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
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/18/2026 has been entered.
Response to Amendments
Acknowledgement is made of Applicant's amendment filed on 02/18/2026, wherein claims 1-2, 11 and 21 are canceled, and new claim 23 is added.
Status of Claims
Claims 3-10, 12-20, and 22-23 are pending and currently under examination.
Response to Arguments
Applicant's remarks filed 02/18/2026 have been fully considered, but NOT persuasive to overcome rejections on the record.
35 USC §103 rejection
Applicant’s argument focused on the limitation of continued treatment for specific patient population “wherein the human patient has already experienced a sustained clinical response to a prior treatment and has the mean CMAI total scores of about 43.7... The claims require identification and selection of patients who have previously achieved this specific quantified clinical response before the continued treatment can be practiced” (Remarks, page 5-6).
Applicant further compares instant Claim 3 with Claim 1 of Tabuteau '419 and argues about the difference in patient population, treatment period, therapeutic purpose and results (Remarks, page 7).
RESPONSE: Applicant’s argument is fully considered, but NOT persuasive. Please note the therapeutic purpose does not further contribute to the patentability of instantly claimed method.
Regarding the limitation of continued treatment recited in amended independent claims 3 and 22, “at least 3 month” or “ at least 6 month” recited in instant claims 6-7, Tabuteau’419 teaches the combination of dextromethorphan and bupropion may be administered twice daily to a human being for at least 5 weeks, at least 6 weeks, … at least 3 months, at least 4 months, at least 5 months, at least 6-months, about 6-12 months, about 1 year or longer for treating depression/ MDD. Since treatment of agitation in Alzheimer is also long term, a skilled artisan in the art would have known relapse of agitation associated with Alzheimer’s would occur if a medication is discontinued or if the medication's effectiveness wanes. It would have been prima facie obvious and logical for a skilled artisan to measure/monitor the treatment outcome (e.g. CMAI, PGI-C score, etc.) and continue administering combination of dextromethorphan and bupropion to the patient having agitation associated with Alzheimer’s for longer period time (e.g. 3 month, 6 month, or longer) wherein the patients in need respond positively to the combination therapy at week 5 (CMAI >30% improvement ) and exhibits no adverse event. In order to sustain the clinical benefit and reduce the likelihood of agitation recurrence, continuation treatment of patient with positive response would have been obvious to a POSA .
Regarding the patient population, as explained in previous office action, there is nothing critical about the 30% threshold of CMAI and PGI score to distinguish this set of population from the responsive patient population who respond to treatment of bupropion/ dextromethorphan combination taught by Tabuteau’419 and Ward. Tabuteau’419 discloses a statistically significantly greater proportion of patients achieved a clinical response on the CMAI (defined as a 30% or greater improvement from baseline) with DM/BU as compared to placebo ( 73% vs 57%) , at the 5 week of treatment ( See [530], Fig. 23-24), which is considered as read on the patient population meeting the specific criteria “30% or greater improvement in CMAI” for at least 4 consecutive weeks as recited in amended 3. Tabuteau’419 also teaches other measurement of treatment outcome, e.g. PGI-C, CGI-C, CGI-S (See [0148], [0250], etc.), wherein both PGI and CGI are directed to clinical Global Impression scores. Tabuteau’419 teaches patient selection in the human being having a reduction in the CGI-S score that is at least about 3, at least about 4, etc. (See [0181]-0183]).
Ward teach Accord study (Phase III) is relapse prevention trial that has inclusion criteria similar to the ADVANCE-1 study, “ Following a 4-week screening period, participants are given AXS-05, to be taken twice daily, for 9 weeks. Responders are then randomized to placebo or AXS-05 for as long as 26 weeks and the primary outcome measure is time from randomization to relapse of agitation symptoms”. The responders selected following the 4-week screening period as disclosed by Ward are considered as read on instantly claimed patient population as recited in claims 3 and 22, although Accord Study result was not published. Further exploration of different population for treatment is also considered as common practice in the art.
Instantly claimed active step of orally administering a dosage form comprising combination of bupropion (105mg) and dextromethorphan (45mg) twice a day are the same as taught by prior art no matter it is maintenance therapy or initial treatment. As noted in Claim Interpretation section, recitations of treatment outcome/ intended results of the active method step do not materially change the claimed method since such limitations do not result in manipulative difference in method steps of the claims.
