DETAILED ACT ION
Status of the Claims
Claims 1-20 are pending in the instant application and are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
The U.S. effective filing date has been determined to be 01/12/2023, the filing date of the U.S. Provisional Application No. 63/479,700.
Objections – Specification
Applicant has filed two Specification documents on 02/09/2026 in which the examiner finds no markups - Applicant has provided the full text of the Specification in duplicate without any markings as required – “Applicants are also permitted to amend the specification by submitting a substitute specification, provided the requirements of 37 CFR 1.125(b) and (c) are met. Under 37 CFR 1.125, a clean version of the substitute specification, a separate marked up version showing the changes in the specification relative to the previous version, and a statement that the substitute specification contains no new matter are required.” [emphasis added] (MPEP §714(II)(B)). Also see, 37 CFR 1.121 “(ii) The full text of any replacement paragraph with markings to show all the changes relative to the previous version of the paragraph. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived;” (37 CFR 1.121(b)(1)(ii)).
Claim Rejections - 35 USC § 112(a)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-20 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Scope of the Claimed Invention:
Applicant claims a method of treating delirium in a patient in need thereof, wherein the delirium results from excess activation of the cytokine system and comprises a decline from a previous baseline mental functioning that develops over a short period of time and includes disturbances in attention, consciousness, and cognition, the method comprising: administering nitrous oxide and oxygen to a patient by inhalation, and administering B-12 and/or folic acid to the patient, thereby treating delirium (instant claim 1).
The scope of “wherein the delirium results from excess activation of the cytokine system and comprises a decline from a previous baseline mental functioning that develops over a short period of time and includes disturbances in attention, consciousness, and cognition,” actually should be considered, as discussed below.
The examiner notes that nitrous oxide also known as “laughing gas” has when administered with oxygen (e.g. 50/50 mix) resulting so-called conscious sedation.
Disclosure of the Prior Art:
Smith et al. (“Cytokine profiles in intensive care unit delirium,” 2022, Acute and Critical Care, Vol. 37, No. 3, pp. 415-428) teaches cytokine profiles in intensive care unit delirium (title, see whole document). Smith et al. teaches that: “Delirium is a neuropsychiatric syndrome that involves altered cognition, impaired aware-ness, inattention, disorganized thinking, and fluctuating arousal. Its onset can be acute or subacute, it can occur in hypo- or hyperactive forms, and its consequenc-es can be devastating. Patients who experience delirium are at increased risk of death, dementia, and institutionalization. Furthermore, the economic burden of delirium is profound. […] Despite the prevalence of delirium and significant advances in the understanding of this syndrome made over the past decade, knowledge of its underlying pathophysiologic mechanisms remains incomplete.” (§Introduction, 1st paragraph). And that: “Delirium results from a variable combination of predisposing factors unique to the individual and precipitating factors. Acute stressors associated with delirium are well characterized and include critical illness and surgery, both of which are associated with the release of inflammatory cytokines. The objective of our study was to further characterize the association between various precipitating factors with the development of delirium, including a comprehensive analysis of cytokine responses in those patients that developed delirium versus those that did not.” (§Introduction, 3rd paragraph). And further that: “In this study, we sought to determine whether cytokine pro files associated with delirium vary based on the precipitating condition. Our focus was on delirium resulting from sepsis, coronavirus disease 2019 (COVID-19), and recent surgery. This study is novel in that it is the first to investigate relative levels of inflammatory cytokines that result from several conditions known to be associated with delirium.” (§Introduction, 4th paragraph).
Smith et al. teaches that: “Table 4 provides the cytokines associated with the develop-ment of delirium. Those cytokines found to be significantly elevated include the proinflammatory cytokines TNF-α, IL-6 and IL-18; the chemokines CCL2, CCL3, CXCL1, CXCL10 and IL-8; and the anti-inflammatory cytokines IL-1RA and IL-10. No significant difference was seen in levels of G-CSF, GM-CSF, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-12, and IL-17A between those patients that developed delirium and those that did not.” (p. 417, col. 2, last paragraph; p. 424, col. 1, lines 1-4). And that: “We identified several cytokines associated with delirium in our ICU patient population. Interestingly, CCL2, CXCL10, and TNF-a showed a statistically significant elevation in those patients that developed delirium in the setting of both sepsis and COVID-19 relative to the group that recently had surgery and developed delirium.” (p. 242, col. 1, 2nd paragraph).
Smith et al. teaches that: “It is established that inflammation is associated with delir-ium; however, the exact mechanism by which this occurs has yet to be elucidated.” (§Discussion, 2nd paragraph). And that: “Considering the cytokine profile typical of delirium seen in both the sepsis and COVID-19 groups, the cytokine pattern TNFα, in our surgery group is curious. Levels of CCL2, and CXCL10 are decreased in those patients that recently had surgery and developed delirium relative to both the sepsis and COVID-19 groups. In the surgical group, the preeminent cytokine elevations were G-CSF and CCL3. This finding may suggest the existence of an alternative, non–TNF-α driven pathway of peripheral inflammation that resulted in delirium in our surgical patients.” (§Discussion, 3rd paragraph). And finally that: “In conclusion, our study demonstrates a statistically significant association between several cytokines and the development of delirium. However, the cytokine profile appears to be variable and contingent upon the delirium precipitating factors. In both sepsis and COVID-19, CCL2, CXCL10, and TNF-α predominate. In our surgical population, G-CSF is elevated and CXCL10 is decreased in patients that developed delirium. These findings provide support of the delirium syndrome representing a manifestation of distinct pathophysiological processes” (last paragraph).
Slooter (“Delirium, what’s in a name?” 2017, British Journal of Anaesthesia Vol. 119, No. 2, pp. 283–285) teaches that: “Delirium has been known since ancient times. Hippocrates [460–370 Before Common Era (BCE)] may have been the first to describe the syndrome that he called ‘phrenitis’, marked by confusion and restlessness that fluctuated unpredictably and that was associated with physical illness. Many other names have been used, including acute mental status change, confusional state, confusion, acute brain dysfunction, brain failure, encephalopathy, postoperative psychosis and acute organic syndrome. Of these, the term delirium (derived from the Latin word delirare, deviate from a straight track) has gained acceptance. Besides a more uniform terminology, an important recent achievement includes publication of criteria to define delirium. Although criticized, the criteria of the Diagnostic and Statistical Manual of Mental Disorders (5th edition, DSM-5) have become standard. According to these criteria, a patient can be considered delirious when all items listed in Table 1 are present at the same time. In essence, this means that a patient has acutely developed disturbed attention with other cognitive deficits, which is not solely due to underlying dementia and is caused by a physical condition.” (p. 283, col. 1, lines 1-14). And discloses Table 1 as follows:
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(p. 284). Slooter further teaches that: “Although terminology has become more uniform, there is variability regarding which tests should be used to make the diagnosis of delirium. In addition, there is still confusing heterogeneity in the literature […].” (p. 283, col. 1, last paragraph). And that: “Another reason for limited progress may be that the definition of delirium is quite broad. Although the DSM-5 definition of delirium is well established, the opinion of clinicians of what looks like delirium may be a separate issue. An example of a case that fulfils DSM-5 criteria for delirium while not being considered delirious by many clinicians is a patient with subarachnoid haemorrhage who develops attention deficits and a decreased level of consciousness due to delayed cerebral ischaemia. Another example is a neurologically intact patient who undergoes conscious sedation for a medical procedure such as endoscopy.” (p. 283, col. 2, 2nd paragraph). And further that: “Studies on different delirium aetiologies are difficult to perform as it is usually impossible to assign one specific cause for delirium.” (p. 283, col. 2, 3rd paragraph, lines 7-9).
