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
The office acknowledges Applicants amendments, IDS and arguments filed on 7/17/2025 in response to the office action mailed 2/28/2025. Claims 1, 2, 12 and 13 have been amended and claims 10-11 have been cancelled. Applicants arguments have been fully considered but found not to be persuasive. The arguments are addressed below. The modified rejections necessitated by the amendments are presented below. The action is made final. For the sake of compact prosecution the examiner made several attempts were made to contact the attorney of record (as attorney Rosie Kim is no longer with the firm) to discuss the case but could not be reached. Claims 1-9, 11-22 are pending and are examined based on the merits herein.
Response to Applicants Arguments
103 rejection: Applicants argue that claim 1 has been amended to include the limitations of claim 11 which was not rejected being obvious over Tabuteau in view of Iosifescu. Hence the rejection has to be withdrawn. Further argued is that because Iosifescu and Auvelity are noted to be 2022 publications, which Applicant respectfully submits do not qualify as prior art because the present Application claims priority to earlier applications filed as early as January 7, 2019, and the most recent continuation-in-part Application in the priority chain appears to be U.S.
In response, applicants arguments have been fully considered. The support for the limitation of ‘orally administering a tablet once daily for three consecutive days, and twice daily starting on day four, to a human being in need thereof and to the administration of the bilayer is not found in the parent applications or the provisional applications. It is noted that the priority provisional application, 62789488, filed 01/07/2019 or the most recent CIP application is, 17/373,299, which was filed on July 12, 2021 do not have support in the specification for the above specific limitation and for bilayer tablets and administration of the bilayer tablets in treating depression and with the administration dosage as claimed. Hence the priority of the current application is the filing date of this application which is, 3/11/2024. Accordingly, Iosifescu and Auvelity noted to be 2022 publications are prior art of record. The modified rejections (reflecting the new scope of independent claim 1 is provided below.
ODP rejections:
In response, applicants arguments have been fully considered. The amendments to claim 1 necessitated the modified rejections (reflecting the new scope of independent claim 1) is provided below.
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, 12-22 are rejected under 35 U.S.C. 103 as being unpatentable over Tabuteau (US 10940124) and Iosifescu et al (J Clin Psychiatry 83:4, July/August 2022) and further in view of Auvelity (2022, label).
Tabuteau is explicit in teaching a method of treating major depressive disorder, comprising administering a drug combination to a human being in need thereof, wherein the drug combination comprises: a bupropion, in an amount that is about 105 mg of bupropion hydrochloride, wherein the bupropion is administered once a day for the first three days and twice a day thereafter for at least 11 days; and a dextromethorphan, in an amount that is about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of a dextromethorphan in the free base form or another salt form, wherein the dextromethorphan is administered once a day for the first three days and twice a day thereafter for at least 11 days (claim 1) and dextromethorphan and bupropion is in a single dosage form (claim 14). Further taught is that some embodiments include a method of rapidly relieving the symptoms of depression, comprising administering a combination of bupropion and dextromethorphan once daily or twice daily to a human being in need thereof, wherein the human being experiences a therapeutic effect within 2 weeks of the first day that the combination of bupropion and dextromethorphan is administered (col. 12, lines 22-28). Administering a combination of bupropion and dextromethorphan may result in a rapid treatment effect, e.g. within about 1 week, within about 2 weeks of beginning the treatment (see col. 18, last para, lines 61-64). The patients in the trial study included 23% of them had received prior first line treatment for depression (Example 3). The patient population to be treated for depression include Asian descent, e.g. Japanese, Chinese Korean (See col. 19, lines 29-21, 35, 38, 41-43) and it includes male (see col. 20, last two lines bridging col. 21, line 1). The reference teaches some embodiments include administration of a tablet that contains bupropion in a form that provides sustained release and dextromethorphan in a form that provides immediate release (col. 64, lines 14-17). The reference teach in example 1 the subjects include metabolizers of dextromethorphan as determined by CYP2D6 genetic testing for combination therapy with dextromethorphan and bupropion. The reference teaches that in some embodiments, the human being that is treated with a combination of dextromethorphan and bupropion, e.g. for a type of depression, has, or is selected for having, a Clinical Global Impression-Severity (CGI-S) score that is at least about 4, about 4-5, about 5-6, or about 6-7 etc. (See col. 23, lines 15-22).
