DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments
Applicant’s amendments to the claims of May 28, 2026, in response to the Office Action of January 9, 2026, are acknowledged.
Response to Arguments
The examiner has considered Applicant’s declaration and arguments in their entirety. The examiner notes, however, that Applicant’s declaration does not provide a comparison to the closest prior art. The data provided by Applicant is a comparison of nalbuphine to “placebo at the end of treatment.” See Decl. @ par. 26. As the appropriate standard at this point is a determination if the prior art establishes a prima facie showing of obviousness. The Declaration has been considered and is responded to below for all that it teaches and for the statements provided therein.
The examiner expounds on his rejection below and attempts to address Applicant’s arguments therein.
Rhame establishes that oral nalbuphine at claimed dosages will treat symptoms, including cough of respiratory conditions and is unexpectedly safe due to a limit on respiratory depression; and nalbuphine has a respiratory depressant effect and analgesic effect similar to morphine with a better safety profile.
Rhame teaches a method of treating respiratory diseases and symptoms thereof, including cough, comprising orally administering an effective amount of nalbuphine:
In accordance with the present invention, it has been discovered that nalbuphine and related compounds may be used in the successful treatment of respiratory diseases and their symptoms. For example, the present invention relates to the treatment of asthma, cough, cough with pruritis, chronic obstructive pulmonary disease, dyspnea, the symptoms of the listed diseases, and other respiratory diseases and their symptoms.
Rhame, Specification, paragraph 0017 (emphasis added);
The subject invention involves the use of a safe and effective amount of nalbuphine for the treatment of respiratory diseases and the symptoms associated with respiratory diseases, such as colds, flu, allergic and vasomotor rhinitis, asthma, and bronchitis, of humans and lower animals, especially humans. Treatment of both upper respiratory symptoms, such as nasal congestion runny nose, sneezing, and post-nasal drip, as well as lower respiratory symptoms, such as bronchoconstriction and cough are contemplated in accordance with the present invention.
Rhame, Specification, paragraph 0024 (emphasis added);
In particular, the nalbuphine compositions of the present invention can be administered orally, for example, as tablets, coated tablets, dragees, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
Rhame, Specification, paragraph 0056 (emphasis added).
Rhame does not specifically teach that the symptom of the respiratory disease is chronic cough. It is commonly known in the art however, that chronic cough is a common symptom of almost all chronic respiratory conditions such as chronic obstructive pulmonary disease (COPD).
Rhame teaches that nalbuphine has similar efficacy to morphine: “Nalbuphine is known as having an analgesic potency essentially equivalent to that of morphine on a milligram basis.” (Rhame, Specification, paragraph 0003).
Rhame also reports:
nalbuphine has a respiratory depressant capacity similar to that of morphine. The authors recognized, however, that nalbuphine possesses a ceiling effect for respiratory depression. Stated differently, the dose effect curve for respiratory depression by nalbuphine was flatter than that of morphine, and maximum respiratory depression occurred after 30 mg of nalbuphine per 70 kg body weight was administered. Additionally, doses in excess of 30 mg/70 kg failed to increase respiratory depression beyond that induced by morphine at 20 mg/70 kg. This ceiling effect demonstrates a unique safety factor for nalbuphine among analgesics.
Among the several advantages found to be achieved by the present invention, therefore, may be noted the provision of a novel method for the treatment of respiratory diseases. Additionally, the successful use of nalbuphine to treat respiratory diseases is unexpected due to the recognized side effects of nalbuphine, including respiratory depression. See par. 15. In fact, if nalbuphine is administered with morphine, which is shown to treat RCC, it can partially block or reverse the opioid-induced respiratory depression caused by mu agonist analgesics. See par. 7.
While the respiratory capacity and analgesic effects of morphine and nalbuphine are recognized as equivalent, only nalbuphine has a ceiling. See par.’s 3 and 6.
As shown above, Rhame teaches the daily administration of nalbuphine for the treatment of chronic respiratory conditions such as COPD and associated symptoms. Rhame also teaches that nalbuphine can be used for the treatment of pain over an extended period of time (Rhame, Specification, paragraph 0009). While Rhame does not teach that the administering is for at least at least about 8 weeks, 10 weeks, 12 weeks, 24 weeks or 50 weeks, one of ordinary skill in the art would understand that control of symptoms of a chronic respiratory disease would inherently mean daily administration for as long as symptoms persist.
Rhame does not teach that any condition is cured by administration of nalbuphine, but rather that nalbuphine temporarily alleviates symptoms such as bronchoconstriction and cough over its duration of action, implying that long-term daily administration is required for effective symptom control. Symptomatic treatment in no way indicates a lack of administration at the argued cutoff time of 8 weeks. This would be particularly the case when treatment would work for 6 weeks and 7 weeks.
Pavard teaches morphine does treat chronic cough and cites Morice which references “Opiate Therapy” in chronic cough; and Pavard indicates that chronic cough is “a common symptom of almost all chronic respiratory” conditions.
Moreover, Pavard explains at the end of page 1380, “there is evidence of the effectiveness of a slow-release formulation of morphine in a population with distressing, unexplained cough.” Pavard is citing an article by Morice et al., “Opiate Therapy in Chronic Cough,” American Journal of Respiratory and Critical Care Medicine, Volume 175, Issue 4, February 2007, Pages 312–315. Morice explains that patients treated with morphine for 12 weeks (i.e., 3 months) showed a similar improvement in cough between 5 and 10 mg treated groups. It was concluded to be effective in chronic cough.
