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 .
DETAILED ACTION
Claims 1, 4, 7, 10, 15 and 21-24 are pending in the instant application.
Claims 1, 4, 7, 10, 15 and 21-24 are examined herein.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 12 March 2026 is acknowledged and considered.
Response to arguments of 23 February 2026
Applicant’s arguments (Remarks of 23 February 2026, pages 4-6) against the rejection of claims 1, 4, 7, 10, 15 and 21-24 under 35 U.S.C. 103 over Hauser, in view of Simons, in further view of Sokol, have been considered.
Applicant argues (page 5, second paragraph) that the Declaration under 37 CFR 1.132 submitted on February 2025 provides evidence of unexpected results.
In response, the Declaration under 37 CFR 1.132, signed by Ms. Jacqueline Iversen, co-inventor, submitted on 24 February 2025, was acknowledged and has been thoroughly considered in the office action mailed on May 30, 2025. These considerations are reproduced below, for Applicant’s convenience.
Ms. Iversen had argued unexpected results with the instantly claimed method, based on a literature reference by Verster et al. (post-filing data by inventor).
On 13 August 2024, Applicant submitted a reference by Verster et al. (2021) showing that, when a pharmaceutical composition consisting of ibuprofen and ketotifen as active agents (SJP-005) is administered about 48 hours before cessation of opioid administration (in a rat model), the composition is effective for inhibiting withdrawal symptoms, as compared to when the composition is administered on the same day as cessation of opioid administration (Figs. 3, 4, page 1457, right column).
In the office action mailed on 23 October 2024, the examiner noted that Verster et al. contains post-filing data, not present in the Specification as filed. The Specification does not show any advantage in administering the composition containing ibuprofen and ketotifen two days prior to the subject’s last dose opioid, as now claimed; the Specification teaches that the composition containing ibuprofen and ketotifen can be administered either before or after the subject’s last dose of opioid ([0028], [0029]). The Specification does not seem to focus on finding the ideal timing of treatment initiation with the composition of ibuprofen and ketotifen.
In the Declaration of 24 February 2025, Ms. Iversen, co-inventor, explains the methods used in the reference by Verster et al. (points 5, 6, Declaration), and presents the results (points 7, 8, Declaration) of the study.
Ms. Iversen argues (point 8, Declaration) that starting treatment with SJP-005, a pharmaceutical composition consisting of ketotifen and ibuprofen as active agents, before opioid cessation yields unexpectedly superior results. The studies showed that animals were withdrawal symptoms free at an earlier stage upon treatment with SJP-0005when compared to placebo; this effect was significant when SJP-005 was first administered 2 days before morphine cessation, but not when SJP-005 was first administered on the same day as morphine cessation (Fig. 3 vs. Fig. 4).
Thus, Ms. Iversen argues (Declaration, points 7, 8) unexpected results corresponding to a specific timing of treatment initiation, namely treatment beginning 48 hours (2 days) before the subject’s last dose of an opioid (as instantly claimed), in a method of inhibiting symptoms associated with opioid withdrawal with a pharmaceutical composition consisting of ketotifen and ibuprofen as active agents.
In response, the examiner acknowledges the data presented, but maintains that determining the timing of treatment initiation, [or the dose of active agents, or the length of treatment, or the frequency of drug administration] in order to optimize efficacy in a method of treatment, are well within the skill of the artisan, in this case the physician. Decisions related to treatment regimen in a known method of treatment, with a known drug, and decisions related to length of treatment regimen, or ideal timing of treatment initiation, are routinely made by doctors/medical practitioners.
Further, while Verster performs statistical analysis of the data and concludes that the reduction in opioid withdrawal symptoms was statistically significantly different from placebo when treatment with the composition containing ibuprofen and ketotifen (SJP-005) was initiated 2 days before morphine cessation (in rats) (page 1456, right column under Discussion), Verster also teaches that administration of SJP-005 4 days before morphine cessation was associated with a lower incidence of opioid withdrawal symptoms. Figure 4 also shows instances of reduction in number of withdrawal symptoms when SJP-005 is administered starting on the same day as morphine cessation. Although data may not be statistically significant, the data in Verster seem to support that SJP-005 is effective to treat opioid withdrawal symptoms when administered before or at the time of the subject’s last dose of opioid. The instantly claimed method of inhibiting symptoms associated with opioid withdrawal encompasses any reduction in symptoms, no matter how small, and does not require statistical significance over a patient population.
In response to the argument (points 10-11, Declaration) that Hauser teaches that ibuprofen was given in a separate administration for the patient's electric injury, for pain from his injury, Hauser administers a combination of hydroxyzine and ibuprofen to a patient suffering from opioid withdrawal. Hauser teaches administration of a drug combination- a H1 antihistamine which is hydroxyzine and ibuprofen- to the same patient population as instantly claimed- patient suffering from opioid withdrawal symptoms. Even though Hauser does not teach that ibuprofen is administered “to inhibit opioid withdrawal symptoms”, administration of the same drug combination to the same patient population is expected to have the same therapeutic effect.
