DETAILED ACTION
The receipt is acknowledged of applicant’s amendment filed 11/03/2025.
Claims 1, 2, 5, 8, 10-12 and 27-33 are pending and subject of this office action.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 .
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1, 2, 5, 8, 10-12 and 27-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fleming et al. (WO 2015/034822, hereinafter Fleming-WO) in view of any of the article by Ergometrine (from “Indian Medical Gazette”), or the article by Dahlof et al. (“Systemic adsorption of adrenaline after aerosol, eye-drop and subcutaneous administration to healthy volunteers”), and the above combination further in view of Hill (US 2007/0293582), Carver et al. (US 2010/0291160), Rawas-Qalaji et al. (US 2007/0202163), and Fleming (US 2015/0005356, hereinafter Fleming-US), all references are of record.
Applicant Claims
Claim 1 is directed to a method of treating at least one of hypotension associated with septic shock or the effects of adrenal insufficiency, the method comprising:
providing at least a first dosage of a liquid 1-epinephrine formulation to a patient by administering said first dosage to the nasal mucosa, and
administering at least a second dosage, following the first dosage, of the liquid 1-epinephrine formulation sublingually or buccally inside said patient’s mouth,
wherein the liquid l-epinephrine formulation is an aqueous formulation,
wherein the liquid 1-epinephrine formulation is adapted for transmucosal absorption, and is formulated with one or more excipient for extended release, and
the patient’s blood pressure is raised after administering the second dosage.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Fleming-WO teaches method of treating anaphylaxis or anaphylactic shock by administering an intranasal composition comprising epinephrine (title, abstract). The intranasal composition comprises 1-50 mg epinephrine (¶ 0034). The composition is applied to the mucosal surface of the nasal cavity by inhaler or spray (¶¶ 0056, 0167). The composition can be in the form of aqueous liquid (¶¶ 0146, 0171-0175, 0209). The anti-anaphylactic dose of epinephrine is from 0.1-10 mg (¶ 0021). The unite dose can be repeated every 5 to 20 minutes as necessary (¶¶ 0022, 0028). The intranasal administration treats patients with hypotension, and increases arterial blood pressure. Hypotension can be due to septic shock (¶¶ 0054-0057, 0161; claims 66-68). Intranasal epinephrine is administered prior to arrival of professional medical help (¶ 0166).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
While Fleming-WO teaches multiple doses of liquid aqueous epinephrine administered from inhaler or sprayer, and while teaches intranasal administration to the nasal mucosa that would inevitably permits both nasal mucosal delivery and oral mucosal delivery that may spread to sublingual area, the reference does not explicitly teach the second liquid dose of epinephrine is administered to the buccal or sublingual mucosa as instantly claimed by claim 1. Fleming-WO is silent regarding excipient for extended release.
Ergometrine teaches administering adrenaline (epinephrine) solution by vaporizer provides uniform and successful oral inhalation, i.e. buccal delivery, of adrenaline solution without discomfort and side effects of hypodermic injection of adrenaline (see the provided article).
Dahlof teaches both repeated nasal inhalation and repeated oral inhalation, i.e. buccal delivery, of adrenaline to treat upper airway hyper-reactive conditions, and teaches nasal inhalation of adrenaline is similar to oral inhalation but long lasting (see the entire document, and in particular abstract).
Hill teaches treating anaphylaxis using different dosage forms so that if first and second dosage forms are ineffective or not tolerated, ephedrine is continued to be administered via alternate route of administration (¶ 0007). The reference teaches the first and second dose are injection, and the following doses are sublingual (0017).
Carver teaches sublingual doses suitable to deliver epinephrine to treat anaphylaxis (¶¶ 0003-0009, 0149). The dose can equivalently be tablet or liquid, and both are easily administered and can be used to treat anaphylaxis using epinephrine because the liquid dose would be available (¶¶ 0029, 0048, 0099). The reference teaches sublingual formulations that can be equally administered by sublingual route or nasally (¶ 0101). The references teaches sustained release formulations (¶¶ 0099, 0104).
