Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
  • A61K31/423—Oxazoles condensed with carbocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin

Definitions

• liver diseases particularly NAFLD or NASH patients suffering from liver stiffness or liver fibrosis, NAFLD or NASH patients with elevated ALT levels, NAFLD or NASH patients with elevated LDL-C, and NAFLD or NASH patients with healthy triglyceride levels.
• Nonalcoholic fatty liver disease is a condition in which excess fat builds up in the liver.
• NAFLD includes nonalcoholic fatty liver (“NAFL”) where there is no evidence of hepatocellular injury, and nonalcoholic steatohepatitis (“NASH”), which is characterized by steatosis, inflammation, and ballooning.
• NAFL nonalcoholic fatty liver
• NASH nonalcoholic steatohepatitis
• Most NAFLD develops as a result of obesity, diabetes mellitus, dyslipidemia, or hypertension.
• the numbers of patients with NAFLD and NASH are increasing worldwide owing to an increasingly obese population, and the prevalence is estimated to be 20-30% and 2-6%, respectively.
• Pemafibrate is a selective PPARa modulator that is approved for the treatment of hyperlipidemia in Japan.
• Pemafibrate is described chemically as (R)-2-[3-[[N-(benzoxazol-2-yl)- N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, and has the following chemical structure:
• Pemafibrate regulates the expression of a gene cluster mainly related to lipid and sugar metabolism of the liver. It also increases gene expression for b-oxidation and lipid transport and enhances energy metabolism by the induction of mitochondrial uncoupling protein (“UCP”) 3 gene expression.
• UDP mitochondrial uncoupling protein
• a non-clinical study in low density lipoprotein (“LDL”) receptor knockout mice and KK-A mice fed with an MCD (methionine-choline-deficient) diet has shown that pemafibrate suppresses ballooning of hepatocytes and fat deposition and reduces the number of Kupffer cells. See US 2016/0136138 A1 to Shibata et al.
• Anhydrous tofogliflozin is described chemically as 6-((4-ethylphenyl)methyl)-3',4',5',6'- tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-l(3H),2'-(2H)pyran)-3',4',5'-triol, and has the following chemical structure:
• the United States Adopted Name (“USAN”) tofogliflozin applies to the monohydrate, which is the form used as a drug.
• the International Nonproprietary Name (“INN”) tofogliflozin applies to the anhydrous compound and the drug form is referred to as tofogliflozin hydrate.
• tofogliflozin refers to the chemical compound 6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'- (hydroxymethyl)spiro(isobenzofuran-l(3H),2'-(2H)pyran)-3',4',5'-triol, and thus includes all hydrated, solvated, crystalline, and amorphous forms thereof of the compound.
• Tofogliflozin has previously been developed by Hoffman La-Roche Inc. and by Chugai Pharmaceutical Co, Ltd. for the treatment of type 2 diabetes mellitus (T2DM).
• Tofogliflozin is a potent and selective inhibitor of SGLT2, which is localized to the renal tubules and is responsible for reabsorption of glucose from the renal filtrate.
• a non-clinical study in an HHC mouse model of NASH has shown that a combination of pemafibrate and tofogliflozin reduces the size of lipid droplet in animal hepatocytes, with a resulting improvement in hepatocyte ballooning. See US 2020/0022960 Al to Sasaki et al.
• the invention provides a method of treating liver stiffness or liver fibrosis in a patient with noncirrhotic NASH or NAFLD and a NASH CRN fibrosis score of > 1 and ⁇ 4 comprising administering to the patient a therapeutically effective amount of: (a) pemafibrate or a pharmaceutically acceptable salt thereof; (b) tofogliflozin or a pharmaceutically acceptable salt thereof; or (c) a combination thereof.
• the invention provides a method of treating lobular inflammation in a patient with noncirrhotic NASH or NAFLD comprising administering to the patient a therapeutically effective amount of: (a) pemafibrate or a pharmaceutically acceptable salt thereof; (b) tofogliflozin or a pharmaceutically acceptable salt thereof; or (c) a combination thereof.
• the method is undertaken without worsening of fibrosis in a patient having a NASH CRN fibrosis score of > 1 and ⁇ 4.
• the invention provides a method of improving liver function as measured by ALT activity in a patient with noncirrhotic NASH or NAFLD, a NASH CRN fibrosis score of > 1 and ⁇ 4, and an ALT score > 2X ULN, comprising administering to the patient a therapeutically effective amount of: (a) pemafibrate or a pharmaceutically acceptable salt thereof; (b) tofogliflozin or a pharmaceutically acceptable salt thereof; or (c) a combination thereof.