Ms. Iversen argues (Declaration, point 12) that case 2 in Hauser is a single individual; the report only estimates the follow-up period; does not indicate whether the subject was entirely free of symptoms; the report does not guarantee that the subject was compliant with the regimen and free of opioid use; and withdrawal symptoms and their duration vary depending on the severity and length of the user’s addiction. In response, the instantly claimed method of inhibiting symptoms associated with opioid withdrawal encompasses any reduction in symptoms, no matter how small, and does not require statistical significance over a patient population.
In response to the argument (points 10, 13, Declaration) related to unexpected results with a combination of drugs ketotifen (or hydroxyzine in Hauser) and ibuprofen administered 48 hours before the last dose of an opioid is administered, the examiner’s position is that decisions related to treatment regimen in a known method of treatment, with a known drug, and decisions related to length of treatment regimen, or ideal timing of treatment initiation, are routinely made by doctors/medical practitioners. Determining the optimum timing of treatment initiation, [or the dose of active agents, or the length of treatment, or the frequency of drug administration] in order to achieve the best efficacy in a method of treatment, are well within the skill of the artisan, in this case the physician.
Applicant argues (Remarks of 23 February 2026, page 5, last two paragraphs, page 6, first paragraph) that Hauser does not teach that ibuprofen is administered to inhibit opioid withdrawal symptoms; rather, Hauser teaches oral ibuprofen administered to the patient for pain from his electrical injury. Applicant even argues that “there is no basis to assume that the subject in Hauser was experiencing opioid withdrawal symptoms”. In response, Hauser clearly teaches that hydroxyzine has been used successfully in clinical practice for 20 years to treat acute opioid withdrawal. This teaching by Hauser cannot be contested. Further, Hauser teaches administration of ibuprofen to treat pain in a patient suffering from opioid withdrawal. It is noted that pain is a symptom of opioid withdrawal. Since Hauser administers a combination of hydroxyzine and ibuprofen to a patient suffering from opioid withdrawal, Hauser teaches administration of a drug combination- a HI antihistamine which is hydroxyzine and ibuprofen- to the same patient population as instantly claimed- patient suffering from opioid withdrawal symptoms. Even though Hauser does not teach that ibuprofen was administered to treat pain as a symptom of opioid withdrawal in the patient, administration of the same drug combination to the same patient population is expected to have the same effect.
Applicant argues (page 5, last two paragraphs) that there is no suggestion in Hauser that ibuprofen should be taken for two to eight weeks, and that it is administered before the last dose of opioid is taken. In is maintained that decisions related to treatment regimen in a known method of treatment, with a known drug, and decisions related to length of treatment regimen (in this case 2 to 8 weeks), or ideal timing of treatment initiation, are routinely made by doctors/medical practitioners. Determining the optimum timing of treatment initiation, [or the dose of active agents, or the length of treatment, or the frequency of drug administration] in order to achieve the best efficacy in a method of treatment, are well within the skill of the artisan, in this case the physician.
For all the reasons above, the rejection of the claims under 35 U.S.C. 103 over Hauser, in view of Simons, in further view of Sokol, is herein maintained, and is reproduced below.
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 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 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.
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, 7, 10, 15 and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Hauser et al. (MD Magazine 2006, 52 (6), 1-7, https://www.mdmag.com/journals/resident-and-staff/2006/2006-06/2006-06_10, accessed 6 December 2019, cited in PTO-892 of 1 June 2023), in view of Simons et al. (WAO Journal 2008, 145-155, cited in PTO-892 of 1 June 2023), in further view of Sokol et al. (Ann Allergy Asthma Immunol 2013, 111 (6), 433-436, cited in PTO-892 of 1 June 2023).
Hauser teaches a method of inhibiting symptoms associated with opioid withdrawal in a human subject in need thereof (Case 2, page 5 of 7), comprising administering to the subject antihistamine hydroxyzine orally 50 mg 4 times daily, and oral ibuprofen 800 mg every 6 to 8 hours as needed, which corresponds to 2400 mg to 3200 mg daily, as in instant claims 1, 15, for pain, as in instant claim 10.
Hauser teaches that the subject had been taking 80 mg/day of methadone for the past 3 months and did not wish to return to this practice; on day 2 of hospitalization, the subject was started on hydroxyzine oral and oral ibuprofen, which seems consistent with hydroxyzine and ibuprofen being administered after last dose of opioid was taken.
Hauser teaches that, on day 3, he was feeling much better and had no symptoms of withdrawal; the subject was discharged with a prescription for oral hydroxyzine, which he self-tapered over the next week, and, at 5 months follow-up, the patient had a negative urine drug screen.
