DETAILED ACTION
This office action is in response to applicant’s filing dated June 18, 2025.
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 .
Status of Claims
Claims 1, 3-9, 26, 27, and 31-38 are pending in the instant application. Acknowledgement is made of Applicant's remarks and amendments filed June 18, 2025. Acknowledgement is made of Applicant's amendment of claims 1, 3-9, 26, and 27; cancelation of claims 2, 10-25, and 28-30; and addition of new claims 31-38.
Applicants elected without traverse Group I, drawn to a method for treating a patient suffering from a major depressive disorder, which comprises treating said patient with a 5HT3-antagonist in combination with an effective daily dose of pramipexole or a pharmaceutically acceptable salt thereof as the elected invention and ondansetron as the elected 5HT3 antagonist species in the reply filed on September 15, 2021. The requirement is still deemed proper.
New claims 31-38 are directed to the elected species and thus are presently under examination.
Claims 1, 3-9, 26, 27, and 31-38 are presently under examination as they relate to the elected species: ondansetron.
Ondansetron is also known as 1,2,3,9-tetrahydro-9- methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one as evidenced by the instant specification (see page 16, lines 21-23).
Priority
The present application is a 371 of PCT/US2018/028885 filed on April 23, 2018, which claims benefit of US Provisional Application No. 62/489,016 filed on April 24, 2017. The effective filing date of the instant application is April 24, 2017.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on June 18, 2025 and June 26, 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Objections and/or Rejections and Response to Arguments
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
Modified Objections and/or Rejections
Modifications Necessitated by Claim Amendment
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 nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 9, 26, 27, 31-33, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Bryson et al (WO 2012/083269 A1, cited in a previous Office Action) in view of Legarda Ibanez (US 2011/0034442 A1, cited in a previous Office Action).
Regarding claims 1, 3, and 37, Bryson teaches a method of treating a depressive disorder in a subject, said method comprising sublingual administration of a pharmaceutical composition comprising a dopamine agonist, pramipexole in an amount effective to treat said subject (claims 23, 25, 67, and 82), further comprising administration of an effective amount of an anti-emetic agent (claim 83), wherein said anti-emetic agent is ondansetron (claim 84). Bryson teaches by “depressive disorder” is meant any psychological or psychiatric disorder associated with symptoms of depressed mood; treatable depressive disorders may be characterized by an inhibition or reduction of dopaminergic function in the nucleus accumbens, e.g., major depression (page 17, lines 18-20; page 29, lines 9-11). Bryson teaches the formulations can be administered in therapeutically effective amounts; an amount is administered which prevents, reduces, or eliminates the symptoms of depression (page 29, lines 30-32); and typical dose ranges are from about 0.1 mg to about 20 mg of pramipexole, or a salt thereof, given up to five times per day. This reads on an effective daily dose. Thus, Bryson teaches a method of treating major depression comprising administering pramipexole in combination with the elected 5HT3 agonist, ondansetron.
Bryson does not explicitly teach ondansetron is administered in the claimed amount.
However, Legarda Ibanez teaches a method for treating a patient with a central nervous system (CNS) disorder comprising administering to the patient a therapeutically effective amount of a combination comprising ondansetron (claim 11), wherein the CNS disorder is depression (claim 14); wherein said therapeutically effective amount of ondansetron is from 1 mg to 8 mg per dose (claim 17).
It would have been prima facie obvious to one of ordinary skill in the art to utilize the amount of ondansetron taught by Legarda Ibanez as a starting point for optimizing the amount of ondansetron utilized to treat major depression since Legarda Ibanez teaches ondansetron is useful for treating depression and because dosage is a result-effective variables, i.e., a variable that achieves a recognized result. Therefore, the determination of the optimum or workable dosages would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Regarding claim 9, Bryson teaches the sublingual formulations may be in unit dosage form in the shape of, for example, a lozenge, a pill, a tablet, a fil, or a strip or in non-unit dosage forms such as a gel (page 29, lines 16-19 and claims 23 and 24); a pharmaceutical composition comprises a low molecular weight polymer including hydroxypropyl methyl cellulose. This reads on a pharmaceutically acceptable carrier.