• the invention provides a method of lowering LDL-C in a patient with noncirrhotic NASH or NAFLD, a NASH CRN fibrosis score of > 1 and ⁇ 4, and an LDL-C concentration > 100 mg/dL comprising administering to the patient a therapeutically effective amount of: (a) pemafibrate or a pharmaceutically acceptable salt thereof; (b) tofogliflozin or a pharmaceutically acceptable salt thereof; or (c) a combination thereof.
• any of the foregoing methods including those that rely on pemafibrate, can be practiced in patients with normal triglyceride levels.
• a specification refers to one or more specifications for use in the presently disclosed methods and systems.
• An ingredient includes mixtures of two or more such ingredients, and the like.
• the word “or” or like terms as used herein means any one member of a particular list and also includes any combination of members of that list.
• the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps.
• the element can also be described as “consisting of’ or “consisting essentially of’ the component, step or condition, or the plurality of components, steps or conditions.
• “Therapeutically effective amount” means that amount which, when administered to a human for supporting or affecting a metabolic process, or for treating or preventing a disease, is sufficient to cause such treatment or prevention of the disease or supporting or affecting the metabolic process.
• drug therapy drug administration
• drug administration drug administration
• the therapy can be accomplished through any suitable route of administration using any acceptable dosage form, and that the drug can be administered as the free base or acid, a salt, or an ester or other prodrug moiety.
• each of the individual active ingredients in the combination contributes to the achievement of the recited endpoint or therapeutic objective. Furthermore, it will be understood in preferred embodiments that each of the active ingredients contributes to a statistically significant clinical benefit in a suitably powered population of patients.
• both of the individual active ingredients will contribute to the achievement of at least one of the endpoints or therapeutic objectives, preferably all of the endpoints and objectives, preferably to a statistically significant clinical benefit in a suitable powered population of patients, and any endpoints or therapeutic objectives not jointly contributed to will be achieved by at least one of the active ingredients, preferably to a statistically significant clinical benefit.
• the term “about” will compensate for variability allowed for in the pharmaceutical industry and inherent in products in this industry, such as differences in product strength due to manufacturing variation and time-induced product degradation, as well as differences due to waters of hydration and different salts.
• the term allows for any variation which in the practice of good manufacturing practices, would allow the product being evaluated to be considered therapeutically equivalent or bioequivalent in humans to the recited strength of a claimed product.
• the term allows for any variation within 5% of the recited specification or standard.
• the term allows for any variation within 10% of the recited specification or standard.
• test methodology or diagnostic instrument is performed based on the version in effect on May 1, 2021, unless otherwise stated to the contrary herein.
• a range of from 50 or 80 to 100 or 70 can alternatively be expressed as a series of ranges of from 50 to 100, from 50 to 70, and from 80 to 100.
• a series of upper bounds and lower bounds are related using the phase “and” or “or”, it will be understood that the upper bounds can be unlimited by the lower bounds or combined with the lower bounds, and vice versa.
• a range of greater than 40% and/or less than 80% includes ranges of greater than 40%, less than 80%, and greater than 40% but less than 80%. Unless otherwise specified by the term “between,” the boundaries of the range (lower and upper ends of the range) are included in the claimed range.
• treatment means to reduce the occurrence of a symptom or condition, or to relieve or alleviate at least one symptom associated with such condition, or to slow or reverse the progression of such condition, or to manage or affect the metabolic processes underlying such condition.
• the term also denotes to arrest, or to “prevent,” i.e. to delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
• the term will be understood to require relief or alleviation of at least one symptom associated with the condition.
• Biomarker test assays unless otherwise indicated herein, all biomarker test assays referred to herein are performed in accordance with standard procedures employed during the 2001-2002 cycle of the National Health and Nutrition Examination Survey.
