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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 17 July 2026, has been entered.
Status of the Claims
Amendments to the Claims and Arguments/Remarks filed 17 July 2026, in response to the Office Correspondence dated 21 April 2026, are acknowledged.
The listing of Claims filed 17 July 2026, are been examined.
Claims 2-4, 10, 15, 45, 47, 50, 51, 53, and 56-65 are pending. Claims 1, 5-9, 11-14, 16-44, 46, 48-49, 52, and 54-55 are canceled. No claims are amended.
Response to Amendment
Claims 60-65 were previously rejected under 35 U.S.C. §112(b) as indefinite because the specification allegedly did not explain how the breath-level trigger and breath-slope trigger function together, identify numerical pressure and slope thresholds, or explain how conflicts between the triggers are resolved. Upon reconsideration, applicant’s arguments are persuasive.
Claims 60, 62, and 64 objectively define the two recited detection criteria including the breath-level trigger detects a breath when a threshold pressure is reached upon inspiration; and the breath-slope trigger detects a breath when a slope of a pressure waveform indicates inspiration. The specification expressly describes embodiments in which at least two separate triggers function together, identifies the level-trigger and slope-trigger criteria, explains that the slope trigger may more accurately detect short or shallow breaths, states that combining the triggers improves overall breath-detection accuracy, and describes fixed, adjustable, programmable, and relatively different sensitivity settings for the triggers.
The claims therefore inform a person of ordinary skill that both a pressure-level criterion and a pressure-waveform-slope criterion are used to detect inspiration. Whether the two triggers are configured with particular numerical thresholds, relative sensitivities, Boolean logic, priority rules, or conflict-resolution settings concerns implementation breadth rather than uncertainty in the claim boundary. Accordingly, the rejection of claims 60-65 under 35 U.S.C. §112(b) is withdrawn.
The prior calculation purporting to derive an approximately 115 mcg/kg IBW/hr dose from Av-Gay is withdrawn and superseded. The rejections under 35 U.S.C. §103 are restated as new grounds to the extent they rely upon the corrected dose analysis and newly cited prior art.
The previously made provisional nonstatutory double-patenting rejections are maintained. Claims 60-65 were added in the previously entered amendment and an additional provisional nonstatutory double-patenting rejections of claims 60-65 are made, as outlined further below.
No claims have been amended or added, however, because a new factual analysis is presented and newly cited prior art materially alter the grounds applied to the pending claims, this action is made non-final.
Claim Objections
Claims 2-4, 50, 59, 61, 63, and 65 are objected to because of the following informalities:
Claims 2, 4, and 50 recite “an inhaled nitric oxide.” Because nitric oxide is recited as a substance rather than as one member of a countable class, the article “an” should be deleted.
Claim 2 recites “leading to development of a disease state.” The phrase should be amended to recite “leading to the development of a disease state.”
Claims 3, 4, and 50 recite “SARS-CoV2”. The conventional nomenclature is “SARS-CoV-2,” and the claims should be amended for consistency with the specification and clarity to should be “SARS-CoV-2”. In addition, claim 4 recites “SARS-CoV2 virus.” The applicant should revise the phrase to “SARS-CoV-2”, as virus is redundant.
Claim 50 inconsistently refers to both “the nitric oxide” and “the inhaled nitric oxide.” The applicant should use consistent terminology.
Claim 59 redundantly recites both “one or more of” and “and/or.” The applicant should employ a single, unambiguous formulation for the listed alternatives.
Claims 61, 63, and 65 recite “timing for administration,” whereas the corresponding independent claims recite “timing of administration.” The applicant should use consistent terminology.
Appropriate correction is required. See MPEP §608.01(m), including form paragraph 7.29.01 regarding objections based on spelling, terminology, and other claim informalities.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. § 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. § 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2, 10, 15, 56, 60, and 61 are rejected under 35 U.S.C. § 112(a) or 35 U.S.C. § 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. While being enabling for the treatment of SARS-CoV-2 infection/COVID-19 using the disclosed pulsed inhaled-nitric-oxide treatment platform, does not reasonably provide enablement for the substantially broader claimed scope encompassing bacterial and protozoal infections generally. The specification therefore does not enable one of ordinary skill in the art to use the invention commensurate in scope with these claims.
The enabled subject matter is the SARS-CoV-2/COVID-19 respiratory-infection embodiment of claims 2, 10, 15, 56, 60, and 61 directed to pulsed inhaled NO treatment of SARS-CoV-2 infection and COVID-19, wherein the specification expressly identifies treatment of COVID-19 using the claimed breath-coordinated delivery methodology, describes NO as having activity against SARS-related coronavirus, provides human COVID-19 treatment data, and expressly discloses high-dose pulsed iNO administration from approximately 250 to 1200 mcg/kg IBW/hr and short daily treatment periods.
Thus, the SARS-CoV-2/COVID-19 pulmonary-infection species falling within the “viral infection” alternative of claims 2, 10, 15, 56, 60, and 61 is considered enabled. However, claims 2, 10, 15, 56, 60, and 61 extends far beyond that supported and enabled subject matter. Claims 2, 10, 15, 56, 60, and 61 are directed broadly to any viral, bacterial, or protozoal infection, leading to any disease state in a patient, without restriction to a respiratory infection, pulmonary site, particular pathogen, particular class of pathogens having a demonstrated sensitivity to NO, or an infection for which inhaled NO reaches the infected tissue at a therapeutically effective exposure. The specification does not provide a representative disclosure demonstrating therapeutic use of the claimed high-dose, short-duration inhaled-NO regimen across the full bacterial or protozoal scope. The specification does not provide representative working examples demonstrating treatment across bacterial infections, protozoal infections, or materially diverse viral infections.
To determine if the claims are enabled, the factors set forth in In re Wands, 858 F.2d 731 (Fed. Cir. 1988) were applied as follows (see MPEP §2164.01(a)):
Breadth of the claims- The claims encompass multiple biological kingdoms and classes of pathogens, numerous anatomical sites of infection, acute and chronic disease states, patients with substantially different pulmonary function, and organisms having materially different sensitivities to NO.
Nature of the invention- The invention concerns therapeutic treatment of infection in a patient using a potentially toxic reactive gas. Therapeutic success depends upon achieving sufficient exposure at the infected tissue while limiting methemoglobinemia, nitrogen dioxide exposure, pulmonary injury, and systemic toxicity.
State of the prior art- The record establishes that inhaled NO delivery and certain antimicrobial effects were known, but it does not establish that a common dose and intermittent schedule was predictably effective across the full claimed range of viral, bacterial, and protozoal infections.
Level of ordinary skill- A person of ordinary skill would possess substantial knowledge of pulmonary medicine, respiratory gas delivery, infectious disease, pharmacology, and clinical dosing. A high level of skill, however, does not replace missing guidance regarding which pathogens, disease states, tissue compartments, or patients respond to the claimed regimen.
Predictability of the art- Antimicrobial and clinical responses to NO are not shown to be sufficiently predictable across the claimed pathogen classes. Differences in organism susceptibility, infection location, tissue penetration, host response, ventilation, and toxicity materially affect outcome.
Amount of direction or guidance- The specification supplies general dose, pulse, and treatment-duration parameters but does not provide a pathogen-by-pathogen selection procedure, an objective susceptibility threshold, a dose-selection algorithm tied to organism sensitivity, or clinical criteria for determining when the claimed intermittent regimen will be therapeutically effective.
Presence or absence of working examples- The working examples concern COVID-19 patients and substantially lower-dose, longer-duration administration. No working example demonstrates treatment of a bacterial or protozoal infection using the claimed high-dose intermittent regimen.
Quantity of experimentation- Practicing the full scope would require screening diverse pathogens, determining effective pulmonary or tissue exposure, conducting dose-response and toxicity studies, selecting pulse and duration parameters, and performing disease-specific animal or clinical studies. Such experimentation would not merely involve routine verification of a generally applicable protocol; it would amount to a research program for identifying which portions of the genus are operative.
Considering the factors set forth in In re Wands, the scope of enablement bears a reasonable correlation to the disclosed SARS-CoV-2/COVID-19 respiratory embodiment, but is not commensurate with the substantially broader bacterial and protozoal scope sought by claim 2. Claims 10, 15, 56, 60, and 61 depend directly or indirectly from claim 2 and retain the bacterial and protozoal alternatives. Their additional pulse-timing, additional-gas, respiratory-support, breath-trigger, and pulse-delay limitations do not narrow the infection genus to the enabled SARS-CoV-2/COVID-19 species or another adequately supported class.
Claims 2, 10, 15, 56, 60, and 61 are therefore rejected under §112(a) because the scope of the enabling disclosure is not commensurate with the full bacterial and protozoal scope of the claims. Claim 3 is not included in this scope-of-enablement rejection because claim 3 limits claim 2 to the SARS-CoV-2/COVID-19 species identified above as falling within the enabled scope.
Claims 4, 45, 47, 57, 59, 62, and 63 are rejected under 35 U.S.C. § 112(a) or 35 U.S.C. § 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. While the specification provides sufficient enabling guidance for a limited SARS-related coronavirus antiviral use of pulsed inhaled NO within the claimed administration parameters, it does not reasonably provide enablement commensurate with the full breadth of the claimed in-patient SARS-CoV-2 replication-inhibition result throughout the entire claimed dose and treatment-duration scope. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claims 4, 45, 47, 57, 59, 62, and 63 are rejected because the specification does not enable the full scope of the claimed method of inhibiting SARS-CoV-2 replication in a patient without undue experimentation. Claim 4 requires an in-patient antiviral result, “inhibiting viral replication of SARS-CoV-2”, using the claimed high-dose, breath-coordinated, intermittent regimen.
The specification expressly teaches that NO plays a role in suppressing viral replication, relies upon Akerström’s demonstration that NO inhibits SARS-CoV replication, identifies a method for inhibiting SARS-CoV-2 replication, discloses pulsed iNO administration to SARS-CoV-2/COVID-19 patients, expressly identifies high-dose administration beginning at 250 mcg/kg IBW/hr, and reports successful administration of 250 mcg/kg IBW/hr to a COVID-19 patient. The specification therefore supplies a concrete inhaled-NO platform and expressly identifies the intended SARS-CoV-2 antiviral application.
The state of the art also provides guidance relevant to that limited enabled scope. Akerström demonstrates direct inhibition of SARS-CoV replication by NO; Av-Gay teaches high-concentration pulsed inhaled NO for SARS/coronavirus respiratory infection; and Goldstein teaches pulsed inhaled NO dosing in a weight-normalized range encompassing doses recited by claim 4. Taken together with the disclosure, this record provides sufficient technical guidance that the Examiner does not question enablement of at least a limited SARS-related coronavirus antiviral embodiment employing the known pulsed-NO delivery technology and operating within a supported portion of the disclosed dose/timing parameters.