Iosifescu teach patients with major depressive disorder received dextromethorphan-bupropion (45 mg-105 mg tablet) or placebo, orally (once daily for days 1–3, twice daily thereafter) for 6 weeks (p e1 Methods). In this phase 3 trial in patients with MDD, treatment with dextromethorphan-bupropion (AXS-05) resulted in significant improvements in depressive symptoms compared to placebo starting 1 week after treatment initiation and was generally well tolerated (See Conclusion, p e1). The reference teaches the MADRS is a 10-item clinician-rated questionnaire ranging from 0 to 60, with higher scores representing more severe depression (see e2, Endpoints). See Fig. 2 for MADRS totals scores, remission and clinical response of dextromethorphan-bupropion administration clinical trial studies. The reference teaches that In this randomized, placebo-controlled trial, dextromethorphan-bupropion (AXS-05) demonstrated statistically significant antidepressant efficacy on the primary endpoint and the majority of secondary endpoints across multiple symptom-specific and global measures. Treatment with dextromethorphan-bupropion resulted in statistically significantly greater reductions in MADRS total score than placebo starting at week 1 and continuing at every time point thereafter (Discussion, e7, col. 1, last para). The patient population selected for the trial had a score on the Clinician Global Impression-Severity (CGI-S)19 scale of 4 or higher (range, 1 to 7, with higher scores indicating greater severity of illness); patients include male and Asian (See e2 Patient Population, Table 1).
Tabuteau and Iosifescu teachings as discussed above. The previous rejections are incorporated herein.
The above references are not explicit in teaching the bilayer tablet comprising dextromethorphan and bupropion.
Auvelity is the label for extended-release tablets comprising dextromethorphan hydrobromide and bupropion hydrochloride, for oral use (See p 1, lines 5-6). Auvelity is a combination of dextromethorphan and bupropion indicated for the treatment of major depressive disorder (MDD) in adults (p 1, para 4). It is taught that it is a round bilayer tablet for oral administration and supplied as dextromethorphan hydrobromide 45mg/bupropion hydrochloride 105 mg, bottles of 30 tablets (see p 16, para 5, p 22, para 3-4).
A person skilled in the art from Auvelity would have found it obvious before the effective filing date of the invention to formulate a bilayer tablet comprising dextromethorphan and bupropion or to use the Auvelity tablet in the method of Tabuteau for treating depression. A person of ordinary skill in the art would have been motivated to formulate such a bilayer tablet comprising DM and bupropion with a reasonable amount of success or use the commercially available tablet containing the same agents (in the same dosage amounts) for depression therapy. From the teachings of Tabuteau a person skilled in the art before the filing date of the invention would have found it obvious to administer orally a tablet once daily for 3 consecutive days and twice daily after that to a human subject with depression, a tablet comprising 45 mg of dextromethorphan and 105 mg of bupropion hydrochloride. As to the limitation of ‘rapidly relieving the symptoms of depression’ and wherein the human being experiences a therapeutic effect within 2 weeks, within 1 week of the first day that the tablet is administered, it is noted that (i) Tabuteau teach that administering a combination of bupropion and dextromethorphan may result in a rapid treatment effect, e.g. within about 1 week, within about 2 weeks of beginning the treatment (ii) Iosifescu teach that the tablet comprising dextromethorphan-bupropion (AXS-05) resulted in significant improvements in depressive symptoms starting 1 week after treatment initiation (iii) administration of the tablet comprising the same active agents to patients with depression and in the same dosage regimen would result in the same pharmacological effects. A person skilled in the art would have found it obvious to arrive at the instantly claimed method with a reasonable expectation of success. A person skilled in the art would have motivated to administer the tablet comprising dextromethorphan and bupropion in subjects to treat symptoms associated with depression from the teachings of Tabuteau. Thus claims 1-2 are addressed.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to measure the depression scores of the subjects with rating scale, for e.g. MADRS to classify the depression and to define the severity of the disease from Iosifescu’s teachings. As to claim limitations of reduction in MADRS scale as in claims 3-7, it is noted that administration of the same agents, same dosage and same dosage form (herein tablet comprising dextromethorphan hydrobromide (45 mg) and bupropion hydrochloride (105 mg)) is administered to the same set of patients, e.g. depression patients would necessarily result in the same or similar pharmacological effects. A person of ordinary skill in the art would have found it obvious from Iosifescu that the score between 18-34 is classified as moderate depression. From the teachings of Tabuteau and Iosifescu one of ordinary skill in the art would have been motivated to employ bupropion and dextromethorphan, in the dosage and dosing regimen herein claimed, to treat patients with moderate or severe depression (MADRS score of 25-35). Thus claims 8-9 are addressed. Claims 12-13 are addressed by Tabuteau’s teaching that the tablet can contain bupropion in a sustained release form and dextromethorphan in an immediate release form. Claim 14 is addressed by the reference’s teaching that the subject being co-administered with dextromethorphan and bupropion is a metabolizer of CYP2D6. It is noted that there is no specific definition in the specification for non-poor metabolizer. The limitation ‘non-poor’ is being examined with a generic definition of non-poor metabolizer as a metabolizer of CYP2D6 here. As to claim 15 limitation of ‘wherein the human being becomes a CYP2D6 poor metabolizer after the treatment’, it is noted that the same pharmaceutical combination of drugs in the same dosage form and same dosage amount to the same set of patients (depression) is administered and hence one skilled in the art can expect substantially similar or same pharmacological effects. As to claims 16-19, 22, Tabuteau teach that the patients include Asian descent (e.g. Korean, Japanese, Chinese) and also male subjects for the treatment of depression with dextromethorphan-bupropion combination. As to claim 20, a trial study includes 23% of subjects who already had first line treatment. Hence a skilled artisan would have found it obvious to include human subjects who had first line depression treatment prior to the current one. As to claim 21, in regards to CGI, Tabuteau teaching selecting patients with CGI of at least or greater than 4 and Iosifescu’s trial studies included subjects with a CGI greater than 4.
