IP Library Granted Patent US 12,247,324
Granted Patent B2
US 12,247,324 · App. 18/154,522 · Granted Mar 11, 2025

Systems and methods for manufacturing a silk fibroin solution and powders containing silk fibroin

Inventors: Amanda Baryshyan (Ipswich, MA); Nick Zhang (Newton, MA); Jesse Groner (Cambridge, MA); Adam Behrens (Boston, MA); Nicole Marco (Somerville, MA); Samantha Roman (Cambridge, MA); Rebeca Lopez-Garcia (Mexico City, MX); Lindsay Perrea (Allston, MA); Colin Preston (Salem, MA); Laith Abu-Taleb (Gaithersburg, MD); Linda Michelle Rauch (Amherst, MA); Herve Irenee Garant, III (West Bath, ME); John Patrick Ellersick (Cambridge, MA)
Assignee: Cambridge Crops, Inc.
D01F4/02A23L3/3526B01D1/16B01D11/0257B01D11/0261B01D37/048B01D61/14B01D61/146B01D61/147B01D61/22B01D63/10C07K1/145C07K1/34C07K14/43586A23V2002/00B01D2315/10B01D2315/16D10B2211/04D10B2211/22
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Quick Facts
Patent No.
US 12,247,324
App. No.
18/154,522
Granted
Mar 11, 2025
Kind
B2
Abstract

The disclosure relates to systems and methods for improving the manufacturing of silk solutions and powders containing silk fibroin obtained from silkworm cocoons. The systems include a reactor vessel to degum, rinse, and dissolve the silk fibroin protein from silk inputs to obtain a purified silk fibroin-based solution. The reactor vessel may include a combination of inputs and outputs for introducing and removing different components used or generated during the disclosed processes. The systems may include any combination of heat exchangers, holding tanks, filtration modules, and post-treatment equipment as necessary to obtain the silk powder. The solutions and powders can be used to improve the post-harvest preservation of perishables and to improve the performance of packaging, including biodegradable packaging.

Claims (35)

1. A silk manufacturing system comprising:

a first processing substation comprising at least one reactor vessel configured to receive silk inputs, extract silk fibroin proteins therefrom, and produce a silk fibroin-based solution, such that the silk fibroin-based solution is substantially free of sericin, wherein the first processing substation is configured to extract the silk fibroin proteins via degumming, rinsing, and dissolving processes within a single one of the at least one reactor vessel, wherein the at least one reactor vessel is sized to have an aspect ratio of height to diameter as defined by a work volume of about 0.5 to about 5.0 and is further configured to operate with a packing density of silk inputs of about 1% and about 30%;

a second processing substation in fluid communication with the first processing substation, the second processing substation configured to receive and purify the silk fibroin-based solution from the first processing substation, wherein the second processing substation comprises a filtration module comprising at least one membrane configured to substantially remove a second compound from the silk fibroin-based solution and produce a purified silk fibroin-based solution;

a reservoir disposed between the first and second processing substations and configured to at least one of hold or condition the silk fibroin-based solution; and

a pump assembly disposed between the first and second processing substations and configured to transfer the silk fibroin-based solution between the first processing substation, the reservoir, and the second processing substation.

2. The system of claim 1 further comprising a heat exchange system configured to adjust a temperature of the silk fibroin-based solution prior to or after any one of the processing substations.

3. The system of claim 1 , wherein the second processing substation is configured to purify the silk fibroin-based solution via diafiltration.

4. The system of claim 1 , wherein the second processing substation is configured to purify the silk fibroin-based solution via tangential flow filtration.

5. The system of claim 1 , wherein the purified silk fibroin-based solution comprises less than about 650 ppm of one or more salts or non-organic particulates.

6. The system of claim 1 further comprising a third processing substation in fluid communication with the second processing substation, the third processing substation configured to receive and powderize the purified silk fibroin-based solution.

7. The system of claim 1 further comprising a fourth processing substation in fluid communication with the second processing substation, the fourth processing substation configured to receive and sterilize the purified silk fibroin-based solution.

8. The system of claim 7 , wherein the fourth processing substation comprises a microfiltration module.

9. The system of claim 8 , wherein the microfiltration module comprises:

a first microfiltration stage having a pore size between about 0.7 μm and about 5 μm; and

a second microfiltration stage disposed downstream of the first microfiltration module, the second microfiltration stage having a pore size between about 0.05 μm and about 0.8 μm.