Slooter further teaches that: “Not all patients with an acute disorder of cognition fulfil DSM-5 criteria for delirium. One possibility for not fulfilling criteria is that the patient shows a very mild form of delirium. The term subsydromal delirium has been used to describe patients with some delirium features, but who do not fulfil all diagnostic criteria for delirium. Another possibility for not fulfilling delirium criteria of an acute disorder of cognition is that it represents a separate entity, as could be the case in isolated postoperative hallucinations after cardiac surgery with possible opioid overdose.” p. 284, col. 1, 2nd paragraph).
Wilson et al. (“Delirium,” Nat Rev Dis Primers., Vol. 6(1): 90, Author manuscript PMC edition provided, pp. 1-64) is cited as teaching delirium, including that: “The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) is the most commonly used diagnostic system upon which a reference standard diagnosis is made, although many other delirium screening tools have been developed owing to the impracticality of using DSM-5 in many settings. […] Effective implementation of delirium detection, treatment and prevention strategies remains a major challenge for healthcare organizations globally.” (p. 2, Abstract, lines 8-12, 16 and 17).
Wilson et al. teaches that: “Delirium remains grossly under-diagnosed and undetected, with fewer than half of delirium cases in hospital typically being detected. Multiple reasons exist for underdiagnosis, including, amongst others, a general lack of delirium training at all levels including in undergraduate education, attitudes such as the perception that delirium is not ‘owned’ by (that is, the responsibility of) certain specialties or groups of practitioners, the use of imprecise alternative terms such as ‘confusion’, and a lack of perception that delirium is important. It is now clear that successful implementation of delirium detection, treatment and risk reduction is a complex challenge, requiring an educational programme addressing both attitudes and skills, supported by audit, using tools with proven implementability that are tailored to the population to be tested.” (p. 19, §Challenges in detecting delirium, 1st paragraph).
Wilson et al. teaches that: “What remains less well understood is whether delirium is a singular condition that should be studied regardless of phenotype or aetiology or is really a grouping of various types of deliria that are better studied as distinct physiological conditions.” (p. 28, §Delirium categorization, 1st paragraph).
Disclosure of the Instant Application:
The instant Specification provides a broad definition of delirium encompassing four bullet points, Clinical Features/Signs and Symptoms, Causes (pp. 5-10). The instant Specification suggests that the Pathophysiology “Mechanisms are not fully understood” (p. 10, line 5), but suggest various Hypothesis (p. 10, last two bullet points, p. 11, first four bullet points).
The instant Specification discloses that: “The human immune system is a complex system of adaptive and innate responses that provides protection from external and internal threats. The cells of the immune system (e.g., neutrophils and macrophages) communicate via cytokines, which are hormone-like proteins produced by a variety of immune cells. Cytokines are important mediators of the immune response, which initiate, perpetuate, or downregulate the response. Cytokines include interleukins (IL), tumor necrosis factors (TNF), and transforming growth factors (TGF-β 1-3). Certain cytokines are considered proinflammatory (IL-1, IL- 6, and TNF-α.), and others are antiinflammatory (IL-4, IL-10, and IL-13).” (paragraph bridging pp. 15-16). And that: “Delirium is an acute decline in cognition, and is associated with acute inflammatory states. Studies examining the relationship of acute inflammation on cognitive decline in patients with delirium showed that acute systemic inflammatory events were associated with an increase in serum levels of TNF-α and a 2-fold increase in rate of cognitive decline over a 6-month period. Subjects with higher baseline levels of TNF-α were more likely to have delirium and were associated with a 4-fold increased rate of cognitive decline over a 6- month period compared to those with low TNF-α levels.” (p. 16, lines 5-11).
The instant Specification discloses that: “Dysregulation of cytokines is believed to be the key inciter of neurodegeneration and subsequent cognitive impairment in delirium that results from activation of the systemic inflammatory cascade. Therapeutic and investigational uses of interleukins in human and rat models induce symptoms of delirium, alter acetylcholine levels and activity, and mediate exotoxic neurodegeneration. Risk factors for cytokine dysregulation include age as well as acute illness, infection, and trauma. Aging alters CNS and peripheral levels of certain cytokines even in the absence of disease or inflammation. Further, studies in mice indicate that aging brains are predisposed to exacerbated neuroinflammatory cytokine responses as a result of changes in glial reactivity. It is also becoming clear that the impact of peripheral inflammatory signals on the brain depends on existing levels of inflammation, as occurs in dementia or other direct brain lesions. Administration of therapeutic levels of systemic cytokines in oncology patients can result in neuropsychiatric side effects, including impaired thought processing. Peripheral cytokines (along with prostaglandins) are also thought to be responsible for the central behavioral changes seen with the syndrome of "sickness behavior," which refers to a constellation of symptoms associated with illness and delirium, such as lethargy, decreased learning, reduced mobility, reduced social activity, and increased sleep. Sickness behavior is seen in conditions associated with systemic inflammation, such as infection or acute flares of chronic disease.” (p. 17, lines 6-22, p. 18, lines 1-2). And that: “Cytokine dysregulation can lead to neuronal injury through a variety of mechanisms, including (1) altered neurotransmission, (2) apoptosis, and (3) activation of microglia and astrocytes which leads to production of free radicals, complement factors, glutamate, and nitric oxide. Also, the consequences of "sickness behavior" induced by cytokine dysregulation, including altered sleep, anorexia, and impaired nutrition may further impair cognition. Activation of the inflammatory cascade alters peripheral and/or central cytokines, leading to a central neurodegenerative inflammatory process that becomes clinically apparent as cognitive impairment when the cognitive reserve is breached.” (p. 18, lines 3-10).
The instant Specification discloses that: “Nitrous oxide has unique properties besides central anxiety control or sedation. Studies in nitrous oxide have shown that it has the ability to suppress the tachykinins, substance P and glutamate in the dorsal root, trigeminal and vagus sensory ganglia. Clinical observation has shown that this suppression lasts about 6-8 hours with the use of conscious sedation levels (e.g., about 50% nitrous oxide/about 50% oxygen. Substance P triggers immune cells to produce cytokines. Glutamate increases excitatory stimulation of the brain. Since the half-life of Substance P, glutamate and the cytokines is seconds to minutes, the effect should be immediate.” (p. 19, lines 13-19).
The instant Specification discloses administering nitrous oxide and oxygen consistent with the knowledge in the prior art (p. 19, line 20, through p. 20).
The instant Specification discloses three Examples: (1) A 68 year old male patient suffers from delirium. The patient weighs about 170 lbs. The patient primarily has an issue with inattention, memory impairment, and delusions. He receives 50% nitrous oxide/50% oxygen by inhalation for appointments 30 minutes each visit for a week. Within minutes of the administration of the nitrous oxide, he is completely lucid. He is capable of recalling many events he couldn't recall before the administration. His focus level significantly improves after the administration. The patient and his family reports significant improvement in the brain function without administering medications such as haloperidol. After the administration, substance P and glutamate blood levels are measured to be lower than before. The patient optionally receives additional treatments such as non-pharmacologic treatment and active exercise. The patient also receives B-12 and/or folate vitamin supplements.” (paragraph bridging pp. 22-23).
And Example 2: “A 78 year old female patient suffers from delirium with alcohol dependence. The patient weighs about 145 lbs. The patient primarily has an issue with inattention, disorientation, hallucinations, and language disturbances. She receives 50% nitrous oxide/50% oxygen by inhalation for appointments every 6 hours for one day. Within minutes of the administration of the nitrous oxide, she is completely lucid. She is capable of having proper conversation. Her cognition level significantly improves after the administration. The patient and her family reports significant improvement in the brain function without administering medications such as benzodiazepines. After the administration, substance P and glutamate blood levels are measured to be lower than before. The patient optionally receives additional treatments such as non-pharmacologic treatment and active exercise.” (p. 23, lines 10-19).