Tabuteau’419 and Ward disclosed efficacy/clinical response meeting CMAI criteria (30% reduction from baseline) and safety of DM/BU combination in patients having agitation associated with Alzheimer's disease at week 5. Ward further disclosed the clinical design of Accord study (Phase III) for relapse of agitation after 5 week (9 weeks, 26 weeks). A skilled artisan in the art would have known treating agitation associated with Alzheimer’s is long-term and relapse of agitation would occur if a medication is discontinued or if the medication's effectiveness wanes. It would have been prima facie obvious and logical to one of ordinary skill in the art to select those patients who was responsive to the treatment and have experienced a sustained clinical response to the combination of bupropion and dextromethorphan during the initial trial period because the skilled artisan would have recognized that they are responsive to the treatment and would benefit from the combination in the long-term treatment. Also, the skilled artisan would have been motivated to continue the treatment which showed promising clinical response for additional period of time if needed with the reasonable expectation of success of maintaining such clinical response or reducing relapse of agitation.
Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR v. Teleflex, 127 S.Ct. 1727, 1741 (2007). The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.” Id. at 1742.
Applicant argues about the distinct therapeutic goals and “unexpected discovery of the ACCORD study” from initial treatment (Remarks, page 9).
RESPONSE: Tabuteau '419 and Ward already teaches DM/BU combination exhibits efficacy of treating agitation associated with Alzheimer's disease for 5 weeks. A skilled artisan would reasonably expect DM/BU combination continue having efficacy of controlling agitation/reducing relapse of agitation in the continued treatment in absence of evidence to the contrary. As such, the efficacy of DM/BU combination in continued treatment after 5 weeks is NOT unexpected.
Double patenting rejection:
Similar as response to 35 USC 103 rejection, Applicant argues again about the patient population and a person of ordinary skill in the art would not have had a reasonable expectation of success that continuing treatment in patients who has already achieved a sustained clinical response would result in the claimed relapse reduction and/or prevention outcomes(Remarks, page 11-12).
RESPONSE: Although reference claims do not recite the specific population in a maintenance therapy as Applicant argues, Ward teaches 4-week screening period and continuing treatment for longer period of time 9 weeks or as long as 26 weeks wherein the primary outcome measure is time from randomization to relapse of agitation symptoms as elaborated in 35USC §103 rejection and above response. It would have been prima facie obvious and logical to one of ordinary skill in the art to evaluate/monitor patient’s clinical response to DM/BU combination based on the combined teachings of reference claims and Ward and reasonably expect DM/BU combination continue having efficacy in the maintenance therapy in absence of evidence to the contrary. As such, the double patenting rejections on the record are maintained.
Please note claims 3-10, 12-20, and 22-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending application No. 19/255,952. Notice of Allowance of 19/255,952 was mailed on 03/13/2026 and issue fee was paid on 05/13/2026.
Priority
This application 19/219,972 filed 05/27/2025 is a continuation of International Pat. App. No. PCT/US2023/081292, filed November 28, 2023; which claims the benefit of U.S. Provisional App. Nos. 63/385,205, filed November 28, 2022; 63/589,325 filed October 11, 2023; and 63/589,525, filed October 11, 2023.
U.S. Provisional App. No. 63/385,205 disclosed Example 8 wherein agitation CMAI total score changes (>30%) from baseline at week 5 (See [543], Figures 22, 23, 24), and study design of ACCORD: “ a total of 178 patients were treated with open-label AXS-05 for up to 9 weeks and assessed for efficacy. The primary timepoint for open-label efficacy assessments was 5 weeks, and the key secondary timepoint was 2 weeks” (See [534], [543]), but does not disclose evaluation of treatment outcome on agitation associated with Alzheimer’s at least 3 month or for at least 6 month.
Information Disclosure Statement
The information disclosure statements filed 02/04/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the reference listed in IDS are being considered by the Examiner.