The deficiency instead concerns the applicant’s attempt to claim the antiviral endpoint across every administration falling anywhere within approximately 250-1200 mcg/kg IBW/hr, every daily treatment duration from approximately 15 minutes to four hours, for at least five days, in any patient, without a disclosed dose-exposure-response relationship demonstrating that the entire scope achieves in-patient SARS-CoV-2 replication inhibition.
To determine if the claims are enabled, the factors set forth in In re Wands, 858 F.2d 731 (Fed. Cir. 1988) were applied as follows (see MPEP §2164.01(a)):
Breadth of the claims- Claim 4 covers the entire approximately 250-1200 mcg/kg IBW/hr range, daily treatment periods from approximately 15 minutes to four hours, treatment of any patient, and any clinically meaningful degree of replication inhibition. Claim 4 extends across an approximately 4.8-fold dose range, approximately 16-fold variation in daily treatment duration, treatment courses of at least five days without an upper endpoint, any patient, and any degree of inhibition sufficient to satisfy the claimed functional endpoint.
Nature of the invention- The claim requires a biological antiviral result in a human patient, not merely delivery of NO or improvement in pulmonary hemodynamics. The limitation concerns an antiviral biological response in infected tissue. The therapeutic administration technology itself is well developed in the disclosure, but the claimed result depends upon the relationship among NO exposure, dose, treatment time, tissue concentration, virus, and patient.
State of the art- Laboratory observations concerning coronavirus susceptibility to NO do not by themselves establish an in vivo dose-exposure-response relationship for pulsatile inhaled NO in SARS-CoV-2 patients. Akerström supplies evidence supporting NO-mediated inhibition of SARS coronavirus, and Av-Gay supplies a pulmonary pulsed-NO treatment platform for SARS/coronavirus infection. This supports enablement of a limited antiviral embodiment. The references do not establish that every combination throughout the claimed dose/time ranges produces equivalent in-patient viral-replication inhibition.
Skill in the art- Skilled clinicians and pharmacologists could conduct the required studies, but the need for skilled investigation does not make the experimentation routine. It does not establish that the entire claimed dose/time matrix produces the claimed functional antiviral endpoint.
Predictability of the art- Translation from in vitro viral inhibition to clinical inhibition in infected airway and pulmonary tissues is not shown to be predictable. The art provides a reason to expect antiviral activity against SARS-related coronavirus under appropriate NO exposure conditions, but the magnitude of replication inhibition across widely different total daily exposures is not shown to be uniformly predictable.
Amount of direction or guidance- The specification does not identify a target tissue NO concentration, exposure threshold, viral-load reduction criterion, biomarker, or dosing-adjustment procedure tied to viral replication. The specification provides extensive delivery parameters and identifies the antiviral purpose, but does not correlate the full range of doses and daily treatment periods with viral-load reduction, tissue antiviral exposure, or another quantitative measure of SARS-CoV-2 replication.
Presence or absence of working examples- No working example directly measures inhibition of SARS-CoV-2 replication in a patient treated with the claimed regimen. The human examples demonstrate administration to COVID-19 patients, including administration at 250 mcg/kg IBW/hr, and clinical respiratory outcomes. They do not measure replication throughout the full claimed range.
Quantity of experimentation- Determining operative embodiments would require controlled dose-ranging studies with serial viral measurements, pharmacodynamic assessment, tissue-exposure analysis, and safety monitoring. Once outside the limited SARS-related antiviral embodiments supported by the disclosure and state of the art, determining whether materially different dose/time combinations throughout the remaining scope satisfy the claimed in-patient replication endpoint would require antiviral dose-response and pharmacodynamic evaluation not supplied by the specification.
Therefore, a limited enabled antiviral subset within claim 4 is enabled, but the specification does not reasonably enable the claimed SARS-CoV-2 replication-inhibition result commensurate with the entire dose, treatment-duration, and patient scope claimed. Accordingly, undue experimentation would be required to practice the full scope of the claimed antiviral method. The dependent claims 45, 47, 57, 59, 62, and 63 retain that excessive functional scope and do not narrow the parent claim to a demonstrated antiviral dose/exposure subset. They are therefore rejected for the same reason.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. § 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. § 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2, 10, 15, 56, 60, and 61 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The specification recites the subject matter of claims 2 and 4 nearly verbatim in paragraphs ¶[0012] and ¶[0014], however, the passages merely state desired functional results and do not demonstrate possession of the full claimed therapeutic subject matter. A mismatch exists between the results actually measured (i.e., oxygenation, oxygen use, respiratory support, and discharge) and the substantially broader therapeutic results claimed (i.e., treatment of any bacterial or protozoal infection).
Independent claim 2 recites a method for treating “a viral, bacterial, or protozoal infection leading to development of a disease state in a patient”, by administering inhaled nitric oxide according to the recited breath-coordinated, pulsatile dosing regimen. Under the broadest reasonable interpretation, the bacterial and protozoal alternatives are not limited to a respiratory infection, a pulmonary pathogen, a particular bacterial or protozoal species, a particular anatomical site of infection, a particular mechanism of susceptibility to nitric oxide, a particular disease state, an infection characterized by a particular minimum NO sensitivity, or a pathogen for which inhaled NO reaches the infected tissue at a therapeutically effective exposure.
Claim 2 therefore encompasses treatment of substantially any bacterial or protozoal infection that leads to any disease state in a patient, provided that the recited inhaled-NO regimen is administered and produces the claimed treatment result. The specification ¶[0012] recites substantially the same generic method and concludes that “the viral, bacterial, or protozoal infection is treated.” The paragraph does not identify a bacterial or protozoal species, an infected tissue, a disease state, or characteristics by which one of ordinary skill in the art could recognize which bacterial and protozoal infections are successfully treated by the claimed regimen.
The specification Background states that endogenous NO production is upregulated by macrophages as a defense mechanism against some bacterial, viral, and protozoal infections. The specification then identifies in-vitro inhibition of SARS-CoV and reports clinical pulmonary effects in SARS patients (¶[0009]), however does not identify any bacterial or protozoal species treated by inhaled NO, much less by the claimed pulse dose, daily treatment period, and multiday regimen.
The specification ¶[0053] states generally that pulsed delivery may be useful as an antimicrobial and mentions pneumonia and non-tuberculous mycobacterium. That passage does not identify a particular non-tuberculous mycobacterium species, does not identify the causative organism of the referenced pneumonia, does not report treatment of either condition, does not disclose that the claimed 250-1200 mcg/kg IBW/hr regimen treats such an infection, and does not describe bacterial species representative of the substantial biological diversity encompassed by claim 2.
Specification ¶[0089] again generically states that methods for treating SARS-CoV-2 infection, a bacterial infection, or another viral infection are taught. Specification ¶[0097] states that reduction in respiratory symptoms associated with a viral, bacterial, or protozoal infection may occur with iNO treatment. Those paragraphs do not identify a protozoal species and do not provide representative bacterial species, experimental observations, or identifying characteristics correlating bacterial or protozoal infection with successful treatment by the claimed regimen.
The working disclosure is directed to COVID-19. Examples 1 and 2 concern hospitalized or otherwise treated patients having confirmed or suspected SARS-CoV-2 infection and evaluate oxygen requirements, oxygen saturation, escalation of respiratory support, hospitalization, and clinical status (¶[0102]-[0119]). The examples do not treat a bacterial or protozoal infection and do not identify an operative bacterial or protozoal embodiment of claim 2. Thus, the applicant fails to demonstrate possession of the claimed genus.
The generic statements in ¶[0012],¶ [0089], and ¶[0097] identify the outer boundary of a desired treatment genus but do not demonstrate that the inventors possessed methods that successfully treat the full bacterial and protozoal scope.
The bacterial branch encompasses organisms having materially different cellular envelopes, respiratory and metabolic pathways, intracellular or extracellular locations, tissue tropisms, susceptibilities to reactive nitrogen species, mechanisms of pathogenicity, acute or chronic infection patterns, and accessibility to inhaled pulmonary NO. The protozoal branch likewise encompasses diverse unicellular eukaryotic pathogens infecting pulmonary and nonpulmonary tissues and having materially different life-cycle stages, cellular structures, and locations within the patient.
The specification does not disclose a representative variety of bacterial and protozoal treatment embodiments reflecting that diversity. It also does not disclose an identifying property, susceptibility assay, NO-exposure threshold, tissue-distribution criterion, common mechanism, or other correlation by which a person of ordinary skill could recognize which members of the claimed infection genus are successfully treated by the recited inhaled-NO protocol.
Mere recognition that endogenous NO participates in host defense against some infections does not describe possession of a method for treating any bacterial or protozoal infection falling within claim 2. Similarly, the isolated reference to pneumonia or non-tuberculous mycobacterium does not demonstrate possession of the materially broader genus. The specification therefore provides, at most generic statements that treatment of bacterial and protozoal infections is desired; a narrow, unworked reference to non-tuberculous mycobacterium and pneumonia; and detailed clinical disclosure concerning a different species, SARS-CoV-2 infection and COVID-19.
Disclosure of a limited embodiment or statement of a desired result does not support a functionally defined genus where the disclosure does not show possession of species representative of the full scope or common attributes identifying the operative genus (see MPEP §2163). Disclosure of verbatim/substantially similar language in the specification does not resolve the deficiency. The original claim or a verbatim summary statement does not satisfy the written description requirement because it merely recites a broad functional result without demonstrating possession of what achieves that result throughout the claimed scope. Ariad specifically confirms that original claims remain subject to the written-description requirement and that claim language amounting only to a plan or desired functional result may be insufficient (Ariad v. Eli Lilly, 598 F.3d, 1336 (Fed. Cir. 2010) (en banc)).
Here, ¶[0012] states that bacterial or protozoal infection “is treated,” but does not describe representative successful bacterial or protozoal embodiments or common identifying characteristics connecting the claimed regimen to that treatment result. The passage therefore asserts the result sought without demonstrating possession of the claimed therapeutic genus.
Claims 10, 15, 56, 60, and 61 depend, directly or indirectly, from claim 2 and retain the unsupported bacterial and protozoal treatment alternatives. Claim 10 limits the portion of inspiration during which NO is delivered, claim 15 adds administration with another gas, claim 56 adds reduction or elimination of supplemental oxygen or mechanical-breathing requirements, claim 60 adds breath-level and breath-slope triggers, and claim 61 adds a pulse-delay interval. None of these limitations identifies a bacterial or protozoal species, narrows the infection to a disclosed representative class, or supplies an identifying characteristic correlating the claimed treatment protocol with successful treatment of the claimed bacterial or protozoal genus. Claims 10, 15, 56, 60, and 61 therefore fail to comply with the written-description requirement for the same reasons as claim 2.
Thus, the originally-filed disclosure does not reasonably convey to a person of ordinary skill that the inventors possessed the full scope of treating any bacterial or protozoal infection by the claimed method. Accordingly, claims 2, 10, 15, 56, 60, and 61 are rejected under 35 U.S.C. §112(a) for lack of adequate written description. The rejection is limited to the bacterial and protozoal alternatives. The rejection does not, on this ground, determine whether the specification adequately describes the narrower SARS-CoV-2/COVID-19 species recited in claim 3.
