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 .
Status of the Claims
Claims 5, and 22-28 previously were canceled. Accordingly, claims 1-4 and 6-21 remain pending and under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9/26/2025 has been considered by the examiner.
Specification
The amendment to the specification filed 9/25/25 has been entered.
Withdrawn Rejections
The rejection of claims 1-4, 6, 11, and 13-21 under 35 U.S.C. 103 as being unpatentable over Crystal in view of Facey and Foss is withdrawn in view of Applicant’s amendments to claim 1. Subsequently, the rejection of claim 12 further in view of Wyse is withdrawn.
Response to Arguments
Applicant’s arguments filed 9/25/25 (hereafter, “Remarks”) have been fully considered and are addressed as follows. Applicant’s delineation of the rejections of record and legal standards as on pages 7 and 8 of Remarks is noted.
On pages 8 and 9 of Remarks, Applicant argues that the claimed methods would not have been obvious based on Crystal, Facey, and Foss, taking the position that naloxone and naltrexone have shorter half-lives than nalmefene as in the claims. In reply, Applicant’s argument is not persuasive in view of the new grounds of rejection necessitated by amendment as outlined below. The combination of cited references provides rationale for selecting nalmefene or a salt thereof for use in a method as claimed.
Applicant argues that there is a need for an opioid antagonist that can be administered quickly and easily as a prophylactic measure by certain populations if contacted with opioids. In reply, Applicant’s argument has been considered however is not persuasive because establishing long-felt need requires objective evidence that an art recognized problem existed in the art for a long period of time without a solution. A persistent need and failure of resolution by others has not been objectively established in the record per requirements detailed in MPEP 716.04.
Applicant argues on page 10 of Remarks that Wyse does not cure the alleged deficiency of Crystal, Facey, and Foss. In reply, the relevance of Wyse is maintained as applied below.
New Grounds of Rejection Necessitated by Amendments filed 9/25/25
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, 6-11, and 13-21 are rejected under 35 U.S.C. 103 as being unpatentable over WO2016/007729A1 (Crystal et al.; hereafter, “Crystal”) in view of “Glass” (Glass et al, “Comparison of Potency and Duration of Action of Nalmefene and Naloxone; Anesth Analg 1994; 78: 536-41; newly cited); “Risk Assessment of Individuals Exposed to Clandestine Drug Production”, University of Pittsburgh, 2002 (hereafter, “Facey”); and US 2004/0167148A1 (Foss et al., hereafter “Foss”).
The instant claims are drawn to a method comprising prophylactically self-administering from an auto-injection device a parenteral injection of a pharmaceutical formulation comprising an effective amount of nalmefene free base and/or one or more salts thereof using an auto-injection device, as further specified in the claims. It is noted that “an opioid agonist” is newly recited in the last line of claim 1, and nalmefene free base and/or an equivalent amount of a salt thereof is recited earlier in the claim; it is understood in this application that an opioid agonist is a generic group of which nalmefene is a species, as further addressed below.
Crystal teaches packaged drug products comprising an opioid receptor agonist and antagonist in a delivery device which may be a hand-held autoinjector device (see abstract, in particular)(limitations of claim 1). Crystal teaches parenteral administration of opioid receptor antagonists (see [0221] and [0223])(limitations of claims 1 and 2) and specifies nalmefene in particular (see [0194]) at least as an equivalent to naloxone which is disclosed to be used preventatively for instance (see [013]). Crystal teaches the state of the art with regard to dosage and for instance suggests for treatment of known or suspected narcotic (opioid) overdose in an adults an initial dose of 0.4 mg to 2 mg of naloxone hydrochloride intravenously indicated with repetition up to 10 mg if necessary (see [0257]). Further regarding claim 2, the opioid agonist exposure referenced above appears o constitute an incident of exposure thereby meeting the claim language of “incidental exposure” as in claim 2; as to a description of what constitutes an incident as in claim 2, limitations are not imported from the specification into the claim. Crystal teaches formulations further comprising in combination with naloxone salt sodium chloride as an isotonicity agent to a target pH (see Crystal claims 22 and 23 teaching an entirely included range of isotonicity agent) as well as an amount of acid to achieve a pH of 3.5-5.5 as well as water to desired volume (see Crystal claim 21)(limitation of claim 3). Crystal teaches subcutaneous delivery (see [025])(limitation of claim 4 ) and for a solution of 100 microliters an isotonicity agent in an amount of 0.2 to 1.2 mg (see [085]), a range overlapping with the instantly claimed range of 2.7 mg to 4.5 mg for instance when dosed at 300 microliters for instance (limitations of instant claims 6 and 7) and further specifies isotonicity agent to be sodium chloride for instance (see Crystal claim 177)(limitation of claim 11). Further regarding claim 13, Crystal teaches sodium chloride as an equivalent tonicity agent(see [0249]; see also Table 14)(limitation of claim 13). As to claim 14, Crystal teaches that formulations may be in certain embodiments free of antimicrobial preservatives (see [056])(limitation of claim 14) and further regarding claim 15 may be storage stable for about 12 months at about 25 degrees Celsius (see [063])(limitation of claim 15). As to claim 20, Crystal teaches the state of the art wherein naloxone prevents the effects of opioids including respiratory depression (see [0256])(limitation of claim 20).