Claim Interpretation,
Independent claims 3 and its dependent claims recites limitation of intended treatment outcome. “reducing relapse of agitation in Alzheimer's disease in a human patient in need thereof” recited in independent claims 3 and 22, “the percentage of human patients with agitation relapse is lower with continued treatment with the oral administration of the dosage form than taking a placebo” recited in claim 12, “statistically increases the time to relapse of agitation symptoms” recited in claim 13 and 14, “reduces the risk of relapse of Alzheimer’s disease agitation as compared to a placebo” in claim 15, and “significantly prevents relapse of Alzheimer's disease agitation as compared with placebo” in claim 23, these recitations are construed as intended results of the active method step of orally administering a dosage form comprising combination of bupropion and dextromethorphan, and do not materially limit the claimed method since such limitations do not result in manipulative difference in method steps of the claims. If the prior art teaches and suggests the same method step as instantly claimed (i.e., orally administering the same dosage form comprising bupropion and dextromethorphan in the same amount twice a day to the human patient having agitation associated with AD), the method of the prior art would have achieved the intended results recited in instant claims and read on instant claimed methods. The burden of proof is shifted to the Applicant to show that the subject matter of the prior art does not possess the characteristic to achieve the intended result under 35 U.S.C. 103.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 15 and 23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Clam 15 recites “wherein the continued treatment with oral administration of the dosage form to the human patient reduces the risk of relapse of Alzheimer's disease agitation as compared to a placebo”. It’s not clear how to assess and compare the risk of Alzheimer's disease agitation since the risk would be different in different subjects.
New claim 23 recites “continued treatment significantly prevents relapse of Alzheimer's disease agitation as compared with placebo”. Instant specification ([0086]) disclosed the key secondary endpoint to assess relapse prevention, was the percentage of patients who relapsed. A POSA would not be reasonably appraised the scope of the claim because it is not clear whether “significantly prevents” requires complete elimination of relapse, reduction in frequency of severity or merely delay or recurrence, and for how long, days, months or years without relapse.
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 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 non-obviousness.
Claims 3-10, 12-20, and 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over Tabuteau (WO 2021/202419), “Tabuteau’419”, Applicant’s IDS dated 06/11/2025), in view of Ward et al ( Expert Opinion On Investigational Drugs, 2022, VOL. 31, NO. 8, 773–780, Applicant’s IDS dated 06/11/2025, “ AXS-05: an investigational treatment for Alzheimer’s disease-associated agitation” ), and Auvelity Prescribing Information (dextromethorphan hydrobromide and bupropion hydrochloride extended-release tablets, for oral use, revised 08/2022)(maintained) .
Tabuteau’419 teaches a method of treating neurological disorder (e.g. agitation associated with Alzheimer's disease, depression, etc.) in a human patient, comprising orally administering a combination of bupropion hydrochloride (BU) and dextromethorphan hydrobromide (DM) (e.g. 105 mg bupropion hydrochloride BU and 45 mg dextromethorphan hydrobromide DM), twice daily, to a human subject (See abstract, [0248], Experiments 3-10, Embodiments 1- 186, claims 1-11).
Regarding the limitation of treatment outcome/ intended result, Tabuteau’419 teaches treatment outcome were measured based on variety of questionnaire/assessment for neurological disorders, including Cohen-Mansfield Agitation Inventory (CMAI), Patient Global Impression of Change (PGIC), etc. wherein the person's score in the assessments may improve by at least about 30%, at least about 40%, at least about 50%, about 45-55%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100% as compared to baseline or placebo (See [0148]-[0149], [0250], Figures 24).
Tabuteau’419 specifically discloses clinical trial to evaluate the efficacy and safety of DM/BU combination in patients having agitation associated with Alzheimer's disease wherein combination of DM/BU ( e.g. 45 mg DM and 105 mg BU) are administered twice daily for 5 weeks (See Example 8, [524]-[531]). Tabuteau’419 teaches administering combination of DM/BU twice daily met the primary endpoint by demonstrating a statistically significant mean reduction in the Cohen Mansfield Agitation Inventory (CMAI) total score compared to placebo at Week 5 (See [526], Table 9). Tabuteau’419 further discloses a statistically significantly greater proportion of patients achieved a clinical response on the CMAI (defined as a 30% or greater improvement from baseline) with DM/BU as compared to placebo ( 73% vs 57%) , at the 5 week of treatment ( See [527], [530], Fig. 23-24)(which reads on instantly claimed 30% or greater improvement in CMAI recited in claim 3). Tabuteau’419 also teaches assessment consistent with clinicians' global assessments of change measured using the modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change for Agitation (mADCS-CGIC), Clinical Global Impression -Severity(CGI-S), wherein DM/BU demonstrated statistically significantly greater improvement in agitation as compared to placebo (See [0530]). Tabuteau’419 specifically discloses DM/BU rapidly improved agitation symptoms and was safe and well tolerated in the trial (See [528]-[531]).