Regarding claim 26 and 27, Bryson teaches the pharmaceutical compositions of the invention can provide a rapid-dissolving, rapid absorption solid oral dosage form (page 20, lines 27-28).
Taken together, all this would result in the practice of the method of claims 1, 3, 9, 26, 27, and 37 with a reasonable expectation of success.
Regarding claims 31-33, the cited art does not explicitly teach a pharmaceutical composition comprising pramipexole and ondansetron in separate compositions with pharmaceutical carrier or vehicle. However, Bryson teaches apomorphine and pramipexole are alternatively useful as dopamine agonists (page 6, lines 7-9). Bryson teaches in certain instances it may be desirable to incorporate the anti-emetic into the sublingual formulation for simultaneous administration in combination with apomorphine, or apomorphine prodrug. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to formulate the dopamine agonist, pramipexole in a pharmaceutical composition and the anti-emetic agent, ondansetron in a pharmaceutical composition and administer the two compositions concurrently or sequentially in view of the teachings of Bryson.
Taken together, all this would result in the practice of the method of claims 31-33 with a reasonable expectation of success.
Claims 4-8 and 34-36 are rejected under 35 U.S.C. 103 as being unpatentable over Bryson et al (WO 2012/083269 A1, cited in a previous Office Action) in view of Legarda Ibanez (US 2011/0034442 A1, cited in a previous Office Action) as applied to claims 1, 3, 9, 26, 27, 31-33, and 37 above, and further in view of Maj (US 6,667,329 B1, cited in the IDS filed February 2, 2021).
Bryson and Legarda Ibanez teach all the limitations of instant claims 4-8 and 34-36 (see above 103 rejection). In particular, Bryson teaches a method of treating major depression comprising administering pramipexole in combination with the elected 5HT3 agonist, ondansetron. Bryson teaches the use of pramipexole or a salt thereof (page 12, lines 36-38) and in certain instances the formulation of the invention includes the hydrochloride salt of the dopamine agonist (page 29, lines 28-29). The cited art do not explicitly teach the pramipexole is pramipexole dihydrochloride monohydrate.
However, Maj teaches a method of treating depression or depressive states in a host in need of such treatment, the method comprising administering to the host the pharmaceutical composition (claim 17); wherein a pharmaceutical composition for treating depression comprises (a) 2-amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole, one of the enantiomers thereof, or one of the acid addition salts thereof; and (b) second antidepressant (claim 1) wherein the composition comprises 2-amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole dihydrochloride monohydrate (claim 4). Maj teaches 2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole is pramipexole (abstract).
As such, since Bryson and Legarda Ibanez teach a method of treating major depression comprising administering pramipexole or a salt thereof and ondansetron, and since Maj teaches that pramipexole dihydrochloride monohydrate is a pramipexole acid addition salt useful for treating depression, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute one functional equivalence (any pramipexole) for another (pramipexole dihydrochloride monohydrate) with an expectation of success, since the prior art establishes that both function in similar manner.
Regarding the amount of pramipexole of instant claims 5-8 and 34-36, Bryson teaches in an embodiment of any of the above pharmaceutical compositions, the pharmaceutical composition is in a unit dosage form including from 0.1 to 100 mg or 0.1 to 20 mg of pramipexole, or an acid addition salt thereof (e.g., from 0.1 to 0.5 mg, 0.2 to 2 mg, 0.5 to 3 mg, 1 to 4 mg, 3 to 7 mg, 6 to 11 mg, 9 to 15 mg, 13 to 18 mg, or 16 to 20 mg of pramipexole, or an acid addition salt thereof); for example, each unit dosage form can contain 0.2 ± 0.1 mg, 0.5 ± 0.25 mg, 1 ± 0.5 mg, 2 ± 0.5 mg, 3 ± 1 mg, 4 ± 1.5 mg, 6 ± 2 mg, 10 ± 3 mg, 14 ± 3 mg, 18 ± 3 mg, or 20 ± 5mg of pramipexole, or an acid addition salt thereof (page 12, line 36-page 13, line 4). MPEP 2144.05 states: 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). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
Regarding the amount of ondansetron of instant claim 5, Legarda Ibanez teaches a method for treating a patient with a central nervous system (CNS) disorder comprising administering to the patient a therapeutically effective amount of a combination comprising ondansetron (claim 11), wherein the CNS disorder is depression (claim 14); wherein said therapeutically effective amount of ondansetron is from 1 mg to 8 mg per dose (claim 17).
