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 .
DETAILED ACTION
Claims 1-35 are pending in the present application file.
Election/Restrictions
Applicant’s election of Group I (claims 1-35; drawn to a method of treating neurological ventilatory insufficiency) without traverse in the reply filed January 26, 2026 is acknowledged by the Examiner.
As per MPEP 803.02, the examiner will determine whether the entire scope of the claims is patentable. Applicants' elected invention is not allowable over the prior art as indicated in the rejection under 35 U.S.C 103.
As the Applicant’s elected species has been found not allowable, the Markush-type claims have been rejected and claims to the nonelected invention held withdrawn from further consideration. Claims 1-35 have been examined to the extent that they embrace and are readable on the elected embodiment and the above identified nonelected species. Claims 1-35 have been found to be not allowable over the prior art.
Priority
The following continuity data is acknowledged in the present application file:
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126
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Information Disclosure Statement
The Information Disclosure Statement(s) filed 02/08/2024 and 07/24/2024 have been acknowledged by the Examiner. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the Examiner.
Specification
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because the abstract largely repeats information that is given in the title and for the use of phrases which are implied (e.g., "disclosed in certain embodiments" and "as disclosed herein"). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Interpretation
The preamble in the instant claim for method “of treating neurological ventilatory insufficiency”, has been interpreted as an intended outcome for the recited method.
Regarding an intended use limitation, MPEP 2111.02(II) notes:
“If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. See Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020)”.
Claims which limit or further define the intended outcome of treating neurological ventilatory insufficiency do not impart further limitation on the active steps of the method or the subjects to which the method is to be applied. The active steps of the recited method comprise administration of a compound of formula (I) to patient having neurological ventilatory insufficiency and either no or inadequate spontaneous ventilation. If the prior art structure is capable of performing the intended use, then is meets the claim.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 25 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 25 recites “The method of claim 24, wherein the decrease is at least 5%, at least 25% at 1 hour, 2 hours, 3 hours or 4 hours after dosing”. It is unclear what is intended by “at least 5%, at least 25%”. One of ordinary skill in the art would not be appraised to the required decrease and required timeframe for achieving the desired decrease in the present method.
Applicant can amend claim 25 to recite “at least 5% or at least 25%” to overcome this rejection.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-35 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2013/181217 A2 (Mannion et al.; Published 12/05/2013), in view of Rey (Rey, E., et al. "Low‐dose doxapram for treatment of apnoea following early weaning in very low birthweight infants: a randomized, double‐blind study." Acta Paediatrica 87.11 (1998): 1180-1184.) and McLeod (McLeod, J. F., et al. "GAL-021, a new intravenous BKCa-channel blocker, is well tolerated and stimulates ventilation in healthy volunteers." British journal of anaesthesia 113.5 (2014): 875-883.).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Mannion discloses a method of preventing or treating a breathing control disorder or disease in a subject in need thereof comprising administration of a compound of formula (I), including a compound of present claim 2. See pg. 43 claim 4 and Compound XXXV in Example 9A on page 82. Mannion discloses compounds corresponding to compounds of present formula (I) on pages 24-37. Mannion discloses compositions comprising the inventive compounds and a pharmaceutically acceptable carrier. See pgs. 52-54.
Mannion discloses administration of the compositions of the present invention to a patient, preferably a mammal or avian, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a breathing control disorder in the patient (see present claims 3-4). See pg. 57, lines 19-22.
Mannion discloses in one embodiment, the breathing disorder or disease is selected from the group consisting of narcotic-induced respiratory depression, anesthetic-induced respiratory depression, sedative-induced respiratory depression, anxiolytic-induced respiratory depression, hypnotic-induced respiratory depression, alcohol-induced respiratory depression, analgesic-induced respiratory depression, sleep apnea, apnea of prematurity, obesity -hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, altitude sickness, hypoxia, hypercapnia and chronic obstructive pulmonary disease (COPD). In another embodiment, the respiratory depression is caused by an anesthetic, a sedative, an anxiolytic agent, a hypnotic agent, alcohol or a narcotic (see present claim 6). See pg. 49, lines 16-25. Regarding present claims 7-8, Mannion discloses where patient has or is treated for condition other than drug, opioid or anesthetic induced respiratory depression such as apnea of prematurity, altitude sickness and chronic obstructive pulmonary disease (COPD).
Mannion provides where in another embodiment, the formulation is administered to the subject in conjunction with the use of a mechanical ventilation device or positive airway pressure device (see present claim 10). See pg. 3, lines 30-32.
Mannion discloses where the formulation is administered to the subject by an inhalational, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal or intravenous route (see present claim 12). See pg. 52, last para.
