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
Claims 1, 4, 7, 9, 11-36, and 40-56 are pending.
Claim 36 is withdrawn.
Claims 2-3, 5-6, 8, 10, 36-39 are cancelled.
Priority
Applicant’s claim for benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. This application is a national stage entry of and claims priority to Application Serial No. PCT/US2020/030620, filed 04/30/2020. The application also claims priority to provisional application 62/842021 filed 05/02/2019.
Information Disclosure Statement
All references from IDS(s) received 10/29/2021, 02/1/2023, and 08/18/2023 have been considered unless marked with a strikethrough.
Response to Arguments
Applicant's arguments filed 7/15/2025 have been fully considered but they are not persuasive. In a non-final dated 4/16/2025, Claims 1, 4, 7, 9, 11-35, 38-56 were examined upon their merits.
In a non-final dated 4/16/2025, Claims 1, 4, 7, 9, 11-35, 38-56 were rejected 35 U.S.C. 103. In response, Applicant amended claims 1, 4, 41, and 55. Specifically, the Applicant amended claims 1, 4, and 41 to include “wherein the subject has brain contusion within the supratentorial brain parenchyma totaling > 3 mL in volume and a score of 5 to 14 on the Glasgow Coma Scale (GCS).” The applicant amended claim 55 to seemingly fix a typo (amended “glyclazide” to “glicazide”).
With respect to the 103 rejection for claims 1, 4, 7, 9, 11-35 and 40, the Examiner does not find the argument persuasive. The applicant argues that the prior art provided by the Examiner (“Simard”) does not disclose the subject has brain contusion with lesions within the supratentorial brain parenchyma totaling > 3 mL in volume and a score of 5 to 14 on the GCS. The Examiner agrees that Simar does not teach this, however, the secondary reference (“Jacobson”) used for claims 1, 20, 41-56 does disclose overlapping ranges. Therefore, the 103 rejection is combined. Specifically, Jacobson teaches a method of treating a subject where prior to treatment the subject shows radiological evidence of intracerebral blood induced by the traumatic brain injury. The intracerebral blood can be due to a focal contusion with a minimum volume of at least about 0.5 mLs or at least about 1 mL (para 0059). Since Jacobson teaches a focal contusion with a volume over 1mL, this would be considered an overlapping range with the amended claims. Further, Jacobson teaches an example with subjects exhibiting moderate or severe TBI (Glasgow Coma Scale score 4-12) or with mild TBI (GCS 13-14) (Example 2, para 0122). This would also be considered an overlapping range with the amended claims. With respect to the biological location, the instant claims recite the contusion with the supratentorial brain parenchyma. The Examiner understand this to be a contusion that exists above the tentorium. The tentorium to create a separation between the cerebrum and cerebellum, therefore the contusion would be in the cerebrum (in the upper part of the brain). Therefore, any contusion in the cerebrum would meet this limitation of the instant claim.
Further, the Examiner argues that the applicant has not provided any evidence or argument to the criticality of the GCS score or volume of the contusion presented in the claims. Therefore, these fall under routine optimization. See the revised rejection for further detail.
“The law is replete with cases in which the difference between the claimed invention and the prior art is some range or other variable within the claims. . . . In such a situation, the applicant must show that the particular range is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range.”
In reWoodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205 (CCPA 1946) (“Where the issue of criticality is involved, the applicant has the burden of establishing his position by a proper showing of the facts upon which he relies.”)
In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955): "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." Therefore, a skilled artisan would be motivated to optimize the ratio specific to a patient’s response and tolerability. See MPEP 2144.05(II)(A).
New/Maintained Rejections
Claim Interpretation
CNS contusion: Examiner assumes “expansion” of cerebral contusion includes secondary injury. The specification first mentions an expansion in leading “to an increase in hematoma volume, but also to the
evolution of perihematomal edema surrounding the lesion itself. After initial trauma, increased
osmotic flux leads to the lysis of endothelial cells and the loss of capillary structural integrity. This
results in the extravasation of blood, and the resultant expansion of the initial contusion. Moreover,
loss of capillary structure permits the development of perihematomal vasogenic edema. Further,
cytotoxic edema is another sequela that worsens contusion progression. Such sequelae cause
significant secondary brain injury (paragraph 0002).”