Claims 4, 45, 47, 57, 59, 62, and 63 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 4 is not limited merely to administering inhaled NO to a patient having COVID-19, improving pulmonary perfusion, improving oxygenation, reducing supplemental oxygen, reducing respiratory support, or treating clinical symptoms associated with COVID-19. Claim 4 affirmatively requires that the administered regimen inhibit viral replication of SARS-CoV-2 in the patient. This is an in-vivo antiviral endpoint. The claimed endpoint requires that the breath-coordinated pulsed-NO regimen produce inhibition of SARS-CoV-2 replication within the treated patient, rather than merely produce pulmonary vasodilation or symptomatic respiratory improvement.
Specification ¶[0014] states that a method for inhibiting viral replication of SARS-CoV-2 in a patient is taught, recites the delivery steps, and concludes that viral replication is inhibited. The paragraph does not provide a measurement, observation, example, mechanism particular to SARS-CoV-2 in a patient, or other factual disclosure demonstrating that the recited clinical regimen actually possesses the claimed antiviral property. The scientific discussion in ¶[0009] concerns endogenous NO as part of immune response, in-vitro studies involving the earlier SARS-CoV virus, in-vitro cellular-survival observations involving SARS-CoV, and a small clinical SARS study reporting arterial oxygenation and respiratory-support outcomes. It does not report inhibition of SARS-CoV-2 replication in a patient and does not establish that the presently claimed 250-1200 mcg/kg IBW/hr pulsed regimen produces that result.
Example 1 describes a randomized study of 125 mcg/kg IBW/hr administered for 8-24 hours daily. Its stated objectives concern efficacy and safety in COVID-19 patients. The disclosed outcome scale measures death, hospitalization, ventilation, oxygen requirement, ongoing medical care, and limitations on activity. The example does not identify inhibition of viral replication as a measured endpoint.
Example 2 describes an expanded-access program in COVID-19 patients. The collected measures were oxygen-flow requirements, oxygen saturation, escalation of respiratory support, intubation, hospitalization, and clinical status. The reported results concern oxygenation, supplemental-oxygen requirements, respiratory support, tolerance, and discharge. They do not report serial viral-load measurements, quantitative SARS-CoV-2 replication assays, viral culture, time to viral clearance, changes in cycle-threshold values, or another measure demonstrating inhibition of viral replication in the patient.
The specification reports that one subject received 250 mcg/kg IBW/hr, tolerated the dose, responded clinically, and was discharged without supplemental oxygen. Specification ¶[0116] does not report any measurement of SARS-CoV-2 replication for that subject. The RT-PCR testing described in the examples is used to establish eligibility or infection status. It is not disclosed as a longitudinal measurement demonstrating that the claimed treatment inhibits replication. Specification ¶[0117] states that pulsed iNO targets the pulmonary vasculature as well as the virus, but the reported series concerns improvements in oxygenation and discharge. Specification ¶[0119] states that early treatment would allow physicians to target viral load and further states that if the benefits of iNO are confirmed in a randomized controlled trial, the result would have important implications. The prospective language of ¶[0119], viewed together with the absence of a measured viral-replication endpoint, indicates that reduction of viral load was presented as a proposed or expected benefit requiring confirmation, rather than as an antiviral result shown to have been possessed for the claimed clinical protocol.
Thus, the specification adequately describes a pulsed-NO delivery platform, administration to COVID-19 patients, improvement in oxygenation, reduction of supplemental-oxygen requirements, certain respiratory-support outcomes, and general scientific literature suggesting antiviral activity of NO against SARS-CoV under in-vitro conditions. Those disclosures do not, without more, demonstrate possession of the specifically claimed method that inhibits SARS-CoV-2 replication in a patient using the claimed dose and treatment schedule.
The distinction is material. Pulmonary vasodilation and improvement in oxygenation are physiological effects that may occur without inhibition of viral replication. Clinical improvement or discharge therefore does not necessarily establish the antiviral endpoint recited in claim 4. The specification does not disclose a patient in whom SARS-CoV-2 replication was measured before and after the claimed treatment, a demonstrated reduction in patient viral load attributable to the treatment, a pharmacodynamic relationship between the claimed pulse dose and an antiviral NO exposure at infected tissue, an in-vivo SARS-CoV-2 model treated according to the claimed regimen, a validated surrogate demonstrating inhibition of replication, or an explanation establishing that inhibition of SARS-CoV-2 replication necessarily results from the claimed administration protocol. Thus, ¶[0014] states the desired antiviral result but the disclosure does not provide factual or technical content demonstrating that the inventors possessed a clinical method that achieves that result.
In Nuvo Pharm. (Ireland) Designated Activity Co. v. Dr. Reddy's Labs. Inc., 923 F.3d 1368, 1376-82 (Fed. Cir. 2019), the Federal Circuit held that a specification must provide support for a claimed effectiveness limitation where the effectiveness was not necessarily inherent in the otherwise described formulation. A specification that merely recites components, doses, or a proposed result without showing possession of the claimed effectiveness may fail the written-description requirement. Likewise, Ariad v. Eli Lilly, 598 F.3d, 1350-54 (Fed. Cir. 2010) (en banc), explains that a method claim defined by achievement of a functional result is not adequately described merely by stating the result that one hopes to obtain. The disclosure must demonstrate that the inventor possessed the claimed method achieving that result.
While specification ¶[0014] and the originally filed claim language expressly recite inhibition of SARS-CoV-2 replication in a patient, that express recitation has been considered but does not resolve the deficiency. The recitation identifies the result claimed but does not provide a description demonstrating possession of a clinical embodiment that achieves that result. Original claim language is subject to the same possession inquiry as later-added claim language, particularly where the claim is defined by a function or result (see MPEP § 2161). The present record does not establish that every administration falling within claim 4 necessarily inhibits SARS-CoV-2 replication in the patient.
Claims 45, 47, 57, 59, 62, and 63 depend, directly or indirectly, from claim 4 and retain the unsupported in-patient viral-replication-inhibition endpoint. Claim 45 limits delivery to the first half of inspiration, claim 47 adds administration with another gas, claim 57 adds reduction or elimination of supplemental oxygen or mechanical-breathing requirements, claim 59 adds one or more additional therapeutic agents, claim 62 adds breath-level and breath-slope triggers, and claim 63 adds a pulse-delay interval. None of those additional limitations provides a description of an embodiment in which SARS-CoV-2 replication was inhibited in a patient or establishes that such inhibition necessarily results from the claimed regimen.
The combination therapies of claim 59 do not cure the deficiency. The specification identifies various additional therapeutic agents in ¶[0100], but does not disclose that administration of any listed agent together with the claimed pulsed-NO protocol produced the specifically claimed SARS-CoV-2 replication-inhibition endpoint. Claims 45, 47, 57, 59, 62, and 63 therefore fail to comply with the written-description requirement for the same reasons as claim 4.
In conclusion, The originally filed disclosure does not reasonably convey to a person of ordinary skill that the inventors possessed the claimed method of inhibiting SARS-CoV-2 replication in a patient using the recited breath-coordinated pulsed-NO regimen. Accordingly, claims 4, 45, 47, 57, 59, 62, and 63 are rejected under 35 U.S.C. §112(a) for lack of adequate written description.
To overcome these rejections, the applicant may identify specific portions of the originally filed disclosure that demonstrate possession of the full bacterial or protozoal treatment scope and the in-patient SARS-CoV-2 replication-inhibition endpoint; provide persuasive evidence explaining why a person of ordinary skill would understand from the originally filed disclosure that the inventors possessed the claimed therapeutic subject matter, provided such evidence explains the disclosure and does not supply missing descriptive matter; amend claim 2 to remove or appropriately narrow the unsupported bacterial and protozoal treatment alternatives; and/or amend claim 4 and its dependent claims to recite an endpoint adequately described by the original disclosure, such as an appropriate oxygenation or respiratory-support outcome, provided the amendment is otherwise supported and does not introduce new matter. Any declaration or other evidence submitted in response must demonstrate what a person of ordinary skill would have understood from the disclosure as originally filed. Evidence cannot cure a failure of written description by adding information that was not conveyed by the original application.
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 2-4, 10, 15, 45, 47, 50, 51, 53, and 56-65 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.
Each independent claim 2, 4, and 50 recites a nitric-oxide dose of “about 250 mcg/kg IBW/hr to about 1200 mcg/kg IBW/hr.” The specification indicates that “IBW” refers to ideal body weight and provides dosing calculations employing an assumed ideal body weight, including an exemplary 75-kilogram value. The specification, however, does not identify the formula, patient characteristics, reference table, or other objective procedure by which ideal body weight is to be determined.
This omission materially affects the scope of the claims because the claimed dose is defined by dividing the amount of nitric oxide delivered per unit time by the patient’s IBW. Different recognized equations for calculating ideal body weight can assign different IBW values to the same patient (i.e., clinically material variation among recognized IBW equations, including differences of up to approximately 14% in male patients and 19% in female patients). Consequently, the same absolute amount of nitric oxide administered to the same patient may fall within or outside the claimed range depending upon which IBW formula is selected, particularly near the lower and upper claim boundaries. Neither the claim nor the specification provides an objective basis for selecting among the available formulas.
The modifier “about” does not resolve the uncertainty because it does not identify which IBW value is first used to calculate the claimed dose. Although the specification supplies a general definition of “about,” that definition does not establish the denominator to which the claimed dose range is applied. Accordingly, a person of ordinary skill would not be informed with reasonable certainty whether a given administration regimen satisfies the claimed dose limitation.
Claims depending from claims 2, 4, and 50, directly and indirectly, are included in this rejection because they do not cure the defect noted above. The applicant may overcome the rejection by amending the claims or specification, without introducing new matter, to identify an objective IBW calculation method, recognized equation, incorporated clinical standard, or other definite procedure for determining the patient’s IBW.
Further, claims 56-58 are rejected for reciting, “wherein a need for supplemental oxygen or a time in need of mechanical breathing is reduced or eliminated.”
The phrase “a time in need of mechanical breathing” does not identify with reasonable certainty what is being measured or reduced. It is unclear whether the phrase refers to the duration during which the patient clinically requires mechanical ventilation, the duration during which the patient actually receives mechanical ventilation, the period during which a physician determines that mechanical assistance is indicated, a delay before mechanical ventilation becomes necessary, time on invasive mechanical ventilation, time on noninvasive breathing assistance, or any period involving CPAP, BiPAP, intubation, or another form of assisted breathing.
The specification refers more conventionally to the time a patient is on mechanical breathing assistance, a ventilator, or intubation, but the claims do not adopt that language or define “mechanical breathing.” The grammatical construction also makes it unclear whether “reduced or eliminated” modifies the patient’s clinical need, the duration of the need, or the duration of actual treatment. The applicant is required to amend the claims to identify the intended clinical parameter (e.g., “wherein the patient’s need for supplemental oxygen is reduced or eliminated, or a duration during which the patient requires mechanical breathing assistance is reduced”).
