) , the device comprising:
a delivery portion (patient interface 3, see Fig. 1; “The gaseous mixture 2 enriched with nitric oxide and oxygen is then provided at the downstream patient interface 3 to be inhaled as a medicament by the patient.” see page 24, lines 7-8);
an oxygen source (source of gaseous oxygen 22, see Fig. 1);
a breath sensitivity portion to detect a breath pattern in the patient including a total inspiratory time of a single inspiration, the breath portion comprising a breath sensitivity setting (“…the device may comprise a flow rate sensor which is in communication with the controller. The flow rate sensor may detect a flow change or an absolute flow rate in e.g. a conduit of the application device to the patient interface and may hence derive or determine a breathing phase. The measured value or change is then provided as an input to the controller to, e.g., determine and/or adjust the application of the gaseous mixture.” see page 14, lines 27-31);
a breath detection algorithm for determining the dose of nitric oxide (“Furthermore, the controller 8 may be programmed to cause the gaseous mixture 2 to be provided at a variable dose…Furthermore, when implementing an algorithm to cause a target cumulative dose of the gaseous mixture 2 to be applied…” see page 28, lines 30-34); and
a portion for administering the dose of nitric oxide to the patient through a series of pulses (“This may also be combined with the application in at least a pulse throughout an inhalation cycle, for example, by applying multiple short high dose bursts to individual breaths, e.g. one in every 2 - 30 breaths.” see page 15, lines 31-33)
wherein, when the breath sensitivity portion detects a breath pattern, the breath detection algorithm calculates the timing of the dose of nitric oxide (“The algorithm may therefore be programmed to evaluate different variables such as, e.g., a pre-set patient-specific (total daily) dose of the gaseous mixture to be applied, a desired dose to be gradually applied and limits at which the gaseous mixture is to be applied, the actual applied dose and/or the actual cumulative dose applied, the duration of the application of the gaseous mixture, the time of day, etc.” See page 11, lines 28-33; The flow rate sensor and controller will be in communication to determine a breathing pattern and application pattern during a period of time (to calculate the timing) as seen in page 14, lines 31-35, to page 15, lines 1-2) and the portion targets a portion of the total inspiratory time to administer the dose of nitric oxide (Jafri teaches controlling the application of the gaseous mixture throughout the inhalation cycle, and further teaches the application of the gaseous mixture may be more beneficial at the beginning of the inspiratory phase (and therefore targets a portion of the total inspiratory time to deliver the gaseous mixture including nitric oxide) as seen on page 28, lines 11-28) ;
but does not further teach a drug cartridge comprising nitric oxide;
wherein the breath sensitivity portion comprises a breath level trigger for detecting a breath when a threshold level of pressure is reached upon inspiration and a breath slope trigger for detecting when a slope of a pressure waveform indicates inspiration,
wherein the breath sensitivity portion further includes an arming pressure threshold,
wherein the portion for administering the dose of nitric oxide is armed when the arming pressure threshold is reached,
wherein delivery of at least ninety-nine percent of the dose of nitric oxide occurs in a first third portion of the total inspiratory time, and
wherein the at least two separate triggers are set at different relative sensitivity levels.
However, Miller teaches a drug cartridge (reaction chamber 110, see Fig. 7) comprising nitric oxide (“an inhaler 100 may include a reaction chamber 110 configured to supply nitric oxide.” See [0070]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the device by Jafri to use a reaction chamber as taught by Miller which can be removed from the inhaler to allow use of a separate reaction chamber, or refilling and reuse of the same reaction chamber (see [0071]).
However, Kohlmann teaches wherein delivery of at least ninety-nine percent of the dose of nitric oxide occurs in the first third portion of the total inspiratory time (Kohlmann teaches providing pulse doses of a pharmaceuticals gas with a desired flow profile to maximize therapeutic benefits (see [0035]) and nitric oxide to be provided as a therapeutic pharmaceutical drug as seen in [0003]. Kohlmann further teaches delivering a dose of a pharmaceutical gas into the patient's inspiratory gas flow, preferably during the first ½ of the inspiratory cycle as seen in [0071]. Wherein the dose per breath is delivered within the volume of source (V.sub.d) per breath (see [0072]), such that the time taken to deliver V.sub.d is 0.28 seconds of a 1.66 second inspiratory time (which is within the first 17% of inspiratory time) as seen in [0076]-[0079]. As such, Kohlmann teaches the delivery of the whole (100%) dose of nitric oxide within the first third portion of the total inspiratory time).
Jafri recites “…application of the gaseous mixture may be more beneficial during a specific breathing phase, e.g. at the beginning of the inspiratory breath for optimal spreading throughout the respiratory system… (see page 28, second paragraph)” and adjusting the application of the gaseous mixture to provide an optimal patient specific application (see page 14, last paragraph to page 15, first paragraph). It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the method by Jafri to deliver the entire dose of nitric oxide within the first third of the total inspiratory time as taught by Kohlmann to time the delivery pharmaceutical gas at various points during inspiration to provide benefits to patients (see [0005]), such as within the first third of inspiratory time.