Further, Pavard teaches that chronic cough is a common symptom of almost all chronic respiratory conditions and is responsible for over a third of referrals to pulmonology:
Chronic cough is defined as cough lasting for more than 8 weeks. This definition is based on evidence that a cough lasting longer than this duration is unlikely to be due to a respiratory tract infection. Chronic cough is a common symptom of almost all chronic respiratory, and some non-respiratory conditions. Several recognisable causes of chronic cough, such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, lung cancer, an inhaled foreign body, pulmonary tuberculosis, sarcoidosis, idiopathic pulmonary fibrosis, and heart failure will be obvious after clinical assessment, spirometry, and chest radiography... Cough is the primary focus of referral in 38% and the sole focus in 10% of patients seen in a typical adult respiratory clinic.
Pavard, page 1375 (emphasis added).
Ryan teaches chronic cough and chronic pain have similar neurobiological mechanisms and pathologies of chronic cough and chronic pain show substantial homologies”; and each centrally active neuromodulator active through different receptors and modes of action including gabapentin, pregablin, morphine, and tramadol “had positive effects on cough-specific quality of life and/or cough severity in patients with refractory CC or CC associated with a neuropathic disease.”
Ryan teaches RCC to have similarities with neuropathic pain. Similarities between CC and neuropathic pain are addressed. Pain medications gabapentin and pregabalin reduce cough frequency. See Abstract. Central and peripheral sensitization of the cough reflex is involved in RCC and the term sensory neuropathic cough is now often recognized in the guidelines. Ryan explains that cough reflex hypersensitivity (CRS) is a key feature of RCC and CC has been labeled as cough hypersensitivity syndrome. Patients with RCC have marked CRS. More importantly, the incidence of CC and chronic pain are common and the high prevalence in women is also consistent with chronic pain. “The basis neurolobiological mechanisms and pathologies of refractory CC and chronic pain show substantial homologies.” See p689, 4th full par. Based on numerous described similarities between RCC and neuropathic pain, Ryan explains that it is important to understand the mechanism of drug therapy so that drugs designed for the treatment of pain can be repurposed for cough. See p690, 2nd full par. Tramadol was noted as one agent that was studied and appeared to improve neurogenic cough. Numerous pain medications were shown to have an effect. See Table 4.
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Nalbuphine is a centrally active neuromodulator. This provides a reasonable expectation of success that nalbuphine will also have a positive effect on CC. A basis for this is the homology of neurolobiological mechanisms among CC and chronic pain; the equivalent analgesic effect of nalbuphine and morphine, and a similar respiratory depressant effect of nalbuphine and morphine wherein nalbuphine is safer; and the surprising ability of nalbuphine to treat conditions and symptoms in which cough and CC is common. See below teachings of Rhame.
Ryan further notes, “Due to tramadol’s effects on neuropathic pain it may be considered a developing therapy for refractory CC.” See p704, 8th full par. While morphine is an available treatment, it can have undesirable side effects. See p708, 2nd full par.
Ryan teaches that chronic cough “that persists despite assessment and treatment according to an accepted guideline is termed refractory chronic cough, idiopathic chronic cough, or unexplained cough” (Ryan, page 687). Therefore, refractory chronic cough, idiopathic chronic cough, or unexplained cough are considered synonyms in the art. Additionally, Ryan also teaches that morphine is useful in the treatment of refractory chronic cough (CC): “The primary available therapies for refractory CC include gabapentin, speech pathology, and morphine” (Ryan, page 708). Ryan teaches that tramadol is not a preferred treatment for chronic cough because it is not well studied and is associated with undesirable side effects:
Tramadol has been associated with serotonin syndrome when taken with serotonergic medications in case reports [Citation105–Citation107] although in a large recent study this was found to be very unlikely even in overdose [Citation108]. There have been significant adverse effects such as seizures reported suggesting that the decision to prescribe tramadol should be carefully considered [Citation108,Citation109]. A recent Cochrane Systematic review found that there is only modest information to support tramadol use in neuropathic pain [Citation110]. Interestingly, in a trial by Sindrup et al. [Citation111], there was a significant therapeutic effect of tramadol on paresthesia, allodynia, and touch-evoked pain – similar characteristics to those described in neuropathic CC.
To date, there are no RCTs on the use of tramadol for neurogenic or refractory CC. However, due to tramadol’s effects on neuropathic pain it may be considered a developing therapy for refractory CC.
Ryan, page 704.
A prima facie showing of obviousness is established for the record.
There is no showing of record of an unexpected result based on the use of oral nalbuphine. The data and declaration provide arguments provide a showing as compared to placebo. In other words, nalbuphine works to treat chronic cough. The examiner does not dispute this.
Rhame teaches symptomatic treatment of cough in almost every conceivable condition, including those in which chronic cough is a common symptom. Symptomatic treatment means that if a cough exists at week 7 or 8 or 9, e.g., such cough would be treated with nalbuphine. While Applicant argues that a cough at 8 weeks differs from a cough at 7 weeks, the examiner notes that Rhame teaches treating the symptoms of cough in subjects with symptoms. There is no restriction on when these symptoms can be treated in Rhame.
Moreover, chronic cough is common in most chronic respiratory conditions including many in which Rhame teaches cough can be treated. Further, morphine can treat chronic cough with a downside of AEs. Nalbuphine is similar in analgesic effect and respiratory depression to morphine but with unexpected advantages of being safer.
