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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/17/2026 has been entered.
Status of Claims
Claims 1, 3-12, and 20-28 are pending.
Priority
Instant application 17/637,512, filed 02/23/2022 claims priority as follows:
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Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
All references from IDS(s) received 08/26/2022, 04/17/2025, 07/28/2025, and 02/17/2026 have been considered unless marked with a strikethrough.
Response to Amendment/Arguments
The amendment filed 02/17/2026 has been entered. Applicant has amended claim 1.
Claim 1 was previously objected to in the Office action mailed 10/17/2025. In view of the amendment to claim 1, applicant has overcome the objection. Therefore, the prior objection to claim 1 is withdrawn.
Claims 1, 3-12, and 20-28 were previously rejected under 35 U.S.C. 103 as being unpatentable over Pedersen (US 20130085106 A1, published 2013) in view of McGregor (WO2017004674A1, published 2017). Applicant’s arguments filed 02/17/2026 have been fully considered and are persuasive. See the Remarks at pages 6-12.
In particular, the claimed method of treating opioid withdrawal or symptoms of that withdrawal using compounds of Formula (I) is not obvious over the cited references because the references, taken together, fail to provide a reasonable expectation of success for the claimed indication. Pedersen teaches that oxytocin receptor (OTR) agonism can alleviate opioid withdrawal symptoms through a specific receptor-mediated mechanism (abstract, para. [0040], para. [0022]). However, McGregor expressly discloses at [0220] that SOC-1 (the compound of Formula (I) recited in claim 3) is not an OTR agonist, nor an OTR antagonist, and not a positive allosteric modulator of the OTR, and that screening against numerous receptors and transporters failed to identify its molecular target. Because the compounds of Formula (I) operate through a fundamentally different and unknown mechanism from the direct OTR agonism taught in Pedersen, a person of ordinary skill could not have connected these references with a mechanistic rationale to predict that compounds of Formula (I) would be effective against the specific physical and/or somatic symptoms of opioid withdrawal. The pharmaceutical arts are recognized as unpredictable, and the Federal Circuit has consistently held that a reasonable expectation of success requires more than speculation, particularly when the proposed modification involves a compound with no identified target acting through an uncharacterized pathway. See MPEP 2143.02.
While McGregor at para. [0219] notes that SOC-1 produces an “overall similar” pattern of neural activation and behavioral effects as oxytocin in prosocial behavior models, that same paragraph discloses that SOC-1 also activates brain regions that oxytocin does not, suggesting a divergent pharmacological signature. A POSITA would have recognized that phenotypic similarity in prosocial behavior and drug self-administration assays does not reliably predict therapeutic equivalence in the mechanistically distinct context of opioid withdrawal, which involves symptoms mediated by specific neural circuits not studied in McGregor. Moreover, McGregor demonstrates SOC-1’s efficacy only in models of voluntary drug-seeking behavior, a pharmacologically distinct phenomenon from the acute physiological withdrawal syndrome claimed in the instant application. The instant application’s examples 1-4 demonstrate that SOC-1 dose-dependently inhibits somatic withdrawal signs (e.g. jumping, paw tremors, diarrhea) and modulates neural activation in eight withdrawal-related brain regions (e.g. central amygdala, lateral parabrachial nucleus, lateral septum, etc.). These results were not predictable from the prior art.
Therefore, the prior rejection under 35 U.S.C. 103 is withdrawn.
Claims 1, 3-12, and 20-28 were previously rejected on the ground of nonstatutory double patenting as being unpatentable over U.S. Patent No. 11,890,287 in view of Pedersen. The ‘287 patent is an issued patent in the same family as the McGregor publication discussed above. For the same reasons identified above, the prior nonstatutory double patenting rejection is withdrawn.