Claim 59 is also rejected as indefinite. Claim 59 recites administering one or more agents selected from a list that includes “favilar.”
Neither claim 59 nor the specification provides a chemical name, generic drug name, active ingredient, structural definition, formulation, manufacturer, or other objective identification of “favilar.” It is therefore unclear whether “favilar” is a misspelling, a proprietary or trade designation, a particular active pharmaceutical ingredient, or a particular commercial formulation.
If “favilar” is intended as a trademark or trade name, use of the trade name to define the administered therapeutic product does not provide a stable or objective claim boundary because the composition sold under a trade designation may change and the trade designation does not itself define the product (see MPEP §2173.05(u)). If the term is a typographical error, the intended generic name must be supplied by correctly stating the term (e.g., “favipiravir” as an additional therapeutic).
Further, claims 61, 63, and 65 are rejected as indefinite. Claims 60, 62, and 64 require use of both a breath-level trigger that detects a breath when a threshold pressure is reached, and a breath-slope trigger that detects the breath when a slope of a pressure waveform indicates inspiration. Claims 61, 63, and 65 then require, “a pulse delay of about 50 milliseconds to about 200 milliseconds after detection of the breath.”
The specification explains that the two triggers may have different sensitivities and that the slope trigger may detect short or shallow breaths differently from the level trigger. The triggers therefore need not detect the onset of the same inspiration at the same instant. The claims do not specify whether the 50-200 millisecond delay begins when the level trigger detects the breath, when the slope trigger detects the breath, when either trigger first detects the breath, only after both triggers have detected the breath, when the later trigger detects the breath, or from a separate controller-generated breath-detection event. The distinction affects the actual time at which the NO pulse begins and therefore affects whether a particular delivery process falls within the claims.
Although the specification expressly supports pulse delays of 50, 100, or 200 milliseconds and a range of 50-200 milliseconds, disclosure of the numerical range does not resolve which trigger event supplies time zero. The applicant is required to identify the event from which the pulse delay is measured. For example, subject to applicant’s intended scope and original support, a claim could specify that the delay begins after “the first of the breath-level trigger or breath-slope trigger detects the breath,” or, “both the breath-level trigger and the breath-slope trigger indicate inspiration.”
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, and 47 are rejected under 35 U.S.C. § 103 as being unpatentable over Av-Gay et al. (US20160279165A1; published 29 September 2016, hereinafter “Av-Gay”) in view of Akerström et al. (Nitric Oxide Inhibits the Replication Cycle of Severe Acute Respiratory Syndrome Coronavirus, J. Virol. 2005 Feb; 79:1966-1969; hereinafter “Akerström”), and further in view of Goldstein (US20130239962A1; published 19 September 2013).
Av-Gay teaches treatment of respiratory infections caused by bacterial, viral, and fungal pathogens (¶[0089], ¶[0091]-[0092]), expressly identifies coronavirus and SARS among contemplated viral pathogens (¶[0110]), and describes intermittent, breathing-cycle-coordinated pulsed delivery of gaseous nitric oxide at a concentration of at least 160 ppm (¶[0111]-[0115]).
Av-Gay teaches that the antimicrobial amount and exposure of nitric oxide may vary according to the target microorganism (¶[0160]-[0162] and Table 1) and expresses antimicrobial exposure in ppm-hours (¶[0169]-[0171]). Thus, these teachings support pathogen-dependent adjustment of concentration and exposure, however, they do not expressly disclose a 250-1200 mcg/kg IBW/hr range.
Av-Gay expressly describes administering 160 ppm nitric oxide for 30 minutes, five times daily, for five consecutive days (¶[0163]). Av-Gay additionally teaches first administration periods of approximately 10-45 minutes, including approximately 30 minutes (¶[0175]-[0178]), one to six cycles per day, including five 30-minute cycles (¶[0179]-[0181]), and courses lasting one to seven days, expressly including five days (¶[0182]).
Av-Gay teaches a device responsive to the patient’s breathing cycle that delivers nitric oxide in pulses during inhalation (¶[0183). Pulse delivery begins after a pulse-delay period and occupies less than the complete inhalation period (¶[0184]-[0186]). Av-Gay further teaches determining the inhalation period from sensed flow and exemplifies a pulse delay equal to 20% of the inhalation period, a pulse-delivery period equal to 60%, and cessation during the remaining 20% (¶[0187]). Thus, Av-Gay’s 20%-delay and 60%-delivery example means that delivery begins during the first half of inspiration, but much of the delivery continues into the second half. Av-Gay does not explicitly establish that the entire dose is delivered exclusively within the first half (see Goldstein below).
Av-Gay teaches the inhalant may be a gas mixture (¶[0203]-[0205]) and oxygen concentration and FiO₂ may be controlled in the inhalant (¶[0208]-[0210]). These passages support administration of NO in a gas mixture that may include oxygen.
Av-Gay does not expressly disclose a 250-1200 mcg/kg IBW/hr. A conversion from its ppm concentration requires assumptions regarding minute ventilation or inspiratory flow, respiratory rate, patient IBW, temperature and pressure, pulse-delivery volume, inspiratory duty cycle, and whether dose is measured during active treatment or averaged over another period (see Goldstein below for weight-normalized dose range).
In summary, Av-Gay therefore teaches the claimed breath detection, determination of timing based on the detected breath pattern, pulsatile administration over a portion of a single inspiration, and claimed daily and multiday treatment schedule.
Akerström demonstrates that nitric oxide inhibits the replication cycle of SARS-CoV in infected cells. Akerström reports that NO generated from SNAP inhibited SARS-CoV replication in a concentration-dependent manner and inhibited viral protein and RNA synthesis (p. 1966, Abstract). In SARS-CoV-infected Vero E6 cells, SNAP reduced viral progeny in a dose-dependent manner (p. 1966, left-to-right columns, paragraph beginning “To investigate the role of NO in SARS CoV infection…”), reduced viral nucleocapsid-protein expression (p. 1966, right col., paragraph beginning “The inhibitory effect of NO on SARS CoV infection…”), and significantly inhibited viral RNA production (p. 1967, right col., paragraph beginning “To investigate whether NO inhibits the viral RNA replication process…”).
Akerström does not disclose SARS-CoV-2, inhaled clinical treatment, pulsatile delivery, the claimed IBW-normalized dose, or the claimed daily schedule. Although Akerström’s experiments were conducted in vitro and involved generated NO rather than a clinical pulsatile inhalation regimen, the reference supplies direct evidence that coronavirus replication is susceptible to NO-mediated inhibition. Akerström is evidence of susceptibility of SARS-CoV replication to NO and a reason to investigate NO against a SARS-related coronavirus.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to seek to apply Av-Gay’s expressly antimicrobial, inhaled-NO treatment platform to a coronavirus respiratory infection. One of ordinary skill in the art would have had reason to use Av-Gay’s system against SARS-related coronavirus infection in view of Akerström’s antiviral findings. The proposed combination does not require bodily incorporation of Akerström’s experimental apparatus into Av-Gay. Akerström supplies the therapeutic application and mechanistic expectation and Av-Gay supplies the clinical inhalation and treatment platform. The fact that Akerström does not establish clinical certainty does not defeat obviousness. A reasonable expectation of success does not require absolute predictability or proof that every patient will obtain the claimed result.
Goldstein supplements the teachings of Av-Gay and Akerström. Goldstein teaches administering nitric oxide as an inspiratory pulse or bolus (¶[0005]-[0007]) and expressly discloses a dose range of 0.001-4.5 mg/kg/hr (¶[0009]; ¶[0015]), which encompasses the claimed 0.25-1.2 mg/kg/hr range. Goldstein expressly relates its 0.001-4.5 mg/kg/hr dose range to pulmonary indications or use of nitric oxide as an antimicrobial agent (¶[0032]) and teaches that the dose may be determined according to patient ideal body weight based on height and gender and expressed in mg/kg/hr or mg/kg/breath (¶[0033]). However, Goldstein does not tie every portion of its broad dose range to treatment of infection, SARS-CoV, SARS-CoV-2, or the claimed five-day intermittent regimen. The reference supplies teachings of express IBW-normalized dosing, the encompassing dose range, inspiratory pulse administration, and timing within inspiration.
Goldstein teaches administering the pulse during only a portion of the breathing cycle and expressly states that, in certain embodiments, the pulse is administered during the first half of inspiration (¶[0034]). Thus, Goldstein expressly meets the “within a first half of the total inspiratory time” limitation more clearly than Av-Gay.
Goldstein teaches user-entered variables may include dose, age, height, sex, and weight (¶[0038]), a processor calculates pulse volume and pulse schedule using respiratory rate and NO concentration (¶[0040]), a pressure sensor detects subatmospheric pressure during inspiration and signals the processor to open a valve and deliver a pulse (¶[0041]), and positive pressure during expiration may be used to determine inspiratory and expiratory periods and respiratory rate (¶[0042]). These paragraphs support breath-responsive pulse timing and calculation of the pulse delivered dose.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to use Av-Gay’s breath-coordinated, intermittent inhaled-NO system to treat a SARS-related coronavirus respiratory infection because Av-Gay identifies coronavirus and SARS among the contemplated infections, select an antiviral application in view of Akerström’s demonstration that NO inhibits SARS-CoV replication, and program the system using a patient-normalized dose within Goldstein’s disclosed range because Goldstein teaches IBW-based NO dosing, inspiratory pulse delivery, antimicrobial use, and the claimed dose range.
The references teach adjustment of concentration, dose, pulse volume, and exposure duration to balance antimicrobial efficacy and tolerability. The applicant has not submitted comparative evidence establishing that the endpoints of about 250 or about 1200 mcg/kg IBW/hr define a critical therapeutic transition, or that the claimed range produces an unexpected result relative to immediately adjacent doses.
Each reference performs its ordinary disclosed function in the combination. Av-Gay supplies the infection-treatment regimen and breath-coordinated delivery architecture, Akerström supplies evidence supporting the coronavirus antiviral application, and Goldstein supplies express IBW-normalized dose and first-half inspiratory pulse teachings. Application of known dosing and pulse-delivery techniques to a known inhaled-NO platform for the same general therapeutic purpose, with predictable control over the mass of NO delivered, is thus, obvious (see MPEP §2143 and KSR International Co. v. Teleflex Inc., 550 U.S. 398, 417-21 (2007)).
Instant claim 3 specifies SARS-CoV-2 infection and COVID-19. Av-Gay expressly identifies coronavirus and SARS infections, while Akerström provides evidence of NO-mediated inhibition of a closely related SARS coronavirus. Applying the disclosed coronavirus treatment to SARS-CoV-2 would have been an obvious species application with a reasonable, although not certain, expectation of antiviral benefit.
