CLAIMS 12-20 and 31-47 ARE PRESENTED FOR EXAMINATION
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 .
Prosecution Reopened
The indicated allowability of claims 12-20 and 31-47 is withdrawn in view of the newly discovered reference relied upon below.
Applicant is advised that the Notice of Allowance mailed February 06, 2026 is vacated. If the issue fee has already been paid, applicant may request a refund or request that the fee be credited to a deposit account. However, applicant may wait until the application is either found allowable or held abandoned. If allowed, upon receipt of a new Notice of Allowance, applicant may request that the previously submitted issue fee be applied. If abandoned, applicant may request refund or credit to a specified Deposit Account.
Claim Objection
Claim 45 is objected to as being dependent upon a rejected base claim, but is otherwise in condition for allowance.
Claim Rejection - 35 USC § 103
Claims 12-20, 31-44, 46 and 47 are rejected under 35 U.S.C. § 103 as being obvious over Vorasayan et al, Stroke, vol 50(11), pp. 3021-3027, (2019 in view of Tran et al., International Publication Number WO 2023/168379, published on September 7, 2023 (priority to March 3, 2022), Zhang et al., Neuropsychiatric Disease and Treatment, vol. 19, pp. 355-361 (2022); and 3) Xu et al., Frontiers in Neurology, pp. 1-9, July 2022, each already of record.
Similar to the claimed invention, Vorasayan teaches treating patients who have suffered LHI with glibenclamide. The patients had lesion volumes greater than 50 cm3, i.e., 156 cm3, (see the Table at pg. 3023, col. 1, sixth entry from the bottom). The teachings in Vorasayan meet the patient criteria (LHI and a NIHSS less than or equal to 20), and is a continuous infusion of the glibenclamide. Vorasayan teaches at pg. 3022, col. 1, second paragraph under “Methods” that intravenous tissue plasminogen activator was permitted, (line 3 vs. present claim 47). Also patient who underwent decompressive craniectomy are mentioned at pg. 3022, col. 2, lines 3-5, (compare to present claim 46).
Vorasayan sets forth in the Abstract the following about LHI patients and the intravenous glibenclamide:
“Prior studies have shown a linear relationship between computed tomography (CT)–derived radio density and water uptake, or brain edema, within stroke lesions. To test the hypothesis that intravenous glibenclamide (glyburide; BIIB093) reduces ischemic brain water uptake, we quantified the lesional net water uptake (NWU) on serial CT scans from patients enrolled in the phase 2 GAMES-RP Trial (Glyburide Advantage in Malignant Edema and Stroke)…
In this phase 2 post hoc analysis, intravenous glibenclamide reduced both water accumulation and mass effect after large hemispheric infarction. This study demonstrates NWU is a quantitative and modifiable biomarker of ischemic brain edema accumulation.”
Vorasayan, Abstract (emphasis added).
Vorasayan also teach a continuous infusion of glibenclamide:
“All subjects had a clinical diagnosis of anterior circulation LHI and were randomized to intravenous glibenclamide or placebo. Intravenous tissue-type plasminogen activator was permitted, but endovascular thrombectomy was an exclusion criterion based on the original trial design. Intravenous glibenclamide was given as a 0.13 mg bolus intravenous injection for the first 2 minutes, followed by an infusion of 0.16 mg/h for the first 6 hours and then 0.11 mg/h for the remaining 66 hours. Of the 86 patients randomized, 3 did not receive any drug treatment. Of the remaining 83 subjects (the modified intention-to-treat sample), 2 did not have available CT scans, resulting in a cohort of 81 for the current study.”
Vorasayan, page 3022, left column, last full paragraph (emphasis added).
Vorasayan also teaches that the LHI patients receiving glibenclamide had a baseline NIHSS of 20 in a table having the “Clinical Characteristics of the Cohort”:
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Vorasayan, Table 1 in-part, page 3023.
Although Vorasayan teaches that the LHI patients were administered a continuous infusion of glibenclamide, he does not explicitly teach that the infusion formulation is “reconstituted formulation is reconstituted from a lyophilized powder comprising the SUR1-TRPM4 channel inhibitor using a diluent such that the reconstituted formulation has a pH outside of the buffering capacity of the buffering agent” as required by claim 1.
However, one of ordinary skill in the art would have had a reasonable expectation of success in selected this formulation because it was known in the art at the time to have advantageous stability characteristics. For example, see Tran who teaches a reconstituted from a lyophilized powder comprising glibenclamide, a diluent, and has a pH outside of the buffering capacity of the buffering agent and which is free of cyclodextrins. The buffering agent has a pKa of 7.7 to 9.2 and the lyophilized powder further comprises the buffering agent, a base and a sugar alcohol.
