Patent Grant
11096905
The present invention relates to the use of cannabidiol (CBD) in the treatment of atonic seizures. In one embodiment the patients suffering from atonic seizures are children and young adults. CBD appears particularly effective in reducing atonic seizures in patients suffering with etiologies that include: Lennox-Gastaut Syndrome; Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; Aicardi syndrome; CDKL5 and Dup15q in comparison to other seizure types.
In these patients treatment with CBD reduced the occurrence of atonic seizures by greater than 50% in a large proportion, namely 63%, of patients. This was surprising given that the proportion of patients benefitting from a greater than 50% reduction in total seizures was significantly less, (46%), in all subjects treated.
Preferably the CBD used is in the form of a highly purified extract of cannabis such that the CBD is present at greater than 98% of the total extract (w/w) and the other components of the extract are characterised. In particular the cannabinoid tetrahydrocannabinol (THC) has been substantially removed, to a level of not more than 0.15% (w/w) and the propyl analogue of CBD, cannabidivarin, (CBDV) is present in amounts of up to 1%. Alternatively, the CBD may be a synthetically produced CBD.
In use the CBD may be given concomitantly with one or more other anti-epileptic drugs (AED). Alternatively the CBD may be formulated for administration separately, sequentially or simultaneously with one or more AED or the combination may be provided in a single dosage form. Where the CBD is formulated for administration separately, sequentially or simultaneously it may be provided as a kit or together with instructions to administer the one or more components in the manner indicated. It may also be used as the sole medication, i.e. as a monotherapy.
Epilepsy occurs in approximately 1% of the population worldwide, (Thurman et al., 2011) of which 70% are able to adequately control their symptoms with the available existing anti-epileptic drugs (AED). However, 30% of this patient group, (Eadie et al., 2012), are unable to obtain seizure freedom from the AED that are available and as such are termed as suffering from intractable or “treatment-resistant epilepsy” (TRE).
Intractable or treatment-resistant epilepsy was defined in 2009 by the International League Against Epilepsy (ILAE) as “failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom” (Kwan et al., 2009).
Individuals who develop epilepsy during the first few years of life are often difficult to treat and as such are often termed treatment-resistant. Children who undergo frequent seizures in childhood are often left with neurological damage which can cause cognitive, behavioral and motor delays.
Childhood epilepsy is a relatively common neurological disorder in children and young adults with a prevalence of approximately 700 per 100,000. This is twice the number of epileptic adults per population.
When a child or young adult presents with a seizure, investigations are normally undertaken in order to investigate the cause. Childhood epilepsy can be caused by many different syndromes and genetic mutations and as such diagnosis for these children may take some time.
The main symptom of epilepsy is repeated seizures. In order to determine the type of epilepsy or the epileptic syndrome that a patient is suffering from an investigation into the type of seizures that the patient is experiencing is undertaken. Clinical observations and electroencephalography (EEG) tests are conducted and the type(s) of seizures are classified according to the ILEA classification described below and in
The International classification of seizure types proposed by the ILAE was adopted in 1981 and a revised proposal was published by the ILAE in 2010 and has not yet superseded the 1981 classification.
From
Focal (partial) seizures where the seizure originates within networks limited to only one hemisphere, are also split into sub-categories. Here the seizure is characterized according to one or more features of the seizure, including aura, motor, autonomic and awareness/responsiveness. Where a seizure begins as a localized seizure and rapidly evolves to be distributed within bilateral networks this seizure is known as a bilateral convulsive seizure, which is the proposed terminology to replace Secondary Generalized Seizures (generalized seizures that have evolved from focal seizures and are no longer remain localized).
Focal seizures where the subject's awareness/responsiveness is altered are referred to as focal seizures with impairment and focal seizures where the awareness or responsiveness of the subject is not impaired are referred to as focal seizures without impairment.
Atonic seizures involve the loss of muscle tone, causing the person to fall to the ground. These are sometimes called ‘drop attacks’ and are usually brief (less than 15 seconds). Atonic seizures can occur without warning while standing, sitting and walking and the patient often suffers from trauma due to falling.
Atonic seizures are often associated with Lennox-Gastaut Syndrome but also occur, and may be symptomatic of other types of epileptic syndromes including: Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; Aicardi syndrome; CDKL5 and Dup15q.
Epileptic syndromes often present with many different types of seizure and identifying the types of seizure that a patient is suffering from is important as many of the standard AED's are targeted to treat or are only effective against a given seizure type/sub-type.
One such childhood epilepsy syndrome is Lennox-Gastaut syndrome. Lennox-Gastaut syndrome is a severe form of epilepsy. Seizures usually begin before the age of 4. Seizure types, which vary among patients, include tonic (stiffening of the body, upward deviation of the eyes, dilation of the pupils, and altered respiratory patterns), atonic (brief loss of muscle tone and consciousness, causing abrupt falls), atypical absence (staring spells), and myoclonic (sudden muscle jerks). There may be periods of frequent seizures mixed with brief, relatively seizure-free periods.
Most children with Lennox-Gastaut syndrome experience some degree of impaired intellectual functioning or information processing, along with developmental delays, and behavioural disturbances.
Lennox-Gastaut syndrome can be caused by brain malformations, perinatal asphyxia, severe head injury, central nervous system infection and inherited degenerative or metabolic conditions. In 30-35 percent of cases, no cause can be found.
The first line treatment for atonic seizures, including the treatment of atonic seizures in patients with Lennox-Gastaut syndrome usually comprises a broad spectrum AED, such as sodium valproate often in combination with lamotrigine. Other AED that may be considered include rufinamide, felbamate, clobazam and topiramate.
AED such as carbamezapine, gabapentin, oxcarbazepine, pregabalin, tiagabineor and vigabatrin are contra-indicated in atonic seizures.
Common AED defined by their mechanisms of action are described in the following tables:
From these tables it can be seen that there is only one drug currently approved for use in the treatment of atonic seizures, namely clonazepam. This medication works by the GABA mechanism.
Over the past forty years there have been a number of animal and human studies on the use of the non-psychoactive cannabinoid cannabidiol (CBD) to treat seizures.
A study in 1978 provided 200 mg/day of pure CBD to four adult patients, two of the four patients became seizure free, whereas in the remainder, seizure frequency was unchanged (Mechoulam and Carlini, 1978).
Cunha et al. reported that administration of CBD to eight adult patients with generalized epilepsy resulted in a marked reduction of seizures in 4 of the patients (Cunha et al., 1980) and Consroe et at, (1982) determined that CBD was able to prevent seizures in mice after administration of pro-convulsant drugs or an electric current.
In contrast to the studies described above, an open label study reported that 200 mg/day of pure CBD was ineffective in controlling seizures in twelve institutionalized adult patients (Ames and Cridland, 1986).
All of the studies described above focused on the treating subjects suffering from generalised epilepsy and did not look at the treatment of specific seizure sub-types.
More recently, WO 2011/001169 describes the use of CBD in the treatment of focal seizures, WO 2012/093255 describes the use of CBD in combination with standard anti-epileptic drugs in the treatment of epilepsy and WO 2013/045891 describes a composition comprising CBD and CBDV for use in the treatment of epilepsy.
In November 2013 the company GW Pharmaceuticals made a press release to state that they were intending to treat Dravet Syndrome with CBD as it had received orphan drug designation. The company made a further press release in February 2014 that that they were intending to treat Lennox-Gastaut Syndrome with CBD as it had also received orphan drug designation.
