DNA aptamers for inhibiting reverse transcriptases

Abstract

Disclosed are DNA aptamers. Related compositions and kits are also provided. Also disclosed are methods for amplifying a target DNA sequence using the DNA aptamers, and methods of identifying the DNA aptamers.

Description

[0001] Leydig 772843 P2023-4023-WO 1

[0002] DNA APTAMERS FOR INHIBITING REVERSE TRANSCRIPTASES CROSS-REFERENCE TO PRIOR APPLICATION This patent application claims benefit to U.S. Provisional Patent Application No. 63 / 571,790, filed March 29, 2024, which is hereby incorporated by reference in its entirety. INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY Incorporated by reference in its entirety herein is a computer-readable nucleotide / amino acid sequence listing submitted concurrently herewith and identified as follows: One 139,096 Byte Extensible Markup Language (XML) file named “772843.xml,” created on March 28, 2025. BACKGROUND OF THE INVENTION Aptamers are small RNA or DNA molecules that can form secondary and tertiary structures capable of specifically binding proteins or other cellular targets. Reverse transcriptases (RTases) are enzymes involved with viral genome replication utilizing the RNA-dependent DNA polymerase and RNase H activities of RTase. RTases derived from retroviruses were first discovered in 1970 by David Baltimore and Howard Temin and since have revolutionized molecular biology through many uses such as RT-PCR and sequencing isolated RNA. The three most commonly used RTases for cDNA synthesis are derived from the retroviruses, Moloney murine leukemia virus (MMLV), avian myeloblastosis virus (AMV), and human immunodeficiency virus type 1 (HIV-1) (Coffin, et al., Annu. Rev. Virol., 3(1): 29-51 (2016)). There are instances when unwanted reverse transcriptase function is deleterious. Accordingly, there exists an unmet need for controlling reverse transcriptase function. BRIEF SUMMARY OF THE INVENTION An aspect of the invention provides a DNA aptamer comprising a nucleotide sequence that has at least 95% sequence identity to at least one of SEQ ID NOs: 2-101. Further aspects of the invention provide compositions and kits relating to the DNA aptamers of the invention. Leydig 772843 P2023-4023-WO 2 Still further aspects of the invention provide methods of amplifying a target DNA sequence, the method comprising (a) providing a composition of an aspect of the invention, the composition further comprising at least one oligonucleotide primer, and at least one sample comprising at least one target DNA sequence, wherein the composition is at a temperature of from about 20 ℃ to about 30 ℃, and wherein the reverse transcriptase is bound to the at least one DNA aptamer, (b) elevating the temperature of the composition to release the reverse transcriptase from the at least one DNA aptamer, (c) hybridizing the at least one oligonucleotide primer to the at least one sample comprising at least one target DNA sequence, and (d) initiating DNA polymerase activity and extending the primer with the DNA polymerase to provide additional target DNA sequences. An additional aspect of the invention provides methods for identifying at least one DNA aptamer that inhibits at least one reverse transcriptase, the method comprising (a) providing a DNA aptamer pool comprising DNA aptamers, (b) allowing the DNA aptamers to be in proximity to the at least one reverse transcriptase in the presence of a RNA aptamer, (c) separating DNA aptamers with high affinity for the at least one reverse transcriptase from the DNA aptamers with low affinity for the at least one reverse transcriptase, and (d) amplifying the DNA aptamers with high affinity for the at least one reverse transcriptase to obtain an enriched DNA aptamer pool, wherein the at least one DNA aptamer that inhibits at least one reverse transcriptase may be identified from the enriched DNA aptamer pool. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS Figures 1A and 1B are a set of graphs showing the results following sequencing of enriched DNA aptamer pools created using a modified Systematic evolution of ligands by exponential enrichment (SELEX) protocol with (Figure 1B) and without (Figure 1A) an RNA aptamer added. DETAILED DESCRIPTION OF THE INVENTION An aspect of the invention provides a DNA aptamer comprising a nucleotide sequence that has at least about 95% sequence identity (i.e., 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 at least one of SEQ ID NOs: 2-101. A further aspect provides a DNA aptamer comprising a nucleotide sequence that has at least about 95% sequence identity (i.e., at least Leydig 772843 P2023-4023-WO 3 about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity) to at least one SEQ ID NO of a DNA aptamer of Table 1. Table 1 Name SEQ ID Sequence NO: C G C A C C A C T Leydig 772843 P2023-4023-WO 4

[0003] M21_10 SEQ ID GTTCAGTCCCTACGGCGCTAACATGTAGATGCGTAAT NO: 11 AAATTCACCATGAAGTTCTTAATTAGCCACCGTGCTAC G C C C G C C C G A C Leydig 772843 P2023-4023-WO 5

[0004] M21_22 SEQ ID GTTCAGTCCCTACGGCGCTAACTCAGTGGAATCGAGC NO: 23 CGCATCGAGACAGGGATCAGCTCAGGCCACCGTGCTA G G G C G C C A A C C Leydig 772843 P2023-4023-WO 6

[0005] M21_34 SEQ ID GTTCAGTCCCTACGGCGCTAACCACTTGGCAAATATTC NO: 35 GGAGCATGTCGGTCTTACTTGTATGCCACCGTGCTACA C T A G C A C T A A C Leydig 772843 P2023-4023-WO 7

[0006] M21_46 SEQ ID GTTCAGTCCCTACGGCGCTAACCAAACACTACCTGCCC NO: 47 TGCGGCCGGATTTAAGCTTTCCTAGCCACCGTGCTACA G C G C C T C C C C A C A T A Leydig 772843 P2023-4023-WO 8

[0007] M21+RN SEQ ID GTTCAGTCCCTACGGCGCTAACGGCTATGCCGCCTTTT A 8 NO: 59 GGTATCGTATGTTGAGCGACCTAGGCCACCGTGCTAC T A A A C A C G T C C A Leydig 772843 P2023-4023-WO 9

[0008] M21+RN SEQ ID GTTCAGTCCCTACGGCGCTAACTAAGCGTTTTCCAATT A 20 NO: 71 TTCGCTAAAATTCGCAGGCATAAGGCCACCGTGCTAC G C A C G C G G G A C A Leydig 772843 P2023-4023-WO 10

[0009] M21+RN SEQ ID GTTCAGTCCCTACGGCGCTAACACTCCCTGCCCGACGG A 32 NO: 83 CCGGATTTAAGTCGTCTATGGTGAGCCACCGTGCTACA T A T A C A C C C T A C C C A C Leydig 772843 P2023-4023-WO 11

[0010] M21+RN SEQ ID GTTCAGTCCCTACGGCGCTAACCCGCTATCAAATATTT A 44 NO: 95 GCCTTTGGGGATGGCTTAATATTTGCCACCGTGCTACA A C C A A A G C Q 3 Leydig 772843 P2023-4023-WO 12

[0011] SC2 SEQ ID CTGCAGATTTGGATGATTTCTCC Forward NO: 110 3 p / r r G r G r r G r r U T A T A Leydig 772843 P2023-4023-WO 13

[0012] M21+RN SEQ ID GTTCAGTCCCTACGGCGCTAACCGATTGCCTTTGAGGT A 9 C3 NO: 122 ATGGCTTATCGTTTTTGACTCGCCGCCACCGTGCTACA T A T A T A G G G G G G Leydig 772843 P2023-4023-WO 14

[0013] M21 DNA SEQ ID ATGACTTTAAATATTGAGGATGAGCATCGTTTACATGA Sequence NO: 132 GACATCAAAAGAACCCGACGTGAGCTTAGGGTCAACG A T T A G A C T C T G G G A A T G T A C T T G G Leydig 772843 P2023-4023-WO 15

[0014] GCGCTTCTGCTTGATACGGATCGTGTACAATTTGGACC AGTTGTAGCTTTGAATCCAGCTACTTTGCTTCCCCTTC T C G G T A A G C D T L P R G L L S G S Leydig 772843 P2023-4023-WO 16

[0015] M21+RN SEQ ID GTTCAGTCCCTACGGCGCTAACGGTGACCTTTTCCTAA A 11 3Ph NO: 134 AAGGAGTTTGGCTTTGCGATTTTGGCCACCGTGCTACA C A N,N-diethyl-4-(4-nitronaphthalen-1-ylazo)-phenylamine; 3IABkFQ refers to Iowa BlackTMFQ quencher, which has a broad absorbance spectra ranging from 420 to 620 nm with peak absorbance at 531 nm; YakYel refers to Yakima YellowTMdye (trademark of ELITechGroup); TexRd-XN refers to 5’ Texas RedTM-X (NHS Ester) (trademark of Molecular Probes / Life Technologies); TAO refers to a quencher; 3IAbRQSp refers to a quencher; CY5 refers to a red dye; 3Phos refers to 3’ phosphorylation; 3SpC3 refers to 3’ C3 Spacer; 3ddC refers to a 3’ Dideoxy-C; 3InvdT refers to 3’ inverted dT; and 3AmMO refers to a 3’ amino modifier. In Table 1, rC refers to RNA cytosine base, rU refers to RNA uracil base, rA refers to RNA adenine base, and rG refers to RNA guanine base. The DNA aptamer can be any suitable length, i.e., can comprise any number of amino acids, provided that the DNA aptamers retain their biological activity, e.g., their ability to specifically bind a reverse transcriptase. In an aspect of the invention, the DNA aptamer comprises of from about 50 to about 90 nucleotides (i.e., from about 55 to about 89 nucleotides, from about 60 to about 88 nucleotides, from about 65 to about 87 nucleotides, from about 70 to about 86 nucleotides, from about 72 to about 85 nucleotides, from about 74 to about 85 nucleotides, from about 76 to about 85 nucleotides, from about 78 to about 84 nucleotides, from about 79 to about 84 nucleotides, from about 81 to about 83 nucleotides, or about 82 nucleotides). In this regard, the DNA aptamer comprises about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 81, about 82, about 83, about 84, about 85, or about 90 nucleotides. The DNA aptamer can comprise adapter sequences. In this regard, the adapter sequence can be any suitable length. For example, the adapter sequence can be from about 5 to about 30 nucleotides, from about 10 to about 25 nucleotides, from about 15 to about 25 Leydig 772843 P2023-4023-WO 17 nucleotides, from about 20 to about 22 nucleotides, or about 21 nucleotides. The DNA aptamer can comprise about two adapter sequences. In an aspect of the invention, the DNA aptamer comprises a nucleotide sequence that has at least about 95% (i.e., 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 at least one of SEQ ID NOs: 29 (M21_28), 45 (M21_44), 60 (M21+RNA_9), 72 (M21+RNA_21), 76 (M21+RNA_25), 78 (M21+RNA_27), 79 (M21+RNA_28), 81 (M21+RNA_30), 82 (M21+RNA_31), 83 (M21+RNA_32), 90 (M21+RNA_39), 91 (M21+RNA_40), 93 (M21+RNA_42), 94 (M21+RNA_43), 95 (M21+RNA_44), 121 (M21+RNA_9_3Phos), 134 (M21+RNA_11_3Phos), and 135 (M21+RNA_47_3Phos). In an aspect of the invention, the DNA aptamer comprises a nucleotide sequence that has at least about 95% (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 at least one of SEQ ID NOs: 121 (M21+RNA_9_3Phos), 134 (M21+RNA_11_3Phos), and 135 (M21+RNA_47_3Phos). The DNA aptamer of an aspect of the invention, wherein the DNA aptamer comprises at least one (e.g., 1 or 2) 1-20 bp (1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1- 11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1 bp) truncation. The DNA aptamer may be truncated for any suitable reason, including reduction of the size of the DNA aptamer to the change affinity (e.g., increase affinity) for a reverse transcriptase. In an aspect, the DNA aptamer comprises one about 20 bp truncation. The DNA aptamer may be modified to increase the stability of the DNA aptamer. The DNA aptamers can be, e.g., glycosylated, amidated, carboxylated, phosphorylated, esterified, N-acylated, cyclized via, e.g., a disulfide bridge, or converted into an acid addition salt and / or optionally dimerized or polymerized, or conjugated. For example, the 3’ or 5’ end can be phosphorylated, or a C3 spacer, dideoxy-C, or invented dT may be added, or an amino modifier could be used. The modification could also prevent or reduce non-specific binding and amplification. In an aspect of the invention, the DNA aptamer comprises a nucleotide sequence that has at least 95% (i.e., 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 at least one of SEQ ID NO: NOs: 121-125. In an aspect of the invention, the DNA aptamer comprises 3’-phosphorylation. In an aspect of the invention, the DNA aptamer has binding affinity (Kd) for a reverse transcriptase. The binding affinity can be calculated using any suitable means. In Leydig 772843 P2023-4023-WO 18 some aspects of the invention, the DNA aptamer has high specificity for the reverse transcriptases and / or has high binding affinity for a reverse transcriptase and does not specifically bind proteins that are not reverse transcriptases (e.g., the DNA aptamer binds the reverse transcriptases with at least 10, 100, 1,000, 10,000, or 100,000-fold higher affinity than non-reverse transcriptases). In a further aspect of the invention, the DNA aptamer specifically binds a reverse transcriptase and has high binding affinity for a reverse transcriptase. In an aspect of the invention, the DNA aptamer binds the reverse transcriptase at from about 20 ℃ to about 30 ℃ (e.g., from about 21 ℃ to about 29 ℃, from about 22 ℃ to about 28 ℃, from about 23 ℃ to about 27 ℃, from about 24 ℃ to about 26 ℃, or about 25 ℃), such that the reverse transcriptase is inhibited. In a further aspect of the invention, the DNA aptamer fails to inhibit a reverse transcriptase at from about 45 ℃ to about 55 ℃ (e.g., from about 46 ℃ to about 54 ℃, from about 47 ℃ to about 53 ℃, from about 48 ℃ to about 52 ℃, from about 49 ℃ to about 51 ℃, or about 50 ℃). An aspect of the present invention provides a user the ability to tightly control reverse transcriptase, by controlling the DNA aptamer’s ability to bind, and therefore, inhibit the function of reverse transcriptase. The DNA aptamer can not only be turned “on” and “off,” by a user by adjusting the temperature, but also the DNA aptamer is stable enough to be sequentially switched between on and off. In this regard, the DNA aptamers of the present invention have the feature of having reversible binding and inhibition. These features of the DNA aptamers of the present invention open new possibilities for new laboratory assays with increased functionality. For example, compositions comprising the DNA aptamers of the present invention can be used in a “master mix” for large scale PCR assays and used with automation because the master mixes inhibit the reverse transcriptase acivity at room temperature for a long period of time (e.g., at least 4 hours). The DNA aptamers of an aspect of the invention are useful for any application where unwanted reverse transcriptase function is problematic. Reverse transcriptase has diverse functions including RNA-dependent DNA polymerase activity, terminal transferase activity, and ability to facilitate template switching in cDNA synthesis. Reverse transcriptases are known to interfere with probe-based qPCR when template is added and that is thought occur through qPCR reagent consumption and the uncharacterized production of PCR-interfering nucleic acid products. Accordingly, the DNA aptamers of an aspect of the Leydig 772843 P2023-4023-WO 19 invention solve this problem by binding and inhibiting reverse transcriptases, and therefore preventing reverse transcriptase function until it is needed. It was also found that the DNA aptamers of the present invention reversibly inhibit reverse transcriptase at relatively low DNA aptamer to reverse transcriptase ratios and concentrations. This also provides an efficient and cost effective product. Any suitable reverse transcriptase may be used. In an aspect of the invention, the reverse transcriptase is derived from Moloney murine leukemia virus (MMLV), avian myeloblastosis virus (AMV), or human immunodeficiency virus type 1 (HIV-1). In an aspect of the invention, the reverse transcriptase is derived MMLV. In a further aspect of the invention, the reverse transcriptase comprises a nucleotide sequence that has at least 95% (i.e., 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 SEQ ID NO: 132 (M21). The M21 protein described herein may include functional variants thereof. The functional variant can, for example, comprise the sequence of the parent protein with at least one conservative amino acid substitution. Conservative amino acid substitutions are known in the art, and include amino acid substitutions in which one amino acid having certain physical and / or chemical properties is exchanged for another amino acid that has the same chemical or physical properties. For instance, the conservative amino acid substitution can be an acidic amino acid substituted for another acidic amino acid (e.g., Asp or Glu), an amino acid with a nonpolar side chain substituted for another amino acid with a nonpolar side chain (e.g., Ala, Gly, Val, Ile, Leu, Met, Phe, Pro, Trp, Val, etc.), a basic amino acid substituted for another basic amino acid (Lys, Arg, etc.), an amino acid with a polar side chain substituted for another amino acid with a polar side chain (Asn, Cys, Gln, Ser, Thr, Tyr, etc.), etc. Alternatively or additionally, the functional variants can comprise the amino acid sequence of the parent protein with at least one non-conservative amino acid substitution. In this case, it is preferable for the non-conservative amino acid substitution to not interfere with or inhibit the biological activity of the functional variant. Preferably, the non-conservative amino acid substitution enhances the biological activity of the functional variant, such that the biological activity of the functional variant is increased as compared to the parent protein. The aptamers and reverse transcriptases described herein can comprise, consist essentially of, or consist of the specified nucleic acid sequence or sequences described herein, such that other components of the sequences, e.g., other nucleic acids, do not materially change the biological activity of aptamers and reverse transcriptases. Leydig 772843 P2023-4023-WO 20 The aptamers can be produced via any suitable means. For example, the aptamers can be synthetic or recombinant. The aptamers can be isolated and / or purified. The DNA aptamer compositions may be purified using any suitable means. For example, by polyacrylamide gel electrophoresis (PAGE)-purification. The term “isolated” as used herein means having been removed from its natural environment. The term “purified” as used herein means having been increased in purity, wherein “purity” is a relative term, and not to be necessarily construed as absolute purity. For example, the purity can be at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or can be about 100%. Also provided herein are compositions comprising at least one DNA aptamer of an aspect of the invention. The compositions of the present invention may also include at least one reverse transcriptase. In an aspect of the invention, the reverse transcriptase is M21. The compositions may comprise any suitable excipient. In an aspect of the invention, the compositions further comprise deoxynucleotide triphosphates (dNTPs), a buffer, or a combination thereof. The excipient can be any of those conventionally used for the particular inventive DNA aptamers under consideration. In an aspect of the invention, the DNA aptamer is present in the composition at a reverse transcriptase:aptamer ratio of from about 1:2 to about 1:8 (i.e., from about 1:2 to about 1:8, from about 1:3 to about 1:8, from about 1:4 to about 1:8, from about 1:5 to about 1:8, from about 1:5 to about 1:7, from about 1:5.5 to about 1:6.5, or about 1:6). The compositions can comprise any several DNA aptamers. For example, the composition can comprise three DNA aptamers: a first DNA aptamer (aptamer1), a second DNA aptamer (aptamer2), optionally a third DNA aptamer (aptamer3), and optionally a fourth aptamer (aptamer4) etc. In an aspect of the invention, the composition comprises a reverse transcriptase:aptamer1:aptamer2 ratio of from about 1:2:2 to about 1:8:8 (i.e., from about 1:2:2 to about 1:8:8, from about 1:3:3 to about 1:8:8, from about 1:4:4 to about 1:8:8, from about 1:5:5 to about 1:8:8, from about 1:5:5 to about 1:7:7, from about 1:5.5:5.5 to about 1:6.5:6.5, or about 1:6:6). In an aspect of the invention, the first DNA aptamer comprises a nucleotide sequence that has at least 95% (i.e., 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 SEQ ID Leydig 772843 P2023-4023-WO 21

