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 .
Application Status
2. Applicant's submission filed on February 2, 2026 has been reviewed by the examiner and entered of record in the file.
3. Claims 1 and 103 are amended. Claims 2, 3, 5, and 9-16 are canceled.
4. Claims 6 and 18 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, without traverse, there being no allowable generic or linking claim. Applicant previously elected the species of naloxone as the single opioid antagonist and haloperidol as the single antipsychotic agent.
5. Claims 1, 4, 17, and 103 are under examination with the elected species and are the subject of this office action.
Claim Objections
6. Claim is objected to for reciting “and a combinations thereof” (line 7) which includes both a single combination and the plural “combinations.” Appropriate correction is requested.
7. Claim 4 is objected to for depending from claim 3, which has been canceled. It is noted that claim 6, presently withdrawn, is also dependent upon claim 3. The examiner interprets the dependency of claim 4 as depending from independent claim 1.
Previous Claim Rejections - 35 USC § 112(a)
6. Claims 1-4, 7, 8, 16 and 103 were previously rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of providing opioid overdose rescue to a patient in need thereof comprising the concurrent administration of: the combination of nalmefene at a dose of 4 mg with haloperidol at a dose of 80 mg (Example 1) OR the combination of naloxone at a dose of 2 mg with haloperidol at a dose of 80 mg (Example 2), does not reasonably provide enablement for a method of administering any opioid antagonist in combination with any antipsychotic agent to the patient.
7. In view of Applicant’s amendatory changes to limit the opioid antagonist to naloxone, nalmefene, or a combination thereof, and to limit the antipsychotic agent to haloperidol, the previous enablement rejection is withdrawn.
Previous Claim Rejections - 35 USC § 103
8. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
9. Claims 1, 4, and 17 remain rejected under 35 U.S.C. 103 as being unpatentable over Kerensky et al., Addiction Science & Clinical Practice (2017), in view of Sigmon et al., Am J Drug Alcohol Abuse (2012), in view of Cipriani et al., Cochrane Library (2010), and Physicians’ Desk References (2001): Haldol (cited on Applicant’s IDS of February 9, 2023),
Claim 1, as amended, is directed to a method of providing opioid overdose to a patient comprising:
administering to a patient identified in need of rescue from opioid overdose a therapeutically effective amount of opioid antagonist to counteract the opioid overdose, wherein the opioid antagonist is selected from the group consisting of naloxone, nalmefene, or a combination thereof, (more specifically naloxone or a pharmaceutically acceptable salt thereof (claims 4 and 17)), and another therapeutically effective amount of an antipsychotic agent to counteract a manic behavior, wherein the antipsychotic agent is haloperidol or a pharmaceutically acceptable salt thereof, and
wherein both the opioid antagonist and the antipsychotic agent are concurrently administered intramuscularly to the patient.
10. Kerensky et al. teach the administration of naloxone, a potent opioid antagonist, for emergency treatment of known or suspected opioid overdose (page 2, left column, first paragraph). A patient that has overdosed on opioids meets the limitation of a patient identified in need of rescue from opioid overdose, required by claim 1. Kerensky et al. additionally teaches that naloxone can be administered intramuscularly (IM), (page 2, left column, first paragraph).
23. Kerensky et al. does not teach the administration of haloperidol.
24. However, Sigmon et al. teach that when naloxone is administered for opioid overdose rescue, adverse effects may occur:
“[a]dministration of an opioid antagonist (e.g., naloxone, naltrexone) while receptors are still occupied by an agonist displaces opioids from their receptors and results in the sudden onset of withdrawal. If these symptoms are precipitated by naloxone, for example, when treating an opioid overdose, they typically resolve within 45 minutes because naloxone is short acting… It is also important to keep in mind that opioid withdrawal, particularly antagonist-precipitated withdrawal… may feature altered sensorium, disorientation, hypomania, and psychosis (34,35).”
(page 3, under “Antagonist-Precipitated Withdrawal”).
25. And, Cipriani et al. teach that haloperidol is an effective treatment for acute mania and psychosis, i.e., “[t]here is some evidence that haloperidol is an effective treatment for acute mania and it reduces psychotic symptoms when present and overall severity of psychiatric illness,” [emphasis added] (page 17, right column under “Implications for practice”).
26. As such, one skilled in the art would be motivated to administer haloperidol to mitigate the mania induced by naloxone treatment for opioid overdose rescue in a patient in need thereof.
27. And, Physicians’ Desk Reference teaches that the intramuscular administration of Haldol® (i.e., haloperidol) is utilized “for prompt control of the acutely agitated patient with moderately severe to very severe symptoms” (page 2336, middle column, under “Intramuscular Administration”). Thus, one of skill in the art seeking to treat a patient suffering from manic behavior would be motivated to administer haloperidol intramuscularly to obtain rapid relief of said mania.