Rawas-Qalaji teaches buccal route of administration could be useful for drug administration to unconscious patient, and buccal mucosa has low enzymatic activity relative to nasal mucosa, thus potential for drug inactivation due to biochemical degradation is less rapid and less extensive than nasal route (¶¶ 0005, 0006). The reference teaches sustained release sublingual dosage form comprising up to 100 mg and administer ephedrine for more than 3 hours (¶¶ 0054, 0146-0147, claims 11, 21). The reference teaches the type and proportion of excipient used to formulate the tablet control the extent of hardness and rate of disintegration required (¶¶ 0082-0084).
Fleming-US teaches treating anaphylaxis by administering intranasal pharmaceutical composition comprising up to 10 mg epinephrine. The reference teaches controlled or extended release formulations of liquid aqueous epinephrine are advantageous. The aqueous formulation comprises excipients (abstract; ¶¶ 0018,0022, 0074-0079).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP §2142-2143)
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the present invention to treat anaphylaxis and raise blood pressure in subject in need thereof by administering multiple doses of liquid aqueous epinephrine from an inhaler or spay devices to the nasal mucosa and down to the airway as taught by Fleming, and further administer the same liquid epinephrine formulation to the buccal mucosa using the same device as taught by any of Ergometrine or Dahlof. One would have been motivated to do so because Ergometrine teaches administering epinephrine as a solution to the buccal mucosa provides uniform and successful delivery of epinephrine without discomfort and side effects of hypodermic injection, and because Dahlof teaches both repeated oral or buccal delivery is similar to nasal inhalation. One would reasonably expect to treat anaphylaxis and raise the blood pressure in patient in need thereof by administering multiple doses of liquid aqueous epinephrine by intranasal inhalation and further deliver same epinephrine formulation by different route of administration, e.g. to the buccal mucosa using the same intranasal epinephrine formulation to prolong the time of action of epinephrine without the discomfort and side effects of injection.
Further, it would have been obvious to one having ordinary skill in the art before the effective filing date of the present invention to treat anaphylaxis and raise the blood pressure using repeated intranasal and buccal doses of epinephrine that can be in an aqueous liquid form as taught by Fleming-WO combined by any of Ergometrine or Dahlof that teach administering repeated doses of liquid aqueous epinephrine, nasal and buccal, and use alternate route to administer a subsequent dose, other than route used to administer the first dose, such as sublingual dose as taught by Hill. One would have been motivated to do so because Hill teaches that using different dosage forms such as sublingual following the first dose compensates for if first dosage form are ineffective or not tolerated, so epinephrine is continued to be administered via alternate route of administration. One would reasonably expect treat anaphylaxis using one or two aqueous liquid intranasal doses of epinephrine followed by sublingual dosage administration wherein epinephrine administration is continued and tolerated by the patient.
Further, one having ordinary skill in the art before the effective fling date of the present invention would have replaced the subsequent sublingual or buccal doses by liquid sublingual or buccal doses taught by Carver because Carver teaches sublingual doses can equally be tablet or liquid, and both are easily administered and can be used to treat anaphylaxis using epinephrine, and it is expected that the liquid sublingual dose would be available and handy after administering the first nasal dose. Liquid sublingual dose is taught by Carver as easy to administer, which would have motivated one skill in the art to successfully administer second liquid sublingual dose used for the first nasal dose that is available and handy after administering the first nasal dose. Further, it is expected that the same liquid formulation suitable for mucosal administration can be administered to mucosa either of the nose or the mouth.
Furthermore, one having ordinary skill in the art would have selected buccal delivery route for a subsequent epinephrine dose following the aqueous liquid nasal epinephrine dose taught by combination of the above references because Rawas-Qalaji teaches buccal route of administration could be useful for drug administration to unconscious patient, and buccal mucosa has low enzymatic activity relative to nasal mucosa, thus potential for drug inactivation due to biochemical degradation is less rapid and less extensive than nasal route. One would reasonably expect effective treatment of anaphylaxis using liquid nasal administration of epinephrine followed by sublingual or buccal administration of epinephrine.
Additionally, one having ordinary skill in the art would have delivered epinephrine from sustained release formulation as taught by Rawas-Qalaji and Fleming-US based on suitability of such sustained release formulations to deliver drugs that raise blood pressure, e.g. epinephrine, and further because Fleming-US teaches sustained release formulations of epinephrine is advantageous in treating anaphylaxis.
Regarding aqueous formulation as claimed by claim 1, both Fleming references teaches aqueous formulation.
Regarding the limitation “excipient for extended release” as claimed by claim 1, Rawas-Qalaji and both Fleming references teaches excipients are responsible for the controlling the dissolution and disintegration of the formulation.
