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 the Claims
Per Applicant’s amendment to the claims, submitted on 12/22/2025, claims 5 and 36 are amended, and claims 6-7, 37, 45 are canceled. Currently, claims 1-5, 33-36, and 46-53 are pending in the instant application.
Claim Rejections - 35 USC § 112 Second Paragraph – Withdrawn
Rejections of claims 5, 7, 36, and 45:
In light of Applicant’s amendments, the rejections are hereby withdrawn. Claims 5 and 36 have been amended to remove the previously indicated indefinite language. Claims 7 and 45 are canceled.
Claim Rejections - 35 USC § 112 Second Paragraph – Necessitated by Amendment
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.
Claims 46-47 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.
Claim 46 is indefinite for reciting “The method of claim 6” because a person of ordinary skill in the art would not reasonably be able to understand the metes and bounds of the claim. The instant claim provides improper antecedence because claim 6 has been canceled.
Claim 47 is indefinite for reciting “The method of claim 6” because a person of ordinary skill in the art would not reasonably be able to understand the metes and bounds of the claim. The instant claim provides improper antecedence because claim 6 has been canceled.
Claim Rejections - 35 USC § 112 First Paragraph - Withdrawn
Rejections of claims 6, 37, and 53:
In light of Applicant’s arguments and amendments to the claims, the rejections are hereby withdrawn. Claims 6 and 37 are canceled. Applicant’s arguments with regards to claim 53 are acceptable.
Claim Rejections - 35 USC § 103 – Maintained
Claim(s) 1-3, 46-47, and 53 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han (previously referenced) in view of Bowlby (previously referenced).
Claim(s) 4-5 and 48 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han (previously referenced) in view of Bowlby (previously referenced), and further in view of Murrough (previously referenced).
Claim(s) 33-34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han (previously referenced) in view of Melrose (previously referenced), and Bowlby (previously referenced).
Claim(s) 35-36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han (previously referenced) in view of Melrose (previously referenced) and Bowlby (previously referenced), and further in view of Murrough (previously referenced).
Claim(s) 49 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han in view of Bowlby (previously referenced), and further in view of Burke (previously referenced).
Claim(s) 50-51 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han (previously referenced) in view of Bowlby, and further in view of Corya (previously referenced).
Claim(s) 52 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han (previously referenced) in view of Bowlby, and further in view of Lobato (previously referenced).
Response to Applicant Remarks:
Applicant’s arguments are not persuasive. Accordingly, the obviousness rejections under 35 USC 103 are hereby maintained.
Applicant contends that the instant invention is non-obvious over Han in view of Bowlby. Primarily that the Han prior art does not provide one of ordinary skill in the art motivation to treat treatment resistant depression (TRD) using KCNQ selective potassium channel openers (Remarks pages 3-4). Applicant provides that a person of ordinary skill would have no motivation to look towards Han because Han does not teach the treatment of TRD. More specifically that Han’s reference to van Dam teaches the use of KCNQ channel openers for the treatment of depression, rather than TRD. Applicant asserts that because Han (and its reference to van Dam) teaches the treatment of depression and not explicitly TRD, that there would be no reasonable expectation that TRD could be treated by administering a KCNQ channel opener (Remarks page 4, paragraph 2-3). To clarify the current status of the Han prior art, Han explicitly states the following (page 682):
“These findings provided the rationale for a small scale clinical trial of ezogabine in treatment resistant depressed patients who exhibit prominent anhedonia symptoms and reduced functional magnetic resonance imaging signals in the NAc. Ezogabine reversed both of these abnormalities [66], thus setting the stage for a larger clinical trial now underway.”
Han indicates patients having treatment resistant depression, citation [66] references van Dam, wherein van Dam does not disclose treatment resistance in depression patients treated with ezogabine. While Applicant is not incorrect that Han cites van Dam, who does not disclose TRD, it would still remain that the treatment of TRD using KCNQ channel openers would be obvious in view of Han.
What must first be established are the differentiating factors between depression and TRD. The main differentiating factor between the two conditions being that TRD comprises a lack of response to at least one prior antidepressive treatment. Applicant has not provided an argument as to why one of ordinary skill would not be motivated to use the teachings of Han other than that depression and TRD are differentiated by said aforementioned factor. As iterated in the previous Office Action, Han teaches not only the administration of KCNQ channel openers, but the mechanism of action by which they operate (i.e., effect on NAc neurons and upregulation of VTA). Absent of evidence of the contrary, a person of ordinary skill in the art would have no reason to believe this wouldn’t be effective in treating patients suffering from TRD because any prior failed antidepressive treatment could encompass any number or variation of treatments unrelated to the mechanism of KCNQ openers.