10. The system of claim 8 , wherein the microfiltration module further comprises one or more holding tanks, wherein the tanks may be configured to provide additional processing, including one or more of storing the solution, temperature control of the solution, or adjusting the solution concentration to address turbidity or sterility levels.

11. The system of claim 6 , wherein the third processing substation comprises a spray dryer.

12. The system of claim 6 , wherein the powderized silk fibroin-based solution has a water activity level of less than 0.9.

13. The system of claim 6 further comprising a post-treatment system configured to receive a silk fibroin powder from the third processing substation and to at least one of: condition the silk fibroin powder, test the silk fibroin powder, or package the silk fibroin powder in a food-safe container.

14. The system of claim 1 , wherein the at least one reactor vessel further comprises a handling structure for controlling at least one of movement or position of the silk inputs within the at least one reactor vessel.

15. The system of claim 1 further comprising a pre-treatment system configured to condition the silk inputs prior to or at introduction to the first processing substation.

16. The system of claim 1 , wherein the silk inputs come from a Bombyx mori silkworm.

17. The system of claim 1 , wherein the at least one membrane is a spiral wound membrane.

18. A silk manufacturing system comprising:

a first processing substation comprising at least two single reactor vessels configured in parallel, each vessel configured to receive silk inputs, extract silk fibroin proteins therefrom, and produce a silk fibroin-based solution, such that the silk fibroin-based solution is substantially free of sericin, wherein the first processing substation is configured to extract the silk fibroin proteins via degumming, rinsing, and dissolving processes within each vessel and output a combined stream of the silk fibroin-based solutions from each vessel, wherein the at least two single reactor vessels each further comprises a handling structure configured to restrict at least one of movement or position of the silk inputs within each reactor vessel; and

a second processing substation in fluid communication with the first processing substation, the second processing substation configured to receive and purify the silk fibroin-based solution from the first processing substation, wherein the second processing substation comprises a filtration module configured to receive the combined stream of the silk fibroin-based solutions and comprising at least one membrane configured to substantially remove a second compound from the silk fibroin-based solution and produce a purified silk fibroin-based solution.

19. A silk manufacturing system comprising:

a first processing substation comprising at least one reactor vessel configured to receive silk inputs, extract silk fibroin proteins therefrom, and produce a silk fibroin-based solution, such that the silk fibroin-based solution is substantially free of sericin, wherein the first processing substation is configured to extract the silk fibroin proteins via degumming, rinsing, and dissolving processes within a single one of the at least one reactor vessel, wherein the at least one reactor vessel further comprises a handling structure configured to restrict at least one of movement or position of the silk inputs within the at least one reactor vessel.

20. The system of claim 18 further comprising a third processing substation in fluid communication with the second processing substation, the third processing substation configured to receive and powderize the purified silk fibroin-based solution.

21. The system of claim 20 , wherein the third processing substation comprises a spray dryer.

22. The system of claim 20 , wherein the powderized silk fibroin-based solution has a water activity level of less than 0.9.

23. The system of claim 18 , wherein the second processing substation is configured to purify the silk fibroin-based solution via diafiltration.

24. The system of claim 18 , wherein the second processing substation is configured to purify the silk fibroin-based solution via tangential flow filtration.