Further, central and peripheral sensitization of the cough reflex is involved in RCC and the term sensory neuropathic cough is now often recognized in the guidelines. Ryan explains that cough reflex hypersensitivity (CRS) is a key feature of RCC and CC has been labeled as cough hypersensitivity syndrome. The incidence of CC and chronic pain are common and the high prevalence in women is also consistent with chronic pain. “The basis neurolobiological mechanisms and pathologies of refractory CC and chronic pain show substantial homologies.” See p689, 4th full par. Based on numerous described similarities between RCC and neuropathic pain, Ryan explains that it is important to understand the mechanism of drug therapy so that drugs designed for the treatment of pain can be repurposed for cough. See p690, 2nd full par. Tramadol was noted as one agent that was studied and appeared to improve neurogenic cough. Numerous pain medications were shown to have an effect. See Table 4.
There is a reasonable expectation of success that cough can be treated when it has become chronic cough as Rhame teaches treating cough in each instance. The use of similar drugs with similar efficacies is shown and nalbuphine is recognized as having a better safety profile than morphine, e.g. If a patient with COPD, e.g., is coughing after 8 weeks and they are treated for cough as taught by Rhame and as obvious in view of Rhame, Pavard, and Ryan, they are necessarily identified as having a chronic cough that has lasted 8 weeks. This identified subject has RCC. Selecting a subject for treatment is also identifying such subject.
Those portions of Applicant’s arguments not addressed by the above are now responded to. There does not appear to be a showing of unexpected results as compared to the closest prior art. Applicant is merely alleging that a prima facie showing is not established.
Applicant argues that the rejection is based on a false premise that RCC is not a distinct subject.
The examiner recognizes that RCC is a distinct subject. However, the prior art renders obvious administration of the claimed agent, nalbuphine, to a subject with claimed respiratory conditions and a cough. When that cough lasts for 8 weeks, such subject has RCC. This is a subject that is taught to be treated. Selecting a subject for treatment is also identifying such subject. To administer a claimed agent to a subject with a chronic cough at 8 weeks, that subject has necessarily been identified. Further, there is reason to believe that cough as a chronic symptom of conditions in which it is known to be a common symptom includes those subjects contemplated by Rhame. Moreover, the combination of prior art strengthens this understanding. Morphine treats CC as well as other centrally active opioid analgesics. Neurogenic cough and neuropathic pain have many similarities and nalbuphine is similar to morphine as an analgesic and a respiratory depressant.
Applicant argues that Rhame is directed to treat a respiratory disease and not RCC.
The examiner notes that Rhame is directed to treating symptoms in a subject. That symptomatic treatment includes cough. Symptomatic treatment means that when a subject is coughing, nalbuphine would be administered orally to that subject. Such teaching does not indicate impart a cutoff for treatment at 8 weeks.
Applicant argues that the definition that chronic cough is a cough that lasts for 8 weeks despite treatment and that this includes those with IPF, COPD, and other conditions in which a cough persists is incorrect.
The examiner notes that the definition of chronic cough in the Specification at paragraph 36 is a cough that lasts at least 8 weeks. Participants in the study in the Specification must have IPF and a chronic cough (>8 weeks). The examiner notes that if a subject has a chronic cough for greater than 8 weeks and they have a condition such as IPF and COPD they could have chronic cough. The cough is not caused by the condition per se but is explained to be neurogenic at 8 weeks. This includes subjects with neurogenic cough and COPD, IPF, or any other condition. If a subject has a cough at all, the prior art teaches administration of oral nalbuphine at a claimed dosage. The examiner also notes that the instant Specification explicitly states that the origin of the chronic cough can be a condition, including e.g., asthma, GERD, chronic bronchitis) “or unexplained origin.” The Specification indicates that the “origin” of the cough is an underlying condition. See par. 3.
Applicant argues that the cited reference fail to teach a patient with a cough that has persisted despite optimized guideline directed treatment.
The examiner notes that chronic cough is defined by the Specification as a cough that persists for at least 8 weeks.
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As noted int the art and above this is synonymous with RCC
Declarant argues that nalbuphine is sedating and therefore Ryan teaches away from using nalbuphine.
The examiner notes that nalbuphine is well-recognized in the art as having a better safety profile than morphine. Paragraph 6 of Rhame refers to a unique safety profile for nalbuphine among analgesics. Further, tramadol is well-known to be sedating and is explicitly taught to treat RCC. According to: https://www.healthline.com/health/drugs/does-tramadol-make-you-sleepy (date accessed August 26, 2026), “Sleepiness is one of its most commonly reported side effects, with rates increasing at higher doses.”
Declarant argues that morphine and tramadol differ from nalbuphine.
The examiner notes that tramadol and morphine are shown to treat RCC and nalbuphine similarly treats neuropathic pain and is already well established to treat cough as a symptom in most conditions in which chronic cough can occur. Morphine is a full mu-opioid agonist and tramadol is a weak mu-opioid agonist. Nonetheless, they each treat RCC. Pregabalin and gabapentin also operate under different modes of analgesia. Gabapentin blocks a voltage gated calcium channel. Thus, it is not the specific mechanism having positive effects on CC. The analgesia decreases the sensitization to peripheral stimuli, including increased cough reflex sensitivity. This is termed “hyperalgesia/hypertussivity.” See Ryan p689, 3rd full par. As quoted above,
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Nalbuphine is a centrally active neuromodulator.
The examiner also notes that Jegga also teaches treating IPF, which is the only condition referred to in the instant Specification in any Example. As evidenced by Trushenko et al., “Updates on the Prevalence and Quality of Life, and Management of Chronic Cough in Interstitial Lung Diseases,” Diagnostics 2025, 15, 1139, the prevalence of chronic cough in IPF is up to 87%. See Table 1. Jegga teaches treating these subjects with nalbuphine, and those subjects do not appear to tacitly exclude 87% of subjects with IPF that also have CC. Jegga also claims treating those subjects with an opioid inhibitor of a mu or kappa receptor. This includes all forms of mu and kappa receptors and combinations thereof. See prior art claims 1-3.
