Classifications

• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
  • C12N9/14—Hydrolases (3)
  • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
  • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
  • A61K38/46—Hydrolases (3)
  • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
  • A61K38/488—Aspartic endopeptidases (3.4.23), e.g. pepsin, chymosin, renin, cathepsin E
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
  • A61K38/46—Hydrolases (3)
  • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
• • 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
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
  • C12N9/14—Hydrolases (3)
  • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
  • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
  • C12N9/52—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• NCGS non-celiac gluten sensitivity
• the polypeptide comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1. In some aspects, the polypeptide comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1. In some aspects, the polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 1.
• amino acid residue corresponding to amino acid 467 of SEQ ID NO: 6 is a Ser. In some aspects, the amino acid residue corresponding to amino acid 267 of SEQ ID NO: 6 is a Glu. In some aspects, the amino acid residue corresponding to amino acid 271 of SEQ ID NO: 6 is an Asp.
• amino acid residue corresponding to amino acid 278 of SEQ ID NO: 3 is a Ser. In some aspects, the amino acid residue corresponding to amino acid 78 of SEQ ID NO: 3 is a Glu. In some aspects, the amino acid residue corresponding to ammo acid 82 of SEQ ID NO: 3 is an Asp.
• ammo acid residue corresponding to amino acid 467 of SEQ ID NO: 6 is a Ser. In some aspects, the amino acid residue corresponding to amino acid 267 of SEQ ID NO: 6 is a Glu. In some aspects, the amino acid residue corresponding to amino acid 271 of SEQ ID NO: 6 is an Asp.
• the polypeptide comprises a histidine tag, wherein the histidine tag is fused at the C-temrinus of the polypeptide.
• the histidine tag comprises the amino acid sequence set forth in SEQ ID NO: 17 (GSTENLYFQSGALEHHHHHH).
• the histidine tag comprises a cleavable histidine tag, including but not limited to a cleavable histidine tag comprising the amino acid sequence set forth in SEQ ID NO: 15 , wherein XN is an linker of between 1 -25 amino acid residues.
• the cleavable histidine tag comprises the ammo acid sequence set forth in SEQ ID NO: 16
• the present disclosure is directed to a polypeptide comprising an amino acid sequence an amino acid sequence having at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1, wherein the first amino acid at the N-terminus of the polypeptide is a Ser (S); wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 8.
• the present disclosure is directed to a method for degrading gluten in a food item, comprising contacting the food item with an amount effective to degrade the gluten with the polypeptide or the pharmaceutical composition described herein, thereby degrading the gluten in the food item.
• the present disclosure is directed to a method for degrading gliadin in a food item, comprising contacting the food item with an amount effective to degrade the gliadin with the polypeptide, or the pharmaceutical composition of described herein, thereby degrading the gliadin in the food item.
• the present disclosure provides gliadinases that are capable of degrading gliadin peptides.
• Some aspects of the present disclosure are directed to a polypeptide comprising an amino acid sequence having at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1, wherein the first amino acid at the N-terminus of the polypeptide is a Ser (S).
• the polypeptide does not comprise a Met (M) at the N-terminus of the polypeptide.
• the polypeptide comprises the ammo acid sequence set forth in SEQ ID NO: 8. 1. Definitions
• Celiac disease and “celiac sprue disease” are used interchangeably and refer to a condition characterized by an inflammatory’ reaction to immunogenic peptides in gluten, the major protein in wheat flour, and to related proteins.
• a-gliadin Upon ingestion, a-gliadin is partially degraded by gastric and intestinal proteases to oligopeptides, referred to herein as “gliadins.” Gliadins are resistant to further proteolysis in gastric conditions due to their unusually high proline and glutamine content.
• polypeptides of the second aspect of the disclosure comprises one or more amino acid substitution from SEQ ID NO: 3 at one or more residues selected from the group consisting of 32D/N/QZH, 73E, 79S/T/A, 80L/T, 81 A/T/V, I30A, 165E/Q/R/Y, 169S/Q/T, 179F/Q, 2I0Q, 213S/Q, 217S, 235K, 260E/N/Q, 272R, and 274A/L/M/Q/R/T/V.
• the polypeptide comprises (i) an A at position 130, (ii) an F at position 179, (iii) a Q at position 210, (iv) a Q at position 260, (v) a T at position 274, or any combination of (i)-(v), based on the numbering of SEQ ID NO: 3.
• the polypeptide comprises 73E, 80T, 81V, 165Q, 169S, 210Q, and 260Q. (Kuma050 genus).
• the polypeptide comprises (i) an E at position 73, (ii) a T at position 80, (iii) an M at position 320, (iv) a Q at position 165, (v) an S at position 169, (vi) a Q at position 210 (vii) a Q at position 260, (viii) a T at position 274, or any combination of (i)-(vii), based on the numbering of SEQ ID NO: 3.
• the polypeptide comprises 130A, 131M, 179F, 210Q, 2.60Q, and 274T. (Kuma070 genus).
• the present disclosure provides polypeptides that include at least one mutation that improves production of the polypeptide.
• mutations that improve production provide improvements in one of three categories: 1. altering purification method; 2. increase in yield; and 3. decreasing the probability that enzymatic seif-processing would occur during purification, thereby simplifying analysis. Addition of a His tag that is removable by the proteolytic activity of the polypeptides disclosed herein falls into category 1 ; the R105H mutant appears to improve yield by ⁇ 2-fold, placing this mutation into category 2; and mutations in positions 171-174 place these mutants into category 3.
• the present disclosure provides isolated nucleic acids encoding the polypeptide of any aspect of the disclosure.
• An exemplary nucleic acid that encodes the Kuma062-M is shown below.
• isolated nucleic acid sequence may comprise RNA or DNA.
• isolated nucleic acids are those that have been removed from their normal surrounding nucleic acid sequences in the genome or in cDNA sequences.