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1-7, 12-13, 15-19, 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of US 10780064 and Iosifescu et al (J Clin Psychiatry 83:4, July/August 2022) and in view of Auvelity (2022, label).
The instant method claims are directed to a method of rapidly relieving the symptoms of depression, comprising orally administering a tablet once daily for three consecutive days, and twice daily starting on day four, to a human being in need thereof; wherein the tablet comprises about 45 mg of dextromethorphan hydrobromide, and about 105 mg of bupropion hydrochloride, wherein the tablet is a bilayer tablet and wherein the human being experiences a therapeutic effect within 2 weeks of the first day that the tablet is administered. The dependent claims are limited to, the therapeutic effect is experienced within a week after administration of DM and bupropion, reduction in the human patient’s MADRS scale/score, bilayer tablet, release tablet, human being non-poor metabolizer or poor metabolizer (after the treatment), subjects limited to Asian, Chinese, Korean, Japanese, male, selected to having received prior first line treatment, CGI score of at least about 4.
‘064 reference claims are directed to a method of treating major depressive disorder, comprising administering a drug combination to a human being in need thereof, wherein the drug combination comprises: a bupropion, in an amount that is about 105 mg of bupropion hydrochloride, or a molar equivalent amount of a bupropion in a free base or another salt form, wherein the bupropion is administered once a day for the first three days and twice a day thereafter for at least 11 days; and a dextromethorphan, in an amount that is about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of a dextromethorphan in a free base or another salt form, wherein the dextromethorphan is administered once a day for the first three days and twice a day thereafter for at least 11 days; wherein the human being selected for being of Asian descent; wherein the human being experiences a significantly greater reduction in Montgomery-Åsberg Depression Rating Scale score after receiving the drug combination, as compared to what would be experienced from receiving the same amount of the bupropion; wherein the dextromethorphan is formulated for immediate release; bupropion is formulated for sustained release; wherein the bupropion and the dextromethorphan are in a single dosage form; the therapeutic effect is experienced within a 2 weeks or within a week after administration of DM and bupropion; the human being selected include Chinese, Korean, Japanese.
Iosifescu teachings as discussed above.
The reference claims and Iosifescu do not teach the bilayer tablet as claimed.
Auvelity teachings as above.
A person skilled in the art from Auvelity would have found it obvious before the effective filing date of the invention to formulate a bilayer tablet comprising dextromethorphan and bupropion and use the bilayer tablet in the method of treating depression. A person skilled in the art would have found it obvious to administer bilayer tablet comprising bupropion and dextromethorphan to human subjects with depression, once a day for three consecutive days followed by twice a day starting day four. It is noted that administration of the same agents in combination to treat depression in the same set of subjects would substantially result in same pharmacological effects including the rapid relief of depression symptoms, the therapeutic effects observed within 2 weeks, within 1 week, the reduction in MADRS score and the human being becomes a CYP2D6 poor metabolizer after the treatment. Thus claims 1-7 would have been obvious over the patent reference claims. Claims 12-13 are addressed by the reference claims teachings of the tablet with DM (immediate release) and bupropion (extended release), in a single dosage form and in the amounts as claimed. As to claim 15 limitation of ‘wherein the human being becomes a CYP2D6 poor metabolizer after the treatment’, it is noted that the same pharmaceutical combination of drugs in the same dosage form and same dosage amount to the same set of patients (depression) is administered and hence one skilled in the art can expect substantially similar or same pharmacological effects. As to claims 16-19, the reference claims teach the same subjects in the method; it is noted that Japanese is an Asian descent. As to claim 22, it would have been obvious to a skilled person in the art to treat depression in a male subject as all humans experience depression.
