DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Amendments to the Claims and Arguments/Remarks filed 23 March 2026, in response to the Office Correspondence dated 29 December 2025, are acknowledged.
The listing of Claims filed 23 March 2026, have been examined. Claims 2-4, 10, 15, 45, 47, 50, 51, 53, and 56-65 are pending. Claims 2, 4, 50, and 59 are amended and are supported by the originally-filed disclosure. Claims 1, 5-9, 11-14, 16-44, 46, 48-49, 52, and 54-55 are canceled and new claims 60-65 have been added.
Response to Amendment
The applicant’s amendments replacing “the dose” with properly introduced language have been reviewed. The antecedent basis issue is overcome. The rejection of claims 2, 4, and 50 under § 112(b) for lack of antecedent basis is withdrawn.
The applicant has removed or clarified the “algorithm” limitation in claims 2, 4 and 50. The claims now recite concrete steps (e.g., “determining timing based on breath pattern”). The rejection under § 112(b) for indefiniteness based on “algorithm” is withdrawn for claims 2, 4, and 50 and the dependent claims 3, 10, 15, 20, 27, 45, 47-49, 51, and 53-58.
The applicant amended claim 59 to recite, “administering one or more of an anti-IL-6 antibody, hydroxychloroquine, chloroquine, favilar [favipiravir?], remdesivir, a vaccine, an anti-inflammatory, and/or a steroid”. The rejection of claim 59 under 35 U.S.C. § 112(b) is withdrawn for ambiguous combinatorial scope.
The rejections of claims 2-4, 10, 15, 45, 47, 50, 51, 53, and 56-59 under 35 USC § 103 and double patenting are maintained. Newly added claims 60-65 necessitate new grounds for rejection under 35 U.S.C. § 112(b) and 35 USC § 103, as set forth below.
Maintained Rejections
The following rejections are maintained from the previous Office Correspondence dated 29 December 2025, since the art which was previously cited continues to read on the amended/newly cited 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 patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. § 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. § 102(b)(2)(C) for any potential 35 U.S.C. § 102(a)(2) prior art against the later invention.
Claims 2-4, 10, 15, 45, 47, 50, 51, and 53 are rejected under 35 U.S.C. § 103 as being unpatentable over Av-Gay et al. (US20160279165A1; published 29 September 2016, hereinafter referred to as “Av-Gay”) in view of Akerström et al. (Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus. J Virol. 2005 Feb;79(3):1966-9) and in further view of Goldstein (US20130239962A1; published 19 September 2013).
Av-Gay expressly teaches of treating a human subject in need of inhalation NO using a breathing cycle-coordinated pulse delivery system for treating bacterial, viral and/or fungal upper and/or lower respiratory tract infection (¶[0088], ¶[0092], ¶[0115]). The method is described NO as useful for a "broad range of bacteria, parasites, fungi and viruses" (¶[0004]) and for diseases "associated with a pathogenic microorganism" (¶[0089]), including viral infections such as those caused by coronavirus and SARS (¶[0110]). The method requires breathing cycle-coordinated pulse delivery inhalation, which inherently involves detecting the patient's breath pattern, including the inhalation period (Ti). The system is configured to detect the various phases of the breathing cycle, namely the onset of the inhalation and the exhalation periods (¶[0186]).
The core the invention by Av-Gay is the delivery of NO in pulses during a pulse delivery period (¶[0184]) that comprises only a portion of the total inhalation period (¶[0185] and ¶[0187]; see also Drawing Figures 1 and 2). The timing of the NO pulse is determined algorithmically based on the detected breath cycle. Av-Gay teaches that the pulse delay period is automatically set to 20% of the inhalation period and the pulse delivery period can be set to 60% of the inhalation period, based on the sensed flow (¶[0187]). The limitation that delivery occurs "within a first half of the total inspiratory time" is expressly taught by Av-Gay, which describes a "pulse delay period" followed by the pulse delivery (¶[0185]), and exemplifies setting the pulse delay to 20% of Ti, meaning delivery occurs in the remaining 80%, beginning within the first half (¶[0187]), thus teaching the limitation of instant claims 10, 45 and 51.
It would be obvious to apply the invention taught by Av-Gay to the SARS-CoV-2 causing COVID-19 as a species of the coronavirus genus, particularly in light of the pandemic providing strong motivation to do so (see In re Kubin, 561 F.3d 1351, 1357 (Fed. Cir. 2009)) and the effective dose is a matter of experimental optimization per pathogen.