Tran teaches an improved formulation of the drug glyburide (a.k.a., glibenclamide, a second generation sulfonylurea SUR1-TRPM4 channel inhibitor) that avoids many of the problems of previous formulations, such as stability problems and dose administration errors, and that the drug has use in diabetes as well as certain infarctions, including the claimed hemispherical infarction:
“Glyburide has been suggested as a therapy for various disorders including but not limited to Large Hemispherical Infarction (LHI), acute stroke (ischemic and hemorrhagic), traumatic brain injury (TBI), spinal cord injury (SCI), myocardial infarction (MI), brain contusion (BC), edema, traumatic brain injury, subarachnoid hemorrhage, spinal cord injury, shock (including hemorrhagic shock), organ ischemia, ventricular arrhythmias, to prevent CNS edema, reduce mortality and preserve neurological function.”
Tran, paragraph 0003 (emphasis added); and:
“[We] have discovered that the concentration of glyburide is reduced in glyburide solutions placed in various types of pharmaceutical containers due to various processes including instability, degradation, and sorption of glyburide to such containers. Glyburide is practically insoluble within the typical pH range for pharmaceutically acceptable infusion solutions (pH 5-9), which presents challenges for obtaining stable glyburide formulations that can be dosed to patients over time. It is also necessary and critical to control the stability of the stored glyburide formulation and the diluted dosing solution (e.g., after ~ 100-fold dilution of the stored glyburide formulation) for infusion.”, [Tran, paragraph 0006].
Tran also mentions the use of their formulation for patients that have suffered strokes a number of times (e.g., paragraphs 0007, 0030, 0058, 00100, and others).
Tran’s method of treatment starts with a dried lyophilized concentrate of the drug with a buffer outside of pH range of the reconstituted buffer, as required by claim 1 and which has a pKa of 7.7 to 9.2 as required by claim 14:
“[0067] In one aspect, the method and formulation of the present disclosure includes compounding a glyburide formulation including glyburide, and a base as specified herein to form a lyophilized powder. In one aspect, the method and formulation of the present disclosure includes combining the lyophilized powder with a buffering agent of the present disclosure. In one aspect, the method and formulation of the present disclosure includes reconstituting the lyophilized powder in a buffering agent of the present disclosure. In one aspect, the buffering agent has a pKa of 7.7 to 9.2, 7.8 to 9.1, 7.9 to 9.0, 8.0 to 8.9, 8.05 to 8.8, 8.1 to 8.7, or any specific pKa in the specified ranges. For example, and without limiting the foregoing disclosure, the buffering agent may be a Tris, a lysine, an arginine, an ethylenediamine, an imidazole, a 4-(2-Hydroxyethyl)morpholine, a triethanolamine, a glucamine, a deanol (dimethylaminoethanol), phosphate, phosphate-buffered saline (PBS) or a combination thereof. In one aspect, the buffering agent of the present disclosure has buffering capacity in a pH range of 7 to 9. In one aspect the Tris may be a combination of Tris HCl and Tris-base. In one aspect, the lysine is lysine-HCl. In one aspect, the arginine is arginine HCl, (emphasis added).
[0068] In one aspect, the present disclosure includes methods and lyophilized formulations comprising glyburide, a base, and a sugar alcohol, combined with a separate buffering agent of the present disclosure, wherein the combination has a pH outside of the buffering capacity of the buffering agent, and the combination is suitable (including safe, in a sustained therapeutically effective amount, and tolerable) for infusion to a human for a period of 24 hours or more. In one aspect, the formulation (reconstituted formulation) has a pH of greater than 9.0, greater than 9.5, greater than 10.0, or greater than 10.5, e.g., 9.3 to 11, whereas the buffering agent has buffering capacity in a pH range of 7 to 9.”
Tran, paragraphs 0067 and 0068 (emphasis added).
See also, claims 1 and 31.
Tran also teaches a continuous infusion of an IV solution (i.e., as claimed) :
“[0092] In some aspects, a diluted glyburide formulation of the present disclosure is diluted into an IV infusion bag, thereby reducing the amount of infusion liquids administered to the subject. For example, in some aspects, a diluted glyburide formulation of the present disclosure is diluted into a 250 mL IV infusion bag. In some aspects, a diluted glyburide formulation of the present disclosure is diluted into a 500 mL IV infusion bag. In view of the increased solubility, stability, and minimized sorption to medical containers, the formulation of the present disclosure makes it possible to use a more concentrated dosing formulation, thereby delivering a consistent therapeutic dose over the infusion period while using significantly less infusion fluids.
[0093] In some aspects, the present disclosure provides a method for decreasing the volume of infusion liquids administered to the subject by about 25-50% over the infusion period, e.g., from about 2 L to -1 L for a four day infusion period or from about 1.5 L to -0. 75 L for a three day infusion period.
