DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status of the Application
This Office Action is in response to applicant’s arguments filed on 4/7/26. Claims 1-51, 64-68 have been cancelled. Claims 52-63 are pending. Claim 52 has been amended. Claims 52-63 are examined herein.
The claim amendments have rendered the 103 rejection of the last Office Action moot, therefore hereby withdrawn. The following new rejection will now apply.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived 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 pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 52-63 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Smith (US Patent 6,207,674, of record) in view of Bell (Diabetes, obesity and Metabolism vol. 15, pp.291-300; Published Online Oct 2012, of record), Akerele et al. (Am J. Addict (2008), vol. 17, pp.176-180, of record), Morphine Dosage (Drug.com, 2010 p.1-7, of record), and Babul (US Patent Application 2010/0249045, of record).
The instant claims are drawn to a composition consisting of a NMDA antagonist (dextromethorphan), a CYP2D6 inhibitor (quinidine), and morphine in the claimed ratios.
Smith taught a patient taking narcotic pain-killer (morphine sulfate) and two-antidepressants [col. 7, ln 10-21]. The treatment regimen was administered a combination dextromethorphan and quinidine [col.7, ln 37-40]. The combination of dextromethorphan (30 mg) and quinidine (75 mg) packaged together in single capsules and administered twice daily [col. 7, ln 52-55]. Dextromethorphan in combination with morphine potentiate the pain-relieving effects of morphine and allowing such patients to use lower doses dosages of morphine [col. 7, ln 30-34]. In addition, quinidine along with dextromethorphan can increase the level of dextromethorphan in the blood of the patient [col. 7, ln 35-37].
However, Smith does not explicitly teach a composition consisting of dextromethorphan hydrobromide monohydrate, quinidine sulfate, morphine sulfate, and the claimed ratio of 1:1:1.
Bell teaches the advantages of fixed combination therapy offers the alternative to separately dispensed, individual medication [i.e., loose-pill combinations (LPCs)] and have four key advantages that directly contribute to improved medication concordance [p.291, col. 2, para.2]. First, they offer a means by which the number of medications and the dosing/timing schedule may be simplified, which reduces the frequency of missed doses [p.291, col. 2, para.2]. Second, lower doses of two agents in fixed combinations may offer greater efficacy in combination than that achieved with a higher or maximal dose of a single agent [p.291, col.2, para. 2]. Third, when treatment (in this case glycaemic) goals are obtained utilizing lower doses of agents in combination, the risk of adverse events that are more likely to occur with the higher doses of monotherapy can be avoided [p.291, col.2, para.2]. Lastly, from a practical perspective, fixed combinations are typically less costly than free combination of the two agents and should offer a financial advantage for patients, since the cost of fixed combination often is more than the cost of one the monotherapies [p.291, col.2, para. 2].
Akerele et al. teaches dextromethorphan and quinidine combination for heroin detoxification [title]. Participants were randomly assigned to receive a dextromethorphan/quinidine (30mg/30 mg) single capsule daily [p.3, para. 1].
Drugs.com teaches that immediate release tablets of morphine are commercially available at an initial dose of 15 to 30 mg orally every 4 hours as needed [p.1].
Babul et al. teaches oral pharmaceutical compositions of opioid agonists [abstract and entire document]. The compositions and methods include (i) one or more abusable drugs (i.e., one or more opioid agonist); and (ii) ADER and (iii) optionally other therapeutic agents [0091]. The term "abusable drugs”, are limited to one or more "opioid agonist” or “opioid receptor agonist” [0061]. Opioids agonist include morphine and pharmaceutical acceptable salts such as morphine sulfate [0385, example 15 and 17]. The ADER, other abuse deterrent or abuse resistant substances include one or more aversive agents such as bittering agents [0408]. Bittering agents include quinidine [0414]. A co-administered drug (in the same or different dosage form, by any route if administration) may be used to provide additive, complementary, superadditive or synergistic therapeutic analgesic effects including NMDA receptor antagonist such as dextromethorphan [0438]. “Pharmaceutically acceptable salts” are well known in the art and include those of inorganic acids, such as hydrochloride, sulfate, hydrobromide and phosphate; and those of organic acids, such as formate, tartrate [0052]. Therefore, dextromethorphan hydrobromide monohydrate and quinidine sulfate are obvious absent a showing of unexpected results.