Applicant argues that Rhame does not refer to refractory chronic cough and Rhame does not teach nalbuphine to be similar to morphine.
The examiner notes that this is addressed above. Ryan explains, “The basis neurolobiological mechanisms and pathologies of refractory CC and chronic pain show substantial homologies.” See p689, 4th full par. Further, the above agent through different modes of action are ach taught as centrally active neuromodulators that have shown benefit in RCC or CC associated with a neuropathic disease. Moreover, Rhame makes explicit comparisons to morphine noting that nalbuphine has similar efficacy to morphine: “Nalbuphine is known as having an analgesic potency essentially equivalent to that of morphine on a milligram basis.” (Rhame, Specification, paragraph 0003). Rhame also reports: nalbuphine has a respiratory depressant capacity similar to that of morphine. However, nalbuphine was noted as demonstrating a unique safety factor for nalbuphine among analgesics.
Applicant argues that there is no reasonable expectation of success based on a high treatment failure rate.
The examiner notes that treatment includes the amelioration of a symptom. The use of nalbuphine to treat cough as a symptom of conditions in which CC is common is well established. Even further, nalbuphine has an equivalent analgesic effect and respiratory depression efficacy similar to morphine. A problem with morphine is the safety profile. Nalbuphine is established as safer because it has a respiratory depressant ceiling. There is a reasonable expectation of success that an agent known to treat cough, wherein a link between treatment of neuropathic pain and neurogenic cough is established, wherein effects on neuropathic pain make an agent a consideration for a developing therapy for refractory CC, wherein chronic cough and chronic pain have similar neurobiological mechanisms and pathologies of chronic cough and chronic pain show substantial homologies;” and wherein the primary available therapies for refractory CC include gabapentin, speech pathology, and morphine” which focus on different central receptors. Tramadol is postulated as an additional that is postulated for use in treating CC.
When a subject with a cough as a symptom of COPD, asthma, or any other condition that lasts for more than 8 weeks, the teachings of Rhame indicate that it can be treated symptomatically as a cough. Rhame teaches treating symptoms and if that symptom is cough it can be treated with oral nalbuphine at a claimed dosage. If cough persists for more than 8 weeks, the treatment of cough is treatment for RCC and that treatment is neurogenic cough based on the definitions in the instant Specification. Administration to a subject necessarily includes identifying that subject. This alone is a motivation to administer the claimed drug to the claimed subject population even if the cough was not identified as being a neurogenic cough. Moreover, Rhame teaches nalbuphine to be similar to morphine as an analgesic and a respiratory depressant and the distinction among these agents is that nalbuphine is safer. Even further, morphine is taught to treat CC. Morphine, tramadol, pregabalin, gabapentin, and amitriptyline are taught to be centrally active neuromodulators that have been shown to treat CC. Nalbuphine is also a centrally acting neuromodulator. Moreover, each of these agents works through different modes of action. This is why merely having different modes of action does not mean it will not work. Even further, these pain medications are taught to be closely linked to neurogenic cough as “The basis neurolobiological mechanisms and pathologies of refractory CC and chronic pain show substantial homologies.” Repurposing pain drugs for treatment of CC has also been contemplated. In totality, there is a reasonable expectation of success that nalbuphine will treat chronic cough when administered orally to a subject.
Additional Prior Art.
However, in performing his due diligence, the examiner did identify the following prior art. As such, it is set forth below in a new Non-Final Action as this appears to be the most pertinent prior art.
The examiner cites Fulop et al., (US2016/0052931).
Fulop teaches morphine derivatives that are deuterated and provide higher analgesic activity reducing adverse events of the same. These can be used to treat pain or as an antitussive agent. See Abstract. The deuterated morphine derivative compound includes one of Formula (I) and it includes deuterated nalbuphine, wherein R5 is absent and R3 is (C1-C6) alkyl-cycloalkyl. Formula (I) does include nalbuphine. More importantly Formula (I) is taught to include deuterated nalbuphine and is claimed in prior art claim 1. Moreover, prior art claim 19 includes treatment of the following conditions: dyspnea, cough, intractable coughing, chronic coughing, psychogenic cough, reflex cough, and includes stereoisomers, enantiomers, etc., of the compound of Formula (I).
Formula (I) is set forth below:
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, wherein R1 and R2 are OH; R6 is hydrogen; X is OH; R5 is absent; R3 is C1 alkyl-C4 cycloalkyl.
This further strengthens the examiner’s position that nalbuphine would work to treat the claimed subject population.
As such, the examiner notes that this action is Non-Final as the is compelled to strengthen the rejection of record with the above Fulop et al., (US2016/0052931). Fulop teaches oral administration. Oral dosages can be from 8 to 20 mg. See par. 4. A dosage can be ideally from 0.1 mg/kg to 10 mg/kg. See par. 103. Various excipients and carriers can be used.
Status of the Claims
Claims 1 and 4-29 are pending and examined.
Claim Rejections - 35 USC § 103
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.
Claims 1 and 4-28 are rejected under 35 U.S.C. 103 as being unpatentable over Fulop et al., (US2016/0052931), in view of Rhame et al., (US2008/0207667), in view of Pavard et al., (The Lancet, Volume 371, Issue 9621, 1375 – 1384), and in view of Ryan et al. (Expert Opinion on Pharmacotherapy, vol. 19, no. 7, p. 687-711, April 2018).