And Example 3: “ A 72 year old male patient suffers from cognitive impairment with drug dependence. The patient weighs about 171 lbs. The patient is withdrawn from an intensive care unit. He suffers from sensory impairment and requires assistance for self-care. While he is not currently diagnosed with delirium, his family wants to prevent him from developing any potential delirium. He receives 50% nitrous oxide/50% oxygen by inhalation for appointments every 8 hours for two weeks. Within minutes of the administration of the nitrous oxide, he is completely lucid. She is capable of having proper conversation. His cognition level significantly improves after the administration. The patient and his family reports significant improvement in the brain function without administering medications such as benzodiazepines. After the administration, substance P and glutamate blood levels are measured to be lower than before. The patient optionally receives additional treatments such as non-pharmacologic treatment and active exercise. The patient also receives B-12 and/or folate vitamin supplements.” (p. 24, 1st paragraph).
Discussion:
The claims are rejected for lack of written description because the claims recite “a method of treating delirium in a patient in need thereof, wherein the delirium results from excess activation of the cytokine system and comprises a decline from a previous baseline mental functioning that develops over a short period of time and includes disturbances in attention, consciousness, and cognition,” where the breadth of scope of delirium, as defined in the claims, not fully supported by the as-filed Specification. And the prior art, at best, demonstrates an association with excess cytokine levels (Smith et al. “It is established that inflammation is associated with delirium; however, the exact mechanism by which this occurs has yet to be elucidated.” (§Discussion, 2nd paragraph); “In conclusion, our study demonstrates a statistically significant association between several cytokines and the development of delirium. However, the cytokine profile appears to be variable and contingent upon the delirium precipitating factors. In both sepsis and COVID-19, CCL2, CXCL10, and TNF-α predominate. In our surgical population, G-CSF is elevated and CXCL10 is decreased in patients that developed delirium. These findings provide support of the delirium syndrome representing a manifestation of distinct pathophysiological processes” (last paragraph)). The as-filed Specification provides no experimental data demonstrating that “delirium results from activation of the cytokine system”. Additionally, the scope of “neuroexcitatory substances” in claim 11 is broad in comparison to what is shown, and only “normal blood glutamate level” is described in the as-filed Application. Additionally no guidance to any specific testing protocols for: (1) establishing if the “delirium results from excess activation of the cytokine system” or not, and/or (2) normalized levels of neuroexcitatory substances, is/are described. Applicant has only shown three examples of elderly human patients 68, 78 and 72 for Examples 1, 2 and 3, respectively. Therefore, support for the full scope of any patient of any age/weight for the claimed method of treating delirium by administering nitrous oxide and/or oxygen is properly rejected as failing to comply with the written description requirement as the claims 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
Response to Arguments:
Applicant's arguments filed 02/09/2026 have been fully considered but they are not persuasive.
Applicant’s argument that “Applicant respectfully traverses. The specification contains an express definition of delirium (acute confusional state) and describes predisposing and precipitating factors, clinical features, and the proposed mechanism involving inflammatory mediators and neuroexcitatory substances. The specification then describes, in detail, a treatment protocol using inhaled nitrous oxide and oxygen to mitigate cytokine overproduction by suppressing neuroexcitatory mediators (including substance P and glutamate).” (p. 7, 5th paragraph).
In response the examiner argues that: (1) the treatment protocol of treating a patient with nitrous oxide is not in question as this is well-established and widely utilized in healthcare; (2) you have shown two neuroexictory substances, and no actual protocol for measuring the same. The amendment further raises the issue of what exactly “delirium results from excess activation of the cytokine system” should be consider. The examiner sees no experimental protocol for measuring “the cytokine system” or establishing if, or if not, any particular “delirium” results from the same.
Applicant further argues that: “The clinical examples further illustrate the claimed invention by describing administration of a 50/50 nitrous oxide/oxygen mixture by inhalation, rapid restoration of lucidity, and measured reductions in substance P and glutamate levels. These examples are consistent with the broader disclosure that delirium is a syndrome characterized by common clinical features across diverse precipitating conditions, and that the disclosed mechanism and dosing guidance may be titrated to patient needs.” (p. 7, 1st full paragraph).
In response the examiner argues that none of the claims recite “reductions in substance P and glutamate levels” only claims 12-13, and 15 suggest “normalizes” with respect to glutamate and substance P, where the latter is not limited to any level.
Claim Rejections - 35 USC § 112(b)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 1 is rejected as being indefinite because the scope of “wherein the delirium results from excess activation of the cytokine system and comprises a decline from a previous baseline mental functioning that develops over a short period of time and includes disturbances in attention, consciousness, and cognition” in “A method for treating delirium” is unclear in the context of the claims in light of the Specification, and the ordinary level of skill in the art. Particularly it is unclear what the scope of: (1) “excess activation of the cytokine system”, (2) a decline from a previous baseline mental functioning that develops over a short period of time, and/or (3) disturbances in attention, consciousness, and cognition. Claims 2-20 are rejected as depending from claim 1 and doing nothing to clarify the scope of “delirium”. Appropriate clarification is required.
Claim Rejections - 35 USC § 112(d)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 7 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 recites “A method of treating delirium in a patient in need thereof, […] the method comprising: administering nitrous oxide and oxygen to a patient by inhalation, […].” Claim 5 recite “The method of claim 1, wherein the administering nitrous oxide and oxygen comprises providing to an adult who weights about 150 lbs. […].” Claim 7 recites “The method of claim 5, wherein at least one of a composition a duration, an interval, and a total amount of the nitrous oxide and oxygen provide to the adult, or to a child, is adjusted for age, weight, or a combination thereof. Where claim 5 limits the administration to “an adult who weights about 150 lbs. for between about 1 minute and about 1 hour every 4-8 hours.” A child is not an adult “an adult who weights about 150 lbs.”, and “a duration, an interval […] is adjusted for age, weight, or a combination thereof.” is not further limiting of the duration “for between about 1 minute and about 1 hour” or the interval of “every 4-8 hours” as required by the parent claim. Therefore, claim 7 is broader than the parent claim expanding the scope of “an adult” to “a child” and the duration and interval to any such duration or interval.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to Arguments:
Applicant's arguments filed 02/09/2026 have been fully considered but they are not persuasive.
Applicant argues that: “Claims 5-10 have been amended to expressly depend from, and further limit, the administration step of the parent claim(s) (e.g., "wherein the administering ... comprises providing... "), thereby incorporating all limitations of the claims from which they depend and further limiting the scope. Accordingly, the§ 112(d) issue is overcome.” (p. 8, 3rd paragraph).
In response the examiner argues that the claim 7 remains rejected as, for example, the patient class includes “a child” where the parent claim 5 is limited to “an adult”. Additionally, the “duration” and “interval” are limited in claim 5 but open-ended in claim 7 “adjusted for age, weight, or a combination thereof.”
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-10, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Gilman (“Mini-Review: A Brief History of Nitrous Oxide (N2O) Use in Neuropsychiatry,” 2019, Bentham Science; Current Drug Research Reviews, Vol. 11, pp. 12-20) in view of Lichtigfeld et al. (“The treatment of alcoholic withdrawal states with oxygen and nitrous oxide,” 1982 South African Medical Journal, Vol. 61, No. 10, pp. 349-351); Farmer et al. (The neuropsychiatric effects of nitrous oxide and low vitamin B12,” 2022, BJPsych Advances, vol. 28, pp. 216–225) and Sweetman (“Martindale – The complete drug reference,” 3rd ed, 2002, entries for Alcohol, Nitrous Oxide, Folic Acid, and Vitamin B12, pp. 1625-1628, 1789-1791, 1940-1943, and 1980-1983 respectively).
Applicants Claims
Applicant claims a method of treating delirium in a patient in need thereof, wherein the delirium results from excess activation of the cytokine system and comprises a decline from a previous baseline mental functioning that develops over a short period of time and includes disturbances in attention, consciousness, and cognition, the method comprising: administering nitrous oxide and oxygen to a patient by inhalation, and administering B-12 and/or folic acid to the patient, thereby treating delirium (instant claim 1).