[0016] NO: 121 (M21+RNA_9_3Phos), the second DNA aptamer comprises a nucleotide sequence that has at least 95% (i.e., 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 SEQ ID NO: 134 (M21+RNA_11_3Phos), and the third DNA aptamer comprises a nucleotide sequence that has at least 95% (i.e., 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 SEQ ID NO: 135 (M21+RNA_47_3Phos). In a further aspect of the invention, the first DNA aptamer comprises a nucleotide sequence that has at least 95% (i.e., 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 SEQ ID NO: 121 (M21+RNA_9_3Phos), the second DNA aptamer comprises a nucleotide sequence that has at least 95% (i.e., 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 SEQ ID NO: 134 (M21+RNA_11_3Phos), and the third DNA aptamer comprises a nucleotide sequence that has at least 95% (i.e., 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 SEQ ID NO: 135 (M21+RNA_47_3Phos), and wherein the composition comprises a reverse transcriptase:aptamer1:aptamer2:aptamer3 ratio of from about 1:2:2:2 to about 1:8:8:8. In an aspect of the invention, the composition comprises a reverse transcriptase:aptamer1:aptamer2:aptamer3 ratio of about 1:6:6:6. In an aspect of the invention, the composition comprises a RNA aptamer. Any suitable RNA aptamer may be used. In an aspect of the invention, the RNA aptamer comprises a sequence that has at least 95% (i.e., 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 SEQ ID NO: 1. An aspect of the invention provides a kit comprising a DNA aptamer of the present invention or a composition of the present invention. The kit can contain instructions, a container for holding the DNA aptamer or composition, and any other components necessary or useful for performing the kit. A further aspect of the invention is using the DNA aptamers in PCRs. In this regard, an aspect of the invention provides a method for amplifying a target DNA sequence, the method comprising: (a) providing a composition of an aspect of the invention, the composition further comprising at least one oligonucleotide primer, and at least one sample Leydig 772843 P2023-4023-WO 22 comprising at least one target DNA sequence, wherein the composition is at a temperature of from about 20 ℃ to about 30 ℃ (e.g., from about 21 ℃ to about 29 ℃, from about 22 ℃ to about 28 ℃, from about 23 ℃ to about 27 ℃, from about 24 ℃ to about 26 ℃, or about 25 ℃), and wherein the reverse transcriptase is bound to the at least one DNA aptamer, (b) elevating the temperature of the composition to release the reverse transcriptase from the at least one DNA aptamer, (c) hybridizing the at least one oligonucleotide primer to the at least one sample comprising at least one target DNA sequence; and (d) initiating DNA polymerase activity and extending the primer with the DNA polymerase to provide additional target DNA sequences. In an aspect of the invention, the composition is at a temperature of from about 20 ℃ to about 30 ℃ for at least about 4 hours (i.e., about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, or more) in step (a). In a further aspect, the composition is elevated to a temperature of from about 45 ℃ to about 55 ℃ (e.g., from about 46 ℃ to about 54 ℃, from about 47 ℃ to about 53 ℃, from about 48 ℃ to about 52 ℃, from about 49 ℃ to about 51 ℃, or about 50 ℃) in step (b). In this regard, a further aspect of the invention provides a method for identifying at least one DNA aptamer that inhibits at least one reverse transcriptase, the method comprising: (a) providing a DNA aptamer pool comprising DNA aptamers, (b) allowing the DNA aptamers to be in proximity to the at least one reverse transcriptase in the presence of a RNA aptamer, (c) separating DNA aptamers with high affinity for the at least one reverse transcriptase from the DNA aptamers with low affinity for the at least one reverse transcriptase, and (d) amplifying the DNA aptamers with high affinity for the at least one reverse transcriptase to obtain an enriched DNA aptamer pool, wherein the at least one DNA aptamer that inhibits at least one reverse transcriptase may be identified from the enriched DNA aptamer pool. Unexpectedly, it was found that the presence of a RNA aptamer was required for identification of the DNA aptamers. One skilled in the art would be able to determine what “proximity” refers to. Similarly, one skilled in the art would be able to determine cut offs for “high affinity” and “low affinity.” In a further aspect of the invention, the RNA aptamer comprises a sequence that has at least 95% (i.e., 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 SEQ ID NO: 1. In another aspect of the invention, the reverse transcriptase comprises a nucleotide sequence that has at least 95% (i.e., at least about 95%, at least about 96%, at least about Leydig 772843 P2023-4023-WO 23

[0017] 97%, at least about 98%, at least about 99%, or about 100%) sequence identity to SEQ ID NO: 132. The method disclosed herein may include the use of probes which include dyes / fluophores and quenchers for quantifying binding. Some of the oligonucleotides disclosed herein include a fluorophore, which may include, but is not limited to, 6- carboxyfluorescein (FAM), 2'7'-dimethoxy-4'5'-dichloro-6-carboxyfluorescein (JOE), tetrachlorofluorescein (TET), 6-carboxyrhodamine (R6G), N,N,N;N'-tetramethyl-6- carboxyrhodamine (TAMRA), 6-carboxy-X-rhodamine (ROX); 1-dimethylaminonaphthyl-5- sulfonate, 1-anilino-8-naphthalene sulfonate, 2-p-toluidinyl-6-naphthalene sulfonate, 5-(2'- aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS), a coumarin dye, an acridine dye, indodicarbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5), indodicarbocyanine 5.5 (Cy5.5), 3- 1-carboxy-pentyl)-3'-ethyl-5,5'-dimethyloxacarbocyanine (CyA); 1H,5H,11H,15H- Xantheno[2,3,4-ij:5,6,7-i'j']diquinolizin-18-ium, 9-[2(or 4)-[[[6-[2,5-dioxo-1- pyrrolidinyl)oxy]-6-oxohexyl]amino]sulfonyl]-4(or 2)-sulfophenyl]-2,3,6,7,12,13,16,17- octahydro-inner salt (TR or TexasRedTM), a BODIPY™ dye, Yakima YellowTMdye, benzoxaazole, stilbene and pyrene. Some of the oligonucleotides disclosed herein include a quencher. Suitable quenchers may include dabcyl, EclipseTMquencher, BHQ1, BHQ2 and BHQ3, Iowa BlackTMFQ, Iowa BlackTMRQ-n1, or Iowa BlackTMRQ-n2 (Integrated DNA Technologies, Inc.). Examples of Non-Limiting Aspects of the Disclosure Aspects, including embodiments, of the invention described herein may be beneficial alone or in combination, with one or more other aspects or embodiments. Without limiting the foregoing description, certain non-limiting aspects of the disclosure numbered (1)-(30)are provided below. As will be apparent to those of skill in the art upon reading this disclosure, each of the individually numbered aspects may be used or combined with any of the preceding or following individually numbered aspects. This is intended to provide support for all such combinations of aspects and is not limited to combinations of aspects explicitly provided below: (1) A DNA aptamer comprising a nucleotide sequence that has at least 95% sequence identity to at least one of SEQ ID NOs: 2-101. (2) The DNA aptamer of aspect 1, wherein the DNA aptamer consists of from about 50 to about 90 nucleotides. Leydig 772843 P2023-4023-WO 24 (3) The DNA aptamer of aspect 1 or 2, comprising a nucleotide sequence that has at least 95% sequence identity to at least one of SEQ ID NOs: 29 (M21_28), 45 (M21_44), 60 (M21+RNA_9), 72 (M21+RNA_21), 76 (M21+RNA_25), 78 (M21+RNA_27), 79 (M21+RNA_28), 81 (M21+RNA_30), 82 (M21+RNA_31), 83 (M21+RNA_32), 90 (M21+RNA_39), 91 (M21+RNA_40), 93 (M21+RNA_42), 94 (M21+RNA_43), 95 (M21+RNA_44), 121 (M21+RNA_9_3Phos), 134 (M21+RNA_11_3Phos), and 135 (M21+RNA_47_3Phos). (4) The DNA aptamer of any one of aspects 1-3, comprising a nucleotide sequence that has at least 95% sequence identity to at least one of SEQ ID NOs: 121 (M21+RNA_9_3Phos), 134 (M21+RNA_11_3Phos), and 135 (M21+RNA_47_3Phos). (5) The DNA aptamer of any one of aspects 1-4, wherein the DNA aptamer comprises at least one 1-20 bp truncation. (6) The DNA aptamer of aspect 1 or 2, wherein the DNA aptamer comprises 3’- phosphorylation. (7) The DNA aptamer of any one of aspects 1-5, wherein the DNA aptamer has binding affinity for a reverse transcriptase. (8) The DNA aptamer of any one of aspects 1-7, wherein the DNA aptamer inhibits a reverse transcriptase at from about 20 ℃ to about 30 ℃. (9) The DNA aptamer of any one of aspects 1-8, wherein the DNA aptamer fails to inhibit a reverse transcriptase at from about 45 ℃ to about 55 ℃. (10) The DNA aptamer of any one of aspects 7-9, wherein the reverse transcriptase is derived from Moloney murine leukemia virus (MMLV), avian myeloblastosis virus (AMV), or human immunodeficiency virus type 1 (HIV-1). (11) The DNA aptamer of any one of aspects 7-10, wherein the reverse transcriptase comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 132. (12) A composition comprising at least one DNA aptamer of any one of aspects 1-11. (13) The composition of aspect 12, wherein the at least one DNA aptamer is polyacrylamide gel electrophoresis (PAGE)-purified. (14) The composition of aspect 12 or 13, wherein the composition further comprises a reverse transcriptase. Leydig 772843 P2023-4023-WO 25 (15) The composition of any one of aspects 12-14, wherein the composition further comprises deoxynucleotide triphosphates (dNTPs), a buffer, or a combination thereof. (16) The composition of any one of aspects 12-15, wherein the DNA aptamer is present in the composition at a reverse transcriptase:aptamer ratio of from about 1:2 to about 1:8. (17) The composition of any one of aspects 12-15, wherein the composition comprises a first DNA aptamer (aptamer1), a second DNA aptamer (aptamer2), and optionally a third DNA aptamer (aptamer3). (18) The composition of aspect 17, wherein the composition comprises a reverse transcriptase:aptamer1:aptamer2 ratio of from about 1:2:2 to about 1:8:8. (19) The composition of aspect 17, wherein the first DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 121 (M21+RNA_9_3Phos), the second DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 134 (M21+RNA_11_3Phos), and the third DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 135 (M21+RNA_47_3Phos). (20) The composition of aspect 17, wherein the first DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 121 (M21+RNA_9_3Phos), the second DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 134 (M21+RNA_11_3Phos), and the third DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 135 (M21+RNA_47_3Phos), and wherein the composition comprises a reverse transcriptase:aptamer1:aptamer2:aptamer3 ratio of from about 1:2:2:2 to about 1:8:8:8. (21) The composition of aspect 17, wherein first DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 121 (M21+RNA_9_3Phos), the second DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 134 (M21+RNA_11_3Phos), and the third DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 135 (M21+RNA_47_3Phos), and wherein the composition comprises a reverse transcriptase:aptamer1:aptamer2:aptamer3 ratio of about 1:6:6:6. (22) The composition of any one of aspects 12-20, further comprising a RNA aptamer, optionally wherein the RNA aptamer comprises a sequence that has at least 95% sequence identity to SEQ ID NO: 1. Leydig 772843 P2023-4023-WO 26 (23) A kit comprising the DNA aptamers of any one of aspects 1-11, or the composition of any one of aspects 12-22. (24) A method for amplifying a target DNA sequence, the method comprising: a. providing a composition of any one of aspects 12-22, the composition further comprising at least one oligonucleotide primer, and at least one sample comprising at least one target DNA sequence, wherein the composition is at a temperature of from about 20 ℃ to about 30 ℃, and wherein the reverse transcriptase is bound to the at least one DNA aptamer; b. elevating the temperature of the composition to release the reverse transcriptase from the at least one DNA aptamer; c. hybridizing the at least one oligonucleotide primer to the at least one sample comprising at least one target DNA sequence; and d. initiating DNA polymerase activity and extending the primer with the DNA polymerase to provide additional target DNA sequences. (25) The method of aspect 24, wherein the composition is at a temperature of from about 20 ℃ to about 30 ℃ for at least 4 hours in step (a). (26) The method of aspect 24, wherein the composition is at a temperature of from about 20 ℃ to about 30 ℃ for at least 12 hours in step (a). (27) The method of aspect 24, wherein the composition is elevated to a temperature of from about 45 ℃ to about 55 ℃ in step (b). (28) A method for identifying at least one DNA aptamer that inhibits at least one reverse transcriptase, the method comprising: a. providing a DNA aptamer pool comprising DNA aptamers; b. allowing the DNA aptamers to be in proximity to the at least one reverse transcriptase in the presence of a RNA aptamer; c. separating DNA aptamers with high affinity for the at least one reverse transcriptase from the DNA aptamers with low affinity for the at least one reverse transcriptase; and d. amplifying the DNA aptamers with high affinity for the at least one reverse transcriptase to obtain an enriched DNA aptamer pool, wherein the at least one DNA aptamer that inhibits at least one reverse transcriptase may be identified from the enriched DNA aptamer pool. Leydig 772843 P2023-4023-WO 27 (29) The method of aspect 28, wherein the RNA aptamer comprises a sequence that has at least 95% sequence identity to SEQ ID NO: 1. (30) The method of aspect 28 or 29, wherein the reverse transcriptase comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 132. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. EXAMPLE 1 This example demonstrates the isolation of DNA aptamers of an aspect of the invention that bind to MMLV reverse transcriptase mutants. A 40 bp randomized DNA oligo pool flanked by two 21 bp adapter sequences (total aptamer length of 82 bp) was used to perform 10 rounds of SELEX with M21 RTase both in the presence or absence of a previously described reverse transcriptase RNA aptamer (Chen, et al., Biochemistry, 33(29): 8746-56 (1994)). The enriched aptamer pools were sequenced by NGS for every round after enrichment (Figures 1A and 1B and Tables 2A and 2B). These results demonstrated that DNA aptamer enrichment occurred much earlier in experiments containing RNA aptamer. This finding was unexpected. Without being bound to any particular theory, the DNA aptamer enrichment may have occurred earlier due to a conformational change in the reverse transcriptase enzyme resulting in opening of the DNA exit channel when an RNA template is present. Enriched aptamer sequences obtained from SELEX experiments in the presence and absence of RNA aptamer were rank ordered by percent enrichment (Table 1). The top 50 enriched aptamers for both conditions were chemically synthesized by IDT as 100 nmol DNA oligonucleotides to be used in follow up studies. Typically, “one-step” RT-qPCR reactions allow end-users to convert RNA templates to cDNA and perform quantitative PCR using a single master-mix and cycling program. In these reactions, the presence of reverse transcriptase can decrease qPCR signal in later cycles dramatically if reactions are not run immediately after loading. Evaluation of reverse transcriptase inhibition by DNA aptamers will therefore be evaluated using one-step qPCR reactions where template is added and plates are held at room temperature for several hours before running. Leydig 772843 P2023-4023-WO 28 Table 2A