Hauser teaches (page 4 of 7, under Safety and side effects) that the authors have 20 years of experience with antihistamine hydroxyzine for the acute treatment of heroin, methadone and other opioid withdrawal; there have been no serious medical complications or deaths. Patients welcomed the relief from nausea, diarrhea, abdominal cramping and vomiting, which are GI symptoms associated with opioid withdrawal.
Hauser teaches that, once a clear diagnosis of opioid withdrawal has been established, the patient is started on a scheduled dose of oral hydroxyzine 50 to 100 mg 4 times daily; this protocol was used in hundreds of patients treated for opioid withdrawal who reported use of heroin, oxycodone, hydrocodone or methadone. Hausen teaches (page 4 of 7, under Clinical Experience with Hydroxyzine for Opioid Withdrawal) that this protocol offers a simple and safe method of withdrawal that alleviates major symptoms of opioid withdrawal.
Hauser does not teach ketotifen administered in the method, as in the instant claims, at a daily dose of 2 mg.
Hauser does not teach the method comprising administering 2400 mg to 3200 mg/day ibuprofen and 2 mg/day ketotifen, in a composition comprising 1200 mg to 1600 mg ibuprofen and 1 mg ketotifen, as in instant claim 4, 15, administered every twelve hours, as in instant claims 21, 22.
Hauser does not teach ibuprofen and ketotifen as a tablet, as in claim 7.
Hauser does not teach administration of therapeutic agents beginning 48 hours or less before the subject’s last dose of an opioid, as in instant claims 23, 24, during an opioid withdrawal period of two to eight weeks, as in the instant claims.
Simons teaches (Table 2) that hydroxyzine, ketotifen, cetirizine, desloratadine, fexofenadine, are H1 antihistamines.
Sokol teaches that the recommended dose of ketotifen is 1 mg twice daily, which corresponds to 2 mg/day ketotifen, as in instant claims 1, 15, administered as a composition comprising 1 mg ketotifen, as in instant claims 4, 15, every twelve hours, as in instant claims 21, 22.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Hauser and Simmons to arrive at the instant invention. The person of ordinary skill in the art would have motivated to administer ketotifen and ibuprofen in a method of inhibiting symptoms associated with opioid withdrawal, because Hauser teaches that H1 antihistamine hydroxyzine, in combination with NSAID ibuprofen, are effective to inhibit symptoms of opioid withdrawal, and Simmons teaches that hydroxyzine and ketotifen are H1 antihistamines. Thus, the person of ordinary skill in the art would have replaced H1 antihistamine hydroxyzine with another H1 antihistamine, which is ketotifen, in a combination with NSAID ibuprofen, and would have administered said combination to treat opioid withdrawal, with the expectation of achieving therapeutic effect.
Further, the person of ordinary skill in the art would have determined the daily dose of ibuprofen and ketotifen needed to achieve therapeutic effect, because such an optimization of drug dose in order to optimize therapeutic effect is well within the skill of the artisan. The person of ordinary skill in the art would have administered oral ibuprofen 2400 mg to 3200 mg daily, as taught by Hauser, for pain, in combination with ketotifen, and would have determined the daily dose of ketotifen to be used in the method, acknowledging that oral 1 mg/twice daily is safe and effective as antihistaminic (Sokol). One of ordinary skill would have adjusted the amounts of ibuprofen and ketotifen to be administered daily in the method of inhibiting symptoms associated with opioid withdrawal, and the frequency of administration, for example, twice as day, as in instant claims 21, 22 (as taught by Sokol), because determining the dose of therapeutic agents in order to obtain maximum therapeutic effect is routine optimization in any method of treatment.
Further, combining the two active ingredients in one unit dose as a tablet, as in instant claim 7, is obvious, because combining two known active ingredients in one tablet, is well within the skill of the artisan.
Further, starting administration of the drug regimen 48 hours before the last dose of opioid is taken, as in instant claims 23, 24, and continuing administration for an opioid withdrawal period of two to eight weeks, are obvious in a method of inhibiting symptoms of opioid withdrawal, because decisions related to treatment regimen in a known method of treatment, with a known drug, and decisions related to length of treatment regimen, or ideal timing of treatment initiation, are routinely made by doctors/medical practitioners. In this case, a person of ordinary skill in the art would have been motivated to administer the therapeutic agent before the subject’s last dose of opioid for prevention of opioid withdrawal symptoms, and would have optimized the length of the treatment regimen, because such optimization of timing of treatment initiation and length of treatment regimen in the method of treatment in order to optimize therapeutic effect, is routine, well within the skill of the artisan.
As such, claims 1, 4, 7, 10, 15 and 21-24 are rejected as prima facie obvious.
Conclusion
Claims 1, 4, 7, 10, 15 and 21-24 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IRINA NEAGU whose telephone number is (571)270-5908. The examiner can normally be reached Mon-Fri 8-5.
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/IRINA NEAGU/Primary Examiner, Art Unit 1629