Determination of the scope
and content of the prior art (MPEP 2141.01)
Gillman teaches that: “Nitrous oxide (N2O) and its psychotropic properties have been known to man for more than two centuries. The pioneers investigated its psychotropic properties with either pure N2O or a mixture of the gas with oxygen. It was only much later, i.e. in the 20th Century that the potential of the gas to investigate and treat psychiatric conditions occurred, predominantly at anaesthetic concentrations. Not until the early 1980’s was it first used in neuropsychiatry at much safer, lower concentrations, where anaesthesia is avoided. Here, it was titrated so doses seldom exceeding 40% N2O with accompanying concentration of oxygen of 60% or more. Apart from administering a personalised dose for each patient, this titration technique much reduces or almost totally avoids side effects. The most recent research features a fixed 50% mixture of N2O with oxygen applied via a full-face mask. Unfortunately, doses of 50% tend to produce more unpleasant side-effects, since the amounts of N2O are not tailored to the needs of each subject and are also usually above the requirements of most subjects. Table 1 highlights the main milestones in history of the use of N2O in neuropsychiatry since the 18th Century.” (p. 12, 1st paragraph).
Gillman teaches that: “Joseph Priestley synthesised nitrous oxide (N2O) and reported on his findings in 1772. In the last few years of the 18th Century, Humphry Davy investigated the chemistry of the gas as well as its psychotropic properties. In 1800, he published the observations on the gas in his classical book ‘Researches, chemical and philosophical; chiefly concerning nitrous oxide: or dephlogisticated nitrous air, and its respiration’. He breathed both 100% N2O and mixtures of the gas diluted with oxygen or air. He also introduced the gas to a number of friends and associates, including the poets Coleridge and Southey.” (p. 12, 2nd paragraph).
Gillman teaches that: “At that time, practically nothing was known about the dangers of N2O, except that if air was excluded and the pure gas breathed, warm-blooded animals died within minutes. Davy was clearly an extremely brave, if a foolhardy young man, whose scientific curiosity outweighed any potential dangers of asphyxiation or other, as yet unknown, toxic effects of the gas. Apart from describing its analgesic actions, he was also the first to mention its psychotropic properties; including anxiolysis and euphoria. In addition, he also noted how the gas ameliorated an alcoholic withdrawal state that he himself had experienced. An observation only further researched, almost 2 centuries later. Davy’s book is teeming with other insightful and accurate observations that attest to his perspicacity and brilliance as a scientist.” [emphasis added](p. 12, 3rd paragraph).
Gillman teaches that: “In modern dentistry, for safety, N2O is always mixed
with at least 30% oxygen and titrated for maximum anxiolytic efficacy to doses rarely exceeding 40%. Nonetheless, higher doses are very occasionally used, but only for the rare hypo-responder.” (instant claims 1-4, N2O administered with at least 30% oxygen).
Gillman teaches that: “As must be clear, most subjects require concentrations of N2O, mixed with more than 50% oxygen for the optimal psychotropic effects and so as to avoid and/or minimise unpleasant side-effects [3, 26, 28]. These doses of N2O below 50% (provided a nasal mask is used) limit nausea and vomiting and avoid over-sedation and/or anaesthesia. The importance of avoiding a facial anaesthetic mask is obviously crucial for safety and efficacy. Indeed, 22% of subjects given a mixture of N2O (30% diluted with oxygen) in oxygen for 30 minutes, via a facial mask, were nauseated and one vomited, indicating the problem of giving even these relatively low concentrations of gas through a facial mask as opposed to the nasal masks favoured in dentistry and by others who have investigated the neuropsychiatric actions of the gas.” (p. 15, col 1, 5th paragraph).
Gillman teaches that: “However, it was only in the 1980’s that the low-dose dental titration technique was studied for its potential usefulness to investigate and treat psychiatric conditions, including substance abuse. In 1994, the term psychotropic analgesic nitrous oxide (PAN) was introduced to clearly distinguish between anaesthetic doses used for anaesthesia and non-anaesthetic psychotropic concentrations obtained in dentistry by using the low-dose titration method with a nasal mask. All of the research on PAN was premised on the notion that the gas had opioid properties. (p. 15, paragraph bridging cols. 1-2).
Gillman teaches that: “The first case of substance abuse, since the time that
Humphry Davy effectively treated his own hangover with N2O, occurred in 1972.” (p. 15, col. 2, 3rd paragraph). And that: “The earliest research, using PAN (i.e. the low-dose dental titration technique) in psychiatry was published in 1982. Here, in an open trial of 98 chronic alcoholics, the gas seemed to offer a rapid and safe relief of symptoms following mild to moderate alcoholic withdrawal states. The positive response was believed to be, at least partially, due to the opioid properties of N2O. These authors noted that in many patients, the symptoms of depression were also lifted by the gas. Another study by an independent researcher, also found that the gas treatment was effective for alcohol withdrawal across various ethnic groups. A further study showed that PAN could be successfully and safely used in an outpatient setting.” (p. 15, col. 2, 4th paragraph).
Gillman teaches that: “The long history of the use of opioids in psychiatry further supports the notion that N2O produces its psychotropic actions via opioid actions. For example, from the 17th century onwards, opioids had been used to treat various psychiatric conditions including depression, psychosis and delirium tremens. The latter review articles, add further weight to the rationale for using low-dose, non-anaesthetic concentrations of N2O (as a gaseous opioid) to investigate and treat the endogenous opioid system directly in man.” (p. 16, col. 2, 2nd paragraph). And that: “In 1984, when the opioid properties of N2O had been firmly established, two patients suffering from neuroleptic-induced akathisia were studied to investigate a possible role for the opioid system in a neurological condition. The first patient was given an intravenous bolus injection of naloxone with no improvement. In the second case, PAN was administered with immediate improvement in the patient’s condition, which lasted for 6 hours. The authors concluded that the opioid system was underactive in neuroleptic-induced akathisia.” (p. 16, col. 2, 3rd paragraph).
Gillman teaches that: “Lichtigfeld and Gillman reported their findings with PAN in a range of psychiatric conditions, in 1985. A positive response was found in the following conditions: alcohol and opiate withdrawal states, post-alcoholic depression, reactive depressions some acute and chronic anxiety states.” (p. 16, col. 2, last paragraph).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of Gillman is that Gillman does not expressly teach treating delirium with nitrous oxide, or administering folic acid and/or Vitamin B12.
Lichtigfeld et al. teaches treatment of alcoholic withdrawal states with oxygen and nitrous oxide (title, see whole document). Lichtigfeld et al. teaches that: “Ninety-eight White male patients between the ages of 22 and 60 years (mean 37 years) admitted to an alcohol treatment centre (Northlea Hospital, Johannesburg) for alcohol withdrawal treatment were investigated.” (p. 349, col. 2, §Patients and methods). And that: “Blood pressure and pulse rate were measured before and after
administration of O2. The gases were administered with a Quantiflex relative analgesia dental machine. This is not a closed circuit system but adequate gas concentrations are obtained. Initially, pure O2 at 8 l/min was given for 20 minutes. This was followed (if necessary) by N2O and O2 (O2 level not less than 3 l/min and the N2O level between 3 and 6 l/min), again for 20 minutes. After receiving N2O the patients were oxygenated for a further 20 minutes. Only just enough N2O was given to reverse the depression; this is possible since the Quantiflex system enables one to titrate the N2O required. Some patients reported euphoria, but this was incidental to the study and can be avoided. In 24 patients this procedure was repeated on recurrence of symptoms (within the first 24 hours).” (paragraph bridging pp. 349-350).
Lichtigfeld et al. teaches that: “It would appear from the results of our treatment that the symptoms of the physical and affective disturbances are both adequately dealt with by administration of O2 where necessary followed by N2O/O2. This therapy results in a marked decrease in the use of sedatives, thereby encouraging patient compliance and co-operation. Although we have not treated any severe cases of delirium tremens with this method, 2 patients with mild symptoms responded favourably and it is likely that the more severe cases would be helped as well.” [emphasis added](p. 350, col. 2, 3rd paragraph)(instant claims 1-20, treating delirium by administering nitrous oxide and oxygen).