Again the rationale was to treat a disease as opposed to the type of seizure that the subject experienced.
It has additionally been suggested that cannabis which is enriched in CBD may be efficacious in the treatment of epilepsy. A case study of a child with Lennox-Gastaut syndrome showed improvement in seizure frequency after treatment with CBD in an oily solution was reported in 2005 (Pelliccia et al. 2005).
Porter and Jacobson (2013) report on a parent survey conducted via a Facebook group which explored the use of cannabis which was enriched with CBD in children with treatment-resistant epilepsy. It was found that sixteen of the 19 parents surveyed reported an improvement in their child's epilepsy. The children surveyed for this paper were all taking cannabis that was purported to contain CBD in a high concentration although the amount of CBD present and the other constituents including THC were not known for many of the cases. Indeed, whilst CBD levels ranged from 0.5 to 28.6 mg/kg/day (in those extracts tested), THC levels as high as 0.8 mg/kg/day were reported. Providing children with TRE with a cannabis extract that comprises THC, which has been described as a pro-convulsant (Consroe et al., 1977), at a potentially psychoactive dose of 0.8 mg/kg/day, is a concern.
In addition a paper published in June 2014 describes the use of a high-CBD strain to treat a patient with Dravet Syndrome; the patient's seizure frequency was stated to be reduced by the treatment (Maa et al. 2014).
A document published after the priority application was filed discloses the use of CBD in the treatment of refractory epilepsy in the treatment of Tuberous Sclerosis Complex in patients having focal onset seizures (Geffrey et al., 2014).
Whilst the potential of cannabis and the cannabinoids, including CBD, to treat epilepsy has been rekindled, to date there has been little in the way of real data to support its efficacy in patients.
The applicant has found that CBD shows significant efficacy in reducing atonic seizures, by greater than 50% in a large proportion, namely 63%, of patients. By way of comparison the proportion of patients benefitting from a greater than 50% reduction in total seizures was significantly less, (46%), in all subjects treated.
It is additionally worth noting that the patients being treated were treatment resistant to existing AED and so consequently these figures are even the more remarkable.
In accordance with a first aspect of the present invention there is provided cannabidiol (CBD) for use in the treatment of atonic seizures.
Preferably the atonic seizures are treatment-resistant.
Preferably the atonic seizures associated with Lennox-Gastaut Syndrome; Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; Aicardi syndrome, CDKL5 or Dup15q.
In one embodiment the CBD is for use in combination with one or more concomitant anti-epileptic drugs (AED).
In a further embodiment the CBD is present as a highly purified extract of cannabis which comprises at least 95% (w/w) CBD, more preferably 98% (w/w) CBD. Preferably the extract comprises less than 0.15% THC. More preferably the extract further comprises up to 1% CBDV.
In an alternative embodiment the wherein the CBD is present as a synthetic compound.
In a further embodiment of the invention the one or more AED is selected from the group consisting of: clobazam; clonazepam, levetiracetam; topiramate; stiripentol; phenobarbital; lacsamide; valproic acid; zonisamide; perampanel; and fosphenytoin.
Preferably the number of different anti-epileptic drugs that are used in combination with the CBD is reduced. Alternatively the dose of the one or more anti-epileptic drugs that are used in combination with the CBD is reduced.
Preferably the dose of CBD is greater than 5 mg/kg/day.
In accordance with a second aspect of the present invention there is provided a method of treating atonic seizures comprising administering cannabidiol (CBD) to a subject.
In accordance with a third aspect of the present invention there is provided a composition for use in the treatment of atonic seizures characterised by atonic seizures comprising cannabidiol (CBD), a solvent, a co-solvent, a sweetener, and a flavouring.
Preferably the solvent is sesame oil, the co-solvent is ethanol, the sweetener is sucralose, the flavouring is strawberry flavour and the CBD is present at a concentration of between 25/mg/ml and 100 mg/ml.
More preferably the composition comprises cannabidiol (CBD) at a concentration of between 25 to 100 mg/ml, ethanol at a concentration of 79 mg/ml, sucralose at a concentration of 0.5 mg/ml, strawberry flavouring at a concentration of 0.2 mg/ml and sesame q.s. to 1.0 ml.
Definitions of some of the terms used to describe the invention are detailed below:
The cannabinoids described in the present application are listed below along with their standard abbreviations.
The table above is not exhaustive and merely details the cannabinoids which are identified in the present application for reference. So far over 60 different cannabinoids have been identified and these cannabinoids can be split into different groups as follows: Phytocannabinoids; Endocannabinoids and Synthetic cannabinoids (which may be novel cannabinoids or synthetically produced phytocannabinoids or endocannabinoids).
“Phytocannabinoids” are cannabinoids that originate from nature and can be found in the cannabis plant. The phytocannabinoids can be isolated from plants to produce a highly purified extract or can be reproduced synthetically.
“Highly purified cannabinoids” are defined as cannabinoids that have been extracted from the cannabis plant and purified to the extent that other cannabinoids and non-cannabinoid components that are co-extracted with the cannabinoids have been removed, such that the highly purified cannabinoid is greater than or equal to 95% (w/w) pure.
“Synthetic cannabinoids” are compounds that have a cannabinoid or cannabinoid-like structure and are manufactured using chemical means rather than by the plant.
Phytocannabinoids can be obtained as either the neutral (decarboxylated form) or the carboxylic acid form depending on the method used to extract the cannabinoids. For example it is known that heating the carboxylic acid form will cause most of the carboxylic acid form to decarboxylate into the neutral form.
“Treatment-resistant epilepsy” (TRE) or “intractable epilepsy” is defined as per the ILAE guidance of 2009 as epilepsy that is not adequately controlled by trials of one or more AED.
“Childhood epilepsy” refers to the many different syndromes and genetic mutations that can occur to cause epilepsy in childhood. Examples of some of these are as follows: Dravet Syndrome; Myoclonic-Absence Epilepsy; Lennox-Gastaut syndrome; Generalized Epilepsy of unknown origin; CDKL5 mutation; Aicardi syndrome; bilateral polymicrogyria; Dup15q; SNAP25; and febrile infection related epilepsy syndrome (FIRES); benign rolandic epilepsy; juvenile myoclonic epilepsy; infantile spasm (West syndrome); and Landau-Kleffner syndrome. The list above is non-exhaustive as many different childhood epilepsies exist.
“Atonic Seizures” are defined as a convulsive type of epileptic seizure which causes the muscles to relax and the patient to flop or fall.
“Mixed seizures” are defined as the existence of both generalised and focal seizures in the same patient.
The terms “50% responder” and “50% reduction in seizure” are both terms used in clinical studies. In the present application the terms define the percentage of subjects that experienced a greater than or equal to 50% reduction in the number of seizures during treatment with CBD in comparison to the number experienced during the baseline period before the CBD was administered.
Preparation of Highly Purified CBD Extract
The following describes the production of the highly-purified (>98% w/w) cannabidiol extract which has a known and constant composition which was used for the expanded access trials described in Examples below.
In summary the drug substance used in the trials is a liquid carbon dioxide extract of high-CBD containing chemotypes of Cannabis sativa L. which had been further purified by a solvent crystallization method to yield CBD. The crystallisation process specifically removes other cannabinoids and plant components to yield greater than 95% CBD w/w, typically greater than 98% w/w.
