DETAILED ACTION
Status of Claims
The amendment filed 11/06/25 is acknowledged. Claims 4, 11, and 15 are cancelled. Claims 1, 2, 3, 12, 14, 16, and 18-20 are amended. Claims 21 and 22 are new. Claims 1-3, 5-10, 12-14, and 16-22 are pending and under examination.
Withdrawn Rejections
35 U.S.C. 112
The rejection of claims 3 and 18 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in view of the amendments to these claims.
The rejection of claims 3, 4, 12 and 18 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention is withdrawn in view of the amendments to these claims and the cancellation of claim 4.
35 U.S.C. 102
The rejection of claim 14 under 35 U.S.C. 102(a)(1) as being anticipated by Sanchez et al. is withdrawn in view of the amendment to independent claim 14 requiring a specific dose of administration.
The rejection of claims 1 and 7 under 35 U.S.C. 102(a)(1) as being anticipated by Tornoee et al. is withdrawn in view of the amendment to independent claim 1 requiring a specific time of administration.
35 U.S.C. 103
The rejection of claims 8, 11, and 16 - 18 as being unpatentable under 35 U.S.C 103 over Sanchez et al., in view of Bierbower et al. is withdrawn in view applicant arguments.
The rejection of claim 4 as being unpatentable under 35 U.S.C 103 over Vigil et al. in view of Kumar et al. is withdrawn in view of the cancellation of claim 4.
The rejection of claim 15 as being unpatentable under 35 U.S.C 103 over Vigil et al. in view of Dekmak et al. is withdrawn in view of the cancellation of claim 15.
The rejection of claim 19 as being unpatentable under 35 U.S.C 103 over Vigil et al. in view of Villoslada et al. is withdrawn in view of the amendment of claim 19 to remove prevention of hypersomnia and instead prevent epilepsy.
The rejection of claim 9 as being unpatentable under 35 U.S.C 103 over Zhao et al. in view of Price et al. is withdrawn in view of the amendment to independent claim 1 requiring a specific time of administration.
Maintained Rejections
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 102
Claims 1-3, 5, 6, 10, 12, and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Vigil et al.
Claims 1-3, 5, 6, 10, and 12, are drawn to a method of treating brain injury or dysfunction following a TBI; claim 20 is drawn to a method of reducing susceptibility to seizures or cognitive dysfunction following TBI.
The modification of this rejection was necessitated by the amendment to claim 1 to include administration within 1 hour of TBI.
Vigil et al. discloses a poster abstract [see p. A114] disclosing a method of treating TBI induced epilepsy and neuronal swelling comprising administering the M-channel opener retigabine (RTG) (instant claim 3) to mice 30 minutes after traumatic brain injury (TBI) (instant claims 1 and 12). Vigil et al. discloses using a model of blunt TBI injury (instant claim 10). RTG upregulates the activity of KCNQ2 and 3 subunits [as evidenced by Tatulian et al., see abstract] (instant claims 2 and 20) and Vigil et al. discloses that enhancing M-channel currents reduces neuronal excitability (instant claims 5 and 20). Vigil et al. discloses that animals treated with RTG had reduced TBI-induced neuronal swelling and CD40L levels and displayed no seizure activity compared to 33% of vehicle-only treated mice. Vigil et al. therefore administered a therapeutically effective amount (instant claims 1 and 12). Administering a therapeutically effective amount of an M-channel opener after the subject experiences a traumatic brain injury, which leads to a reduction in neural excitability, will necessarily result in the reduction in cellular energy demand in the brain (instant claim 6).
Therefore, claims 1-3, 5, 6, 10, 12, and 20 are rejected under 35 U.S.C. 102(a)(1).
Response to Arguments – Vigil et al.
Applicant argues that Vigil et al. does not disclose or suggest the limitations of amended claims 1 and 20 of administering the therapeutically effective amount within 1 hour of TBI, the limitation of amended claim 14, which now specifies that the therapeutically effective amount is 0.03 mg/kg or 0.3 mg/kg of body weight of the subject; and the limitation of new claim 21 wherein the at least one traumatic brain injury is a repetitive traumatic brain injury resulting from either repetitive blast exposure or shockwaves.