Farmer et al. teaches The neuropsychiatric effects of nitrous oxide and low vitamin B12 (title, see whole document). Farmer et al. teaches that: “Nitrous oxide (N2O) can be commonly found as a component in prescribed medication. Alongside this, it is used as a recreational substance. In its prescribed form, N2O is a gas indicated for use in combination with other anaesthetic agents and for short-term analgesia when used in a 50:50 combination with oxygen as Entonox®. This is beneficial where rapid onset and clearance are needed.” (p. 216, col. 1, lines 1-8). And that: “Contraindications for medical use of N2O include respiratory or cardiac risk factors such as pneumothorax and persistent signs of confusion; caution should also be used if there is a risk of exacerbating folate or vitamin B12 deficiency (Heads of Medicines Agencies 2019).” (p. 216, col. 2, lines 1-6).
Farmer et al. teaches that: “There are multiple mechanisms proposed to account for the neurotoxicity associated with both nitrous oxide use and low vitamin B12.” (p. 221, col. 1, last paragraph). And that: “Neurotoxicity is linked to NMDA antagonism, altered cerebral blood flow and enzyme inhibition, with each process being modulated by existing brain conditions.” And further that: “NMDA receptors are excitatory receptors that respond to endogenous glutamate.” (p. 221 col. 2, lines 1-6). Farmer et al. teaches that: “Folate functioning is also altered when B12 is low or inactive, and this in itself can have neuropsychiatric complications, with both folate and B12 implicated in monoamine synthesis alongside methionine cycles.” (p. 221 col. 2, 4th paragraph, lines 6-10).
Farmer et al. teaches that: “When discussing the neuropsychiatric presentations of low vitamin B12, many case reports described a positive symptom response to supplementation.” (p. 222, col. 1, §Utility of vitamin supplementation).
Farmer et al. teaches that: “For patients using N2O-containing compounds, consider the impact on B12 levels” and that “B12 and folate should be routinely checked when establishing a diagnosis in patients presenting with psychiatric symptoms” (p. 223, Box 1, 1st two bullet points).
Sweetman is cited as teaching the adverse effects of alcohol use/abuse including that: “After prolonged periods of excessive alcohol consumption, a drop in blood-alcohol concentration may precipitate a withdrawal syndrome characterised by tremor, agitation, feelings of dread, nausea, vomiting, and sweating; hallucinations, seizures, and delirium tremens may also develop.” (pp. 1625-1628, particularly p. 1626, col. 1, lines 16-22). And that: “The condition may be self-limiting without the need for therapeutic intervention or it may progress to the severe and potentially fatal condition of delirium tremens (DTs), often characterised by delirium, disorientation, and hallucinations. In some cases generalised tonic-clonic seizures occur within 24 hours of alcohol withdrawal and are followed by delirium tremens.” (p. 1626, col. 1, last paragraph, line 7 through col. 2, line 4).
Sweetman if further cited for the use of Nitrous Oxide (p. 1789-1791), and particularly that: “The symptoms of acute alcohol withdrawal (p.1626) are usually managed with benzodiazepines but nitrous oxide has been reported1 to reduce symptoms when tried in alcohol withdrawal. In mild to moderate cases a single inhalation of up to 20 minutes’ duration of a nitrous oxide-oxygen mixture in analgesic doses has been used.” (p. 1790, col. 3, §Uses and Administration, §Alcohol withdrawal syndrome).
Sweetman is further cited for teaching folic acid (pp. 1940-1944) and Vitamin B12 (pp. 1980-1983) including that: “Folic acid may also be given by intramuscular, intravenous, or subcutaneous injection as the sodium salt.” (p. 1941, col. 2, §Uses and Administration, 6th paragraph). And that: “Oral doses of up to 1000 micrograms of cyanocobalamin have also been used. In patients with normal gastrointestinal absorption, doses of 1 to 25 micrograms daily are considered sufficient as a dietary supplement.” (p. 1982, col. 1, lines 10-14).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer nitrous oxide and oxygen to a patient suffering a neuropsychiatric disorder such as delirium tremens, as suggested by Gillman and Lichtigfeld et al., because improvement was shown in treating alcohol dependent patients with delirium tremens, as suggested by Lichtigfeld et al., and “The long history of the use of opioids in psychiatry further supports the notion that N2O produces its psychotropic actions via opioid actions. For example, from the 17th century onwards, opioids had been used to treat various psychiatric conditions including depression, psychosis and delirium tremens. The latter review articles, add further weight to the rationale for using low-dose, non-anaesthetic concentrations of N2O (as a gaseous opioid) to investigate and treat the endogenous opioid system directly in man.” (Gilman, p. 16, col. 2, 2nd paragraph); and further to supplement Vitamin B12 and or folic acid (Vitamin B9) because the metabolism of Vitamin B12 and folic acid (folate) have been shown to be depressed by use of nitrous oxide, where supplementation is suggested by Farmer et al. to improve symptom response to the same. Given that Applicants’ Specification exemplifies “A 78 year old female patient suffers from delirium with alcohol dependence.” (Example 2), the limitation “wherein the delirium results from excess activation of the cytokine system and comprises a decline from a previous baseline mental functioning that develops over a short period of time and includes disturbances in attention, consciousness, and cognition” is considered inherent in treating delirium tremens, as suggested by the cited combination of prior art (MPEP 2112).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because the use of nitric oxide and oxygen for various neuropsychiatric conditions is well-established, as suggested by Gillman, and has been shown to improve delirium tremens. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Response to Arguments:
Applicant's arguments filed 02/09/2026 have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually (pp. 8-9), one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to Applicant’s position that: “In short, Applicant respectfully submits that the proposed combination relies on hindsight reconstruction.” (p. 9, 4th paragraph), it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant further argues that: “The cited references do not identify delirium (as claimed) as a target for nitrous oxide/oxygen therapy directed to cytokine-system activation, and they do not teach administering vitamin B-12 and/or folic acid as part of such delirium therapy. Applicant respectfully submits that the Office Action has not established a prima facie case of obviousness for the amended claims.” (p. 9, 4th paragraph).
In response the examiner argues that Applicant’s own Specification includes Example 2 within the scope of the claimed invention, that includes “A 78 year old female patient suffers from delirium with alcohol dependence.” treated with 50/50 nitrous oxide/oxygen, which is clearly suggested by the cited combination of prior art. Therefore the “nitrous oxide/oxygen therapy directed to cytokine-system activation”. Farmer et al. clearly suggest that: “For patients using N2O-containing compounds, consider the impact on B12 levels” and that “B12 and folate should be routinely checked when establishing a diagnosis in patients presenting with psychiatric symptoms” (p. 223, Box 1, 1st two bullet points). And in a patient with low B12 and/or folate (folic acid), one of ordinary skill in the healthcare field would have administered supplemental B12 and/or folate to avoid complications associated with low levels of the same.
Claims 11-18 are rejected under 35 U.S.C. 103 as being unpatentable over Gilman in view of Lichtigfeld et al.; Farmer et al. and Sweetman as applied to claims 1-10, 19 and 20 above, and further in view of Van der Mast (“Pathophysiology of Delirium,” 1998, Journal of geriatric psychiatry and neurology Vol. 11, No. 3, pp. 138-145); Kugel et al. (“Effect of Nitrous Oxide on the Concentrations of Opioid Peptides, Substance P, and LHRH in the Brain and β-Endorphin in the Pituitary,” 1991; Anesthesia Progress, Vol. 38, No. 6, pp. 206-211) and Leibowitz et al. (“Blood Glutamate Scavenging: Insight into Neuroprotection,” 2012, International journal of molecular sciences, Vol. 13, No. 8, pp. 10041-10066).
Applicants Claims
Applicant claims a method of treating delirium in a patient in need thereof, as discussed above.