• Such isolated nucleic acid sequences may comprise additional sequences useful for promoting expression and/or purification of the encoded protein, including but not limited to polyA sequences, modified Kozak sequences, and sequences encoding epitope tags, export signals, and secretory signals, nuclear localization signals, and plasma membrane localization signals. It will be apparent to those of skill in the art, based on the teachings herein, what nucleic acid sequences will encode the polypeptides of the disclosure.
• the expression vector must be replicable in the host organisms either as an episome or by integration into host chromosomal DNA.
• the expression vector comprises a plasmid.
• the disclosure is intended to include other expression vectors that serve equivalent functions, such as viral vectors.
• the present disclosure provides recombinant host cells comprising the nucleic acid expression vectors of the disclosure.
• Any host cell capable of producing a recombinant protein can be used in the methods disclosed herein.
• the host cells can be either prokaryotic or eukaryotic.
• the host cell is a prokaryotic cell.
• suitable prokaryotic host cells include Escherichia colt, Bacillus subtilis, Caulobacter crescentus, Rodhobacter sphaeroides , Pseudoalteromonas haloplanktis, Shewanella sp.
• a method of producing a polypeptide according to the disclosure is an additional part of the disclosure.
• the method comprises the steps of (a) culturing a host according to this aspect of the disclosure under conditions conducive to the expression of the polypeptide, and (b) optionally, recovering the expressed polypeptide.
• the expressed polypeptide can be recovered from the cell free extract, cell pellet, or recovered from the culture medium . Methods to purify recombinantly expressed polypeptides are well known to the man skilled in the art.
• the present disclosure provides pharmaceutical compositions, comprising the polypeptide, nucleic acid, nucleic acid expression vector, and/or the recombinant host cell of any aspect or aspect of the disclosure, and a pharmaceutically acceptable carrier.
• the pharmaceutical compositions of the disclosure can be used, for example, in the methods of the disclosure described below.
• the pharmaceutical composition may comprise in addition to the polypeptides, nucleic acids, etc. of the disclosure (a) a lyoprotectant; (b) a surfactant; (c) a bulking agent; (d) a tonicity adjusting agent; (e) a stabilizer; (f) a preservative and/or (g) a buffer.
• the buffer in the pharmaceutical composition is a Tris buffer, a histidine buffer, a phosphate buffer, a citrate buffer or an acetate buffer.
• the pharmaceutical composition may also include a lyoprotectant, e.g. sucrose, sorbitol or trehalose.
• the pharmaceutical composition includes a preservative e.g.
• Exemplary' tonicity adjusting agents include sucrose, sorbitol, glycine, methionine, mannitol, dextrose, inositol, sodium chloride, arginine and arginine hydrochloride.
• the pharmaceutical composition additionally includes a stabilizer, e.g., a molecule which, when combined with a protein of interest substantially prevents or reduces chemical and/or physical instability of the protein of interest in lyophilized or liquid form.
• Exemplary stabilizers include sucrose, sorbitol, glycine, inositol, sodium chloride, methionine, arginine, and arginine hydrochloride.
• polypeptides, nucleic acids, etc. of the disclosure may be the sole active agent in the pharmaceutical composition, or the composition may further comprise one or more other active agents suitable for an intended use.
• compositions described herein generally comprise a combination of a compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient. Such compositions are substantially free of non-pharmaceutically acceptable components, i.e., contain amounts of non-pharmaceutically acceptable components lower than permitted by US regulatory' requirements at the time of filing this application.
• the composition further optionally comprises an additional pharmaceutically acceptable carrier, diluent, or excipient.
• the pharmaceutical compositions described herein are solid pharmaceutical compositions ⁇ e.g., tablet, capsules, etc.).
• the compositions described herein could also be provided as a dietary' supplement as described by the US regulatory’ agencies.
• compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by any suitable route.
• the pharmaceutical compositions and formulations are designed for oral administration.
• Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may' be necessary' or desirable.
• compositions can be in any suitable form, including but not limited to tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, tor example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
• the present disclosure provides methods for treating DCiac sprite or non-celiac gluten sensitivity (NCGS), comprising administering to an individual with celiac sprue or NCGS an amount effective to treat the celiac sprue or NCGS of one or more polypeptides selected from the group consisting of the polypeptides of the of the disclosure, or using one or more of these polypeptides to process food for consumption by individuals with celiac sprue or NCGS.
• NCGS non-celiac gluten sensitivity
• the method comprises administering to a subject affected with celiac sprue or NCGS a polypeptide comprising an amino acid sequence having at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1.
• tire method comprises administering to a subject affected with celiac sprue or NCGS a polypeptide comprising an amino acid sequence having at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1 .
• the method comprises administering to a subject affected with celiac sprue or NCGS a polypeptide comprising an ammo acid sequence having at least about 95% sequence identity to tire ammo acid sequence set forth in SEQ ID NO: 1 .
• the method comprises administering to a subject affected with celiac sprue or NCGS a polypeptide comprising an amino acid sequence having at least about 96% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1.
• the method comprises administering to a subject affected with celiac sprue or NCGS a polypeptide comprising an amino acid sequence having at least about 97% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1.
• the method comprises administering to a subject affected with celiac sprue or NCGS a polypeptide comprising an amino acid sequence having at least about 98% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1. In certain aspects, the method comprises administering to a subject affected with celiac sprue or NCGS a polypeptide comprising an amino acid sequence having at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1. In certain aspects, the method comprises administering to a subject affected with celiac sprue or NCGS a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 1.
