IP Library › Granted Patent US 12,396,444
Granted Patent B2
US 12,396,444 · App. 17/810,029 · Granted Aug 26, 2025

Mouse comprising a humanized TRKB locus

Inventors: Alexander O. Mujica (Elmsford, NY); Yajun Tang (White Plains, NY); Jeffrey D. Lee (New York, NY); Min Gao (Woodcliff Lake, NJ); Susan D. Croll (New Paltz, NY); Lynn Macdonald (Harrison, NY); Ying Hu (Scarsdale, NY); Carmelo Romano (Tarrytown, NY)
Assignee: REGENERON PHARMACEUTICALS, INC.
A01K67/0278A01K67/0271A61K49/0008C12N5/10C12N9/12C12Y207/10001A01K2207/15A01K2217/072A01K2227/105A01K2267/03A01K2267/0318C07K2319/02C07K2319/03C07K2319/033C07K2319/035
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Quick Facts
Patent No.
US 12,396,444
App. No.
17/810,029
Granted
Aug 26, 2025
Kind
B2
Abstract

Non-human animal genomes, non-human animal cells, and non-human animals comprising a humanized TRKB locus and methods of making and using such non-human animal genomes, non-human animal cells, and non-human animals are provided. Non-human animal cells or non-human animals comprising a humanized TRKB locus express a human TRKB protein or a chimeric transthyretin protein, fragments of which are from human TRKB. Methods are provided for using such non-human animals comprising a humanized TRKB locus to assess in vivo efficacy of human-TRKB-targeting reagents such as nuclease agents designed to target human TRKB.

Claims (26)

1. A genetically modified mouse whose genome comprises a genetically modified endogenous mouse TrkB locus comprising a humanized TrkB gene encoding a humanized tropomyosin receptor kinase B (TRKB) protein comprising:

an endogenous mouse TRKB protein signal peptide;

a human TRKB protein extracellular domain;

an endogenous mouse TRKB protein transmembrane domain; and

an endogenous mouse TRKB protein cytoplasmic domain,

wherein the humanized TrkB gene is under the control of an endogenous mouse TrkB promoter, wherein the humanized TRKB protein comprises the amino acid sequence as set forth in SEQ ID NO: 4,

wherein the humanized TrkB gene comprises a replacement of an endogenous mouse TrkB genomic sequence comprising a region starting from the codon in exon 2 encoding amino acid 32 through exon 10, including all introns between exons 2 and 10, with a corresponding human TrkB genomic sequence comprising a region starting from the codon in exon 2 encoding amino acid 32 through exon 10, including all introns between exons 2 and 10,

wherein the genetically modified mouse expresses the humanized TRKB protein,

wherein the genetically modified mouse is homozygous for the genetically modified endogenous mouse TrkB locus, and

wherein the genetically modified mouse exhibits reduced (a) body weight and (b) total body fat mass upon treatment with a human TRKB agonist antibody relative to a control genetically modified mouse not treated with the antibody.

2. The genetically modified mouse of claim 1 , wherein the human TRKB protein extracellular domain comprises the sequence set forth in SEQ ID NO: 60.

3. The genetically modified mouse of claim 1 , wherein the human TRKB protein extracellular domain is encoded by the nucleotide sequence set forth in SEQ ID NO: 72.

4. The genetically modified mouse of claim 1 , wherein the endogenous mouse TRKB protein signal peptide comprises the sequence set forth in SEQ ID NO: 51.

5. The genetically modified mouse of claim 1 , wherein the endogenous mouse TRKB protein signal peptide is encoded by the nucleotide sequence set forth in SEQ ID NO: 63.

6. The genetically modified mouse of claim 1 , wherein the endogenous mouse TRKB protein transmembrane domain comprises the sequence set forth in SEQ ID NO: 53.

7. The genetically modified mouse of claim 1 , wherein the endogenous mouse TRKB protein transmembrane domain is encoded by the nucleotide sequence set forth in SEQ ID NO: 65.

8. The genetically modified mouse of claim 1 , wherein the endogenous mouse TRKB protein cytoplasmic domain comprises the sequence set forth in SEQ ID NO: 54.

9. The genetically modified mouse of claim 1 , wherein the endogenous mouse TRKB protein cytoplasmic domain is encoded by the nucleotide sequence set forth in SEQ ID NO: 66.