As further support, Akerström teaches that NO possesses antiviral properties and specifically inhibits the replication cycle of the severe acute respiratory syndrome coronavirus (SARS-CoV) (Abstract and page 1967, last paragraph). This reference provides the specific motivation for one of ordinary skill in the art to use the high-dose, pulsed delivery method of Av-Gay, which is already designed for treating infections, for the particular purpose of treating a SARS-CoV viral infection (with specific strains causing a disease such as COVID-19) . The combination is obvious because Av-Gay provides an effective delivery platform NO and Akerström identifies a specific therapeutic application of NO for antiviral treatment of SARS-CoV, thus teaching the limitations of instant claims 2-4.
Av-Gay teaches that the in vitro concentration and regimen delivering an "effective amount" of NO for antimicrobial effect in variable based on the pathogen (¶[01561]-[0164]). Av-Gay specifies that the inhalant comprises NO at a concentration of at least 160 ppm during the pulse delivery period (claim 1 and ¶[0025]). One of ordinary skill in the art, informed by the delivery parameters taught by Av-Gay and standard medical practice for calculating inhaled drug delivery would be able to use a straightforward and predictable conversion from the concentration (ppm) to dosage range expressed as mcg/kg IBW/hr.
A common regimen described is 160 ppm for 30 minutes, repeated up to 5 times a day (¶ [0180]-[0181]), equating to a maximum daily exposure time of 2.5 hours (150 minutes) or 10.4% (0.104) hourly dose (2.5 hours / 24 hours). Assuming standard parameters for a typical adult of a minute ventilation (VE) of 6 L/min (a standard resting value), an ideal patient body weight (IBW) of 70 kg (standard reference weight), the density of NO gas of 1.34 g/L (at standard temperature and pressure) and the conversion factors 1 ppm NO = 1.34 mg/m³ and 1,000 mcg = 1 mg, the following calculation can be made:
1) Mass flow rate NO inhaled continuously per minute= Concentration x Minute Ventilation x Density of NO= 160 ppm x 6 L/min x 1.34 mg/m³
6 L/min converted to m³/min: 6 / 1000 = 0.006 m³/min
Mass flow rate = 160 x 0.006 m³/min x 1.34 mg/m³ = 1.2864 mg/min
2) Adjust the continuous rate to reflect non-continuous pulse delivery cycles
Adjusted mass flow rate = 1.2864 mg/min * 0.104 = 0.1338 mg/min
3) Convert to an hourly dose and normalize to patient weight
Hourly dose = 0.1338 mg/min * 60 min/hr = 8.028 mg/hr
Dose per kg = 8.028 mg/hr / 70 kg = 0.1147 mg/kg/hr
Convert mg to mcg (micrograms): 0.1147 mg/kg/hr * 1000 mcg/mg = ~115 mcg/kg/hr
Thus, for a standard 70 kg adult under the described pulsed regimen (e.g., 160 ppm for 30 minutes, 5x/day), the calculated dose is approximately 115 mcg/kg IBW/hr. The claims specific the pulsed delivery of ≥160 ppm NO or ≥115 mcg/kg IBW/hr, which encompasses the instant claim 2 range of about 500-1200 mcg/kg IBW/hr.
Choosing this specific instant claimed range would have been obvious to a person of ordinary skill in the art given that Av-Gay discloses adjustable dosing of NO are required to be effective depending on the target pathogen (ranging from 400-2000 ppm/hr) and that the effective doses can be determined by routine experimentation for a particular pathogen to optimize the dose for effectiveness against a given pathogen (Table 1; ¶[0161]). Thus, specifically selecting the ≥160 ppm NO or ≥115 mcg/kg IBW/hr, of 500-1200 mcg/kg IBW/hr NO effective dose and duration would have been a matter of routine optimization for a given target pathogen in view of known pulsatile inhaled NO toxicity thresholds in clinical practice.
Further, Goldstein method of delivering nitric oxide to a patient, comprising administering every breath or intermittently during inspiration a dose of inhaled nitric oxide as a “pulse” or “bolus” at a delivery concentration of greater than 2000 ppm. In one or more embodiments, the delivery concentration ranges from 2000-10,000 ppm and according to one or more embodiments, the dose is in the range of 0.001 to 4.5 mg/kg/hr [1-4500 mcg/kg/hr for a 70 kg patient] (¶[0005]-[0009]). Thus, the instant claimed sub-range of 500-1200 mcg/kg IBW/hr is encompassed with in the wider range taught by Goldstein. Selecting a narrower range within a disclosed broader range is prima facie obvious absent evidence of criticality or unexpected results (see In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003)). The claimed dosing overlaps predictable outcomes from known inhaled NO administration and reflects routine dose titration.