[0018] Leydig 772843 P2023-4023-WO 29

[0019] Table 2B EXAMPLE 2 This example demonstrates reverse transcriptase inhibition by DNA aptamers of an aspect of the invention using one step RT-qPCR. DNA aptamers were tested in the context of one step RT-qPCR where a synthetic RNA genome respiratory virus panel (Influenza A, Influenza B, SARS-CoV-2, and Human RNase P) was amplified and signal (Ct and fluorescence intensity) was measured running plates on the instrument immediately after template addition (time point = 0) or holding plates two hours at 25 ℃ before running the instrument (time point = 2 hrs). All 100 DNA aptamers were tested with and without RNA aptamer in the context of one step RT-qPCR. For the binding of RNA aptamer to M21 RTase, equal volumes of RNA aptamer (2.4 µM, Table 1) and M21 RTase (0.724 µM, Table 1) were mixed and incubated at room temperature for 15 minutes. Following incubation, a third volume of DNA Aptamer (1.45 µM, Table 1) was added to the RNA aptamer bound RTase and incubated at room temperature for a further 15 minutes. After incubation, the RNA and DNA aptamer Leydig 772843 P2023-4023-WO 30 bound RTase was placed on ice. For the binding of DNA aptamer to M21 RTase, equal volumes of DNA aptamer (1.45 µM, Table 1) and M21 RTase (0.724 µM, Table 1) were mixed and incubated at room temperature for 15 minutes. After incubation, the DNA aptamer bound RTase was placed on ice. For the standard one-step procedure, the RNA and DNA aptamer bound RTases (6.03 nM final) were added to a reaction mixture containing the following: Integrated DNA Technologies PrimeTimeTM1-Step 4X Broad-Range Master Mix formulated without Reverse Transcriptase (1X) and FluVID primers and probe sets (Table 1). The assay master mix and synthetic RNA ultramers (50 copies per well, Table 1) were mixed at a 4:1 ratio for a final volume of 20 µL. The reaction proceeded either immediately or two hours after the addition of template at room temperature on a qPCR (QuantStudioTM7 Flex) using the following method: 50 ⁰C hold for 15 minutes, 95 ⁰C hold for 30 seconds, followed by 95 ⁰C for 5 seconds and 55 ⁰C for 45 seconds for 45 cycles. The reactions were analyzed and reported by threshold cycle (Ct, with threshold determined by the 0-hour incubation timepoint) and endpoint fluorescence (delta Rn) values (Tables 3 and 4). Of the 100 aptamers tested, 15 aptamers showed a significant increase in on-deck reaction mix stability over the RNA aptamer alone as assessed by endpoint fluorescence and cycle threshold. These 15 aptamers include: M21_28, M21_44, M21+RNA_9, M21+RNA_21, M21+RNA_25, M21+RNA_27, M21+RNA_28, M21+RNA_30, M21+RNA_31, M21+RNA_32, M21+RNA_39, M21+RNA_40, M21+RNA_42, M21+RNA_43, and M21+RNA_44. It is interesting to note that the best aptamers were the same whether RNA aptamer was added or not, and yet the best aptamers were obtained from SELEX experiments where the RNA aptamer was included. Without being bound to any particular theory, these results suggest that RNA was important to isolate the best DNA aptamers, but that the RNA aptamer provides little to no additive benefit over these new DNA aptamers, which was unexpected. EXAMPLE 3 This example demonstrates that the DNA aptamers of an aspect of the invention inhibit reverse transcriptase at different concentrations. This example provides a procedure used to evaluate a dose range of some of the DNA aptamers from Example 2 and the resulting effect on reverse transcriptase inhibition using one step RT-PCR. To further “challenge” the candidate DNA aptamers, qPCR reactions were held for 0 or 4 hours at 25 ℃ after template addition before running the Leydig 772843 P2023-4023-WO 31 instrument. The DNA aptamers were tested by first binding the DNA aptamer at various ratios (1:2, 1:3, 1:5, and 1:10 RTase:Aptamer) to M21 RTase, adding the aptamer bound RTase to a reaction mixture containing a qPCR master mix with multiplexing primers and probes and testing the on-deck rection mix stability of the generated one-step RT-qPCR master mix after template addition. For the binding of DNA aptamer to M21 RTase, equal volumes of DNA aptamer at varying concentrations (1.45 µM, 2.17 µM, 3.62 µM, and 7.24 µM, Table 1) and M21 RTase (0.724 µM, Table 1) were mixed and incubated at room temperature for 15 minutes. After incubation, the DNA aptamer bound RTase was placed on ice. For the standard one- step procedure, the DNA aptamer bound RTases (6.03 nM final) were added to a reaction mixture containing the following: Integrated DNA Technologies PrimeTimeTM1-Step 4X Broad-Range Master Mix formulated without Reverse Transcriptase (1X) and FluVID primers and probe sets (Table 1). The assay master mix and synthetic RNA ultramers (50 copies per well, Table 1) were mixed at a 4:1 ratio for a final volume of 20 µL. The reaction proceeded either immediately or four hours after the addition of template at room temperature on a qPCR (QuantStudioTM7 Flex) using the following method: 50 ⁰C hold for 15 minutes, 95 ⁰C hold for 30 seconds, followed by 95 ⁰C for 5 seconds and 55 ⁰C for 45 seconds for 45 cycles. The reactions were analyzed and reported by threshold cycle (Ct, with threshold determined by the 0-hour incubation timepoint) and endpoint fluorescence (delta Rn) values (Table 5). While all the conditions with DNA aptamers yielded improved on-deck reaction mix stability over the RNA only control, there wasn’t substantial improvement as the concentration of aptamer increased, suggesting that the 1:2 ratio of M21: Aptamer is sufficient to achieve maximum effect. EXAMPLE 4 This example demonstrates reverse transcriptase inhibition by combinations of DNA aptamers of an aspect of the invention. This example provides a procedure used to evaluate combining the DNA aptamers of an aspect of the invention and looking for an additive effect on reverse transcriptase inhibition by one step qPCR. Aptamers were challenged by holding reactions at 0 or 4 hours at 25 ℃ after template addition before running the instrument. The DNA aptamers were tested by first binding two DNA aptamers to M21 RTase, adding the aptamer bound RTase to a reaction mixture containing a qPCR master mix with multiplexing primers and probes and Leydig 772843 P2023-4023-WO 32 testing the on-deck reaction mix stability of the generated one-step RT-qPCR master mix after template addition. For the binding of DNA aptamers to M21 RTase, equal volumes of two DNA aptamers (1.45 µM, Table 1) and M21 RTase (0.724 µM, Table 1) were mixed and incubated at room temperature for 15 minutes. After incubation, the DNA aptamer bound RTase was placed on ice. For the standard one-step procedure, the DNA aptamer bound RTases (6.03 nM final) were added to a reaction mixture containing the following: Integrated DNA Technologies PrimeTimeTM1-Step 4X Broad-Range Master Mix formulated without Reverse Transcriptase (1X) and FluVID primers and probe sets (Table 1). The assay master mix and synthetic RNA ultramers (50 copies per well, Table 1) were mixed at a 4:1 ratio for a final volume of 20 µL. The reaction proceeded either immediately or four hours after the addition of template at room temperature on a qPCR (QuantStudioTM7 Flex) using the following method: 50 ⁰C hold for 15 minutes, 95 ⁰C hold for 30 seconds, followed by 95 ⁰C for 5 seconds and 55 ⁰C for 45 seconds for 45 cycles. The reactions were analyzed and reported by threshold cycle (Ct, with threshold determined by the 0-hour incubation timepoint) and endpoint fluorescence (delta Rn) values (Table 5). Of all the combinations tested, 5 were selected as the best based on high endpoint fluorescence, low Ct, and low variance. These combinations were: M21_44 + M21+RNA_31, M21+RNA_9 + M21+RNA_27, M21+RNA_9 + M21+RNA_30, M21+RNA_31 + M21+RNA_44, and M21+RNA_43 + M21+RNA_44. EXAMPLE 5 This example further demonstrates the effectiveness of combinations of DNA aptamers of the present invention. In this study, the DNA aptamers were combined at different ratios in the presence or absence of RNA aptamer. These DNA aptamers were challenged by incubation of the qPCR reactions for 0, 4, and 12 hours at 25 ℃ after template addition before running on the instrument. The DNA aptamers were tested by first binding RNA aptamer to M21 RTase where appropriate, followed by binding one or two DNA aptamers to M21 RTase, adding the aptamer bound RTase to a reaction mixture containing a qPCR master mix with multiplexing primers and probes and testing the on-deck reaction mix stability of the generated one-step RT-qPCR master mix after template addition. Leydig 772843 P2023-4023-WO 33 For the conditions that contained RNA aptamer, equal volumes of RNA aptamer (2.4 µM, Table 1) and M21 RTase (0.724 µM, Table 1) were mixed and incubated at room temperature for 15 minutes. Following incubation, a third volume of DNA Aptamer containing either one or two DNA aptamers with final concentrations of 0.724 µM, 1.45 µM, or 3.62 µM for 1:1:3.3, 1:2:3.3, or 1:5:3.3 M21:DNA Aptamer:RNA Aptamer (or 1:1:1:3.3, 1:2:2:3.3, 1:5:5:3.3 M21:DNA Aptamer 1:DNA Aptamer 2: RNA Aptamer for the combinations), respectively (Table 1), were added to the RNA aptamer bound RTase and incubated at room temperature for a further 15 minutes. For the conditions that didn’t contain RNA aptamer, equal volumes of M21 RTase (0.724 µM, Table 1) and DNA Aptamer containing either one or two DNA aptamers with final concentrations of 0.724 µM, 1.45 µM, or 3.62 µM for 1:1, 1:2, or 1:5 (or 1:1:1, 1:2:2, 1:5:5 for the combinations), respectively (Table 1), were added to a third volume of IDTE pH 7.5 and incubated at room temperature for 15 minutes. After incubation, the DNA aptamer bound RTase was placed on ice. For the standard one-step procedure, the DNA aptamer bound RTases (6.03 nM final) were added to a reaction mixture containing the following: Integrated DNA Technologies PrimeTimeTM1-Step 4X Broad-Range Master Mix formulated without Reverse Transcriptase (1X) and FluVID primers and probe sets (Table 1). The assay master mix and synthetic RNA ultramers (50 copies per well, Table 1) were mixed at a 4:1 ratio for a final volume of 20 µL. The reaction proceeded either immediately, four hours, or twelve hours after the addition of template at room temperature on a qPCR (QuantStudioTM7 Flex) using the following method: 50 ⁰C hold for 15 minutes, 95 ⁰C hold for 30 seconds, followed by 95 ⁰C for 5 seconds and 55 ⁰C for 45 seconds for 45 cycles. The reactions were analyzed and reported by threshold cycle (Ct, with threshold determined by the 0-hour incubation timepoint) and endpoint fluorescence (delta Rn) values (Table 7). Of all the conditions tested, M21+RNA_9 + M21+RNA_27 consistently performed as one of the best in terms of based on high endpoint fluorescence, low Ct, and low variance. In fact, M21+RNA_9 + M21+RNA_27 was even able to achieve successful amplification of the RNaseP and SARS-CoV-2 targets following 12 hours of incubation at room temperature, though the InfA and InfB were not able to clear the cycle threshold from no incubation condition. In nearly all cases, addition of the RNA aptamer yielded lower endpoint fluorescence than the corresponding condition absent the RNA aptamer. Leydig 772843 P2023-4023-WO 34

[0020] EXAMPLE 6 This example demonstrates that extension blocking 3’ modifications do not interfere with combined DNA aptamer inhibition of reverse transcriptase activity. In this study, 3’ DNA modifications were added to the terminal base of DNA aptamers that prevent extension by a DNA polymerase. The goal of these experiments was to find 3’ modifications that do not interfere with inhibition of reverse transcriptase by the combined DNA aptamers. These chemically modified DNA aptamers were synthesized by IDT as 100 nmol DNA oligonucleotides. These DNA aptamers were challenged by incubation of the qPCR reactions for 4 hours at 25 ℃ after template addition before running on the instrument. The DNA aptamers were tested by binding one or two DNA aptamers to M21 RTase, adding the aptamer bound RTase to a reaction mixture containing a qPCR master mix with multiplexing primers and probes and testing the on-deck reaction mix stability of the generated one-step RT-qPCR master mix after template addition. For these experiments, equal volumes of M21 RTase (0.724 µM, Table 1) and DNA Aptamer containing either one or two DNA aptamers with final concentrations of 0.724 µM, 1.45 µM, or 3.62 µM for 1:1, 1:2, or 1:5 (or 1:1:1, 1:2:2, 1:5:5 for the combinations), respectively (Table 1), were added to a third volume of IDTE pH 7.5 and incubated at room temperature for 15 minutes. After incubation, the DNA aptamer bound RTase was placed on ice. For the standard one-step procedure, the DNA aptamer bound RTases (6.03 nM final) were added to a reaction mixture containing the following: Integrated DNA Technologies PrimeTimeTM1-Step 4X Broad-Range Master Mix formulated without Reverse Transcriptase (1X) and FluVID primers and probe sets (Table 1). The assay master mix and synthetic RNA ultramers (50 copies per well, Table 1) were mixed at a 4:1 ratio for a final volume of 20 µL. The reaction proceeded four hours after the addition of template at room temperature on a qPCR (QuantStudioTM7 Flex) using the following method: 50 ⁰C hold for 15 minutes, 95 ⁰C hold for 30 seconds, followed by 95 ⁰C for 5 seconds and 55 ⁰C for 45 seconds for 45 cycles. The reactions were analyzed and reported by threshold cycle (Ct) and endpoint fluorescence (delta Rn) values (Table 8). Generally, most 3’ blocking extensions were well-tolerated and the resulting DNA aptamers and DNA aptamer combinations functioned well to inhibit reverse transcriptase activity in one-step qPCR reactions. The DNA aptamers containing 3’ phosphate modifications appeared to produce slightly more consistent data than other modifications or unmodified aptamers. Leydig 772843 P2023-4023-WO 35