Mannion discloses where the subject is further administered a composition comprising at least one additional compound useful for treating the breathing control disorder or disease. Mannion provides the at least one additional compound is selected from the group consisting of acetazolamide, almitrine, theophylline, caffeine, methyl progesterone, a serotinergic modulator, a cannabinoid and an ampakine (see present claims 13-14). See claims 7-8 of Mannion.
Mannion provides several working examples to study the effect of a compound of formula (I) on minute ventilation, respiratory rate and several other pharmacodynamic parameters in healthy human subjects. See e.g. Example 28 on pgs. 179-190.
Mannion teaches on pg. 179:
The first study (GAL-021-101) was a single, ascending dose study in healthy subjects. Mild/moderate burning sensation at the infusion site was the only adverse event that differed from placebo from drug-treated subjects. At the highest dose (0.96 mg/kg/h) stimulation of minute ventilation and reduction of end tidal CO2 10 (ETCO2) were noted.
The second study (GAL-021-102) extended the dose range explored during the initial study by a factor of 2 and established the maximum respiratory stimulatory dose in the healthy subjects without concomitant use of opioids or anesthetic agents. At the 0.96 mg/kg/h, similar changes in minute ventilation was 15 noted with greater effects at the highest dose (1.92 mg/kg/h).
See present claim 15.
Mannion provides the following regarding dosing in the first study of Example 128:
Eight intravenous dose levels were administered with the first seven doses being fixed rate infusions (0.1-0.96 mg/kg/h) for 1, 2, 3, or 4 hours and the last used a loading dose (0.72 mg/kg/h for 1 hour) followed by a maintenance dose (0.36 mg/kg/h for 3 hours).
See present claims 16-18 and 20.
Mannion discloses during the second study, hyperventilation occurred at the high dose (1.92 mg/kg/h) to establish a PD maximum dose in healthy subject untreated with respiratory depressive agents. The stimulation of minute ventilation was similar in the two studies at the 0.96 mg/kg/h infusion rate (-16%) with greater stimulation at the high dose (25%). The drug was well behaved pharmacokinetically with a rapid concentration rise during the initial infusion period and rapid decline with cessation of the infusion.
See present claims 7-8. Regarding present claim 11, Mannion has disclosed the administration of a compound of formula (I) to healthy patients and does not disclose where any healthy patient previously used a ventilator device or used a ventilator device during the study.
Mannion discloses a third study, a two-part, four-treatment period, double blinded, 20 placebo controlled, crossover, stepped infusion study, evaluated ventilatory PD effects of N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine hydrogen sulfate (XXXVI) on respiratory drive in a model of opioid induced respiratory depression. See pg. 180-182. Mannion teaches where a second rapid infusion (2.0 mg/kg/h) and greater maintenance infusion (1.1 mg/kg/h) were used to assess the primary endpoint (minute ventilation) at high steady state concentration (see present claim 19).
Regarding the effects on minute ventilation and end tidal carbon dioxide Mannion discloses in the paragraph bridging pgs. 182-183,
End-tidal CO2 decreased in parallel to minute ventilation increases with an integrated reduction of ~6% (Figure 38B). The onset of effects on minute ventilation and ETCO2 were rapid with > half maximal effect observed by the 7.5 minutes (first assessment point). A similar pattern of changes in minute ventilation, tidal volume and respiratory rate (Figures 38C-D) were observed with NOX-T3 inductance plethysmography -based system with -24% increase in minute ventilation.
See present claims 21-25.
Mannion discloses where subjects experienced an increase in tidal volume after 7.5 minutes of administration (see present claims 26-31). See pg. 182, lines 18-28 and Figure 37 of Mannion. Mannion provides where the patient exhibits an increase in respiratory rate following administration of a compound of formula (I) (see present claims 32-34). See Fig 33A, 38C, 41C and 43C.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
Mannion does not disclose the subject matter of present claim 5 or 9, particularly the treatment of an infant with a post-menstrual age of less than 37 weeks or where the patient has discontinued use of a ventilator device prior to or following administration of a compound of formula (I).
Mannion does not disclose wherein the patient exhibits stable heart rate and mean arterial pressure for at least 30 minutes at least 1 hour after dosing. See present claim 35.
Finding of prima facie obviousness --- rationale and motivation (See
MPEP § 2142-2143)
Rey discloses administration of doxapram in combination with caffeine for the treatment of apnea of prematurity in infants <34 weeks and postnatal age <5d following weaning of mechanical ventilation (see present claim 5). See abstract. Rey provides where extubation occurred 8 hours after the first dose and was well tolerated for subjects (see present claim 11).