Regarding the limitation of formulation/dosage form of instant claims 8-10 and 18-20, Tabuteau’419 discloses that combination of DM and BU may be formulated for oral administration with inert diluent or with an edible carrier, enclosed in hard or soft hell gelatin capsules or compressed into tablets(See [0351],[448]) (which reads on oral solid dosage form).
Regarding the pharmaceutical excipient/carrier limitation of instant claim 9 and 19, Tabuteau’419 teaches tablets/capsules embodiments of therapeutic compounds may contain one or more of the following: a binder, an excipient (e.g. dicalcium phosphate); a disintegrating agent, and the like; a lubricant (e.g. magnesium stearate), a sweetening agent such as sucrose, lactose, or saccharin, etc. (See [449]).
Regarding the limitation of instant claims 10 and 20, Tabuteau’419 teaches the dextromethorphan and the bupropion are orally administered in a solid dosage form (e.g. tablet) that provides immediate release for the dextromethorphan and sustained release (extended release) for the bupropion (See [0351], [0352], Embodiment 148-165). Tabuteau’419 teaches embodiments that contains bupropion in a form that provides sustained release (extended release) and dextromethorphan in a form that provides immediate release wherein particles of bupropion hydrochloride could be blended with microcrystalline cellulose and hydroxypropyl methylcellulose to form an admixture of blended powders and then be combined with immediate release dextromethorphan in a single tablet (See [352])(which also reads on instant claims 9 and 19).
A skilled artisan in the art would have known AXS-05 (combination of 45mg dextromethorphan HBr and 105 mg of bupropion HCl) is approved by FDA in August 2022, known as AUVELITY for the treatment of major depressive disorder (MDD) in adults by oral administration and is available as round bilayer tablets. “Each tablet contains 45 mg dextromethorphan hydrobromide (equivalent to 32.98 mg dextromethorphan base) in an immediate-release formulation and 105 mg bupropion hydrochloride (equivalent to 91.14 mg bupropion base) in an extended-release formulation. Each tablet contains the following inactive ingredients: carbomer homopolymer, colloidal silicon dioxide, crospovidone, glyceryl monocaprylocaprate, l-cysteine hydrochloride monohydrate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, red iron oxide, sodium lauryl sulfate, stearic acid, talc, titanium dioxide, and yellow iron oxide (See Auvelity Prescribing information revised 08/2022, Section 11 Description, page 16).
Tabuteau’419 collectively teaches a method of treating/maintaining response in patients having agitation associated with Alzheimer’s comprising orally administering combination of 45 mg DM and 105 mg BU in solid dosage form twice daily wherein patient’s CMAI at week 5 is 30% or greater improvement.
Tabuteau’419 is silent about specific treatment outcome limitation, e.g. “reducing relapse of agitation in Alzheimer's disease in a human patient in need thereof” recited in claims 3 and 22 , and other intended treatment outcome recited in claims 12-15 and 23. As noted in Claim Interpretation section, these recitations of intended treatment outcome are construed as intended results of the active method step of orally administering a dosage form comprising combination of bupropion and dextromethorphan, and do not materially limit the claimed method since such limitations do not result in manipulative difference in method steps of the claims. Since Tabuteau’419 teaches and suggests the same method step as instantly claimed (i.e., orally administering the same dosage form comprising bupropion and dextromethorphan in the same amount twice a day to human patient having agitation associated with AD), the intended results as recited in instant claims would have been achieved by practicing the method taught by Tabuteau’419. For example, Tabuteau’419 discloses measurement of treatment outcome in neurological disorders including PGI-C as well as CMAI ([0250]) and patients receiving the same combination of bupropion and dextromethorphan for major depressive disorder MDD/depression were assessed by PGI-C score (See Example 6, 9-10). A skilled artisan would have known to evaluate/monitor PGI-C score as well as CMAI in treating agitation associated with Alzheimer’s and expect to have instant claimed PGI-scores as a result of receiving the BU/DM combination therapy because products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances.