[0021] EXAMPLE 7 This example demonstrates the range of binding periods between reverse transcriptases and DNA aptamers of an aspect of the invention. This example provides a procedure used to determine the optimal binding period between the MMLV RTase and DNA aptamers to maximize the benefit to on-deck reaction mix stability using one step RT-PCR. DNA aptamers were tested in the context of one step RT-qPCR where a synthetic RNA genome respiratory virus panel (Influenza A, Influenza B, SARS-CoV-2, and Human RNase P) was amplified and signal (Ct and fluorescence intensity) was measured running plates on the instrument after holding plates six hours at 25 ℃ before running the instrument (time point = 6 hrs). A single, top-performing DNA aptamer was bound to the M21 RTase for 15, 20 and 30 minutes and the effect on on-deck reaction mix stability was tested in the context of one step RT-qPCR. For the binding of DNA aptamer to M21 RTase, equal volumes of DNA aptamer (2.9 µM, Table 1) and M21 RTase (0.724 µM, Table 1) were mixed and incubated at room temperature for either 15, 20 or 30 minutes. After incubation, the DNA aptamer bound RTase was placed on ice. For the standard one-step procedure, the DNA aptamer bound RTases (6.03 nM final) were added to a reaction mixture containing the following: Integrated DNA Technologies PrimeTimeTM1-Step 4X Broad-Range Master Mix formulated without Reverse Transcriptase (1X) and FluVID primers and probe sets (Table 1). The assay master mix and synthetic RNA ultramers (50 copies per well, Table 1) were mixed at a 4:1 ratio for a final volume of 20 µL. The reaction proceeded six hours after the addition of template at room temperature on a qPCR (QuantStudioTM7 Flex) using the following method: 50 ⁰C hold for 15 minutes, 95 ⁰C hold for 30 seconds, followed by 95 ⁰C for 5 seconds and 55 ⁰C for 45 seconds for 45 cycles. The reactions were analyzed and reported by threshold cycle (Ct) and endpoint fluorescence (delta Rn) values (Table 9). The 20 and 30 minute binding period showed a marked improvement over the 15 minute binding in terms of on-deck reaction mix stability. EXAMPLE 8 This example demonstrates the reverse transcriptase inhibition by combinations of DNA aptamers of the present invention using one step RT-qPCR. Leydig 772843 P2023-4023-WO 36 Pairs of DNA aptamers have been shown to have beneficial effects on improving on-deck reaction mix stability compared to single DNA aptamers. Previous data has demonstrated M21+RNA_9_3Phos as one of the best DNA aptamers as a stand-a-lone aptamer. In response, the DNA aptamers (100 in total) were paired with M21+RNA_9_3Phos, bound to reverse transcriptase and tested in the context of one step RT- qPCR where a synthetic RNA genome respiratory virus panel (Influenza A, Influenza B, SARS-CoV-2, and Human RNase P) was amplified and signal (Ct and fluorescence intensity) was measured running plates on the instrument after holding plates six hours at 25 ℃ before running the instrument (time point = 6 hrs). For the binding of DNA aptamers to M21 RTase, equal volumes of M21+RNA_9_3Phos and an unmodified DNA aptamer (1.45 µM each Table 1) and M21 RTase (0.724 µM, Table 1) were mixed and incubated at room temperature for 1 hour. After incubation, the DNA aptamer bound RTase was placed on ice. For the standard one-step procedure, the DNA aptamer bound RTases (6.03 nM final) were added to a reaction mixture containing the following: Integrated DNA Technologies PrimeTimeTM1-Step 4X Broad- Range Master Mix formulated without Reverse Transcriptase (1X) and FluVID primers and probe sets (Table 1). The assay master mix and synthetic RNA ultramers (50 copies per well, Table 1) were mixed at a 4:1 ratio for a final volume of 20 µL. The reaction proceeded six hours after the addition of template at room temperature on a qPCR (QuantStudioTM7 Flex) using the following method: 50 ⁰C hold for 15 minutes, 95 ⁰C hold for 30 seconds, followed by 95 ⁰C for 5 seconds and 55 ⁰C for 45 seconds for 45 cycles. The reactions were analyzed and reported by threshold cycle (Ct) and endpoint fluorescence (delta Rn) values (Table 10). Of the 100 aptamers paired with M21+RNA_9_3Phos, two pairs outperformed the others: M21+RNA_9_3Phos with M21+RNA_11 and M21+RNA_9_3Phos with M21+RNA_47. M21+RNA_11 and M21+RNA_47 were ordered with the 3’ Phosphorylation modification for further study. EXAMPLE 9 This example demonstrates reverse transcriptase inhibition by DNA aptamers of an aspect of the invention at different concentrations. This example provides a procedure used to evaluate a dose range of the best paired DNA aptamers from Example 8 and the resulting effect on reverse transcriptase inhibition using one step RT-PCR. The aptamers were challenged by holding reactions 6 Leydig 772843 P2023-4023-WO 37 hours at 25 ℃ after template addition before running the instrument. The DNA aptamers were tested by first binding two DNA aptamers at various ratios (1:2:2, 1:3:3, 1:4:4, 1:6:6 and 1:8:8 RTase:Aptamer 1:Aptamer 2) to M21 RTase, adding the aptamer bound RTase to a reaction mixture containing a qPCR master mix with multiplexing primers and probes and testing the on-deck reaction mix stability of the generated one-step RT-qPCR master mix after template addition. For the binding of DNA aptamers to M21 RTase, equal volumes of two DNA aptamers (1.45 µM, 2.18 µM, 2.90 µM 4.34 µM, 5.79 µM, Table 1) and M21 RTase (0.724 µM, Table 1) were mixed and incubated at room temperature for 25 minutes. After incubation, the DNA aptamer bound RTase was placed on ice. For the standard one-step procedure, the DNA aptamer bound RTases (6.03 nM final) were added to a reaction mixture containing the following: Integrated DNA Technologies PrimeTimeTM1-Step 4X Broad- Range Master Mix formulated without Reverse Transcriptase (1X) and FluVID primers and probe sets (Table 1). The assay master mix and synthetic RNA ultramers (50 copies per well, Table 1) were mixed at a 4:1 ratio for a final volume of 20 µL. The reaction proceeded six hours after the addition of template at room temperature on a qPCR (QuantStudioTM7 Flex) using the following method: 50 ⁰C hold for 15 minutes, 95 ⁰C hold for 30 seconds, followed by 95 ⁰C for 5 seconds and 55 ⁰C for 45 seconds for 45 cycles. The reactions were analyzed and reported by threshold cycle (Ct) and endpoint fluorescence (delta Rn) values (Table 11). An improvement of on-deck reaction mix stability was observed by increasing the ratio of RTase to aptamer for both aptamer pairs up to the 1:6:6 dose, at which point further addition of the aptamer pairs (1:8:8) provided no additional benefit. As such, the 1:6:6 ratio was determined to be the optimal concentration of the pair aptamers. EXAMPLE 10 This example demonstrates reverse transcriptase inhibition by combinations of DNA aptamers of an aspect of the invention at different concentrations. In this study, DNA aptamers were combined and investigated at different ratios to achieve additive benefits to on-deck reaction mix stability. These DNA aptamers were challenged by incubation of the qPCR reactions six hours at 25 ℃ after template addition before running on the instrument. The DNA aptamers were tested by binding three DNA aptamers at various ratios (1:4:4:4, 1:5:5:5, and 1:6:6:6 RTase:Aptamer 1:Aptamer 2:Aptamer 3) to M21 RTase, adding the aptamer bound RTase to a reaction mixture Leydig 772843 P2023-4023-WO 38 containing a qPCR master mix with multiplexing primers and probes and testing the on-deck reaction mix stability of the generated one-step RT-qPCR master mix after template addition. For the binding of pairs DNA aptamers to M21 RTase, equal volumes of two DNA aptamers (4.34 µM, Table 1) and M21 RTase (0.724 µM, Table 1) were mixed and incubated at room temperature for 25 minutes. For the binding of three DNA aptamers to M21 RTase, equal volumes of three DNA aptamers (2.90 µM, 3.62 µM, 4.34 µM, Table 1) and M21 RTase (0.724 µM, Table 1) were mixed and incubated at room temperature for 25 minutes. After incubation, the DNA aptamer bound RTase was placed on ice. For the standard one-step procedure, the DNA aptamer bound RTases (6.03 nM final) were added to a reaction mixture containing the following: Integrated DNA Technologies PrimeTimeTM1- Step 4X Broad-Range Master Mix formulated without Reverse Transcriptase (1X) and FluVID primers and probe sets (Table 1). The assay master mix and synthetic RNA ultramers (50 copies per well, Table 1) were mixed at a 4:1 ratio for a final volume of 20 µL. The reaction proceeded six hours after the addition of template at room temperature on a qPCR (QuantStudioTM7 Flex) using the following method: 50 ⁰C hold for 15 minutes, 95 ⁰C hold for 30 seconds, followed by 95 ⁰C for 5 seconds and 55 ⁰C for 45 seconds for 45 cycles. The reactions were analyzed and reported by threshold cycle (Ct) and endpoint fluorescence (delta Rn) values (Table 11). Of all conditions tested, the combination of M21+RNA_9_3Phos + M21+RNA_11_3Phos + M21+RNA_47_3Phos (1:6:6:6 ratio) consistently performed the best in terms of based on high endpoint fluorescence, low Ct, and low variance compared to all other conditions for both the two and three aptamer as well as displaying substantial improvement over RNA aptamer, currently used in IDT PrimeTimeTM1-Step 4X Broad-Range Master Mix.

[0022] Leydig 772843 P2023-4023-WO 39 - T R D3820632835675854426620858pStel l 20 40 30 40 50 50 6 3 3 2.22e dt. . . . . . . . . .0.3.S-ec0 1 0 0 0 0 0yohC nC sO heM2rh n0Ttae 30800524365603783 1 5 9 1TC.2.1.20 1 9 5 4.3.8.3.9 1 1 5 9 8e4. . . .4.4.miTemirPotnoitiddaetalp metgniwollofsru .oh2dnasruoh0tiaytiliibatls a a ae nr hguc ramaN AoS C N AoS C N AoS C teT N R R R aTreA p N meD? or NoNoNoNoNoNoNoNoNoNoNoNoN tdmetAem oaorN RatrgfepotA n nI(oit xi1_1 1 1 2 2 2 2 3 3 3 3 4a1_1_1_1_1_1_1_1_1_1_1_1_1uM larre 2 2 2 2 2 2 2 2 2 2 2 2 2vetM M M M M M M M M M M M M Es.amat3 Mpe A lbR a C TPq Leydig 772843 P2023-4023-WO 40723 7 9 3 6 9 8 9 8 1 2 8 1 344 0 4 3 5 4 4 3 1 3 1 4 1 2492444.0473.5399731212011407.0177.4359013148052 BfP-2 A B P-2 A B P-2 B P-2 B PneIsS a R - VfnfnesS R - VfnfnesS R -AVf fnesS R -Af fnesN Ao I I aC N Ao I I aN AonI I aVN AonI I aN R S R S C R S C R S C RoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN4_4_4_5_5_5_5_6_6 6 6 7 7 7 7 8 8 81 1 1 1 1 1 1 1_1_1_1_ _ _ _ _ _ _2 2 2 2 2 2 2 2 2 2 212121212121212

[0023] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 41 2503008485936 7 6 0 3 5 4 6 4 1 5 511 9 1 8 4 1 6 8 7 9 5 6-S ReAVonInIsaRV n neN Ao I IsaRV n neN Ao I IsaR AVonIneIsaR AVonIS C R S C R S C N R S C N R S C o NoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN 8_9_9_9_9_ 01010101111111112121212 31212121212 _1_1_1_1_1_1_1_1_1_ _1_1_

[0024] M M M M M2 2 2 2 2 2 2 2 212121212M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 42902785731769909024359 9 0 0 1 5 3 151 4 3 0 0 4 7 2.0811.539272193777022.0768.4359732183852 BfP-neS2-A B P-2-A B P-2-A B P-2-A B PIsf f eaRV n nIsSf f eaRV n nIsSf f eaRV n n sS RVfnfnesN Ao IC N Ao IN Ao I I aN Ao I I aN R S R S C R S C R S C RoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN313 3 4 4 4 4 5 5 5 5 6 6 6 6 7 7 7_1_1_1_1_1 1 1 1 1 1 1 1 1 1 1 1 11 1 1 1 1_1_1_1_1_ _ _ _ _ _ _ _ _2 2 2 2 2 2 2 2 2121212121212121212

[0025] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 43 117835450288248741251326186633984022-S Re e eAVonInIsaRVonInIsaRVonInIsaRVonIneIsaRVonIS C N A N A N A N A R S C R S C R S C R S C o NoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN 71818 8 8 9 9 9 9 0 0 0 0 1 1 1 1 2_ _1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 21_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _21212121212121212121212121212121212

[0026] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 44010095854735040999587 9 8 4 6 6 1 043 1 2 3 6 3 4 1.0330.53135858277003.1281.5371334183812 BfP-neS2-A B P-S2-A B P-2-A B P-2-A B PIsf f eaRV n nIsf f eaRV n nIsSf f eaRV n nIsS RVfnfnesN Ao IC N Ao IC N Ao I aN Ao I I aN R S R S R S C R S C RoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN222 2 3 3 3 3 4 4 4 4 5 5 5 5 6 6 6_2_2_2_2_2 2 2 2 2 2 2 2 2 2 2 2 21 1 1 1 1_1_1_1_1_ _ _ _ _ _ _ _ _2 2 2 2 2 2 2 2 2121212121212121212

[0027] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 45 388684358325217145162872755000694895-S Re e eAVonInIsaRVonInIsaRVonInIsaRVonIneIsaRVonIS C N A N A N A N A R S C R S C R S C R S C o NoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN 62727 7 7 8 8 8 8 9 9 9 9 0 0 0 0 1_ _2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 31_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _21212121212121212121212121212121212

[0028] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 46550178902429886345668 2 4 1 1 3 6 957 2 1 4 0 9 0 7.0853.530611180166785.0429.4376262385432 BfP-neS2-A B P-2-A B P-2-A B P-2-A B PIsf f eaRV n nIsSf f eaRV n nIsSf f eaRV n n sS RVfnfnesN Ao IC N Ao IN Ao I I aN Ao I I aN R S R S C R S C R S C RoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN131 1 2 2 2 2 3 3 3 3 4 4 4 4 5 5 5_3_3_3_3_3 3 3 3 3 3 3 3 3 3 3 3 31 1 1 1 1_1_1_1_1_ _ _ _ _ _ _ _ _2 2 2 2 2 2 2 2 2121212121212121212

[0029] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 47 707291195079052946084127179650396784-S Re e eAVonInIsaRVonInIsaRVonInIsaRVonIneIsaRVonIS C N A N A N A N A R S C R S C R S C R S C o NoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN 53636 6 6 7 7 7 7 8 8 8 8 9 9 9 9 0_ _3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 41_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _21212121212121212121212121212121212

[0030] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 48955550524319492079469 8 0 3 4 5 3 941 1 8 9 5 4 8 4.0913.533326193739196.0877.4382492404052 BfP-neS2-A B P-2-A B P-2-A B P-2-A B PIsf f eaRV n nIsSf f eaRV n nIsSf f eaRV n n sS RVfnfnesN Ao IC N Ao IN Ao I I aN Ao I I aN R S R S C R S C R S C RoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN040 0 1 1 1 1 2 2 2 2 3 3 3 3 4 4 4_4_4_4_4_4 4 4 4 4 4 4 4 4 4 4 4 41 1 1 1 1_1_1_1_1_ _ _ _ _ _ _ _ _2 2 2 2 2 2 2 2 2121212121212121212

[0031] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 49 7409407259355 3 3 6 7 3 2 2 5 3 5 426 9 0 9 1 6 9 9 4 4 8 5-S Re eAVonInIsaRV nN Ao InIsaRV n neN Ao I IsaRV n neN Ao I IsaRV nN Ao IS C R S C R S C R S C R S C o NoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN 44545 5 5 6 6 6 6 7 7 7 7 8 8 8 8 9_ _4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 41_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _21212121212121212121212121212121212

[0032] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 503419885 7 0 1 1 6 7 6 6 2 7 0 9 0 367 9 9 3 5 6 6 2 8 8 7 1 5 8 4.0214.530917182979425.0671.4304443323072 BfPne-S2-A BfPe-S2-A BfPe-S2-A BfPe-S2-A BfPeIsaRVfn n sRVfn n sRVfn n sRfn sN Ao I I aAo I I aAo I I aAVonI I aS C N S C N S C N S C N R R R R RoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN949 9 0 0 0 01_4_4_5_5_5_5_ _1 1 1 2 2 2 2 3 3 3A_ _ _ _ _ _ _ _ _ _1212121212121A A A A A A A A A A 2 N N N N N N N N N N N

[0033] M M M M M M M R+ R R R R R R R R R R 1 +1+1+ +1+1+1+ +1+1+ 22 212 2 2 212 2 212M M M M M M M M M M M Leydig 772843 P2023-4023-WO 51 018242961232887418114102478334379264-S RnesRnesRnesRnesRAVonI I aS AVonI I aVonI I aVonI I aVonIC N R S C N A R S C N A R S C N A R S C o NoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN 3_4_4A_4A_4A_5A_5A_5A_5 6 6 6 6 7 7 7 7 8A A_A_A_A_A_A_A_A_A_A_A N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R+ R+ R R R R R R R R R 11 1 1 1 1 1+1+1+1+ +1+1+ + + 22 2 212 2 2 212 2 2 212 2 2121212

[0034] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 52427347232437360 3 4 6 0 8 1 6 5 9 747 0 4 7 6 5 6 7 7 5 3.0634.5389951170911514.0631.536256752012 BfP-2neIsS -AfBfP-2a RV n nesS -AfBfP-2nesS -AfBfPe-2sS -AfBfPesN Ao I I aRV nN Ao I I aRV n nN Ao I I aR AVonInI aS C C C N C N R R S R S R S RoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN8_8 9 9 90 0 0 0 1 1 1 2 2 2A_8A_A_A_A_9A_A1 1 11_ _ _1_1_1_1_1_1_1_1_N N N N N N N A A A A A A A A A A A R+ R R R R R R N N N N N N N N N N N1+21+ + 2121+ + + R 2121212+ R 1 + R+ R+ R+ R+ R+ R+ R+ R+ R+ 2121 1 1 1 1 1 1 1 1

[0035] M M M M M M M2 2 2 2 2 2 2 2 2M M M M M M M M M M M Leydig 772843 P2023-4023-WO 53 396735067342108840906020339381835859-S RV n nesRV n nesRnesRnesRAo I I aN Ao I I aVN AonI I aV nN Ao I I aV nN Ao IS C R S C R S C R S C R S C o NoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN 21313131314141414 5 5 5 5 6 6 6 6 7_ _ _ _ _ _ _ _1_1_1_1_1 1 1 1 1 1A A A A A A A A A A A A_A_A_A_A_A_A N N N N N N N N N N N N N N N N N N R+ R 1 + R 1 + R 1 + R R 1 +1+ R 1 + R 1 + R R R R R R R R R R 1 +1+1+ + + + + + + + 22 2 2 2 2 2 2 2 21212121212121212