Accordingly, the outstanding obviousness rejections of the claims is hereby maintained. A reiteration of the outstanding rejections will be provided below for the purposes of convenience and clarity.
Reiterated Rejections:
Claim 1 recites a method for treating a human patient suffering from treatment resistant depression (TRD) comprising administering an effective amount of a KCNQ selective potassium channel opener and a pharmaceutically acceptable carrier or diluent.
Han provides an overview of the neural pathology of depression and resilience. Relevant to the instant claims is the relationship between ventral tegmental area (VTA) neurons and KCNQ in mice considered as either resilient or susceptible in the chronic social defeat stress (CSDS) model. Han teaches that KCNQ channel function is significantly upregulated in VTA-NAc neurons in resilient mice as compared to susceptible mice (page 682)1. Furthermore, induced KCNQ overexpression in the neurons of susceptible mice reversed depression-like behavioral abnormalities (page 682)2. By administering KCNQ “openers” such as ezogabine to susceptible mice, VTA neuronal hyperactivity and depression-like behaviors were able to be normalized (page 682)3. Han further indicates that such observed effect in the administration of ezogabine provides rationale for such treatment to be useful in patients suffering from TRD. Furthermore, Han states that a small clinical trial was carried out on patients with TRD exhibiting anhedonia symptoms and reduced functional magnetic resonance imaging signals in NAc, wherein ezogabine was successful in reversing both abnormalities (page 682). Accordingly, Han teaches a method of treating TRD by administering ezogabine
Han does not explicitly teach the use of pharmaceutically acceptable carriers or diluents, however it would be obvious to include such components because Bowlby teaches that such carriers and diluents are common components in oral dosage forms of ezogabine.
With regards to the inclusion of pharmaceutically acceptable carriers and diluents, Bowlby teaches oral dose forms of ezogabine (a.k.a. retigabine) comprising pharmaceutically acceptable carriers and excipients (paragraph [0039])4, and further provides exemplary capsule formulations as provided below (specification [0039]):
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Given that the teachings of Han are drawn to administration of ezogabine to human patients, it would be obvious to include carriers or diluents such as exemplified by the oral dosage forms of Bowlby, as there would be a reasonable expectation of successful administration. Furthermore, carriers and diluents are commonly used in dosage administration forms, the use of such components such as the above would be well within the understanding of a person of ordinary skill in the art.
In summary, Han teaches a method of treating TRD by administering ezogabine to human patients, while Bowlby teaches the common use of pharmaceutically acceptable carriers and diluents in oral dosage forms of ezogabine. It would have been prima facie obvious at the time of invention for a person of ordinary skill in the art to combine the teachings of Han and Bowlby to develop a method of treating TRD by administering a composition comprising ezogabine and pharmaceutically acceptable carriers and diluents, as there would be a reasonable expectation that: 1) ezogabine would be effective for treatment of TRD, and 2) such a composition would be effective for administration of ezogabine.
Claim 2 further limits the method of claim 1 wherein the KCNQ selective potassium channel opener is ezogabine.
Han teaches the administration of ezogabine.
Claim 3 further limits the method of claim 1 wherein the patient has not responded to two adequate antidepressant treatments.
While Han does not explicitly state TRD patients having not responded to two adequate antidepressant treatments, it would still be obvious to treat such patients using ezogabine. TRD is generally understood to be a disease wherein a patient having depression has inadequate response to at least one adequate antidepressant treatment. A patient having inadequate response to two treatments would still fall within the bounds of a TRD diagnosis. Without evidence of the contrary, there would still be reasonable expectation that ezogabine would be successful in the treatment of such patients at least for the pharmacodynamic reasons set forth by Han with regards to KCNQ openers.
Claim(s) 4-5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han in view of Bowlby, and further in view of Murrough (NCT02149836, 2016-04-13).
Claim 4 further limits the method of claim 1 wherein the effective amount is 900 mg per day.
As discussed above, the combined teachings of Han and Bowlby obviate a method for treating TRD in a human patient, wherein the method comprises the administration of ezogabine.
