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WO 2018/226900 A2 13 December 2018 (13.12.2018) W !P O PCT

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WO 2018/226900 A2 13 December 2018 (13.12.2018) W !P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/226900 A2 13 December 2018 (13.12.2018) W !P O PCT (51) International Patent Classification: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, CI2N 15/1 (2006.01) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US2018/036360 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, 06 June 2018 (06.06.2018) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Langi English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/5 15,907 06 June 2017 (06.06.2017) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicant: ZYMERGEN INC. [US/US]; 5980 Horton MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Street, Suite 105, Emeryville, California 94608 (US). TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (72) Inventors: SUNSPIRAL, Vytas; c/o Zymergen Inc., KM, ML, MR, NE, SN, TD, TG). 5980 Horton Street, Suite 105, Emeryville, California 94608 (US). FREDLUND, Jennifer; c/o Zymergen Inc., Declarations under Rule 4.17: 5980 Horton Street, Suite 105, Emeryville, California — as to applicant's entitlement to applyfor and be granted a 94608 (US). ABDULLA, Hassan; c/o Zymergen Inc., patent (Rule 4.1 7(H)) 5980 Horton Street, Suite 105, Emeryville, California — as to the applicant's entitlement to claim the priority of the 94608 (US). BOCCAZZI, Paolo; c/o Zymergen Inc., earlier application (Rule 4.17(Hi)) 5980 Horton Street, Suite 105, Emeryville, California Published: 94608 (US). POUST, Sean; c/o Zymergen Inc., 5980 — without international search report and to be republished Horton Street, Suite 105, Emeryville, California 94608 upon receipt of that report (Rule 48.2(g)) (US). CLETO, Sara da Luz Areosa; c/o Zymergen — with sequence listing part of description (Rule 5.2(a)) Inc., 5980 Horton Street, Suite 105, Emeryville, Cali fornia 94608 (US). CHAIKIND, Brian; c/o Zymergen Inc., 5980 Horton Street, Suite 105, Emeryville, Cali fornia 94608 (US). VAUGHAN, Dylan; c/o Zymergen Inc., 5980 Horton Street, Suite 105, Emeryville, Califor nia 94608 (US). BRUNO, Kenneth S.; c/o Zymergen Inc., 5980 Horton Street, Suite 105, Emeryville, Califor nia 94608 (US). WESTFALL, Patrick; c/o Zymergen Inc., 5980 Horton Street, Suite 105, Emeryville, Califor nia 94608 (US). SZEWCZYK, Edyta; c/o Zymergen Inc., 5980 Horton Street, Suite 105, Emeryville, California 94608 (US). ROTHSCHILD-MANCINELLI, Kyle; c/o Zymer gen Inc., 5980 Horton Street, Suite 105, Emeryville, Cali fornia 94608 (US). FONG, Arthur, Muir, III; c/o Zymer gen Inc., 5980 Horton Street, Suite 105, Emeryville, Cali fornia 94608 (US). (74) Agent: HOLLY, David Christopher et al; Cooley LLP, 1299 Pennsylvania Avenue, N.W., Suite 700, Washington, District of Columbia 20004 (US). (81) Designated States (unless otherwise indicated, for every < kind of national protection available): AE, AG, AL, AM, © AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, o CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (54) Title: A HTP GENOMIC ENGINEERING PLATFORM FOR IMPROVING FUNGAL STRAINS 00 (57) Abstract: The present disclosure provides a HTP genomic engineering platform for improving filamentous fungal cells that is o computationally driven and integrates molecular biology, automation, and advanced machine learning protocols. This integrative plat form utilizes a suite of HTP molecular tool sets to create HTP genetic design libraries, which are derived from, inter alia, scientific insight and iterative pattern recognition. IN THE UNITED STATES PATENT & TRADEMARK RECEIVING OFFICE INTERNATIONAL PCT PATENT APPLICATION A HTP GENOMIC ENGINEERING PLATFORM FOR IMPROVING FUNGAL STRAINS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. Provisional Application No. 62/515,907, filed on June 06, 2017, which is hereby incorporated by reference in its entirety for all purposes. FIELD [0002] The present disclosure is directed to automated fungal genomic engineering. The disclosed automated genomic engineering platform entails the genetic manipulation of filamentous fungi to generate fungal production strains as well as facilitate purification thereof. The resultant fungal production strains are well-suited for growth in sub-merged cultures, e.g., for the large-scale production of products of interest (e.g., antibiotics, metabolites, proteins, etc.) for commercial applications. STATEMENT REGARDING SEQUENCE LISTING [0003] The Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is ZYMR 008 03WO SeqList_ST25.txt. The text file is ~ 47 KB, was created on June 6, 2018, and is being submitted electronically via EFS-Web. BACKGROUND [0004] Eukaryotic cells are preferred organisms for the production of polypeptides and secondary metabolites. In fact, filamentous fungi are capable of expressing native and heterologous proteins to high levels, making them well-suited for the large-scale production of enzymes and other proteins for industrial, pharmaceutical, animal health and food and beverage applications. However, use of filamentous fungi for large-scale production of products of interest often requires genetic manipulation of said fungi as well as use of automated machinery and equipment and certain aspects of the filamentous fungal life cycle can make genetic manipulation and handling difficult. [0005] For example, DNA introduced into a fungus integrates randomly within a genome, resulting in mostly random integrated DNA fragments, which quite often can be integrated as multiple tandem repeats (see for example Casqueiro et al, 1999, J. Bacteriol. 181:1181-1 188). This uncontrolled "at random multiple integration" of an expression cassette can be a potentially detrimental process, which can lead to unwanted modification of the genome of the host. [0006] Additionally, present transfection systems for filamentous fungi can be very laborious (see for review Fincham, 1989, Microbiol. Rev. 53: 148-170) and relatively small scale in nature. This can involve protoplast formation, viscous liquid handling (i.e. polyethylene glycol solutions), one- by-one swirling of glass tubes and subsequent selective plating. Further, conditions for protoplasting can be difficult to determine and yields can often be quite low. Moreover, the protoplasts can contain multiple nuclei such that introduction of a desired genetic manipulation can lead to the formation of heterokaryotic protoplasts that can be difficult to separate from homokaryotic protoplasts. [0007] Further, typical filamentous fungal cells, including those derived from protoplasts, grow as long fibers called hyphae that can form dense networks of hyphae called mycelium. These hyphae can contain multiple nuclei that can differ from one another in genotype. The hyphae can differentiate and form asexual spores that can be easily dispersed in the air. If the hyphae contain nuclei of different genotypes, the spores will also contain a mixture of nuclei. Due to this aspect of fungal growth, genetic manipulation inherently results in a mixed population that must be purified to homogeneity in order to assess any effect of the genetic changes made. Further, in an automated environment, the spores can cause contamination of equipment that could negatively impact the ability to purify strains and may contaminate any other work performed on the equipment. [0008] To mitigate the aerial dispersal of spores, the filamentous fungi can be grown in submerged cultures. However, the mycelium formed by hyphal filamentous fungi growth in submerged cultures can affect the rheological properties of the broth. Generally, the higher the viscosity of the broth, the less uniform the distribution of oxygen and nutrients, and the more energy required to agitate the culture. In some cases, the viscosity of the broth due to hyphal filamentous fungal growth becomes sufficiently high to significantly interfere with the dissolution of oxygen and nutrients, thereby adversely affecting the growth of the fungi and ultimately the yield and productivity of any desired product of interest. [0009] Thus, there is a great need in the art for new methods of engineering filamentous fungi, which do not suffer from the aforementioned drawbacks inherent with traditional strain building programs in fungi and greatly accelerate the process of discovering and consolidating beneficial mutations. SUMMARY OF THE DISCLOSURE [0010] The present disclosure provides a high-throughput (HTP) genomic engineering platform for coenocytic organisms such as, for example filamentous fungi that does not suffer from the myriad of problems associated with traditional microbial strain improvement programs. While the methods provided herein are tested in filamentous fungi, it is
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