• the method comprises administering to a subject affected with celiac sprue or NCGS a polypeptide comprising an amino acid sequence having at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 8.
• the method comprises administering to a subject affected with celiac sprue or NCGS a polypeptide comprising an amino acid sequence having at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 8.
• the method comprises administering to a subject affected with celiac sprue or NCGS a polypeptide comprising an amino acid sequence having at least about 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 8. In certain aspects, the method comprises administering to a subject affected with celiac sprue or NCGS a polypeptide comprising an ammo acid sequence having at least about 96% sequence identity to the ammo acid sequence set forth in SEQ ID NO: 8. In certain aspects, the method comprises administering to a subject affected with celiac sprue orNCGS a polypeptide comprising an amino acid sequence having at least about 97% sequence identity to the amino acid sequence set forth in SEQ ID NO: 8.
• the method degrades at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 98%, at least about 99%, or about 100% of the gluten or gliadin m the food item.
• the methods disclosed herein can degrade gluten or gliadin in a food item in less than about 1.5 hours, less than about I hour, less than about 45 minutes, less than about 40 minutes, less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, less than about 15 minutes, less than about 10 minutes, or less than about 5 minutes. In some aspects, the methods disclosed here can degrade gluten or gliadin in a food item under a pH value less than about 6.5, less than about 6.0, less than about 5.5, less than about 5.0, less than about 4.5, less than about 4.0, less than about 3.5, or less than about 3.0.
• polypeptides of the present disclosure show superior activity in degrading peptides having a PQLP (SEQ ID NO: 9) or PQQP (SEQ ID NO: 10) motif (such as PFPQPQLPY (SEQ ID NO: 11) and/or PFPQPQQPF (SEQ ID NO: 12)), which are substrates representative of gliadin) at pH 4 compared to KumaO 10/011 and other polypeptides disclosed as useful for treating celiac sprue (WO2015/023728).
• the polypeptides of the disclosure constitute significantly improved therapeutics tor treating celiac sprue and NCGS.
• the pharmaceutical composition and/or formulation of a polypeptide disclosed herein is administered orally.
• routes of oral administration include the use of tablets, pills, lozenges, elixirs, suspensions, emulsions, solutions, syrups, or any combination thereof.
• a pharmaceutical composition comprising a polypeptide disclosed herein is administered to a subject before the subject ingests a substance, e.g., food, comprising one or more gluten protein.
• a pharmaceutical composition comprising a polypeptide disclosed herein is administered to a subject at the same time the subject ingests a substance, e.g., food, comprising one or more gluten protein.
• a pharmaceutical composition comprising a polypeptide disclosed herein is administered to a subject after the subject ingests a substance, e.g., food, comprising one or more gluten protein.
• both ELISA-based methods were used to assess the ability of gliadinase to decrease the amount of all three families of immunogenic gliadin: ⁇ -, CD-, and ⁇ -gliadin.
• an in-house G12 ⁇ based ELISA method was used. This in -house-developed method, while less expensive than the commercially available kits, is less reliable in quantification of low concentrations of gluten. Thus, this method was only used to assess relative differences between samples.
• Example 1 Bread slurries were generated with the following pH levels: 3.9, 4.5, 5.0, 5.5, and 5.9. pH 5.9 was the pH of the bread slurry when only water, no HQ, was added to the slurry after mashing with artificial saliva.
• Table 7 shows that Kuma062-M can degrade gluten effectively at various pH values.
• Example 1 The vanilla milkshake was estimated (roughly, by comparisons to milkshakes of similar size from McDonalds®) to contain 10 grams of protein, while the hamburger paty was estimated to contain 7 grams of protein. pH of the meal in gastric digestion was 4.0-4.5. The amount of hamburger bun in the control meal was adjusted to the same am ount of bun as hi the hamburger and shake meal. Volume of gastric digestion of hamburger and shake meal was 500 mL; control meal was also adjusted to 500 mL. Aliquots of meal slurries after mashing and blending were portioned into smaller tubes, and glutenase enzyme and pepsin were added to these aliquots. Enzyme concentrations were 700 pg/mL or 70 pg/mL. for Kuma062-M. Meal was digested for 30 minutes or 5 minutes. Aspergillus Niger-derived prolyl endoprotease (AN-PEP) and EPB2/SCPEP were also included in this study.
• AN-PEP Aspergillus N
• E6 The polypeptide of any one of E1 to 5, comprising the ammo acid sequence set forth in SEQ ID NO: 1.
• a polypeptide comprising an ammo acid sequence an ammo acid sequence having at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 8.
• E15 The polypeptide of any one of E11 to 14, comprising an ammo acid sequence having at least 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 8.
• E16 The polypeptide of any one of E11 to E15, comprising the amino acid sequence set forth in SEQ ID NO: 8.
• E 18 The polypeptide of any one of E11 to E 17, wherein the amino acid resi due corresponding to amino acid 78 of SEQ ID NO: 3 is a Glu.
• E19 The polypeptide of any one of E11 to EI8, wherein the amino acid residue corresponding to amino acid 82 of SEQ ID NO: 3 is an Asp.
• E20 The polypeptide of any one of E11 to E19, which is capable of cleaving gliadin.
• a polypeptide comprising an amino acid sequence an ammo acid sequence having at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about
• E28 The polypeptide of any one of E21 to E27, wherein the amino acid residue corresponding to amino acid 267 of SEQ ID NO: 6 is a Glu.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Organic Chemistry (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Wood Science & Technology (AREA)
• Genetics & Genomics (AREA)
• Zoology (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Molecular Biology (AREA)
• Biochemistry (AREA)
• General Engineering & Computer Science (AREA)
• Biotechnology (AREA)
• Biomedical Technology (AREA)
• Microbiology (AREA)
• Immunology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Epidemiology (AREA)
• Gastroenterology & Hepatology (AREA)
• Nutrition Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Peptides Or Proteins (AREA)
• Micro-Organisms Or Cultivation Processes Thereof (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Priority Applications (9)