Neither Han nor Bowlby explicitly teach the administration of ezogabine at an amount of 900 mg per day. However it would have been obvious to administer said amount because Murrough teaches such a dosing scheme for the treatment of depressive symptoms in major depressive disorder (MDD).
Murrough teaches a study design for a method of treatment of major depressive disorder (MDD). More specifically, Murrough teaches the treatment of MDD by administration of ezogabine, which is a KCNQ selective potassium channel opener. Study design comprises a progressive titration scheme over 5 weeks of dosing to a final dose of 300 mg three times daily for a total of 900 mg; a summary of the titration scheme is provided below (Arms and Interventions):
Week 1: 100mg of Ezogabine by mouth three times per day (total daily dose = 300mg)
Week 2: dose will be increased to 150 mg Ezogabine by mouth three times per day (total daily dose = 450mg)
Week 3: dose will be increased to 200mg of Ezogabine by mouth three times per day (total daily dose = 600mg)
Week 4: dose will be increased to 250mg of Ezogabine by mouth three times per day (total daily dose = 750mg)
Week 5: dose will be increased to 300mg of Ezogabine by mouth three times per (total daily dose = 900mg)
Participants will continue to take 900mg of Ezogabine per day
While the teachings of Murrough are directed towards MDD rather than TRD, Murrough indicates that ezogabine is capable of ameliorating depressive symptoms by upregulating KCNQ channels in the VTA (Detailed Description)5. The mechanism of action described by Murrough for the treatment of MDD appears to be identical to the teachings of Han with regards to the treatment of TRD. Accordingly, a person of ordinary skill in the art would have reasonable expectation that the dosing scheme introduced by Murrough would not only be effective for MDD, but for TRD as well.
In summary, Han teaches the treatment of TRD by administering ezogabine, Bowlby teaches oral composition of ezogabine comprising pharmaceutically acceptable carriers, and Murrough teaches a dosing scheme for ezogabine administration to human patients suffering from a depressive disorder (MDD). It would have been prima facie obvious at the time of inventio for a person of ordinary skill in the art to combine the teachings of the aforementioned to arrive at the claimed method as there would have been reasonable expectation that a 900 mg/day dose of ezogabine would have been effective in treating depressive symptoms of TRD.
Claim 5 further limits the method of claim 4 wherein the effective amount is three 300 mg of ezogabine three times per day.
Murrough teaches the administration of ezogabine at three doses of 300 mg/day.
Claim(s) 33-34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han in view of Melrose (Open Journal of Depression, 2017, 6, 1-13) and Bowlby
Claim 33 recites a method of treating a patient suffering from persistent depressive disorder (PDD) comprising administering to a patient in need of such treatment a pharmaceutical formulation comprising an effective amount of a KCNQ-selective potassium channel opener, and a pharmaceutically acceptable carrier or diluent.
Han provides an overview of the neural pathology of depression and resilience. Relevant to the instant claims is the relationship between ventral tegmental area (VTA) neurons and KCNQ in mice considered as either resilient or susceptible in the chronic social defeat stress (CSDS) model. Han teaches that KCNQ channel function is significantly upregulated in VTA-NAc neurons in resilient mice as compared to susceptible mice (page 682)6. Furthermore, induced KCNQ overexpression in the neurons of susceptible mice reversed depression-like behavioral abnormalities (page 682)7. By administering KCNQ “openers” such as ezogabine to susceptible mice, VTA neuronal hyperactivity and depression-like behaviors were able to be normalized (page 682)8. Han further indicates that such observed effect in the administration of ezogabine provides rationale for such treatment to be useful in patients suffering from TRD. Furthermore, Han states that a small clinical trial was carried out on patients with TRD exhibiting anhedonia symptoms and reduced functional magnetic resonance imaging signals in NAc, wherein ezogabine was successful in reversing both abnormalities (page 682). Accordingly, Han teaches a method of treating TRD by administering ezogabine
Han does not explicitly teach the treatment of persistent depressive disorder (PDD), or the use of a pharmaceutically acceptable carrier or diluent. However, it would be obvious to utilize the teachings of Han in treating PDD because Melrose teaches PDD as a disorder having depressive symptoms, and it would be further obvious to combine ezogabine with pharmaceutically acceptable carriers or diluents because Bowlby teaches such carriers as common ingredients in ezogabine oral dosage forms.