A person of ordinary skill in the art at the time of the invention would have found it prima facie obvious to develop a pharmaceutical composition consisting of dextromethorphan, quinidine and morphine sulfate because Smith taught administering an oral dose of dextromethorphan and quinidine composition to a patient taking morphine sulfate and Bell teaches the advantages of combining several pharmaceutical agents into a single pharmaceutical compositions. The skilled artisan would have understood the therapeutic benefits of combining morphine sulfate, dextromethorphan and quinidine and formulating into a single oral composition because Smith taught that dextromethorphan in combination with morphine potentiate the pain-relieving effects of morphine and allowing such patients to use lower doses dosages of morphine and quinidine along with dextromethorphan can increase the level of dextromethorphan in the blood of the patient assisting in the pain-relieving effects of morphine. Also, the skilled artisan would have been motivate to combine three pharmaceutical active agents because Bell taught that dosing/timing will be simplified, lower doses of several agents fixed combinations may offer greater efficacy and using lower doses reduces the risk of adverse effects. Therefore, the skilled artisan would have found ample motivation and instruction to formulate a pharmaceutical composition comprising of dextromethorphan, quinidine and morphine sulfate from the teachings of Smith in combination with Bell since Smith taught the therapeutic benefits associated with simultaneous administration of morphine, dextromethorphan and quinidine and how such combination unweans/ lowers the dose of morphine in a patient. Bell teaches the advantage of fixed dose combination therapies which include dosing/timing schedule which may be simplified (which reduces the frequency of missed doses) as well as lower costs to the patient.
In regards to the limitation wherein the composition comprises morphine:dextromethorphan:quinidine in a ratio of 1:1:1, the teaching of Smith demonstrates a combination of 30 mg dextromethorphan and 75 mg of quinidine and Akerele et al. demonstrates that a single capsule dose of dextromethorphan/ quinidine at 30 mg each component. The skilled artisan would have found ample motivation and instruction to include the ratio of dextromethorphan to quinidine in that the amount instantly claimed since the teachings of Smith demonstrates including dextromethorphan in lower ratio than quinidine and Akerele et al. taught to incorporate dextromethorphan to quinidine in equal amounts. Therefore, the amounts taught by Smith and Akerele et al. overlap with the instantly claimed ratios. The instantly claimed amounts of morphine (opioid agonist) fall within the range of acceptable amounts administered as taught by drugs.com (15 mg to 30 mg every 4 hours) and further the prior art emphasis that morphine should be administered as needed. Such teachings provide instruction and motivation to formulate an oral dosage of morphine incorporating the amounts instantly claimed since such amounts are incorporate in commercially available oral dosages. In regard to the ratios of morphine to dextromethorphan and quinidine the teachings of Smith in view of Akerele et al. and Drugs.com demonstrate the therapeutic benefits of administering all three pharmaceutical actives in combination, further taught an overlapping amount ratio of quinidine and dextromethorphan and morphine can be administered as needed by the patient. Furthermore, Smith taught using the combination of dextromethorphan/quinidine to wean off a patient form pain-relieving narcotic such as morphine sulfate, which would have been expected to be included in the pharmaceutical composition in higher ratio for the therapeutic benefits of the combination with dextromethorphan and quinidine. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) See MPEP 2144.05 (I).
It would, therefore, have been prima facie obvious to a person of ordinary skill in the art to modify the teachings disclosed by Smith in view of Bell, Akerele et al. and Drugs.com with reasonable expectation of success. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art at the time the invention was made.
Conclusion
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Yong S. Chong whose telephone number is (571)-272-8513. The examiner can normally be reached Monday to Friday: 9 AM to 5 PM EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam Milligan, can be reached at (571)-270-7674. The fax phone number for the organization where this application or proceeding is assigned is (571)-273-8300.
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/Yong S. Chong/Primary Examiner, Art Unit 1623
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