• the invention provides a method of treating liver stiffness or liver fibrosis in a patient with noncirrhotic NASH or NAFLD and a NASH CRN fibrosis score of > 1 and ⁇ 4 comprising administering to the patient a therapeutically effective amount of: (a) pemafibrate or a pharmaceutically acceptable salt thereof; (b) tofogliflozin or a pharmaceutically acceptable salt thereof; or (c) a combination thereof.
• the invention provides a method of treating lobular inflammation in a patient with noncirrhotic NASH or NAFLD comprising administering to the patient a therapeutically effective amount of: (a) pemafibrate or a pharmaceutically acceptable salt thereof; (b) tofogliflozin or a pharmaceutically acceptable salt thereof; or (c) a combination thereof.
• the method is undertaken without worsening of fibrosis, in a patient having a NASH CRN fibrosis score of > 1 and ⁇ 4.
• the invention provides a method of improving liver function as measured by ALT activity in a patient with noncirrhotic NASH or NAFLD, a NASH CRN fibrosis score of > 1 and ⁇ 4, and an ALT score > 2X ULN, comprising administering to the patient a therapeutically effective amount of: (a) pemafibrate or a pharmaceutically acceptable salt thereof; (b) tofogliflozin or a pharmaceutically acceptable salt thereof; or (c) a combination thereof.
• the invention provides a method of lowering LDL-C in a patient with noncirrhotic NASH or NAFLD, a NASH CRN fibrosis score of > 1 and ⁇ 4, and an LDL-C concentration > 100 mg/dL, comprising administering to the patient a therapeutically effective amount of: (a) pemafibrate or a pharmaceutically acceptable salt thereof; (b) tofogliflozin or a pharmaceutically acceptable salt thereof; or (c) a combination thereof.
• the invention can further be understood with reference to various subembodiments which can modify any of the principal embodiments. It will be understood that these subembodiments can be combined in any manner that is both mathematically and physically possible to create additional subembodiments, which in turn can modify any of the principal embodiments.
• the methods can be practiced using either pemafibrate individually, tofogliflozin individually, or pemafibrate and tofogliflozin in combination.
• the methods are practiced by administering to the patient a therapeutically effective amount of pemafibrate or a pharmaceutically acceptable salt thereof.
• the methods are practiced by administering to the patient a therapeutically effective amount of tofogliflozin or a pharmaceutically acceptable salt thereof.
• the methods are practiced by administering to the patient a therapeutically effective amount of the combination.
• a preferred therapeutically effective amount of pemafibrate when orally administered, whether individually or in combination, is from 0.1 to 0.8 mg/day, or from 0.2 to 0.4 mg/day, in one, two or three divided doses.
• a particularly preferred dose is 0.4 mg/day.
• a preferred therapeutically effective amount of tofogliflozin when orally administered, whether individually or in combination is from 5 to 60 mg/day, or from 10 to 40 mg/day.
• a particularly preferred dose is 20 mg/day of tofogliflozin or a pharmaceutically acceptable salt thereof.
• the preferred dosing regimen is a single dosage form, preferably tablet, administered once daily.
• the invention provides an orally administered unit dosage form comprising about 0.4 mg of pemafibrate or a pharmaceutically acceptable salt thereof and about 20 mg of tofogliflozin or a pharmaceutically acceptable salt thereof.
• the patient treatable by the methods of the current invention can be characterized by several diagnostic criteria.
• the patient at the time of commencing the method, the patient has a vibration-controlled transient elastography CAP score > 290 dB/m.
• the patient at the time of commencing the method, the patient has a LSM > 7 kilopascals (kPa) and ⁇ 19 kPa.
• the patient at the time of commencing the method, has an AST concentration > 20 U/L, 30 U/L, 40 U/L, or 50 U/L.
• the patient has: (a) a vibration-controlled transient elastography CAP score > 290 dB/m; (b) a LSM > 7 kilopascals (kPa) and ⁇ 19 kPa; and (c) an AST concentration > 20 U/L.
• the patient can also be characterized histologically.
• NAS NAFLD activity score
• the patient has: (a) a NAS > 4; (b) a NASH CRN steatosis score > 1; (c) a NASH CRN lobular inflammation score > 1 ; and (d) a NASH CRN ballooning score > 1.
• the patient can also be characterized histologically in addition to enzyme liver activity.
• the patient has: (a) a NAS > 4; (b) a NASH CRN steatosis score > 1; (c) a NASH CRN lobular inflammation score > 1; (d) a NASH CRN ballooning score > 1; and (e) an ALT concentration > IX, 2X, or 3X of ULN.
• the patient can be characterized by liver imaging and/or liver enzyme activity.
• the patient at the time of commencing the method, has a hepatic fat fraction on MRI-PDFF > 10%, 12.5%, 15%, or 17.5%.
• the patient at the time of commencing the method, has liver stiffness on MRE > 2.5 kPa, 2.75 kPa, or 3 kPa.