Melrose provides an overview of persistent depressive disorder. Persistent depressive disorder is stated by Melrose to be a recurrent, prolonged depressive disorder with no clearly demarcated episodes (page 1)9. Melrose further indicates that individuals qualify for a diagnosis of PDD or dysthymia when they have not been free of depressive symptoms for longer than 2 months over a 2 year period and have not experienced an episode of major depression or mania (page 2)10. The teachings of Melrose indicate that PDD or a diagnosis thereof is predicated largely on the duration of depressive symptoms. Given that the teachings of Han are not only directed towards the treatment of TRD, but also the treatment of depressive symptoms and behaviors by administration of KCNQ openers, there would be a reasonable expectation of success in ameliorating depressive symptoms and behaviors in patients suffering from PDD.
With regards to the inclusion of pharmaceutically acceptable carriers and diluents, Bowlby teaches oral dose forms of ezogabine (a.k.a. retigabine) comprising pharmaceutically acceptable carriers and excipients (paragraph [0039])11, and further provides exemplary capsule formulations as provided below (specification [0039]):
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Given that the teachings of Han are drawn to administration of ezogabine to human patients, it would be obvious to include carriers or diluents such as exemplified by the oral dosage forms of Bowlby, as there would be a reasonable expectation of successful administration. Furthermore, carriers and diluents are commonly used in dosage administration forms, the use of such components such as the above would be well within the understanding of a person of ordinary skill in the art.
In summary, Han teaches the use of KCNQ openers such as ezogabine for the amelioration of depressive symptoms and behaviors, Melrose teaches that PDD is a depressive disorder wherein depressive symptoms last in duration from 2 months to 2 years, and Bowlby teaches oral dosage forms of ezogabine comprising pharmaceutically acceptable carriers. It would have been prima facie obvious at the time of invention for a person of ordinary skill in the art to combine the teachings of the aforementioned to develop a method of treating PDD by administering a composition comprising ezogabine and pharmaceutically acceptable carriers, as there would have been reasonable expectation that such treatment would ameliorate depressive symptoms of PDD.
Claim 34 further limits the method of claim 33 wherein the KCNQ-selective potassium channel opener is ezogabine.
As discussed above, Han teaches ezogabine.
Claim(s) 35-36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han in view of Melrose (Open Journal of Depression, 2017, 6, 1-13) and Bowlby, and further in view of Murrough.
Claim 35 further limits the method of claim 34 wherein the effective amount is 900 mg per day.
As discussed above, the teachings of Han in view of Melrose and Bowlby obviate a method of treating PDD by administering a composition of ezogabine and pharmaceutically acceptable carriers.
None of Han, Melrose, or Bowlby explicitly teach the administration of 900 mg of ezogabine per day. However it would have been obvious to administer said amount because Murrough teaches such a dosing scheme for the treatment of depressive symptoms in major depressive disorder (MDD).
Murrough teaches a study design for a method of treatment of major depressive disorder (MDD). More specifically, Murrough teaches the treatment of MDD by administration of ezogabine, which is a KCNQ selective potassium channel opener. Study design comprises a progressive titration scheme over 5 weeks of dosing to a final dose of 300 mg three times daily for a total of 900 mg; a summary of the titration scheme is provided below (Arms and Interventions):
Week 1: 100mg of Ezogabine by mouth three times per day (total daily dose = 300mg)
Week 2: dose will be increased to 150 mg Ezogabine by mouth three times per day (total daily dose = 450mg)
Week 3: dose will be increased to 200mg of Ezogabine by mouth three times per day (total daily dose = 600mg)
Week 4: dose will be increased to 250mg of Ezogabine by mouth three times per day (total daily dose = 750mg)
Week 5: dose will be increased to 300mg of Ezogabine by mouth three times per (total daily dose = 900mg)
Participants will continue to take 900mg of Ezogabine per day
While the teachings of Murrough are directed towards MDD rather than PDD, Murrough indicates that ezogabine is capable of ameliorating depressive symptoms by upregulating KCNQ channels in the VTA (Detailed Description)12. The mechanism of action described by Murrough for the treatment of MDD appears to be identical to the teachings of Han with regards to the treatment of TRD and depressive symptoms. Furthermore, Melrose indicates that MDD is often comorbid with PDD and that both conditions have shared depressive symptoms (pages 2-3)13. Accordingly, a person of ordinary skill in the art would have reasonable expectation that the dosing scheme introduced by Murrough would not only be effective for MDD, but for ameliorating depressive symptoms of PDD as well.
