DETAILED ACTION
Claims 1-20 are pending in the instant application.
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 .
Priority
The instant application is a CON of PCT/US2023/069286 filed 06/28/2023 which claims priority to the U.S. Provisional Application Serial No. 63/357471 filed June 30, 2022.
Information Disclosure Statement
The information disclosure statement (IDS) is in compliance with the provisions of 37 CFR 1.97, except where noted. Accordingly, the information disclosure statement was considered by the examiner. Please see attached initialed Forms 1449.
Claim Rejections - 35 USC § 103
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.
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Tabuteau (US 2020/0338022 A1), Nofziger (Evaluation of dextromethorphan with select antidepressant therapy for the treatment of depression in the acute care psychiatric setting, mhc, 2019), and Kotlyar et al. (Inhibition of CYP2D6 activity by bupropion, J Clin Psychopharmacol. 2005).
Tabuteau discloses dosage forms, drug delivery systems, and methods related to sustained release of dextromethorphan with bupropion (Abstract). The combination of dextromethorphan and bupropion is a novel and oral NMDA receptor antagonis with multimodal activity for the treatment of central nervous system (CNS) disorders ([0231]). Tabuteau discloses a method of treating neurological disorder comprising administering about 150 mg/day to about 300 mg/day of bupropion and about 15 mg/day to about 60 mg/day of dextromethorphan ([0043]). Tabuteau discloses that dextromethorphan is rapidly metabolized in the human liver. This rapid hepatic metabolism may limit systemic drug exposure in individuals who are extensive metabolizers. Human beings can be: 1) extensive metabolizers of dextromethorphan-those who rapidly metabolize dextromethorphan; 2) poor metabolizers of dextromethorphan- those who only poorly metabolize dextromethorphan; or 3) intermediate metabolizers of dextromethorphan ([0135]). Another potential benefit of co-administration of dextromethorphan and bupropion is that it may be useful to reduce the potential for an adverse event, such as somnolence, associated with treatment by dextromethorphan. This may be useful, for example, in human patients at risk of experiencing adverse events as a result of being treated with dextromethorphan ([0336]). A therapeutically effective amount of a therapeutic compound may vary depending upon the circumstances. For example, a daily dose of dextromethorphan may in some instances range from about 0.1 mg to about 1000 mg ([0439]). A daily dose of bupropion may in some instances range from about 10 mg to about 1000 mg ([0440]).
Nofziger discloses that dextromethorphan (DMX) is extensively metabolized via CYP2D6 (Abstract). Current literature suggests DMX has preliminary efficacy when combined with a CYP2D6 inhibitor (pg 77, left col, 2nd to last paragraph).
Kotlyar conducted a study to assess the effect of bupropion on CYP2D6 activity; twenty-one subjects completed the study in which dextromethorphan was administered to smokers at baseline and after 17 days of treatment with either bupropion or placebo. Those receiving dextromethorphan and bupropion, dextromethorphan/dextrorphan (active metabolite) ratio increased significantly. Bupropion is a potent inhibitor of CYP2D6 (Abstract).
Tabuteau discloses a combination therapy (dextromethorphan/bupropion) for treatment of CNS disorders. Nofziger discloses that dextromethorphan with a CYP2D6 inhibitor has been used within the art. Kotlyar discloses that dextromethorphan with bupropion has synergistic effects. Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined teachings of above to arrive at a method of treating a CNS disorder by administering a combination of dextromethorphan and bupropion. Since bupropion inhibits CYP2D6, a clinician would routinely consider decreasing the dose of the combination therapy to avoid side effects. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claim 2, Tabuteau discloses that Phenotypic determination of dextromethorphan metabolizer status was performed by calculating the dextromethorphan/ dextrorphan metabolic ratio as described in Jurica et al. Journal of Clinical Pharmacy and Therapeutics, 2012, 37, 486-490. Plasma concentrations of dextromethorphan and dextrorphan 3 hours after dosing were used, with a dextromethorphan/dextrorphan ratio of 0.3 or greater indicating a poor metabolizer phenotype ([0672]). Likewise, one of ordinary skill in the art would determine the phenotype of dextromethorphan metabolism before administering such a drug.
Regarding claim 3, the dose is discussed above. Furthermore, one of ordinary skill in the art would routinely adjust the dosage of a drug being administered if such a drug is metabolized by CYP.
Regarding claim 4, the dose is taught above.
Regarding claim 5, Tabuteau discloses that the dextromethorphan is an immediate release (claim 5).
Regarding claim 6, Tabuteau discloses that bupropion is formulated as sustained release (claim 6).
Regarding claims 7-8, decreasing the dosage (for example from twice daily administration to once daily administration) of the combination therapy for poor CYP2D6 metabolizers would be an obvious consideration from a clinician. A poor CYP2D6 metabolizer would have an increased plasma level of dextromethorphan and thus an increase in AUC level. One of ordinary skill in the art would routinely adjust the dose as needed.