Claims 1-7, 12-13, 15, 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of US 10940124 (‘124) or claims 1-20 of US 10925842 (‘842) or claims 1-20 of US 10966942 (‘942) in view of Auvelity (2022, label).
The instantly claimed method as discussed above.
‘124 reference claims are directed to a method of treating major depressive disorder, comprising administering a drug combination to a human being in need thereof, wherein the drug combination comprises: a bupropion, in an amount that is about 105 mg of bupropion hydrochloride, or a molar equivalent amount of a bupropion in the free base form or another salt form, wherein the bupropion is administered once a day for the first three days and twice a day thereafter for at least 11 days; and a dextromethorphan, in an amount that is about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of a dextromethorphan in the free base form or another salt form, wherein the dextromethorphan is administered once a day for the first three days and twice a day thereafter for at least 11 days; wherein the bupropion and the dextromethorphan are in a single dosage form; wherein the human being is selected for having a Clinical Global Impression-Severity score that is at least about 4; and wherein the human being experiences a greater reduction in Montgomery-Asberg Depression Rating Scale (MADRS) score after receiving the drug combination, as compared to what would be experienced from receiving the same amount of the bupropion alone. The dependent claims are limited to bupropion and the dextromethorphan are administered orally; in solid dosage form; wherein the dextromethorphan is formulated for immediate release; bupropion is formulated for sustained release; the therapeutic effect is experienced within a 2 weeks or within a week after administration of DM and bupropion.
‘842 reference claims are directed to a method of treating major depressive disorder, comprising administering a drug combination to a human being in need thereof, wherein the drug combination comprises: a bupropion, in an amount that is about 105 mg of bupropion hydrochloride, or a molar equivalent amount of a bupropion in the free base form or another salt form, wherein the bupropion is administered once a day for the first three days and twice a day thereafter for at least 11 days; and a dextromethorphan, in an amount that is about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of a dextromethorphan in the free base form or another salt form, wherein the dextromethorphan is administered once a day for the first three days and twice a day thereafter for at least 11 days; wherein the bupropion and the dextromethorphan are in a single dosage form; wherein the human being is selected for having received prior first line treatment in their current major depressive episode; and wherein the human being experiences a greater reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score after receiving the drug combination, as compared to what would be experienced from receiving the same amount of the bupropion alone. The dependent claims are limited to bupropion and the dextromethorphan are administered orally; in solid dosage form; wherein the dextromethorphan is formulated for immediate release; bupropion is formulated for sustained release; the therapeutic effect is experienced within a 2 weeks or within a week after administration of DM and bupropion.
‘942 reference claims are to a method of treating major depressive disorder, comprising administering a drug combination to a human being in need thereof, wherein the drug combination comprises: a bupropion, in an amount that is about 105 mg of bupropion hydrochloride, or a molar equivalent amount of a bupropion in the free base form or another salt form, wherein the bupropion is administered once a day for the first three days and twice a day thereafter for at least 11 days; and a dextromethorphan, in an amount that is about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of a dextromethorphan in the free base form or another salt form, wherein the dextromethorphan is administered once a day for the first three days and twice a day thereafter for at least 11 days; wherein the bupropion and the dextromethorphan are in a single dosage form; wherein the human being is selected for being male; and wherein the human being experiences a greater reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score after receiving the drug combination, as compared to what would be experienced from receiving the same amount of the bupropion alone. The dependent claims are limited to bupropion and the dextromethorphan are administered orally; in solid dosage form; wherein the dextromethorphan is formulated for immediate release; bupropion is formulated for sustained release; the therapeutic effect is experienced within a 2 weeks or within a week after administration of DM and bupropion.
The reference claims do not teach the bilayer tablet as claimed.
Auvelity teachings as above.