However, Liu teaches wherein the breath sensitivity portion comprises a breath level trigger for detecting a breath when a threshold level of pressure is reached upon inspiration and a breath slope trigger for detecting when a slope of a pressure waveform indicates inspiration (Liu teaches processor 40 identifying an inspiratory trigger moment of the patient according to the measured pressure change that reflects the self-respiratory effort of the patient wherein the inspiratory trigger moment can be a trend (taken as breath slope trigger) and amplitude (taken as breath level trigger) as seen in Figs. 2 and 7-8 and [0064]-[0065], [0075] and [0115]-[0117]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the method by Jafri in view of Kohlmann to include the processor identifying multiple triggers as taught by Liu to reduce delay and avoid ineffective trigger (see [0007] and [0038]).
However, Collins teaches an arming pressure threshold, and
wherein the portion for administering the dose of nitric oxide is armed when the arming pressure threshold is reached (Collins teaches a patient exhaling into a mouthpiece and out of the aperture for a predetermined period of time at a threshold level of positive pressure to achieve a qualifying breath as seen in Col. 14, lines 13-20, which can be measured by a pressure sensor (see Col. 9, lines 47-60). When the qualifying breath is reached, medication is dispensed into a chamber as seen in Col. 14, lines 13-20, arming the inhaler device).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the method by modified Jafri to include an arming pressure threshold to arm the delivery device for a subsequent dose as taught by Collins for a mechanism to reload the delivery device after an exhalation and prior to an inhalation for maximum inhalation of dose/medicine (see Col. 9, line 65 to Col. 10, line 4).
However, Kimm teaches wherein the at least two separate triggers are set at different relative sensitivity levels (Kimm teaches using different types of trigger mechanisms, including Trigger #1 which is a pressure trigger that tests the patient pressure against a threshold pressure with a relatively high sensitivity level as seen in Fig. 3 and [0074] and [0094]. Kimm further teaches at least three other triggers with different sensitivity levels, compared to each other and Trigger #1, as seen in Fig. 3 and [0074] and [0095]-[0097]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the method by modified Jafri to have the multiple triggers set at different relative sensitivity levels as taught by Kimm to increase the system’s sensitivity to the patient initiating inspiratory effort (see [0042]).
Regarding claim 19, modified Jafri teaches the device of claim 16, and Miller further teaches wherein the drug cartridge is replaceable (“…an inhaler 100 may include a reaction chamber 110 at a distal end of the inhaler 100. The reaction chamber 110 may be included within the body of the inhaler 100, or the reaction chamber 110 may be separable from the inhaler. Thus, a reaction chamber 110 may be configured to provide an individual dose of nitric oxide and then be removed from the inhaler 100 to allow use of a separate reaction chamber, or refilling and reuse of the same reaction chamber.” See [0071]).
Regarding claim 20, modified Jafri teaches the device of claim 16, but does not further teach wherein the nasal delivery portion is selected from the group consisting of a nasal cannula, a face mask, an atomizer, and a nasal inhaler.
However, Miller further teaches wherein the nasal delivery portion is selected from the group consisting of a nasal cannula, a face mask, an atomizer, and a nasal inhaler (“Similarly, an inhaler 100 may be configured to include a nasal cannula 142. A nasal cannula 142 may be configured so that nitric oxide delivered with the inhaler 100 is directed into the nostrils of a user.” See [0086]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the device by modified Jafri to use a nasal cannula for the nasal delivery portion as taught by Miller since a practitioner in the art would recognized that it is a well-known nasal delivery device in the art.
Claims 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Jafri (WO 2016207227 A1) in view of in view of Kohlmann (US 20160106949 A1), Miller (US 20140216452 A1), Liu (US 20210093816 A1), Collins (US 9555201 B2) and Jafari (US 20020053345 A1; hereinafter known as Kimm), as applied to claim 16 above, and further in view of Deane (US 7841343 B2).
Regarding claim 17, modified Jafri teaches the device of claim 16, but does not further teach wherein the breath sensitivity setting is fixed or adjustable from a value of least sensitive to a value of most sensitive.
However, Deane teaches wherein the breath sensitivity setting is fixed or adjustable from a value of least sensitive to a value of most sensitive (“In one implementation, the conserver may be adjusted to operate over a range of sensitivity levels. The sensitivity levels may be pre-set discrete values that are pre-selected. In another implementation, two operating modes are user selectable. The two operating modes can represent a night or sleep mode and a day or activity mode. The sensitivity of the conserver may be different in each mode to allow for different activity levels and breathing characteristics.” see Col. 3, lines 8-15).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the device by modified Jafri to allow the breath sensitivity level to be fixed or adjustable as taught by Deane to give flexibility to the user to control the sensitivity level as they wish for comfort and effectiveness (see Col. 3, line 13-18).
Regarding claim 18, modified Jafri teaches the device of claim 16, but does not further teach wherein the breath sensitivity setting is fixed at most sensitive.
However, Deane teaches wherein the breath sensitivity setting is fixed at most sensitive (“… the threshold pressure may continue to decrease until either a breath is detected or a bolus is automatically fired. In this implementation, the threshold pressure may linearly or asymptotically approach zero, or a value less than signal noise on the pressure sensor, resulting in an automatic bolus firing.” See Col. 3, line 65 to Col. 4, line 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the device by modified Jafri to decrease the sensitivity threshold pressure to approach zero as taught by Deane to be able to detect the breath of the user even if they are not fully breathing (see Col. 3, line 65 to Col. 4, line 3).
Conclusion
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.
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/TINA ZHANG/Examiner, Art Unit 3785
/BRANDY S LEE/Supervisory Patent Examiner, Art Unit 3785
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