Av-Gay teaches administering NO in combination with at least one additional gas (e.g., oxygen; a standard feature of inhalation therapies), which involves an inhalant gas mixture (¶[0067]) and in which controlling concentration of O2 and FiO2 levels is specified for the invention (claims 16 and 17), thus teaching the limitation of instant claims 15, 47 and 53.
Treatment durations of 15 minutes to 4 hours over a course of a treatment period and periods of at least five days are disclosed by Av-Gay. Av-Gay teaches a first time period of about 30 minutes (¶[0181]; claim 10), and repeated in cycles from 1 to 6 per day (claim 12), over a period from 1 day to 7 days (claim 14), and wherein longer time periods of intermittent NO administration are also contemplated (¶[0183]). This encompassing the claimed ranges of instant claims 20, 27, 48, 49, 54 and 55.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to use the invention of Av-Gay for treating severe respiratory infections, including by coronavirus infection as taught by Akerström, with high-dose pulsed NO at the doses taught by Goldstein for delivering nitric oxide to a patient and adjusting the dose of NO specifically to be effective in the administration protocol for the SARS-CoV2 target pathogen, motivated by the teachings of Av-Gay that adjustable dosing of NO are required to be effective depending on the target pathogen and determined by routine experimentation for a particular pathogen with a reasonable expectation of success.
Claim 2, 4, 50, and 56-59 are rejected under 35 U.S.C. § 103 as being unpatentable over Av-Gay et al. (US20160279165A1; published 29 September 2016, hereinafter referred to as “Av-Gay”) in view of Akerström et al. (Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus. J Virol. 2005 Feb;79(3):1966-9) and in further view of Goldstein (US20130239962A1; published 19 September 2013), and Chen et al. (Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in Beijing. Clin Infect Dis. 2004 Nov 15;39(10):1531-5; Epub 2004 Oct 22, hereinafter referred to as “Chen”).
Av-Gay, Akerström and Goldstein teach the limitations of instant claims 2, 4, and 50, as described above, from which instant claims 56-59 depend, however does not teach specific limitations of instant claims 56-59.
A method of treating severe respiratory infections with high-dose pulsed NO inherently aims to and would be expected to improve oxygenation as a clinical outcome, Akerström provides the motivation to apply this method to a coronavirus infection, therefore, claim 50 is also rendered obvious (see also ¶[0163] wherein, “other lung function parameters were improved”). The result of reducing or eliminating the need for supplemental oxygen or mechanical ventilation is an inherent and expected outcome of successfully treating a severe respiratory infection with a therapy that improves oxygenation.
Further, Chen teaches a method of treating patients with severe acute respiratory syndrome (SARS) using inhaled nitric oxide, resulting in improved arterial oxygenation and enabled the reduction/discontinuation of inspired oxygen therapy and ventilator treatment support (page 1, Abstract). The discussion section states, “NO is also a potent antimicrobial agent and exerts an inhibitory effect on several viruses. A recent study on clinical isolates of coronavirus showed that glycyrrhizin (from the liquorice root) inhibited the replication of the SARS-associated virus [10]. This effect was presumably mediated via NO release. We have recently shown that the NO donor S-nitroso-N-acetylpenicillamine greatly increased the survival rate of SARS coronavirus-infected Vero E6 cells. It is thus tempting to attribute our results to inhaled NO treatment.” (page 3, right column, paragraph 4), thus instant claims 56-58 are rendered obvious as well.
Av-Gay discloses, “An elevation of inflammatory markers is associated with a phenomenon called “cytokine storm”, which has been observed in subjects undergoing NO inhalation treatment.” (¶[0278]) and hence according to some embodiments of the invention, monitoring inflammatory cytokines such as, IL-6 serum levels in the subject is carried out to ensure a less than 2 acceptable deviation units from a baseline change (¶[0283]), thus providing the motivation further administer an anti-IL-6 antibody, anti-inflammatory, and/or a steroid in addition to the NO to mitigate an unacceptable increase in inflammatory cytokine levels detected by the monitoring or to be used to prevent or treat the development a cytokine storm in patients administered inhaled NO.
