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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/17/25 has been entered.
Status of the Claims
Claims 9 and 21 have been canceled. Claims 1-8, 10-20, and 22-27 remain pending and under current examination.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/17/25 (2) have been considered by the examiner.
Withdrawn Rejections
All rejections of claims 9 and 21 are withdrawn in view of Applicant’s cancelation of these claims. The rejection of claims 1-10, 12-20, and 22-27 under 35 U.S.C. 103 as being unpatentable over Crystal in view of Face and Foss is withdrawn in view of the amendments filed 10/17/2025. Subsequently, the rejection of claim 11 further in view of Wyse is withdrawn.
Response to Arguments
Applicant’s arguments filed 10/17/2025 (hereafter, “Remarks”) have been fully considered and are addressed as follows. Applicant’s delineation of the legal standard and rejections of record as on pages 6 and 7 of Remarks is noted.
Applicant argues that Crystal, Face, and Foss do not render obvious the method as recited in the amended claims, emphasizing that naloxone and naltrexone in the prior art have shorter half-lives than nalmefene specified 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 asserts that there is a need for an opioid antagonist that can be quickly administered as a prophylactic measure by a specified population if contacted with opioids. In reply, Applicant’s argument has been considered however is not persuasive because establishing long-felt need as evidence of nonobviousness 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 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 10/17/2025
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 1-8, 10, 12-20, and 22-27 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 self-administering a parenteral injection of a pharmaceutical formulation comprising a specified amount of nalmefene and/or an equivalent amount of a salt and/or solvent thereof using an auto-injection device, as further specified in the claims. It is noted that “an opioid agonist” newly recited in the last line of claim 1 is interpreted as a genus to the specific nalmefene and/or equivalent amount of a salt and/or solvate thereof named earlier in the claim.
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 nalemefene 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])(limitation of claim 2). Further regarding claim 1, the opioid agonist exposure referenced above appears to constitute an incident of exposure thereby meeting the claim language of “incidental exposure” as in claim 1; limitations are not imported from the specification into the claim. Crystal teaches formulations further comprising naloxone salt sodium chloride as an isotonicty 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). To this ends, Crystal teaches hydrochloric acid (see [0055], [060], [061])( limitation of claim 10).
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 5 and 6) and further specifies isotonicity agent to be sodium chloride for instance (see Crystal claim 17)(limitation of claim 12; see also [0249]; see also Table 14). As to claim 13, Crystal teaches that formulations may be in certain embodiments free of antimicrobial preservatives (see [056]) and further regarding claim 14 may be storage stable for about 12 months at about 25 degrees Celsius (see [063]). As to claim 19, Crystal teaches the state of the art wherein naloxone prevents the effects of opioids including respiratory depression (see [0256])(limitation of claim 20).
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 Crystal 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 opioid overdose or a symptom thereof in a subject caused by incidental exposure, which may be considered an actual incidental exposure, however Crystal does not identify the target population as in the instant claims. 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 20, 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 7-9).
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.
Further regarding the effects of performing the method steps otherwise addressed above and in regard to Tmax properties recited in claims 1 and 22-25, Crystal teaches a Tmax of less than 30 minutes (see [0137])(limitation of claims 1, 22, and 23) and occupancy at Tmax of opioid antagonist at the opioid receptors in the respiratory control center of the patient at greater than about 99% (see [0139])(limitation of claims 24-25); as noted above, Glass specifies naloxone and nalmefene to have “equipotency” with regard to plasma characteristics upon administration of a control dosage. As to claims 26 and 27, Crystal also teaches the patient to be free from respiratory depression for at least about 1 hour, 2 hours, 4 hours, and 6 hours following treatment (see [0140]).
Further, Crystal’s method encompasses auto-injection of an opioid antagonist parenterally in the context of treating an opioid overdose or apparent symptoms thereof. Crystal generally teaches prophylactic treatment by its teaching of prevention. Foss further elaborates on prophylactic treatment providing a reasonable expectation of success for applying Crystal’s method prophylactically, which is understood to prevent opioid overdose or a symptom thereof solely as a result of actual or suspected incidental exposure by a human subject to an opioid agonist.
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 15-18. Specifically, in this scenario and further regarding claim 1 as amended, 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 taught by Facey as detailed above and further in view of Foss’ rationale for prophylactic treatment (“solely” as in claim 1). 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 Foss and Facey, and making separable known steps would have been desirable in this particular scenario.
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 and Foss both teach naltrexone and nalmefene as equivalently useful opioid antagonists, and Glass provides rationale for choosing nalmefene over naltrexone. It would have been prima facie obvious to one of ordinary skill in the art to prophylactically administer a method and formulation of Crystal 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 and in view of nalmefene’s advantage of naloxone and naltrexone analogs as taught by Glass.
Claim 11 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 1-8, 10, 12-20, and 22-27 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 for the products and methods of Crystal and Glass. 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.
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/AUDREA B CONIGLIO/ Primary Examiner, Art Unit 1617