DETAILED ACTION
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 .
Response to Amendments
Applicant’s amendments to the claims of July 14, 2025, in response to the Office Action of April 15, 20225, are acknowledged.
Response to Arguments
In view of the Amendments to the claims, a new rejection is set forth below as necessitated by the same. In particular, Applicant has limited the claims to include DEX and BUP as the sole active agents. This obviates the previously cited prior art which included additional agents. Further and as explained below, the claims including DEX HBr are not entitled to the earliest priority date claimed. As such, prior art filed by Applicant is applied to reject these claims. In particular, the DEX HBr is not mentioned in parent application 16/246,347, among others.
For those claims that include the hydrobromide salt form of DEX, an earlier publication from the present family of applications has been applied below in a rejection.
In an effort to address the new limitation that the sole APIs in the claimed composition are DEX and BUP, the examiner applies Berg, (US20090111846), in view of Tod et al., “Quantitative Prediction of Cytochrome P450 (CYP) 2D6-Mediated Drug Interactions," Clin Pharmacokinetic 2011;50(8):519-530.
As noted in the Non-Final Office Action, any allegation of unexpected results is required to be presented in each application in which it is alleged. The examiner will not rely on allegations of unexpected results filed in a related application to obviate an obviousness rejection in this matter. The examiner is determining herein if a prima facie showing of obviousness in established in view of the cited prior art.
With respect to traversal of the DP rejections, the examiner notes that treatment includes amelioration of a symptom. In this case, anxiety is known to be a symptom of depression. The Specification explicitly lists it as such. Further, the cited prior art teaches treating depression and anxiety with the claimed combination. BUP is known to potently inhibit CYP2D6 leading to a predictable increase in PK, such as AUC and Cmax, of DEX. Further and as evidenced by Dr. Beth Salcedo in her article “The Comorbidity of Anxiety and Depression,” Dr. Salcedo states: “In mental health, one of the more common comorbidities is that of depression and anxiety. Some estimates show that 60% of those with anxiety will also have symptoms of depression, and the numbers are similar for those with depression also experiencing anxiety.” Not only are they thought to have similar mechanisms of action, by they have many overlapping symptoms. Thus, while they are distinct disorders, treatment includes treating symptoms which overlap in most instances. Additionally, the prior art teaches treating both anxiety and depression with DEX potentiated by BUP. More importantly, the subjects being claimed in the issued patents and patent applications cited below are explicitly taught to have anxiety as a symptom thereof even if the condition the subject is described to have is depression or MDD. A subject would be treated with depression or anxiety in view of the prior art and they would be treated if they have MDD or another form of depression if anxiety is a symptom because DEX and BUP treat both. For each DP rejection below in which the issued claims are directed to a subject with depression, the examiner noted that anxiety is claimed to be a symptom.
As such, the Double Patenting Rejections are maintained.
Status of the Claims
Claims 1-14 are pending and examined.
Priority Date of the Claims
The instant claims include multiple limitations including: dextromethorphan hydrobromide. Dextromethorphan hydrobromide does not find support in parent application 16/246,347 nor 16/130,898. As such, this particular limitation and the claims comprising this limitation do not have priority prior to the filing date of the instant application, which is March 6, 2023. Claims 2, 5, and 8-10 are rejected below. Tabuteau et al., (US2015/0126544) (published on May 7, 2015) is applied below as Tabuteau qualifies as prior art with respect to claims 2, 5, and 8-10.
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.
Claims 1-14 are rejected under 35 U.S.C. 103 as being unpatentable over Berg, (US20090111846) (cited in IDS), in view of Tod et al., “Quantitative Prediction of Cytochrome P450 (CYP) 2D6-Mediated Drug Interactions," Clin Pharmacokinetic 2011;50(8):519-530 (cited in IDS).