[0094] In some aspects, due to the advantages of the present invention, a diluted glyburide formulation can be administered at a slower rate than prior art intravenous glyburide formulations. For example, the infusion rates can be decreased to about 40% the rate of infusion used for infusing prior art intravenous glyburide formulations, e.g., 11.5 ml/hour for first six hours and 8 ml/hour thereafter versus 29 ml/hour for first six hours and 20 ml/hour thereafter compared to prior art intravenous glyburide formulations.”
Tran, paragraphs 0092-0094 (emphasis added).
Although Tran teaches almost all of the limitations of the claims regarding ingredient amounts and proportions, pH values, he does not explicitly teach the specifically claimed amounts/proportions, pH ranges, the patient has LHI and experiencing a wake-up stroke or that the patient has undergone a mechanical thrombectomy.
However, one of ordinary skill in the art would have a reasonable expectation of success in treating this patient population as well, because these patients are treated similarly to those discussed in Tran for those who have brain edema, are treated relatively early to the wake-up stroke following the proper radiological imaging. For example, see Vorasayan, Zhang and Xu.
Vorasayan teaches a treatment method with IV glibenclamide in patients who have experienced ischemic stroke and large hemispheric infarction, and the serious complications reflected by a decreasing level of alertness. Although its prevalence among all patients with stroke is 2% to 8%, malignant cerebral edema occurs in 32% to 50% of patients with LHI. The presumed pathological sequence is a difference in ion gradients due to ion channel dysfunction and disruption of blood-brain barrier permeability that leads to excess water accumulation. In turn, the excess water entry causes lesional swelling and mass effect that impinges on adjacent, intact brain tissue.”, (Vorasayan, page 3021 (citations omitted)); and:
“Preclinical studies have shown that SUR1 (sulfonylurea receptor 1)-regulated ion channels participate in the formation of ionic and vasogenic edema after stroke.19,20 Inhibition of SUR1 by intravenous glibenclamide (also known as intravenous glyburide) prevents brain water accumulation and reduces mass effect in animal models of stroke.19 In the current study, we sought to determine whether water uptake can be modified by an investigational treatment in patients, thereby highlighting water uptake as a potential intermediate end point for clinical studies of edema. We studied patients enrolled in the GAMES-RP Trial (Glyburide Advantage in Malignant Edema and Stroke)5 (NCT01794182; https://www. clinicaltrials.gov), comparing net water uptake (NWU) on serial CT scans in placebo-treated subjects to patients treated with intravenous glibenclamide.”, (Vorasayan, page 3022); and:
“All subjects had a clinical diagnosis of anterior circulation LHI and were randomized to intravenous glibenclamide or placebo. Intravenous tissue-type plasminogen activator was permitted, but endovascular thrombectomy was an exclusion criterion based on the original trial design. Intravenous glibenclamide was given as a 0.13mg bolus intravenous injection for the first 2 minutes, followed by an infusion of 0.16 mg/h for the first 6 hours and then 0.11 mg/h for the remaining 66 hours. Of the 86 patients randomized, 3 did not receive any drug treatment. Of the remaining 83 subjects (the modified intention-to-treat sample), 2 did not have available CT scans, resulting in a cohort of 81 for the current study. (Vorasayan, page 3022 (Section titled “Patient Characteristics”)); and:
“We next evaluated the effect of intravenous glibenclamide treatment on MLS and NWU (Table 2). In the original trial study results, intravenous glibenclamide reduced MLS in cross-sectional analysis at 4 days after stroke onset.5 Accordingly, when analyzed over time, patients treated with intravenous glibenclamide had a similar reduction in MLS (Figure 3A; n=264; β=−1.50; 95% CI, −2.71 to −0.28; P=0.016). When the day 4 MR-derived MLS measurement was included together with the CT-derived measurements, this result was further strengthened (n=314; β=−1.72; 95% CI, −2.99 to −0.46; P=0.008). When examining NWU, intravenous glibenclamide treatment also led to reduced NWU accumulation over time (Figure 3B; β=−2.80; 95% CI, −5.07 to −0.53; P=0.016). There was a similar decrease in water uptake in both gray matter NWU (Figure 3C; β=−3.02; 95% CI, −5.04 to −0.99; P=0.003) and white matter NWU (Figure 3D; β=−3.59; 95% CI, −6.17 to −1.02; P=0.006). Including age in the models for MLS and NWU did not change the independent effect of glibenclamide treatment on edema.”, (Vorasayan, page 3024 (emphasis added)).