Chen explicitly discloses co-administration of antiviral medication (ribavirin, 0.5–1.0 g/day) and steroid treatment (methylprednisolone, 40–160 mg/day) with the inhaled NO (page 1, right column, paragraph 6). In addition, antiviral agents like remdesivir were being actively investigated and deployed for COVID-19. Hence, the addition of other therapeutics presented in instant claim 59 is a predictable combination of known anti-inflammatory agents or steroids used to combat cytokine storms associated with inhaled NO treatment or additional antiviral treatments.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to use the invention of Av-Gay A for treating severe respiratory infections, including by coronavirus infection as taught by Akerström, with high-dose pulsed NO inherently expected to improve oxygenation other lung function parameters which is intrinsically expected to result of reducing the need for supplemental oxygen or mechanical ventilation, as also taught by Chen. The addition of other known therapeutics in combination with inhaled NO treatment represent routine optimization of a treatment regimen within the commonplace practice of combining multiple therapeutic modalities with different mechanisms of action to treat a complex disease.
Claim Rejections – Nonstatutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
Instant claim 2 is provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 1, 11 and 12 of co-pending Application No. US 17/055,365 (referred to hereafter as Shah). This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Although the claims at issue are not identical, they are not patentably distinct from each other because Shah claim 1 asserts, “A method for delivery of a dose of nitric oxide to a patient in need…”, which would include any patient, including treating a viral, bacterial, or protozoal infection in a patient harboring a viral, bacterial, or protozoal infection leading to development of a disease state, as per instant claim 2. Claim 11 includes, “wherein the nitric oxide delivery has an antimicrobial effect.”, which would even more specifically encompass instant claim 2 bacterial or protozoal infections.
Claim 12 is more specific than claim 1, specifying, “A method for treating a cardiopulmonary disease in a patient…”. Claim 12 encompasses instant claim 2 (e.g., cardiopulmonary diseases caused by viral infections including influenza virus causing respiratory syncytial virus (RSV) or SARS-CoV-2 (COVID-19) causing acute respiratory distress syndrome (ARDS); bacterial infections including Streptococcus pneumoniae and Legionella pneumophila causing pneumonia or Mycobacterium tuberculosis causing tuberculosis; protozoal infections including Toxoplasma gondii causing pneumonia or Babesia spp. causing ARDS).
Instant claims 2-4, and 50 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 1 and 12 of co-pending Application No. US17/055,365 (referred to hereafter as Shah). This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Although the claims at issue are not identical, they are not patentably distinct from each other because, as cited above, Shah claim 1 includes any patient in need for any reason, which would encompass treating patients with SARS -CoV2 viral infections leading to the development of COVID-19, as per instant claim 3, inhibiting viral replication of SARS-CoV2 virus in a patient, as per instant claim 4, and improving oxygenation of a patient suffering from SARS-CoV2 infection or COVID-19, as per instant claim 50.
Shah claim 12 further specifies wherein the method is used to treat cardiopulmonary disease in a patient, more specifically encompassing instant claims 3, 4, and 50.
Instant claims 2 and 10, 4 and 45 and 50 and 51 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claim 4 of co-pending Application No. US17/055,365 (referred to hereafter as Shah). This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Although the claims at issue are not identical, they are not patentably distinct from each other because, as cited above, Shah claim 1 includes any patient in need for any reason, encompassing instant claims 2, 4 and 50. Further, Shah claim 4 claims “wherein delivery of the dose of nitric oxide occurs within the first half of the total inspiratory time.”, as in the limitation recited for instant claims 10, 45 and 51.
Instant claims 2, 4, and 50 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 12 and 26 of co-pending Application No. US17/055,365 (referred to hereafter as Shah). This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Although the claims at issue are not identical, they are not patentably distinct from each other because, as cited above, Shah claim 1 includes any patient in need for any reason, encompassing instant claims 2, 4 and 50. Further, Shah claim 12 states “c) Delivering said dose of nitric oxide to said patient in a pulsatile manner over a portion of the total inspiratory time for a period of time required for a therapeutically effective amount of nitric oxide to be delivered to said patient.”, and claim 26 states, “The method of claim 1, wherein the dose of nitric oxide is a therapeutically effective dose.”, thus would encompass the administration dose range of 75-200 mcg/kg IBW/hr, as prescribed by instant claims 12, 46 and 52.