Claims 1, 3-12, and 20-28 were previously rejected on the ground of nonstatutory double patenting over U.S. Patent No. 11,033,555 in view of Pedersen. The ‘555 patent is an issued patent in the same family as the McGregor publication discussed above. For the same reasons identified above, the prior rejection nonstatutory double patenting rejection is withdrawn.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-12, and 20-28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), the following factors are considered to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Breadth of the claims:
The claims encompass a method of treating opioid withdrawal or a symptom associated with the opioid withdrawal, comprising administering to a subject in need thereof an effective amount of a compound of formula (Ia), or a pharmaceutically acceptable salt and/or prodrug thereof. The choices for Z (NH, O, S, S(O), SO2) in formula (Ia) represent fundamentally different pharmacophores. An NH bridge and an SO2 bridge create different electronic environments, hydrogen-bonding profiles, and steric properties. Combined with extensive R2 and R3 variability (including open-ended “optionally substituted” language without enumerating the optional substituents), the genus encompasses a large number of compounds. The open-ended “prodrug” coverage further expands the claim scope. Further, the claim encompasses treating any symptom of or “associated with” opioid withdrawal (20+ enumerated symptoms plus the open-ended “associated with” language”), in any subject, by any route, at any effective dose.
Nature of the invention:
The invention relates to a new therapeutic use (treating opioid withdrawal) with a genus of compounds with an unknown mechanism of action. The specification characterizes the discovery as “surprising” (page 9, lines 10-13). The application does not disclose any receptor binding data, target engagement studies, or any mechanistic rationale for the compounds of formula (Ia).
State of the prior art and predictability in the art:
Relevant prior art includes MCGREGOR (WO 2017004674 A1; cited previously) and KASSIOU (WO 2018107216 A1; cited in IDS).
MCGREGOR teaches the Formula (Ia) genus for treating social disorders and substance use disorders. MCGREGOR only tested SOC-1/Compound 1 and disclosed that SOC-1 is not an OTR agonist, antagonist, or positive allosteric modulator (para. [0220]). The molecular target is unknown despite screening against numerous receptors and transporters. The compound activates oxytocinergic signaling through an unidentified upstream mechanism. MCGREGOR does not teach treating opioid withdrawal.
KASSIOU teaches a structurally related family of pyrazolo-benzodiazepine compounds, sharing the same core scaffold of Formula (Ia), as confirmed, direct OTR agonists. The inventors used IP1 accumulation assays in OTR or ViaR-expressing HEK-293 cells to characterize receptor activity. Multiple compounds were tested and shown to have measurable OTR agonist potency.
Taken together, MCGREGOR and KASSIOU establish that within the same core pyrazolo-benzodiazepine chemical space from which Formula (Ia) is drawn, small structural modifications produce compounds with fundamentally different mechanisms of action. Some derivatives are direct OTR agonists (KASSIOU). Others, like SOC-1, are not OTR agonists at all and work through an unknown target (MCGREGOR). A skilled artisan reading the prior art would understand that the Formula (Ia) genus is mechanistically heterogeneous, i.e., different genus members almost certainly operate through different pharmacological pathways. This heterogeneity eliminates any basis for assuming that untested genus members would share the withdrawal-attenuating activity demonstrated only for SOC-1.
The prior art demonstrates that structurally similar pyrazolo-benzodiazepines can have mechanistically divergent pharmacological profiles. Therefore, even within the genus of Formula (Ia), a skilled artisan cannot predict whether (i) a given genus member will act as a direct OTR agonist, an indirect oxytocin modulator (like SOC-1), or something else entirely; or (ii) if it acts through the same unknown mechanism as Compound 1, it would retain sufficient potency to be therapeutically effective. Without knowing the target of SOC-1, there is no way to screen compounds (computationally or biochemically). The only path is full behavioral testing in the animal withdrawal model (for each compound and/or each prodrug thereof).
Pharmacological activity in general is a very unpredictable area. Note also that in cases involving physiological activity, such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
Level of ordinary skill in the art:
The person of ordinary skill would be a medicinal chemist or pharmacologist or with an advanced degree (e.g. Ph.D.) and possess several years of professional experience, with some familiarity for opioid receptor pharmacology and preclinical animal models of opioid withdrawal. Such a person would recognize the unpredictability of CNS pharmacology, particularly when the molecular target is unknown.
The amount of direction provided:
The specification provides limited direction for compounds of Formula (Ia) and symptoms associated withdrawal. 16 species compounds are enumerated on pages 21 and 22. Symptoms are discussed in the specification at page 29, lines 11-30 and page 30, lines 1-20. A broad general dosage range is provided (0.001-30 mg/kg).