Fulop teaches morphine derivatives that are deuterated and provide higher analgesic activity reducing adverse events of the same. These can be used to treat pain or as an antitussive agent. See Abstract. The deuterated morphine derivative compound includes one of Formula (I) and it includes deuterated nalbuphine, wherein R5 is absent and R3 is (C1-C6) alkyl-cycloalkyl. Formula (I) does include nalbuphine. More importantly Formula (I) is taught to include deuterated nalbuphine and is claimed in prior art claim 1. Moreover, prior art claim 19 includes treatment of the following conditions: dyspnea, cough, intractable coughing, chronic coughing, psychogenic cough, reflex cough, and includes stereoisomers, enantiomers, etc., of the compound of Formula (I).
Formula (I) is set forth below:
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, wherein R1 and R2 are OH; R6 is hydrogen; X is OH; R5 is absent; R3 is C1 alkyl-C4 cycloalkyl.
Fulop teaches oral administration. Oral dosages can be from 8 to 20 mg. See par. 4. A dosage can be ideally from 0.1 mg/kg to 10 mg/kg. See par. 103. Various excipients and carriers can be used.
Further, Rhame teaches treating respiratory diseases with nalbuphine. See par. 1. Nalbuphine is known to have a potency with respect to analgesia that is equivalent to morphine on a milligram basis. See par. 3. Controlled release formulations are known in the art. See par. 9. Rhame teaches nalbuphine for treating respiratory diseases. See par. 12. The ability to treat respiratory diseases was unexpected in view of the side effect of respiratory depression. See par. 15. A salt of nalbuphine can also be used and it this includes the hydrochloride form. See par. 21. Further, treatment includes treatment of respiratory diseases and their symptoms, including: “asthma, cough, cough with pruritis, chronic obstructive pulmonary disease, dyspnea, the symptoms of the listed diseases, and other respiratory diseases and their symptoms.” See par. 17. Conditions also include colds, flu, asthma, bronchitis, nasal congestion, lower respiratory symptoms, cough, and others. See par. 24. These conditions are chronic/persistent. Dosage can be optimized and frequency of administration “can be readily determined by one of ordinary skill in the art” using known techniques. See par. 37. Formulations can be in many forms including sustained release capsules, tablets, and more. See par. 54. Rhame claims treating symptoms associated with diseases affecting the respiratory or pulmonary system of humans and those symptoms include: cough with pruritis, COPD, dyspnea, pulmonary hypertension, or pulmonary symptoms, distress associated with cardiac disease, among others. See prior art claims 1 and 2. Dosages can range from 0.285 to 0.57 mg/kg per day and from a broad range of 0.1 to 1 mg/kg per day. This includes about 20 mg to 40 mg per day and from 7 mg to 70 mg per day. See par. 40. Magnesium stearate and other excipients are contemplated. Tablets, e.g., can be made to sustain release over time. See par. 56.
Pavard teaches that chronic cough is a common symptom of almost all chronic respiratory conditions and is responsible for over a third of referrals to pulmonology:
Chronic cough is defined as cough lasting for more than 8 weeks.1 This definition is based on evidence that a cough lasting longer than this duration is unlikely to be due to a respiratory tract infection.2 Chronic cough is a common symptom of almost all chronic respiratory, and some non-respiratory conditions. Several recognisable causes of chronic cough, such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, lung cancer, an inhaled foreign body, pulmonary tuberculosis, sarcoidosis, idiopathic pulmonary fibrosis, and heart failure will be obvious after clinical assessment, spirometry, and chest radiography... Cough is the primary focus of referral in 38% and the sole focus in 10% of patients seen in a typical adult respiratory clinic.
See page 1375 (emphasis added).
Ryan teaches that chronic cough “that persists despite assessment and treatment according to an accepted guideline is termed refractory chronic cough, idiopathic chronic cough, or unexplained cough” (Ryan, page 687). Therefore, refractory chronic cough, idiopathic chronic cough, or unexplained cough are considered synonyms in the art. Additionally, Ryan teaches that morphine is useful in the treatment of refractory chronic cough (CC): “The primary available therapies for refractory CC include gabapentin, speech pathology, and morphine.” See p708.
Rhame teaches nalbuphine has similar effects to morphine in treating cough, and both Pavard and Ryan teach morphine will treat refractory chronic cough. Thus, even if Rhame and Jegga were somehow interpreted as not including RCC, the combination of prior art provides a proper nexus for treatment of the same. More particularly, the analgesic and respiratory potential of nalbuphine are noted to be similar to that of morphine. See par.’s 3, 6, 7, and others.
It would have been prima facie obvious prior to the filing of the instant application to arrive at the claimed methods in view of Fulop, Rhame, Pavard, and Ryan. One would be motivated to do so because Fulop teaches treating claimed conditions with a compound that is inclusive of deuterated nalbuphine. The deuterium assists in the safety profile. Moreover, Rhame teach treating conditions, including IPF, COPD, and other chronic respiratory conditions with similar dosages of nalbuphine wherein a cough that persists symptomatically would yield a neurogenic cough. In view of Fulop, it is abundantly clear that a chronic cough can be treated with nalbuphine. This communicates that regardless of the mechanism by which cough exists, there is a reasonable and predictable expectation that the claimed agent will treat the same. Even further, morphine is taught to treat RCC by additional prior art. Similarly, Pavard teaches that most chronic respiratory conditions including many taught by Rhame include a cough that lasts for more than 8 weeks despite treatment. A POSA would understand from Fulop, Rhame, Ryan, and Pavard that the claimed agent will treat the claimed conditions. Not only is this explicit, but there are multiple references that teach the ability of morphine and similar compounds to have a claimed effect irrespective of the specific receptor of action. The suggestion that is not explicit provides additional motivation that morphine similar compounds and those centrally active pain compounds would similarly work for neurogenic cough. This is probably the basis for the explicit disclosure of Fulop. Moreover, similarly structured compounds often work similarly. As such, there is a reasonable and predictable expectation of success that the claimed agents would work to treat claimed subjects with or without deuterium.