25. The system of claim 18 , wherein the at least one membrane is a spiral wound membrane.

26. The system of claim 19 , wherein the at least one reactor vessel is sized to have an aspect ratio of height to diameter as defined by a work volume of about 0.5 to about 5.0.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 6, 2024
From: BARYSHYAN, AMANDA; ZHANG, NICK; GRONER, JESSE; BEHRENS, ADAM; MARCO, NICOLE; ROMAN, SAMANTHA; LOPEZ-GARCIA, REBECA; PERREA, LINDSAY; PRESTON, COLIN; ABU-TALEB, LAITH; RAUCH, LINDA MICHELLE; GARANT, HERVE IRENEE, III; ELLERSICK, JOHN PATRICK
To: CAMBRIDGE CROPS, INC. D/B/A MORI
Reel/Frame 069511/0654 →
SECURITY INTEREST Recorded Oct 9, 2024
From: CAMBRIDGE CROPS, INC.
To: FIRST-CITIZENS BANK & TRUST COMPANY
Reel/Frame 068850/0861 →
Continuity (5)
Continuation 17650570 · Feb 10, 2022
Provisional Application 63231399 · Aug 10, 2021
Provisional Application 63212283 · Jun 18, 2021
Provisional Application 63191441 · May 21, 2021
Related Publication 20230175172A1 · Jun 8, 2023
References Cited (133)
US 3246990A · Thompson et al. · 1966 [cited by applicant]
US 3464827A · Tsuchiya et al. · 1969 [cited by applicant]
US 4233212A · Otoi et al. · 1980 [cited by applicant]
US 4608203A · Akasaka et al. · 1986 [cited by applicant]
US 4940662A · Yamazaki et al. · 1990 [cited by applicant]
US 5853764A · Tsubouchi · 1998 [cited by applicant]
US 6592794B1 · Bachrach · 2003 [cited by applicant]
US 6800310B2 · Squire et al. · 2004 [cited by applicant]
US 7553634B1 · Lakhotia et al. · 2009 [cited by applicant]
US 8309689B2 · Yang et al. · 2012 [cited by applicant]
US 8354501B2 · Kaplan et al. · 2013 [cited by applicant]
US 9175052B2 · Gerardi et al. · 2015 [cited by applicant]
US 9731052B2 · Kaplan et al. · 2017 [cited by applicant]
US 9925299B2 · Kaplan et al. · 2018 [cited by applicant]
US 10271561B2 · Omenetto et al. · 2019 [cited by applicant]
US 10433574B2 · Froseth et al. · 2019 [cited by applicant]
US 10533037B2 · Wang et al. · 2020 [cited by applicant]
US 11584784B2 · Baryshyan · 2023 [cited by examiner]
US 11585016B2 · Baryshyan · 2023 [cited by examiner]
US 20050197496A1 · Perreault · 2005 [cited by applicant]
US 20060273279A1 · Kaplan et al. · 2006 [cited by applicant]
US 20080166469A1 · Schweizer et al. · 2008 [cited by applicant]
US 20090110651A1 · Moussou et al. · 2009 [cited by applicant]
US 20100228010A1 · Shirataki · 2010 [cited by examiner]
US 20110014287A1 · Altman et al. · 2011 [cited by applicant]
US 20110212504A1 · Liu · 2011 [cited by examiner]
US 20130115588A1 · Davis · 2013 [cited by examiner]
US 20140329224A1 · Arnold · 2014 [cited by examiner]
US 20140378661A1 · Lo et al. · 2014 [cited by applicant]
US 20150183841A1 · Lo et al. · 2015 [cited by applicant]
US 20150337008A1 · Montagner et al. · 2015 [cited by applicant]
US 20160046679A1 · Kluge et al. · 2016 [cited by applicant]
US 20160185817A1 · Zhu et al. · 2016 [cited by applicant]
US 20160206780A1 · Wang · 2016 [cited by applicant]
US 20160215030A1 · Bressner et al. · 2016 [cited by applicant]
US 20170245508A1 · Yang et al. · 2017 [cited by applicant]
US 20180110256A1 · Melonas et al. · 2018 [cited by applicant]
US 20180310604A1 · Rubin · 2018 [cited by applicant]
US 20180352833A1 · Zhang et al. · 2018 [cited by applicant]
US 20190001272A1 · Leisk et al. · 2019 [cited by applicant]
US 20190069590A1 · Neal et al. · 2019 [cited by applicant]
US 20190070088A1 · Altman et al. · 2019 [cited by applicant]
US 20190309467A1 · Altman et al. · 2019 [cited by applicant]
US 20200178576A1 · Behrens et al. · 2020 [cited by applicant]
US 20210094982A1 · Ludemann-Hombourger et al. · 2021 [cited by applicant]
US 20220177530A1 · Altman · 2022 [cited by applicant]
CN 103739691A · 2014 [cited by applicant]
CN 106435763A · 2017 [cited by applicant]
CN 107043412A · 2017 [cited by applicant]
CN 108294164A · 2018 [cited by applicant]