In summary, Han teaches the treatment of TRD and depressive symptoms by administering ezogabine, Melrose teaches that PDD is a depressive disorder wherein depressive symptoms last in duration from 2 months to 2 years which has comorbidity with MDD, Bowlby teaches oral composition of ezogabine comprising pharmaceutically acceptable carriers, and Murrough teaches a dosing scheme for ezogabine administration to human patients suffering from a depressive disorder (MDD). It would have been prima facie obvious at the time of inventio for a person of ordinary skill in the art to combine the teachings of the aforementioned to arrive at the claimed method as there would have been reasonable expectation that a 900 mg/day dose of ezogabine would have been effective in treating depressive symptoms of PDD.
Claim 36 further limits the method of claim 35 wherein the effective amount is three 300 mg of ezogabine administered three times per day.
Murrough teaches the administration of 300 mg of ezogabine three times per day.
Claim 46 further limits the method of claim 6 wherein the method comprises orally administering ezogabine to the patient.
Bowlby teaches oral dosage forms of ezogabine.
Claim 47 further limits the method of claim 6 wherein the method comprises administering ezogabine parenterally to the patient.
Han indicates that local infusion of KCNQ openers to the VTA was capable of reversing depressive like symptoms in test animals (page 682)14. Infusion administration would be considered as a parenteral route of administration.
Claim(s) 48 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han in view of Bowlby, and further in view of Murrough.
Claim 48 further limits the method of claim 1 wherein the method comprises administering between about 5mg/kg and about 20 mg/kg body weight of KCNQ Channel opener to the patient.
As discussed above, the teachings of Han in view of Bowlby obviate a method of treating TRD by administering a composition comprising ezogabine and pharmaceutically acceptable carriers.
Neither Han nor Bowlby explicitly teach a dosing in a range from 5-20 mg/kg, however it would be obvious for a person of ordinary skill in the art to dose in such a range because Murrough teaches dosing amounts within such a range for the treatment of depressive symptoms in MDD.
Murrough teaches administration of ezogabine to patients suffering from MDD for the amelioration of depressive symptoms. More specifically, a titration scheme wherein the final daily dosing amount of ezogabine is 300 mg, three times per day, for a total dosing amount of 900 mg/day. For a human of average weight (about 65 kg), the final daily dosing amount would be about 13.85 mg/kg, which falls squarely within the recited range.
Given the teachings of the aforementioned, it would have been prima facie obvious at the time of invention for a person of ordinary skill in the art to administer ezogabine within the recited range because there would have been a reasonable expectation that such dosing would be successful in alleviating depressive symptoms of TRD.
Claim(s) 49 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han in view of Bowlby, and further in view of Burke (US 20120288544 A1).
Claim 49 further limits the method of claim 1 wherein the method comprises administering the KCNQ Channel opener with an enteric coating.
As discussed above, the teachings of Han in view of Bowlby obviate a method of treating TRD by administering a composition comprising ezogabine and pharmaceutically acceptable carriers.
Neither Han nor Bowlby explicitly teach the use of an enteric coating. However, it would be obvious for a person of ordinary skill in the art to utilize such a coating because Burke teaches the use of enteric coatings for ezogabine oral dosage forms in order to facilitate controlled release in the intestines.
Burke teaches compositions comprising ezogabine (retigabine) and an enteric coating. Burke provides an exemplary composition as follows (page 11):
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As can be seen from the above table, Burke utilizes an enteric film coating comprising elements which facilitate modified release. Burke further indicates that ezogabine is a compound with pH dependent solubility, wherein the compound is more soluble in the acidic conditions of the stomach compared to the neutral conditions of the lower intestine (paragraph [0008])15. As ezogabine has greater solubility in the stomach due to lower pH, it would be obvious to a person of ordinary skill in the art to make use of an enteric coating for orally administered ezogabine in order to provide protection during delivery to the intestines for uptake.
Claim(s) 50-51 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han in view of Bowlby, and further in view of Corya (DEPRESSION AND ANXIETY 23:364–372 (2006)).
Claim 50 further limits the method of claim 1 wherein the method further comprises administering an anti-depressant to the patient.