The Cannabis sativa L. plants are grown, harvested, and processed to produce a botanical extract (intermediate) and then purified by crystallization to yield the CBD (drug substance).
The plant starting material is referred to as Botanical Raw Material (BRM); the botanical extract is the intermediate; and the active pharmaceutical ingredient (API) is CBD, the drug substance.
Both the botanical starting material and the botanical extract are controlled by specifications. The drug substance specification is described in Table 5 below.
The purity of the CBD drug substance achieved is greater than 98%. The other cannabinoids which may occur in the extract are: CBDA, CBDV, CBD-C4 and THC.
Distinct chemotypes of Cannabis sativa L. plant have been produced to maximize the output of the specific chemical constituents, the cannabinoids. One type of plant produces predominantly CBD. Only the (−)-trans isomer occurs naturally, furthermore during purification the stereochemistry of CBD is not affected.
Production of the Intermediate
An overview of the steps to produce a botanical extract, the intermediate, are as follows:
1. Growing
2. Decarboxylation
3. Extraction No. 1—using liquid CO2
4. Extraction No. 2—‘winterization’ using ethanol
5. Filtration
6. Evaporation
High CBD chemovars were grown, harvested and dried and stored in a dry room until required. The botanical raw material (BRM) was finely chopped using an Apex mill fitted with a 1 mm screen. The milled BRM was stored in a freezer for up to 3 months prior to extraction.
Decarboxylation of CBDA to CBD was carried out using a large Heraeus tray oven. The decarboxylation batch size in the Heraeus is approximately 15 Kg. Trays were placed in the oven and heated to 105° C.; the BRM took 96.25 minutes to reach 105° C. Held at 105° C. for 15 Minutes. Oven then set to 150° C.; the BRM took 75.7 minutes to reach 150° C.; BRM held at 150° C. for 130 Minutes. Total time in the oven was 380 Minutes, including 45 minutes cooling and 15 Minutes venting.
Extraction No 1 was performed using liquid CO2 at 60 bar/10° C. to produce botanical drug substance (BDS) which was used for crystallisation to produce the test material.
The crude CBD BDS was winterised in Extraction No 2 under standard conditions (2 volumes of ethanol at minus 20° C. for around 50 hours). The precipitated waxes were removed by filtration and the solvent evaporated using the rotary evaporator (water bath up to 60° C.) to yield the BDS.
Production of the Drug Substance
The manufacturing steps to produce the drug substance from the intermediate botanical extract are as follows:
1. Crystallization using C5-C12 straight chain or branched alkane
2. Filtration
3. Optional recrystallization from C5-C12 straight chain or branched alkane
4. Vacuum drying
Intermediate botanical extract (12 kg) produced using the methodology above was dispersed in C5-C12 straight chain or branched alkane (9000 ml, 0.75 vols) in a 30 litre stainless steel vessel.
The mixture was manually agitated to break up any lumps and the sealed container then placed in a freezer for approximately 48 hours.
The crystals were isolated by vacuum filtration, washed with aliquots of cold C5-C12 straight chain or branched alkane (total 12000 ml), and dried under a vacuum of <10 mb at a temperature of 60° C. until dry before submitting the drug substance for analysis. The dried product was stored in a freezer at minus 20° C. in a pharmaceutical grade stainless steel container, with FDA food grade approved silicone seal and clamps.
Production of the Drug Product
The drug product is presented as an oral solution. The oral solution presentation contains 25 mg/ml or 100 mg/ml CBD, with the excipients sesame oil, ethanol, sucralose and flavouring. Two product strengths are available to allow dose titration across a wide dose range.
The 25 mg/ml solution is appropriate at lower doses and the 100 mg/ml solution at higher doses.
The drug product formulation is as described in Table 6 below:
The drug substance, CBD is insoluble in water. Sesame oil was selected as an excipient to solubilize the drug substance.
A sweetener and fruit flavouring are required to improve palatability of the sesame oil solution.
Ethanol was required to solubilize the sweetener and the flavouring.
The composition can be substantially equivalent, by which is meant the functional ingredients can vary from the qualitative composition specified in Table 6 by an amount of up to 10%.
Example 1 below describes the use of a highly purified cannabis extract comprising cannabidiol (CBD) in an expanded access treatment program in children with TRE.
Materials and Methods
Of 137 children and young adults with severe, childhood onset treatment-resistant epilepsy (TRE), twenty-seven suffered from epilepsy that was characterised by atonic seizures. These subjects were tested with a highly purified extract of cannabidiol (CBD) obtained from a cannabis plant. All subjects presented with atonic type seizures, often in addition to other seizures. The participants in the study were part of an expanded access compassionate use program for CBD.
The epileptic syndromes that these patients suffered from were as follows: Lennox-Gastaut Syndrome; Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; Aicardi syndrome, CDKL5 and Dup15q.
All patients entered a baseline period of 4 weeks when parents/caregivers kept prospective seizure diaries, noting all countable seizure types.
The patients then received a highly purified CBD extract (greater than 98% CBD w/w) in sesame oil, of known and constant composition, at a dose of 5 mg/kg/day in addition to their baseline anti-epileptic drug (AED) regimen.
The daily dose was gradually increased by 2 to 5 mg/kg increments until intolerance occurred or a maximum dose of 25 mg/kg/day was achieved.
Patients were seen at regular intervals of 2-4 weeks. Laboratory testing for hematologic, liver, kidney function, and concomitant AED levels was performed at baseline, and after 4 weeks of CBD therapy.
All patients were taking at least two concomitant anti-epileptic drugs. These included clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacsamide; valproic acid; zonisamide. The average number of concomitant antiepileptic drugs being taken was 2.7. The majority took either clobazam and/or valproic acid.
Results
There were 27 children and young adult patients all of whom suffered from atonic seizures received treatment with CBD for at least 12 weeks.
A summary of the 50% responders, based on 12 weeks of treatment are summarized in Table 7 below.
Table 7 shows that after 3 months of therapy, a remarkable 63% of patients had an equal to or greater than >50% reduction in atonic seizures, these data infer that the CBD is very effective at reducing this type of seizure.
These data indicate that CBD significantly reduces the number of atonic seizures in a high proportion of patients that do not respond well to existing AED.
It was surprising that in this group of patients which are treatment-resistant such a high number were able to gain an effect. The fact that nearly two thirds of the patients (63%) benefitted from at least a fifty percent reduction in the number of atonic seizures that they suffered from was remarkable.
Furthermore when these data are compared to the other sub-types of generalised seizure, it can clearly be seen that CBD was able to selectively reduce the occurrence of atonic seizures. Table 8 below details these findings.