EP 0352330A1 · 1990 [cited by applicant]
EP 1869238B1 · 2009 [cited by applicant]
EP 2154990B1 · 2013 [cited by applicant]
EP 2475677B1 · 2018 [cited by applicant]
EP 2934187B1 · 2019 [cited by applicant]
EP 3645063A1 · 2020 [cited by applicant]
JP 2010254596A · 2010 [cited by applicant]
WO WO2007016524A2 · 2007 [cited by applicant]
WO WO2012145739A1 · 2012 [cited by applicant]
WO WO2014145002A2 · 2014 [cited by applicant]
WO WO2015134865A1 · 2015 [cited by applicant]
WO WO2019094700A1 · 2019 [cited by applicant]
WO WO2019236525A1 · 2019 [cited by applicant]
WO WO2020028918A1 · 2020 [cited by applicant]
Brimmer, “Sugar Reductions Strategies for Frosted and Coated Cereal”, Naturally Colorful, Aug. 16, 2022, https://sensientfoodcolors.com/en-us/dry-grocery/sugar-reduction-strategies-frosted-coated-cereal/. [cited by applicant]
Burrington, “Keeping the crunch in breakfast cereals”, Natural Products Insider, Jun. 1, 2001, https://www.naturalproductsinsider.com/archive/keeping-crunch-breakfast-cereals. [cited by applicant]
USPTO, Third Party Submission Under 37 CFR 1.290 for U.S. Appl. No. 18/075,496, filed Sep. 26, 2023, pp. 1-16. [cited by applicant]
Ajisawa, “Dissolution of silk fibroin with calcium chloride/ethanol aqueous solution,” J. Seric. Sci. Jpn., 67(2):91-94, (1998). [cited by applicant]
Ali et al., “Gum arabic as a novel edible coating for enhancing shelf-life and improving postharvest quality of tomato ( [cited by applicant]
Basal et al., “Antibacterial Properties of Silk Fibroin/Chitosan Blend Films Loaded with Plant Extract,” Fibers and Polymers, 11(1):21-27, (2010). [cited by applicant]
Boulet-Audet et al., “Dry-Spun Silk Produces Native-Like Fibroin Solutions,” Biomacromolecules, 17(10):3198-3204, (2016). [cited by applicant]
Cheng et al., “Differences in regenerated silk fibroin prepared with different solvent systems: From structures to conformational changes,” J. Appl. Polym. Sci., 41959:1-8, (2015). [cited by applicant]
Day, BPF. “Fruit and Vegetables.” Principles and Applications of Modified Atmosphere Packaging of Foods, Springer-Verlag, 1993, pp. 114-133. [cited by applicant]
Freddi et al., “Swelling and dissolution of silk fibroin ( [cited by applicant]
Fuchs et al., “Effect of Edible Coatings on Postharvest Quality of Fresh Green Asparagus,” Journal of Food Processing and Preservation, 32:951-971, (2008). [cited by applicant]
Furuhata et al., “Dissolution of silk fibroin in lithium halide/organic amide solvent systems,” J. Seric. Sci. Jpn., 63(4):315-322, (1994). [cited by applicant]
Gobin et al., “Structural and mechanical characteristics of silk fibroin and chitosan blend scaffolds for tissue regeneration,” J Biomed Mater Res A, 74(3):465-473, (2005). [cited by applicant]
Gong et al., “Two distinct beta-sheet fibrils from silk protein,” Chem Commun (Camb), (48):7506-7508, (2009). [cited by applicant]
Haggag et al., “Degumming of Silk Using Microwave-Assisted Treatments,” Journal of Natural Fibers, 4(3):1-22, (2007). [cited by applicant]
Hino et al., “Change in secondary structure of silk fibroin during preparation of its microspheres by spraydrying and exposure to humid atmosphere,” J Colloid Interface Sci, 266(1):68-73, (2003). [cited by applicant]
Hu et al., “Determining Beta-Sheet Crystallinity in Fibrous Proteins by Thermal Analysis and Infrared Spectroscopy,” Macromolecules, 39:6161-6170, (2006). [cited by applicant]
International Search Report and Written Opinion for PCT/US19/65268, mailed Mar. 23, 2020. [cited by applicant]
Jaramillo-Quiceno et al., “Water-annealing treatment for edible silk fibroin coatings from fibrous waste,” J. Appl. Polym. Sci, 48505:1-8, (2019). [cited by applicant]
Kamalha et al., “Analysis of the secondary crystalline structure of regenerated [cited by applicant]