Tabuteau’419 collectively discloses the same method step as instantly claimed (i.e., orally administering the same dosage form comprising bupropion and dextromethorphan in the same amount twice a day to human patient having agitation associated with AD).
Tabuteau’419 is silent about administering combination of dextromethorphan and bupropion to a patient having agitation associated with Alzheimer’s for continued treatment.
Regarding the limitation of continued treatment, “at least 3 month” or “ at least 6 month” recited in instant claims 6-7, Tabuteau’419 teaches the combination of dextromethorphan and bupropion may be administered twice daily to a human being for at least 5 weeks, at least 6 weeks, … at least 3 months, at least 4 months, at least 5 months, at least 6-months, about 6-12 months, about 1 year or longer for treating depression/ MDD (See Example 6, 9-10, [533], Table 12). A skilled artisan in the art would have known relapse of agitation associated with Alzheimer’s would occur if a medication is discontinued or if the medication's effectiveness wanes. It would have been obvious and logical for a skilled artisan to measure/monitor the treatment outcome (e.g. CMAI, PGI-C score, etc.) and continue administering combination of dextromethorphan and bupropion to the patient having agitation associated with Alzheimer’s for longer period time (e.g. 3 month, 6 month, or longer) wherein the patients in need respond positively to the combination therapy at week 5 (CMAI >30% improvement ) and exhibits no adverse event.
Ward reviews medications used for treatment of agitation in patients with Alzheimer’s disease and extensively teaches AXS-05 is a novel formulation of dextromethorphan and bupropion,
administered twice daily, that is being investigated in Phase I, II/III clinical trials for treating agitation in patients with Alzheimer’s Disease (See full article).
Regarding instantly claimed combination therapy, Ward teaches AXS-05 is combination of dextromethorphan and bupropion (CYP2D6 inhibitor to boost concentrations of dextromethorphan) for treating agitation in patients with Alzheimer’s Disease (See page 774, Article highlights, Drug summary)
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Ward teaches ADVANCE-1 is a phase II/phase III clinical trial (NCT03226522) completed in 2020 (See page 774, Box 1; page 776, Clinical efficacy),“ patients were maintained at 45 mg dextromethorphan/105 bupropion twice daily. The primary endpoint was change in the CMAI from baseline to week 5, and multiple secondary endpoints were identified, including a definition of clinically significant response as a reduction of at least 30% from baseline in the CMAI as compared to placebo… wherein CMAI score began to differ significantly from the bupropion and placebo groups by week 2. Five-week reductions in the CMAI score were −15.4 for the AXS-05 group, −10.0 for the bupropion group, and −11.5 for the placebo group. Statistical comparisons between changes in the CMAI for the AXS-05 were significant with a p-value of <0.001 in comparison to bupropion and 0.010 in comparison to placebo. Clinical response (defined as a 30% reduction in baseline CMAI) was also assessed; by week 5, 73.2% of patients in the AXS-05 group met response criteria, vs 57.1% of patients in the placebo group” (See page 777, left column)(which reads on instantly claimed CMAI limitation).
Ward also teaches two additional ongoing studies investigating efficacy and safety of AXS-05 for patients with AD and agitation, The Assessing Clinical Outcomes in Alzheimer’s Disease Agitation (ACCORD) study (NCT04797715) is a phase III relapse prevention trial that has inclusion criteria similar to the ADVANCE-1 study, “ Following a 4-week screening period, participants are given AXS-05, to be taken twice daily, for 9 weeks. Responders are then randomized to placebo or AXS-05 for as long as 26 weeks and the primary outcome measure is time from randomization to relapse of agitation symptoms” (See page 777, left and right column)( which reads on instantly claimed longer treatment period and limitation of agitation relapse). Please note the study design/ description of ACCORD (NCT04797715) is available at clinicaltrials.gov since 05/2021 (See NCT04797715, version 1, available on 05/11/2021).
Ward teaches “AXS-05 represents a potentially safer alternative to medications that are currently used off-label for the treatment of agitation in patients with AD, such as antipsychotics. It may also be especially useful for the approximate 52% of patients with AD and comorbid depression” (See page 777, Conclusion, Expert opinion).