From Table 8 it can be seen that when the number of atonic seizures recorded is compared with other generalised seizure types such as tonic seizures (49% of patients experienced a greater than 50% reduction in seizure), tonic-clonic seizures (43% of patients experienced a greater than 50% reduction in seizure), and myoclonic seizures (43% of patients experienced a greater than 50% reduction in seizure) the fact that nearly two thirds (63%) of patients experiencing atonic seizures had a greater than 50% reduction in the number of seizures that occurred is very surprising.
| Number | Date | Country | Kind |
|---|---|---|---|
| 1418171 | Oct 2014 | GB | national |
This application is a continuation of U.S. patent application Ser. No. 16/911,914, filed Jun. 25, 2020, now U.S. Pat. No. 10,966,939 which is a continuation of U.S. patent application Ser. No. 16/198,141, filed Nov. 21, 2018, now U.S. Pat. No. 10,849,860, which is a continuation of U.S. patent application Ser. No. 15/449,535, filed Mar. 3, 2017, now U.S. Pat. No. 10,137,095, which is a continuation of Ser. No. 14/881,969, filed Oct. 13, 2015, now U.S. Pat. No. 10,111,840 which claims priority to GB 1418171.3, filed Oct. 14, 2014. Each of these applications is incorporated herein by reference in its entirety,
| Number | Name | Date | Kind |
|---|---|---|---|
| 6383513 | Watts et al. | May 2002 | B1 |
| 6403126 | Webster | Jun 2002 | B1 |
| 6949582 | Wallace | Sep 2005 | B1 |
| 8293786 | Stinchcomb | Oct 2012 | B2 |
| 8603515 | Whittle | Dec 2013 | B2 |
| 8673368 | Guy et al. | Mar 2014 | B2 |
| 9017737 | Kikuchi et al. | Apr 2015 | B2 |
| 9023322 | Van Demme et al. | May 2015 | B2 |
| 9066920 | Whalley et al. | Jun 2015 | B2 |
| 9125859 | Whalley et al. | Sep 2015 | B2 |
| 9095554 | Lewis et al. | Oct 2015 | B2 |
| 9168278 | Guy et al. | Oct 2015 | B2 |
| 9259449 | Raderman | Feb 2016 | B2 |
| 9474726 | Guy et al. | Oct 2016 | B2 |
| 9522123 | Whalley et al. | Dec 2016 | B2 |
| 9630941 | Elsohly et al. | Apr 2017 | B2 |
| 9680796 | Miller et al. | Jun 2017 | B2 |
| 9730911 | Verzura et al. | Aug 2017 | B2 |
| 9949936 | Guy et al. | Apr 2018 | B2 |
| 9949937 | Guy et al. | Apr 2018 | B2 |
| 9956183 | Guy et al. | May 2018 | B2 |
| 9956184 | Guy et al. | May 2018 | B2 |
| 9956185 | Guy et al. | May 2018 | B2 |
| 9956186 | Guy et al. | May 2018 | B2 |
| 10092525 | Guy et al. | Oct 2018 | B2 |
| 10111840 | Guy et al. | Oct 2018 | B2 |
| 10137095 | Guy et al. | Nov 2018 | B2 |
| 10583096 | Guy et al. | Mar 2020 | B2 |
| 10603288 | Guy et al. | Mar 2020 | B2 |
| 10709671 | Guy et al. | Jul 2020 | B2 |
| 10709673 | Guy et al. | Jul 2020 | B2 |
| 10709674 | Guy et al. | Jul 2020 | B2 |
| 10729665 | Whalley et al. | Aug 2020 | B2 |
| 10765643 | Guy et al. | Sep 2020 | B2 |
| 10849860 | Guy et al. | Dec 2020 | B2 |
| 10918608 | Guy et al. | Feb 2021 | B2 |
| 10966939 | Guy et al. | Apr 2021 | B2 |
| 20040034108 | Whittle | Feb 2004 | A1 |
| 20040049059 | Mueller | Mar 2004 | A1 |
| 20040110828 | Chowdhury et al. | Jun 2004 | A1 |
| 20040147767 | Whittle et al. | Jul 2004 | A1 |
| 20050042172 | Whittle | Feb 2005 | A1 |
| 20050266108 | Flockhart et al. | Dec 2005 | A1 |
| 20060039959 | Wessling | Feb 2006 | A1 |
| 20060167283 | Flockhart et al. | Jul 2006 | A1 |
| 20070060638 | Olmstead | Mar 2007 | A1 |
| 20070099987 | Weiss et al. | May 2007 | A1 |
| 20080119544 | Guy et al. | May 2008 | A1 |
| 20080188461 | Guan | Aug 2008 | A1 |
| 20090264063 | Tinsley et al. | Oct 2009 | A1 |
| 20090306221 | Guy et al. | Dec 2009 | A1 |
| 20100239693 | Guy et al. | Sep 2010 | A1 |
| 20100317729 | Guy et al. | Dec 2010 | A1 |
| 20110028431 | Zerbe et al. | Feb 2011 | A1 |
| 20110038958 | Kikuchi et al. | Feb 2011 | A1 |
| 20110082195 | Guy et al. | Apr 2011 | A1 |
| 20120004251 | Whalley et al. | Jan 2012 | A1 |
| 20120165402 | Whalley et al. | Jun 2012 | A1 |
| 20120183606 | Bender et al. | Jul 2012 | A1 |
| 20120202891 | Stinchcomb et al. | Aug 2012 | A1 |
| 20120270845 | Bannister | Oct 2012 | A1 |
| 20130143894 | Bergstrom et al. | Jun 2013 | A1 |
| 20130209483 | McAllister | Aug 2013 | A1 |
| 20130245110 | Guy et al. | Sep 2013 | A1 |
| 20130296398 | Whalley et al. | Nov 2013 | A1 |
| 20140100269 | Goskonda et al. | Apr 2014 | A1 |
| 20140155456 | Whalley et al. | Jun 2014 | A9 |
| 20140243405 | Whalley et al. | Aug 2014 | A1 |
| 20140335208 | Cawthorne et al. | Nov 2014 | A1 |
| 20140343044 | Ceulemens | Nov 2014 | A1 |
| 20150111939 | Gruening et al. | Apr 2015 | A1 |
| 20150181924 | Llamas | Jul 2015 | A1 |
| 20150320698 | Whalley et al. | Nov 2015 | A1 |
| 20150335590 | Whalley et al. | Nov 2015 | A1 |
| 20150343071 | Vangara et al. | Dec 2015 | A1 |
| 20150359755 | Guy et al. | Dec 2015 | A1 |
| 20150359756 | Guy et al. | Dec 2015 | A1 |
| 20160166498 | Anastassov | Jun 2016 | A1 |
| 20160166514 | Guy et al. | Jun 2016 | A1 |
| 20160166515 | Guy et al. | Jun 2016 | A1 |
| 20160220529 | Guy et al. | Aug 2016 | A1 |
| 20160256411 | Aung-Din | Sep 2016 | A1 |
| 20170007551 | Guy et al. | Jan 2017 | A1 |
| 20170172939 | Guy et al. | Jun 2017 | A1 |
| 20170172940 | Guy et al. | Jun 2017 | A1 |
| 20170172941 | Guy et al. | Jun 2017 | A1 |
| 20170173043 | Guy et al. | Jun 2017 | A1 |
| 20170173044 | Guy et al. | Jun 2017 | A1 |
| 20170181982 | Guy et al. | Jun 2017 | A1 |
| 20170231923 | Guy et al. | Aug 2017 | A1 |
| 20170239193 | Guy et al. | Aug 2017 | A1 |
| 20170246121 | Guy et al. | Aug 2017 | A1 |
| 20170266126 | Guy et al. | Sep 2017 | A1 |
| 20170273913 | Whalley et al. | Sep 2017 | A1 |
| 20180071210 | Wilkhu et al. | Mar 2018 | A1 |
| 20180228751 | Stott et al. | Aug 2018 | A1 |
| 20180338931 | Guy et al. | Nov 2018 | A1 |
| 20190083418 | Guy et al. | Mar 2019 | A1 |
| 20190091171 | Guy et al. | Mar 2019 | A1 |
| 20190167583 | Shah | Jun 2019 | A1 |
| 20190175547 | Stott et al. | Jun 2019 | A1 |