This argument is not found persuasive. Vigil et al. explicitly discloses administration at 30 minutes and therefore meets all limitations of instant claim 1. Instant claims 14 and 21 are not rejected over Vigil et al. and thus arguments regarding their limitations are moot.
Claims 1-3, 10, 12, and 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sanchez et al.
Claims 1-3, 10, 12, and 13 are drawn to a method of treating brain injury or dysfunction following a TBI.
The modification of this rejection was necessitated by the amendment to claim 1 to include administration within 1 hour of TBI.
Sanchez et al. discloses a poster abstract disclosing a method of treating TBI induced epilepsy and neuronal swelling comprising administering 1mg/kg (instant claim 13) of the M-channel opener retigabine (RTG) (instant claim 3) to mice 30 minutes after traumatic brain injury (TBI) (instant claims 1 and 12). Sanchez et al. discloses using the closed-cortical impact model of TBI, which is a model of blunt TBI injury (instant claim 10). RTG upregulates the activity of KCNQ2 and 3 subunits [as evidenced by Tatulian et al., see abstract] (instant claim 2) and Sanchez et al. discloses that enhancing M-channel currents reduces neuronal excitability. Sanchez et al. discloses that animals treated with RTG had reduced TBI-induced neuronal swelling, reduced GFAP and CD40L levels, and displayed no seizure activity compared to 33% of vehicle-only treated mice. Sanchez et al. therefore administered a therapeutically effective amount (instant claims 1 and 12).
Therefore, claims 1-3, 10, 12, and 13 are rejected under 35 U.S.C. 102(a)(1).
Response to Arguments – Sanchez et al.
Applicant argues that Sanchez et al. does not disclose or suggest the limitations of amended claims 1 and 20 of administering the therapeutically effective amount within 1 hour of TBI, the limitation of amended claim 14, which now specifies that the therapeutically effective amount is 0.03 mg/kg or 0.3 mg/kg of body weight of the subject; and the limitation of new claim 21 wherein the at least one traumatic brain injury is a repetitive traumatic brain injury resulting from either repetitive blast exposure or shockwaves.
This argument is found persuasive in part. The amendments to the claims render only the rejection over claim 14 moot and the rejection over that claim is withdrawn. However, Sanchez et al. explicitly teaches administering RTG within 30 minutes of TBI injury, which is within one hour, and therefore meets all the limitations of claim 1. The additional limitations of claims 14, 20, and 21 are not relevant as these claims are not rejected over Sanchez et al.
New Rejections
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 102
Claims 1-3, 5-7, 9, 10, 12, 13, 16-20, and 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hobbs et al.
Claims 1-3, 5-7, 9, 10, 12, 13, and 22 are drawn to a method of treating brain injury or dysfunction following a TBI; claims 16-20 are drawn to a method of reducing susceptibility to seizures or cognitive dysfunction following TBI.
The inclusion of this rejection was necessitated by new claim 22, the amendment of claim 1, the amendment to claim 19, and the amendment to claim 16.
Hobbs et al. discloses a poster abstract [see p. 236-237] disclosing a method of treating TBI induced epilepsy and neuronal swelling comprising administering 1.0 mg/kg (instant claims 13 and 18) of the M-channel opener retigabine (RTG) (instant claim 3) intraperitoneally to mice 30 minutes after traumatic brain injury (TBI) (instant claims 1 and 12). Hobbs et al. discloses using a model of blunt TBI injury (instant claim 10). RTG upregulates the activity of KCNQ2 and KCNQ3 subunits [as evidenced by Tatulian et al., see abstract] (instant claims 2, 20, and 22) and Hobbs et al. discloses that enhancing M-channel currents reduces neuronal excitability (instant claims 5 and 20). Hobbs et al. discloses that animals treated with RTG had reduced TBI-induced neuronal swelling and CD40L levels and displayed no seizure activity compared to 33% of vehicle-only treated mice (instant claims 1 and 16). Hobbs et al. therefore administered a therapeutically effective amount (instant claims 1 and 12). Seizures contribute to metabolic exhaustion and a person at risk of seizures from TBI are therefore at risk of metabolic exhaustion (instant claim 17). Administering a therapeutically effective amount of an M-channel opener after the subject experiences a traumatic brain injury, which leads to a reduction in neural excitability, will necessarily result in the reduction in cellular energy demand in the brain (instant claim 6). Furthermore, instant claims 7, 9, and 19 recite the intended results of wherein the method “prevents the development of chronic traumatic encephalopathy,” “preserving permeability of a blood brain barrier,” and “reduces the risk of developing epilepsy,” and these are interpreted as inherent properties of the claimed method.
