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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/12/2025 has been entered.
Response to Amendment
This office action is in response to the amendment filed on 12/12/2025. As directed by the amendment, claims 1, 9-10, 12 and 16 have been amended and claims 27-29 have been added. As such, claims 1-2, 4, 8-20 and 26-29 are pending in the instant application.
Response to Arguments
Applicant's arguments, see pages 7-10 of Remarks, filed 12/12/2025, 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 Objections
Claim 15 is objected to because of the following informalities:
Claim 15, line 2, recites “…are exposed to a nitric oxide” but should recite “…are exposed to the nitric oxide”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim(s) 27-29 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 27-29 recite “…wherein the breath slope trigger is operable to detect short, shallow breaths.” However, it is unclear what is meant by detecting short shallow breaths (for e.g. what is the respiration rate/time defined for a short breath and what is the volume defined for a shallow breath). The specification provides no further detail.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim(s) 2, 8 and 11 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 2 recites “…wherein delivery of the dose of nitric oxide occurs within the first third of the total inspiratory time.” However, claim 1 recites “…wherein delivery of at least ninety-nine percent of the dose of nitric oxide occurs in the first third of the total inspiratory time.” As such, claim 2 does not further limit claim 1 as claim 1 already recites delivering the dose of nitric oxide within the first third of the total inspiratory time.
Claim 8 recites “…wherein the nitric oxide is delivered in a series of pulses over a period of time.” However, claim 1 recites “…delivering, using a delivery device, the dose of nitric oxide to the patient in a pulsatile manner over the targeted portion of the total inspiratory time…” Claim 1 uses the language of “a pulsatile manner” which is equivalent to the language of “series of pulses over a period of time” in claim 8. As such, claim 8 does not further limit claim 1.
Claim 11 recites “…wherein the nitric oxide delivery has an antimicrobial effect.” It appears that the claim is attempting to define the subject matter in terms of results to be achieved, which merely amounts to a statement of the underlying problem, without providing clear technical features for achieving this result, and which would encompass all possible solutions to the problem. See MPEP 2173.05(g). It is understood from para [0035] of the specification that the steps of claim 1 inherently provide for the intended result, which flows from NO delivery within the first two thirds total breath inspiration time, such that claim 11 is not properly further limiting.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
It should further be noted, although independent claim 12 has a different preamble, it holds almost the same steps as independent claim 1 (except for determine vs calculate for part b of the claims, however, the claim interpretation/limitation is the same), and therefore the intended result will be the same for both claims 1 and 12.
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 1-2, 4, 8, 11-14 and 26-28 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) and Collins (US 9555201 B2).
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, and
wherein delivery of at least ninety-nine percent of the dose of nitric oxide occurs in a first third of the total inspiratory time.
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).
Regarding claim 2, modified Jafri teaches a method of claim 1, and Kohlmann further teaches wherein delivery of the dose of nitric oxide occurs within the first third 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]).
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 8, modified Jafri teaches a method of claim 1, and Jafri further teaches wherein the nitric oxide is delivered in a series of pulses over a period of time (Jafri teaches application of NO and oxygen to patients as seen on page 6, lines 8-13 and page 7, lines 7-16 and further teaches the controller to be programmed to control the application of the gaseous mixture in a pulse throughout an inhalation cycle as seen on page 15, line 19 to page 16, line 2).
Regarding claim 11, modified Jafri teaches a method of claim 1, and Jafri further teaches wherein the nitric oxide delivery has an antimicrobial effect (“Application of a high dose of e.g. nitric oxide in the evening before bed time may expectorate secretions, cause microbial kill, and/or suppress overnight bacterial regrowth.” See page 27, lines 25-27).
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, and
wherein delivery of at least ninety-nine percent of the dose of nitric oxide occurs in a first third of the total inspiratory time.
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).
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 27, modified Jafri teaches the method of claim 1, and Liu further teaches wherein the breath slope trigger is operable to detect short, shallow breaths (Liu teaches accurately identifying the inspiratory trigger moment of the patient according to the trend of the pressure change of the patient as seen in [0075] and further teaches thresholds that can be adjusted through learning of historical data as seen in [0073]. As such, the thresholds for the trend can be adjusted to detect short shallow breaths if needed based on historical data).
Regarding claim 28, modified Jafri teaches the method of claim 12, and Liu further teaches
wherein the breath slope trigger is operable to detect short, shallow breaths (Liu teaches accurately identifying the inspiratory trigger moment of the patient according to the trend of the pressure change of the patient as seen in [0075] and further teaches thresholds that can be adjusted through learning of historical data as seen in [0073]. As such, the thresholds for the trend can be adjusted to detect short shallow breaths if needed based on historical data).
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) and Collins (US 9555201 B2), 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) and Collins (US 9555201 B2), 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 a nitric oxide.
However, Heinonen teaches wherein less than 10% of poorly ventilated (a) areas of a lung or (b) alveoli are exposed to a 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, 19-20 and 29 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) and Collins (US 9555201 B2).
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, and
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.
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).
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.
Regarding claim 29, modified Jafri teaches the device of claim 16, and Liu further teaches
wherein the breath slope trigger is operable to detect short, shallow breaths (Liu teaches accurately identifying the inspiratory trigger moment of the patient according to the trend of the pressure change of the patient as seen in [0075] and further teaches thresholds that can be adjusted through learning of historical data as seen in [0073]. As such, the thresholds for the trend can be adjusted to detect short shallow breaths if needed based on historical data).
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) and Collins (US 9555201 B2)., 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 is fixed or adjustable from a value of least sensitive to a value of most sensitive.
However, Deane teaches wherein the breath sensitivity 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
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Zapol et al. (US 2019/0070383 A1) teaches one or more triggering events and pre-triggering for NO.
Acker (US 20140000596 A1) teaches the criticality of nitric oxide delivery during the first half of inspiration and delaying delivery may decrease the effectiveness.
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/TINA ZHANG/Examiner, Art Unit 3785
/BRANDY S LEE/Supervisory Patent Examiner, Art Unit 3785