Determination of the scope
and content of the prior art (MPEP 2141.01)
Gillman teaches a brief history of nitrous oxide use in neuropsychiatry, as discussed above and incorporated herein by reference.
Lichtigfeld et al. teaches the treatment of alcoholic withdrawal states with oxygen and nitrous oxide, as discussed above and incorporated herein by reference.
Farmer et al. teaches the neuropsychiatric effect of nitrous oxide and low vitamin B12, as discussed above and incorporated herein by reference.
Sweetman teaches the use/administration of alcohol, nitrous oxide, folic acid, and Vitamin B12, as discussed above and incorporated herein by reference.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of Gillman et al. is that Gillman et al. do not expressly teach monitoring the patient’s neuroexcitatory substance levels including substance P and/or glutamate.
Van der Mast teaches that: “Hypotheses about the pathophysiology of delirium are speculative and largely based on animal research. According to the neurotransmitter hypothesis, decreased oxidative metabolism in the brain causes cerebral dysfunction due to abnormalities of various neurotransmitter systems. Reduced cholinergic function, excess release of dopamine, norepinephrine, and glutamate, and both decreased and increased serotonergic and γ-aminobutyric acid activity may underlie the different symptoms and clinical presentations of delirium.” (abstract, lines 1-5). And that: “Only a small proportion of the neurons in the brain are cholinergic or monoaminergic. The most prevalent cerebral neurotransmitters are γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter, and its amino acid precursor glutamate, a major excitatory neurotransmitter. GABA and glutamate, stimulating almost any neuron, are closely involved with the energy-producing citric cycle and, consequently, are very vulnerable to metabolic disturbances.” (p. 140, col. 1, last paragraph).
Kugel et al. teaches that: “The undecapeptide substance P (SP) also appears to play regulatory a role on the release of gonadotropins either directly or through the regulation of LHRH. In addition, SP is implicated in the regulation of pain pathways and has extensive interactions with the endogenous opioid system. This study was therefore designed to evaluate the effects of N2O on, not only the LHRH content of the diencephalon, but also the concentrations of SP, β-endorphin, and metenkephalin in the brain and 3-endorphin in the pituitary gland. Extrahypothalamic areas of the brain were included in order to obtain preliminary information regarding SP and opioid peptides in these interactive neural systems.” (p. 207, col. 1, lines 9-21).
Leibowitz et al. teaches that: “Under normal circumstances, plasma glutamate concentration is 5–100 µM/L [1], the whole blood concentration is 150–300 µM/L [47,48] while in the brain’s ECF it is only 0.3–2 µM/L.” (p. 10044, 2nd paragraph, lines 4-6).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer nitrous oxide and oxygen to a patient suffering a neuropsychiatric disorder such as delirium tremens, as suggested discussed above, and further to monitor neuroexcitatory levels of glutamate and/or substance P, as suggested by Van der Mast and Kugel et al., the normal level of plasma glutamate concentration being in the range of 5-100 μM/L, as taught by Leibowitz et al. in order to ensure normal levels are occurring or achieved through administering (or stopping administering) the nitrous oxide/oxygen mix as deemed appropriate by the attending physician.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because the use of nitric oxide and oxygen for various neuropsychiatric conditions is well-established, as suggested by Gillman, and has been shown to improve delirium tremens, and monitoring neuroexcitatory levels of glutamate and/or substance P in the blood would have been within the ordinary level of skill in the art. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Response to Arguments:
Applicant's arguments filed 02/09/2026 have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually (pp. 8-9), one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant further argues that: “The Office Action's proposed combination thus requires assembling disparate teachings from unrelated contexts (i.e., alcohol withdrawal management, safety discussions regarding vitamin deficiency, and neuroprotection literature) and applying them to Applicant's claimed delirium treatment protocol without a sufficient rationale. Even if each reference is considered, none teaches or suggests the claimed integrated monitoring-and-redosing regimen for delirium, nor the specific monitoring endpoints disclosed in the specification. The claimed subject matter therefore is not obvious.” (p. 10, 2nd paragraph).
In response the examiner argues the prior art provides a clear link between the alcohol withdrawal with delirium tremens and nitrous oxide treatment, as well as the glutamate system and nitrous oxide treatment, as well as Vitamins B12 and folate associated with nitrous oxide treatment. Therefore the cited prior art provides a clear link between the cited combination of prior art references.
Claims 1-10, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over BESSIER (US 2012/0045528 A1; published February, 2012) in view of Smith et al. (“Cytokine profiles in intensive care unit delirium,” 2022, Acute and Critical Care, Vol. 37, No. 3, pp. 415-428); VALET (WO 2017/140684 A2; published August, 2017); Farmer et al. (The neuropsychiatric effects of nitrous oxide and low vitamin B12,” 2022, BJPsych Advances, vol. 28, pp. 216–225) and Sweetman (“Martindale – The complete drug reference,” 3rd ed, 2002, entries for Alcohol, Nitrous Oxide, Folic Acid, and Vitamin B12, pp. 1625-1628, 1789-1791, 1940-1943, and 1980-1983 respectively).
Applicants Claims
Applicant claims a method of treating delirium in a patient in need thereof, wherein the delirium results from excess activation of the cytokine system and comprises a decline from a previous baseline mental functioning that develops over a short period of time and includes disturbances in attention, consciousness, and cognition, the method comprising: administering nitrous oxide and oxygen to a patient by inhalation, and administering B-12 and/or folic acid to the patient, thereby treating delirium (instant claim 1).
Determination of the scope
and content of the prior art (MPEP 2141.01)
BESSIER teaches nitric oxide gas for treating chronic pain (title, see whole document), and particularly that: “The invention relates to a gas mixture that contains nitrous oxide (N2O) for use as a breathable drug for the treatment of chronic pain in a mammal, in particular a pain from neuropathic, iatrogenic, dysfunctional or inflammatory origin, in particular in humans. The proportion of N2O ranges from 15 to 45 vol. %. The gas mixture is administered for a sufficient duration for obtaining a delayed pain hypersensitivity reduction that can be observed at least 6 hours after the end of the inhalation of the gas mixture by said mammal. The pain hypersensitivity is selected from allodynias and hyperalgesias.” (abstract)(instant claims 1-3).
BESSIER teaches the pain includes: “neuropathic pain related to a surgical act which has damaged a nerve pathway and post-operative neuropathic pain; ” ([0029]).
BESSIER teaches that: “The gas mixture of the invention can be used in the context of a therapeutic treatment method in which said N2O based gas mixture is administered by inhalation […].” ([0040]). And that: “The administration time ranges, depending on the patient, between a few minutes and several hours, for example between 5 minutes and 4 or 5 hours. The inhalation can be repeated several times in a row, for example several days in a row.” ([0044])(instant claims 5-10, frequency and duration). MPEP §2144.05 - In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
BESSIER teaches that: “Furthermore, nitrous oxide is a gas which has strong
N-methyl-D-aspartate (NMDA) receptor antagonist properties, […] Nitrous oxide inhibits glutamatergic transmission in spinal dorsal horn neurons […].” ([0046]).
BESSIER teaches that: “However, in the context of the present invention, the gas mixture containing nitrous oxide is no longer used preventively, as in the case of the prevention of post-operative hyperalgesia, but curatively in order to treat patients with chronic pain and thus to obtain a delayed pain hypersensitivity reduction for said patients.” ([0048]).
BESSIER teaches treatment with nitrous oxide at 50% ([0080] to [0087])(instant claim 4). Regarding instant claims 5-9 reciting an adult who weighs about 150 lbs., BESSIER teaches treating human patients “the mammal is selected from a human being, namely a man or a woman, including children and newborns;” ([0016], [0038]). BESSIER does not expressly teach treating an adult who weighs about 150 lbs., however fairly implies a patient class that would have include the same.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of BESSIER is that BESSIER does not expressly teach treating delirium, “wherein the delirium results from excess activation of the cytokine system and comprises a decline from a previous baseline mental functioning that develops over a short period of time and includes disturbances in attention, consciousness, and cognition”, or administering folic acid and/or Vitamin B12.