Instant claims 10 and 45 require delivery within the first half of total inspiratory time. Goldstein expressly teaches administering the pulse during the first half of inspiration (se described above). Instant claims 15 and 47 require NO administration with at least one additional gas. Av-Gay administers NO as part of an inhalant gas mixture and contemplates controlled oxygen concentration and FiO2 (described above). Goldstein likewise discloses NO in a carrier gas and delivery in a patient breathing circuit (described above). Accordingly, instant claims 2-4, 10, 15, 45, and 47 are unpatentable over the cited combination.
Claims 2, 4, 50, 51, 53, 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 “Av-Gay”) in view of Akerström et al. (Nitric Oxide Inhibits the Replication Cycle of Severe Acute Respiratory Syndrome Coronavirus, J. Virol. 2005 Feb; 79:1966-1969; hereinafter “Akerström”), and further in 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 “Chen”).
Av-Gay, in view of Akerström, in further view of Goldstein, teach the limitations of instant claims 2 and 4, as described above, from which instant claims 56-59 depend, however do not explicitly teach the specific limitations of instant claims 56-59.
Av-Gay, Akerström, and Goldstein teach the underlying breath-coordinated, pulsatile, patient-normalized NO administration method for coronavirus infection for the reasons stated above.
Chen reports that inhaled NO improved arterial oxygenation and permitted reductions in supplemental oxygen and airway-pressure support in SARS patients (p. 1531, Abstract, left col.). During treatment, oxygen saturation increased from approximately 93% to 99%, supplemental oxygen was reduced from approximately 6 L/min to 2 L/min, and CPAP or BiPAP was reduced or discontinued in all four patients receiving such support (p. 1532, Results, right col., paragraph beginning “Inhaled NO therapy…”). Chen further reports that the PaO2/FiO2 ratio more than doubled and that pressure support could be eliminated (p. 1533, Discussion, right col., paragraph beginning “The improvement of arterial oxygenation…”). Chen’s reported outcomes are directly parallel to “reducing or eliminating the need for supplemental oxygen” and “reducing or eliminating the time in need of mechanical breathing.”
Although Chen employed a lower-concentration continuous regimen, those limitations do not negate its express teaching that inhaled NO can improve oxygenation and reduce respiratory support in patients with severe coronavirus respiratory disease. Chen supports expected oxygenation and respiratory-support outcomes, rather than a direct disclosure of the claimed dose or pulse schedule.
Chen expressly reports coadministration of the antiviral ribavirin at 0.5-1.0 g/day and the steroid methylprednisolone at 40-160 mg/day during inhaled-NO treatment (p. 1531, Methods, right col., final paragraph to p. 1532, left col.).
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to employ Av-Gay’s pulsed regimen, at a dose selected according to Goldstein, in a SARS-related coronavirus patient to obtain both the antimicrobial benefit suggested by Akerström and thepulmonary vasodilatory and oxygenation benefit demonstrated by Chen. Chen provides an express clinical basis for expecting improvement in oxygenation and a corresponding reduction in supplemental-oxygen or ventilatory-support requirements.
Instant claim 51 is additionally taught by Goldstein’s first-half inspiratory pulse disclosure. Instant claim 53 is additionally taught by the inhalant and oxygen/carrier-gas teachings of Av-Gay and Goldstein. Instant claims 56–58 recite reducing or eliminating the need for supplemental oxygen or the time during which mechanical breathing is needed. These results are not relied upon merely as inherent consequences of treating infection. Chen expressly reports reduced supplemental oxygen and reduced or discontinued ventilatory-pressure support.
Instant claim 59 recites administering “one or more of” several listed agents, including an anti-inflammatory or steroid. The claim is satisfied by any one of the recited alternatives. Chen expressly administered methylprednisolone, a steroid, together with inhaled NO treatment. It is therefore unnecessary for the cited combination to establish the obviousness of every alternative listed in claim 59. Accordingly, instant claims 50, 51, 53, and 56-59 are unpatentable over the cited combination.
Claims 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 “Av-Gay”) in view of Akerström et al. (Nitric Oxide Inhibits the Replication Cycle of Severe Acute Respiratory Syndrome Coronavirus, J. Virol. 2005 Feb; 79:1966-1969; hereinafter “Akerström”), and further in view of Goldstein (US20130239962A1; published 19 September 2013), Pelletier and Chekal (US20080078392A1; published 03 April 2008, hereinafter “Pelletier”), 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 “Chen”).
Av-Gay, in view of Akerström, in further view of Goldstein, teach the limitations of instant claims 2, 4, and 50, as described above, from which instant claims 60-65 depend, however do not explicitly teach the specific limitations of instant claims 60-65.
The combinations applied above teach the underlying infection-treatment, SARS-CoV-2 replication-inhibition, and oxygenation-improvement methods, including detecting an inspiration and coordinating pulsatile gas delivery with the detected breathing cycle.
Pelletier teaches breath-actuated gas delivery using a pressure signal obtained from a cannula. Specifically, Pelletier teaches conventional breath detection measures pressure in a nasal cannula at the beginning of inspiration (¶[0002]), a pressure transducer converts pressure into a signal, and gas delivery begins once the pressure drop exceeds a predetermined threshold (¶[0003]), a shallow breath may not cross the absolute-pressure threshold (¶[0004]), and filtering can delay breath confirmation, and a substantial portion of inspiration may occur within the first approximately 200 milliseconds (¶[0005]). The reference identifies a need for improved accuracy and reduced breath-confirmation time (¶[0006]). Pelletier ¶[0003] describes the claimed type of breath-level trigger, but as conventional background technology- a pressure transducer detects inspiratory pressure, and gas delivery is initiated when the pressure drop exceeds a predetermined threshold.
Pelletier further teaches generating a pressure-change-rate signal by differentiating the pressure waveform and comparing the resulting rate signal with a detection threshold to detect the beginning of inspiration. Pelletier explains that conventional breath-actuated gas systems detect inspiration when cannula pressure crosses a predetermined pressure threshold (¶[0002]-[0004]) but may miss shallow breaths or introduce detection delay (¶[0004]-[0006]). Pelletier improves detection by differentiating the pressure signal to obtain a pressure-change-rate signal (¶[0025]-[0027]), comparing that rate signal with a threshold indicating onset of inspiration (¶[0028]-[0030]), and delivering gas in response to the resulting breath-detection signal (¶[0031]). This constitutes a breath-slope trigger, because the time derivative or rate of change of the pressure signal is evaluated to identify inspiration.
Pelletier does not expressly state that the conventional pressure-level trigger and the disclosed slope/rate trigger are operated simultaneously in one system. However, Pelletier teaches that absolute-pressure threshold triggering was known (¶[0002]-[0004]) and slope/rate triggering as a way to improve detection of shallow breaths and reduce delay (¶[0005]-[0007] and ¶[0025]-[0031]), wherein one of ordinary skill in the art would have had reason to add the slope criterion to an existing level-triggered gas-delivery system to obtain complementary or redundant detection. Therefore, it would have been obvious to retain the known level criterion and add Pelletier’s rate criterion, not that Pelletier expressly teaches the claimed two-trigger combination. One would be motivated to make the combination to retain the established absolute-pressure criterion for breaths that reliably cross the level threshold while adding the pressure-rate criterion to improve detection of short or shallow inspirations and reduce detection latency.
Thus, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to modify Av-Gay’s breath-actuated NO system would have been motivated to retain the known absolute-pressure trigger while adding Pelletier’s pressure-rate trigger as an additional detection criterion. Employing both criteria in parallel provides predictable redundancy: the absolute-pressure criterion detects inspirations that cross the level threshold, while the rate criterion provides earlier or more reliable detection of short or shallow inspirations that may not cross the level threshold promptly.
The modification represents use of a known breath-detection improvement in a similar breath-actuated gas-delivery device to obtain the predictable result of more reliable and timely gas triggering (MPEP §2143). Pelletier, expressly establishes both known trigger architectures and explains why the rate/slope architecture remedies deficiencies of the conventional level architecture. Implementing both known criteria in the existing breath-actuated gas-delivery controller would have required no change in the therapeutic operation of the system and would have yielded the predictable benefit of improved detection across differing breath patterns. Accordingly, instant claims 60, 62, and 64 are unpatentable over the cited combinations further in view of Pelletier.
As set forth above, the combined references teach administering inhaled nitric oxide in a breath-coordinated pulsatile manner, detecting the patient’s breath or onset of inspiration, determining administration timing based upon the detected breath pattern, and employing both an absolute pressure-level criterion and a pressure-waveform-rate or slope criterion for breath detection.
Instant claims 61 and 63 further require, “wherein the timing for administration of the dose of inhaled nitric oxide includes a pulse delay of about 50 milliseconds to about 200 milliseconds after detection of the breath.” Av-Gay expressly teaches this additional timing concept.
Av-Gay explains that the nitric-oxide “pulse delivery period starts during the inhalation period, after a period of time which is referred to herein as the ‘pulse delay period.’” (¶[0185]). Av-Gay further teaches that the inhalation device is configured to detect the phases of the patient’s breathing cycle, including the onset of inhalation, and coordinates the pulse delay with that detected breathing phase such that the pulse-delay period begins when increased inspiratory intake is detected at the onset of inhalation (¶[0186]). Thus, the pulse is not delivered until expiration of a delay period initiated in response to detection of the onset of the breath.
Av-Gay additionally teaches determining the duration of the inhalation period by sensing inhalant flow and automatically setting the pulse-delay period to 20% of the inhalation period (¶[0187]). Accordingly, Av-Gay expressly treats the magnitude of the delay between detection/onset of inspiration and commencement of the NO pulse as an adjustable timing parameter correlated with the detected breath.
Most significantly, Av-Gay expressly discloses “the pulse delay period ranges from 0 ms to 2500 ms.” (¶[0037]; claim 4). The detailed description likewise discloses a pulse-delay range of 0-2500 milliseconds. Av-Gay therefore expressly describes a continuous pulse-delay range that fully encompasses the claimed approximately 50-200 millisecond interval. The claimed interval of approximately 50-200 milliseconds lies wholly within Av-Gay’s disclosed 0-2500 millisecond interval.
Where the prior art discloses a range that encompasses a narrower claimed range, a prima facie case of obviousness ordinarily exists (see MPEP §2144.05; In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003)). The numerical breadth of Av-Gay’s 0-2500 millisecond disclosure, is not solely relied upon, however. Pelletier provides an express technical reason for selecting an early portion of that range, including delays no greater than approximately 200 milliseconds.
Pelletier teaches breath-actuated gas delivery systems in which inspiration is detected from a pressure signal. Pelletier explains that, once the pressure drop associated with inspiration crosses a predetermined threshold, the breath detector signals the gas-delivery system (¶[0003]). Pelletier further recognizes that signal processing and filtering can delay confirmation of inspiration and expressly states that reducing such delay is desirable because a majority of the volume inhaled during a breath may be completed within approximately the first 200 milliseconds following onset of inhalation (¶[0005]-[0006]).