• the patient at the time of commencing the method, has an ALT concentration > IX, 2X, or 3X of ULN.
• the patient has: (a) a hepatic fat fraction on MRI-PDFF > 10%; (b) liver stiffness on MRE > 2.5 kPa; and (c) an ALT level > ULN.
• the patient at the time of commencing the method, has an LDL-C concentration greater than 110 or 120 mg/dL.
• the patient has a BMI greater than 22, 28, or 32 kg/m 2 .
• the patient has a fasting plasma glucose concentration > 100 mg/dL.
• the patient has a fasting TG level ⁇ 200, 175, or 150 mg/dL.
• the patient has a NASH CRN fibrosis score of 1, 2, 3, > 1 and ⁇ 4, or > 2 and ⁇ 4.
• the patient has an ALT concentration ⁇ 5 x ULN.
• the method comprises (a) a histological improvement in the patient’s NAS of > 2 points; and (b) no worsening of the patient’s NASH CRN fibrosis score.
• the method comprises (a) histological resolution of steatohepatitis defined as: (i) absence of fatty liver disease; or (ii) isolated or simple steatosis without steatohepatitis and a NAS of 0-1 for inflammation, 0 for ballooning, and any value for steatosis; and (b) no worsening of NASH CRN fibrosis score.
• the method comprises (a) improvement in the patient’s NASH CRN inflammation score > 1; (b) improvement in the patient’s NASH CRN ballooning score > 1; and (c) improvement in the patient’s NASH CRN steatosis score > 1.
• the method comprises (a) improvement in the patient’s NASH CRN fibrosis score > 1; (b) no worsening of the patient’s NASH CRN ballooning score; (c) no worsening of the patient’s NASH CRN inflammation score; and (d) no worsening of the patient’s NASH CRN steatosis score.
• the method comprises (a) a liver fat content decrease as measured by MRI-PDFF of > 30%; and/or (b) a > 30% decrease in ALT to ⁇ 40 U/L.
• hepatic fat fraction > 10% on MRI-PDFF
• liver stiffness > 2.5 kPa
• elevated ALT >40 U/L for men, >30 U/L for women
• BMI body mass index
• HbAlc > 8%
• impaired renal function estimated glomerular filtration rate, eGFR, ⁇ 30 mL ⁇ min 1 ⁇ 1.73 1 ⁇ m 2 or on dialysis
• cirrhosis biliary obstruction
• chronic liver diseases other than NAFLD chronic liver diseases other than NAFLD.
• Subjects took their assigned medication (pemafibrate 0.2 mg tablet or placebo) orally, one tablet, twice daily, for 72 weeks. Study visits were set every 4 weeks from the start of treatment to week 24 and every 8 weeks from week 24 onwards. Liver fat content and liver stiffness were measured at screening examinations that took place pre-randomization and subsequently at weeks 0, 24, 48, and 72.
• Imaging assessment procedures were performed blinded. The equipment used in all facilities was standardized to a 3.0T MR Imaging System (GE Healthcare, Little Chalfont, UK). As an application, IDEAL-IQ for MRI-PDFF and MR-touch for MRE were used. Detailed imaging conditions are described in the “Imaging Procedure Manual” and imaging procedures were standardized throughout all tests. Imaging was performed during fasting ( > 4 h postprandial) and the timing of testing (pre-breakfast/post-breakfast to pre-lunch/post-lunch) was unified for each patient throughout the study.
• the primary efficacy endpoint was percent change in hepatic fat content, as measured using MRI-PDFF. Liver stiffness measured using MRE was a secondary endpoint and similarly assessed percent change from baseline values. Other efficacy endpoints included liver function, fibrosis and inflammatory markers, and lipid markers.
• Data are Mean (SD) or n (%).
• Example 2 A Multicenter, Placebo-Controlled, Randomized, Double-Blind, 48-Week Study Evaluating Pemafibrate, Tofoglifozin, and the Combination of Pemafibrate and Tofoglifozin in Patients with NASH and Liver Fibrosis
• Probable patients with noncirrhotic NASH with liver fibrosis will first be identified using a FibroScan vibration-controlled transient elastography controlled attenuation parameter score > 290 dB/m, FibroScan liver stiffness measurement > 7 kilopascals (kPa) and ⁇ 19 kPa, and aspartate aminotransferase (AST) > 20 U/L.
• Probable NASH patients will receive confirmatory liver biopsy for eligibility which will also be used as a baseline assessment for the histological assessments.
• fibrosis stage of 1 or greater and below 4 on NASH CRN fibrosis staging system and
• the primary objective of this study is to evaluate efficacy in patients with noncirrhotic NASH with liver fibrosis. Efficacy determination will be based upon liver histological improvement in NAFLD activity score (NAS) > 2 points and no worsening of fibrosis score at Week 48 as the primary endpoint.
• NAS NAFLD activity score
• the primary efficacy endpoint is improvement from baseline in disease activity and no worsening of liver fibrosis on the NASH Clinical Research Network (CRN) fibrosis score at Week 48.
• the improvement in disease activity is defined as improvement in NAS > 2 points.