A person skilled in the art from Auvelity would have found it obvious before the effective filing date of the invention to formulate a bilayer tablet comprising dextromethorphan and bupropion and use the bilayer tablet in the method of treating depression. A person skilled in the art would have found it obvious to administer bilayer tablet comprising bupropion and dextromethorphan to human subjects with depression, once a day for three consecutive days followed by twice a day starting day four. Both the instant application and the patent(s) teach oral administration of bupropion and dextromethorphan to human subjects with depression, once a day for three consecutive days followed by twice a day starting day four. It is noted that administration of the same agents in combination (and in a single dosage form) to treat depression in the same set of subjects would substantially result in same pharmacological effects including the rapid relief of depression symptoms, the therapeutic effects observed within 2 weeks, within 1 week, the reduction in MADRS score and the human being becomes a CYP2D6 poor metabolizer after the treatment. Thus claims 1-7 would have been obvious over the patent reference claims. Claims 12-13 are addressed by the reference claims teachings of the tablet with DM (immediate release) and bupropion (extended release) and in the amounts as claimed. As to claim 15 limitation of ‘wherein the human being becomes a CYP2D6 poor metabolizer after the treatment’, it is noted that the same pharmaceutical combination of drugs in the same dosage form and same dosage amount to the same set of patients (depression) is administered and hence one skilled in the art can expect substantially similar or same pharmacological effects. As to claim 22, it would have been obvious to a skilled person in the art to treat depression in a male subject as all humans experience depression.
Claims 1-7, 15, 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over the following reference patent(s) in view of Auvelity (2022, label).
The instantly claimed method(s) as above.
1. Claims 1-27 of US 11364233 reference claims are directed to a method of increasing a plasma level of dextromethorphan, comprising co-administering a bupropion and a dextromethorphan to a human being who is a non-poor metabolizer of dextromethorphan, wherein the human being receives about 70 mg to about 150 mg of the bupropion and about 30 mg to about 60 mg of the dextromethorphan once a day for three consecutive days followed by twice a day for at least 5 consecutive days, the treatment is for depression. The method of claim 1, wherein about 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, is co-administered with about 44 mg to about 46 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan, to the human being once a day for 3 consecutive days followed by twice a day for at least 5 consecutive days.
2. Claims 1-29 of U.S. 11147808 reference claims are directed to a method of decreasing the fluctuation index of dextromethorphan, comprising co-administering a bupropion and a dextromethorphan to a human being who is a non-poor metabolizer of dextromethorphan, wherein the human being receives about 70 mg to about 150 mg of the bupropion and about 30 mg to about 60 mg of the dextromethorphan once a day for three consecutive days followed by twice a day for at least 5 consecutive days, wherein the fluctuation index of dextromethorphan on the eighth day is about 20% to about 30%, and the fluctuation index of dextromethorphan on the eighth day is reduced by at least about 70% as compared to the fluctuation index of dextromethorphan that would result from administering 60 mg of the dextromethorphan alone once a day for three consecutive days followed by twice a day for at least 5 consecutive days, the treatment is for depression. The method of claim 1, wherein about 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, is co-administered with about 44 mg to about 46 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan, once a day for three consecutive days followed by twice a day for at least 5 consecutive days.
3. Claims 1-5, 7-10, 13-18 of US 11123343 reference claims are directed to a method of treating treatment resistant depression, comprising administering: bupropion, at a daily dose that is about 150 mg to about 250 mg, and dextromethorphan, at a daily dose that is about 60 mg to about 100 mg, to a human being in need thereof for at least 8 consecutive days, wherein the bupropion and the dextromethorphan are administered in a dosage form containing both the bupropion and the dextromethorphan as the only therapeutically active compounds; wherein the bupropion is bupropion hydrochloride, or the free base or another salt form of bupropion and the dextromethorphan is dextromethorphan hydrobromide, or the free base or another salt form of dextromethorphan; wherein the daily doses of the bupropion and the dextromethorphan are orally administered once a day or are a total of twice daily doses; and wherein the dosage form provides immediate release of dextromethorphan and sustained release of bupropion; and wherein a therapeutic effect upon the human being is observed.
4. Claims 1-4, 6-13, 15-18 of US 11020389 reference claims are directed to a method of treating major depressive disorder, comprising: orally administering a dosage form once a day or twice a day for at least seven consecutive days, to a human being suffering from major depressive disorder, wherein the dosage form contains, as the only therapeutically active compounds in the dosage form, about 40 mg to about 50 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base form or another salt form of dextromethorphan, and about 90 mg to about 110 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion; and wherein the dosage form provides immediate release of dextromethorphan and sustained release of bupropion.