Khalifa et al., “Application of sericin to modify textile supports,” The Journal of Textile Institute, 103(4):370-377, (2012). [cited by applicant]
Khan et al., “Physical properties and dyeability of silk fibers degummed with citric acid,” Bioresour Technol, 101(21):8439-8445, (2010). [cited by applicant]
Kim et al., “Formulation of Biologically-Inspired Silk-Based Drug Carriers for Pulmonary Delivery Targeted for Lung Cancer,” Sci Rep, 5:11878, (2015). [cited by applicant]
Kluge et al., “Optimizing molecular weight of lyophilized silk as a shelf-stable source material,” ACS Biomater. Sci. Eng., 1-35, (2016). [cited by applicant]
Kluge et al., “Silk-based blood stabilization for diagnostics,” Proc Natl Acad Sci U S A, 113(21):5892-5897, (2016). [cited by applicant]
Koh et al., “Structures, mechanical properties and applications of silk fibroin materials,” Progress in Polymer Science, 46:86-110, (2015). [cited by applicant]
Kundu et al., “Isolation and processing of silk proteins for biomedical applications,” Int J Biol Macromol, 70:70-77, (2014). [cited by applicant]
Kweon et al., “Dissolution and Characterization of Regenerated [cited by applicant]
Li et al., “Silk-based stabilization of biomacromolecules,” J Control Release, 219:416-430, (2015). [cited by applicant]
Li et al., “Regenerated silk materials for functionalized silk orthopedic devices by mimicking natural processing,” Biomaterials, 110:24-33, (2016). [cited by applicant]
Li et al., “Enhanced Stabilization in Dried Silk Fibroin Matrices,” Biomacromolecules, 18:2900-2905, (2017). [cited by applicant]
Li et al., “Fabrication and characterization of microencapsulated n-octadecane with silk fibroin-silver nanoparticles shell for thermal regulation,” Journal of Materials Research, 34(12):2047-2056, (2019). [cited by applicant]
Lin et al., “Cold plasma treated thyme essential oil/silk fibroin nanofibers against [cited by applicant]
Liu et al., “Exploring the Structural Transformation Mechanism of Chinese and Thailand Silk Fibroin Fibers and Formic-Acid Fabricated Silk Films,” Int J Mol Sci, 19(11), 2018). [cited by applicant]
Lu et al., “Stabilization of Enzymes in Silk Films,” Biomacromolecules, 10:1032-1042, (2009). [cited by applicant]
Lu et al., “Stabilization and Release of Enzymes from Silk Films,” Macromol. Biosci., 10:359-368, (2010). [cited by applicant]
Malay et al., “Relationships between physical properties and sequence in silkworm silks,” Sci Rep, 6:27573, (2016). [cited by applicant]
Marelli et al., “Silk Fibroin as Edible Coating for Perishable Food Preservation,” Sci Rep, 6:25263, (2016). [cited by applicant]
Marelli et al., Supporting Information, “Silk Fibroin as Edible Coating for Perishable Food Preservation,” Sci Rep, 6:25263, (2016). [cited by applicant]
Meng et al., “Controllable in situ synthesis of silver nanoparticles on multilayered film-coated silk fibers for antibacterial application,” J Colloid Interface Sci, 461:369-375, (2016). [cited by applicant]
Meshram et al., “Extraction of lithium from primary and secondary sources by pre-treatment, leaching and separation: A comprehensive review,” Hydrometallurgy, 150:192-208, (2014). [cited by applicant]
Pawcenis et al., “Size exclusion chromatography for analyses of fibroin in silk: optimization of sampling and separation conditions,” Appl. Phys. A, 114:301-308, (2014). [cited by applicant]
Pritchard et al., “Encapsulation of Oil in Silk Fibroin Biomaterials,” J. Appl. Polym. Sci., 39990:1-11, (2014). [cited by applicant]
Rnjak-Kovacina et al., “The effect of sterilization on silk fibroin biomaterial properties,” Macromol Biosci, 15(6):861-874, (2015). [cited by applicant]
Rockwood et al., “Materials fabrication from Bombyx mori silk fibroin,” Nat Protoc, 6(10):1612-1631, (2011). [cited by applicant]
Sah et al., “The extraction of fibroin protein from Bombyx mori silk cocoon: Optimization of process parameters,” International Journal of Bioinformatics Research, 2(2):33-41, (2010). [cited by applicant]