| 20190247324 | Whalley et al. | Aug 2019 | A1 |
| 20190314296 | Wright et al. | Oct 2019 | A1 |
| 20190321307 | Guy et al. | Oct 2019 | A1 |
| 20190365667 | Wright et al. | Dec 2019 | A1 |
| 20200000741 | Guy et al. | Jan 2020 | A1 |
| 20200138738 | Guy et al. | May 2020 | A1 |
| 20200179303 | Guy et al. | Jun 2020 | A1 |
| 20200206152 | Stott et al. | Jul 2020 | A1 |
| 20200206153 | Whalley et al. | Jul 2020 | A1 |
| 20200237683 | Whalley et al. | Jul 2020 | A1 |
| 20200297656 | Guy et al. | Sep 2020 | A1 |
| 20200352878 | Guy et al. | Nov 2020 | A1 |
| 20200368179 | Guy et al. | Nov 2020 | A1 |
| 20210015789 | Guy et al. | Jan 2021 | A1 |
| 20210052512 | Guy et al. | Feb 2021 | A1 |
| 20210059949 | Wilkhu et al. | Mar 2021 | A1 |
| 20210059960 | Wilkhu et al. | Mar 2021 | A1 |
| 20210059976 | Wilkhu et al. | Mar 2021 | A1 |
| 20210093581 | Guy et al. | Apr 2021 | A1 |
| Number | Date | Country |
|---|---|---|
| 2737447 | Oct 2012 | CA |
| 2859934 | Mar 2016 | CA |
| 101040855 | Sep 2007 | CN |
| 103110582 | May 2013 | CN |
| 10 2012 105 063 | Dec 2013 | DE |
| 2 448 637 | May 2012 | EP |
| 2384707 | Aug 2003 | GB |
| 2434097 | Jul 2007 | GB |
| 2434312 | Jul 2007 | GB |
| 2450753 | Jan 2009 | GB |
| 2456183 | Jul 2009 | GB |
| 2471523 | Jan 2011 | GB |
| 2478595 | Sep 2011 | GB |
| 2479153 | Oct 2011 | GB |
| 2471565 | Jul 2012 | GB |
| 2478072 | Dec 2012 | GB |
| 2478074 | Dec 2012 | GB |
| 2492487 | Jan 2013 | GB |
| 2487712 | Oct 2015 | GB |
| 2531282 | Apr 2016 | GB |
| WO 2002064109 | Aug 2002 | WO |
| WO 2003099302 | Dec 2003 | WO |
| WO 2004016246 | Feb 2004 | WO |
| WO 2004016277 | Feb 2004 | WO |
| WO 2006054057 | May 2006 | WO |
| WO 2006017892 | Dec 2006 | WO |
| WO 2006133941 | Dec 2006 | WO |
| WO 2007083098 | Jul 2007 | WO |
| WO 2007138322 | Dec 2007 | WO |
| WO 2008019146 | Feb 2008 | WO |
| WO 2008094181 | Aug 2008 | WO |
| WO 2008129258 | Oct 2008 | WO |
| WO 2008144475 | Nov 2008 | WO |
| WO 2008021394 | Dec 2008 | WO |
| WO 2008146006 | Dec 2008 | WO |
| WO 2009007697 | Jan 2009 | WO |
| WO 2009007698 | Jan 2009 | WO |
| WO 2009020666 | Feb 2009 | WO |
| WO 2011001169 | Jan 2011 | WO |
| WO 2011121351 | Oct 2011 | WO |
| WO 2012033478 | Mar 2012 | WO |
| WO 2012093255 | Jul 2012 | WO |
| WO 2013032351 | Mar 2013 | WO |
| WO 2015142501 | Sep 2015 | WO |
| WO 2015184127 | Dec 2015 | WO |
| WO 2015193667 | Dec 2015 | WO |
| WO 2015193668 | Dec 2015 | WO |
| WO 2016059405 | Apr 2016 | WO |
| WO 2016084075 | Jun 2016 | WO |
| WO 2015187988 | Jul 2016 | WO |
| WO 2016118391 | Jul 2016 | WO |
| WO 2016147186 | Sep 2016 | WO |
| WO 2016022936 | Nov 2016 | WO |
| WO 2016199148 | Dec 2016 | WO |
| WO 2017168138 | Oct 2017 | WO |
| WO 2018002636 | Jan 2018 | WO |
| WO 2018002637 | Jan 2018 | WO |
| WO 2018037203 | Mar 2018 | WO |
| Entry |
|---|
| [No Author Listed] “Orphan Drug Designation Granted for Epidiolex in Dravet syndrome by the FDA-Seven Expanded Access INDs granted by FDA to US physicians to treat with Epidiolex 125 children suffering from intractable epilepsy syndromes,” GW Pharmaceuticals Press Release dated Nov. 14, 2013. |
| [No Author Listed] GW Pharmaceuticals Provides Update on Orphan Program in Childhood Epilepsy for Epidolex, GW. Pharm. Available online Nov. 14, 2013, Retrieved Feb. 10, 2017. |
| [No Author Listed] “What are the Highest CBD Strains?” accessed Feb. 16, 2017, published Oct. 15, 2014. |
| [No Author Listed] “Cannabidiol Therapy for Aicardi Syndrome” Aug. 2014, 4 pages. |
| [No Author Listed] “Convulsive Disorders and Their Interference with Diiving,” Medicos., Retrieved Feb. 10, 2017, Retrieved from internet: URL https://www.medicosporlaseguridadvial.com/en/clinical-subjects/neurologic-diseases/convulsive-disorders-and-their-interference-with-driving/, 2014. |
| [No Author Listed] “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers,” FDA Guidance for Industry, Jul. 2005. |
| [No Author Listed] “GW Pharmaceuticals Announces Epidiolex Receives Fast Track Designation from FDA for the Treatment of Dravet Syndrome,” GW Pharmaceuticals Press Release dated Jun. 6, 2014. |
| Annex to the Communication-Opposition for Application No. 10734541.5, dated Jan. 28, 2016. |
| [No Author Listed] Canabinoid. Wikipedia. Retrieved on Jul. 9, 2015 from https://en.wikipedia.org/wiki/Cannabinoid. |
| Arzimanoglou et al., “All children who experience epileptic falls do not necessarily have Lennox-Gastaut syndrome . . . but many do,” Epileptic Disord. 2011, 13, S3-S13 (2011). |
| Brown et al., Child Neurology Foundation, “LGS” (Lennox-Gastaut Syndrome), available at http://www.childneurologyfoundation.org/disorders/lgs-lennox-gastaut-syndrome. |
| “Cannabidiols: Potential Use in Epilepsy & Other Neurological Disorders.” Cannabidol Conference at NYU School of Medicine, Oct. 2013. NYU Langone Health. Retreived from the Internet Nov. 2019. <URL: http://faces.med.nyu.edu/research-education/cannabidiol-conference>. |
| Charlotte's Web [ online], “Whole-Plant Cannabinoids Outperform Single Molecule Compounds,” CWHemp.com, Jan. 11, 2017, retrieved on Jun. 16, 2017, URL https://www.cwhemp.com/blog/whole-plant-cw-hemp-cannabinoids, 6 pages. |
| Chiu, P. et al., “The Influence of Cannabidiol and Δ-Tetrahydrocannabinol on Cobalt Epilepsy in Rats,” Epilepsia, 20:365-375 (1979). |
| Cilio, Maria Roberta, M.D., Ph.D. of the Pediatric Epilepsy and Clinical Neurophysiology for the University of California, San Francisco presents her talk on “CBD in Children with Treatment-Resistant Epilepsies: Planned Trials in Dravet and Lennox-Gastaut Syndromes,” at NYU School of Medicine's Cannabidiol Conference (Oct. 4, 2013). Video published online. <http://faces.med.nyu.edu/research-education/cannabidiol-conference>. |
| Combined Search and Examination Report dated Jan. 4, 2012 for Application No. GB: 1116789.7. |
| Combined Search and Examination Report dated Mar. 25, 2011 for Application No. GB: 1100043.7. |