10. The genetically modified mouse of claim 1 , wherein the endogenous mouse TRKB protein signal peptide comprises the sequence set forth in SEQ ID NO: 51, the endogenous mouse TRKB protein transmembrane domain comprises the sequence set forth in SEQ ID NO: 53, and the endogenous mouse TRKB protein cytoplasmic domain comprises the sequence set forth in SEQ ID NO: 54.

11. The genetically modified mouse of claim 1 ,

wherein the endogenous mouse TRKB protein signal peptide is encoded by the nucleotide sequence set forth in SEQ ID NO: 63, the endogenous mouse TRKB protein transmembrane domain is encoded by the nucleotide sequence set forth in SEQ ID NO: 65, and the endogenous mouse TRKB protein cytoplasmic domain is encoded by the nucleotide sequence set forth in SEQ ID NO: 66.

12. The genetically modified mouse of claim 1 , wherein the humanized TRKB protein is encoded by the nucleotide sequence set forth in SEQ ID NO: 12.

13. A method of assessing activity of a human-TRKB-targeting reagent in vivo, comprising:

(a) administering the human-TRKB-targeting reagent to the genetically modified mouse of claim 1 ; and

(b) assessing the activity of the human-TRKB-targeting reagent in the genetically modified mouse of step (a) as compared to an untreated control mouse.