As such, claims 1, 4, and 17 are prima facie obvious.
28. Claim 103 remains rejected under 35 U.S.C. 103 as being unpatentable over Kerensky et al., Addiction Science & Clinical Practice (2017), in view of FDA News Release (2014), in view of Sigmon et al., Am J Drug Alcohol Abuse (2012), in view of Cipriani et al., Cochrane Library (2010), and in view of Physicians’ Desk References (2001): Haldol (cited on Applicant’s IDS of February 9, 2023), and, further in view of Guidance for Industry and FDA Staff (2013).
Claim 103, as amended, is directed to a method of providing opioid overdose to a patient comprising:
administering to a patient identified in need of rescue from opioid overdose a therapeutically effective amount of opioid antagonist to counteract the opioid overdose, wherein the opioid antagonist is selected from the group consisting of naloxone, nalmefene, or a combination thereof, and another therapeutically effective amount of an antipsychotic agent to counteract a manic behavior, wherein the antipsychotic agent is haloperidol or a pharmaceutically acceptable salt thereof, and
wherein an autoinjector is used to concurrently administer both the opioid antagonist and the antipsychotic agent intramuscularly to the patient.
29. Kerensky et al. teach the administration of naloxone, a potent opioid antagonist, for emergency treatment of known or suspected opioid overdose (page 2, left column, first paragraph). A patient that has overdosed on opioids meets the limitation of a patient identified in need of rescue from opioid overdose, required by claim 103. Kerensky et al. additionally teaches that naloxone can be administered intramuscularly (IM), (page 2, left column, first paragraph). And FDA teaches the advantages of administering naloxone via auto-injector:
“Evzio® (naloxone hydrochloride injection) rapidly delivers a single dose of the drug naloxone via a hand-held auto-injector that can be carried in a pocket or stored in a medicine cabinet.
It is intended for the emergency treatment of known or suspected opioid overdose, characterized by decreased breathing or heart rates, or loss of consciousness.
Evzio® is the first combination drug-device product designed to deliver a dose of naloxone for administration outside of a health care setting. Making this product available could save lives by facilitating earlier use of the drug in emergency situations.”
(FDA 2014, page 1).
As such, one of skill in the art would be motivated to administer naloxone to a patient in need thereof via auto-injector based on safety, portability and efficiency of emergency administration outside of a hospital setting.
30. Kerensky et al. are silent to the administration of haloperidol.
31. However, Sigmon et al. teach that when naloxone is administered for opioid overdose rescue, adverse effects may occur:
“[a]dministration of an opioid antagonist (e.g., naloxone, naltrexone) while receptors are still occupied by an agonist displaces opioids from their receptors and results in the sudden onset of withdrawal. If these symptoms are precipitated by naloxone, for example, when treating an opioid overdose, they typically resolve within 45 minutes because naloxone is short acting… It is also important to keep in mind that opioid withdrawal, particularly antagonist-precipitated withdrawal… may feature altered sensorium, disorientation, hypomania, and psychosis (34,35).”
(Page 3, under “Antagonist-Precipitated Withdrawal”).
32. And, Cipriani et al. teach that haloperidol is an effective treatment for acute mania, i.e., “[t]here is some evidence that haloperidol is an effective treatment for acute mania and it reduces psychotic symptoms when present and overall severity of psychiatric illness,” [emphasis added] (page 17, right column under “Implications for practice”).
33. As such, one skilled in the art would be motivated to administer haloperidol to mitigate the mania induced by naloxone treatment for opioid overdose rescue in a patient in need thereof.
34. And, Physicians’ Desk References teaches that the intramuscular administration of Haldol® (i.e., haloperidol) is utilized “for prompt control of the acutely agitated patient with moderately severe to very severe symptoms” (page 2336, middle column, under “Intramuscular Administration”). Thus, one of skill in the art seeking to treat a patient suffering from manic behavior would be motivated to administer haloperidol intramuscularly to obtain rapid relief of said mania.
35. FDA Staff 2013 teaches the advantages of auto-injectors:
“Pen, jet, and related injectors may provide an innovative approach to deliver drugs or biological products, and they may enhance safety, improve dosing accuracy, and increase patient compliance, particularly in self-administration settings. For example, these injectors are designed to provide an accurate method of injecting a dose of drug/biological product contained in a cartridge, reservoir, or syringe through an automatically or manually inserted hypodermic needle(s) or through a high velocity jet.
They are intended for use by a healthcare provider or for self-administration by a patient. Injectors may be designed for single use or multiple uses, and may be disposable or reusable. For example, a single use injector may be used in acute intervention for treatment or prevention while a multi-dose injector may be used as part of a single patient long term treatment regimen.”
(See under Background, page 4).