[0036] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 5407543106191634811 3 0 8 7 1 0 1 6 138 4 8 1 8 1 0 9 1 2.0922.5305401246761866.0796.4368462240282 BfP-neIsS2-AfBfP-2a RV nesS -AfBfP-2nesS -AfBfP-2nesS -AfBfPnesN AonI I aRV nI I aRV nI I aRV nI I aC N AoN AoN AoN R S R S C R S C R S C RoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN717 7 8 8 8 8 9 9 9 9 0 0 0 0 1 1 1_1_1_1_1_1_1_1_1_1_1 2 2 2 2 2 2 2A A A A A A A A A A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N R+ R1+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+21212121212121212121212121212121212

[0037] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 55 067972985546340467217594676200537725-S RV n nesRV n nesRnesRnesRAo I I aN Ao I I aVN AonI I aV nN Ao I I aV nN Ao IS C R S C R S C R S C R S C o NoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN 12222222223232323 4 4 4 4 5 5 5 5 6_ _ _ _ _ _ _ _2_2_2_2_2 2 2 2 2 2A A A A A A A A A A A A_A_A_A_A_A_A N N N N N N N N N N N N N N N N N N R+ R 1 + R 1 + R 1 + R R 1 +1+ R 1 + R 1 + R R R R R R R R R R 1 +1+1+ + + + + + + + 22 2 2 2 2 2 2 2 21212121212121212

[0038] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 5653544590140569918 7 2 8 7 5 7 3 4 324 2 6 2 9 0 4 6 9 0.0231.531053745731072.0959.3360721199682 BfP-neIsS2-AfBfP-2a RV nesS -AfBfP-2nesS -AfBfP-2nesS -AfBfPnesN AonI I aRV nI I aRV nI I aRV nI I aC N AoN AoN AoN R S R S C R S C R S C RoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN626 6 7 7 7 7 8 8 8 8 9 9 9 9 0 0 0_2_2_2_2_2_2_2_2_2_2 2 2 2 2 3 3 3A A A A A A A A A A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N R+ R1+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+21212121212121212121212121212121212

[0039] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 57 4749552698218198928 3 9 0 3 8 1 3 222 1 4 0 1 6 2 0 8-S RV n nesRV nesRnesRnesRAo I I aN AonI I aV nN Ao I I aV nN Ao I I aAVonIS C R S C R S C R S C N R S C o NoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN 03131313132323232 3 3 3 3 4 4 4 4 5_ _ _ _ _ _ _ _3_3_3_3_3 3 3 3 3 3A A A A A A A A A A A A_A_A_A_A_A_A N N N N N N N N N N N N N N N N N N R+ R 1 + R 1 + R 1 + R R 1 +1+ R 1 + R 1 + R R R R R R R R R R 1 +1+1+ + + + + + + + 22 2 2 2 2 2 2 2 21212121212121212

[0040] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 5841640807271204037 0 3 4 0 1 0 0 0 751 7 7 6 0 6 5 7 5 8.0748.4304781470511902.0522.4327471417642 BfP-neIsS2-AfBfP-2a RV nesS -AfBfP-2nesS -AfBfP-2nesS -AfBfPnesN AonI I aRV nI I aRV nI I aRV nI I aC N AoN AoN AoN R S R S C R S C R S C RoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN535 5 6 6 6 6 7 7 7 7 8 8 8 8 9 9 9_3_3_3_3_3_3_3_3_3_3 3 3 3 3 3 3 3A A A A A A A A A A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N R+ R1+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+21212121212121212121212121212121212

[0041] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 59 424394273498355267344219665906190539-S RV n nesRV n nesRnesRnesRAo I I aN Ao I I aVN AonI I aV nN Ao I I aV nN Ao IS C R S C R S C R S C R S C o NoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN 93040404041414141 2 2 2 2 3 3 3 3 4_ _ _ _ _ _ _ _4_4_4_4_4 4 4 4 4 4A A A A A A A A A A A A_A_A_A_A_A_A N N N N N N N N N N N N N N N N N N R+ R 1 + R 1 + R 1 + R R 1 +1+ R 1 + R 1 + R R R R R R R R R R 1 +1+1+ + + + + + + + 22 2 2 2 2 2 2 2 21212121212121212

[0042] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 6057363869939660325 8 3 8 2 9 7 2 7 411 3 6 2 3 4 5 2 2 7.0093.5320721977561677.0503.4304831564992 BfP-neIsS2-AfBfP-2a RV nesS -AfBfP-2nesS -AfBfP-2nesS -AfBfPnesN AonI I aRV nI I aRV nI I aRV nI I aC N AoN AoN AoN R S R S C R S C R S C RoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoNoN444 4 5 5 5 5 6 6 6 6 7 7 7 7 8 8 8_4_4_4_4_4_4_4_4_4_4 4 4 4 4 4 4 4A A A A A A A A A A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N R+ R1+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+21212121212121212121212121212121212

[0043] M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 61 46017488788082213775611766949894-S R - f fnes- f fnes- f fnes- f f esAVonI I aR AVonI I aR AVonI I aRVonInI aS C N S C N C N A C N R R S R S R o NoNoNoNoNoNoNoNos s s sNe o oYeYeYe oY N N N 849r_494949405050505e yl rne yl ryryr r rneln eln e e eA_A_A_A_A_A_A_A_AmaN N N N N N N N NtOmaptOmatOmatOmat mat matR+ R+ R+ R+ R+ R+ R+ R+ R+ApApApApApoApoA 121 1 1 12 2 2 2A A A Ao2 2 2 21 1 1 1N N N N N N N

[0044] M M M M M M M M M R R R R Leydig 772843 P2023-4023-WO 62 - T9 0 684A A A AeR eldtlCDS95. 303. 005.0 v e)t 3 5 45 naldtC D6237808 peARlcloS.0.0.03.A A A 0 N N N Natlm eet yChsdghern6832888(ni.s 0 hTtae1.1.43e7cwrC . A A A AnoeM534.34343N N N Nec llm saeorftospanR7 0 92urlf uoAatD16hNtnec leS, 385, 839,1-S R Ao I aS C N Ao omsnegR S ChseA rho erhc raNuteT T t oo o o oy “bsaareA N?sreseseN N N N Ndedp eDAeY Y Y tro kr mpa et deetNmRatrmmasearoo rpgA e wa rdlfotnrI1_1_1_e et lma o et lo et lo et laota ohn(o xe121212al rt al rt al rt al rtdstp ,er itiaMmaM M M pnmo pnAeCmo pnpn 1 hCmoCmo 1-tul reN TeTe eC2 no av tselo

[0045] NoNoT NoT No sNeiltbaEa pm aci .Tfi4 MaS rlopelbR C Fma aT P q Leydig 772843 P2023-4023-WO 6367107 5 9 2 0 2 5 7 4 3 8 4 5 8 4 8 5 6 1 73.0 2. 511. 5119.0 5. 006. 100. 9126.0 6. 806. 507. 1034.0 1. 117.A81 N1.A40 N1. 606. 114. 4980.0 4. 209. 503.0359.4.3347,9 ,410,9 ,8273.0.165.4.3832,1,4876,9,432-VoCI-S R R R R R RA S A S A S A S A S A Sseseseseseseseseseseseseseseses s s s s s s s sY Y Y Y Y Y Y Y Y Y Y Y Y Y YeYeYeYeYeYeYeYeYeY1_2_2_2_2_3_3_3_3_4_4_4_4_5_5_5_5_6_6_6 6 7 7 71 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1_1_1_ _ _2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2121212

[0046] M M M M M M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 6414093 0 8 7 9 8 9 0 8 4 6 0 0 0 0 6 6 2 6 0 0 23.0 1. 714. 1168.0 6. 626. 107. 2118.0 2. 635. 3142.0 15.0 7. 607. 9044.0 44.0 5. 102. 6137.0 20.0 7. 406. 9087.2 1.0845.4.3018,1,1762,7,21344.0.597.4.3828,3,4833,7,532-VoCI-S R R R R R RA S A S A S A S A S A Sseseseseseseseseseseseseseseseseseseseseses s sY Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y YeYeYeY7_8_8_8 8 9 9 9 90 0 0 0 1 1 1 1 2 2 2 2 3 3 31_ _ _ _ _ _121212121212121212 _11_1_1_1_1_1_1_1_1_1_1_1_1_1_212121212121212121212121 1 1

[0047] M M M M M M M M M2 2 2M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 6568627 706 4 5 6 6 5 5 9 0 7 9 6 7 5 1 5 9 4 1 46.0 0. 500.2 35.0 0. 614. 4084.0 30.0 3. 701. 6143.0 45.0 4. 806. 1150.1 44.0 7. 010. 3145.0 12.0 4. 206. 1094.0 3.0998.6.3939,1,578,4 ,2201.0.498.3.3700,,21678,2,832-VoCI-S R R R R R RA S A S A S A S A S A Sses s s s s s s s s s s s s s s s s s s s s s sYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeY314141414151515151616 6 6 7 7 7 7 8 8 8 8 9 9 9_ _ _ _ _ _ _ _ _ _1_1_1_1 1 1 1 1 1 1 1 1 1 11 1 1 1 1 1 1 1 1 1 1 1 1_1_1_1_1_ _ _ _ _ _ _2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 212121212121212

[0048] M M M M M M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 6641261 4574508 2 2 7 4 7 1 3 8 9 5 6 1 4 4 27.0 5. 409.0 3.0 9.0 7.A60 N7.A40 N9. 705. 900. 910. 108. 106. 601. 620. 002. 510. 912. 9470.0 0. 803. 422.0098.4.3006,3,1607,0 ,7994.0.703.4.3695,15,312,0,142-VoCI-S R R R R R RA S A S A S A S A S A Sseses s s s s s s s s s s s s s s s s s s s s sY YeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeY91020202021212121222222 2 3 3 3 3 4 4 4 4 5 5 5_ _ _ _ _ _ _ _ _ _ _2_2_2_2 2 2 2 2 2 2 2 2 21 1 1 1 1 1 1 1 1 1 1 1 1 1_1_1_1_ _ _ _ _ _ _2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 212121212121212

[0049] M M M M M M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 6755482 41551 1 2 0 7 0 0 9 1 9 5 1 8 5 9 1 0 79.1 7. 303.0 3.0 6. 109. 6094.2 26.0 7. 832. 2053.0 45.0 3. 001. 8323.4 4.A00 N8. 200. 031. 030. 906. 009. 700.0042.7.3530,5 ,479,4 ,2648.0.122.3.3996,4,3106,6,832-VoCI-S R R R R R RA S A S A S A S A S A Sses s s s s s s s s s s s s s s s s s s s s s sYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeY52626262627272727282828 8 9 9 9 9 0 0 0 0 1 1 1_ _ _ _ _ _ _ _ _ _ _2_2_2_2 2 2 3 3 3 3 3 3 31 1 1 1 1 1 1 1 1 1 1 1 1 1_1_1_1_ _ _ _ _ _ _2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 212121212121212

[0050] M M M M M M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 6877046 349 9 5 1 6 7 6 8 4 8 4 9 7 6 8 8 3 2 4 24.0 2. 105.0 31.0 3. 102. 6022.0 36.0 6. 907. 9116.0 27.0 4. 203. 4053.0 36.0 6. 801. 619. 4079.0 0. 001. 8148.1 3.0882.4.3706,8,1127,9 ,9433.0.700.5.3705,,21026,5,332-VoCI-S R R R R R RA S A S A S A S A S A SsesesesesYesYesYesYesYesYesYesYesYes s s s s s s s s s sY Y Y YeYeYeYeYeYeYeYeYeYeYeY132323232333333333434 4 4 5 5 5 5 6 6 6 6 7 7 7_ _ _ _ _ _ _ _ _ _3_3_3_3 3 3 3 3 3 3 3 3 3 31 1 1 1 1 1 1 1 1 1 1 1 1_1_1_1_1_ _ _ _ _ _ _2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 212121212121212

[0051] M M M M M M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 6956966 050 5 0 6 4 1 4 0 2 1 1 2 3 7 6 5 9 5 5 60.2 4. 507.0 05.0 1. 413. 3108.0 18.0 4. 712. 7138.0 22.0 2. 403. 8045.0 32.0 5. 323. 5048.1 30.0 4. 504. 6067.0 5.0506.6.3404,4 ,910,4 ,2864.0.828.3.3548,7,5242,7,632-VoCI-S R R R R R RA S A S A S A S A S A Sses s s s s s s s s s s s s s s s s s s s s s sYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeY738383838393939393040 0 0 1 1 1 1 2 2 2 2 3 3 3_ _ _ _ _ _ _ _ _ _4_4_4_4 4 4 4 4 4 4 4 4 4 41 1 1 1 1 1 1 1 1 1 1 1 1_1_1_1_1_ _ _ _ _ _ _2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 212121212121212

[0052] M M M M M M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 7008015 371 6 9 7 5 0 6 9 6 2 3 3 2 6 3 9 6 3 4 39.0 8. 609.0 41.0 6. 807. 7031.2 25.0 1. 143. 4103.1 14.0 3. 705. 2212.1 29.0 9. 207. 4030.0 22.0 8. 904. 0037.0 3.0145.4.3467,5,2368,8 ,8051.0.657.3.3483,4,1691,9,642-VoCI-S R R R R R RA S A S A S A S A S A SsesesesesYesYesYesYesYesYesYesYesYes s s s s s s s s s sY Y Y YeYeYeYeYeYeYeYeYeYeYeY344444444454545454646 6 6 7 7 7 7 8 8 8 8 9 9 9_ _ _ _ _ _ _ _ _ _4_4_4_4 4 4 4 4 4 4 4 4 4 41 1 1 1 1 1 1 1 1 1 1 1 1_1_1_1_1_ _ _ _ _ _ _2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 212121212121212

[0053] M M M M M M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 7125977 0114807116749662478 3 4 5 1 9 2 8 4 9 9 53.0 2. 912.0 1.1 2.1 7.0 2.0 0.50.0 6.0 5.0 0. 750. 710. 5121.2 55.31. 703. 7028 7.0 1.10. 004. 6014.2 2.0375.4.3656,1,1324,4 ,7283.0.793.4.3208,2,2948,1,042-VoCI-S R R R R R RA S A S A S A S A S A Sses s s s s s s s s s s s s s s s s s s s s s sYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeYeY940 0 0 01 1 1 1 2 2 2 2 3 3_5 5_ _ _ _ _ _ _ _ _ _3_3_4_4_4_4_5_5_5_1_1_51_51_1A A A A A A A A A A A A A A A A A A A2 2 2 2 2N N N N N N N N N N N N N N N N N N N

[0054] M M M M M R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R R R R R 11 1 1 1 1 1 12121+ + + + + 22 2 2 2 2 2 2121212121212121212M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 72449884522055203116407118532 8 3 9 2 8 2 5 8 9 42.0 3.0 0.1 3.40.1 2.0 6.0 4.60.0 8.0 6.1 2.30. 400. 1054.0 1. 240. 107. 1045.1 5. 850. 002. 8049.0 3.0510.4.3059,2,1309,8,11034.0.906.4.3737,0 ,6062,9,832-VoCI-S R R R R R RA S A S A S A S A S A Sseseseseseseseseseseses s s s s s s s s s s s sY Y Y Y Y Y Y Y Y Y YeYeYeYeYeYeYeYeYeYeYeYeYeY5_6_6_6_6 7 7 7 7 8 8 8 8 9 9 9 90 0 0 0 1 1 1A A A A_A_A_A_A_A_A_A_A_A_A_A_A_A1_1_1_1_1_1_1_N N N N N N N N N N N N N N N N N A A A A A A A R+ R R R R R R R R R R R R R R R R N N N N N N N1+21+ 21+ 21+ 21+ 21+ 21+ + + + + + + + + + R 212121212121212121212+ R 1 + R 1 + R 1 + R 1 + R 1 + R+ M M M M M M M M M M2 2 2 2 2121

[0055] M M M M M M M2M M M M M M M Leydig 772843 P2023-4023-WO 73281517181524740701198737729606353 8 4 7 0 3 7 80.0 2.0 5.0 1.20.0 4.0 0.1 3.80.0 1.0 1.1 3.90.0 5.0 4.0 1. 320. 708. 0081.0 5. 110. 503. 3026.1 3.0533.4.3243,0,1417,3,41884.0.891.4.3008,1,5484,1,342-VoCI-S R R R R R RA S A S A S A S A S A Sseseseseseseseseseseseseseseseseseseseses s s sY Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y YeYeYeYeY1121212121313131314141414151515 5 6 6 6 6 7 7 7_A_A_A_A_A_A_A_A_A_A_A_A_A_A_1A_1A_1A_1A_1A_1A_1A_1A_1A_AN N N N N N N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R1 1 1 1 1+ + + + + + + + + + + +2 2 2 2 212121212121212121212121212121212121212