It would have been obvious to one of the ordinary skilled in the art before the effective filing date of instantly claimed invention to further explore the method of treating agitation associated with Alzheimer’s with combination of dextromethorphan and bupropion (e.g. treatment outcome, period of treatment time, relapse, etc.), based on combined teachings of prior art and general knowledge of treating neurological disorder (e.g. agitation associated with Alzheimer’s, depression), and arrived instantly claimed invention with reasonable expectation of success. Before the effective filing date of instantly claimed invention, method of treating/maintaining response in patients having agitation associated with Alzheimer’s comprising orally administering combination of 45 mg DM and 105 mg BU in solid dosage form (AXS-05) twice daily wherein patient exhibit positive response with 30% or greater improvement of CMAI at week 5 was already known as taught by Tabuteau’419 and Ward. A skilled artisan in the art would also know relapse of agitation associated with Alzheimer’s would occur if a medication is discontinued or if the medication's effectiveness wanes. Adjusting treatment period based on evaluation of treatment outcome/assessment of patient’s response is within the knowledge of a skilled artisan in the art. A skilled artisan would be motivated to measure/monitor the treatment outcome (e.g. CMAI, PGI-C score, etc.) and continue administering combination of dextromethorphan and bupropion to the patient having agitation associated with Alzheimer’s for longer period time (e.g. 3 month, 6 month) wherein the patients in need respond positively to the combination therapy at week 5 and exhibits no adverse event. Further exploration of longer treatment period while monitoring treatment outcome ( e.g. CMAI, PGI-C score) would provide an effective long term treatment for agitation associated with Alzheimer’s while lowering relapse risk and improve the qualities of patients and caregivers.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and exploration/optimization of administration regimen (e.g. treatment period) for intended treatment outcome based on the general knowledge of treating neurological disorder (e.g. agitation associated with Alzheimer’s, depression). Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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 3-10, 12-20, and 22-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11007189 B2 in view of Ward et al. (Expert Opinion On Investigational Drugs, 2022, VOL. 31, NO. 8, 773–780, Applicant’s IDS dated 06/11/2025, “ AXS-05 : an investigational treatment for Alzheimer’s disease-associated agitation” ).
References claims are directed to a method of treating agitation in a human patient with Alzheimer's disease, comprising administering a drug combination of bupropion and dextromethorphan to the human patient wherein administering the drug combination is more effective in treating agitation in the human patient than administering a placebo.
Reference claim 6 recites the drug combination is administered for at least 30 consecutive days.
Reference claims 7-8 and 11-12 recites solid dosage form and limitation that read on instant solid dosage form. Reference claim 16 recites administering 105 mg of bupropion hydrochloride twice a day.
Reference claims are directed to administering the same or similar BU/DM combination to the same subject (patients having agitation associated with Alzheimer’s). The difference of instant claims and reference claims are recitation of treatment outcome (e.g. CMAI, PGI-C, etc.) and extended longer treatment period. As noted in Claim Interpretation section, recitations of treatment outcome/ intended results of the active method step do not materially change the claimed method since such limitations do not result in manipulative difference in method steps of the claims.
Ward’s collective teachings are elaborated in preceding 103 rejection and applied as before. Ward teaches The Assessing Clinical Outcomes in Alzheimer’s Disease Agitation (ACCORD) study (NCT04797715) is a phase III relapse prevention trial that has inclusion criteria similar to the ADVANCE-1 study, “ Following a 4-week screening period, participants are given AXS-05, to be taken twice daily, for 9 weeks. Responders are then randomized to placebo or AXS-05 for as long as 26 weeks and the primary outcome measure is time from randomization to relapse of agitation symptoms”.
A skilled artisan in the art would know relapse of agitation associated with Alzheimer’s would occur if a medication is discontinued or if the medication's effectiveness wanes. It would have been prima facie obvious to one of ordinary skilled in the art to continue administering the combination of dextromethorphan and bupropion for those patients responsive to the treatment in order to observe a long-term treatment efficacy or maintain such clinical responses or reduce agitation relapse. Adjusting treatment period and dosage based on evaluation of treatment outcome/assessment of patient’s response is within the general knowledge of a skilled artisan in the art. A skilled artisan would have known to measure the treatment outcome (e.g. CMAI, PGI-C score, etc.) and continue administering BU/DM combination wherein the patient is responsive to the treatment to reduce/delay agitation relapse as indicated by Ward. The skilled artisan would have been motivated to continue the treatment which showed promising clinical response for additional period of time on the reasonable expectation of success of maintaining such clinical response/reducing or delaying agitation relapse. Instantly claimed treatment outcome could have been achieved by practicing reference claimed method teaching administering the same or similar BU/DM combination to the same subject (patients having agitation associated with Alzheimer’s). Thus, instant invention as a whole would have been prima facie obvious to one of ordinary skill in the art as evidenced by reference claims and Ward, especially in the absence of evidence to the contrary.