McLeod discloses GAL-021 (which corresponds to a compound of present claim 2) as a treatment for ventilatory insufficiency. Regarding GAL-021 and the development of the compound for treatment,
GAL-021 is being developed as an i.v. therapeutic agent for short-term use to stimulate ventilation in patients with acute respiratory insufficiency, including such conditions as opioid-induced respiratory depression and post-anaesthetic atelectasis. GAL-021 is intended to increase minute ventilation by increasing tidal volume and secondarily through increasing respiratory rate (RR). It is in these postoperative care settings that GAL-021 will likely provide benefit by stimulating ventilatory drive without antagonizing μ-opioid receptors, reversing analgesia, or acting as a generalized CNS stimulant. The current study was the initial, first-in-human (FIH), GAL-021 clinical study with the primary objectives of determining safety, tolerability, pharmacokinetics (PKs), and ventilatory pharmacodynamics (PDs) of the compound.
See present claims 1-4, 12, 21-23 and 26-34.
McLeod discloses the following regarding the increase in the minute ventilation:
At the highest infusion rate, minute ventilation increased rapidly, exceeding 1/2-maximal effect (14.5%) at the first point assessed at 7.5 min (Fig. 2a), had a sustained effect (14.5–18.9%) until infusion cessation, and gradually declined thereafter.
(See pg. 878, rc, first para).
The rapid increase in minute ventilation with ½ maximum effect attained at 7.5 min would support GAL-021 use in treating acute respiratory depression with further refinement of the loading/maintenance dosing approach explored in Period 9.
(See pg. 881, second para).
See present claims 16 and 21-23.
McLeod provides the following regarding heart rate and mean arterial pressure observed during treatment:
No clinically significant changes in blood chemistry, haematological parameters, PFT, or ECG occurred in any treatment group. Heart rate was more variable and increased generally during the day in all treatments without clinically meaningful differences from placebo-treatment. No significant changes in diastolic and systolic BP were observed across dose levels. During Periods 1–3, no mean arterial pressure changes were noted. During Periods 4 and 5 (second exposure), small mean arterial BP increased by 3.3–4.2%. The same subjects returned for a third treatment (Periods 7–9) with larger total exposures and had no significant change in mean arterial pressure (0.2–0.6%).
(See pg. 878, lc, second para).
See present claim 35.
Mannion discloses a method of preventing or treating a breathing control disorder or disease in a subject in need thereof comprising administration of a compound of formula (I), including a compound of present claim 2. McLeod also discloses a method of treating a ventilatory insufficiency comprising the compound of present claim 2.
Rey discloses administration of doxapram in combination with caffeine for the treatment of apnea of prematurity in infants <34 weeks and postnatal age <5d following weaning of mechanical ventilation (see present claim 5).
It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
As Mannion, Rey and McLeod all disclose a method of treating a breathing disorder or ventilatory insufficiency comprising administration of compounds of formula (I) to patients with either inadequate spontaneous breathing, it would have been prima facie obvious for one of ordinary skill in the art to combine the disclosures to arrive at the present invention. There would be a reasonable expectation of success for the treatment of a neurological ventilatory insufficiency based on the various data from studies and trials provided in the prior art. It is well within the skill of the ordinary artisan to combine administration of the pharmaceutical composition comprising a compound of formula (I) with an additional agent, such as almitrine, doxapram, or caffeine, or in conjunction with ventilator device support.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05,II.A.
Regarding claim 9, it is within the skill in the ordinary artisan to manage therapeutic administration of a pharmaceutical composition to patients which have discontinued use of a ventilator device prior to administration or patients that are following a weaning protocol to discontinue ventilator device support. One of ordinary skill would adjust the administration of a compound of formula (I) in conjunction with ventilator device during routine optimization.
Regarding claims 21-35, Mannion and McLeod disclose where administration of compound of formula (I) leads to an increase in minute ventilation, tidal volume and respiratory rate. Nonetheless, claims 21-35 are interpreted as intended results or outcomes for the method of present claim 1.
Claims which limit or further define the intended outcome of treating neurological ventilatory insufficiency do not impart further limitation on the active steps of the method or the subjects to which the method is to be applied. See MPEP 2111.02.
A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art is capable of performing the intended use, if meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997). See MPEP 2112.02 (II). When the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978). "While the references do not show a specific recognition of that result, its discovery by appellants is tantamount only to finding a property in the old composition." 363 F.2d at 934, 150 USPQ at 628 (emphasis in original)).
As the prior art discloses the administration of a compound of formula (I) to a patient having a neurological ventilatory insufficiency, the prior art discloses the properties and results of present claims 21-35.
Conclusion
Claims 1-35 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to QUINCY A MCKOY whose telephone number is (703)756-4598. The examiner can normally be reached Monday - Thursday 8:00 - 6:00.
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/QUINCY A. MCKOY/
Patent Examiner, Art Unit 1626
/KAMAL A SAEED/Primary Examiner, Art Unit 1626