DETAILED ACTION
Status of Application
The response filed 10/16/2025 has been received, entered and carefully considered. The response affects the instant application accordingly:
Claim 1 has been amended.
Applicant had previously elected the mode of administration to be intravenous, and the disease species of hemorrhage which was expanded to include traumatic brain injury for the examination. Claim 7 is withdrawn as being drawn to a non-elected invention.
Claims 1-14 are pending.
Claims 1-6, 8-14 are present for examination at this time.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Standing Grounds of Rejection
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 1-6, 8-14 are rejected under 35 U.S.C. 103 as being unpatentable over by Nikolian et al. (Valproic acid decreases brain lesion size and improves neurologic recovery in swine subjected to traumatic brain injury, hemorrhagic shock, and polytrauma) in view of Abushakara et al. (U.S. Pat. 2015/0306043).
Rejection:
Nikolian et al. teaches treating a patient/subject (swine) subjected to traumatic brain injury and hemorrhagic shock (hemorrhage) with the administration intravenously a single dose of 150mg/kg valproic acid in isotonic saline (isotonic sodium chloride solution) over 3 hours (180min) at a concentration of 100mg/ml. The treatment schedule was chosen to recreate a battlefield injury at a remote location where first responders would initiate treatment while waiting extrication. The treatment is safe, decreases brain lesion size, and those treated with had faster neurocognitive recovery and less neurologic injury (abstract; Figure 1; Shock, Resuscitation, and Treatment; Discussion; Page 1072 2nd column second paragraph; see full document specifically areas cited). As the valproic acid/saline is safely administered to the patient (at room temperature) the solution is expected to be stable at room temperature. While the valproic acid was not given in the field/emergency medical setting, the treatment schedule was done to recreate a battlefield injury at a remote location where first responders would initiate treatment while waiting extrication wherein it would be implicit if not prima facie obvious to administer it in the field and/or emergency medical setting as designed by the setting with a reasonable expectation of success.
Nikolian et al. does not expressly teach the infusion of 150mg/kg at 100mg/ml to be 2 hours or less, or the dependent recited concentrations (at least 200mg/ml or at least 300mg/ml); but does expressly teach treating a patient/subject (swine) with traumatic brain injury and hemorrhagic shock (hemorrhage) with intravenous administration of a single dose of 150mg/kg valproic acid in isotonic saline over 3 hours (180min) at a concentration of 100mg/ml for battlefield injuries at a remote location where first responders would initiate treatment while waiting extrication which decreases brain lesion size, have faster neurocognitive recovery, and less neurologic injury.
Abushakara et al. teaches that valproic acid is known to be in liquids at concentrations from 50mg/5ml-500 mg/ml ([132], 10mg/ml-500mg/ml).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have infuse the valproic acid quickly given the emergent conditions (i.e. battlefield) including at higher concentrations including 200 and 300mg/ml as suggested by Abushakara et al. and produce the claimed invention; as it is prima facie obvious given the emergent conditions (i.e. battlefield) administer the valproic acid as quickly as possible to treat the patient (i.e. less than 3 hours e.g. 2 hours, 1 hour, 20 mins) and to formulate the composition at known concentrations for valproic acid like 300mg/ml and 500mg/ml where less time is needed to administer the valproic acid (the higher active concentration needs less time to achieve the desired dose) in order to arrive at the desired therapeutic profile sooner with a reasonable expectation of success absent evidence of criticality for the recited concentration/time span.
Response to Arguments:
Applicant's arguments are centered on the assertion that Nikolian et al. does not teach administering valproic acid within 120 mins or less, and the assertion of unexpected results citing Page 10 lines 7-10 of the specification.
This has been fully considered but not persuasive. Nikolian et al. teaches treating a patient with traumatic brain injury and hemorrhagic shock (hemorrhage) with intravenous administration of a single dose of 150mg/kg valproic acid in isotonic saline over 3 hours (180min) at a concentration of 100mg/ml designed for battlefield injuries at a remote location where first responders would initiate treatment while waiting extrication, wherein it is prima facie obvious given the emergent conditions (i.e. battlefield awaiting extraction) to administer the valproic acid as quickly as possible (i.e. less than 3 hours e.g. 2 hours, 1 hour, 20 mins) to stabilize the a patient as quickly as possible (i.e. for extraction) with a reasonable expectation of success absent evidence of criticality for the dose/time period claimed. Applicant’s argument is also against the reference individually, and one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
As it is also prima facie obvious to formulate the composition at known concentrations for valproic acid like 300mg/ml and 500mg/ml as suggested by Abushakara et al. where less time is needed to administer the valproic acid (the higher active concentration needs less time to achieve the desired dose) in order to arrive at the desired therapeutic profile sooner with a reasonable expectation of success absent evidence of criticality for the recited concentration/time span which has not been presented.
In regards to Applicant’s assertion of unexpected results, Applicant cites the Example 1 of the specification with the assertion that VPA at 150mg/kg over 3 hours improved survival while VPA at 100mg/kg over 3 hours did not, but VPA at 100mg/kg over 2 hours did improve survival; and asserts that delivering less VPA over a shorter amount of time would have an equivalent treatment effect to the protocol of Nikolian and that there is no teaching/suggestion that administering such a dose could be administered at this rate without adverse effects. This is fully considered but not persuasive. First, Example 1 is not commensurate in scope with the independent claim. The independent claim is broader with regards to the conditions and dosage (e.g. at least 100mg/kg i.e. 500mg/kg; acute medical need i.e. traumatic brain injury, cardiac arrest, acute manic event) than that of Example 1 which is to a hemorrhage/trauma model directed to IV administration of saline, 150mg/kg of VPA over 3 hours, and 100mg/kg of VPA over 2 hours and 3 hours which is not the breath instantly claimed. Second, Applicant did not fully present the findings of the Example 1 where the patients treated with saline had a survival rate of 17%, VPA at 100mg/kg over 3 hours was 0% survival, VPA at 100mg/kg over 2hours had 67% survival, and VPA at 150 mg/kg over 3 hours had 83% survival (wherein it was greater than and not equivalent to that of VPA 100 over 2 hrs as asserted by Applicant) – but Applicant’s own specification addresses that while the subjects with VPA 100mg/kg over 2 hours survived longer than those treated at that dose over 3 hours- it was not statistically different than those treated with saline (NS) wherein the assertion of unexpected results is not persuasive.
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(Page 11 line 25-26 of specification). It is also noted that there is no concentration of VPA disclosed in the example to ascertain the full dose given in the example.
As for the assertion that one would not expect administering such a dose could be administered at this rate without adverse effects. This is fully considered but not persuasive as adjustment and optimization of the concentration of the valproic acid and rate of infusion to quickly deliver the active under emergent conditions is prima facie obvious and within the skill of one in the art to attain the desired therapeutic profile (administration of the active quickly to the patient in emergent conditions with the least adverse effects (e.g. little to none)) with a reasonable expectation of success absent evidence of criticality for the recited concentration/time span which has not been presented.
Accordingly, the rejection stands.
Conclusion
Claims 1-6, 8-14 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GIGI GEORGIANA HUANG whose telephone number is (571)272-9073. The examiner can normally be reached Monday-Thursday 9:00-5:00pm.
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/GIGI G HUANG/Primary Examiner, Art Unit 1613