It would have been prima facie obvious to one of ordinary skill in the art to utilize the amount of pramipexole taught by Byron as a starting point for optimizing the amount of ondansetron and pramipexole dihydrochloride monohydrate and the amount of ondansetron taught by Legarda Ibanez utilized to treat major depression since Byron teaches a combination of ondansetron and pramipexole salt is useful for treating major depression disorder and Legarda Ibanez teaches ondansetron is useful for treating depression and because dosage is a result-effective variables, i.e., a variable that achieves a recognized result. Therefore, the determination of the optimum or workable dosages would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Taken together, all this would result in the practice of the method of claims 4-8 and 34-36 with a reasonable expectation of success.
New Objections and/or Rejections
Necessitated by Claim Amendment
Claim 38 is rejected under 35 U.S.C. 103 as being unpatentable over Bryson et al (WO 2012/083269 A1, cited in a previous Office Action) in view of Legarda Ibanez (US 2011/0034442 A1, cited in a previous Office Action) as applied to claims 1, 3, 9, 26, 27, 31-33, and 37 above, and further in view of ZOFRAN® (ZOFRAN Tablets, ZOFRAN ODT, ZOFRAN Oral Solution Highlights of prescribing information, GlaxoSmithKline; Revised date 10/2016).
Bryson and Legarda Ibanez teach all the limitations of instant claim 38 (see above 103 rejection). In particular, Bryson teaches a method of treating major depression comprising administering pramipexole in combination with the elected 5HT3 agonist, ondansetron. Bryson teaches the use of pramipexole or a salt thereof (page 12, lines 36-38). The cited art does not explicitly teach the ondansetron is ondansetron hydrochloride dihydrate.
However, ZOFRAN® teaches the active ingredient in ZOFRAN tablets and ZOFRAN oral solution is ondansetron hydrochloride as the dihydrate, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT3 receptor type; chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate (page 11, Description, 1st paragraph).
As such, since Bryson and Legarda Ibanez teach a method of treating major depression comprising administering pramipexole or a salt thereof and ondansetron, and since ZOFRAN® teaches that an FDA approved commercially available composition comprising ondansetron comprises ondansetron hydrochloride as the dihydrate form, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute one functional equivalence (any ondansetron) for another (ondansetron hydrochloride dihydrate) with an expectation of success, since the prior art establishes that the ondansetron hydrochloride dihydrate form is FDA approved and commercially available.
Response to Arguments
The Declaration of Dr. Kathleen E. Clarence-Smith under 37 CFR 1.132 filed June 18, 2025 is insufficient to overcome the rejection of record and is addressed in the response to arguments set forth below.