Claims 1 and 4-29 are rejected under 35 U.S.C. 103 as being unpatentable over Fulop et al., (US2016/0052931), in view of Rhame et al., (US2008/0207667), in view of Pavard et al., (The Lancet, Volume 371, Issue 9621, 1375 – 1384), in view of Ryan et al. (Expert Opinion on Pharmacotherapy, vol. 19, no. 7, p. 687-711, April 2018), and in view of Baichwal et al., (U.S. Pat. No. 8,394,812) (applicant is co-inventor of the ‘812 patent).
Fulop teaches morphine derivatives that are deuterated and provide higher analgesic activity reducing adverse events of the same. These can be used to treat pain or as an antitussive agent. See Abstract. The deuterated morphine derivative compound includes one of Formula (I) and it includes deuterated nalbuphine, wherein R5 is absent and R3 is (C1-C6) alkyl-cycloalkyl. Formula (I) does include nalbuphine. More importantly Formula (I) is taught to include deuterated nalbuphine and is claimed in prior art claim 1. Moreover, prior art claim 19 includes treatment of the following conditions: dyspnea, cough, intractable coughing, chronic coughing, psychogenic cough, reflex cough, and includes stereoisomers, enantiomers, etc., of the compound of Formula (I).
Formula (I) is set forth below:
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, wherein R1 and R2 are OH; R6 is hydrogen; X is OH; R5 is absent; R3 is C1 alkyl-C4 cycloalkyl.
Fulop teaches oral administration. Oral dosages can be from 8 to 20 mg. See par. 4. A dosage can be ideally from 0.1 mg/kg to 10 mg/kg. See par. 103. Various excipients and carriers can be used. Extended release forms are contemplated. See par. 16, e.g.
Further, Rhame teaches treating respiratory diseases with nalbuphine. See par. 1. Nalbuphine is known to have a potency with respect to analgesia that is equivalent to morphine on a milligram basis. See par. 3. Controlled release formulations are known in the art. See par. 9. Rhame teaches nalbuphine for treating respiratory diseases. See par. 12. The ability to treat respiratory diseases was unexpected in view of the side effect of respiratory depression. See par. 15. A salt of nalbuphine can also be used and it this includes the hydrochloride form. See par. 21. Further, treatment includes treatment of respiratory diseases and their symptoms, including: “asthma, cough, cough with pruritis, chronic obstructive pulmonary disease, dyspnea, the symptoms of the listed diseases, and other respiratory diseases and their symptoms.” See par. 17. Conditions also include colds, flu, asthma, bronchitis, nasal congestion, lower respiratory symptoms, cough, and others. See par. 24. These conditions are chronic/persistent. Dosage can be optimized and frequency of administration “can be readily determined by one of ordinary skill in the art” using known techniques. See par. 37. Formulations can be in many forms including sustained release capsules, tablets, and more. See par. 54. Rhame claims treating symptoms associated with diseases affecting the respiratory or pulmonary system of humans and those symptoms include: cough with pruritis, COPD, dyspnea, pulmonary hypertension, or pulmonary symptoms, distress associated with cardiac disease, among others. See prior art claims 1 and 2. Dosages can range from 0.285 to 0.57 mg/kg per day and from a broad range of 0.1 to 1 mg/kg per day. This includes about 20 mg to 40 mg per day and from 7 mg to 70 mg per day. See par. 40. Magnesium stearate and other excipients are contemplated. Tablets, e.g., can be made to sustain release over time. See par. 56.
Pavard teaches that chronic cough is a common symptom of almost all chronic respiratory conditions and is responsible for over a third of referrals to pulmonology:
Chronic cough is defined as cough lasting for more than 8 weeks.1 This definition is based on evidence that a cough lasting longer than this duration is unlikely to be due to a respiratory tract infection.2 Chronic cough is a common symptom of almost all chronic respiratory, and some non-respiratory conditions. Several recognisable causes of chronic cough, such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, lung cancer, an inhaled foreign body, pulmonary tuberculosis, sarcoidosis, idiopathic pulmonary fibrosis, and heart failure will be obvious after clinical assessment, spirometry, and chest radiography... Cough is the primary focus of referral in 38% and the sole focus in 10% of patients seen in a typical adult respiratory clinic.
See page 1375 (emphasis added).
Ryan teaches that chronic cough “that persists despite assessment and treatment according to an accepted guideline is termed refractory chronic cough, idiopathic chronic cough, or unexplained cough” (Ryan, page 687). Therefore, refractory chronic cough, idiopathic chronic cough, or unexplained cough are considered synonyms in the art. Additionally, Ryan teaches that morphine is useful in the treatment of refractory chronic cough (CC): “The primary available therapies for refractory CC include gabapentin, speech pathology, and morphine.” See p708.
Rhame teaches nalbuphine has similar effects to morphine in treating cough, and both Pavard and Ryan teach morphine will treat refractory chronic cough. Thus, even if Rhame and Jegga were somehow interpreted as not including RCC, the combination of prior art provides a proper nexus for treatment of the same. More particularly, the analgesic and respiratory potential of nalbuphine are noted to be similar to that of morphine. See par.’s 3, 6, 7, and others.
Baichwal teaches sustained release formulations of nalbuphine or salts therefor comprising oral unit dosages having locust bean gum, xanthan gum, mannitol, and calcium sulfate dihydrate. See col. 2, lines 43-47. Nalbuphine is present from 1 to 100 mg, or about 20 mg, or about 40 mg, or about 60 mg. See col. 5, lines 14-15. Further, hydroxypropyl celluloses can be used as exemplary hydrophilic compounds. Fumaric acid is taught for 180 mg formulations. See Examples 24-28.