14. A mouse cell isolated from the genetically modified mouse of claim 1 , wherein the mouse cell's genome comprises the genetically modified endogenous mouse TrkB locus comprising the humanized TrkB gene encoding the humanized TRKB protein comprising the amino acid sequence as set forth in SEQ ID NO: 4, wherein the mouse cell expresses the humanized protein.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 31, 2025
From: MUJICA, ALEXANDER O.; TANG, YAJUN; LEE, JEFFREY D.; GAO, MIN; MACDONALD, LYNN; CROLL, SUSAN D.; HU, YING; ROMANO, CARMELO
To: REGENERON PHARMACEUTICALS, INC.
Reel/Frame 070685/0870 →
Continuity (4)
Continuation 16206330 · Nov 30, 2018
Provisional Application 62661373 · Apr 23, 2018
Provisional Application 62592905 · Nov 30, 2017
Related Publication 20220361464A1 · Nov 17, 2022
References Cited (144)
US 5942435A · Wheeler · 1999 [cited by applicant]
US 6586251B2 · Economides et al. · 2003 [cited by applicant]
US 7060429B2 · Krueger · 2006 [cited by examiner]
US 7294754B2 · Poueymirou et al. · 2007 [cited by applicant]
US 7576259B2 · Poueymirou et al. · 2009 [cited by applicant]
US 7659442B2 · Poueymirou et al. · 2010 [cited by applicant]
US 10329582B2 · Lee et al. · 2019 [cited by applicant]
US 10385359B2 · Lee et al. · 2019 [cited by applicant]
US 11419318B2 · Mujica et al. · 2022 [cited by applicant]
US 20020146416A1 · Presta et al. · 2002 [cited by applicant]
US 20080078000A1 · Poueymirou et al. · 2008 [cited by applicant]
US 20130111616A1 · Macdonald et al. · 2013 [cited by applicant]
US 20130111617A1 · Macdonald et al. · 2013 [cited by applicant]
US 20130117873A1 · Wang et al. · 2013 [cited by applicant]
US 20140134662A1 · Flavell et al. · 2014 [cited by applicant]
US 20140178879A1 · Economides et al. · 2014 [cited by applicant]
US 20140235933A1 · Lee et al. · 2014 [cited by applicant]
US 20140245466A1 · Macdonald et al. · 2014 [cited by applicant]
US 20140310828A1 · Lee et al. · 2014 [cited by applicant]
US 20150089678A1 · Murphy et al. · 2015 [cited by applicant]
US 20150143558A1 · McWhirter et al. · 2015 [cited by applicant]
US 20150143559A1 · McWhirter et al. · 2015 [cited by applicant]
US 20150282463A1 · Murphy et al. · 2015 [cited by applicant]
US 20150320021A1 · Wang et al. · 2015 [cited by applicant]
US 20150327524A1 · Murphy et al. · 2015 [cited by applicant]
US 20150342163A1 · Voronina et al. · 2015 [cited by applicant]
US 20150366174A1 · Burova et al. · 2015 [cited by applicant]
US 20150376628A1 · Schoenherr et al. · 2015 [cited by applicant]
US 20150376651A1 · Frendewey et al. · 2015 [cited by applicant]
US 20160145646A1 · Frendewey et al. · 2016 [cited by applicant]
US 20160157469A1 · Burova et al. · 2016 [cited by applicant]
US 20160157470A1 · Gurer · 2016 [cited by examiner]
US 20160345549A1 · Gurer et al. · 2016 [cited by applicant]
US 20170164588A1 · Olson et al. · 2017 [cited by applicant]
US 20180139940A1 · Macdonald et al. · 2018 [cited by applicant]
US 20190159436A1 · Mujica et al. · 2019 [cited by applicant]
US 20190290783A1 · Voronina et al. · 2019 [cited by applicant]
US 20200015462A1 · Murphy et al. · 2020 [cited by applicant]
CN 101157730A · 2008 [cited by applicant]
CN 105829542A · 2016 [cited by applicant]
RU 2425880C2 · 2009 [cited by applicant]
WO WO2002003071A2 · 2002 [cited by applicant]
WO WO2009053442A1 · 2009 [cited by applicant]
WO WO2014130706A1 · 2014 [cited by applicant]
WO WO2014172489A2 · 2014 [cited by applicant]
WO WO2015088643A1 · 2015 [cited by applicant]
WO WO2015127158A1 · 2015 [cited by examiner]
WO WO2015200334A1 · 2015 [cited by applicant]
WO WO2015200805A2 · 2015 [cited by applicant]
WO WO2016044745A1 · 2016 [cited by applicant]
WO WO2016081923A2 · 2016 [cited by applicant]
WO WO2017087780A1 · 2017 [cited by applicant]
WO WO2019108983A1 · 2019 [cited by applicant]
WO WO2015042557A1 · 2022 [cited by applicant]
Patil et al.,Indian Journal of Public Health research & Development, vol. 2, No. 1, 106-109 (Year: 2011). [cited by examiner]
Zhu, F Nature communications 10.1., 1-13 (Year: 2019). [cited by examiner]
Perreault et al PLOS One, e62616, 1-13 (Year: 2013). [cited by examiner]
Koponen et al Mol. Cell. Neurosci. 26, 166-181 (Year: 2004). [cited by examiner]
Harari et al PLOS One, 9, e84259, 1-12 (Year: 2014). [cited by examiner]
Luberg et al (ournal of Neurochemistry, 113, 952-964 (Year: 2010). [cited by examiner]