The instant application shares at least one common inventor/applicant with the reference patent. Further, the continuing data of instant application is not related to the reference patent and thus no 35 USC 121 shield exists. See MPEP 804.01.
Claims 3-10, 12-20, and 22-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending application No. 19/255,952. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Please note Notice of Allowance of 19/255,952 was mailed on 03/13/2026 and issue fee was paid on 05/13/2026.
Although the claims at issue are not identical, they are not patentably distinct from each other,
References claims are directed to a method of maintaining a clinical response in the treatment of agitation associated with Alzheimer's disease or reducing relapse of agitation in Alzheimer's disease in a human patient wherein the human patient has experienced a sustained clinical response as a result of receiving a combination of bupropion and dextromethorphan, comprising administering a drug combination of bupropion and dextromethorphan to the human patient wherein administering the drug combination is more effective in treating agitation in the human patient than administering a placebo.
Reference claims 1 and 3 recite a sustained clinical response comprises a 30% or greater improvement from baseline in the human patients Cohen- Mansfield Agitation Inventory (CMAI) total score which is maintained for at least 4 consecutive weeks. Reference claim 2 recites a sustained clinical response further comprises maintaining a Patient Global Impression of Change (PGI-C) score of 3 or less for at least 4 consecutive weeks.
Reference claim 5-7 and 17-19 recite the drug combination is administered for at least 4 weeks, at least 3 months or at least 6 months (which reads on instant claims 5-7).
Reference claims 8-15 and 20-26 recite solid dosage form and limitation that read on instant solid dosage form. Reference claim 16 recites administering 105 mg of bupropion hydrochloride twice a day.
Reference claims 27-30 recite treatment outcome that read on instant claims 12-15, e.g. wherein the percentage of human patients with agitation relapse is lower with administration of the dosage form than taking a placebo, delays the time to relapse of agitation symptoms as compared to a placebo, etc.
Reference claims are directed to administering the same or similar BU/DM combination to the same subject wherein the human patient has experienced a sustained clinical response as a result of receiving a combination of bupropion and dextromethorphan. Although reference claims do not explicitly recite “ continued treatment”, the scope of reference claims essentially overlaps with instant claims. It would have been prima facie obvious to one of ordinary skilled in the art to continue administering the combination of dextromethorphan and bupropion for those patients responsive to the treatment in order to observe a long-term treatment efficacy or maintain such clinical responses or reduce agitation relapse as taught by reference claims. A skilled artisan would have reasonably expectation of success based on the teaching of treatment outcome by reference claims.
The instant application shares at least one common inventor/applicant with the reference patent. Further, the continuing data of instant application is not related to the reference patent and thus no 35 USC 121 shield exists. See MPEP 804.01.
There are over 200 patent documents with Tabuteau as the inventor in IDS and in PDP. The following double patenting rejections are summarized with similar obviousness rationale as previously elaborated in double patenting rejection over US 11007189 B2 in view of Ward.