Smith et al. teaches cytokine profiles in intensive care unit delirium (title, see whole document). Smith et al. teaches that: “Delirium is a neuropsychiatric syndrome that involves altered cognition, impaired awareness, inattention, disorganized thinking, and fluctuating arousal. Its onset can be acute or subacute, it can occur in hypo- or hyperactive forms, and its consequences can be devastating. Patients who experience delirium are at increased risk of death, dementia, and institutionalization. Furthermore, the economic burden of delirium is profound. […] Despite the prevalence of delirium and significant advances in the understanding of this syndrome made over the past decade, knowledge of its underlying pathophysiologic mechanisms remains incomplete.” (§Introduction, 1st paragraph). And that: “Delirium results from a variable combination of predisposing factors unique to the individual and precipitating factors. Acute stressors associated with delirium are well characterized and include critical illness and surgery, both of which are associated with the release of inflammatory cytokines. The objective of our study was to further characterize the association between various precipitating factors with the development of delirium, including a comprehensive analysis of cytokine responses in those patients that developed delirium versus those that did not.” (§Introduction, 3rd paragraph). And further that: “In this study, we sought to determine whether cytokine pro files associated with delirium vary based on the precipitating condition. Our focus was on delirium resulting from sepsis, coronavirus disease 2019 (COVID-19), and recent surgery. This study is novel in that it is the first to investigate relative levels of inflammatory cytokines that result from several conditions known to be associated with delirium.” (§Introduction, 4th paragraph).
Smith et al. teaches that: “Table 4 provides the cytokines associated with the development of delirium. Those cytokines found to be significantly elevated include the proinflammatory cytokines TNF-α, IL-6 and IL-18; the chemokines CCL2, CCL3, CXCL1, CXCL10 and IL-8; and the anti-inflammatory cytokines IL-1RA and IL-10. No significant difference was seen in levels of G-CSF, GM-CSF, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-12, and IL-17A between those patients that developed delirium and those that did not.” (p. 417, col. 2, last paragraph; p. 424, col. 1, lines 1-4). And that: “We identified several cytokines associated with delirium in our ICU patient population. Interestingly, CCL2, CXCL10, and TNF-a showed a statistically significant elevation in those patients that developed delirium in the setting of both sepsis and COVID-19 relative to the group that recently had surgery and developed delirium.” (p. 242, col. 1, 2nd paragraph).
Smith et al. teaches that: “It is established that inflammation is associated with delirium; however, the exact mechanism by which this occurs has yet to be elucidated.” (§Discussion, 2nd paragraph). And that: “Considering the cytokine profile typical of delirium seen in both the sepsis and COVID-19 groups, the cytokine pattern TNFα, in our surgery group is curious. Levels of CCL2, and CXCL10 are decreased in those patients that recently had surgery and developed delirium relative to both the sepsis and COVID-19 groups. In the surgical group, the preeminent cytokine elevations were G-CSF and CCL3. This finding may suggest the existence of an alternative, non–TNF-α driven pathway of peripheral inflammation that resulted in delirium in our surgical patients.” (§Discussion, 3rd paragraph). And finally that: “In conclusion, our study demonstrates a statistically significant association between several cytokines and the development of delirium. However, the cytokine profile appears to be variable and contingent upon the delirium precipitating factors. In both sepsis and COVID-19, CCL2, CXCL10, and TNF-α predominate. In our surgical population, G-CSF is elevated and CXCL10 is decreased in patients that developed delirium. These findings provide support of the delirium syndrome representing a manifestation of distinct pathophysiological processes” (last paragraph).
VALET teaches compositions for the treatment of post-operative cognitive dysfunction (title, see whole document), and particularly that: “The present invention relates to methods and pharmaceutical compositions for the treatment of post-operative cognitive dysfunction. In particular, the present invention relates to a method of treating post-operative cognitive dysfunction in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an APJ receptor agonist.” (abstract).
VALET teaches that: “Postoperative cognitive dysfunction (POCD) is characterized by a persistent decline of cognitive performance after surgery and is associated with increased mortality in elderly patients. Estimated prevalence in patients over the age of 60 is 15-25% with approximately 10% exhibiting symptoms 3 months after surgery. Risk factors for POCD include increasing age, preoperative cognitive dysfunction and perioperative infection. There is currently no adequate treatment. Consistent evidence is accumulating for the role of inflammatory processes arising due to surgical trauma and subsequent complications. The hippocampus seems especially vulnerable to the inflammation. Peripheral infection and aging interact to impair hippocampal memory consolidation and aged rodents are more vulnerable to cognitive decline after a peripheral immune challenge ([…]). Central inflammatory responses, specifically cytokine increases in the hippocampus following surgery, have been repeatedly reported in rat and mouse models of POCD.” (p. 1, lines 10-21).
VALET teaches that: “Apelin is a peptide synthetized and secreted by var10us tissues and retrieved in different species as a 77 amino-acids precursor. After endopeptidase cleavages, apelin is found in the circulation as four major isoforms: apelin-36, apelin 17, apelin-13 and the pyroglutaminated apelin-13. Apelin-13 is described as the most stable isoform in biological fluids. Apelin binds APJ, a G-protein coupled receptor present in the same tissues that its endogenous ligand apelin. Apelin/ APJ complex is involved in osteogenesis, inflammation and neuroprotection. For example, in vitro apelin treatment of MC3T3-El osteoblasts shows a dose-dependent increase of proliferation associated to a decrease of apoptosis. Apelin is also associated to inflammatory processes. Indeed, even if the mechanisms are not fully understood, apelin production is increased by pro inflammatory cytokines such as TNFalpha and thus could counteract inflammatory processes. Another very interesting property of apelin is its neuroprotective effect.” (p. 2, lines 3-14).
VALET teaches that: “The inventors hypothesized that apelin could potentially be secreted in response to surgery-mediated inflammation and protect against neuronal injuries associated to POCD. To validate this hypothesis we chronically treated young and aged mice by daily i.p administration of apelin and determined the impact of the treatment on memory, pain and stress after tibial fracture surgery. Moreover, to better assess the role of apelin during tibial surgery-mediated POCD, we measured the consequences of apelin administration on proinflammatory profile modification (TNFalpha, IL6 ... ) in tissues.” (p. 3, lines 2-8).
VALET teaches that: “As used herein the term "postoperative cognitive dysfunction" or "POCD" has its general meaning in the art and refers to a cognitive impairment experienced after surgery. POCD is a cognitive disorder including deterioration in memory, attention, learning, and speed of information processing. POCD can manifest as short-term symptom, or last for extended periods of time. In some circumstances, POCD can cause a permanent alteration of cognitive functions. Indeed, POCD is commonly observed after anesthesia. Methods for diagnosing POCD in a subject are known in the art.” (p. 3, lines 14-20).
VALET teaches that: “In some embodiments, the APJ receptor agonist of the present invention is administered concomitantly or sequentially with an anesthetic to the subject.” (p. 5, lines 25-26). VALET teaches that: “As used herein, the term "anesthetic" has its general meaning in the art and refers to a drug that causes anesthesia, e.g., which is generally administered to facilitate a surgery, to relieve non-surgical pain or to enable diagnosis of a disease or disorder. Non-limiting examples of inhalational anesthetics include […] nitrous oxide […]. Any of the inhalational anesthetics can be used alone or in combination with other medications to maintain anesthesia. For example, nitrous oxide can be used in combination with other inhalational anesthetics.” (p. 5, lines 5-8, 11 & 19-22).