Berg teaches a method for treating depression and anxiety by administering a combination of dextromethorphan and quinidine, wherein 10 mg to 200 mg dextromethorphan is administered and 1 to less than about 50 mg is administered per day (prior art claim 1). Dextromethorphan acts as a non-competitive antagonist of N-methyl-D-aspartate-sensitive ionotropic glutamate receptor (par. 51). Additionally, Cytochrome P450 2D6 is the key enzyme that breaks down dextromethorphan to dextrorphan. Quinidine is a drug that inhibits the activity of the key enzyme that breaks down dextromethorphan, thereby increase the concentration of dextromethorphan in plasma (par. 52). Berg indicates that there is a need to develop treatments that treat those with depression and anxiety, which includes 10-30% of subjects. Subjects were administered a combination of DEX/QUI twice daily for 28 consecutive days (par. 28). Additionally, “common dosage forms” can be administered by sustained release, delayed release, or controlled release (par. 155). They can be administered as oral formulations in the form of a solid preparation, such as a tablet with carriers. See par.’s 154-156.
Berg does not teach bupropion for use with dextromethorphan.
Tod teaches in Table II, that 300 mg bupropion (daily) had an inhibition ratio on Cytochrome P450 2D6 that is similar to quinidine. Bupropion is confirmed as a strong inhibitor of CYP2D6 based on the metabolites erythrohydroxybupropion and threohydroxybupropion in vivo (p526, 1st par). Further, Figure 3 shows that the predicted AUC ratios in the presence of various inhibitors notes that the combinations of DEX/QUI and DEX/BUP yield the highest predicted AUC ratio.
The examiner believes that a person having ordinary skill in the art would be able to optimize the concentration of bupropion to use with the dosage of dextromethorphan taught by Berg based on the known mechanism of action and whether or not the DEX is immediate release or sustained release, e.g. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the instant application to combine the teachings of Berg and Tod to arrive at a method of treating anxiety and/or depression by administering a combination of dextromethorphan and a CYP2D6 inhibitor, such as quinidine or bupropion. One would have been motivated to do so because Berg teaches such combination with prevent the enzymatic conversion of dextromethorphan to dextrorphan. Such prevention will prolong the efficacy of the DEX. Further, such combination is taught by Berg to treat anxiety and/or depression and the overall dosage of DEX and BUP taught by the prior art are substantially similar and overlap claimed dosages. Thus, a person having ordinary skill would have a reasonable expectation of success in administering DEX/BUP and optimizing the concentration of each agent whether the formulation is an IR or a SR formulation based on the known mechanisms of action of each agent and the known efficacy in treating the claimed subject population having depression.
Applicant can obviate this rejection by providing unexpected results in the form of an affidavit that is commensurate in scope with the claimed subject matter.
Claims 2, 5, and 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Tabuteau et al., (US2015/0126544) (published on May 7, 2015), in view of Nelson, (U.S. Pat. No. 4,316,888).
Tabuteau teaches dextromethorphan with bupropion and pharmaceutically acceptable salts of the same, and an excipient for treating conditions including depression, anxiety, and generalized anxiety disorder. See par. 96 and prior art claim 1. Dextromethorphan solid forms can comprise 20 to 50 mg or discreet amounts of about 40 mg and about 50 mg. See par.’s 137 and 139. Further, bupropion solid forms can comprise about 95 mg, 100 mg, 110 mg, and others. See par. 159. Tablet forms can include HPMC, e.g. See par. 131. Dosages can be administered once or twice daily, e.g. See par. 91. Component APIs can be in a single composition or dosage form comprising both agents or separate compositions or dosage forms. See par. 115. The DEX and BUP can be in separate phases in the same composition and one may be sustained release while the other is immediate release. See par.’s 130-131. DEX can be immediate release with sustained release bupropion, e.g. See par. 131. Excipients can be used. See par.’s 181-182.
Nelson teaches dextromethorphan hydrobromide was a known salt form of DEX that was administered orally in the form of a tablet with excipients. See prior art claim 5.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application to arrive at the claimed invention in view of Tabuteau and Nelson. One would be motivated to do so because Tabuteau teaches the claimed subject population, APIs, dosages, form, excipients and the use of salt forms. Further, Nelson teaches the claimed hydrobromide salt form of DEX was known at the time and was able to be administered orally in the form of a tablet. As such, there is a reasonable and predictable expectation of success in using a known HBr salt for of DEX in view of the generic recitation and teachings of using salts of DEX in a claimed method. As such, the claims reciting DEX HBr are rejected.