Also, Simard (US20100311639A1, 2010), as an evidentiary reference, teaches “a contusion injury to the brain is typically aggravated by secondary injury, resulting in expansion of the original lesion and concomitant worsening of neurological outcome.”
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 (i.e., changing from AIA to pre-AIA ) 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.
Claims 1, 4, 7, 9, 11-35, 40-56 are rejected under 35 U.S.C. 103 as being unpatentable over Simard (US20170296555A1; 2016; cited in IDS filed 10/29/2021; “Simard”) in further view of Jacobson (US20180280325A1, 2018; cited in IDS filed 10/29/2021; “Jacobson”).
Simard teaches “A method of treating or reducing ischemic damage in a subject comprising administering an inhibitor of an NCCa-ATP channel that is a SUR1 antagonist and/or a TRPM4 antagonist as a loading bolus dose followed by a constant infusion of a maintenance dose, wherein the bolus dose is 30-90 times the amount of the maintenance dose.” (Claim 34), where the SUR 1 antagonist is glibenclamide (glyburide) (Claim 35). Further, Simard teaches “glibenclamide is extraordinarily effective in reducing hemorrhagic conversion” (Page 44, p. 0466) and “ameliorating pathological manifestations of cerebral ischemia and spinal cord injury” (Page 45, Col. 2, p. 0473). In anticipation of Claims 1 and 55-56, Simard teaches “glibenclamide, will do one or more of the following: (i) minimize secondary injury (formation of edema and hemorrhagic conversion); (ii) minimize lesion size, limiting it to the original site of direct injury; (iii) optimize functional neurological recovery” (Page 12, p. 0118)
With respect to Claim 4, Simard teaches a method for decreasing water content in a CNS tissue of a subject in need thereof after a CNS contusion, as well as inhibiting a CNS contusion progression (such as edema). “The protection via inhibition of the NCCa-ATP channel is associated with a reduction in edema” (Page 14, p. 0143) “In such examples, an antagonist of the NCCa-ATP channel is administered and/or applied. The antagonist modulates the NCCa-ATP channel such that flux through the channel is reduced, ceased, decreased and/or stopped” (Page 14, p. 0144). Further, “The antagonist may prevent or lessen the depolarization of the cells thereby lessening cell swelling due to osmotic changes that can result from depolarization of the cells” (Page 14-15, p. 0144).
Simard also teaches a method for inhibiting disruption of the blood-brain barrier. “The blood-brain barrier (BBB) serves as a critical organ in the maintenance of CNS homeostasis and is disrupted in a number of neurological disorders, including ischemic stroke” (Page 19, p. 0190). Further, “Dysfunction of cerebral capillaries due to ischemia and post-ischemic reperfusion results in a progressive alteration in permeability of the blood brain barrier (BBB), leading to formation of ionic edema, vasogenic edema and hemorrhagic conversion” (Page 20, p. 0203).
Simard teaches the improvement of motor function post-contusion as “glibenclamide treatment was associated with significantly better truncal and lower extremity function” (Page 41, p. 0433). Therefore, all of the requirements of instant claim 4, including a method for decreasing water content, inhibiting BBB disruption, inhibiting contusion progression, and improving post-contusion motor function are taught by Simard.
With respect to Claim 7, in some embodiments, glyburide can be used to reduce hemorrhagic conversion. The pathological sequence within the capillaries can be divided into the 3 stages. The third stage is “characterized by hemorrhagic conversion, due to catastrophic failure of capillaries, during which all constituents of blood extravasate into brain parenchyma” (Page 15, p. 0149). Therefore, in the treatment of hemorrhagic conversion, glyburide treats the stages of the pathological sequence, which includes inhibiting extravasation of blood into the brain parenchyma.
With respect to Claim 9, Simard teaches “a method of preventing cellular swelling and the resulting cellular damage through the therapeutic use of antagonists to the NCCa-ATP channel, alone or in combination with an additional therapeutic compound” (Page 3, p. 0017). Therefore, Simard teaches instant claim 9’s requirement for “a method for inhibiting endothelial cell breakdown” since preventing cellular swelling and the proceeding damage would inherently be inhibiting cell breakdown.