Applicant argues:
While Bryson discloses pramipexole and mentions the use of anti-emetics, Bryson does not contain any data showing that a 5HT3 receptor antagonist, like ondansetron, is effective in suppressing induced nausea by a dopamine agonist, like pramipexole. Bryson merely lists several anti-emetic agents. Ondansetron is the only 5HT3 receptor antagonist disclosed; all other anti-emetic agents disclosed in Bryson have different mechanisms of action. However, Bryson does not discuss the mechanism of action of any of the listed anti-emetic agents. A POSITA reading Bryson, and considering the prior art as a whole, including the references discussed in the Declaration, would not even consider Bryson relevant. A POSITA would not combine ondansetron with any dopamine agonist based on Bryson, because ondansetron would not antagonize the receptors by which dopamine agonists induce emesis and the combination was known to be dangerous. Further, Bryson's Example 11 discloses pre-treatment of subjects with domperidone (a dopamine antagonist) prior to administration of apomorphine as a sublingual film. This combination is consistent with Arnold's teaching to use domperidone to suppress emesis induced by a dopamine agonist, because domperidone antagonizes the dopamine. Thus, to the extent Bryson teaches combining an anti-emetic, a POSITA reading Bryson, and the references discussed in the Declaration (e.g., Andrews, Arnold, Chen, and the APOKYN label), would have been motivated to use domperidone instead of a 5HT3 antagonist, like ondansetron.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
MPEP 2143.02 states:
Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019). As set forth above, Bryson teaches a method of treating major depression in a subject, comprising administering pramipexole, further comprising administration of an effective amount of an anti-emetic agent, wherein said anti-emetic agent is ondansetron. The compositions of Bryson require a dopamine agonist (see claim 23); and teaches combining the dopamine agonist with an antiemetic. Bryson explicitly teaches ondansetron as 1 of 12 explicitly named anti-emetic agents. The skilled artisan would readily envisage a method of treating major depression comprising administering pramipexole, further comprising administration of an effective amount of an anti-emetic agent, wherein said anti-emetic agent is ondansetron from the teachings of Bryson. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). See MPEP 2144.07.
Regarding the argument that ondansetron would not antagonize the receptors by which dopamine agonists induce emesis and the combination was known to be dangerous, it was known in the art before the effective filing date to administer ondansetron to inhibit dopaminergic effects of an antidepressant compound, as evidenced by Lara et al (The Canadian Journal of Psychiatry, 46(4), 2001; 371-371). Lara teaches bupropion, once only an antidepressant prescribed by psychiatrists, is now routinely indicated by any physician to help
patients stop smoking; although usually well tolerated, bupropion may cause nausea, a side effect consistent with dopaminergic stimulation that might affect treatment adherence and effectiveness; It might at first appear that this problem could be handled easily by prescribing the antiemetic metoclopramide, a dopamine D2 antagonist, or by reducing the dosage; this strategy, however, could in theory interfere with the efficacy of bupropion, because its proposed mechanism of action is precisely the enhancement of dopaminergic activity. Lara further teaches a subject experienced moderate nausea with daily bupropion taken for depression; this side effect was successfully treated with the serotonin 5-HT3 antagonist ondansetron; and suggests that ondansetron can be considered before treatment with metoclopramide to minimize putative reduced efficacy. Thus, Lara establishes that it was known in the art to administer ondansetron to treat emesis induced by dopaminergic agonist antidepressant therapy and that ondansetron has the additional benefit of not interfering with the efficacy of the antidepressant.
Applicant argues:
Legarda Ibanez does not cure the deficiencies in Bryson and suffers from its own flaws.
Legarda Ibanez's method requires administering ondansetron in combination with flumazenil, a selective chloride channel modulator, which is completely different class of compounds than pramipexole. Because of this difference, a POSITA would not have had any expectation that the dose of ondansetron taught in Legarda Ibanez method would have any relevance on the effective dose of ondansetron in combination with pramipexole for the currently claimed method. Furthermore, Legarda Ibanez's suggestion that ondansetron is useful for treating depression is contradicted by the prior art. As discussed in the Declaration, several studies have shown that ondansetron is not effective to treat depression, and may have worsened or caused depression. This is likely due to ondansetron blocking the 5HT3 serotonin receptor, whereas most antidepressants inhibit serotonin reuptake.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
As set forth above, Bryson teaches a method of treating major depression in a subject, comprising administering pramipexole, further comprising administration of an effective amount of an anti-emetic agent, wherein said anti-emetic agent is ondansetron. The teachings of Legarda Ibanez were relied upon for their teaching of therapeutically effective doses of ondansetron. As set forth above, it would have been prima facie obvious to one of ordinary skill in the art to utilize the amount of ondansetron taught by Legarda Ibanez as a starting point for optimizing the amount of ondansetron used in combination with pramipexole since Byron teaches a combination of ondansetron and pramipexole salt is useful for treating major depression disorder and Legarda Ibanez teaches amounts ondansetron that are useful for treating depression and because dosage is a result-effective variables, i.e., a variable that achieves a recognized result. Therefore, the determination of the optimum or workable dosages would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation."). Moreover, the amounts taught by Legarda Ibanez (1 mg to 8 mg) encompass amounts of ondansetron known in the art to be therapeutically effective antiemetic doses as evidenced by Lara which teaches administering ondansetron (8 mg orally as needed) to treat emesis induced by an agent that enhances dopaminergic activity.