The instant claims have been limited to nalmefene, where previously naloxone was examined as an opioid antagonist. While Crystal’s examples above pertain to naloxone, it is noted that Crystal teaches naloxone and nalmefene alike as opioid antagonists where it would have been prima facie obvious to substitute one for another in the same or substantially the same applications and amounts and further one would have been motivated to perform routine optimization procedures so as to achieve the desired efficacy and balanced benefits and side effects upon performing said substitution, as is customary in the art (see [0194]). Moreover, Glass, provides rationale for this substitution.
Glass teaches that nalmefene is a pure opiate antagonist structurally similar to naloxone and is known to have a longer duration of action than naloxone at the same dose (see abstract). Glass’ study compares the potency of these two structurally and functionally similar opiate antagonists with regard to various parameters wherein effects of fentanyl were mitigated. Glass concluded that the doses of the two were “equipotent” with regard to dose and plasma concentration (see abstract in particular) and noted that the clearance of naloxone was more rapid than that of nalmefene such that the elimination half-life of naloxone was significantly shorter than that of nalmefene. Further, where Cyrstal and Glass both teach nalmefene and naloxone to be equivalent opioid antagonists having structural similarity, Glass further establishes dose and plasma equipotency and different clearance times; accordingly, Glass provides rationale for selecting nalmefene from the opiate antagonists generally disclosed in Crystal in a situation where slower clearance would be considered desirable. Accordingly, one would have been motivated to choose nalemefene from Crystal’s opioid antagonists generally disclosed based on Glass’s teaching that nalmefene provides slower clearance suggesting desirably longer efficacy of treatment in the body upon administration.
Crystal’s methods are construed to teach at least a method for preventing a symptom of opioid overdose, however it is not apparent that Crystal necessarily teaches “actual or suspected incidental exposure… to an opioid agonist” as described by Applicant or prevention itself as in the scenario described in the last four lines of claim 1 as amended. Facey cures tis deficiency.
Facey teaches that fire fighters, law enforcement officers, and emergency medical personnel responding to methamphetamine lab sites are at an increased health risk (see “Objective” page 12). Facey delineates waste materials found at “dump sites” (page 19) including chemical residues (see page 10) and describes harmful exposure pathways including dermal contact and inhalation and further speaks of harms of improper ventilation and use of respirators (pages 19 and 31) in environments that may be considered the same or substantially the same as at least a “drug raid” as recited in claim 21, suggesting to the ordinary artisan that the incidental exposure harmful illicit drugs may be by inhalation exposure of aerosolized material or incidental transdermal or transmucosal exposure by an aerosolized or powdered form (limitations of claims 8-10).
Crystal and Facey are both directed to problems and solutions pertaining to illicit drugs (opioids and/or methamphetamines). It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to use the products and methods of Crystal in an environment and/or population where law enforcement or cleanup of illicit drug production sites may increase the risk to this population as taught by Facey, with a reasonable expectation of success. One would have been motivated to do so since Facey defines the state of the art with increased risk of harmful exposures through dermal contact and/or inhalation to populations including emergency medical personnel, fire fighters, and law enforcement officers for methamphetamine sites.
The teachings of Crystal and Facey have been delineated above. Crystal does not teach a prophylactic protocol for administration of an opioid antagonist or equivalent, nor does Facey, although as noted above in regard to claim 1 as amended, Crystal does generally teach prophylactic treatment by treating prevention in general. Accordingly, Crystal’s co-packaged drug product includes an opioid agonist the self-administration of which is excluded by the new claim language. Facey and Foss together cure this deficiency based on what these references reasonably would have suggested to the ordinary artisan.