Accordingly, a person of ordinary skill implementing Av-Gay’s breath-coordinated NO system would have had an express reason to select a delay toward the low end of Av-Gay’s disclosed 0-2500 millisecond interval, and particularly a delay at or below approximately 200 milliseconds, in order to initiate delivery sufficiently early in inspiration to deliver the therapeutic gas during the portion of the breath in which a substantial fraction of inspiratory volume is being inhaled.
The proposed modification does not change the principle of operation of either reference. Av-Gay already detects the onset of inhalation, begins a pulse-delay interval based upon the detected inspiratory event, and delivers the NO pulse following the delay. Pelletier merely provides additional guidance concerning selection of the magnitude of that delay, namely, that unnecessary delay should be minimized because a substantial portion of inspiration occurs during the first approximately 200 milliseconds.
A person of ordinary skill would therefore have been motivated to select, through routine programming or adjustment of Av-Gay’s expressly variable pulse-delay parameter, a delay within approximately 50-200 milliseconds after breath detection. Such a selection would predictably retain Av-Gay’s breathing-cycle coordination while placing the NO pulse early enough in inspiration to obtain the delivery advantage recognized by Pelletier.
The lower boundary of approximately 50 milliseconds does not confer patentability. Av-Gay expressly includes every delay from 0 through 2500 milliseconds, including 50, 100, 150, and 200 milliseconds, within its disclosed operating range. Pelletier supplies the reason to operate in the early portion of that interval. Applicant has not identified evidence that approximately 50 milliseconds represents a critical lower threshold or that the approximately 50-200 millisecond interval produces an unexpected result relative to immediately adjacent pulse-delay settings.
Moreover, Av-Gay independently teaches adjusting pulse delay according to the measured inspiratory duration (e.g., automatically setting pulse delay to 20% of inspiratory time) confirming that pulse delay was recognized as an adjustable timing variable affecting where within inspiration the therapeutic pulse is delivered (¶[0187]). Optimizing such a known adjustable parameter to obtain the known objective of early inspiratory gas delivery would have been within the ordinary skill in the art (see In re Aller, 220 F.2d 454, 456 (CCPA 1955); In re Peterson, 315 F.3d at 1330; MPEP §2144.05).
The combination also provides a reasonable expectation of success. Both Av-Gay and Pelletier concern breath-responsive delivery of inhaled gases. Selection of a 50-200 millisecond value requires only programming or setting the delay already expressly contemplated by Av-Gay; it does not require a new delivery mechanism, therapeutic agent, sensor architecture, or operating principle.
Av-Gay itself establishes the required temporal sequence wherein the device detects the onset of inspiration, the pulse-delay period commences in coordination with that detected onset, and NO delivery begins after the pulse-delay period (¶[0185]-[0187]). Thus, when the dual-trigger breath-detection arrangement supplied by the Av-Gay/Pelletier combination detects the breath as recited in instant claims 60 and 62, application of Av-Gay’s pulse-delay control causes NO administration to begin only after the selected delay interval. Accordingly, instant claims 61 and 63 are unpatentable over Av-Gay in view of Akerström and Goldstein, and further in view of Pelletier.
Regarding instant claim 65, he teachings of Av-Gay, Akerström, Goldstein, Chen, and Pelletier with respect to the limitations of instant claims 50 and 64 are incorporated. As previously set forth, the combination teaches the underlying method of improving oxygenation or oxygen saturation in a patient suffering from coronavirus infection using breath-coordinated pulsed inhaled NO, including the dual breath-level and breath-slope detection arrangement required by instant claim 64.
Instant claim 65 additionally requires that “the timing for administration of the dose of inhaled nitric oxide includes a pulse delay of about 50 milliseconds to about 200 milliseconds after detection of the breath.” For the reasons set forth above with respect to instant claims 61 and 63, Av-Gay expressly detects onset of inhalation, initiates a pulse-delay period in coordination with that detected onset, and begins NO pulse delivery after expiration of the pulse-delay period (¶[0185]-[0187]). Av-Gay expressly teaches a pulse-delay range of 0-2500 milliseconds, which encompasses the claimed approximately 50-200 millisecond range (¶[0037] and claim 4). Pelletier expressly teaches that delay in breath-responsive gas delivery should be minimized because a majority of inspiratory volume may be completed during approximately the first 200 milliseconds following onset of inspiration (¶[0005]-[0006]).
One of ordinary skill therefore would have been motivated to select a pulse delay within the low end of Av-Gay’s disclosed range, including approximately 50-200 milliseconds, so that the pulse remains breath-triggered but is delivered early enough in inspiration to reach the patient during the portion of the breath in which substantial inspiratory volume remains available. The claimed range lies inside Av-Gay’s disclosed range and is therefore prima facie obvious absent persuasive evidence of criticality or unexpected results (see MPEP §2144.05; In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003)). The technical reason for selecting the claimed portion of the broader range is independently supplied by Pelletier, thereby avoiding reliance on the claimed invention itself as the motivation for the selection.
Chen is relied upon for the clinical oxygenation limitation of the parent claim and need not separately teach the breath-detection or pulse-delay parameter. The modification of the known NO delivery apparatus to employ the claimed delay would not alter the physiological basis for Chen’s teaching that inhaled NO improves oxygenation; rather, it concerns when during a detected inspiration the already-known NO dose is introduced. Accordingly, instant claim 65 is unpatentable over Av-Gay in view of Akerström and Goldstein and further in view of Chen and Pelletier.
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).
Claims 2-4, 10, 15, 45, and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 11, 22, and 24-26 of co-pending US Application No. 17/055,365 (hereinafter “Shah”), in view of in view of Av-Gay et al. (US20160279165A1; published 29 September 2016, hereinafter “Av-Gay”), Akerström et al. (Nitric Oxide Inhibits the Replication Cycle of Severe Acute Respiratory Syndrome Coronavirus, J. Virol. 2005 Feb; 79:1966-1969; hereinafter “Akerström”), and Goldstein (US20130239962A1; published 19 September 2013).
Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons outlined below. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Shah claim 1 claims a method of delivering nitric oxide to a patient in need by detecting a patient breath pattern including total inspiratory time using a breath-sensitivity control, correlating the detected breath pattern with an algorithm to calculate timing of NO administration, and delivering the NO dose pulsatilely over only a portion of the total inspiratory time.
Shah claim 4, dependent from claim 1, further requires delivery of the NO dose within the first half of total inspiratory time. Shah claim 11, dependent from claim 1, further requires the nitric-oxide delivery to have an antimicrobial effect. Shah claim 12 independently claims treatment of a cardiopulmonary disease using substantially the same breath-pattern detection, timing determination, and pulsatile inspiratory NO administration architecture.
Shah claim 21 claims a breath-detection algorithm for determining the timing of an NO pulse using both a threshold sensitivity and a slope algorithm, with the slope algorithm detecting a breath based upon the rate of pressure decrease. Shah claims 22, 24, and 25 claim breath-triggered pulse delivery of a first gas, administration of a second gas, and specifically nitric oxide as the first gas and oxygen as the second gas. Shah claim 26, dependent from claim 1, expressly requires the NO dose to be therapeutically effective.
These claims collectively establish that Shah had already claimed the core breath-detected, breath-timed, pulsatile inhaled-NO treatment platform, including therapeutically effective dosing, antimicrobial effect, first-half inspiratory delivery, dual breath-detection criteria, and NO/oxygen combination delivery.
Shah claim 1 already claims the essential delivery method of instant claim 2- detecting a breath pattern including total inspiratory time, determining NO administration timing from the breath pattern, and pulsatilely delivering NO during only a portion of inspiration. Shah claim 26 further expressly requires a therapeutically effective dose, and Shah claim 11 expressly characterizes the delivered NO as having an antimicrobial effect.
The principal differences between instant claim 2 and Shah claims 1, 11, and 26 are that instant claim 2 further specifies treatment of a viral, bacterial, or protozoal infection leading to a disease state; a dose of approximately 250-1200 mcg/kg IBW/hr; and treatment for approximately 15 minutes to four hours per day for at least five days. Those differences would have been obvious variations of the Shah-claimed antimicrobial, therapeutically effective, pulsed-NO treatment method.
As described above, Av-Gay expressly teaches using breath-coordinated pulsatile inhaled NO for treatment of microbial respiratory infections, including bacterial and viral infections, and describes NO as effective against a broad range of bacteria, parasites, fungi, and viruses. Av-Gay additionally identifies coronavirus and SARS among contemplated viral pathogens.
Thus, once Shah claim 11 already limits the Shah method to an antimicrobial effect, applying that method therapeutically to a patient infected with a microorganism susceptible to NO would have been a predictable therapeutic use of the antimicrobial effect already claimed.
As described above, Goldstein expressly teaches inhaled-NO doses of 0.001-4.5 mg/kg/hr, including determination based upon ideal body weight. Instant claim 2’s 250-1200 mcg/kg IBW/hr corresponds to 0.25-1.2 mg/kg IBW/hr and falls wholly within Goldstein’s disclosed range.
As described above, Av-Gay further describes 30-minute sessions administered five times daily for five consecutive days. Five 30-minute sessions equal 2.5 hours per day, squarely within instant claim 2’s 15-minute-to-four-hour daily treatment period and satisfying the requirement of at least five days.
Thus, it would have been obvious to one of ordinary skill, starting with Shah’s already-claimed antimicrobial, breath-coordinated, therapeutically effective pulsed-NO treatment method, to select an infection as the disease being treated, an IBW-normalized dose falling within Goldstein’s known range, and the known antimicrobial NO treatment schedule taught by Av-Gay. Such limitations constitute an obvious therapeutic optimization and application of the same fundamental Shah invention, rather than a patentably distinct invention.
Instant claim 3 further limits claim 2 to SARS-CoV-2 infection and COVID-19. As discussed above, Akerström demonstrated that NO inhibits replication of severe acute respiratory syndrome coronavirus and therefore supplies specific evidence that a SARS-related coronavirus is susceptible to the antimicrobial/antiviral action of NO. Av-Gay expressly identifies coronavirus and SARS among infections contemplated for its inhaled-NO treatment.
Accordingly, applying Shah’s claimed antimicrobial pulsed-NO method to the SARS-CoV-2 coronavirus species responsible for COVID-19 would have been an obvious disease-specific use of the same claimed treatment platform. Instant claim 3 therefore does not render the subject matter patentably distinct from Shah claims 1, 11, and 26 when considered with the cited prior art.
Shah claims 1 and 26 already claim breath-pattern detection, timing of administration based on that breath pattern, pulsatile NO administration during only a portion of inspiration, and administration of a therapeutically effective NO dose. Shah claim 11 additionally claims that the NO delivery has an antimicrobial effect.
Instant claim 4 differs principally by specifying SARS-CoV-2 as the target virus, inhibition of SARS-CoV-2 viral replication as the therapeutic endpoint, approximately 250-1200 mcg/kg IBW/hr, and the specified treatment duration.