Applicant argues:
There is no expectation that ondansetron would effectively antagonize pramipexole-induced emesis. A POSITA looking for ways to suppress emesis induced by a dopamine agonist would have considered Andrews and Arnold. Both prior art references describe studies where 5HT3 receptor antagonism by ondansetron was not effective to suppress emesis induced by a dopamine receptor agonist. Because the studies in Andrews and Arnold specifically involve ondansetron and a dopamine agonist, and include pre-clinical and clinical data, a POSITA would have considered Andrews and Arnold more relevant than Bryson and Legarda Ibanez.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
As set forth above, Bryson teaches a method of treating major depression in a subject, comprising administering pramipexole, further comprising administration of an effective amount of an anti-emetic agent, wherein said anti-emetic agent is ondansetron. The compositions of Bryson require a dopamine agonist (see claim 23); and teaches combining the dopamine agonist with an antiemetic. Bryson explicitly teaches ondansetron as 1 of 12 explicitly named anti-emetic agents. The skilled artisan would readily envisage a method of treating major depression comprising administering pramipexole, further comprising administration of an effective amount of an anti-emetic agent, wherein said anti-emetic agent is ondansetron from the teachings of Bryson. The skilled artisan would readily envisage a combination of a dopamine agonist including pramipexole with ondansetron from the teachings of Bryson. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). See MPEP 2144.07.
Regarding the argument that ondansetron would not antagonize the receptors by which dopamine agonists induce emesis and the combination was known to be dangerous, it was known in the art before the effective filing date to administer ondansetron to inhibit dopaminergic effects of an antidepressant compound, as evidenced by Lara et al (The Canadian Journal of Psychiatry, 46(4), 2001; 371-371. Lara teaches bupropion, once only an antidepressant prescribed by psychiatrists, is now routinely indicated by any physician to help
patients stop smoking; although usually well tolerated, bupropion may cause nausea, a side effect consistent with dopaminergic stimulation that might affect treatment adherence and effectiveness; It might at first appear that this problem could be handled easily by prescribing the antiemetic metoclopramide, a dopamine D2 antagonist, or by reducing the dosage; this strategy, however, could in theory interfere with the efficacy of bupropion, because its proposed mechanism of action is precisely the enhancement of dopaminergic activity. Lara further teaches a subject experienced moderate nausea with daily bupropion taken for depression; this side effect was successfully treated with the serotonin 5-HT3 antagonist ondansetron; and suggests that ondansetron can be considered before treatment with metoclopramide to minimize putative reduced efficacy. Thus, Lara establishes that it was known in the art to administer ondansetron to treat emesis induced by dopaminergic agonist antidepressant therapy and that ondansetron has the additional benefit of not interfering with the efficacy of the antidepressant.