| Combined Search and Examination Report dated Sep. 5, 2014 for Application No. GB 1414813.4. |
| Combined Search and Examination Report Under Sections 17 and 18 (3) for International Application No. GB1121919.3, dated Feb. 29, 2012. |
| Combined Search and Examination Report Under Sections 17 and 18 (3) for International Application No. GB 1410771.8, dated Feb. 27, 2018. |
| Combined Search and Examination Report Under Sections 17 and 18 (3) for International Application No. GB 1418166.3, dated Jul. 2, 2015. |
| Combined Search and Examination Report Under Sections 17 and 18 (3) for International Application No. GB 1418170.5, dated Jul. 2, 2015. |
| Combined Search and Examination Report Under Sections 17 and 18 (3) for International Application No. GB 1418171.3, dated Jun. 29, 2015. |
| Combined Search and Examination Report Under Sections 17 and 18 (3) for International Application No. GB 1506550.1, dated Feb. 5, 2016. |
| Communication of a Notice of Opposition for Application No. 107342541.5 dated Dec. 17, 2014. |
| Communication Pursuant to Article 94(3) EPC in European Patent Application No. 10734541.5, dated Oct. 23, 2012. |
| Consroe, et al. “Controlled clinical trial of cannabidiol in Huntington's Disease.” Pharmacology Biochemistry & Behavior, 1991, 40:701-708. |
| Crespel, A. et al., “Lennox-Gastaut Syndrome,” Chapter 14, in Epileptic Syndromes in Infancy, Childhood, and Adolescence, 5th Edition, ed. M. Bureau, et al., pp. 189-216. |
| Decision in IPR2017-00503 dated Jul. 7, 2017. |
| Decision in Opposition proceedings (Art. 101(3)(a) and 106(2) EPC in European Patent Application No. EP2448637, dated Dec. 15, 2016. |
| Declaration of Professor Anthony G.Marson in the Inter Partes Review of U.S. Pat. No. 9,066,920, Dated Dec. 13, 2016. |
| Declaration of Professor Leslie Benet in the Inter Partes Review of U.S. Pat. No. 9,066,920, Dated Nov. 22, 2016. |
| Declaration of Professor H. Steve White in the Inter Partes Review of U.S. Pat. No. 9,066,920, Dated Oct. 24, 2017. |
| Devinsky, Orrin, M.D. of the Department of Neurology for NYU Langone School of Medicine presents his talk on “Cannabidiols: A Brief History,” at NYU School of Medicine's Cannabidiol Conference (Oct. 4, 2013). Video published online. <http://faces.med.nyu.edu/research-education/cannabidiol-conference>. |
| Devinsky, et al. “Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders,” 2014 Epilepsia, 55(6), 791-802. |
| Di Marzo, Vincenzo, Ph.D. Of the Endocannabinoid Research Group Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli, Napoli, Italy presents his talk on “Cannabinoid Pharmacology & Mechanism of Action,” at NYU School of Medicine's Cannabidiol Conference (Oct. 4, 2013). Video published online. <http://faces.med.nyu.edu/research-education/cannabidiol-conference>. |
| Dravet, “The core Dravet syndrome phenotype.” Epilepsia.52 Suppl 2:3-9. doi: 10.1111/j.1528-1167.2011.02994.x. (2011). |
| Drugs of the Future, 39(1): 49-56, Jan. 2014 notes Orphan Drug designation for CBD for Lennox-Gastaut Syndrome. |
| Engel. “Report of the ILAE classification core group.” Epilepsia. Sep. 2006;47(9): 1558-68. |
| Etienne De Meijer. “The Chemical Phenotypes (Chemotypes) of Cannabis,” Chapter 5, Handbook of Cannabis, ed. Roger G. Pertwee, pp. 89-110 (2014). |
| Ex parte Edelstam, Appeal No. 2016/006358, mail date Jun. 21, 2017 (Year: 2017). |
| Ex parte Miller, Appeal 2009-011751, mail date Jul. 8, 2010 (Year: 2010). |
| Examination Report dated Mar. 18, 2014 for Application No. GB1100043.7. |
| Expert Statement of Vincenzo Di Marzo for Application No. EP10734541.5 dated Sep. 9, 2016. |
| Expert Statement of Professor Benjamin J. Whalley for Application No. EP10734541.5 dated Sep. 9, 2016. |
| Expert Statement of Professor Anthony G. Marson for for Application No. EP10734541.5. |
| French, Jacqueline A., M.D. Professor of Neurology at the NYU Epilepsy Center presents her talk on “Trials for Disease Modifying Therapies in Epilepsy,” at NYU School of Medicine's Cannabidiol Conference (Oct. 4, 2013). Video published online. <http://faces.med.nyu.edu/research-education/cannabidiol-conference>. |
| Friedman, Daniel, M.D. Assistant Professor of Neurology at the NYU Comprehensive Epilepsy Center presents his talk on “Pharmacology of CBD in Humans,” at NYU School of Medicine's Cannabidiol Conference (Oct. 4, 2013). Video published online. <http://faces.med.nyu.edu/research-education/cannabidiol-conference>. |
| Gardner [online], “Comes Now Epidiolex (FDA Approves IND Studies of CBD),” BeyondTHC.com, Oct. 22, 2013, retrieved on Jan. 31, 2018, URL http://www.beyondthc.com/comes-now-epidiolex-fda-approves-ind-studies-of-cbd. |
| Guerrini et al., “Lamotrigine and Seizure Aggravation in Severe Myoclonic Epilepsy,” Epilepsia, 39(5):508-512, 1998. |
| Goodman & Gilman, The Pharmacological Basis of Therapeutics (Brunton, Laurence L.; Lazo, John S.; Parker, Keith, eds. (2006); New York: McGraw-Hill. ISBN 0-07-142280-3); Chapter 19, Pharmacotherapy of the Epilepsies. |
| GWPharm [online], “GW Pharmaceuticals Announces Epidiolex(R) Receives Fast Track Designation from FDA for the Treatment of Dravet Syndrome,” GW Pharmaceuticals Press Release, Jun. 6, 2014, retrieved on Mar. 1, 2017, URL https://www.gwpharm.com/about-us/news/gw-pharmaceuticals-announces-epidiolex%C2%AE-receives-fast-track-designation-fda-treatment. |
| INSYS Development Comp Any, Inc. v. GW Pharma Limited and Otsuka Pharmaceutical Co., Ltd., Petitioner's Reply to Response in IPR2017-00503, U.S. Pat. No. 9,066,920, dated Jan. 19, 2018. |
| International Preliminary Report on Patentability in International Application No. PCT/GB2010/051066, dated May 5, 2011. |
| International Preliminary Report on Patentabiliiy for Application No. PCT/GB2015/053030, dated Apr. 18, 2017. |