Barthold, “Genetically altered mice: phenotypes, no phenotypes, and Faux phenotypes,” Genetica, 122(1):75-88, (2004). [cited by applicant]
Birling, et al., “Modeling human disease in rodents by CRISPR/Cas9 genome editing,” Mamm. Genome, 28(7-8):291-301, (2017). [cited by applicant]
Brevini, et al., “No shortcuts to pig embryonic stem cells,” Theriogenology, 74(4):544-550, (2010). [cited by applicant]
Brevini, et al., “Porcine embryonic stem cells: Facts, challenges and hopes,” Theriogenology, 68 Suppl. 1:S206-S213, (2007). [cited by applicant]
Burova, et al., “Characterization of the Anti-PD-1 Antibody REGN2810 and Its Antitumor Activity in Human PD-1 Knock-In Mice,” Mol. Cancer Ther., 16(5):861-870, (2017). [cited by applicant]
Cao, et al., “Isolation and Culture of Primary Bovine Embryonic Stem Cell Colonies by a Novel Method,” J. Exp. Zool. A. Ecol. Genet. Physiol., 311(5):368-376, (2009). [cited by applicant]
Chen, et al., “Neuroprotective effect of TrkB agonist antibody in humanized TrkB rat,” Invest. Ophthalmol. Vis. Sci., 59(9):6134, (2018). [cited by applicant]
Clark, et al., “A future for transgenic livestock,” Nat. Rev. Genet., 4(10):825-833, (2003). [cited by applicant]
Dechiara, T.M., et al., “VelociMouse: Fully ES Cell-Derived FO-Generation Mice Obtained from the Injection of ES Cells into Eight-Cell-Stage Embryos,” Jan. 1, 2009, Methods in Molecular Biology, 530(16): 311-324. [cited by applicant]
Dennis, “Welfare Issues of Genetically Modified Animals,” ILAR J., 43(2):100-109, (2002). [cited by applicant]
Ezashi et al., “Pluripotent Stem Cells From Domesticated Mammals,” Annu. Rev. Anim. Biosci., 4:223-253, (2016). [cited by applicant]
Frendewey, et al., “The Loss-of-Allele Assay for ES Cell Screening and Mouse Genotyping,” Methods Enzymol., 476:295-307, (2010). [cited by applicant]
Geiger, et al., “Functional Characterization of Human Cancer-Derived TRKB Mutations,” PLoS One, 6(2):e16871, 1-12, (2011). [cited by applicant]
Genoway, “Humanized Mouse Model,” retrieved from https://www.genoway.com/services/customized-mouse/knockin-models/humanisation.htm on May 12, 2018. [cited by applicant]
Glik B., Pasternak Dzh. Moleculyarnaya biotehnologiya. Printsipy i primeneniye. Moscow: Mir, 2002, English Translation. [cited by applicant]
Gomez, et al., “Derivation of cat embryonic stem-like cells from in vitro-produced blastocysts lon homologous and heterologous feeder cells,” Theriogenology, 74(4): 498-515, (2010). [cited by applicant]
Graham, et al., “Resources for the design of CRISPR gene editing experiments,” Genome Biol., 16:260, (2015). [cited by applicant]
Guo et al., “Targeted Genome Editing in Primate Embryos,” Cell Res., 25(7):767-768, (2015). [cited by applicant]
Haniu, et al., “Interactions between Brain-derived Neurotrophic Factor and the TRKB Receptor: Identification of Two Ligand Binding Domains in Soluble TRKB by Affinity Separation and Chemical Cross-Linking,” J. Biol. Che… [cited by applicant]
Harari, et al., “Bridging the Species Divide: Transgenic Mice Humanization for Type-1 Interferon Response,” PLoS One, 9(1):e84259, 1-12, (2014). [cited by applicant]
Herndler-Brandstetter, et al., “Humanized mouse model supports development, function, and tissue residency of human natural killer cells,” Proc. Natl. Acad. Sci. U.S.A., 114(45):E9626-E9634, (2017). [cited by applicant]
Hofker Marten H., et al., Transgenic mouse methods and protocols, Methods in molecular biology, 209, p. 51-58, 2002-2003. [cited by applicant]
Hong et al., “Derivation and Characterization of Embryonic Stem Cell Lines Derived from Transgenic Fischer 344 and Dark Agouti Rats,” Stem Cells Dev., 21(9):1571-1586, (2012). [cited by applicant]
Houdebine, “Methods to Generate Transgenic Animals,” pp. 31-48 in “Genetic Engineering in Livestock: New Applications and Interdisciplinary Perspectives,” Ed. Engelhard et al., (2009). [cited by applicant]
Hsu et al., “DNA Targeting Specificity of RNA-guided Cas9 Nucleases,” Nat. Biotechnol., 31(9):827-832, (2013). [cited by applicant]
Hutchison, “Mice with a Conditional Deletion of the Neurotrophin Receptor TrkB Are Dwarfed, and Are Similar to Mice with a MAPK14 Deletion,” PLoS One, 8(6):e66206, 1-10, (2013). [cited by applicant]
Jean, et al., “Pluripotent genes in avian stem cells,” Dev. Growth Differ., 55(1): 41-51, (2013). [cited by applicant]