36. As such, one of skill in the art seeking to administer haloperidol intramuscularly as an acute intervention “to counteract a manic behavior” would reasonably consider utilizing an auto-injector. And, one skilled in the art would be motivated to administer naloxone and haloperidol concurrently with said auto-injector for enhanced safety, improved dosing accuracy, and increased patient compliance.
As such, claim 103 is prima facie obvious.
Response to Arguments
37. Applicant traverses the previous obviousness rejection of claims 1, 4, and 17, over Kerensky, in view of Sigmon and Cipriani, and further in view of “Haldol”. Applicant has amended claims 1 and 103 to recite that the opioid antagonist and the antipsychotic agent are “concurrently administered.”
Applicant previously submitted that the Physicians Desk Reference "Haldol" reference (page 2335, first column, lines 18-20) states that "haloperidol is contraindicated in severe toxic central nervous system depression or comatose states from any cause." Applicant argued that the one of skill in the art “readily understands that a patient identified in need of rescue from opioid overdose falls under the category of subjects with severe toxic nervous system depression or comatose states. Applicant notes that the "Haldol" reference further states (page 2335, middle column, fifth to last paragraph)"[a]s with other antipsychotic agents, it should be noted that Haldol may be capable of potentiating CNS depressants such as anesthetics, opiates, and alcohol," such that the "Haldol" reference not only teaches that haloperidol should not be used when a patient is in severe toxic nervous system depression or comatose state from any cause (such as the instant claimed opioid overdose), but also points out that haloperidol could potentiate the CNS depressant effects of an opiate, an effect opposite to those desired by the present invention.” (Applicant’s Remarks, page 2).
Applicant contends that that the current rejection is unjustly using the benefit of hindsight to reconstruct the invention and is ignoring affirmative teaching of the prior art. Applicant alleges that the prior art clearly states that that haloperidol potentiates the CNS depressant effects of an opiate and is using the claimed invention as a roadmap to recreate the invention. In making the rejection, the Office Action relied upon Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989) and states that "a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments." Applicant submits that in view of the prior art teaching that haloperidol potentiates CNS depressant effects of an opiate, it would be unreasonable for a skilled artisan to administer such an agent to a patient experiencing opiate overdose.
Applicant argues that a previous Office Action further stated that "[t]he prior art's mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed .... " In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). Applicant submits that In re Fulton is not applicable as the prior art does not teach or suggest two alternatives, wherein one of the alternatives is the combination of an antipsychotic agent with an opioid antagonist to provide opioid rescue as recited in the present claims.
38. Applicant's arguments have been fully considered but they are not persuasive. In response to Applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In this case, one of skill in the art before the effective filing date of the claimed invention would have had awareness that naloxone administration for opioid overdose rescue can result in symptoms of mania and psychosis, which would then necessitate the administration of an antipsychotic, with a reasonable expectation of success.
Regarding Applicant’s argument in opposition to the Haldol reference, i.e., that “the prior art clearly states that that haloperidol potentiates the CNS depressant effects of an opiate,” it is noted that a non-enabling reference may qualify as prior art for the purpose of determining obviousness under 35 U.S.C. 103, (Symbol Techs. Inc. v. Opticon Inc., 935 F.2d 1569 (Fed. Cir. 1991)).
39. And, following opioid overdose, Rech et al. support the use of both naloxone and an antipsychotic such as haloperidol to treat symptoms of aggression and psychosis:
“…naloxone may be used as an antidote for desomorphine overdose. Symptoms of aggression and psychosis may be treated with sedation (benzodiazepines, propofol) and antipsychotics (haloperidol or atypical agents such as quetiapine or ziprasi done).”
(Pharmacotherapy 2015, page 196, left column, last paragraph).
40. As stated previously, Applicant’s arguments are predicated on the combined, concurrent administration of naloxone and haloperidol, however the instant claims are not limited to this combination in the amounts demonstrated in the Specification in Example 1 and Example 2. According to MPEP 716.02(d), the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In this case, the claims as drafted presently embrace the administration of an opioid antagonist selected from the group consisting of “naloxone, nalmefene, and a combinations thereof” [sic] in any dosage amount, and the antipsychotic agent haloperidol in any dosage amount; however, the disclosure in the Specification is limited to the administration of: the combination of nalmefene at a dose of 4 mg with haloperidol at a dose of 80 mg (Example 1); and the combination of naloxone at a dose of 2 mg with haloperidol at a dose of 80 mg (Example 2).
As such, the previous obviousness rejection is maintained.
Conclusion
41. In conclusion, claims 1, 4, 6, 17, 18, and 103 are present in the application. Claims 6 and 18 are presently withdrawn from consideration as directed to non-elected species. Claims 1, 4, 17, and 103 are rejected. Claims 1 and 4 are objected to. No claim is currently allowable.
42. THIS ACTION IS MADE FINAL. 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.
42. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached Monday-Friday 8:30AM-5PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JANET L COPPINS/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
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