| International Preliminary Report on Patentability for Application No. PCT/GB2012/052284, dated Mar. 29, 2014. |
| International Search Report and Written Opinion for Application No. PCT/GB2015/051775, dated Dec. 23, 2015. |
| International Search Report and Written Opinion for Application No. PCT/GB2015/051066, dated Jan. 1, 2012. |
| International Search Report and Written Opinion for Application No. PCT/GB2011/050649, dated Sep. 30, 2012. |
| International Search Report and Written Opinion dated Nov. 16, 2012 for Application No. PCT/GB2012/052284, dated Mar. 29, 2014. |
| International Search Report in International Application No. PCT/GB2010/051066, dated Jan. 6, 2011. |
| International Search Report in International Application No. PCT/GB2012/050002, dated Jul. 12, 2012. |
| Jones et al. [online], Info & Metrics / Article Information,“Cannabidiol Displays Antiepileptiform and Antiseizure Properties in Vitro and in Vivo,” J Pharmacol Exp Ther., Feb. 2010, 332(2): 569-577, retrieved on Jun. 25, 2018, URL: http://jpet.aspetjournals.org/content/332/2/569/tab-article-info. |
| Jutras-Aswad, Didier, M.D., M.S. of the Department of Psychiatry for the University of Montreal presents his talk on “CBD in Animal Models and Human Trials of Opiate Abuse,” at NYU School of Medicine's Cannabidiol Conference (Oct. 4, 2013). Video published online. <http://faces.med.nyu.edu/research-education/cannabidiol-conference>. |
| Karler, et al. “The cannabinoids as potential antiepileptics,” J Clin Pharmacol, 21(8-9 Suppl):437S-447S (1981). |
| Katz, Russell (“Rusty”), M.D. former Director of the Division of Neurology Products at the FDA presents his talk on “Dravet and Lennox-Gastaut Syndromes: The Orphan Drug Process,” at NYU School of Medicine's Cannabidiol Conference (Oct. 4, 2013). Video published online. <http://faces.med.nyu.edu/research-education/cannabidiol-conference>. |
| Khan et al., Muheet-e-Azam, vol. II, 887: 147 Persian. |
| Kwan et al., Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. Jun. 2010;51(6):1069-77. doi:10.1111/j.1528-1167.2009.02397.x. Epub Nov. 3, 2009. Erratum in: Epilepsia. Sep. 2010;51(9): 1922. |
| LeafScience.com [online], “What are the Highest CBD Strains?” Oct. 15, 2014, retrieved on Feb. 16, 2017, URL www.leafscience.com/2014/10/15/highest-cbd-strains/. |
| Manno. “Status Epilepticus: Current Treatment Strategies,” The Neurohospitalist. Jan. 2011, 1(1):23-31. |
| Mechoulam et al., “Cannabidiol: An Overview of Some Pharmacological Aspects,” J Clin Pharmacol, 2002, 42:11S-19S. |
| Mechoulam et al., Toward drugs derived from cannabis. Naturwissenschaften. Apr. 1978;65(4): 174-9. |
| Models of Chemically-Induced Acute Seizures 127-152, 2006. |
| Notice of Allowance in U.S. Appl. No. 13/380,305, dated Dec. 10, 2014. |
| Notice of Allowance in U.S. Appl. No. 13/380,305, dated Mar. 19, 2015. |
| Notice of Appeal in European Patent No. EP2448637, dated Feb. 14, 2017. |
| Notice of Opposition to a Europearn Patent No. EP2448637, dated Dec. 5, 2014. |
| Office Action in U.S. Appl. No. 13/380,305, dated Aug. 25, 2014. |
| Opponent Response to the Preliminary Opinion of the Opposition Division in European Patent No. EP2448637, dated Jun. 23, 2016. |
| Opponent Response dated to Sep. The 9, Preliminary 2016, 25 Opinion pages of the Opposition Division in European Patent No. EP2448637, dated Sep. 9, 2016. |
| Opponent Response to the Written Submissions in European Patent No. EP2448637, dated Oct. 12, 2016. |
| Opponent Response to the Written Submissions in European Patent No. EP2448637, dated Oct. 20, 2016. |
| Opponent Response to the Written Submissions in European Patent No. EP2448637, dated Nov. 4, 2016. |
| Patent Owners' Preliminary Response for IPR2017-00503 dated Apr. 11, 2017. |
| PCT International Preliminary Report on Patentability in International Appln. No. PCT/US2017/050868, dated Jun. 18, 2019. |
| PCT International Search Report and Written Opinion in International Appln. No. PCT/US2017/050868, dated Jun. 21, 2018. |
| Petition for Inter Partes Review U.S. Pat. No. 9, 066,920 dates Dec. 16, 2016. |
| Petitioner's Reply to Patent Owner's Response in Inter Partes Review No. IPR2017-00503, filed Jannaiy 19, 2018. |
| Porter et al., Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav. Dec. 2013;29(3):574-7. |
| Resstel et al. 5-HTIA receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol. Jan. 2009;156(1): 181-8. |
| Reply of the Patent Proprietor to the Notice(s) of Opposition in European Patent No. 2448637, dated May 28, 2015, 12 pages. |
| Reply to Communication from the examining Division in Eurppean Patent Application No. 10734541.5 dated Feb. 15, 2013, 54 pages. |
| Reply to EPO Communication in European Patent No. EP2448637, dated Nov. 2, 2016, 45 pages. |
| Reply to Opponent's Written Submission in European Patent No. EP2448637, dated Nov. 4, 2016, 13 pages. |
| Reply to Opponent's Written Submission in European Patent No. EP2448637, dated Oct. 18, 2016, 5 pages. |
| Reply to Preliminary Opinion and Opponent's Observations in European Patent No. EP2448637, dated Sep. 9, 2016, 65 pages. |
| Request for Continued Examination with the Amendment and Information Disclosure Statement in U.S. Appl. No. 13,380,305, filed Mar. 2, 2015, 3 pages. |
| Rohrback, Brian G., Ph.D, MBA President of Infometrix, Inc. presents his talk on “Assays of Cannabinoids,” at NYU School of Medicine's Cannabidiol Conference (Oct. 4, 2013). Video published online. <http://faces.med.nyu.edu/research-education/cannabidiol-conference>. |
| Rosenberg et al., “Cannabinoids and Epilepsy,” Neurotherapeutics, Oct. 2015, 12(4): 747-768. |
| Silva et al., “Position Statement on the Use of Medical Cannabis for the Treatment of Epilepsy in Canada,” Can J. Neurol. Sci., 33:783-786 (2006). |
| Swann et al., The effects of seizures on the connectivity and circuitry of the developing brain. Ment Retard Dev Disabil Res Rev. 2004; 10(2):96-100. |