Zhang teaches that wake-up strokes can cause brain edema, that a significant percentage of the ischemic strokes are wake-up strokes, and that with early radiological analysis of the patient having wake-up strokes, the extent of brain edema can be more properly assessed:
“Ischemic strokes comprise 70% of all stroke cases; the most effective treatment in these cases is thrombolytic therapy within 4.5 h of onset.1,2 However, 25% of patients with ischemic stroke become aware of their symptoms upon awakening from sleep.” (Zhang, Introduction, page 355); and:
“DWI represents the diffusion of water molecules in the body, and it has been reported that patients with ischemic stroke can present DWI signal changes within minutes of onset.10–12 FLAIR is an inversion recovery sequence that highlights the signal contrast between the lesion and surrounding tissues by selecting a delay time (TI) close to the T1 value of the cerebrospinal fluid to produce a significant signal attenuation in the cerebrospinal fluid and tissues with similar T1 attenuation. Pathological studies12 suggested that Intracellular edema can occur early after brain ischemia, the mechanism is that after the ischemia of brain tissue reaches the threshold of cell membrane pump failure, Cell membrane ion pump transport disorder, sodium, calcium ions and water in extracellular fluid enter cells, resulting in cytotoxic brain edema. At this time, the total water content in the ischemic area did not increase, but the ratio of water inside and outside the cells changed, so neither T2WI nor FLAIR showed abnormality. However, the ability of water molecules to diffuse and move in the cell is weaker than that outside the cell, resulting in high DWI signal in the lesion area. Thomalla et al13 found that ischemic stroke could be invisible on FLAIR images within 3 h of stroke onset and proposed the DWI-FLAIR mismatch model. Other researchers reported the mismatch as a marker to identify patients who are within 4.5 h of onset. Thomalla et al8 performed a multicenter observational study in acute ischemic stroke patients within 4.5 h of onset. It showed that DWI–FLAIR mismatch could identify patients within 4.5 h with a specificity of 0.78 and a PPV (positive predictive value) of 0.83. These results were consistent with other studies.” (Zhang, Discussion, page 358).
Xu discloses the development of a new technique for brain edema early-detection, specifically, quantitative net water uptake over the progression of the edema types following the acute ischemic stroke, a patient study that included patients who had wake-up stroke:
“Brain edema is an important pathophysiological process after acute ischemic stroke (AIS). The pathophysiological mechanisms are primarily cytotoxic edema, angiogenic edema, and cerebrospinal fluid influx (1, 2). Progressive edema will lead to irreversible tissue injury, secondary neurological deterioration, and poor outcome (3). Current assessments of brain edema degree are mainly based on follow-up non-contrast computed tomography (NCCT), as brain edema peaks around 3 days after stroke onset (4). Imaging characteristics such as shrunken sulci, low density around infarct core, midline shift, and even brain hernia suggest brain edema indirectly (5). However, there are few neuroimaging markers able to detect brain edema early, directly, and quantitatively, and none of these neuroimaging markers were available in CT until recently (6).”
and:
“Emergency Department at Ningbo First Hospital (Advanced Stroke Center) between July 2017 and September 2019. Inclusion criteria: (1) acute anterior circulation infarction; (2) admission multimodal CT including NCCT, CT angiography (CTA), and CT perfusion (CTP) were completed within 24h after symptom onset. In patients with wake-up stroke, we estimated the time of stroke onset by taking the midpoint between sleep time and wake time (12); (3) follow-up CT scans performed at 24h and 1 week after stroke onset or immediately in case of clinical deterioration; (4) the absence of intracranial hemorrhage, brain tumor, or preexisting infarctions in admission NCCT. The thrombolysis in cerebral infarction (TICI) grading scale is used to define endpoints of successful revascularization (13).” (Xu, Introduction, page 02).
Also, as reported in Table 1, under “Treatment”, 51% of patients underwent a mechanical thrombectomy. The primary reference, Tran, teaches the treatment of stroke patients in general and thus would include patients who either had or not had mechanical thrombectomy. Given that the species of patients is only 2, i.e., with or without mechanical thrombectomy, the general disclosure of the genus of patients treated for stroke, those with mechanical thrombectomy would have been immediately envisioned and thus placed within the possession of the public.
The art taken as whole would lead someone of ordinary skill in the art to recognize that the formulation of Tran would be useful for a range of persons suffering diseases/disorder that are talking, not only limited to those discussed such as LHI, but patients who suffer from the symptom of brain edema caused by acute ischemic strokes where the time of event is unknow, such as in wake-up strokes. Those of ordinary skill in the art would recognize that the degree of success of this treatment would correlate with early detection, accurate radiological analysis, and earliest possible treatment as a means to limit the progression from brain edema to further types of edema and neurological damage.
The determination of the optimum ingredient amounts/proportions and pH ranges within those broadly taught by Tran would have been a matter well within the purview of the artisan having ordinary skill in the art.
Accordingly, the invention as a whole was prima facie obvious at the time it was filed.
None of the present claims are in condition for allowance.
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/RAYMOND J HENLEY III/Primary Examiner, Art Unit 1629 June 02, 2026
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