Therefore, claims 1-3, 5-7, 9, 10, 12, 13, 16-20, and 22 are rejected under 35 U.S.C. 102(a)(1).
Claim Rejections - 35 USC § 103
Claims 1, 8, and 14 are rejected under 35 U.S.C 103 as being unpatentable over Hobbs et al. in view of Porter et al.
Claim 1, 8, and 14 are drawn to a method of treating brain injury or dysfunction following TBI.
The inclusion of this rejection was necessitated by the amendment of claim 14.
The disclosure of Hobbs et al. is discussed above.
Porter et al. discloses that administration of retigabine can be done orally [see p. 150, col. 1, par. 4] (instant claim 8) and teaches that administration at the low dose of 0.01 mg/kg was sufficient to induce full suppression of seizures in the amygdala kindling model of epileptogenesis [see p. 151, col. 1, par. 2]. Epileptogenesis is the process by which epilepsy may occur following TBI.
It would have been obvious to combine these teachings and administer retigabine at an effective dose as low as 0.01 mg/kg to optimize the administered dose and reduce therapeutic amounts while maintaining efficacy. There would have been a reasonable expectation that an effective dose could be identified below 1.0 mg/kg because the art demonstrates that retigabine retains anticonvulsant efficacy at doses substantially below 1 mg/kg and seizure activity is a known consequence of TBI. As such, identification of the claimed 0.03 mg/kg would have been a matter of routine optimization.
Therefore, claims 1, 8, and 14 are rejected under 35 U.S.C 103.
Claims 1 and 21 are rejected under 35 U.S.C 103 as being unpatentable over Hobbs et al. in view of Xiong et al. and in further view of Kovacs et al.
Claim 1 is drawn to a method of treating brain injury or dysfunction following TBI and claim 21 is drawn to a method of treating specific types of brain injury or dysfunction following TBI.
The inclusion of this rejection was necessitated by new claim 21.
The disclosure of Hobbs et al. is discussed above.
Xiong et al. teaches that candidate therapies for TBI should be evaluated in several experimental TBI models with different severities, before translation into clinical trials. Xiong et al. further teaches that CCI and blast/repeated mild TBI are common and established models of TBI used for evaluating therapeutic interventions.
It would be obvious to combine these teachings and apply the retigabine treatment of Hobbs et al. in the blast/repeated concussive model disclosed by Xiong et al. because the art teaches that evaluation across multiple TBI models is desirable to assess the therapeutic potential of candidate treatments. This teaching recognizes variability among injury models but nevertheless reflects the expectation that therapies may be evaluated across such models because of shared symptoms, rather than limiting therapeutics to one model. Furthermore, there would have been a reasonable expectation of success because Hobbs et al. attributes the therapeutic benefits of retigabine to reduction of secondary injury processes, including cytotoxic swelling, pathological inflammatory signaling via CD40L, and seizure activity, which are recognized in the art as relevant consequences of both single TBI and repeated blast, rather than conditions unique to just the CCI model. In specific, seizure activity [See Kovacs et al, abstract], pathological inflammation [see Kovacs et al. p. 1, col. 2, par. 4] edema [see Kovacs et al., p. 4, col. 2, par. 3] are known symptoms of blast-induced TBI. Accordingly, applying a known treatment in another TBI model would have represented a predictable use of a known therapeutic approach according to the state of the art, the drug’s established function, and the drug’s known therapeutic outcomes.
Therefore, claims 1 and 21 are rejected under 35 U.S.C 103.
Conclusion
No claims are 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 Tirone D Johnson whose telephone number is (571)272-1256. The examiner can normally be reached M-F, 9-5 ET.
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/TIRONE D. JOHNSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