Kawamata, et al., “Generation of genetically modified rats from embryonic stem cells,” Proc. Natl. Acad. Sci. U.S.A., 7(32):14223-14228, (2010). [cited by applicant]
Khodarovich et al., “Expression of Eukaryotic Recombinant Proteins and Deriving Them from the Milk of Transgenic Animals,” Applied Biochemistry and Microbiology, 49(9):711-722, (2013). [cited by applicant]
Koponen et al., “Transgenic mice overexpressing the full-length neurotrophin receptor trkB exhibit increased activation of the trkB-PLCgamma pathway, reduced anxiety, and facilitated learning,” Mol. Cell. Neurosci. 26(1… [cited by applicant]
Kumar, et al., “Transgenic Mouse Technology: Principles and Methods,” Methods Mol. Biol., 590:335-362, (2009). [cited by applicant]
Lee et al., “Developing genetically engineered mouse models using engineered nucleases: Current status, challenges, and the way forward,” Drug Discovery Today: Disease Models, 20:13-20, (2016). [cited by applicant]
Lin, et al., “Appetite Enhancement and Weight Gain by Peripheral Administration of TrkB Agonists in Non-Human Primates,” PLoS ONE, 3(4):e1900, 1-7, (2008). [cited by applicant]
Liu, et al., “7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders,” Transl. Neurodegener., 5:2, pp. 2-9, (2016). [cited by applicant]
Luberg et al., “Human TrkB Gene: Novel Alternative Transcripts, Protein Isoforms and Expression Pattern in the Prefrontal Cerebral Cortex During Postnatal Development,” J. Neurochem., 113(4):952-964, (2010). [cited by applicant]
Luikart, et al., “In Vivo Role of Truncated TrkB Receptors During Sensory Ganglion Neurogenesis,” Neuroscience, 117(4):847-858, (2003). [cited by applicant]
Lute, et al., “Human CTLA4 knock-in mice unravel the quantitative link between tumor immunity and autoimmunity induced by anti-CTLA-4 antibodies,” Blood, 106(9):3127-3133, (2005). [cited by applicant]
Maksimenko et al., “Use of transgenic animals in biotechnology: prospects and problems,” Acta Naturae, 5(1):33-46, (2013). [cited by applicant]
Massa, et al., “Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents,” J. Clin. Invest., 120(5):1774-1785, (2010). [cited by applicant]
Medina, et al., “TrkB regulates neocortex formation through the Shc/PLCγ-mediated control of neuronal migration,” EMBO J., 23(19):3803-3814, (2004). [cited by applicant]
Mullins, et al., “Transgenesis in the rat and larger mammals,” J. Clin. Invest. 97(7):1557-1560, (1996). [cited by applicant]
Munoz et al., “Constraints to progress in embryonic stem cells from domestic species,” Stem Cell Rev. Rep., 5(1):6-9, (2009). [cited by applicant]
Munoz, et al., “Conventional pluripotency markers are unspecific for bovine embryonic-derived cell-lines,” Theriogenology, 69(9): 1159-1164, (2008). [cited by applicant]
Nadal-Nicolás, et al., “Brn3a as a Marker of Retinal Ganglion Cells: Qualitative and Quantitative Time Course Studies in Naïve and Optic Nerve-Injured Retinas,” Invest. Ophthalmol. Vis. Sci., 50(8):3860-3868, (2009). [cited by applicant]
NCBI Accession No. NP_001269890.1, (2017). [cited by applicant]
NCBI Accession No. NP_006171.2, (2017). [cited by applicant]
NCBI Accession No. NP_036863.1, (2017). [cited by applicant]
Niemann, “Transgenic farm animals get off the ground. Transgenic Animals in Agriculture, Conference Tahoe City, California, USA. Aug. 24-27, 1997.” Transgenic Res., 7(1): 73-75, (1998). [cited by applicant]
O'Leary, et al., “Design of Potent Peptide Mimetics of Brain-derived Neurotrophic Factor,” J. Biol. Chem., 278(28):25738-25744, (2008). [cited by applicant]
Paris, et al., “Equine embryos and embryonic stem cells: defining reliable markers of pluripotency,” Theriogenology, 74(4): 516-524, (2010). [cited by applicant]
Patil et al., “Transgenic animals and drug development: A review,” Indian Journal of Public Health Research and Development, 2(1):106-109, (2011). [cited by applicant]
PCT International Search Report and Written Opinion of the International Searching Authority for application PCT/US2018/063390 mailed Feb. 26, 2019. [cited by applicant]
Perreault, et al., “Activation of TrkB with TAM-163 Results in Opposite Effects on Body Weight in Rodents and Non-Human Primates,” PLoS One, 8(5):e62616, 1-13, (2013). [cited by applicant]