Claims 3-10, 12-20, and 22-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over the reference claims of the following U.S. Patent Nos. in view of Ward (Expert Opinion On Investigational Drugs, 2022, VOL. 31, NO. 8, 773–780, Applicant’s IDS dated 06/11/2025, “ AXS-05 : an investigational treatment for Alzheimer’s disease-associated agitation” ):
US 11147808 (claims 1, 3, 6, 12, 14, 17-18, 23);
US 11207281 (claims 1, 5, 8 and 16) ;
US11253492 (claims 1, 3, 6, 13, 20, and 27-28) ;
US 11273134 (claims 1, 6, 9, 13, 17, 19) ;
US 11285146 (claims 1, 6, 9, 13, 17 and 19) ;
US 11285118 (claims 1, 6, 9, 13, 17 and 19) ;
US 11291638 (claims 1, 6, 9, 13, 17 and 19);
US 11291665 (claims 1, 6, 9, 13, 17 and 19) ;
US 11298352 (claims 1, 6, 9, 13, 17 and 19) ;
US 11344544 (claims 1, 6, 9, 13, 17 and 19) ;
US 11364233 (claims 1, 5, 8-9, 17, and 26) ;
US 11382874 (claims 1, 6, 9, 13, 17 and 19) ;
US 11419867 (claims 1, 9, 13, 17 and 19) ;
US 11426370 (claims 1, 6, 8, 11, 14 and 16) ;
US 12194036 (claims 1, 3-17, claim 3-17 further teaches solid dosage form) ;
US 12194005 (claims 1, 3 and 10. Claims 1 and 10 further teach dextromethorphan hydrobromide is in an immediate-release formulation, wherein the bupropion hydrochloride is in an extended-release formulation);
US 12239642 (claims 1 -22; claims 4-15 and 19-20 further teach dosage form limitation);
US 12263161 (claims 1-22, claims 4-22 further teaches dosage form limitation);
US 12370154 (claims 1 and 14, US application 18/667581, granted on 07/29/2025).
US 12433884 (claims 1-21, US application 19/182, 463, granted on 10/07/2025).
Although the claims at issue are not identical, they are not patentably distinct from each other because reference claims cited above are drawn to a method for the treatment of agitation associated with Alzheimer's disease comprising orally administering a solid dosage form comprising dextromethorphan and bupropion in the same or overlapping amounts to a human being once or twice a day for at least 8 days or 30 days.
The difference of instant claims and reference claims are recitation of intended result/ treatment outcome (e.g. CMAI, PGI-C, etc.) and extended longer treatment period. As noted in Claim Interpretation section, recitations of treatment outcome/ intended results of the active method step do not materially change the claimed method since such limitations do not result in manipulative difference in method steps of the claims.
Ward’s collective teachings are elaborated in preceding 103 rejection and applied as before. It would have been prima facie obvious to one of ordinary skilled in the art to continue administering the combination of dextromethorphan and bupropion for those patients responsive to the treatment in order to observe a long-term treatment efficacy or maintain such clinical responses or reduce agitation relapse. Adjusting treatment period and dosage based on evaluation of treatment outcome/assessment of patient’s response is within the general knowledge of a skilled artisan in the art. A skilled artisan would have known to measure the treatment outcome (e.g. CMAI, PGI-C score, etc.) and continue administering BU/DM combination wherein the patient is responsive to the treatment. The skilled artisan would have been motivated to continue the treatment which showed promising clinical response for additional period of time on the reasonable expectation of success of maintaining such clinical response or reducing agitation relapse. Instantly claimed treatment outcome could have been achieved by practicing reference claimed method teaching administering the same or similar BU/DM combination to the same or similar subject (patients having agitation associated with Alzheimer’s). Thus, instant invention as a whole would have been prima facie obvious to one of ordinary skill in the art as evidenced by reference claims and Ward, especially in the absence of evidence to the contrary.
The instant application shares at least one common inventor/applicant with the reference patent. Further, the continuing data of instant application is not related to the reference patent and thus no 35 USC 121 shield exists. See MPEP 804.01.
Claims 3-8, 12-18, 21- 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of the following copending application Nos. in view of Ward (Expert Opinion On Investigational Drugs, 2022, VOL. 31, NO. 8, 773–780, Applicant’s IDS dated 06/11/2025, “ AXS-05 : an investigational treatment for Alzheimer’s disease-associated agitation” ):
18/778,708 (claims 16-37, claims 22-37 further teach limitation of dosage form);
18777011 (claims 21-38, claims 24-36 further teach limitation of dosage form );
18/061091 (claims 1-20);
17/930829 (claims 21-45, claims 22-24, 43-45 further teach limitation of dosage form);
17/571110 (claims 21, 25 and 35); and
17/541461 (claims 5, 8, 12, 16, 19).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the instant application and the claims of the copending applications cited above are drawn to a method for treating agitation in Alzheimer’s disease comprising orally co-administering dextromethorphan and bupropion in the same or overlapping amounts to a human being in need thereof once or twice a day. The rationale/reasoning of obviousness rendered by reference claims and Ward are similar as elaborated in previous double patenting rejections. These are provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/L.M./Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628
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