Regarding the limitation liquid formulation as claimed by claim 1, Fleming and Carver both teach liquid nasal formulation.
Regarding claim 2 that the first and second dose are provided at least 5 minutes apart, Fleming teaches 5-20 minutes apart.
Regarding claim 5 that the method is performed until emergency medical service arrive, Fleming teaches intranasal epinephrine is administered prior to arrival of professional medical help.
Regarding claim 8 that a third dose is provides, Fleming teaches repeating the dose as necessary that implies third dose.
Regarding claims 10-12 that the first dose and second dose comprises 1-50 mg epinephrine, comprises 1-15 mg epinephrine, and comprises 2-8 mg epinephrine, respectively, Fleming teaches the intranasal composition comprises 1-50 mg epinephrine (¶ 0034), and anti-anaphylactic dose of epinephrine is from 0.1-10 mg (¶ 0021). The same dose is used as first and second dosage.
Regarding claims 27 and 28 that epinephrine is dispensed into the nasal mucosa prior to administering epinephrine to the buccal or sublingual, or vice versa, as claimed by claims 27 and 28, respectively, it is only two sequence of administering the medication, one claimed by claim 27 and the other by claim 28, and it had been decided by Courts that the indiscriminate selection of "some" from among "many" is considered prima facie obvious. In re Lemin, 141 USPQ 814 (1964); National Distillers and Chem. Corp. V. Brenner, 156 USPQ 163. Note that applicants did not show superior or unexpected results of one sequence of administration versus the other. Using different routes of administering epinephrine sequentially is known in the art and taught by the cited references.
Regarding the dose claimed by claim 29 of “up to about 1000 mg”, at least Rawas-Qalaji teaches up to 100 mg, and Fleming teaches 10 mg for extended release.
Regarding claims 30-33 that the patient experiences increased strength of ventricular contraction and heart rate after the second dose, this is taught by Su liquid nasal epinephrine formulation provides therapeutically effective amount of epinephrine for prolonged blood levels effect of the epinephrine and sustained inotropic action and increased cardiac contractility.
Absent any evidence to the contrary, and based upon the teachings of the prior art, there would have been a reasonable expectation of success in practicing the instantly claimed invention. 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 present invention.
Response to Arguments
Applicant's arguments filed 11/03/2025 have been fully considered but they are not persuasive.
Rejections under 35 U.S.C. § 103
Applicant maintains all prior arguments with respect of the previously cited references as if reiterated here, in their entirety. Regarding Su reference, Applicant notes that Su teaches a formulation that is broadly stated as "comprising a catecholamine" but, aside from a cursory mention that epinephrine is a catecholamine, the entirety of the Su disclosure is directed to formulations of dobutamine. Such a disclosure does not provide a reasonable expectation that substituting epinephrine in the formulation would provide the same results with respect to release kinetics. Further, independent claim 1 as currently amended recites an aqueous sustained release formulation of epinephrine. In contrast, Su teaches that the sustained release formulations comprise fatty acids as a sustained release agent and teaches emulsions in which the active agent is dispersed in the fatty acid-no water is used.
In response to the applicant’s argument against previously cited references, the previous position taken by the examiner is hereby maintained and reiterated.
The argument regarding Su reference is moot in view of no longer relied on Su reference. At least both Fleming references teaches aqueous formulations as claimed.
It has been held that: “There is no new ground of rejection when the basic thrust of the rejection remains the same such that an appellant has been given a fair opportunity to react to the rejection. See In re Kronig, 539 F.2d 1300, 1302-03, 190 USPQ 425, 426-27 (CCPA 1976). Where the statutory basis for the rejection remains the same, and the evidence relied upon in support of the rejection remains the same, a change in the discussion of, or rationale in support of, the rejection does not necessarily constitute a new ground of rejection. Id. at 1303, 190 USPQ at 427 (reliance upon fewer references in affirming a rejection under 35 U.S.C. 103 does not constitute a new ground of rejection). MPEP 1207.03(A), II.”
Conclusion
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 Isis A D Ghali whose telephone number is (571)272-0595. The examiner can normally be reached on Monday through Friday, 8:30 AM to 5:00 PM EST.
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/ISIS A GHALI/ Primary Examiner, Art Unit 1611 /I.G./