5. Claims 1-4, 6-10, 13-23 of US 11129826 reference claims are to a method of treating depression, comprising administering a drug combination comprising: a daily dose of bupropion that is about 200 mg to about 250 mg and a daily dose of dextromethorphan that is about 80 mg to about 100 mg, to a human being in need thereof for at least 8 consecutive days, wherein the bupropion and the dextromethorphan are present in a dosage form, wherein the bupropion and the dextromethorphan are the only therapeutically active compounds in the dosage form; wherein administering the drug combination results in a therapeutic effect upon the human being; wherein the daily doses of the bupropion and the dextromethorphan are orally administered once a day or are a total of twice daily doses; and wherein the dosage form is formulated for immediate release of dextromethorphan and sustained release of bupropion.
6. Claims 1-5, 7-10, 13-27 of US 11229640 reference claims are directed to a method of treating depression, comprising orally administering a dosage form once a day or twice a day to a human being in need thereof, wherein the dosage form comprises about 90 mg to about 125 mg of bupropion and about 40 mg to about 70 mg of dextromethorphan, wherein bupropion and dextromethorphan are the only therapeutically active compounds in the dosage form, and wherein the dosage form is orally administered to the human being for at least 8 consecutive days.
7. Claims 1-4, 6-9, 12-13 of US 11096937 reference claims are directed to a method of treating major depressive disorder, comprising orally co-administering: a daily dose of bupropion that is about 150 mg to about 250 mg and a daily dose of dextromethorphan that is about 60 mg to about 100 mg, to a human being in need thereof for at least 8 consecutive days, wherein the bupropion is bupropion hydrochloride, or the free base or another salt form of bupropion and the dextromethorphan is dextromethorphan hydrobromide, or the free base or another salt form of dextromethorphan; wherein the bupropion and the dextromethorphan are the only therapeutically active compounds to be co-administered; and wherein the dextromethorphan is formulated for immediate release and the bupropion is formulated for sustained release; and wherein co-administering the bupropion and the dextromethorphan results in the human being experiencing a therapeutic effect and is more effective in treating major depressive disorder than orally administering the same amount of the dextromethorphan alone for the same number of consecutive days.
8. Claims 1-4, 6-8, 11-12 of US 11141416 reference claims are directed to a method of treating treatment resistant depression, comprising orally co-administering: a daily dose of bupropion that is about 150 mg to about 250 mg and a daily dose of dextromethorphan that is about 60 mg to about 100 mg, to a human being in need thereof for at least 8 consecutive days, wherein the bupropion is bupropion hydrochloride, or the free base form or another salt form of bupropion and the dextromethorphan is dextromethorphan hydrobromide, or the free base form or another salt form of dextromethorphan; wherein the bupropion and the dextromethorphan are the only therapeutically active compounds to be co-administered; wherein the dextromethorphan is formulated for immediate release and the bupropion is formulated for sustained release; wherein orally co-administering the bupropion and the dextromethorphan results in the human being experiencing a therapeutic effect; and wherein orally co-administering the bupropion and the dextromethorphan is more effective in treating treatment resistant depression than orally administering the same amount of the dextromethorphan alone for the same number of consecutive days.
9. Claims 1-11, 14 of US 11234946 reference claims are directed to a method of increasing dextromethorphan plasma levels, comprising co-administering bupropion and dextromethorphan once a day or twice a day for at least eight consecutive days to a human being for the treatment of depression, who is a non-poor metabolizer of dextromethorphan in need of treatment with dextromethorphan; wherein a daily dose of about 100 mg to about 300 mg of the bupropion is co-administered with the dextromethorphan once a day or twice a day; wherein the bupropion and the dextromethorphan are co-administered in a dosage form containing bupropion and dextromethorphan as the only active pharmaceutical agents; and wherein co-administering the bupropion and the dextromethorphan results in an AUC.sub.0-12 of dextromethorphan on the eighth day that is about 20 times to about 1,000 times the AUC.sub.0-12that would result from administering the same amount of the dextromethorphan without the bupropion for eight consecutive days.
10. Claims 1-4, 6-8, 11-12 of US 11213521 reference claims are directed to a method of treating major depressive disorder, comprising administering a drug combination once a day or twice a day to a human being in need thereof for at least 8 consecutive days, wherein the human being is an extensive metabolizer of dextromethorphan or an intermediate metabolizer of dextromethorphan, wherein the drug combination comprises: about 100 mg to about 110 mg of bupropion hydrochloride, or a molar equivalent amount of a bupropion in the free base form or another salt form; and about 40 mg to about 50 mg of dextromethorphan hydrobromide, or a molar equivalent amount of a dextromethorphan in the free base form or another salt form; wherein the drug combination is orally administered in a single dosage form comprising the bupropion and the dextromethorphan as the only therapeutically active compounds, which provides immediate release of dextromethorphan and sustained release of bupropion; and wherein the method results in the human being experiencing a therapeutic effect and orally administering the dosage form is more effective in treating major depressive disorder than orally administering the same amount of the dextromethorphan alone for the same number of consecutive days.