• the worsening of fibrosis is defined as any numerical increase in the stage.
• the secondary efficacy endpoints of this study include:
• Resolution of steatohepatitis is defined as absent fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS score of 0-1 for inflammation, 0 for ballooning, and any value for steatosis.
• Table 3 describes the histological scoring system for NAFLD used in this example, as described by D.E. Kleiner et al. for the Nonalcoholic Steatohepatitis Clinical Research Network. Hepatology 41:1313-1321, 2005.
• “Few” means rare but definite ballooned hepatocytes as well as
• This category is included to accommodate cases with portal and/or peri portal fibrosis without accompanying
• Total NAS score represents the sum of scores for steatosis, lobular inflammation, and ballooning, and ranges from 0-8. Diagnosis of NASH (or, alternatively, fatty liver not diagnostic of NASH) should be made first, then NAS is used to grade activity. In the reference study, NAS scores of 0-2 occurred in cases largely considered not diagnostic of NASH, scores of 3-4 were evenly divided among those considered not diagnostic, borderline, or positive for NASH. Scores of 5-8 occurred in cases that were largely considered diagnostic of NASH
• MRI-PDFF magnetic resonance imaging-proton density fat fraction.
• MRE magnetic resonance elastography.
• FSM liver stiffness measurement
• AFT alanine transaminase
• FDF cholesterol low-density lipoprotein cholesterol.
• HDF cholesterol High-density lipoprotein cholesterol.
• M2BPGi mac-2 binding protein glycosylation isomer.
• EFF test enhanced liver fibrosis test.
• NASH CRN Nonalcoholic Steatohepatitis Clinical Research Network.
• NAS NAFFD activity score.
• Example 3 SGFT2 Inhibitor versus Sulfonylurea on Type 2 Diabetes with NAFFD
• Hepatic virus infections autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, haemochromatosis, antitrypsin deficiency, Wilsons disease, history of parenteral nutrition and use of drugs known to induce steatosis or hepatic injury caused by substance abuse and or the current or past consumption of more than 20 g of alcohol daily
• Severe retinopathy Malignancy on an active therapeutic regimen or malignancy without complete remission or cure Severe health problems not suitable for the study Pregnant or lactating women
• a total of 40 patients were randomly assigned to receive once-daily tofogliflozin at a dose of 20 mg (20 patients) or to receive once-daily glimepiride (20 patients). All 40 patients (100%) completed the trial. Demographic and baseline clinical characteristics except for gender were similar in both groups. The patients were all Japanese and type 2 diabetes. The mean age was 53.9 years, the mean body weight 82.0 kg, the mean Hemoglobin Ale 8.2%, and the mean NAS 4.45. A total of 18 patients (45%) had stage FI fibrosis, 11 (27.5%) had stage F2, and 5 (12.5%) had stage F3.
• a total of 40 patients were randomly assigned to receive once-daily tofogliflozin at a dose of 20 mg (20 patients) or to receive once-daily glimepiride (20 patients). All 40 patients (100%) completed the trial. Information for the primary and confirmatory secondary outcomes related to a biopsy at week 48 was available for 39 patients (97.5%). For only one patient with a serious adverse event (2.5%).
• the mean ballooning scores were significantly reduced in both groups.
• the mean steatosis scores, percentage of steatosis, lobular inflammation score, and fibrosis score were significantly reduced only in the tofogliflozin group.
• the changes in CPR, lipid profile, oxidative stress markers, and cytokines were similar in both groups.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Gastroenterology & Hepatology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Molecular Biology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (9)

Applications Claiming Priority (2)

Publications (1)

Family

ID=82020168

Family Applications (1)

Country Status (10)

Cited By (2)

Citations (2)

• 2022
  • 2022-05-25 US US18/564,115 patent/US20240277745A1/en active Pending
  • 2022-05-25 AU AU2022282651A patent/AU2022282651A1/en active Pending
  • 2022-05-25 BR BR112023024701A patent/BR112023024701A2/pt unknown
  • 2022-05-25 EP EP22729797.5A patent/EP4346809A1/en active Pending
  • 2022-05-25 CA CA3221073A patent/CA3221073A1/en active Pending
  • 2022-05-25 JP JP2023572876A patent/JP2024520020A/ja active Pending
  • 2022-05-25 CN CN202280050095.0A patent/CN117677385A/zh active Pending
  • 2022-05-25 WO PCT/IB2022/054867 patent/WO2022249071A1/en not_active Ceased
  • 2022-05-25 KR KR1020237044685A patent/KR20240013203A/ko active Pending
  • 2022-05-25 MX MX2023013886A patent/MX2023013886A/es unknown

Patent Citations (2)

Non-Patent Citations (9)

Also Published As

Similar Documents

Legal Events