| Stafstrom et al., “Models of Pediatric Epilepsies: Strategies and Opportunities,” Epilepsia, 47(8):1407-1414 (2006). |
| Statement of Opposition for EP10734541.5, mailed Dec. 5, 2014. |
| Statement of Grounds of Appeal for European Application No. 10734541.5 in the name of GW Pharma and Otsuka Pharmaceutical Co. Limited Appellant/Opponent: Insys Therapeutics Inc., dated Apr. 21, 2017. |
| Statement of Grounds of Appeal for European Application No. 10734541.5 on behalf of the Proprietors: GW Pharma Limited and Otsuka Pharmaceutical Co Limited, dated Apr. 12, 2017. |
| Tanya Lewis, Mystery Mechanisms, The Scientist Magazine, Jul. 29, 2016. |
| Transcript of Dr. H. Steven White's deposition, dated Dec. 29, 2017. |
| Third Party Observations for Application No. AU20 I 2314128, mailed Mar. 19, 2015. |
| Third Party Observations for Application No. EP10734541.5, mailed Apr. 3, 2017. |
| Third Party Observations for Application No. EP1712658.1, mailed Nov. 22, 2013. |
| Wallace et al., Assessment of the role of CB 1 receptors in cannabinoid anticonvulsant effects. Eur J Pharmacal. Sep. 28, 2001;428(1):51-7. |
| Whalley, Benjamin J. Ph.D. of the University of Reading presents his talk on “Cannabis and Epilepsy: Cannabidiol (CBD) and Cannabidavarin (CBDV) in Preclinical Models of Seizure and Epilepsy,” at NYU School of Medicine's Cannabidiol Conference (Oct. 4, 2013). Video published online. <http://faces.med.nyu.edu/research-education/cannabidiol-conference>. |
| “When to Expect Results from CW Hemp Oil”, download Sep. 5, 2017, https://www.cwhemp.com/blog/expecting-results-from-hemp.Wikipedia.org [online], “Cannabinoid,” Wikipedia, Apr. 2003, retrieved on Mar. 1, 2017, URL <https://en.wikipedia.org/wiki/Cannabinoid>. |
| Wikipedia.org [online], “Cannabinoid,” Wikipedia, Apr. 2003, retrieved on Mar. 1, 2017, URL <https://en.wikipedia.org/wiki/Cannabinoid>, 15 pages. |
| Banerjee et al., “Case Report: Aicardi syndrome: A report of five Indian cases,” Neurology India, 54(1):91-93 (2006). |
| cdc.gov [online], “2 to 20 years: Girls Stature-for-age and Weight-for-age percentiles,” National Center for Health Statistics and National Center for Chronic Disease Prevention and Health Promotion, last modified Nov. 2000, https://www.cdc.gov/growthcharts/data/set1clinical/cj411022.pdf, 1 page. |
| Chou, “Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies,” Pharmacol Rev, 58(3):621-681 (2006). |
| Kuhn et al., “Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma,” Blood, 110(9):3281-3290 (2007). |
| Manni et al., “Obstructive Sleep Apnea in a Clinical Series of Adult Epilepsy Patients: Frequency and Features of the Comorbidity,” Epilepsia, 44(6):836-840 (2003). |
| Morelli et al., “The effects of cannabidiol and its synergism with bortezomib in multiple myeloma cell lines. A role for transient receptor potential Vanilloid type-2,” Blood, 110(9):3281-3290 (2014). |
| MyVirtualMedicalCentre [online], “Aicardi syndrome,” mymc.com, Feb. 2004, retrieved on Jan. 25, 2019 at https://www.myvmc.com/diseases/aicardi-syndrome/, 6 pages. |
| Nabissi et al., “Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration,” Oncotarget, 7:77553 (2016). |
| Porter et al., “Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures,” Neurology, 68(15):1197-1204 (2007). |
| Raab et al., “Multiple myeloma,” Lancet, 374(9686):324-339 (2009). |
| Rosenkrantz et al., “Oral and Parenteral Formulations of Marijuana Constituents,” J Pharm Sci, 61(7):1106-1112 (1972). |
| Smith, R. M., “Identification of Butyl Cannabinoids in Marijuana,” Journal of Forensic Sciences, 42:610-618 (1997). |
| Strickley, “Solubilizing Excipients in Oral and Injectable Formulations,” Table VIII, Pharmaceutical Research, 21(2):201-230 (2004). |
| Velasco et al., “Anticancer mechanisms of cannabinoids,” Curr Oncol, 23(2):S23-S32 (2016). |
| U.S. Appl. No. 14/741,829, filed Jun. 17, 2015. |
| U.S. Appl. No. 15/519,244, filed Apr. 14, 2017. |
| U.S. Appl. No. 15/640,033, filed Jun. 30, 2017. |
| U.S. Appl. No. 15/751,563, filed Feb. 9, 2018. |
| U.S. Appl. No. 16/314,569, filed Dec. 31, 2018. |
| U.S. Appl. No. 16/314,583, filed Dec. 31, 2018. |
| U.S. Appl. No. 16/328,209, filed Feb. 25, 2018. |
| U.S. Appl. No. 16/467,639, filed Jun. 7, 2019. |
| U.S. Appl. No. 16/486,750, filed Aug. 16, 2019. |
| U.S. Appl. No. 16/591,702, filed Oct. 3, 2019. |
| U.S. Appl. No. 16/624,106, filed Dec. 18, 2019. |
| U.S. Appl. No. 16/651,751, filed Mar. 27, 2020. |
| U.S. Appl. No. 16/737,707, filed Jan. 8, 2020. |
| U.S. Appl. No. 16/764,701, filed May 15, 2020. |
| U.S. Appl. No. 16/768,241, filed May 29, 2020. |
| U.S. Appl. No. 16/791,940, filed Feb. 14, 2020. |
| U.S. Appl. No. 16/893,018, filed Jun. 4, 2020. |
| U.S. Appl. No. 16/935,005, filed Jul. 21, 2020. |
| U.S. Appl. No. 16/959,350, filed Jun. 30, 2020. |
| U.S. Appl. No. 16/959,354, filed Jun. 30, 2020. |
| U.S. Appl. No. 16/959,357, filed Jun. 30, 2020. |
| U.S. Appl. No. 16/960,665, filed Jul. 8, 2020. |
| U.S. Appl. No. 16/989,605, filed Aug. 10, 2020. |
| U.S. Appl. No. 17/011,715, filed Sep. 3, 2020. |
| U.S. Appl. No. 17/025,130, filed Sep. 18, 2020. |
| U.S. Appl. No. 17/050,956, filed Oct. 27, 2020. |
| U.S. Appl. No. 17/068,326, filed Oct. 12, 2020. |
| U.S. Appl. No. 17/119,873, filed Dec. 11, 2020. |
| U.S. Appl. No. 17/147,005, filed Jan. 12, 2021. |
| U.S. Appl. No. 17/188,766, filed Mar. 1, 2021. |
| U.S. Appl. No. 17/242,075, filed Apr. 27, 2021. |
| Number | Date | Country | |
|---|---|---|---|
| 20210196651 A1 | Jul 2021 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16911914 | Jun 2020 | US |
| Child | 17198965 | US | |
| Parent | 16198141 | Nov 2018 | US |
| Child | 16911914 | US | |
| Parent | 15449535 | Mar 2017 | US |
| Child | 16198141 | US | |
| Parent | 14881969 | Oct 2015 | US |
| Child | 15449535 | US |