11. Claims 1-8, 11-12 of US 11298351 reference claims are directed to a method of treating major depression, comprising: orally administering a dosage form once a day or twice a day for at least 7 days, to a human being suffering from major depression, wherein bupropion and dextromethorphan are the only therapeutically active compounds in the dosage form, wherein the human being receives a daily dose of the bupropion that is about 200 mg to about 250 mg, wherein the daily dose of the bupropion is orally administered once a day or is a total of two twice daily doses of the bupropion, wherein the human being receives a daily dose of the dextromethorphan that is about 60 mg to about 100 mg, wherein the daily dose of the dextromethorphan is orally administered once a day or is a total of two twice daily doses of the dextromethorphan, wherein orally administering the bupropion in combination with the dextromethorphan results in the human being experiencing a therapeutic effect; wherein the dosage form provides immediate release of dextromethorphan and sustained release of bupropion; and wherein orally administering the dosage form is more effective in treating major depression than orally administering the same amount of the dextromethorphan alone for the same number of consecutive days.
12. Claims 1-8, 11-30 of US 11058648 reference claims are directed to a method of treating major depressive disorder comprising: orally administering a dosage form once a day or twice a day for at least 8 consecutive days, to a human being suffering from major depressive disorder; wherein the dosage form contains, as the only therapeutically active agents in the dosage form, about 90 mg to about 115 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion, and about 40 mg to about 70 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base form or another salt form of dextromethorphan.
13. Claims 1-4, 6-8, 11-13 of US 11185515 reference claims are directed to a method of treating major depressive disorder, comprising: orally administering a dosage form to a human being suffering from major depressive disorder, wherein the dosage form is orally administered once a day or twice a day for at least 8 consecutive days, wherein the human being is an extensive metabolizer of dextromethorphan or an intermediate metabolizer of dextromethorphan; wherein the dosage form comprises, as the only therapeutically active compounds, about 90 mg to about 140 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion, and about 40 mg to about 55 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base form or another salt form of dextromethorphan; wherein orally administering the dosage form provides immediate release of dextromethorphan and sustained release of bupropion; and wherein orally administering the dosage form results in the human being experiencing a therapeutic effect and orally administering the dosage form is more effective in treating major depressive disorder than orally administering the same amount of the dextromethorphan alone for the same number of consecutive days.
15. Claims 1-4, 6-8, 11-12 of US 11311534 reference claims are directed to method of treating treatment resistant depression, comprising administering a drug combination once a day or twice a day to a human being in need thereof for at least 8 consecutive days, wherein the human being is an extensive metabolizer of dextromethorphan or an intermediate metabolizer of dextromethorphan, wherein the drug combination comprises: about 100 mg to about 110 mg of bupropion hydrochloride, or a molar equivalent amount of a bupropion in the free base form or another salt form; and about 40 mg to about 50 mg of dextromethorphan hydrobromide, or a molar equivalent amount of a dextromethorphan in the free base form or another salt form; wherein the drug combination is orally administered in a single dosage form comprising the bupropion and the dextromethorphan as the only therapeutically active compounds, which provides immediate release of dextromethorphan and sustained release of bupropion; and wherein orally administering the dosage form results in the human being experiencing a therapeutic effect and is more effective in treating treatment resistant depression than orally administering the same amount of the dextromethorphan alone for the same number of consecutive days.
16. Claims 1-11, 18-15, 18-20 of US 11273134 reference claims are directed to method of increasing dextromethorphan plasma levels, comprising co-administering bupropion and dextromethorphan once a day or twice a day for at least 8 consecutive days to a human being treated for depression, who is an extensive metabolizer of dextromethorphan in need of treatment with dextromethorphan; wherein about 100 mg to about 220 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion, is co-administered with about 40 mg to about 60 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base form or another salt form of dextromethorphan, once a day or twice a day; and wherein the bupropion and the dextromethorphan are the only therapeutically active agents to be co-administered and co-administering the bupropion and the dextromethorphan results in an AUC.sub.0-12 of dextromethorphan on the eighth day that is about 20 times to about 1,000 times the AUC.sub.0-12 that would result from administering the same daily dose of dextromethorphan hydrobromide without bupropion for eight consecutive days.