As discussed above, the teachings of Han in view of Bowlby obviate a method of treating TRD by administering a composition comprising ezogabine and pharmaceutically acceptable carriers.
Neither Han nor Bowlby explicitly teach the further administration of an antidepressant. However, it would be obvious to a person of ordinary skill in the art to modify the teachings of Han and Bowlby to administer an additional antidepressant, because Corya teaches the treatment of TRD using fluoxetine.
Corya teaches the treatment of patients suffering from TRD by administering fluoxetine, which is an SSRI. More specifically, Corya conducts a randomized double blind comparison of a combination of olanzapine + fluoxetine (OFC) against individual treatments of fluoxetine monotherapy, olanzapine monotherapy, and venlafaxine monotherapy. Effectiveness of the treatments was measured by mean reduction in Montgomery-Asberg Depression Rating Scale (MADRS), and response/remission rates recorded during and at the endpoint of the study. Results attained by Corya are provided below (page 368, Fig. 1-2):
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As can be seen from the data above, both the OFC group and the fluoxetine monotherapy group achieved lowered mean MADRS scores. While the OFC group initially provided more rapid score decreases, the difference when compared to the fluoxetine monotherapy group was not statistically different by the study endpoint at 12 weeks. Furthermore, the response at endpoint and remission rate at any time during the study was not significant between the two groups. Essentially, Corya establishes both OFC and fluoxetine monotherapy as being effective treatments for TRD.
Given the teachings of Corya, and without evidence of the contrary, it would have been prima facie obvious for one of ordinary skill in the art to apply said teachings to the teachings of Han and Bowlby and co-administer either OFC or fluoxetine alongside ezogabine, as there would be a reasonable expectation of synergistic effect in treating patients suffering from TRD.
Claim 51 further limits the method of claim 50 wherein the anti-depressant is an SSRI.
Corya teaches fluoxetine which is an SSRI.
Claim(s) 52 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han in view of Bowlby, and further in view of Lobato (Behavioural Brain Research 209 (2010) 249–259).
Claim 52 further limits the method of claim 1 wherein the method further comprises administering a compound that ameliorates or exacerbates symptoms of oxidative stress disorder.
As discussed above, the teachings of Han in view of Bowlby obviate a method of treating TRD by administering a composition comprising ezogabine and pharmaceutically acceptable carriers.
Neither Han nor Bowlby explicitly teach the further administration of a compound that ameliorates or exacerbates symptoms of oxidative stress disorder. However it would be obvious to administer such a compound because Lobato teaches that one such compound, a-tocopherol, provides anti-depressant effect.
Lobato teaches the administration of a-tocopherol in a predictive mouse model of depression. Animals were subject to either short term (acute) dosing, or long term dosing and were assessed for effects on depressive behavior by application of forced swim tests (FST) and tail suspension tests (TST). Lobato indicates that acute administration of a-tocopherol decreased immobility time in both the FST and TST at 10 and 30 mg/kg dose levels, indicating an anti-depressant effect (page 251)16. Furthermore, long term (28 day) administration of a-tocopherol provided a significant decrease in immobility time in the FST at the 10 mg/kg dose level, once more indicating anti-depressant effect (page 251-252)17.
Given the teachings of Lobato, and without evidence of the contrary, it would have been prima facie obvious for one of ordinary skill in the art to apply said teachings to the teachings of Han and Bowlby to co-administer a-tocopherol alongside ezogabine, as there would have been reasonable expectation that of synergistic effect in ameliorating depressive symptoms in a patient suffering from TRD.
Conclusion
Claims 1-5, 33-36, and 46-53 are rejected.
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 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.
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/ERIC TRAN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 “This insight into the molecular and cellular basis of natural resilience as an active stress-coping process offers a new therapeutic direction. Friedman et al. [20] demonstrated that KCNQ channel function was significantly upregulated in the VTA–NAc dopamine neurons of resilient mice, with no effect seen in susceptible mice.”
2 “KCNQ overexpression in these neurons of the susceptible subgroup normalized their pathologic neuronal hyperactivity and reversed the animals’ depression-like behavioral abnormalities.”