Existence of working examples:
The specification’s working examples (Examples 1-4) test only Compound 1 (CMPD1-2HCl and CMPD1-PO4) in a mouse naloxone-precipitated oxycodone withdrawal model. No other Formula (Ia) compound is tested, synthesized, or specifically identified as active. The specification provides no SAR data, no receptor binding data, no target identification, and no mechanistic rationale for extrapolation within the genus. The specification provides no working examples of “prodrugs” of compounds of Formula (Ia). Notably, the MCGREGOR similarly only tested SOC-1/Compound 1. No other compound has been tested.
Regarding symptoms “associated with” opioid withdrawal, the working examples address only somatic symptoms of withdrawal (jumping, tremors, diarrhea). Psychological symptoms (dysphoria, anxiety, insomnia, hallucinations) are covered by the claims but are not supported by any working examples.
See MPEP 2164.02 (“Compliance with the enablement requirement of 35 USC 112, first paragraph, does not turn on whether an example is disclosed ... Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art”).
Quantity of experimentation needed to use the invention based on the content of the disclosure:
The quantity of experimentation needed is undue experimentation. The numerous compounds encompassed by the claim 1 genus require individual synthesis and full behavioral testing in an animal model. The molecular target of the compounds of Formula (Ia) is unknown, preventing target-based screening. Additionally, no SAR data exist to prioritize or deprioritize any structural subset.
Synthesizing and testing hundreds, or thousands, of compounds in a multi-day mouse model of opioid withdrawal, each requiring opioid dosing, compound dosing, naloxone challenge, and behavioral scoring by a blinded experimenter is not routine. It constitutes a systematic research program, not routine optimization.
Therefore, in view of the factors discussed above, claims 99 and 102 are rejected as failing to comply with the enablement requirement.
Consistent with MPEP 2164.04 and in the interest of compact prosecution, the examiner recommends narrowing the chemical genus to SOC-1 or a pharmaceutically acceptable salt thereof (i.e. claim 3, removing prodrug); and narrowing the symptom scope to those which are well-supported by the working examples.
Claim Rejections - 35 USC § 112(b)
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 1, 3-11, and 20-27 are 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.
The phrase “a symptom associated with the opioid withdrawal” fails to inform one of ordinary skill in the art, with reasonably certainty, of the scope of the claimed invention. The term “associated with” denotes a relationship of unspecified type and strength between the symptom and the withdrawal condition. The specification does not define this phrase, does not distinguish it from “symptom of opioid withdrawal”, and does not provide a standard for determining which symptoms fall within its scope and which do not. Every symptom discussed in the specification (see, e.g. page 29, lines 11-30 and page 30, lines 1-20) is a recognized clinical symptom of opioid withdrawal, yet the claim uses broader relational language that could encompass secondary, downstream, comorbid, protracted, or merely correlated conditions. A person of ordinary skill in the art cannot determine, with reasonable certainty, whether treating a condition that co-occurs with but is not a recognized criterion of opioid withdrawal would fall within the claim scope.
In the interest of compact prosecution, the examiner suggests amending “a symptom associated with the opioid withdrawal” to “a symptom of opioid withdrawal” to align the claim language with the specification’s actual disclosure and with the art-recognized symptoms. Alternatively, the examiner suggests amending the claim to introduce particular symptoms recited in claim 12 or 28, particularly in view of the lack of working examples for treating psychological symptoms (e.g. dysphoria, anxiety, insomnia, hallucinations, etc.) noted above in the enablement rejection.
18/044,190
Claims 1, 3-12, and 20-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 36 of copending Application No. 18/044,190 (“the ‘190 application”).
The ‘190 application recites salts of SOC-1 and crystal forms. Claim 36 recites a method for treating or preventing opioid withdrawal and/or a symptom thereof in a subject comprising administering SOC-1. Accordingly, claims 1, 3-12, and 20-28 are directed to subject matter which is recited in the ‘190 application.
This is a provisional nonstatutory double patenting rejection.
Please note that the instant application has the earlier patent term filing date over the ‘190 application. See MPEP 804(I)(B)(1)(b) in this regard:
(b) Provisional nonstatutory double patenting rejection is the only rejection remaining in a utility or plant application
Subsections (i)-(iv) below discuss examination procedures when two or more utility or plant patent applications, filed on or after June 8, 1995, contain provisional nonstatutory double patenting rejections over each of the other application(s). The explanations refer to pairs of applications, but also apply when more than two applications are involved.
(i) Application under examination has the earlier patent term filing date
If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent.
Conclusion
Claims 1, 3-12, and 20-28 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 10:00 am - 6:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621