New Rejections
The following new rejections are made from the previous Office Correspondence dated 29 December 2025, as the Applicant's amendment necessitated the new grounds of rejection presented below based on the amended/newly cited limitations.
Claim Rejections - 35 USC § 112(b)
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 Applicant regards as his invention.
Claims 60-65 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, regards as the invention.
Claims 60, 62, and 64 recite detecting a breath pattern "including utilizing a breath level trigger and a breath slope trigger, wherein the breath level trigger detects a breath when a threshold pressure is reached upon inspiration, and wherein the breath slope trigger detects the breath when a slope of a pressure waveform indicates inspiration”. The specification does not describe how both triggers function together, what threshold pressures are used, what slope values indicate inspiration, or how conflicts between the triggers are resolved. One of ordinary skill in the art would not reasonably be able to ascertain the metes and bounds of the claims with certainty.
Claims 61, 63, and 65 depend from claims 60, 62, and 64, respectively, and incorporate the same indefiniteness and accordingly, are rejected for the same reasons.
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-AlA) 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 patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. § 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. § 102(b)(2)(C) for any potential 35 U.S.C. § 102(a)(2) prior art against the later invention.
Claim 2, 4, 50, and 60-65 are rejected under 35 U.S.C. § 103 as being unpatentable over Av-Gay et al. (US20160279165A1; published 29 September 2016, hereinafter referred to as “Av-Gay”) in view of Akerström et al. (Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus. J Virol. 2005 Feb;79(3):1966-9) and in further view of Goldstein (US20130239962A1; published 19 September 2013), and Weismann and Baum (US5303700A; published 19 April 1994, hereinafter referred to as “Weismann”).
Av-Gay, Akerström and Goldstein teach the limitations of instant claims 2, 4, and 50, as described above, from which instant claims 60 and 61, 62 and 63, and 64 and 65 depend, respectively.
Av-Gay teaches a method and device for breathing cycle-coordinated pulse delivery inhalation of high-concentration (at least 160 ppm) gaseous NO (claim 1) for treating various respiratory infections and diseases including SARS (¶[0339]), with an NO pulse delay period ranging from 0-2500 ms (¶[0037]), comprising detecting breath pattern using a breath level trigger that detects breath when a threshold pressure is reached (¶[0403] and ¶[0406]) and detection of slope of pressure waveform to trigger modulation of inhalation waveform (¶[0420]-[0425]).
Weismann teaches a method for recognizing the respiratory phases of a patient for controlling a ventilating apparatus by detecting breath patterns utilizing a breath slope trigger that detects a breath when a threshold of a slope of a pressure waveform of the respiratory flow curve is reached upon inspiration (claim 1) and a breath level trigger (triggering system that analyzes the respiratory flow curve, which inherently involves threshold-based detection; claim 5 adds the limitation of selecting extreme values as the start of the corresponding time interval, which implies level-based criteria). Thus, teaching a dual triggering system that analyzes multiple characteristics of the respiratory flow curve, including both the slope and the timing relative to zero crossings. Weismann teaches selecting a pulse delay time in the range of 50 ms to 800 ms (claim 8). Weismann’s invention is directed towards ventilator triggering systems generally, not specifically to inhaled nitric oxide delivery.
One of ordinary skill in the art prior to the instant effective filing date seeking to improve the reliability and accuracy of breath detection of Av-Gay’s pulse delivery system to ensure consistent, safe and more efficient NO administration would be motivated to combine the invention of Av-Gay with the dual-trigger breath detection system of Weismann, because both are directed to breath-actuated gas delivery systems. The fields of breath detection and triggering for gas delivery is clearly analogous and one of ordinary skill in the art would reasonably consult references related to ventilator triggering technology for improving a breath detection system for an NO inhalation device.
In addition, Weismann explicitly addresses the problem of reliably detecting onset of inspiration, particularly in patients with irregular breathing patterns or low inspiratory effort. The dual-trigger system (slope and level) taught by Weismann provides a more robust detection mechanism than a single-threshold system. Thus, applying a known technique (Weismann) to a known device ready for improvement (Av-Gay) to yield predictable results (improved breath detection accuracy, reduces false triggering, and more reliable NO pulse timing) is thus, prima facie obvious and one of ordinary skill in the art would have a reasonable expectation of success in combining the teachings.
Response to Arguments
Applicant Arguments/Remarks of the reply, filed 23 March 2026, have been fully considered.