Regarding claim 9, Tabuteau discloses that a method includes once or twice daily administration ([0093]).
Claims 10-20 are rejected under 35 U.S.C. 103 as being unpatentable over Tabuteau (US 2020/0338022 A1), Nofziger (Evaluation of dextromethorphan with select antidepressant therapy for the treatment of depression in the acute care psychiatric setting, mhc, 2019), and Kotlyar et al. (Inhibition of CYP2D6 activity by bupropion, J Clin Psychopharmacol. 2005) as applied to claims 1-9 above, and further in view of Wells et al. (Investigation into the Dissolution Rate Increase on Storage of Wellbutrin SR® 100 mg Tablets, AAPS PharmSciTech, 2010).
Wells discloses composition and attributes of bupropion tablets – bupropion, Hypromellose, microcrystalline cellulose, cysteine hydrochloride monohydrate are mixed to create the composition (pg 115, Tabe 1).
Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined teachings of above to create a dosage form of dextromethorphan and bupropion mixed with cysteine hydrochloride monohydrate. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claim 11, microcrystalline cellulose is routinely used to create pharmaceutical products.
Regarding claim 12, Wells discloses bupropion tablets.
Regarding claims 13-14, adjusting doses is a routine clinical practice for various patients, including different CYP metabolizers. If a drug (dextromethorphan) is metabolized by a CYP enzyme, a poor or extensive metabolizer of such an enzyme would require dose adjustments. Tabuteau discloses figures depicting mean AUC levels for subjects administered dextromethorphan alone or dextromethorphan and bupropion. One of ordinary skill in the art would easily envisage that AUC levels would be different for different treatment groups, phenotype of CYP metabolism, among other characteristics.
Regarding claims 15-19, Tabuteau discloses a method of treating depression ([0094]), agitation, anxiety ([0145]); agitation in Alzheimer’s disease ([0245]), agitation in dementia ([0248]), neuropathic pain ([0268]), generalized anxiety disorder ([0147]).
Regarding claim 20, Tabuteau discloses treatment-emergent adverse event such as falls for people taking dextromethorphan and bupropion. Such an adverse event would be closely monitored clinically.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Although the claims at issue are not identical, they are not patentably distinct because applications claim a method of co-administering a combination of dextromethorphan with bupropion to a human. Below applications claim methods of delivering dextromethorphan and bupropion as listed for some below.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being
unpatentable over the allowed claims of the following U.S. Patent Nos.
1. 9,198,905 (claims 1-18); A method of increasing the metabolic lifetime of dextromethorphan, comprising co-administering hydroxybupropion or bupropion with dextromethorphan to a human being once or twice a day for at least eight consecutive days
2. 9,205,083 (claims 1-14); A method of decreasing dextrorphan plasma levels in a human being comprising co-administering about 150 mg per day to about 560 mg per day of bupropion with dextromethorphan to the human being for at least eight consecutive days.
3. 9,238,032 (claims 1-20);
4. 9,168,234 (claims 1-12); A method of increasing dextromethorphan plasma levels in a human being, comprising co-administering about 150 mg per day to about 500 mg per day of bupropion with dextromethorphan to the human being for at least eight consecutive days
5. 9,402,844 (claims 1-18);
6. 9,278,095 (claims 1-17) ;
7. 9,314,462 (claims 1-17); A method of increasing dextromethorphan plasma levels in the human being that is an extensive metabolizer of dextromethorphan in need of treatment with dextromethorphan, comprising co-administering hydroxybupropion or bupropion with dextromethorphan to a human being once or twice a day for at least eight consecutive days.
8. 9,375,429 (claims 1-27) ;
9. 9,370,513 (claims 1-28);
10. 9,402,843 (claims 1-18);
11. 9,408,815 (claims 1-30):
12. 9,457,025 (claims 1-30);
13. 9,421,176 (claims 1-19);
14. 9,457,023 (claims 1-25);
15. 9,474,731 (claims 1-29);
16. 9,486,450 (claims 1-30);
17. 9,700,553 (claims 1-30);
18. 9,700,528 (claims 1-27);
19. 9,707,191 (claims 1-30);
20. 9,763932 (claims 1-29);
21. 10,105,327 (claims 1-28); A method of treating a human subject with enhanced plasma levels of a dextromethorphan, wherein the human subject is an extensive metabolizer of the dextromethorphan and suffers from treatment-resistant depression, comprising co-administering to the human subject a daily dose of a combination.
22. 10,548,857 (claims 1-22);
23. 10,780,064 (claims 1-23);
24. 10,772,850 (claims 1-28);
25. 10,799,497 (claims 1-14);
26. 10,786,469 (claims 1-24);
27. 10,864,209 (claims 1-14);
28. 10,864,209 (claims 1-12);
29. 10,874,665 (claims 1-15); and
30. 10,881,657 (claims 1-9).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN SEUNGJAI KWON whose telephone number is (571)272-7737. The examiner can normally be reached Mon - Fri 8:00 - 5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A. Wax can be reached at 571-272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