17. Claims 1-4, 7-9, 12-15, 18-20 of US 11207281 reference claims are directed to method of reducing plasma levels of dextromethorphan O-glucouronide associated with treatment with a dextromethorphan, comprising administering a bupropion once a day or twice a day in combination with the dextromethorphan once a day or twice a day for at least 8 consecutive days to a human being in need of treatment with dextromethorphan, for depression wherein the daily dose of the dextromethorphan is about 60 mg to about 200 mg, wherein the bupropion and the dextromethorphan are co-administered in a dosage form containing bupropion and dextromethorphan as the only active pharmaceutical agents, wherein the human being is a non-poor metabolizer of dextromethorphan, wherein on the eighth day that the bupropion is administered in combination with the dextromethorphan to the human being, the human being has a Cmax of dextromethorphan O-glucouronide that is about 50% to about 80% lower than the Cmax of dextromethorphan O-glucouronide that would result from administering the same amount of the dextromethorphan alone to the human being for eight consecutive days.
18. Claims 1-4, 7-10, 14-21, 24-29 of US 11147808 reference claims are directed to method of decreasing the fluctuation index of dextromethorphan, comprising co-administering a bupropion and a dextromethorphan to a human being who is a non-poor metabolizer of dextromethorphan, wherein the human being receives about 70 mg to about 150 mg of the bupropion and about 30 mg to about 60 mg of the dextromethorphan once a day for three consecutive days followed by twice a day for at least 5 consecutive days, wherein the fluctuation index of dextromethorphan on the eighth day is about 20% to about 30%, and the fluctuation index of dextromethorphan on the eighth day is reduced by at least about 70% as compared to the fluctuation index of dextromethorphan that would result from administering 60 mg of the dextromethorphan alone once a day for three consecutive days followed by twice a day for at least 5 consecutive days.
19. Claims 1-7, 10-11, 14-15, 18-20 of US 11285146 reference claims are directed to a method of increasing dextromethorphan plasma levels, comprising co-administering bupropion and dextromethorphan once a day or twice a day for at least 8 consecutive days to a human being who is an extensive metabolizer of dextromethorphan in need of treatment with dextromethorphan, for treating depression; wherein about 100 mg to about 220 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion is co-administered with dextromethorphan hydrobromide, or the free base form or another salt form of dextromethorphan, once a day or twice a day; and wherein the bupropion and the dextromethorphan are the only therapeutically active agents to be co-administered and co-administering the bupropion and the dextromethorphan results in a Cmax of dextromethorphan on the eighth day that is at least about 15 times the Cmax of dextromethorphan that would result from administering the same daily dose of the dextromethorphan without the bupropion for eight consecutive days.
20. Claims 1-4, 7-11, 14-18, 21-25, 28 of US 11253492 reference claims are directed to a method of increasing the elimination half-life of dextromethorphan, comprising co-administering a bupropion and a dextromethorphan once a day or twice a day to a human being for treating depression, who is a non-poor metabolizer of dextromethorphan, wherein the human being receives about 70 mg to about 150 mg of the bupropion and about 30 mg to about 60 mg of the dextromethorphan once a day or twice a day for at least 8 consecutive days, and wherein the elimination half-life of dextromethorphan on day 8 is at least about 200% of the elimination half-life of dextromethorphan that would result when the dextromethorphan is administered alone.
The reference claims do not teach the bilayer tablet as claimed.
Auvelity teachings as above.
A person skilled in the art from Auvelity would have found it obvious before the effective filing date of the invention to formulate a bilayer tablet comprising dextromethorphan and bupropion and use the tablet in the method of treating depression. A person skilled in the art from the reference claims and art would have found it obvious to administer bilayer tablet comprising bupropion and dextromethorphan to human subjects with depression, once a day for three consecutive days followed by twice a day starting day four. Both the instant application and the patent(s) teach oral administration of bupropion and dextromethorphan to human subjects with depression, once a day for three consecutive days followed by twice a day starting day four. It is noted that oral administration of the same agents herein dextromethorphan/salt and bupropion/salt to depressed human subjects would result in the same pharmacological effects including the therapeutic effects of rapidly relieving the symptoms of depression, the therapeutic effects observed within 2 weeks, within 1 week, the reduction in MADRS score and the human being becomes a CYP2D6 poor metabolizer after the treatment. Thus claims 1-7 and 15 would have been obvious over the reference claims. As to claim 22, it would have been obvio