With respect to Claim 11, Simard teaches “A typical dosing regime consists of a loading dose designed to reach a target agent plasma level followed by an infusion of up to 7 days to maintain that target level. One skilled in the art will recognize that the pharmacokinetics of each agent will determine the relationship between the load dose and infusion rate for a targeted agent plasma level. In one example, for intravenous glyburide administration, a 15.7 μg bolus (also called a loading dose) is followed by a maintenance dose of 0.3 μg/min (432 μg/day) for 120 hours (5 days). This dose regime is predicted to result in a steady-state plasma concentration of 4.07 ng/mL. In another example for intravenous glyburide, a 117 μg bolus dose is followed by a maintenance dose of 2.1 μg/min (3 mg/day) for 3 days. This dose is predicted to result in a steady-state plasma concentration of 28.3 ng/mL. In yet another example for glyburide, a 665 μg bolus dose is followed by a maintenance dose of 11.8 μg/min (17 mg/day) for 120 hours (5 days). This dose is predicted to result in a steady-state plasma concentration of 160.2 ng/mL” (Page 4-5, p. 0033). The dosing regimen required by instant claim 11 fall within those taught by Simard.
Simard teaches a method of inhibiting contusion in a subject in need thereof “glibenclamide is beneficial in reducing edema and hemorrhage at the contusion site.”
With respect to claims 12-35, Simard also teaches:
For maximum benefit of the additional agent, the therapy must be started within three hours of the onset (Page 37, p.0377), which is required by instant claim 12.
In particular embodiments, there may be dosing of from very low ranges (e.g. for glyburide 1 mg/day or less) to moderate doses (e.g. 3.5 mg/day) to high doses (e.g. 10-40 mg/day; and even higher) (Page 4, p. 0031)
In other embodiments, Simard teaches there may be dosing of from very low ranges (e.g. 1 mg/kg/day or less; 5 mg/kg bolus; or 1 mg/kg/day) to moderate doses (e.g. 2 mg bolus, 15 mg/day) to high doses (e.g. 5 mg bolus, 30-40 mg/day; and even higher) (Page 4, p. 0028)
After the initial bolus dose, the antagonist may be administered in a dosage of less than 3.5 mg per day (Claim 46).
More specifically, doses of an antagonist to be administered are from about 0.01 nM to about 2000 μM (Page 3, p. 0021)
Various steady state plasma level concentrations.
Although Simard does not teach the specific data points and dosage guidelines (bolus/loading dose, maintenance dose, dosage phase length, maintenance phase length, concentration reiterated in different ways such as molarity, rate ratio, “mg/hour”, X-fold higher/lower etc.) as required by claims 12-35, they do fall within the claimed ranges above and/or can be calculated using the claimed ranges taught by Simard. For example, instant claim 35 recites administering about 10-20 mg of the inhibitor over 96 hours. Simard teaches the inhibitor to dosed up to 3.5 mg/day after the initial bolus dose (Claim 46), which leads to about 14 mg in 96 hours. In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003): "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." Further, the specific dosage guidelines within these claims would be considered routine optimization of variables. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955): "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." The applicant has not determined the criticality of these dosage boundaries within the Specification. Therefore, a skilled artisan would be motivated to optimize doses and administration phase length specific to a patient’s response and tolerability. See MPEP 2144.05(II)(A).
With respect to Claim 40, Simard teaches the formulation to include sugars, including glycols, mannitol, sorbitol. Simard fails to directly teach the ratio of sugar/sugar alcohol to glyburide, or the other sugars listed in instant claim 39. However, adjusting the selected sugar or ratio would be considered routine optimization of variables and thereby considered prima facie obvious (see optimization rationale above incorporated by reference herein). With respect to routine optimization, Simard teaches that mannitol is used in the pharmaceutical composition to stimulate or promote ischemic precondition (Page 24, p. 0043). Thus, mannitol is a result effective variable because it is linked to this functional result. One could optimize the amount of mannitol in order to stimulate or promote optimal ischemic precondition. Simard also teaches mannitol as an additional therapeutic agent (Page 48, p. 0317), where an additional therapeutic agent with or without the antagonist can be administered in a dose of about 0.0001 nM to about 2000 μM, for example (Page 22, p. 0029). Therefore, Simard also teaches an overlapping range of the ratio of mannitol in instant claim 40.
Simard fails to teach the subject with a brain contusion with lesions within the supratentorial brain parenchyma totaling > 3 mL in volume and a score of 5 to 14 on the GCS.