3 “Systemically administrated ezogabine normalized both VTA neuronal hyperactivity and depression-like behaviors seen in susceptible mice [21]. These findings provided the rationale for a small scale clinical trial of ezogabine in treatment resistant depressed patients who exhibit prominent anhedonia symptoms and reduced functional magnetic resonance imaging signals in the NAc. Ezogabine reversed both of these abnormalities [66], thus setting the stage for a larger clinical trial now underway.”
4 “Compounds as described in U.S. Pat. No. 5,384,330, including retigabine, can be administered orally using conventional pharmaceutical excipients or carriers, preferably coated or contained in hard or soft gelatin capsules.“
5 “Ezogabine is known to bind to and activate KCNQ transmembrane K+ ion channels, specifically targeting KCNQ2 in the VTA. Such membrane activity has been show to play a role in previous studies involving a social defeat model of depression. Specifically, data has shown that KCNQ channels were upregulated only in resilient mice and moreover, ezogabine was able to potentiate KCNQ channel activity to result in a fast reversal of the depressed phenotype.”
6 “This insight into the molecular and cellular basis of natural resilience as an active stress-coping process offers a new therapeutic direction. Friedman et al. [20] demonstrated that KCNQ channel function was significantly upregulated in the VTA–NAc dopamine neurons of resilient mice, with no effect seen in susceptible mice.”
7 “KCNQ overexpression in these neurons of the susceptible subgroup normalized their pathologic neuronal hyperactivity and reversed the animals’ depression-like behavioral abnormalities.”
8 “Systemically administrated ezogabine normalized both VTA neuronal hyperactivity and depression-like behaviors seen in susceptible mice [21]. These findings provided the rationale for a small scale clinical trial of ezogabine in treatment resistant depressed patients who exhibit prominent anhedonia symptoms and reduced functional magnetic resonance imaging signals in the NAc. Ezogabine reversed both of these abnormalities [66], thus setting the stage for a larger clinical trial now underway.”
9 “PDD or dysthymia is a recurrent, prolonged depressive disorder with no clearly demarcated episodes.”
10 “Today, the DSM-5 consolidated the diagnoses of dysthymia and chronic depressive disorder into persistent depressive disorder PDD, often still identified as dysthymia… Dysthymia is diagnosed in adults when individuals have not been free of their depressive symptoms for longer than 2 months over a 2-year period and have not experienced an episode of major depression or mania.”
11 “Compounds as described in U.S. Pat. No. 5,384,330, including retigabine, can be administered orally using conventional pharmaceutical excipients or carriers, preferably coated or contained in hard or soft gelatin capsules.“
12 “Ezogabine is known to bind to and activate KCNQ transmembrane K+ ion channels, specifically targeting KCNQ2 in the VTA. Such membrane activity has been show to play a role in previous studies involving a social defeat model of depression. Specifically, data has shown that KCNQ channels were upregulated only in resilient mice and moreover, ezogabine was able to potentiate KCNQ channel activity to result in a fast reversal of the depressed phenotype.”
13 “Dysthymia frequently co-occurs with other psychiatric conditions. Many people with dysthymia also develop major depressive disorder MDD, a condition known as double depression… In both MDD and dysthymia, people experience feelings of hopelessness and are unable to find relief from their despair. When double depression is present, these feelings of hopelessness intensify… Most people with dysthymia develop at least one episode of MDD in their lifetime”
14 “Furthermore, KCNQ Openers^ (potentiators), applied through either local infusion into the VTA or systemic administration, completely reversed the depressive-like symptoms displayed by susceptible animals.”
15 “Retigabine has been found to exhibit marked pH dependent solubility, i.e. it is more soluble in the acidic conditions of the stomach (around pH 2) than in the near neutral conditions of the lower intestine (around pH 7).”
16 “The results depicted in Fig. 1A show that the acute administration of -T by oral route decreased the immobility time in the FST, indicating that this vitamin is effective in producing an antidepressant-like effect in this behavioral model… Fig. 1B shows that the administration of -T by p.o. route also produced a significant effect in the immobility time in the TST”
17 “The effect of long-term administration (28 days) of -T and fluoxetine on the immobility time in the FST is shown in Fig. 3A. The one-way ANOVA revealed a significant effect of treatment [F(3,21) = 8.53; P < 0.01]. Post hoc analyses indicated a significant decrease in the immobility time elicited by the administration of -T at the dose of 10 mg/kg. As shown in Fig. 3B, the long-term treatment with fluoxetine (10 mg/kg) was also able the decrease the immobility time in the FST”