It would have been prima facie obvious prior to the filing of the instant application to arrive at the claimed methods in view of Fulop, Rhame, Pavard, Ryan, and Baichwal. One would be motivated to do so because Fulop teaches treating claimed conditions with a compound that is inclusive of deuterated nalbuphine. The deuterium assists in the safety profile. Moreover, Rhame teach treating conditions, including IPF, COPD, and other chronic respiratory conditions with similar dosages of nalbuphine wherein a cough that persists symptomatically would yield a neurogenic cough. In view of Fulop, it is abundantly clear that a chronic cough can be treated with nalbuphine. This communicates that regardless of the mechanism by which cough exists, there is a reasonable and predictable expectation that the claimed agent will treat the same. Even further, morphine is taught to treat RCC by additional prior art. Similarly, Pavard teaches that most chronic respiratory conditions including many taught by Rhame include a cough that lasts for more than 8 weeks despite treatment. Baichwal teaches a specific formulation of the claimed active API that can be used in extended release form. A POSA would understand from Fulop, Rhame, Ryan, and Pavard that the claimed agent will treat the claimed conditions. Not only is this explicit, but there are multiple references that teach the ability of morphine and similar compounds to have a claimed effect irrespective of the specific receptor of action. The suggestion that is not explicit provides additional motivation that morphine similar compounds and those centrally active pain compounds would similarly work for neurogenic cough. This is probably the basis for the explicit disclosure of Fulop. Moreover, similarly structured compounds often work similarly. As such, there is a reasonable and predictable expectation of success that the claimed agents would work to treat claimed subjects with or without deuterium.
Claims 1 and 4-29 are rejected under 35 U.S.C. 103 as being unpatentable over Fulop et al., (US2016/0052931), in view of Rhame et al., (US2008/0207667), and in view of Pavard et al., (The Lancet, Volume 371, Issue 9621, 1375 – 1384), and in view of Ryan et al. (Expert Opinion on Pharmacotherapy, vol. 19, no. 7, p. 687-711, April 2018), in view of Baichwal et al., (U.S. Pat. No. 8,394,812) (applicant is co-inventor of the ‘812 patent), and in view of Sciascia et al., (U.S. Pat. No. 8,637,538).
Fulop teaches morphine derivatives that are deuterated and provide higher analgesic activity reducing adverse events of the same. These can be used to treat pain or as an antitussive agent. See Abstract. The deuterated morphine derivative compound includes one of Formula (I) and it includes deuterated nalbuphine, wherein R5 is absent and R3 is (C1-C6) alkyl-cycloalkyl. Formula (I) does include nalbuphine. More importantly Formula (I) is taught to include deuterated nalbuphine and is claimed in prior art claim 1. Moreover, prior art claim 19 includes treatment of the following conditions: dyspnea, cough, intractable coughing, chronic coughing, psychogenic cough, reflex cough, and includes stereoisomers, enantiomers, etc., of the compound of Formula (I).
Formula (I) is set forth below:
PNG
media_image3.png
217
172
media_image3.png
Greyscale
, wherein R1 and R2 are OH; R6 is hydrogen; X is OH; R5 is absent; R3 is C1 alkyl-C4 cycloalkyl.
Fulop teaches oral administration. Oral dosages can be from 8 to 20 mg. See par. 4. A dosage can be ideally from 0.1 mg/kg to 10 mg/kg. See par. 103. Various excipients and carriers can be used. Extended release forms are contemplated. See par. 16, e.g.
Further, Rhame teaches treating respiratory diseases with nalbuphine. See par. 1. Nalbuphine is known to have a potency with respect to analgesia that is equivalent to morphine on a milligram basis. See par. 3. Controlled release formulations are known in the art. See par. 9. Rhame teaches nalbuphine for treating respiratory diseases. See par. 12. The ability to treat respiratory diseases was unexpected in view of the side effect of respiratory depression. See par. 15. A salt of nalbuphine can also be used and it this includes the hydrochloride form. See par. 21. Further, treatment includes treatment of respiratory diseases and their symptoms, including: “asthma, cough, cough with pruritis, chronic obstructive pulmonary disease, dyspnea, the symptoms of the listed diseases, and other respiratory diseases and their symptoms.” See par. 17. Conditions also include colds, flu, asthma, bronchitis, nasal congestion, lower respiratory symptoms, cough, and others. See par. 24. These conditions are chronic/persistent. Dosage can be optimized and frequency of administration “can be readily determined by one of ordinary skill in the art” using known techniques. See par. 37. Formulations can be in many forms including sustained release capsules, tablets, and more. See par. 54. Rhame claims treating symptoms associated with diseases affecting the respiratory or pulmonary system of humans and those symptoms include: cough with pruritis, COPD, dyspnea, pulmonary hypertension, or pulmonary symptoms, distress associated with cardiac disease, among others. See prior art claims 1 and 2. Dosages can range from 0.285 to 0.57 mg/kg per day and from a broad range of 0.1 to 1 mg/kg per day. This includes about 20 mg to 40 mg per day and from 7 mg to 70 mg per day. See par. 40. Magnesium stearate and other excipients are contemplated. Tablets, e.g., can be made to sustain release over time. See par. 56.