Foss teaches a naltrexone compound which is the methyl-substituted naltrexone compound for treating opioid users (see title in particular). Foss also teaches the state of the art in which naloxone and nalmefene are equivalently useful as is recognized (see [0005]). Foss teaches administering the naltrexone compound prior to opioid administration or exposure with a recommended prophylactic time for naltrexone about 5 minutes to prevent opioid side effects upon subsequent opioid exposure (see [0026]). Foss more generally teaches an enteral administration time of 20 minutes prior to opioid use, ranges overlapping with those recited in claims 16-19.
Crystal, Facey, and Foss are all directed to harmful effects of illicit drugs and solutions. Crystal and Foss in particular are directed to opioid antagonists which may include naltrexone or its analog methylnaltrexone, and Crystal, Glass, and Foss teach naltrexone and nalmefene as equivalently useful opioid antagonists. It would have been prima facie obvious to one of ordinary skill in the art to prophylactically administer a method and formulation of Crystal and Glass in an environment for instance such as that taught by Facey using the prophylactic protocol of Foss, with a reasonable expectation of success. One would have been motivated to do so since Foss teaches parenteral methylnaltrexone to preferably be administered prior to opioid use/dosage/administration in order to prevent undesired opioid-induced side effects and further in view of these agents’ known equivalence as established above.
In this scenario and further regarding claim 1, the combination of Crystal and Foss reasonably would have suggested to the ordinary artisan that in the instance where prophylaxis is desired as in Foss and Facey, one would have been motivated to modify Crystal by utilizing only the opioid antagonist and not its co-packaged opioid agonist otherwise available for use. In other words, it would have been obvious to exclude the opioid agonist administration step of Crystal in view of the potential incidental exposure as taught by Facey as detailed above and further in view of Foss’ rationale for prophylactic treatment. Moreover, one reasonably would have expected success from doing so in order to minimize unnecessary harms of a method of treating with an opioid agonist such as undesired side effects particularly in a situation which is prophylactic or only potential in nature as in Foss and Facey. To do so would have constituted using a known technique of administering an opioid antagonist in the absence of an opioid agonist in a particular method of prophylactically treating opioid exposure or potential opioid exposure, in order to achieve a known result quickly and effectively and without undesired side effects. Further still, to do so would have constituted making separable method steps as in Crystal based on motivations supplied by Glass, Foss, and Facey, and making separable known steps would have been desirable in this particular scenario.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over WO2016/007729A1 (Crystal et al.; hereafter, “Crystal”) in view of “Glass” (Glass et al, “Comparison of Potency and Duration of Action of Nalmefene and Naloxone; Anesth Analg 1994; 78: 536-41; newly cited); “Risk Assessment of Individuals Exposed to Clandestine Drug Production”, University of Pittsburgh, 2002 (hereafter, “Facey”) and US 2004/0167148A1 (Foss et al., hereafter “Foss”) as applied to claims 1-4, 6-11, and 13-21 above, and further in view of US 2018/0161320A1 (hereafter “Wyse”).
The teachings of Crystal, Glass, Facey, and Foss have been delineated above. While Crystal teaches pH adjustment to a range the same or substantially the same as the range instantly recited, Crystal does not specify sodium hydroxide to be included to do so. Wyse cures this deficiency.
Like Crystal, Wyse teaches naloxone compositions and methods of making and using the same for the treatment of opioid overdose for instance (see abstract, in particular). Wyse specifies sodium hydroxide as an alternative to the hydrochloric acid to adjust pH from about 3 to about 5.5 or more specifically 4 +/- 0.5 (see [0050]).
Crystal and Wyse in particular are both directed to naloxone formulations and the delivery thereof. It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to substitute sodium hydroxide as taught by Wyse in place of hydrochloric acid as taught in Crystal in order to adjust the pH in the opposite direction towards the same or substantially the same end result pH range. One would have been motivated to do so in view of Crystal’s teaching of hydrochloric acid and the same pH range desired and in view of Wyse’s teaching of both sodium hydroxide and hydrochloric acid to the same ends (pH adjustment to the same or substantially the same range).
Conclusion
No claim is allowed.
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.
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/AUDREA B CONIGLIO/ Primary Examiner, Art Unit 1617