Double Patenting Rejections
The nonstatutory double patenting (NSDP) 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 NSDP 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 §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over the allowed claims of the following U.S. Patent Nos., in view of the cited Tabuteau references set forth above, and in view of Berg, (US20090111846), in view of Tod et al., “Quantitative Prediction of Cytochrome P450 (CYP) 2D6-Mediated Drug Interactions," Clin Pharmacokinetic 2011;50(8):519-530.
US 12109178 B2, 1-18 (MDD) (anxiety listed as symptom therein)
US 12036191 B1, 1-30 (MDD) (anxiety listed as symptom therein)
US 11986444 B2, 1-29 (MDD) (anxiety listed as symptom therein)
US 11969421 B2, 1-29 (MDD) (anxiety listed as symptom therein)
US 11896563 B2, 1-20 (depression and reducing risks)
US 11844797 B1, 1-14 (MDD) (anxiety listed as symptom therein)
US 11730706 B1, 1-20 (MDD) (anxiety listed as symptom therein)
US 11717518 B1, 1-23 (MDD) (anxiety listed as symptom therein)
US 11617747 B2, 1-15 (increasing plasma levels)
US 11617728 B2, 1-21 (MDD) (anxiety listed as symptom therein)
US 11596627 B2, 1-17 (MDD) (anxiety listed as symptom therein)
US 11590124 B2, 1-15 (increasing plasma levels)
US 11576909 B2, 1-15 (increasing plasma levels)
US 11576877 B2, 1-27 (MDD) (anxiety listed as symptom therein)
US 11571417 B2, 1-14 (increasing plasma levels)
US 11571399 B2, 1-27 (MDD) (anxiety listed as symptom therein)
US 11541021 B2, 1-14 (depression)
US 11541048 B2, 1-17 (MDD) (anxiety listed as symptom therein)
US 11534414 B2, 5-11 and 16-21 (systemically deliver)
US 11524007 B2, 1-17 (MDD) (anxiety listed as symptom therein)
US 11517543 B2, 1-19 (MDD) (anxiety listed as symptom therein)
US 11517542 B2, 1-17 (MDD) (anxiety listed as symptom therein)
US 11510918 B2, 1-17 (MDD) (anxiety listed as symptom therein)
US 11497721 B2, 1-17 (MDD) (anxiety listed as symptom therein)
US 11478468 B2, 1-19 (MDD) (anxiety listed as symptom therein)
US 11439636 B1, 1-22 (increasing plasma levels)
US 11433067 B2, 4-10 and 14-19 (systemically deliver)
US 11426370 B2, 1-17 (increasing plasma levels)
US 11426401 B2, 1-23 (increasing plasma levels)
US 11419867 B2, 1-20 (increasing plasma levels)
US 11382874 B2, 1-20 (increasing plasma levels)
US 11364233 B2, 1-27 (increasing plasma levels)
US 11357744 B2, 1-14 (increasing plasma levels)
US 11344544 B2, 1-20 (increasing plasma levels)
US 11311534 B2, 1-12 (treatment-resistant depression) (anxiety is a symptom)
US 11298352 B2, 1-20 (increasing plasma levels)
US 11298351 B2, 1-12 (MDD) (anxiety listed as symptom therein)
US 11291638 B2, 1-20 (increasing plasma levels)
US 11291665 B2, 1-20 (increasing plasma levels)
US 11285146 B2, 1-20 (increasing plasma levels)
US 11285118 B2, 1-20 (increasing plasma levels)
US 11273134 B2, 1-20 (increasing plasma levels)
US 11273133 B2, 1-30 (increasing plasma levels)
US 11253491 B2, 1-30 (MDD) (anxiety listed as symptom therein)
US 11253492 B2, 1-28 (increasing elimination half-life)