As described above, Akerström expressly teaches that NO inhibits the replication cycle of SARS coronavirus, including inhibition of viral RNA and protein synthesis. Av-Gay teaches application of inhaled antimicrobial NO to coronavirus/SARS infection. Goldstein teaches the encompassing IBW-normalized dose range. Av-Gay teaches the encompassing multiday treatment schedule.
Accordingly, using Shah’s already-claimed antimicrobial, therapeutically effective pulsatile-NO delivery method for the known NO-sensitive coronavirus antiviral purpose identified by Akerström would have been an obvious use of the Shah method according to its established antimicrobial function. Instant claim 4 therefore is not patentably distinct from the Shah claims.
Shah claim 4 expressly requires delivery of the nitric-oxide dose within the first half of total inspiratory time. Instant claim 10 adds that same limitation to instant claim 2 and instant claim 45 adds that same limitation to instant claim 4. Once the underlying therapeutic subject matter of the respective parent claims is found not patentably distinct for the reasons stated herein, limiting pulse delivery to the first half of total inspiration does not confer patentable distinctness because that precise timing limitation is already claimed by Shah claim 4.
Instant claims 15 and 47 require administration of NO in combination with at least one additional gas. Shah claim 22 claims breath-triggered administration of a pulsed first gas. Shah claim 24 expressly adds administration of a second gas, and Shah claim 25 expressly specifies that the first gas is nitric oxide and the second gas is oxygen. Accordingly, the additional-gas limitation is directly represented in the Shah claim set. The instant claims merely apply that already-claimed NO-plus-additional-gas delivery configuration to the therapeutic uses recited by the respective parent claims. For the reasons supplied for those parent claims, the disease-specific and dosing limitations do not render the claimed method patentably distinct.
Claims 2, 4, 50, 51, 53, and 56-59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 11, 12, 21, 22, and 24-26 of co-pending US Application No. 17/055,365 (hereinafter “Shah”), in view of in view of Av-Gay et al. (US20160279165A1; published 29 September 2016, hereinafter “Av-Gay”), Akerström et al. (Nitric Oxide Inhibits the Replication Cycle of Severe Acute Respiratory Syndrome Coronavirus, J. Virol. 2005 Feb; 79:1966-1969; hereinafter “Akerström”), 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 “Chen”).
Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons outlined below. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Av-Gay, in view of Akerström, in further view of Goldstein, teach the limitations of instant claims 2 and 4, as described above, from which instant claims 56-59 depend, however do not explicitly teach the specific limitations of instant claims 56-59.
Shah claim 1 claims the breath-coordinated pulsed-NO delivery architecture. Shah claim 12 expressly claims use of substantially the same architecture for therapeutically treating cardiopulmonary disease. Shah claim 26 requires a therapeutically effective dose.
Instant claim 50 principally adds a patient suffering from SARS-CoV-2 infection or COVID-19, improvement in oxygenation or oxygen saturation, the 250-1200 mcg/kg IBW/hr dose, and the specified multiday schedule. As described above, Chen expressly demonstrates that inhaled NO administered to patients suffering from SARS improved arterial oxygenation and oxygen saturation and permitted reduction of respiratory support. Thus, improvement of oxygenation is not an unrelated new use of Shah’s claimed NO treatment architecture; it is a known therapeutic physiological result of administering inhaled NO to a patient suffering from severe coronavirus respiratory disease.
As described above, Goldstein supplies the encompassing IBW-normalized dose range, while the treatment-period selection is obvious for the reasons set forth above. Accordingly, instant claim 50 is an obvious disease- and endpoint-specific use of the same therapeutically effective pulsatile-NO treatment platform claimed in Shah and is not patentably distinct.
Shah claim 4 expressly requires delivery of the nitric-oxide dose within the first half of total inspiratory time. Instant claim 51 adds that same limitation to claim 50. Once the underlying therapeutic subject matter of the respective parent claims is found not patentably distinct for the reasons stated herein, limiting pulse delivery to the first half of total inspiration does not confer patentable distinctness because that precise timing limitation is already claimed by Shah claim 4.
Instant claim 53 requires administration of NO in combination with at least one additional gas. Shah claim 22 claims breath-triggered administration of a pulsed first gas. Shah claim 24 expressly adds administration of a second gas, and Shah claim 25 expressly specifies that the first gas is nitric oxide and the second gas is oxygen. Accordingly, the additional-gas limitation is directly represented in the Shah claim set. The instant claims merely apply that already-claimed NO-plus-additional-gas delivery configuration to the therapeutic uses recited by the respective parent claims. For the reasons supplied for those parent claims, the disease-specific and dosing limitations do not render the claimed method patentably distinct.
Instant claims 56-58 further require that a need for supplemental oxygen or time requiring mechanical breathing be reduced or eliminated. As described above, Chen expressly reports that inhaled NO treatment of SARS patients improved arterial oxygenation, reduced supplemental oxygen requirements, and permitted reduction or discontinuation of CPAP, BiPAP, and related respiratory support. Accordingly, reduction in supplemental oxygen or breathing support was a known clinical consequence of successful inhaled-NO therapy in severe coronavirus respiratory disease.
Once the Shah claimed pulsatile, therapeutically effective NO method is used for the coronavirus respiratory conditions addressed by the parent claims, seeking and obtaining the known reduction in supplemental oxygen or respiratory support taught by Chen would have been an obvious therapeutic outcome. Instant claims 56-58 therefore are not patentably distinct from the Shah claimed subject matter.
For the reasons stated above, the underlying method of claim 4 is not patentably distinct from Shah’s claimed antimicrobial pulsatile-NO treatment. Instant claim 59 adds administration of one or more listed therapeutic agents, including, among other alternatives, an anti-inflammatory or steroid. As described above, Chen expressly treated SARS patients receiving inhaled NO with methylprednisolone, a steroid, and ribavirin, an antiviral agent.
Because instant claim 59 is satisfied by administration of at least one listed alternative, Chen’s express coadministration of a steroid with inhaled NO is sufficient to render the additional limitation an obvious treatment modification. Combining Shah’s antimicrobial pulsed-NO treatment with a conventionally co-administered steroid in a severe coronavirus patient therefore would have represented the predictable use of known therapeutic modalities according to their established functions. Accordingly, instant claim 59 is not patentably distinct.
Claims 2, 4, 50, and 60-65 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 11, 12, 21, 22, and 24-26 of co-pending US Application No. 17/055,365 (hereinafter “Shah”), in view of in view of Av-Gay et al. (US20160279165A1; published 29 September 2016, hereinafter “Av-Gay”), Akerström et al. (Nitric Oxide Inhibits the Replication Cycle of Severe Acute Respiratory Syndrome Coronavirus, J. Virol. 2005 Feb; 79:1966-1969; hereinafter “Akerström”), Goldstein (US20130239962A1; published 19 September 2013), Pelletier and Chekal (US20080078392A1; published 03 April 2008, hereinafter “Pelletier”), 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 “Chen”).
Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons outlined below. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Av-Gay, in view of Akerström, in further view of Goldstein, teach the limitations of instant claims 2, 4, and 50, as described above, from which instant claims 60-65 depend, however do not explicitly teach the specific limitations of instant claims 60-65.
Shah claim 21 expressly claims a breath-detection algorithm for determining timing of an NO pulse that uses a threshold sensitivity, and a slope algorithm, where the slope algorithm detects a breath from the rate of pressure decrease.
Instant claims 60, 62, and 64 recite the same breath-detection concepts using the terminology “breath level trigger,” which detects the breath when a pressure threshold is reached, and “breath slope trigger,” which detects inspiration from the slope of a pressure waveform. The difference in terminology does not establish patentable distinctness. A pressure threshold constitutes the claimed breath-level criterion, while the rate of pressure decrease is the mathematical slope of the pressure waveform.
Shah claim 1 additionally places breath-pattern detection directly within the pulsed-NO administration method. Thus, the instant claims merely employ within the Shah claim 1 treatment method the dual threshold/slope breath-detection architecture separately claimed by Shah claim 21.
Even if Shah claim 21 were construed as not expressly requiring every detail of the recited “breath level trigger,” use of both an absolute-pressure threshold and a pressure-rate/slope threshold was conventional in breath-actuated gas delivery, as demonstrated by Pelletier (as described above). Addition or implementation of the known level criterion in Shah’s claimed threshold-and-slope algorithm would therefore have been an obvious variation yielding predictable breath-detection operation. Accordingly, instant claims 60, 62, and 64 are not patentably distinct from Shah’s claimed subject matter.
Instant claims 61, 63, and 65 additionally require a pulse delay of approximately 50-200 milliseconds after detection of the breath.
Shah claims 1 and 21 already claim the breath detection and algorithmic determination of NO pulse timing upon which the instant limitation operates. As described above, Av-Gay expressly teaches a pulse-delay period associated with the detected onset of inspiration and discloses an adjustable pulse-delay range of 0–2500 milliseconds. Thus, approximately 50-200 milliseconds lies entirely within the known operating range for breath-coordinated pulsatile NO administration.
As described above, Pelletier provides a specific reason to select a relatively short delay. Pelletier explains that delayed detection/delivery is undesirable because a substantial portion of inspiratory volume may be inhaled during approximately the first 200 milliseconds of inspiration and therefore teaches minimizing breath-detection delay to provide timely gas delivery.
A person of ordinary skill applying the Shah-claimed breath-detection and pulse-timing algorithm therefore would have been motivated to select an early pulse delay within approximately 50-200 milliseconds to initiate NO delivery sufficiently early within the inspiratory cycle. The modification requires only selection or programming of a known breath-trigger timing parameter and would predictably preserve Shah’s intended early, precise, breath-coordinated delivery. No evidence has been presented that the approximately 50-millisecond lower boundary is critical or that a 50-200 millisecond interval produces an unexpected result relative to nearby delay values. Accordingly, the additional delay limitation is an obvious variation of the Shah-claimed pulse-timing method and does not render instant claims 61, 63, and 65 patentably distinct.
In summary, instant claims 2 and 3 are rejected over Shah claims 1, 11, and 26 in view of Av-Gay, Goldstein, and Akerström. Instant claim 4 is rejected over Shah claims 1, 11, and 26 in view of Av-Gay, Akerström, and Goldstein. Instant claims 10 and 45 are rejected over Shah claim 4 together with the references applicable to instant claims 2 and 4, respectively. Instant claim 15 is rejected over Shah claims 22, 24, and 25 together with the references applicable to instant claim 2. Instant claim 47 is rejected over Shah claims 22, 24, and 25 together with the references applicable to instant claim 4.
Instant claim 50 is rejected over Shah claims 1, 12, and 26 in view of Goldstein, Akerström, and Chen. Instant claim 51 is rejected over Shah claim 4 together with the references applicable to instant claim 50. Instant claim 53 is rejected over Shah claims 22, 24, and 25 together with the references applicable to instant claim 50. Instant claims 56-58 are rejected over Shah claims 1, 11, 12, and 26 in view of Chen and the references applicable to the respective parent claims. Instant claim 59 is rejected over Shah claims 1, 11, and 26 in view of Akerström, Goldstein, and Chen.