[0056] M M M M M M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 747003539021420772372809989505395 4 0 0 2 5 3 5 35.0 2.0 7.0 5.30.1 5.0 9.0 3.10.0 1.0 3.0 7.80.0 8.0 29.0 4. 050. 306. 3033.0 4. 620. 905. 0050.0 8.0965.4.3342,1,1080,9 ,8813.0.180.4.3242,0,2607,7,242-VoCI-S R R R R R RA S A S A S A S A S A Sseseseseseseseseseseseseseseseseseseseses s s sY Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y YeYeYeYeY7181818181919191910202020212121 1 2 2 2 2 3 3 3_A_A_A_A_A_A_A_A_A_A_A_A_A_A_2A_2A_2A_2A_2A_2A_2A_2A_2A_AN N N N N N N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R1 1 1 1 1+ + + + + + + + + + + +2 2 2 2 212121212121212121212121212121212121212

[0057] M M M M M M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 75647999797345344449238118343667886 5 6 7 3 8 3 45.0 5.0 3.0 1.10.0 0.1 3.0 2.40.0 0.1 8.1 1.80.0 4.0 4.0 4. 890. 400. 1162.0 3. 600. 806. 6031.1 2.0798.3.3217,4,2766,4,11192.0.764.4.3303,0,2049,8,932-VoCI-S R R R R R RA S A S A S A S A S A Sseseseseseseseseseseseseseseseseseseseses s s sY Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y YeYeYeYeY3242424242525252526262626272727 7 8 8 8 8 9 9 9_A_A_A_A_A_A_A_A_A_A_A_A_A_A_2A_2A_2A_2A_2A_2A_2A_2A_2A_AN N N N N N N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R1 1 1 1 1+ + + + + + + + + + + +2 2 2 2 212121212121212121212121212121212121212

[0058] M M M M M M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 76492579141971101162567671615126874 4 8 9 8 9 4 63.0 0.1 1.0 1.10.0 4.0 6.0 3.00.0 2.1 5.0 4.80.0 9.0 5.0 4. 550. 711. 0116.0 2. 850. 608. 6037.0 2.0914.4.3323,1 ,3426,1,41180.1.676.4.3716,20,1342,3,042-VoCI-S R R R R R RA S A S A S A S A S A Sseseseseseseseseseseseseseseseseseseses s s s sY Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y YeYeYeYeYeY92030303031313131323232323333 3 3 4 4 4 4 5 5 5_ _ _ _ _ _ _ _ _ _ _ _ _ _3_3_3_3_3_3_3_3_3_3A A A A A A A A A A A A A A A A A A A A A A A_AN N N N N N N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R R1 1 1 1+ + + + + + + + + + + + +2 2 2 21212121212121212121212121212121212121212

[0059] M M M M M M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 772766102194272664246171027592453 1 1 0 2 1 6 9 50.1 3.0 4.0 4.10.0 5.0 7.0 5.20.0 8.0 0.1 1.60.0 6.0 22.0 3. 190. 008. 6022.0 5. 910. 503. 1035.0 1.0222.5.3524,2,2679,6 ,7914.0.851.4.3321,8,2768,9,642-VoCI-S R R R R R RA S A S A S A S A S A Sseseseseseseseseseseseseseseseseseseseses s s sY Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y YeYeYeYeY5363636363737373738383838393939 9 0 0 0 0 1 1 1_A_A_A_A_A_A_A_A_A_A_A_A_A_A_3A_3A_4A_4A_4A_4A_4A_4A_4A_AN N N N N N N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R1 1 1 1 1+ + + + + + + + + + + +2 2 2 2 212121212121212121212121212121212121212

[0060] M M M M M M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 78318074549260751554245844658787002 8 1 1 4 9 5 44.0 3.0 1.0 1.20.0 7.0 9.0 0.20.0 3.0 3.1 1.60.0 5.0 2.0 2. 930. 910. 3093.0 1. 490. 405. 2136.1 0.0892.4.3197,9,1731,7,31394.0.735.4.3653,6 ,2684,3,242-VoCI-S R R R R R RA S A S A S A S A S A Sseseseseseseseseseseseseseseseseseseseses s s sY Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y YeYeYeYeY1424242424343434344444444454545 5 6 6 6 6 7 7 7_A_A_A_A_A_A_A_A_A_A_A_A_A_A_4A_4A_4A_4A_4A_4A_4A_4A_4A_AN N N N N N N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R1 1 1 1 1+ + + + + + + + + + + +2 2 2 2 212121212121212121212121212121212121212

[0061] M M M M M M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 79152018022851668847478135513 482422295 8 78.3.2 4.2.9.1 7 7 7 6 0 303 92 7 80 1 672550104A A A0 0.0 0 0 0.0.0.0.0.0.0.1.1. . . . . .0.0N N N701.5.3012,2,3130,2,11217.0.524.4.3225,6,4437,0,042-VoCI-S R R R R R RA S A S A S A S A S A Ssesesesesesesesesesesesesesesesese oNoNoNoNoNoNoY Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y N748_4848484949494940505050 ylylylyl rerererelololoA_A_A_A_A_A_A_A_A_A_A_5A_ n n n nAO O O O mamamamartrntrntnN N N N N N N N N N N N N A A A Atptptptp o o oR R R R R R R R R R R R A A A A C C C +1+ + + + + + + + + + + R+ N N N N R R R Ro o o o et2121212121212121212121212N N N Na elta etplaplp

[0062] M M M M M M M M M M M M MmemTemeoT T NoNoN Leydig 772843 P2023-4023-WO 80 A N A N841585A N A N3314352-VoC-SRA SoNlortnoCetalpmeTo

[0063] N Leydig 772843 P2023-4023-WO 81 - T R petdlD3S674972923057537755 2772- oehSst 5.3.2.3.8.8.3.3.4. 53.2.5.nerC4 5 0 0 0 1 0 0 1 0 0 0OhMTTeelcna 120158472020497767015637meiTemirPotnoitiddaetalp metgniwollofsruoh4dnasruoh0taytilibat soenr h uc A Bte t fPe-S2-A BfPe-S2-A BfPe-S2-aT ee fn nrg IsaRVfn nIsaRVfn nIsRVe AramIaN Ao IAo I aAoR S C N S C N S C p N N R R D T met dmetoa :e or nim oi 2:2 2 2 3 3 3 3 5 5 5 51:1:1:1:1:1:1:1:1:1:1:1r gfe eot tnoatartpR I P Arn(oit xi9a_9 9 9uM l1_1_1_91_9 9 9 9 9 9 91_1_1_ _ _ _ _arve rte 2 2 2 2 2 2 21212121212M M M M M EsM M M M M M M .amat5 Mpe A lbR a C TPq Leydig 772843 P2023-4023-WO 82000.1.585.5.356748345572454.0.009.3.32269448716 7720114853229833742591417420183276299AfBnfPe-S2-A BfPe-S2-A BfP-S2-A B P-S2-A B PInIsaRVfN AonInIsaRVfC N AonIneIsaRVfnfN Ao IneIsaRVfnfN Ao IneIsaN R S R S C R S C R S C R010 0 0:1 1 1 2:2:2:2:3:3:3 3 5 5 5 50 0 01:1:1:1 1 1 1 1 1 1:1:1:1:1:1:1 1:1 11:1:19_9_9_9_ 4444444444444444444444444 4 412121212 _1_ _ _ _ _ _ _ _ _ _ _4_4_4_212121212121212121 1 1 1 1 1

[0064] M M M M2 2 2 2 2 2M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 83 . . . . -S2-A BfPe-S2-A BfPe-S2-A B P-S2-A B P-S2-A BRfAVonInIsaRVfn n sRf fnesRf fnesRf fnN Ao I I aAVonI I aAVonI I aAVonI IS C R S C N R S C N R S C N R S C 01:2:2:2:2:3 3 3 3 5 5 5 51 1 1 1 1:1:1:1:1:1:1:1:1010:10101 2:21:1:1:1 1:144 9_9_9_9_9_9_9_9_9 9 9 9 9 9 9 91 1_1A A A A A A A A_A_A_A_A_A_A_A_A2_2_2N N N N N N N N N N N N N N N N A A

[0065] M R+ R R R R R R R R R R R R R R R N N 1 + 21+ 21+ 21+ 21+ 21+ + + + + + + + + + R 212121212121212121212+ R 1 + M M M M M M M M M M M M M M M M212M M Leydig 772843 P2023-4023-WO 84831.0169.3390684165256282.0934.3353824880969 Pe-sS2R -A BVfnfPne- s S2R -AfBfP- nesS2R -AfBfP- nesS2R -AfBfP- nesS2R -AfaN Ao I I aVC N AonI I aVC N AonI I aVC N AonI I aVC N AonIR S R S R S R S R S C2:2:3:3:3:3:5:5:5:5: 0 0 0 02:2:2 2 31 1 1 1 1 1 1 1 1 1 1:1 1 1: : :1:1:1:1 1 1 1 1 11212121212121 1 1 1 1 1 1 1 5 5 5 5 5_ _ _ _ _ _2_2_2_2_2_2_2_2_2 2 2 2 2A A A A A A A A A A A A A A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R1 1+ + + + + + + + + + + +2 21212121212121212121212121212121212

[0066] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 85773.0.030.6.3679819996734.0.690.4.330812418442 BfPne-S2-A B P-S2-A B P-S2-A B P-S2-A B P-S2-IsaRVf fN AonIneIsaRVf fC N AonIneIsaRVf fC N AonIneIsaRVf fC N AonIneIsaRVN AoR S R S R S R S C R S C3:3:3:5:5:5:5: 0 0 0 02:2:2:2:3 3 3 31 1 1 1 1 1 1 1:11:11:11:1 1 1 1 1:1:1:1:152525252525 5 5 5 5 5 7 7 7 7 7 7 7 7_ _ _ _ _2_2_2_2_2_2_2_2_2 2 2 2 2 2A A A A A A A A A A A A A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R R1+ + + + + + + + + + + + +2121212121212121212121212121212121212

[0067] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 86972.0.836.5.312804221883156.0.360.4.3774448429072 21164077201448672894376520124761201AfB-2-2- -nfPIneIsS a R -A BVfnfPnesS R -A B PVfnfnesS2R -AfBfPnesS2R -AfBfPnesN Ao I I aN Ao I I aAVonI I aAVonI I aC C N C N C N R S R S R S R S R5:5:5:5: 0 0 0 0:2:2:2:2:3:3 3 3 5 5 51 1 1 1 1 1 1 11:1:1:1 1 1 1 1 1:1:1:1:1:1:1727272727272727 8 8 8 8 8 8 8 8 8 8 8_ _ _2 2 2 2 2 2 2 2 2 2 2 2A A A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R R R1 1 1 1 1 1 1 1 1212121+ + +2 2 2 2 2 2 2 2 212121212121212

[0068] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 87 . . . . -S2-A BfPe-S2-A BfPe-S2-A BfPe-S2-A BfPe-S2-A BRAVfonInIsaRVfonInIsaRVfonInIsaRVfonInIsaRVf fonInIS C N A R S C N A R S C N A R S C N A R S C 5:2 21010 0 0:1:1 1:1:21:21:31:31:31:31:5 5 5 51:1:1:1:101011 1:1:1:1:182828282820303030 0 0 0 0 0 0 0 0 0 0_ _3 3 3 3 3 3 3 3 3 3 3A A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A N N N N N N N N N N N N N N N N N N N R+ R R R R R R R R R R R R R R R R R R 1 +1+1+1+1+1+1+ + + + + + + + + + + + 22 2 2 2 2 2121212121212121212121212

[0069] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 88485.0260.4352007798018570.0106.33598641030201 Pe-sS2R -A BVfnfPne- s S2R -AfBfP- nesS2R -AfBfP- nesS2R -AfBfP- nesS2R -AfaN Ao I I aVonI I aVonI I aVonI I aVonIR S C N A R S C N A R S C N A R S C N A R S C010:1 2:2:2:2:3:3:3:3:5:5:5:5: 0 0 0 02:1:1 1 1 1 1 1 1 1 1 1 1 1 1 1:11:11:11:1 103031313131 1 1 1 1 1 1 1 1 1 1 1 1 2_ _ _ _ _3_3_3_3_3_3_3_3_3 3 3 3 3 3A A A A A A A A A A A A A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R R1+ + + + + + + + + + + + +2121212121212121212121212121212121212

[0070] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 89970.1.917.6.32040231835027.0.408.4.381612059542 BfP-neS2-A B P-S2-A B P-S2-A B P-S2-A B P-S2-IsaRVf fonIneIsaRVf fonIneIsaRVf fonIneIsaRVf fonIneIsaRVN A C N A C N A C N A N AoR S R S R S R S C R S C2:2:2:3:3:3:3:5:5:5:5: 0 0 0 02 2 2 21 1 1 1 1 1 1 1 1 1 1 1:11:11:11: :11:1:1:123232323232 2 2 2 2 2 2 2 2 2 9 9 9 9_ _ _ _ _3_3_3_3_3_3_3_3_3 3 3 3 3 3A A A A A A A A A A A A A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R R1+ + + + + + + + + + + + +2121212121212121212121212121212121212

[0071] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 90339.0.757.5.360756827032824.0.939.3.3401149963278 21154273211156762897357726934574211AfB-2-2- -nfPIneIsS a R -A BVfnfPnesS R -A B PVfnfnesS2R -AfBfPnesS2R -AfBfPnesN Ao I I aN Ao I I aAVonI I aAVonI I aC C N C N C N R S R S R S R S R3:3:3:3:5:5:5 5 2 2 2 2 3 31:1:10 0 0 0: :31 1 1 1 1 1 1 1 1: : : : : :1:1:1:1 1 1 1 1 1 1 1939393939393939 9 9 9 9 0 0 0 0 0 0 0_ _ _3 3 3 3 3 4 4 4 4 4 4 4A A A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R R R1 1 1 1 1 1 1 1 1212121+ + +2 2 2 2 2 2 2 2 212121212121212

[0072] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 91 . . . . -S2-A BfPe-S2-A BfPe-S2-A BfPe-S2-A BfPe-S2-A BRAVfonInIsaRVfonInIsaRVfonInIsaRVfonInIsaRVf fonInIS C N A R S C N A R S C N A N A R S C R S C 3:5:5:5:5: 0 0 0 0:2:2:2:2 3 3 3 3 5 51 1 1 1 1 1 1 1 11:1:1:1 1 1 1:1:1:1:1:1:1:104040404040404040 2 2 2 2 2 2 2 2 2 2_ _4 4 4 4 4 4 4 4 4 4 4A A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A N N N N N N N N N N N N N N N N N N N R+ R R R R R R R R R R R R R R R R R R 1 +1+1+1+1+1+1+ + + + + + + + + + + + 22 2 2 2 2 2121212121212121212121212

[0073] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 92462.0111.4331811144418944.0583.33630743056801 Pe-sS2R -A BVfnfPne- s S2R -AfBfP- nesS2R -AfBfP- nesS2R -AfBfP- nesS2R -AfaN Ao I I aVC N AonI I aVC N AonI I aVC N AonI I aVC N AonIR S R S R S R S R S C5:51:1010 0 0:1 1 1 2:2:2:2:3:3:3:3:5:5:5 501:1:1:1 1 1 1 1 1 1 1 1 1 1:1:1 1:124242424242 3 3 3 3 3 3 3 3 3 3 3 3 3_ _ _ _ _4_4_4_4_4_4_4_4_4 4 4 4 4 4A A A A A A A A A A A A A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R R1+ + + + + + + + + + + + +2121212121212121212121212121212121212

[0074] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 93854.0.759.5.31967163798023.0.645.4.396631943472 BfPne-S2-A B P-S2-A B P-S2-A B P-S2-A B P-S2-IsaRVf fN AonIneIsaRVf fC N AonIneIsaRVf fC N AonIneIsaRVf fC N AonIneIsaRVC N AoR S R S R S R S R S C010 0:1 1 2:2:2:2:3:3:3:3:5:5:5:5: 0 0 0 01:1:1 1 1 1 1 1 1 1 1 1 1 1 1 1:11:11:11:13434344 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4_ _ _4_4_4_4_4_4_4_4_4_4 4 4 4 4 4 4A A A A A A A A A A A A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R R1+ + + + + + + + + + + + +2121212121212121212121212121212121212

[0075] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 94 . . . . 05303 3 5 7 6 0 1275287116285331573586621 9 96910868341 247133671533 5145221AfBnfPe-S2-AfBfPe-2 P-2InIsaRV nInIsS -AfBf eS -aRV n nIsaRVN AoC N Ao IN AoR S R S C R S C 515 5:1 1511:1:1:1re yl rma n e yl rtOma n e yl rtOma n e yl rOma n erOmer ret let let let lat meat meat maalotprtnaloprtnaloprtnaloprtpnAptAptApApApApApmoAeCmoCmoCmoC TeTeTeTA A A Ao o o oN N N N N N N NoNoNoNoN