US 11234946 B2, 1-14 (increasing plasma levels)
US 11229640 B2, 1-27 (depression)
US 11213521 B2, 1-12 (MDD) (anxiety listed as symptom therein)
US 11207281 B2, 1-22 (reducing plasma levels of metabolite)
US 11197839 B2, 16-21 (systemic delivery)
US 11191739 B2, 16-21 (systemic delivery)
US 11185515 B2, 1-13 (MDD) (anxiety listed as symptom therein)
US 11147808 B2, 1-29 (decreasing fluctuation index)
US 11141388 B2, 1-27 (MDD) (anxiety listed as symptom therein)
US 11141416 B2, 1-12 (treatment-resistant depression) (anxiety is a symptom)
US 11129826 B2, 1-23 (depression)
US 11123344 B2, 1-30 (plasma levels)
US 11123343 B2, 1-23 (MDD) (anxiety listed as symptom therein)
US 11096937 B2, 1-13 (MDD) (anxiety listed as symptom therein)
US 11090300 B2, 1-12 (MDD) (anxiety listed as symptom therein)
US 11065248 B2, 1-30 (plasma levels)
US 11058648 B2, 1-30 (MDD) (anxiety listed as symptom therein)
US 11020389 B2, 1-18 (MDD) (anxiety listed as symptom therein)
US 10966974 B2, 1-12 (depression) (anxiety listed as symptom therein)
US 10966942 B2, 1-20 (MDD) (anxiety listed as symptom therein)
US 10966941 B2, 1-22 (plasma levels)
US 10945973 B2, 1-29 (MDD) (anxiety listed as symptom therein)
US 10940124 B2, 1-20 (MDD) (anxiety listed as symptom therein)
US 10933034 B2, 1-12 (depression) (anxiety listed as symptom therein)
US 10925842 B2, 1-20 (MDD) (anxiety listed as symptom therein)
US 10898453 B2, 1-10 (MDD) (anxiety listed as symptom therein)
US 10894046 B, 1-27 (MDD) (anxiety listed as symptom therein)
US 10894047 B2, 1-13 (MDD) (anxiety listed as symptom therein)
US 10881657 B2, 1-9, (MDD) (anxiety listed as symptom therein)
US 10874665 B2, 1-15 (treatment-resistant depression) (anxiety is a symptom)
US 10874663 B2, 1-14 (treatment-resistant depression) (anxiety is a symptom)
US 10874664 B2, 1-10 (treatment-resistant depression) (anxiety is a symptom)
US 10864209 B2, 1-12 (treatment-resistant depression) (anxiety is a symptom)
US 10799497 B2, 1-14 (MDD) (anxiety listed as symptom therein)
US 10786469 B2, 1-24 (plasma levels in depression) (anxiety listed as symptom therein)
US 10780064 B2, 1-23 (MDD) (anxiety listed as symptom therein)
US 10772850 B2, 1-28 (depression) (anxiety listed as symptom therein)
US 10512643 B2, 1-11 (enhancing plasma)
US 10251879 B2, 1-29 (in need of treatment)
US 10105361 B2, 1-30 (reducing trough effect)
US 10105327 B2, 1-28 (enhance plasma)
US 10092561 B2, 1-29 (AUC, pharmacokinetic effect)
US 10080727 B2, 1-22 (increasing metabolic life)
US 10058518 B2, 1-26, (reducing trough effect)
US 9968568 B2, 1-30 (enhancing plasma)
US 9867819 B2, 1-29 (correcting metabolism)
US 9861595 B2, 1-29 (increasing plasma)
US 9763932 B2, 1-29 (enhancing bioavailability)
US 9707191 B2, 1-30 (reducing trough effect)
US 9700528 B2, 1-29 (plasma levels)
US 9474731 B1, 1-20 (metabolic lifetime)
US 9457025 B2, 1-30 (plasma levels)
US 9457023 B1, 1-25, (extending plasma levels)
US 9408815 B2, 1-30 (exposure)
US 9198905 B2, 1-18 (metabolic lifetime)
US 9168234 B2, 1-12 (co-administration).