Pavard teaches that chronic cough is a common symptom of almost all chronic respiratory conditions and is responsible for over a third of referrals to pulmonology:
Chronic cough is defined as cough lasting for more than 8 weeks.1 This definition is based on evidence that a cough lasting longer than this duration is unlikely to be due to a respiratory tract infection.2 Chronic cough is a common symptom of almost all chronic respiratory, and some non-respiratory conditions. Several recognisable causes of chronic cough, such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, lung cancer, an inhaled foreign body, pulmonary tuberculosis, sarcoidosis, idiopathic pulmonary fibrosis, and heart failure will be obvious after clinical assessment, spirometry, and chest radiography... Cough is the primary focus of referral in 38% and the sole focus in 10% of patients seen in a typical adult respiratory clinic.
See page 1375 (emphasis added).
Ryan teaches that chronic cough “that persists despite assessment and treatment according to an accepted guideline is termed refractory chronic cough, idiopathic chronic cough, or unexplained cough” (Ryan, page 687). Therefore, refractory chronic cough, idiopathic chronic cough, or unexplained cough are considered synonyms in the art. Additionally, Ryan teaches that morphine is useful in the treatment of refractory chronic cough (CC): “The primary available therapies for refractory CC include gabapentin, speech pathology, and morphine.” See p708.
Rhame teaches nalbuphine has similar effects to morphine in treating cough, and both Pavard and Ryan teach morphine will treat refractory chronic cough. Thus, even if Rhame and Jegga were somehow interpreted as not including RCC, the combination of prior art provides a proper nexus for treatment of the same. More particularly, the analgesic and respiratory potential of nalbuphine are noted to be similar to that of morphine. See par.’s 3, 6, 7, and others.
Baichwal teaches sustained release formulations of nalbuphine or salts therefor comprising oral unit dosages having locust bean gum, xanthan gum, mannitol, and calcium sulfate dihydrate. See col. 2, lines 43-47. Nalbuphine is present from 1 to 100 mg, or about 20 mg, or about 40 mg, or about 60 mg. See col. 5, lines 14-15. Further, hydroxypropyl celluloses can be used as exemplary hydrophilic compounds. Fumaric acid is taught for 180 mg formulations. See Examples 24-28.
Sciascia teaches oral compositions comprising 15 mg to 60 mg once or twice a day and then titrated at increments of 15 mg to 60 mg to an effective dose. See col. 1, lines 60-62.
“In certain embodiments, the anti-pruritus agent is administered in an oral extended release formulation comprising nalbuphine hydrochloride, mannitol, hydroxypropyl cellulose, locust bean gum, xanthan gum, calcium sulfate dihydrate and magnesium stearate.” Col. 3, lines 5-10.
It would have been prima facie obvious prior to the filing of the instant application to arrive at the claimed methods in view of Fulop, Rhame, Pavard, Ryan, Baichwal, and Sciascia. One would be motivated to do so because Fulop teaches treating claimed conditions with a compound that is inclusive of deuterated nalbuphine. The deuterium assists in the safety profile. Moreover, Rhame teach treating conditions, including IPF, COPD, and other chronic respiratory conditions with similar dosages of nalbuphine wherein a cough that persists symptomatically would yield a neurogenic cough. In view of Fulop, it is abundantly clear that a chronic cough can be treated with nalbuphine. This communicates that regardless of the mechanism by which cough exists, there is a reasonable and predictable expectation that the claimed agent will treat the same. Even further, morphine is taught to treat RCC by additional prior art. Similarly, Pavard teaches that most chronic respiratory conditions including many taught by Rhame include a cough that lasts for more than 8 weeks despite treatment. Baichwal teaches a specific formulation of the claimed active API that can be used in extended release form. A POSA would understand from Fulop, Rhame, Ryan, and Pavard that the claimed agent will treat the claimed conditions. Not only is this explicit, but there are multiple references that teach the ability of morphine and similar compounds to have a claimed effect irrespective of the specific receptor of action. The suggestion that is not explicit provides additional motivation that morphine similar compounds and those centrally active pain compounds would similarly work for neurogenic cough. This is probably the basis for the explicit disclosure of Fulop. Moreover, similarly structured compounds often work similarly. As such, there is a reasonable and predictable expectation of success that the claimed agents would work to treat claimed subjects with or without deuterium.
As such, no claim is allowed.
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).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 and 4-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,660,296, in view of Fulop et al., (US2016/0052931), in view of Rhame et al., (US2008/0207667), and in view of Pavard et al., (The Lancet, Volume 371, Issue 9621, 1375 – 1384), and in view of Ryan et al. (Expert Opinion on Pharmacotherapy, vol. 19, no. 7, p. 687-711, April 2018).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘296 patent are directed to treating IPF and chronic cough associated therewith. Further, nalbuphine is taught by the cited prior art to treat chronic cough and refractory chronic cough as explained in detail in the rejections set forth above. As such, there is a reasonable and predictable expectation of success in arriving at the claimed invention in view of the ‘296 patent and the prior art.
Claims 1 and 4-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent Application No. 19/270,674, in view of Fulop et al., (US2016/0052931), in view of Rhame et al., (US2008/0207667), and in view of Pavard et al., (The Lancet, Volume 371, Issue 9621, 1375 – 1384), and in view of Ryan et al. (Expert Opinion on Pharmacotherapy, vol. 19, no. 7, p. 687-711, April 2018).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘674 patent include interstitial lung disease (ILD) chronic cough and claim 11 notes that IPF is a species of ILD. IPF and ILD are each conditions associated with chronic cough. Further, nalbuphine is taught by the cited prior art to treat chronic cough and refractory chronic cough as explained in detail in the rejections set forth above. As such, there is a reasonable and predictable expectation of success in arriving at the claimed invention in view of the ‘296 patent and the prior art. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
As such, no claim is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
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/JARED BARSKY/Primary Examiner, Art Unit 1628
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