Applications Claiming Priority (2)

Publications (1)

Family

ID=78819631

Family Applications (1)

Country Status (12)

Cited By (1)

Citations (4)

Family Cites Families (1)

• 2021
  • 2021-10-29 MX MX2023004807A patent/MX2023004807A/es unknown
  • 2021-10-29 AU AU2021368118A patent/AU2021368118A1/en active Pending
  • 2021-10-29 CN CN202180068658.4A patent/CN116829166A/zh active Pending
  • 2021-10-29 AR ARP210103015A patent/AR123961A1/es not_active Application Discontinuation
  • 2021-10-29 EP EP21816227.9A patent/EP4237554A1/en not_active Withdrawn
  • 2021-10-29 US US18/034,622 patent/US20250064903A1/en active Pending
  • 2021-10-29 WO PCT/US2021/057197 patent/WO2022094177A1/en not_active Ceased
  • 2021-10-29 KR KR1020237017895A patent/KR20230093323A/ko not_active Withdrawn
  • 2021-10-29 JP JP2023525049A patent/JP2023548083A/ja active Pending
  • 2021-10-29 TW TW110140404A patent/TW202233834A/zh unknown
  • 2021-10-29 CA CA3195929A patent/CA3195929A1/en active Pending
• 2023
  • 2023-05-24 CO CONC2023/0006731A patent/CO2023006731A2/es unknown

Patent Citations (4)

Non-Patent Citations (9)

Also Published As

Similar Documents

Legal Events