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 patents cited above are drawn to a method of administering a combination of dextromethorphan and bupropion to a human being in need of treatment. These dosage combinations are known to treat depression and anxiety, and anxiety is taught to be a symptom of depression in the instant Specification. Further, the use of BUP, which is confirmed as a strong inhibitor of CYP2D6, will be expected to potentiate the effects of DEX for any condition that DEX treats because it will increase the bioavailability and predictably alter AUC and Cmax. The dosages and pharmacokinetic parameters that are a direct product of administration are optimizable through nothing more than routine experimentation. The resulting pharmacokinetic parameters, including AUC, are a result of the administration of the combination of DEX and BUP are optimizable dosages. The advantages of administration are considered a result of the combination not a specific claimed dosage or excipient absent evidence to the contrary. Anxiety is a symptom and common comorbidity of depression. The patents above include administration of the claimed combination to the claimed subject population.
This is a non-provisional NSDP rejection because the claims have been patented.
Claims 1-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the following pending claims of copending Application Nos. and in view of Berg, (US20090111846), in view of Tod et al., “Quantitative Prediction of Cytochrome P450 (CYP) 2D6-Mediated Drug Interactions," Clin Pharmacokinetic 2011;50(8):519-530.
18/333,944 (1-8, 12-20, 22) (anxiety is a listed symptom in disclosure);
18/601,603 (1-15) (symptoms of depression);
17/541,461 claims 1-22 (reducing plasma levels);
17/571,110 claims 21-40 (increasing plasma levels);
18/156,825 (1-30) (nervous system condition, including GAD claim 30);
18/157,266 (1-4, 8-11, 15-16) (anxiety);
18/170,151 (1-22) (nervous system disorder, including anxiety);
18/172,555 (1-30) (nervous system condition, including GAD claim 7);
18/172,617 (1-25) (nervous system condition, including GAD claim 7);
18/173,372 (1-30) (nervous system condition, including GAD claim 7);
18/174,123 (1-24) (nervous system condition, including GAD claim 7);
18/174,278 (1-19) (depressive symptoms);
18/175,865 (1-25) (nervous system condition, including GAD claim 7); and
18/175,862 (1-24) (nervous system condition, including GAD claim 7).
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 patents cited above are drawn to a method of administering a combination of dextromethorphan and bupropion to a human being in need of treatment. These dosage combinations are known to treat depression and anxiety, and anxiety is taught to be a symptom of depression in the instant Specification. Further, the use of BUP, which is confirmed as a strong inhibitor of CYP2D6, will be expected to potentiate the effects of DEX for any condition that DEX treats because it will increase the bioavailability and predictably alter AUC and Cmax. The dosages and pharmacokinetic parameters that are a direct product of administration are optimizable through nothing more than routine experimentation. The resulting pharmacokinetic parameters, including AUC, are a result of the administration of the combination of DEX and BUP are optimizable dosages. The advantages of administration are considered a result of the combination not a specific claimed dosage or excipient absent evidence to the contrary. Anxiety is a symptom and common comorbidity of depression. The patents above include administration of the claimed combination to the claimed subject population. The dosages and pharmacokinetic parameters that are a direct product of administration are optimizable through nothing more than routine experimentation. The resulting pharmacokinetic parameters, including AUC, are a result of the administration of the combination of DEX and BUP are optimizable dosages. The advantages of administration are considered a result of the combination not a specific claimed dosage or excipient absent evidence to the contrary. Anxiety is a symptom and common comorbidity of depression. The patents above include administration of the claimed combination to the claimed subject population.
This is a provisional NSDP rejection because the patentably indistinct claims have not been patented.
As such, no claim is allowed.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D. BARSKY whose telephone number is (571)-272-2795. The examiner can normally be reached on Monday through Friday from 8:30 to 5:30. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Amy L. Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628