Saha et al., “Extraction, Structural and Functional Properties of Silk Sericin Biopolymer from Bombyx mori Silk Cocoon Waste,” J Textile Sci Eng, 9(1):1000390, (2019). [cited by applicant]
Sashina et al., “Dissolution of Silk Fibroin in N-methylmorpholine-N-oxide and Its Mixtures with Organic Solvents,” Russian Journal of Applied Chemistry, 76(1):128-131, (2003). [cited by applicant]
Sashina et al., “Structure and Solubility of Natural Silk Fibroin,” Russian Journal of Applied Chemistry, 79(6):869-876, (2006). [cited by applicant]
Shen et al., “Dissolution behavior of silk fibroin in a low concentration CaCl2-methanol solvent: From morphology to nanostructure,” Int J Biol Macromol, 113:458-463, (2018). [cited by applicant]
Silva et al., “Glycerin and Ethanol as Additives on Silk Fibroin Films: Insoluble and Malleable Films,” J. Appl. Polym. Sci., pp. 115-122, (2013). [cited by applicant]
Sparkes et al., “Analysis of the pressure requirements for silk spinning reveals a pultrusion dominated process,” Nat Commun, 8(1):594, (2017). [cited by applicant]
Srihanam et al., “Silk fibroin microspheres prepared by the water-in-oil emulsion solvent diffusion method for protein delivery,” Korean J. Chem. Eng., 28(1):293-297, (2011). [cited by applicant]
Tabatabai et al., “Acid induced assembly of a reconstituted silk protein system”, pp. 1-16, (2018). [cited by applicant]
Toms et al., “Determination of the Configuration of Silk Fibroin Dissolved in Aqueous Solutions of Lithium Bromide,” Nature, 169:877-878, (1952). [cited by applicant]
Vaithanomsat et al., “Production of Water-Soluble Silk Powder from Bombyx mori Lin. (Nang-Noi Srisakate 1),” Kasetsart J. (Nat. Sci.), 40:152-158, (2006). [cited by applicant]
Vepari et al., “Silk as a Biomaterial,” Prog Polym Sci, 32(8-9):991-1007, (2007). [cited by applicant]
Wang et al., “Colloidal Stability of Silk Fibroin Nanoparticles Coated with Cationic Polymer for Effective Drug Delivery,” ACS Appl Mater Interfaces, 7(38):21254-21262, (2015). [cited by applicant]
Wang et al., “Effect of silk degumming on the structure and properties of silk fibroin,” The Journal of the Textile Institute, 1-7, (2018). [cited by applicant]
Wray et al., “Effect of processing on silk-based biomaterials: reproducibility and biocompatibility,” J Biomed Mater Res B Appl Biomater, 99(1):89-101, (2011). [cited by applicant]
Wu et al., “Control of silk microsphere formation using polyethylene glycol (PEG),” Acta Biomaterialia, 1-49, (2016). [cited by applicant]
Wu et al., “Nanofiltration recovery of sericin from silk processing waste and synthesis of a lauroyl sericinbased surfactant and its characteristics,” RSC Adv., 4:4140-4145, (2014). [cited by applicant]
Yamada et al., “Preparation of undegraded native molecular fibroin solution from silkworm cocoons,” Materials Science and Engineering C, 14:41-46, (2001). [cited by applicant]
Yazawa et al., “Influence of Water Content on the ?-Sheet Formation, Thermal Stability, Water Removal, and Mechanical Properties of Silk Materials,” Biomacromolecules, 17(3):1057-1066, (2016). [cited by applicant]
Zheng et al., “Lithium-free processing of silk fibroin,” Journal of Biomaterials Applications, 31(3):450-463, (2016). [cited by applicant]
Zong et al., “Effect of pH and Copper(II) on the Conformation Transitions of Silk Fibroin Based on EPR, NPR, and Raman Spectroscopy,” Biochemistry, 43:11932-11941, (2004). [cited by applicant]
World Intellectual Property Organization, International Search Report for PCT/US2022/070619, May 24, 2022. [cited by applicant]
WIPO, International Preliminary Report on Patentability dated Nov. 21, 2023, pp. 1-4. [cited by applicant]
EPO, Extended European Search Report dated Oct. 22, 2024, pp. 1-45. [cited by applicant]