However, Jacobson teaches a method of treating a subject where prior to treatment the subject shows radiological evidence of intracerebral blood induced by the traumatic brain injury. The intracerebral blood can be due to a focal contusion with a minimum volume of at least about 0.5 mLs or at least about 1 mL (para 0059). Since Jacobson teaches a focal contusion with a volume over 1mL, this would be considered an overlapping range with the amended claims. Further, Jacobson teaches an example with subjects exhibiting moderate or severe TBI (Glasgow Coma Scale score 4-12) or with mild TBI (GCS 13-14) (Example 2, para 0122). This would also be considered an overlapping range with the amended claims. With respect to the biological location, the instant claims recite the contusion with the supratentorial brain parenchyma. The Examiner understand this to be a contusion that exists above the tentorium. The tentorium to create a separation between the cerebrum and cerebellum, therefore the contusion would be in the cerebrum (in the upper part of the brain). Therefore, any contusion in the cerebrum would meet this limitation of the instant claim.
Further, the applicant has not provided any evidence or argument to the criticality of the GCS score or volume of the contusion presented in the claims. Therefore, these fall under routine optimization. See the revised rejection for further detail.
“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 reWertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In reWoodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)” See MPEP 2144.05(I).
“The law is replete with cases in which the difference between the claimed invention and the prior art is some range or other variable within the claims. . . . In such a situation, the applicant must show that the particular range is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range.”
In reWoodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205 (CCPA 1946) (“Where the issue of criticality is involved, the applicant has the burden of establishing his position by a proper showing of the facts upon which he relies.”)
In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955): "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." Therefore, a skilled artisan would be motivated to optimize the ratio specific to a patient’s response and tolerability. See MPEP 2144.05(II)(A).
Simard fails to teach the administration of glyburide for at least 96 hours and monitoring the functional outcomes of the treatment through methods such as MRI, the Rankin and Glasgow scales, as well as a patient’s blood glucose, as required by instant claims 41-56.
Jacobson teaches the administration of glyburide for at least 96 hours (Claim 10), as required by instant claim 41. With respect to claim 42, the preliminary contusion expansion before treatment increasing from the baseline would be considered a functional outcome.
Jacobson teaches the use of monitoring the subject’s tissue through imaging, as required by instant claim 43, through MRI (claim 46) with 72-96 hours (page 10, p.0105), as required by instant claims 44-46.
Further, Jacobson teaches the monitoring a subject’s blood glucose (Page 1, p. 0013), as well as counteracting a decline in a patient’s blood glucose (Page 1, p. 0009), as required by instant claims 47-48. With respect to instant claims 49-52, these stipulations would be considered routine optimization of monitoring and counteracting a decline in the blood glucose level of a subject receiving glyburide, as taught by Jacobson.
Jacobson also teaches measuring the degree of disability using the Rankin Scale (Claim 47), as well as the use of the Glasgow Outcome Scale (Example 2, p. 0122), as required by instant claims 53 and 54, respectively.
It would have been prima facie obvious to extract the teachings of Simard and apply the method of administering glyburide for at least 96 hours and monitoring the functional outcomes of the treatment through methods such as MRI, the Rankin and Glasgow scales, as well as a patient’s blood glucose, as taught by Jacobson in order to monitor results. Therefore, claims 1, 20, 41-54 would have been obvious to a person who is skilled in the art prior to the effective filing date.
Art Made of Record but not Applied
1. Khalili, H. et al. Effects of Oral Glibenclamide on Brain Contusion Volume and Functional Outcome of Patients with Moderate and Severe Traumatic Brain Injuries: A Randomized Double-Blind Placebo-Controlled Clinical Trial. World Neurosurgery, 2017, 101, 130-136. DOI: 10.1016/j.wneu.2017.01.103
2. Zweckberger, K. et al. Glibenclamide reduces secondary brain damage after experimental traumatic brain injury. Neuroscience, 2014, 272, 199-206. DOI: 10.1016/j.neuroscience.2014.04.040
3. Simard, J.M. et al. Key Role of Sulfonylurea Receptor 1 in Progressive Secondary Hemorrhage after Brain Contusion. Journal of Neurotrauma, 2009, 26, 12. DOI: 10.1089/neu.2009.1021
Conclusion
Claims 1, 4, 7, 9, 11-35, and 40-56 are rejected.
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 NICOLA MARIA BAUER whose telephone number is (703)756-1269. The examiner can normally be reached Monday-Friday 7:30-5 EST.
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/N.M.B./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621