The applicant argues that Av-Gay teaches away from the claimed dose because Av-Gay is “entirely concerned with finding the upper limit of high concentration dose delivery” and corresponds to ~115 mcg/kg/hr and that one of skill would be discouraged from doubling the dose to the claimed range of 250-1200 mcg/kg/hr. This argument is unpersuasive.
Av-Gay teaches adjustable NO dosing depending on pathogen, and iterative optimization of concentration and duration to determine an effective dose by routine experimentation for a particular pathogen (¶[0161], Table 1). Table 1 of Av-Gay lists NO doses ranging from 400-2000 ppm for various pathogens. The examiner’s calculation of 115 mcg/kg/hr from Av-Gay’s 160 ppm example represents only one specific regimen for a pathogen. Akerström establishes NO inhibits coronavirus replication. A person of ordinary skill would understand that optimizing the NO dose for a different pathogen (e.g., SARS-CoV-2) within Av-Gay’s disclosed range of 400-2000 ppm would encompass doses corresponding to the claimed range. Routine dose-escalation studies are standard in the art. This constitutes routine optimization with reasonable expectation of success.
Moreover, the claimed range of 250-1200 mcg/kg/hr is squarely within the range taught by Goldstein (0.001-4.5 mg/kg/hr = 1-4500 mcg/kg/hr); see In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003), wherein selecting a narrow sub-range from a prior art broad range is prima facie obvious absent unexpected results). The applicant has provided no evidence of criticality or unexpected results associated with this specific sub-range. Mere recitation of a range without comparative data showing a surprising effect does not overcome obviousness.
The applicant alleges Av-Gay discourages higher doses due to toxicity. Av-Gay explicitly teaches high concentration pulsed NO (≥160 ppm), yet Goldstein teaches substantially higher doses (up to 4500 mcg/kg/hr). The art collectively teaches balancing efficacy and toxicity via dosing adjustments. A preference for lower toxicity does not constitute teaching away from higher dosing when higher dosing is explicitly disclosed elsewhere and optimization is expected in clinical contexts. Av-Gay discloses 30-minute sessions (claim 10), repeated multiple times per day (claims 11-13), and treatment over multiple days from 1-7 days (claim 14), which reasonably encompass 15 minutes to 4 hours/day for ≥5 days. Accordingly, the rejections under 35 U.S.C. § 103 are maintained.
The applicant argues that Goldstein relates to pulmonary hypertension, not infections, and thus would not motivate combination. This argument fails because Akerström and Chen specifically provide the motivation to use NO against SARS-CoV. Chen explicitly teaches that inhaled NO improves oxygenation in SARS patients (Abstract). The combination of Av-Gay (delivery platform), Akerström (antiviral motivation), and Chen (oxygenation outcome) teach the limitation of claim 50. Goldstein is merely cumulative for the dose range.
Regarding the combination therapy, Av-Gay teaches monitoring inflammatory cytokines including IL-6 during NO therapy (¶[0278] and ¶[0283]). Chen teaches co-administration of steroids (methylprednisolone) and antivirals (ribavirin) with inhaled NO. One of ordinary skill would have been motivated to combine these known therapeutics with NO based on these express teachings.
Thus, the limitations of claims 10, 15, 45, 47, 51, 53, 56-58 continue to be met by Av-Gay and/or Chen and the functional outcomes (e.g., improved oxygenation, reduced ventilation) are inherent or expected clinical results. The rejections under § 103 are maintained.
The applicant states that terminal disclaimers “will be filed when the claims are otherwise in condition for allowance.” This is not a response that obviates the rejection (see MPEP § 804.02). All provisional double patenting rejections over co-pending Application No. 17/055,365 are maintained. No terminal disclaimer has been filed. Until a terminal disclaimer is filed, the claims remain rejected on this ground.
Conclusion
No claims are allowed.
The 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 (87 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA L. SCOTLAND whose telephone number is (571) 272-2979. The examiner can normally be reached M-F 9:00 am to 5:00 pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, Applicant is encouraged to use the USPTO Automated Interview Request (AIR) at: http:/Awww.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’ s supervisor, Robert A. Wax can be reached at (571) 272-0623. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https:/Awww.uspto.gov/patents/apply/patent- center for more information about Patent Center and https:/Awww.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at (866) 217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call (800) 786-9199 (IN USA OR CANADA) or (571) 272-1000.
/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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