Instant claims 60, 62, and 64 are rejected over Shah claims 1 and 21, together with Pelletier if necessary, and the references applicable to the respective parent claims. Instant claims 61, 63, and 65 are rejected Shah claims 1 and 21 in view of Av-Gay and Pelletier, together with the references applicable to the respective parent claims.
To overcome these rejections, the applicant may establish that the examined claims are patentably distinct from the reference claims, appropriately amend or cancel the conflicting claims, file a compliant terminal disclaimer, or change the status or claim scope of the reference application such that the rejections no longer apply.
Response to Arguments
Applicant Arguments/Remarks of the reply, filed 17 July 2026, have been fully considered.
The applicant correctly identifies an error in the prior Office Correspondence’s calculation of the dose allegedly resulting from Av-Gay’s 160-ppm regimen. The prior calculation multiplied the treatment-session delivery rate by 2.5 hours/24 hours, thereby converting the regimen to a 24-hour time-weighted average. That value was then incorrectly characterized as the dose delivered per treatment hour. That methodology is withdrawn.
Using the same assumptions stated in the prior Office Correspondence (i.e., 160 ppm NO, minute ventilation of 6 L/min, ideal body weight of 70 kg, and the stated NO conversion of 1.34 mg/m³ per ppm) the treatment-session calculation is 160=1.2864; 1.2864=77.184; 77.184=1.1026; and 1.1026=1103. Thus, under the assumptions previously employed, Av-Gay’s 160-ppm regimen corresponds to approximately 1103 mcg/kg IBW/hr during the treatment session, not approximately 115 mcg/kg IBW/hr.
Moreover, even if a conservative 60% inspiratory pulse-delivery factor is applied to reflect Av-Gay’s exemplary pulse-delivery period, the resulting value is approximately 1103=662. Both approximately 1103 mcg/kg IBW/hr and approximately 662 mcg/kg IBW/hr fall within the claimed range of about 250 to about 1200 mcg/kg IBW/hr.
Av-Gay expressly teaches determining the inhalation period from sensed flow, setting a pulse delay to 20% of the inhalation period, delivering NO during a following 60% pulse-delivery period, and ceasing delivery during the remaining 20%. The foregoing calculation is not relied upon as establishing that every implementation of Av-Gay necessarily delivers a particular mass dose. Actual delivered mass may vary with ventilation, inspiratory-flow profile, patient weight, pulse volume, and device programming. Rather, the calculation demonstrates that a straightforward implementation of Av-Gay using the same ordinary assumptions previously adopted produces a dose within the claimed range.
Goldstein independently removes any material uncertainty arising from conversion of concentration units. Goldstein expressly discloses pulsatile NO delivery during only a portion of inspiration, a dose of 0.001-4.5 mg/kg/hr, calculation according to ideal body weight, and use of such doses for antimicrobial administration. The claimed range of 0.25-1.2 mg/kg IBW/hr lies within Goldstein’s disclosed range. The applicant’s criticism of the prior 24-hour averaging calculation is therefore persuasive, but it does not overcome the rejection because the corrected calculation and Goldstein’s express weight-normalized disclosure both encompass the claimed dose range.
Av‑Gay teaches an adjustable pulsed NO delivery regimen for treating infections, with concentrations of at least 160 ppm and adjustable dosing (e.g., 400-2000 ppm·hr) determined by the pathogen (Table 1). Goldstein expressly teaches inhaled NO doses in the range of 0.001 to 4.5 mg/kg/hr (i.e., 1-4500 mcg/kg/hr; ¶[0005]-[0009]). The claimed sub-range of 250-1200 mcg/kg IBW/hr lies entirely within Goldstein’s broad disclosure. Selecting a narrow sub-range from a known broader range is prima facie obvious in the absence of unexpected results (see In re Peterson, 315 F.3d 1325, 1329–30 (Fed. Cir. 2003); In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990)). The applicant has provided no comparative data or evidence of criticality that would rebut this inference.
The applicant’s argument that Av‑Gay “teaches away” from higher doses because it expresses safety concerns is unavailing. Av‑Gay itself treats higher doses as acceptable under controlled intermittent administration (¶[0180]-[0183]), and Goldstein demonstrates that substantially higher doses (up to 4.5 mg/kg/hr) were administered to human subjects. A general preference for minimizing toxicity does not rise to the level of a teaching away when the art as a whole recognizes the dose range and when routine optimization would involve balancing efficacy and safety. Neither Av-Gay nor Goldstein teaches that doses within the claimed range must not be used. Both references recognize toxicity or tolerability concerns and teach controlling concentration, pulse duration, flow, exposure time, and monitoring to administer higher NO doses safely.
A reference does not teach away merely because it recognizes a tradeoff or expresses a preference for minimizing adverse effects. Teaching away requires discouragement from the proposed course or an indication that the proposed modification would be inoperative or unsuitable. Here, the references teach controlled intermittent administration as the solution to the identified toxicity concern. Av-Gay additionally reports that 160 ppm for 30 minutes, five times daily, for five days was tolerated in a human safety study. Thus, the claimed dose range would have been arrived at through routine optimization of the NO delivery protocol already taught by Av‑Gay and Goldstein, with a reasonable expectation of success.
The applicant alleges failure to consider the claims as a whole. However, the rejections outlined above do not rest on the mere observation that isolated claim features can be found in unrelated references. Av-Gay teaches the integrated breath-coordinated, pulsatile infection-treatment platform and the claimed treatment schedule. Akerström supplies the coronavirus antiviral teaching. Goldstein supplies an express IBW-normalized dose encompassing the claimed range and first-half inspiratory pulse delivery. Chen supplies the claimed clinical oxygenation and respiratory-support results. Pelletier supplies the additional breath-trigger and delay limitations. The combination therefore assigns each reference a defined role corresponding to an identified difference between the primary reference and the claims.
The applicant alleges impermissible hindsight. This argument is not persuasive. The reason for the combination arises from the references themselves, Av-Gay seeks effective antimicrobial NO delivery while controlling toxicity, Akerström identifies SARS coronavirus replication as susceptible to NO, Goldstein teaches patient-normalized pulsed NO dosing and inspiratory timing, Chen demonstrates oxygenation and respiratory-support benefits in SARS patients, and Pelletier addresses missed or delayed detection of shallow inspirations. The proposed modifications correspond to the problems and solutions expressly recognized in the art and are not derived solely from Applicant’s disclosure.
The applicant argues that Akerström and Chen do not provide a reasonable expectation of success because they relate to SARS‑CoV (not SARS‑CoV‑2) and involve in vitro or limited clinical studies. This argument is unpersuasive.
Akerström alone does not establish clinical efficacy against SARS-CoV-2, and Chen alone does not establish efficacy of the claimed high-dose pulse regimen. The rejection, however, is based upon their combined teachings with Av-Gay and Goldstein.
Before the effective filing date, the combined art supplied an inhaled, pulsed, antimicrobial NO treatment platform directed to respiratory pathogens, including coronavirus and SARS; laboratory evidence that NO inhibits SARS-coronavirus replication; express clinical evidence that inhaled NO improves oxygenation and reduces respiratory support in SARS; and established dose and timing mechanisms for pulsatile, IBW-normalized NO administration.
Akerström establishes that NO inhibits replication of a severe acute respiratory syndrome coronavirus (SARS‑CoV) (Abstract). SARS‑CoV‑2 is a closely related betacoronavirus and the causative agent of COVID‑19. At the time of the invention, it would have been obvious to apply the antiviral effect of NO to the newly emerged SARS‑CoV‑2, particularly in the context of a global pandemic that provided a strong motivation.
Chen demonstrates that inhaled NO improved oxygenation in SARS patients and allowed reduction of supplemental oxygen and ventilator support (Abstract). Although Chen’s study was small and used a low‑concentration regimen, it provides a clear clinical rationale that inhaled NO can improve oxygenation in coronavirus‑induced respiratory failure. The combination of Av‑Gay’s delivery platform, Goldstein’s high‑dose guidance, Akerström’s antiviral motivation, and Chen’s oxygenation outcomes renders the claimed method obvious.
The recitation of a specific therapeutic effect (inhibiting replication of SARS‑CoV‑2, improving oxygenation) does not impart patentability when the effect is the expected result of the obvious combination. These teachings provide a reasonable expectation that applying the known pulsed treatment platform to a SARS-related coronavirus patient would provide at least antiviral and/or pulmonary oxygenation benefit. Obviousness does not require certainty that every treated patient will respond or that the precise magnitude of benefit can be predicted.
The applicant’s argument concerning Weismann is that “Weismann fails to remedy the deficiencies.” The combination of Av‑Gay and Weismann is not dependent on the dose‑or infection‑related teachings, rather it addresses the separate feature of improved breath detection. Av‑Gay already uses breath‑cycle‑coordinated pulse delivery based on detected inspiration (¶[0186]-[0187]). Weismann teaches a dual‑trigger breath‑detection method using both a pressure‑level trigger and a pressure‑slope trigger to reliably identify the start of inspiration, even in patients with irregular breathing (claims 1 and 5). It also teaches a pulse delay (claim 8).
The prior reliance on Weismann for the pulse-delay limitation of claims 61, 63, and 65 is withdrawn. Weismann’s approximately 50-800 millisecond interval is associated with respiratory-signal processing following a zero crossing and preceding recognition of a valid respiratory-phase trigger. It is therefore not the same temporal relationship as the presently claimed pulse delay occurring after detection of the breath and before administration of inhaled NO. The instant rejection instead relies upon Av-Gay’s express post-onset pulse-delay architecture and disclosed 0-2500 millisecond delay range, together with Pelletier’s express teaching favoring early gas delivery within approximately the first 200 milliseconds of inspiration. This revised rationale directly addresses the temporal relationship recited by claims 61, 63, and 65.
One of ordinary skill in the art, seeking to enhance the reliability and safety of Av‑Gay’s breath‑actuated NO delivery, would have been motivated to incorporate Weismann’s proven dual‑trigger approach. The fields of breath‑actuated drug delivery and ventilator triggering are closely analogous, and the combination would yield the predictable benefit of more accurate breath detection and NO pulse timing.
Regarding the obviousness of the co‑administration features of claim 59, Av‑Gay teaches monitoring IL‑6 during NO therapy, which would motivate co‑administration of an anti‑IL‑6 antibody, anti‑inflammatory, or steroid. Chen explicitly co‑administers methylprednisolone and ribavirin. The addition of other known antivirals (e.g., remdesivir, hydroxychloroquine) reflects the routine practice of combining therapeutics with different mechanisms of action to treat a complex viral disease.
Last, the applicant states that terminal disclaimers will be filed when the claims are otherwise in condition for allowance. Until an appropriate terminal disclaimer is filed, the provisional double patenting rejections over the co-pending application remain in effect. The rejections are maintained.
Conclusion
No claims are allowed.
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/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
Prosecution Insights