[0076] R R R R Leydig 772843 P2023-4023-WO 95 - T R pe3 1 8tdtD 345821251060685468017981532S- el lec oCS.h0.0.0.1.0.0 1.0 3.0 0.0 5.0 5.0 6.0nyOC sern4 9 3 7 6269385 13340 0MhT4 hTtCae 62. 87. 71. 65.5.8.4. 377.5 5 961e M735353636363535.36.36.34.36m3iTemirPotnoitiddaetalp metgniwollofsruoh4dnasruoh0taytiliba tsoaN R enT R R r h ucA A A teS S S aTr4 4 4 49 9 9 91 1 1 1eA4_4_4 4_ _ _ _2 2 2 2p N2 1 1_1_1A A A A_ _ _ _mD re 2 2 2 2N N N N A A A A et dM M M MR R R RN R N R N N met mao aor t+ p1+ + +R R2121212+1+ + + rg 21 1 1feA M M M M2 2 2M M M M otnnI(oit xi 8 8 8 8 8 8 8 8 8auM2_2_2_2_2_2_2_2_28_28 8_2_2_lar1etre121212121212121212121212vsamM M M M M M M M M M M M E. at6 MpelA b R a C TPq Leydig 772843 P2023-4023-WO 96722 4 0 0 2 2 9 9 2 4 5 9 7 3 9 6 4 94.0.752.6.3050,5,5482,4,04537.0.274.5.3865,8,8627,4,47AfnI I N - N - N - N - N R S R S R S S R R R R R R A S A S A S A S5252525 7272727 8282828 0 0 0 0 1 1 1_ _ _2_ _ _ _2_ _ _ _2_3_3_3_3_3_3 3A A A A A A A A A A A A A A A A A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+ +1+1+ + + + + + + + + + + + +2 2 212 2 212121212121212121212121212M M M M M M M M M M M M M M M M M M M82828282828282828282828 8 8 8 8 8 8 8_ _ _ _ _ _2 2 2 2 2 2 2 21_ _ _ _ _ _ _ _ _ _ _ _ _2121212121212121212121212121212121212

[0077] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 97 18 6 3 3 8 3 4 0 8 0 9 6 8 2 3 7 2 3. .,,..,, -VoC-S R A S A S A S A S A S 132_32_32_32 9 9 9 9 0 0 0 0 2 2 2 2 3 3_3_3_3_3 3 4 4 4 4 4 4 4 4 4 4A A A A A A A_A_A_A_A_A_A_A_A_A_A_A_A N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+ 21+ 21+ 21+ + 2121+ 21+ 21+ + + + + + + + + + + 21212121212121212121212M M M M M M M M M M M M M M M M M M M 828 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8_2_2_2_2_2 2 2 2 2 2 2 2 2 2 2 2 2 21 1 1 1 1_1_1_1_1_1_ _ _ _ _ _ _ _ _2 2 2 2 2 2 2 2 2 2121212121212121212

[0078] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 98281 6 6 5 8 2 6 8 6 6 2 0 3 8 7 5 6 74.0584.53290,78342,907022.0726.43065,68161,351,1PesaN R R A S A S A S A S A S343 4 4 4 4 1 1 1 1 5 5 5 5 7_4_4_4 4 4 9_9_9_9_2 2 2 2 2 2 2 2 2A A A_A_A_A A A A A_A_A_A_A_ _ _ _ _R R R RN R N N A A A A AN N N N RRN R N R N R N N N N N N N N N +R R R R R R R R R+ + + + + + +1 1 1+1+12121212+1+1+1+ + + + + +212 2 2 2121 1 1 1 1 1M M M2 2 2 2 2 2 2 2 2M M M M M M M M M M M M M M M M82828282828244444444444444444444444 4_ _ _ _ _ _ _ _ _ _ _4 41 1 1 1 1_ _ _ _ _ _ _ _2 2 2 2 21212121212121212121212121212

[0079] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 99058 3 9 6 0 7 6 9 6 1 7 8 0 0 3 4 3 56.0.720.6.3389,8,1426,7,11863.0.381.5.3414,6,2751,6,72,BfnI A S A S A S A S A S72727 8282828 0303030 1 1 1 1 2 2 2 2_ _2 2 3 3 3 3 3 3 3 3 3A A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+ +1+1+1+ +1+1+1+ +1+1+1+ +1+ + +2 212 2 2 212 2 2 212 2 2 212 2121212M M M M M M M M M M M M M M M M M M M4444444444444444444444444444444 4 4 4_ _ _ _ _ _ _ _ _4 4 4 41 1 1 1_ _ _ _ _ _ _ _ _ _2 2 2 2121212121212121212121212121212

[0080] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 100632 7 4 2 6 3 1 7 9 7 3 3 4 2 3 4 0 45.0.399.5.3509,4,6978,31,4231.0.646.5.3898,9,4487,5,37AfnI I N - N - N - N N R S R S S -S R R R R R R R A S A S A S A S9393939 0404040 24242 2 3 3 3 3 4 4 4_ _ _3_ _ _ _4_ _ _4_4_4_4_4_4_4_4 4A A A A A A A A A A A A A A A A A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+ +1+1+ + + + + + + + + + + + +2 2 212 2 212121212121212121212121212M M M M M M M M M M M M M M M M M M M44444444444444444444444 4 4 4 4 4 4 4_ _ _ _ _ _4 4 4 4 4 4 4 41_ _ _ _ _ _ _ _ _ _ _ _ _2121212121212121212121212121212121212

[0081] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 101 71 1 1 1 9 0 5 6 0 6 0 8 0 2 8 6 1 2. .,,. .,, -VoC-S R A S A S A S A S A S 4412121212525252527272727282828 8 0 0_ _ _ _ _A_A_A_A_2 2 3 3A A A A A_A_A_A_A_A_A_A_A_A_A N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+1+1+1+1+1+1+ + + + + + + + + + 22 2 2 2 2 2 2 212121212121212121212M M M M M M M M M M M M M M M M M M M 44 9 9 9 9 9__A_A_A_A_9A_9A_9 9A_ _9_9_9_9_9_9_9_9_9_1 A A A A A A A A A A A 2 N R N R N R N R N R N R N R N R N R N R N N N N N N N N

[0082] MR R R R R R R R+1+ + + + + + + + + + + + + + + + + 21212121212121212121212121212121212M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 102055 0 0 2 4 2 4 1 0 6 8 6 1 9 4 9 4 23.0052.53813,25701,009014.0359.43034,66031,321,1PesaN R R A S A S A S A S A S03031313131323232323939393930 0 0 0 2_ _ _ _ _ _ _A_A_A_4 4 4 4 4A A A A A A A_A_A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+ + + + + + + +2121212121212121+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 212M M M M M M M M M M M M M M M M M M M9_9 9_9_9 9 9 9 9 9 9 9 9 9 9 9 9 9 9A_A A A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+1+1+1+1+1+1+ + + + + + + 212121+ + +2 2 2 2 2 2 2 2 212121212121212

[0083] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 103615 2 1 6 2 8 4 0 4 1 9 8 6 0 5 9 6 52.0.098.5.3889,8 ,216,8,41894.0.812.5.3320,9,1549,5,72,BfnI A S A S A S A S A S2424243434343444444444525252527 7 7 7_ _ _ _ _ _ _ _ _A_A_2 2 2 2A A A A A A A A A_A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+1+1+ + + + + + + 212121+ + + + + + +2 2 2 2 21212121212121212121212M M M M M M M M M M M M M M M M M M M9_9_9 9_9_9_9 9_9_9 91 1 1 1 1 1 1 1A A_A A A A_A A A_A_A2_2_2_2_2_2_2_2_N N N N R N R N R N A A A A A A A AR R R RN R N R N R N R N N N N N N N N +1+ + + + + + + + + +R R R R R R R R212121212121212121212+1+1+1+1+ + + + M M M M M M M M2 2 21 1 1 1

[0084] M M M2 2 2 2 2M M M M M M M M Leydig 772843 P2023-4023-WO 104453 1 0 5 0 7 5 6 5 6 8 5 5 5 5 2 8 06.2.764.8.3831,90 ,1977,05,2365.0.623.5.3854,6,5448,3,67AfnI I N -S N -S N - N - N R R S S R R R R R R R A S A S A S A S8282828 0 0 0 0 1 1 1 1 2 2 2 2 9 9 9_ _ _2_3_3_3_3_3_3_3_3_3_3_3_3_3_3 3A A A A A A A A A A A A A A A A A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+ + + + +2121212121+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 212M M M M M M M M M M M M M M M M M M M121_21_21 1_2_21A_212121212121212121212121212A A A A_A_A_A_A_A_A_A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+1+1+1+ + + + + 2121+ + + + + + + +2 2 2 2 2 21212121212121212121212

[0085] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 105 62 5 9 2 8 4 6 5 3 5 8 8 7 2 5 0 7 8. . ,,..,, -VoC-S R A S A S A S A S A S 9304040404242 2 2 3 3 3 3 4 4 4 4 7 7_ _4 4 4 4 4 4 4 4 4 4 4 2 2A A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+ 21+ 21+ 21+ + + + + + + + + + + + + + 221212121212121212121212121212M M M M M M M M M M M M M M M M M M M 121 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 5 5_2_2_2_2_2_2_2_2_2 2 2 2 2 2 2 2 2 2A A A A A A A A A_A_A_A_A_A_A_A_A_A_A N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+ + + + + + + + + + + + + + + + + + 2121212121212121212121212121212121212

[0086] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 106785 8 2 4 6 3 0 1 1 4 8 8 8 3 2 0 7 20.0692.53099,03986,358362.0348.43985,66681,561,1PesaN R R A S A S A S A S A S72728282828 0 0 0 0 1 1 1 1 2 2 2 2 9_ _2 3 3 3 3 3 3 3 3 3 3 3 3 3A A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+ + + + + + + + + + + + + + + + + +2121212121212121212121212121212121212M M M M M M M M M M M M M M M M M M M525 5 5_2_2_25_25_25_25_25_25 5_2_25A_25A_2525252525252A A A A A A A A A A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+1+1+1+1+1+ + + + + + 2121+ + + + +2 2 2 2 2 2 2 2121212121212121212

[0087] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 107039 1 5 2 5 4 7 0 4 0 7 1 2 4 7 9 6 73.0.082.6.3327,5 ,796,0,11755.0.971.5.3279,0,1601,2,72,BfnI A S A S A S A S A S939 9 0 0 0 0_3 3 4 4 4 4242424243434343444444444A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+1+1+1+1+1+1+1+1+ + + + + + 2121+ +2 2 2 2 2 2 2 2 2 2 2121212121212M M M M M M M M M M M M M M M M M M M5252525252525 5252525 5252525 5252525_ _ _ _ _ _2_ _ _A_2A_2 2A A A A A A A A A_A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+1+1+1+1+ + + + + + 2121+ + + + + +2 2 2 2 2 2 212121212121212121212

[0088] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 108069 6 2 5 0 1 0 0 6 0 0 3 6 9 4 8 09.0.283.6.3066,30,1581,7,64026.0.173.5.3983,4,4431,0,47AfnI I N -S N N -S -S N - N R R R S R R R R R R A S A S A S A S828282820 0 0 0 0 0 0 0 1 1 1 1 2 2 2_ _ _ _3_3_3_3_3_3_3_3_3_3_3_3_3_3_3A A A A A A A A A A A A A A A A A A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+ + + + + 2121+ + + + + + + + + + + +2 2121212121212121212121212121212M M M M M M M M M M M M M M M M M M M727_27_27 7_2_27A_272727272727272727272727272A A A A_A_A_A_A_A_A_A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+1+1+1+ + + + + 2121+ + + + + + + +2 2 2 2 2 21212121212121212121212

[0089] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 109 06 6 2 8 4 2 1 2 7 4 4 0 7 9 5 9 2 2. .,,.. ,,-VoC-S R A S A S A S A S A S 2393939393040 0 0 2 2 2 2 3 3 3 3 4 4_ _4 4 4 4 4 4 4 4 4 4 4 4 4A A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+ 21+ 21+ 21+ + + + + + + + + + + + + + 221212121212121212121212121212M M M M M M M M M M M M M M M M M M M 727 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7_2_2_2_2_2_2_2_2_2 2 2 2 2 2 2 2 2 2A A A A A A A A A_A_A_A_A_A_A_A_A_A_A N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+ + + + + + + + + + + + + + + + + + 2121212121212121212121212121212121212

[0090] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 110625 8 0 5 9 3 2 8 1 6 5 0 9 4 5 5 6 14.0321.53248,03724,568906.0469.43482,87497,601,1PesaN R R A S A S A S A S A S44441313131 2 2 2 2 9 9 9 9 0 0 0 0 2_ _3 3 3 3 3 3 3 3 3 4 4 4 4 4A A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+ + + + + + + + + + + + + + + + + +2121212121212121212121212121212121212M M M M M M M M M M M M M M M M M M M727 8 8_2_2_28_28_28_28_28_28 8_2_28A_28A_2828282828282A A A A A A A A A A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+1+1+1+1+1+ + + + + + 2121+ + + + +2 2 2 2 2 2 2 2121212121212121212

[0091] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 111217 1 7 8 2 7 1 4 3 9 6 0 4 8 1 1 9 49.0.769.5.3554,1,2257,8,11664.0.009.4.3158,9 ,5720,5,62BfnI A S A S A S A S A S242 2 3 3 3 3_4 4 4 4 4 4444444441313131323232323A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+1+1+1+1+1+1+1+1+ + + + + + 2121+ +2 2 2 2 2 2 2 2 2 2 2121212121212M M M M M M M M M M M M M M M M M M M8282828282828 8282828 0303030 0303030_ _ _ _ _ _2_ _ _A_2A_3 3A A A A A A A A A_A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+1+1+1+1+ + + + + + 2121+ + + + + +2 2 2 2 2 2 212121212121212121212

[0092] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 112846 3 8 0 2 0 5 7 9 2 2 7 4 1 1 0 0 42.0.768.6.3109,1,3059,82,3883.0.613.5.3102,6,2865,0,57AfnI I N -S N -S N -S N - N R R R S R R R R R R A S A S A S A S939393930 0 0 0 2 2 2 2 3 3 3 3 4 4 4_ _ _ _4_4_4_4_4_4_4_4_4_4_4_4_4_4_4A A A A A A A A A A A A A A A A A A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+ + + + + 2121+ + + + + + + + + + + +2 2121212121212121212121212121212M M M M M M M M M M M M M M M M M M M030_30_30 0_3_30A_303030303030303030303030303A A A A_A_A_A_A_A_A_A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+1+1+1+ + + + + 2121+ + + + + + + +2 2 2 2 2 21212121212121212121212

[0093] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 113 78 6 3 2 7 9 0 6 5 8 4 9 4 8 3 9 1 1. .,,. .,, -VoC-S R A S A S A S A S A S 4423232323939 9 9 0 0 0 0 2 2 2 2 3 3_ _3 3 3 4 4 4 4 4 4 4 4 4 4A A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+ 21+ 21+ 21+ + + + + + + + + + + + + + 221212121212121212121212121212M M M M M M M M M M M M M M M M M M M 031 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1_3_3_3_3_3_3_3_3_3 3 3 3 3 3 3 3 3 3A A A A A A A A A_A_A_A_A_A_A_A_A_A_A N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+ + + + + + + + + + + + + + + + + + 2121212121212121212121212121212121212

[0094] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 114157 5 2 2 5 6 5 3 2 6 0 0 2 7 4 3 5 50.0367.43593,31466,848771.0147.43592,21367,591,1PesaN R R A S A S A S A S A S34344444444 9 9 9 9 0 0 0 0 2 2 2 2 3_ _4 3 3 3 3 4 4 4 4 4 4 4 4 4A A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+ + + + + + + + + + + + + + + + + +2121212121212121212121212121212121212M M M M M M M M M M M M M M M M M M M131 1 1_3_3_31_31_32_32_32_32 2_3_32A_32A_3232323232323A A A A A A A A A A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+1+1+1+1+1+ + + + + + 2121+ + + + +2 2 2 2 2 2 2 2121212121212121212

[0095] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 115021 8 2 7 9 1 0 4 0 1 9 6 8 3 7 4 0 69.0.806.6.3192,6,2296,5,01553.0.452.5.3609,2,1842,5,72,BfnI A S A S A S A S A S3434344444444404040404242424243434343_ _ _ _ _ _ _ _ _ _ _ _A_A_4A A A A A A A A A A A A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+1+1+1+1+1+1+1+1+ + + + + + 2121+ +2 2 2 2 2 2 2 2 2 2 2121212121212M M M M M M M M M M M M M M M M M M M2323232323232 9393939 9393939 9393939_ _ _ _ _ _3_ _ _A_3A_3 3A A A A A A A A A_A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+1+1+1+1+ + + + + + 2121+ + + + + +2 2 2 2 2 2 212121212121212121212