Farmer et al. teaches The neuropsychiatric effects of nitrous oxide and low vitamin B12 (title, see whole document). Farmer et al. teaches that: “Nitrous oxide (N2O) can be commonly found as a component in prescribed medication. Alongside this, it is used as a recreational substance. In its prescribed form, N2O is a gas indicated for use in combination with other anaesthetic agents and for short-term analgesia when used in a 50:50 combination with oxygen as Entonox®. This is beneficial where rapid onset and clearance are needed.” (p. 216, col. 1, lines 1-8). And that: “Contraindications for medical use of N2O include respiratory or cardiac risk factors such as pneumothorax and persistent signs of confusion; caution should also be used if there is a risk of exacerbating folate or vitamin B12 deficiency (Heads of Medicines Agencies 2019).” (p. 216, col. 2, lines 1-6).
Farmer et al. teaches that: “There are multiple mechanisms proposed to account for the neurotoxicity associated with both nitrous oxide use and low vitamin B12.” (p. 221, col. 1, last paragraph). And that: “Neurotoxicity is linked to NMDA antagonism, altered cerebral blood flow and enzyme inhibition, with each process being modulated by existing brain conditions.” And further that: “NMDA receptors are excitatory receptors that respond to endogenous glutamate.” (p. 221 col. 2, lines 1-6). Farmer et al. teaches that: “Folate functioning is also altered when B12 is low or inactive, and this in itself can have neuropsychiatric complications, with both folate and B12 implicated in monoamine synthesis alongside methionine cycles.” (p. 221 col. 2, 4th paragraph, lines 6-10).
Farmer et al. teaches that: “When discussing the neuropsychiatric presentations of low vitamin B12, many case reports described a positive symptom response to supplementation.” (p. 222, col. 1, §Utility of vitamin supplementation).
Farmer et al. teaches that: “For patients using N2O-containing compounds, consider the impact on B12 levels” and that “B12 and folate should be routinely checked when establishing a diagnosis in patients presenting with psychiatric symptoms” (p. 223, Box 1, 1st two bullet points).
Sweetman is cited as teaching folic acid (pp. 1940-1944) and Vitamin B12 (pp. 1980-1983) including that: “Folic acid may also be given by intramuscular, intravenous, or subcutaneous injection as the sodium salt.” (p. 1941, col. 2, §Uses and Administration, 6th paragraph)(instant claim 20, “wherein […] folic acid […] is administered by […] injection.”). And that: “Oral doses of up to 1000 micrograms of cyanocobalamin have also been used. In patients with normal gastrointestinal absorption, doses of 1 to 25 micrograms daily are considered sufficient as a dietary supplement.” (p. 1982, col. 1, lines 10-14)(instant claim 20 “wherein B-12 […] is administered by mouth”).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer nitrous oxide and oxygen to a post operative patient suffering from pain, as suggested by BESSIER, and/or post-operative cognitive dysfunction, the cognitive dysfunction being related to pro-inflammatory cytokines such as TNF-alpha, as suggested by VALET, thereby treating the same, delirium being also associated with pro-inflammatory cytokines such as TNF-alpha, as suggested by Smith et al., the treatment would have also treated any delirium (includes disturbances in attention, consciousness, and cognition), and further to administer Vitamin B-12 and/or folate (folic acid) to prevent neurotoxicity associated with the nitrous oxide administration, as suggested by Farmer et al., and Sweetman, in order to prevent side-effects and/or complications associated with low levels of Vitamin B-12 and/or folate (folic acid).
Claims 11-18 are rejected under 35 U.S.C. 103 as being unpatentable over BESSIER in view of Smith et al.; VALET; Farmer et al. and Sweetman as applied to claims 1-10, 19 and 20 above, and further in view of Van der Mast (“Pathophysiology of Delirium,” 1998, Journal of geriatric psychiatry and neurology Vol. 11, No. 3, pp. 138-145); Kugel et al. (“Effect of Nitrous Oxide on the Concentrations of Opioid Peptides, Substance P, and LHRH in the Brain and β-Endorphin in the Pituitary,” 1991; Anesthesia Progress, Vol. 38, No. 6, pp. 206-211) and Leibowitz et al. (“Blood Glutamate Scavenging: Insight into Neuroprotection,” 2012, International journal of molecular sciences, Vol. 13, No. 8, pp. 10041-10066).
Determination of the scope
and content of the prior art (MPEP 2141.01)
BESSIER teaches nitric oxide gas for treating chronic pain, as discussed above and incorporated herein by reference.
VALET teaches compositions for the treatment of post-operative cognitive dysfunction, as discussed above and incorporated herein by reference.
Farmer et al. teaches the neuropsychiatric effect of nitrous oxide and low vitamin B12, as discussed above and incorporated herein by reference.
Sweetman teaches the use/administration of alcohol, nitrous oxide, folic acid, and Vitamin B12, as discussed above and incorporated herein by reference.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of Gillman et al. is that Gillman et al. do not expressly teach monitoring the patient’s neuroexcitatory substance levels including substance P and/or glutamate.
Van der Mast teaches that: “Hypotheses about the pathophysiology of delirium are speculative and largely based on animal research. According to the neurotransmitter hypothesis, decreased oxidative metabolism in the brain causes cerebral dysfunction due to abnormalities of various neurotransmitter systems. Reduced cholinergic function, excess release of dopamine, norepinephrine, and glutamate, and both decreased and increased serotonergic and γ-aminobutyric acid activity may underlie the different symptoms and clinical presentations of delirium.” (abstract, lines 1-5). And that: “Only a small proportion of the neurons in the brain are cholinergic or monoaminergic. The most prevalent cerebral neurotransmitters are γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter, and its amino acid precursor glutamate, a major excitatory neurotransmitter. GABA and glutamate, stimulating almost any neuron, are closely involved with the energy-producing citric cycle and, consequently, are very vulnerable to metabolic disturbances.” (p. 140, col. 1, last paragraph).
Kugel et al. teaches that: “The undecapeptide substance P (SP) also appears to play regulatory a role on the release of gonadotropins either directly or through the regulation of LHRH. In addition, SP is implicated in the regulation of pain pathways and has extensive interactions with the endogenous opioid system. This study was therefore designed to evaluate the effects of N2O on, not only the LHRH content of the diencephalon, but also the concentrations of SP, β-endorphin, and metenkephalin in the brain and 3-endorphin in the pituitary gland. Extrahypothalamic areas of the brain were included in order to obtain preliminary information regarding SP and opioid peptides in these interactive neural systems.” (p. 207, col. 1, lines 9-21).
Leibowitz et al. teaches that: “Under normal circumstances, plasma glutamate concentration is 5–100 µM/L [1], the whole blood concentration is 150–300 µM/L [47,48] while in the brain’s ECF it is only 0.3–2 µM/L.” (p. 10044, 2nd paragraph, lines 4-6).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer nitrous oxide and oxygen to a post operative patient suffering from pain, as suggested discussed above, and further to monitor neuroexcitatory levels of glutamate and/or substance P, as suggested by Van der Mast and Kugel et al., the normal level of plasma glutamate concentration being in the range of 5-100 μM/L, as taught by Leibowitz et al. in order to ensure normal levels are occurring or achieved through administering (or stopping administering) the nitrous oxide/oxygen mix as deemed appropriate by the attending physician.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because the use of nitric oxide and oxygen for chronic pain and cognitive dysfunction, and monitoring neuroexcitatory levels of glutamate and/or substance P in the blood would have been within the ordinary level of skill in the art. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Conclusion
Claims 1-20 are pending and have been examined on the merits. The instant Specification is objected to. Claims 1-20 is rejected under 35 U.S.C. 112(a)(written description); claims 1-20 are rejected under 35 U.S.C. 112(b); claims 7 is rejected under 35 U.S.C. 112(d); claims 1-20 are rejected under 35 U.S.C. 103. No claims allowed at this time.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action. Any inquiry concerning this communication or earlier communications from the examiner should be directed to IVAN A GREENE whose telephone number is (571)270-5868. The examiner can normally be reached M-F, 8-5 PM PST.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
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