Poueymirou, et al., “F0 generation mice fully derived from gene-targeted embryonic stem cells allowing immediate phenotypic analyses,” Nat. Biotechnol., 25(1):91-99, (2007). [cited by applicant]
Qian, et al., “Novel Agonist Monoclonal Antibodies Activate TrkB Receptors and Demonstrate Potent Neurotrophic Activities,” J. Neurosci., 26(37):9394-9403, (2006). [cited by applicant]
Rezza, et al., “Unexpected genomic rearrangements at targeted loci associated with CRISPR/Cas9-mediated knock-in,” Sci. Rep., 9(1):3486, (2019). [cited by applicant]
Rios, “BDNF and the central control of feeding: accidental bystander or essential player?,” Trends Neurosci., 36(2):83-90, (2013). [cited by applicant]
Ristevski, “Making better transgenic models: conditional, temporal, and spatial approaches,” Mol. Biotechnol., 29(2):153-163, (2005). [cited by applicant]
Rogalski, et al., “TrkB Activation by Brain-derived Neurotrophic Factor Inhibits the G Protein-gated Inward Rectifier Kir3 by Tyrosine Phosphorylation of the Channel,” J. Biol. Chem., 275(33):25082-25088, (2000). [cited by applicant]
Rogers, et al., “Disruption of the CFTR Gene Produces a Model of Cystic Fibrosis in Newborn Pigs,” Science, 321(5897):1837-1841, (2008). [cited by applicant]
Rybchin V.N., Osnovy geneticheskoy inzhenerii, Saint Petersburg, SHbGTU Publishing House, 2002, p. 411-413, English translation. [cited by applicant]
Selsby et al., “Porcine models of muscular dystrophy,” ILAR J., 56(1):116-126, (2015). [cited by applicant]
Sigmund, “Viewpoint: Are Studies in Genetically Altered Mice Out of Control?,” Arterioscler. Thromb. Vasc. Biol., 20(6):1425-1429, (2000). [cited by applicant]
U.S. Appl. No. 16/206,330, Advisory Action mailed Feb. 19, 2021. [cited by applicant]
U.S. Appl. No. 16/206,330, Final Office Action mailed Jan. 14, 2022. [cited by applicant]
U.S. Appl. No. 16/206,330, Final Office Action mailed Nov. 6, 2020. [cited by applicant]
U.S. Appl. No. 16/206,330, Non-Final Office Action mailed Apr. 30, 2020. [cited by applicant]
U.S. Appl. No. 16/206,330, Non-Final Office Action mailed Jul. 2, 2021. [cited by applicant]
U.S. Appl. No. 16/206,330, Requirement for Restriction/Election mailed Nov. 15, 2019. [cited by applicant]
Valenzuela, et al., “High-throughput engineering of the mouse genome coupled with high-resolution expression analysis,” Nat. Biotechnol., 21(6):652-659, (2003). [cited by applicant]
Wakchaure, et al., “Transgenic Animals: A Review on its Various Dimensions and Applications in Animal Biotechnology,” International Journal of Emerging Technology and Advanced Engineering, 5(11):210-213, (2015). [cited by applicant]
Webster, et al., “Small molecule activators of the Trk receptors for neuroprotection,” BMC Neurosci., 9(Suppl 2):S1, (2008). [cited by applicant]
Xu, et al., “Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor,” Nat. Neurosci, 6(7):736-742, (2003). [cited by applicant]
Yang et al., “Mutant PFN1 Causes ALS Phenotypes and Progressive Motor Neuron Degeneration in Mice by a Gain of Toxicity,” Proc. Natl. Acad. Sci. U.S.A., 113(41):E6209-E6218, (2016). [cited by applicant]
Yang, et al., “A small molecule TrkB/TrkC neurotrophin receptor co-activator with distinctive effects on neuronal survival and process outgrowth,” Neuropharmacology, 110(Pt A):343-361, (2016). [cited by applicant]
Zhao, et al., “Inconsistency between hepatic expression and serum concentration of transthyretin in mice humanized at the transthyretin locus,” Genes to Cells, 13:1257-1268, (2008). [cited by applicant]
Zhou, et al., “Developing tTA transgenic rats for inducible and reversible gene expression,” Int. J. Biol. Sci., 5(2):171-181, (2009). [cited by applicant]
Zhu et al., “Humanising the mouse genome piece by piece,” Nat. Commun. 10(1):1845, (Apr. 23, 2019). [cited by applicant]
Zörner, et al., “Forebrain-Specific trkB-Receptor Knockout Mice: Behaviorally More Hyperactive Than ‘Depressive’,” Biol. Psychiatry, 54(1):972-982, (2003). [cited by applicant]
U.S. Appl. No. 62/592,905, filed Nov. 30, 2017, Expired. [cited by applicant]
U.S. Appl. No. 62/661,373, filed Apr. 23, 2018, Expired. [cited by applicant]
U.S. Appl. No. 16/206,330, filed Nov. 30, 2018, now U.S. Pat. No. 11,419,318, Issued. [cited by applicant]
PCT/US2018/063390, Nov. 30, 2018, WO 2019/108983, Expired. [cited by applicant]
EP 23207807.1 Extended European Search Report mailed Feb. 28, 2024. [cited by applicant]