Applicant argues:
The art teaches away from the claimed invention. As an initial point, both Andrews and Arnold teach that ondansetron will not suppress emesis induced by a dopamine agonist and Arnold also teaches that ondansetron is "not recommended as an alternative to the standard treatment with domperidone" to treat dopaminergic adverse events. The lack of efficacy would have discouraged a POSITA from arriving at the claimed invention. Additionally, multiple publications describe the interaction of a 5HT3 receptor antagonist with a dopamine receptor agonist as dangerous and warn against their concomitant use. For example, the FDA approved prescribing instructions for apomorphine hydrochloride expressly warns against administering a 5HT3 antagonist in combination with the dopamine receptor agonist apomorphine. Consequently, a POSITA would not have combined ondansetron with pramipexole based on Bryson and Legarda Ibanez, because the art teaches the combination is not safe. The discovery that the combination of pramipexole and a 5HT3 receptor antagonist (e.g., ondansetron) was safe and effective, and did not cause profound hypotension and loss of consciousness was surprising and unexpected. Furthermore, since the filing date of this application, even more evidence has emerged that the combination of a dopamine receptor agonist and a 5HT3 receptor antagonist is still expected to be dangerous, further reinforcing the irrelevance of Bryson and Legarda Ibanez. KYNMOBI®, which is apomorphine hydrochloride formulated as a sublingual film, is the pharmaceutical product protected by Bryson. The KYNMOBI label also contraindicates the use of 5HT3 receptor antagonists (e.g., ondansetron) and a dopamine receptor agonist (apomorphine) due to "profound hypotension and loss of consciousness when subcutaneous apomorphine was administered with a 5HT3 antagonist." This further underscores the surprising and unexpected benefit provided by the claimed invention.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
As set forth above, Bryson teaches a method of treating major depression in a subject, comprising administering pramipexole, further comprising administration of an effective amount of an anti-emetic agent, wherein said anti-emetic agent is ondansetron. The compositions of Bryson require a dopamine agonist (see claim 23); and teaches combining the dopamine agonist with an antiemetic. Bryson explicitly teaches ondansetron as 1 of 12 explicitly named anti-emetic agents. The skilled artisan would readily envisage a method of treating major depression comprising administering pramipexole, further comprising administration of an effective amount of an anti-emetic agent, wherein said anti-emetic agent is ondansetron from the teachings of Bryson. The skilled artisan would readily envisage a combination of a dopamine agonist including pramipexole with ondansetron from the teachings of Bryson. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). See MPEP 2144.07.
The Examiner acknowledges that the teachings of Arnold and Andrews suggest that ondansetron will not suppress emesis induced by a dopamine agonist, apomorphine. The Examiner also acknowledges that the apomorphine prescribing information labels discourage combining apomorphine with 5HT3 antagonists including ondansetron. However, apomorphine and pramipexole are different compounds:
Pramipexole:
PNG
media_image1.png
186
355
media_image1.png
Greyscale
Apomorphine:
PNG
media_image2.png
231
339
media_image2.png
Greyscale
and thus would be expected to have different pharmacological properties. Of note, the FDA approved label for Mirapex® (cited in the IDS filed June 18, 2025), dated July 2016, does not contain the same contraindication. Mirapex® lists no contraindications (page 1, left col). Moreover, as set forth above, Lara establishes that it was known in the art to administer ondansetron to treat emesis induced by dopaminergic agonist antidepressant therapy and that ondansetron has the additional benefit of not interfering with the efficacy of the antidepressant. Moreover, it was known in the art before the effective filing date of the invention to combine ondansetron with dopamine agonists to treat neuropsychiatric disorders as evidenced by Lee et al (WO 2016/122218 A2, US 2017/0326127 A1, which is the National Stage entry of WO 2016/122218, is being used as a translation of WO 2016/122218. As such, any reference hereinafter to column and line numbers will be based upon the US publication, but should be interpreted as referring to the corresponding disclosure of the aforementioned WO counterpart). Lee teaches a combination therapy composition for treatment of neuropsychiatric disorders, comprising component 1 as an agonist for reactivating a dysfunctional neural circuit and component 2 as an antagonist for blocking reconsolidation of a reactivated dysfunctional neural circuit (claim 1); wherein component 1 is a pharmacologically effective indirect or direct DA agonist or a pharmaceutically acceptable salt thereof, which exhibits or does not exhibits norepinephrine (NE) and/or serotonin (5-HT) agonistic efficacy (claim 6); wherein component 2 is ondansetron (claim 19 and [0051]). Thus, at the time of the invention, the skilled artisan would have understood that ondansetron was contraindicated in apomorphine therapies but was not contraindicated for all dopamine agonist therapies.
Conclusion
Claims 1, 3-14, 19, 20, and 22-30 are rejected.
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) 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 RAYNA B RODRIGUEZ whose telephone number is (571)272-7088. The examiner can normally be reached 8am-5:00pm, Monday - Thursday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, 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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Rayna Rodriguez/ Primary Examiner, Art Unit 1628