[0096] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 116639 4 3 2 0 1 6 0 6 0 4 0 2 1 1 4 0 91.0.328.6.3026,9,1448,8,83730.1.782.6.3408,41,1290,4,96AfnI I N -S N -S N - N - N R R S S R R R R R R R A S A S A S A S4444444 2 2 2 2 3 3 3 3 4 4 4 4 3 3 3_ _ _4_4_4_4_4_4_4_4_4_4_4_4_4_4_4 4A A A A A A A A A A A A A A A A A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+ + + + +2121212121+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 212M M M M M M M M M M M M M M M M M M M939_39_39 0_3_40A_404040404040404040404242424A A A A_A_A_A_A_A_A_A_A_A_A_A_A_A_ANRN R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R N R +1+1+1+1+1+1+ + + + + 2121+ + + + + + + +2 2 2 2 2 21212121212121212121212

[0097] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 117 64 0 5 9 3 6 5 2 8 6 2 7. .,,..,, -VoC -S NCR -S NC-S NC-S NR R R R R R RA S A S A S A S 3444444 4 4 4 4 4_ _ _4_4_4 4 4 4A A A A A_A_A_A_A N R N R N R N R N R N R N R N R N R +1+1+1+1+ + + + + 22 2 21212121212M M M M M M M M M 242_424242434343434 re yl ryryryr r rneln elele e eA_A_A_A_A_A_A_A_AmatOmatOma nt Oma nt Omat mat maN R N R N R N R N R N R N R N R N RpApApApApAptApA +1+ + + + + + +o o o21212121212121+ 21A A A A 2 N N N N N N N

[0098] M M M M M M M M M R R R R Leydig 772843 P2023-4023-WO 118 6 . . , , 880.A A A A 0 N N N N 840.A A A A 53N N N N 2249,00 4 3833 9 52,1 6 9 5872,4521 4 612, 50, 579,3,47 3 6 3-V2oAfBfP- 2C nIneIsaVo- NCS R -SR RA S A S re et lma oal rettallorettallolrettalorttppnmo pnCmo pnCmo pnmoAe e eCeC o T o T o T T

[0099] N N NoNoN Leydig 772843 P2023-4023-WO 119 eldtDA A A A AMclyoC hSN N N N NTe Csemi h2 rT1 hTt aCe nA A A A A esM N N N N N u miroiPra tcnntlneeR D86 592 810 10 82ovth i cDaS4 1 112noitiddaetalpmetgniwollofsruoh 21dna,sruoh4,sruoh0taytilibat seet at a anp T NInIReAoS CnIr aurtgAaertAoi1 1 1 1:1enIt(Na 0R:01:01:01:1 0: 110pxR mi tet uMoA a mrhroettiNtp e o o o o oR A m N N N N N osw rf a doM nareN13noRhR it m_t Ci at2+1A a Pwp 2ulqa-sA M v TnoE Rit.pa7er re 4 4 4 4 4ett4lSn mat1 _41_41_41_41_1b -e ecp 2 2 2 2 2annA M M M M M T Ooc Leydig 772843 P2023-4023-WO 120 A8N5.0 3A A A A A A A3N N N N N N N7.1 9A N 5945256.15.637656989217.08.4378418752BfnI R S CnI IR S CnI IR:1: : 3 3 3 3:0 1:1:1: 11 010: 11010: 1100:1 3.0:3.0:3.0:3.:0101010 1:3. :1 3. :1 3.13:1 3:1 3o o os s s s s s sN N NeYeYeYeYeYeYeY N13N13N13N1N1N1R_R R R3R3R3+ +_+_+_+_+_12A12A12A12A12A12A M M M M M M 44444444444444444 4_ _ _ _ _ _ _ _4 41 1 1 1 1 1 1 1_1_2 2 2 2 2 2 2 2 212

[0100] M M M M M M M M M M Leydig 772843 P2023-4023-WO 121 A A A07A A A31N N6A N N N.4N.0 2N SR A S CnInIReA S CnInIReA S C :1:1:3. 2 2 2 2: 13 0:02: : : 1:01:01:1 0: 2 202 202 20210:1 0:1 0:1 0se oNoNo o o o o oY N N N N N N N13N1N1N1 1+_3_R3N R R_R3_R3_12A +12A +12A +12A +12A M M M M M 44444444444 4 4 4_ _ _ _4 4 4 41 1 1_ _ _ _ _2 2 2121212121212

[0101] M M M M M M M M M Leydig 772843 P2023-4023-WO 122 A A95A A A1A A A N N.1 8N N N7.0 8N N N A N 6762188180.10.831761900124.09.4308328197AfnI I R S CnI IR S CnI I303: : ::2 3.03 :3.03 :3.0:32:3.2:3.2:3:.2:3. 5050020202.0 2:1 3 2:1 3 2:1 3 2:1 3:1:1ses s s s s s so oYeYeYeYeYeYeYeY N N N13N13N13N1R R R R3+_ _ _ _12A +12A +12A +12A M M M M 444_444444444444444441_21_21_21_21_21_21_21_21_212

[0102] M M M M M M M M M M Leydig 772843 P2023-4023-WO 12356.A9A4A A A0A3 6N2.2N0.1 7N N N7.1 4N7.732508892153.19.438801686395.47.8323338254saN R S CnI IR S CnI IR S 505: :05: 1:1 0: 5 5: 55: 55 5303 3 3 :1 0 0:1 0 0:1 0 0:1 05 3.0:3 0:3 0:305. . .05050o o os s s sN N NoNoNoNeYeYeYeY N1 1R3N3N13N13+_R+_R_R_12A12A +12A +12A M M M M 444 4 4 4 4 4 4 4 4_4 4 4 4 4 4 4 4 41_21_21_21_21_21_21_21_21_212

[0103] M M M M M M M M M M Leydig 772843 P2023-4023-WO 124 24.A1A A31 3N5.0 9A N N N1.2 6A A N N -Vo

[0104] CnI IR S CnI IR S CnI:5::5:3.5::3 5::3 5:3101: 010101 113 5: .13 5: .13 5: .13:1:1:1:1 0:1 0seseseso o o o oY Y YeY N N N N N N13N1N1N1N7R3 3 3 2+_R 12A +_R 12A +_R 1 +_R+_2A12A12A M M M M M 444_441_44_4N N N N N _ R+921212121_R+9A1_R+9R 1_+9R 1_+91_2 2A2A2A2A M M M M M M M M M Leydig 772843 P2023-4023-WO 125 A9N4.0 5A A A4N N N7.2 4A A A7N N N4.4 2A N 0530248.07.53600184743.12.5310433442BfnI R S CnI IR S CnI IR:1:01:13: 10101 03 :03030 :1::3 1 3:1 31 0:1 0:1 01 3. :3. :3. :3.. : . : .0101010 1:1 3 1:1 3 1:1 3o o osesesesesesesN N N Y Y Y Y Y YeY N7N7N7N7N7N7R2R2R2R2R2 2+_+_+_+_+_R_12A12A12A12A12A +12A M M M M M MN N N N N N N N N N R+9_R+9_R+9_R+9_R+9R+9R+9R+9R+9R+91A1A1A1A1_A1_A1_A1_1_1_2 2 2 2 2 2 2 2A2A2A

[0105] M M M M M M M M M M Leydig 772843 P2023-4023-WO 126 A A A5A38N N N0.0 2A A N N N7.0 1 3.0SR A S CnInIReA S CnInIReA S C :1:1:3. 20202: : : : 020202 202 2 2 2 213:1:1:1:1:1 0:1 0 0:1 0 0:1 0se o o o o o o o oY N N N N N N N N N72N7N7N7N7R+_R2_R2_R2_R2_1 + 2 A12A +12A +12A +12A M M M M M N N N N N N N N N R+91_R+9_R+9_R+9_R+9_R+9_R+9_R+9_R+9_2A12A12A12A12A12A12A12A12A

[0106] M M M M M M M M M Leydig 772843 P2023-4023-WO 127 A A34 9A A A56.6A A A N N.1N N N0N N N2.347041163223.11.732366631204.05.5333711586AfnI I R S CnI IR S CnI I303 3 3::02:2:2:252 3. :002 3. :002 3. :3.:020 2:3.13:2:3.13:2:3.13:2:3.13 05:01:1seseseseseseseso oY Y Y Y Y Y YeY N N N72N72N7N7R R R2 2+_ _ _R_12A +12A +12A +12A M M M MN N N N N N N N N N R+9_R+9_R+9_R+9_R+9_R+9_R+9R+9R+9R+91A1A1A1A1A1A1_A1_A1_1_2 2 2 2 2 2 2 2 2A2A

[0107] M M M M M M M M M M Leydig 772843 P2023-4023-WO 12864.00 5 1.72 6 0.A72 6N3.A A A6A 08N N N7.0 1N8.430963240337.22.530682361543.07.3314036529saN R S CnI IR S CnI IR S 5 : : : 05:01: 510: 51050: 5105: 0: 51050: 53 1003 :5 3.03 :3.03 :3.0:3.0505050os s sNoNoNoNoNoNeYeYesYeY N72N72N72N7R R R R2+_+_ _ _12A12A +12A +12A M M M MN N N N N N N N N N R+9_R+9_R+9_R+9_R+9_R+9_R+9_R+9R+9R+91A1A1A1A1A1A1A1_A1_1_2 2 2 2 2 2 2 2 2A2A

[0108] M M M M M M M M M M Leydig 772843 P2023-4023-WO 129 A A26A A A A 02A A N N.N N N N N N -Vo

[0109] CnI IR S CnI IR S CnI:5: ::5:3.5:5 3.5:5 3:.5:5 3. 101 1 1: 13:1 3:1 3:1 3:01:0 011:1:1 0: 110sesYesYesYe oY NoNoNoNoN N7N7N7N7N0R2R2R2R2 3+_+_+_ _R_12A12A12A +12A +12A M M M M M N N N N N N N N N R+90 0 0 01_R+9_R+9_R+9_R+3R 2 A12A12A12A12 _+3R A12 _+3R A12 _+3R A12 _+9_A12A M M M M M M M M M Leydig 772843 P2023-4023-WO 130 A7N7.0 1A A A5N N N57.1 4A A A N N N1.1A N 5311464173.12.634631629484.00.5350918852BfnI R S CnI IR S CnI IR:1:01:13: 10101 03 :03030 :1 3:1 3:1 31 0:1 0:1 01 3. :3. :3. :3.: . : . : .0101010 1:1 3 1:1 3 1:1 3oNoNosNesYesYesYesYesYesYeY N03N0N0N0N0N0R R3R3R3R3R3+_+_+_+_+_+_12A12A12A12A12A12A M M M M M MN N N N +9_+9_+9_+0N N N N N NR R R R3R+03R+03R+03R+9R+9R+912A12A12A12 _A12 _A12 _A12 _A1_2A1_2A1_2A

[0110] M M M M M M M M M M Leydig 772843 P2023-4023-WO 131 A A A40 5A94.62 1A10 5A N N N.0N N.N SR A S CnInIReA S CnInIReA S C :1:1:3. 2020202: : : : 0202 202 202 2 213:1:1:1:1:1 0:1 0:1 0 0:1 0se o o o o oNo o oY N N N N N N N N03N03N03N0N0R R R3 3+_+_ _R_R_12A12A +12A +12A +12A M M M M M N N0N0N0N0N N N N R+91_R+3R 2 A12 _+3R A12 _+3R A12 _+3R A12 _+9_R+9_R+9_R+9_A12A12A12A12A

[0111] M M M M M M M M M Leydig 772843 P2023-4023-WO 132 A A25 2A A A42.3A A A N N.1N N N0N N N A N5101144154.15.831863103136.06.4304637677AfnI I R S CnI IR S CnI I303:0303:2:2:2:25 52 3. :02 3. :02 3.0::02 3.0 2:3.13:2:3.13:2:3.13:2:3.13 0:01:1ses s s s s s so oYeYeYeYeYeYeYeY N N N03N0N0N0R R3R3 3+_A +_A +_R+_121212A12A M M M MN N N N N N N N +01 30 0N NR R R R0R2 _+3A12 _+3+3+9_R+9_R+9_R+9_R+03R+03A12 _A12 _A12A12A12A12A12 _A12 _A

[0112] M M M M M M M M M M Leydig 772843 P2023-4023-WO 13329.A21 9N4.A61 8N5.A90 1N3.A51 9N8.A 09N4.639545157185.31.639622290405.32.6396333776saN R S CnI IR S CnI IR S 5 : : : : 053 :01: 510: 51050: 51050: 51050: 51003 :5 3.03 3 :3.0:3.0:3.0505050o os s s sN NoNoNoNoNeYeYeYeY N03N0N0N0R R3R3 3+_A +_A +_R+_121212A12A M M M MN N N N N N N N +01 302 _+3A12 _+9_R+9_R+9_R+9_R+0N NR R R3R+03R+03R+03A12A12A12A12A12 _A12 _A12 _A12 _A

[0113] M M M M M M M M M M Leydig 772843 P2023-4023-WO 134 A A66A A A A 12A A N N.N N N N N N -Vo

[0114] CnI IR S CnI IR S CnI:5: ::5:3.5:5 3.5:5 3:.5:5 3. 101 1 1: 13:1 3:1 3:1 3:01:0 011:1:1 0: 110sesesese oNoNo o oY Y Y Y N N N N0N0N0N0N4R3R3R3R3 4+_+_+_ _R_12A12A12A +12A +12A M M M M M N N N N N R+91N1N1N1N11_R+9_R+9_R+9_R+3R 2 A12A12A12A12 _+3R A12 _+3R A12 _+3R A12 _+3A12 _A M M M M M M M M M Leydig 772843 P2023-4023-WO 135 A5N4.1 6A A A4N N N1.1 8A A A1N N N4.0 1A N 2627595.00.630894703425.01.5319825172BfnI R S CnI IR S CnI IR:1:: : :0: 1 1: 01 13 01 03 :030301:3 1:3 1:31 0:1 0:1 01 3. :3. :3. :3.0101010 1: .1.1.13:1 3:1 3o os s s s s s sN NoNeYeYeYeYeYeYeY N4R4N44N44N44N44N44+_R A +_R A +_R A +_R A +_R A +_121212121212A M M M M M MN N N N N +11 31 1 1 1N1N N N NR R R R R R R1R1 1 12 _+3A12 _+3+3+3+3+3+3R+3R+3A12 _A12 _A12 _A12 _A12 _A12 _A12 _A12 _A

[0115] M M M M M M M M M M Leydig 772843 P2023-4023-WO 136 A A A7A A A3N20 8N N N7A N N. .0 5N SR A S CnInIReA S CnInIReA S C :1:1:3. 202 2 2: 13:01:0 02: 1:1:1 0: 2 2: 02 2: 02 20210:1 0:1 0:1 0se oNoNoNoNoNo o oY N N N N44N44N44N44N4R_R_R_R R4+ A + A + +_+_121212A12A12A M M M M M N R+1N1N1N1N1N1N1N1N113R 2_+3R A12 _+3R A12 _+3R A12 _+3R A12 _+3R A12 _+3R A12 _+3R A12 _+3A12 _A

[0116] M M M M M M M M M Leydig 772843 P2023-4023-WO 137 A A46.5A A A80.3A A A N N0N N N0N N N A N 4188052275.05.730492476105.00.5399434037AfnI I R S CnI IR S CnI I303:03030 :2:2:2:25 52 3. :02 3. :02 3. :02 3.:02:3.13:2:3.13:2:3.13:2:3.13 0:01:1seseses s s s so oY Y YeYeYeYeYeY N N N4N4N4 4R4_R4_R4N R4+ + +_ _12A12A12A +12A M M M M N1N N N N N N N N NR+1 3R12 _+3R1A12 _+3R1R1R1R1R1R1R1A12 _+3A12 _+3A12 _+3+3+3+3+3A12 _A12 _A12 _A12 _A12 _A

[0117] M M M M M M M M M M Leydig 772843 P2023-4023-WO 13864.0 9A A A6N N N6.0 5A A A4N N N2.A 17N4.431401538181.03.435102794556.07.3383198979saN R S CnI IR S CnI IR S 505: : : : 3 3 3 3 :01: 510: 51050: 51050: 51050: 5100:5 3.0:05 3.0:05 3.0:05 3.0o o o o o oses s sN N N N N N YeYeYeY N44N4N4N4R+_R4_R4_R4_12A +12A +12A +12A M M M M N1N1N1N N N N N N NR+1 3R2 _+3R A12 _+3R1A12 _+3R1R1R1R1R1R1A12 _+3A12 _+3A12 _+3+3+3+3A12 _A12 _A12 _A12 _A

[0118] M M M M M M M M M M Leydig 772843 P2023-4023-WO 139 A A90A A A2A 0 N N31 1A N N.N.N N -Vo

[0119] CnI IR S CnI IR S CnI:5::5:3.5::5 3.5:5 3:.5:5 3. 101 1 1: 13:1 3:1 3:1 3:01:0 011:1:1 0: 110sesesese oNoNoNo oY Y Y Y N N N44N44N4N4N4R_R R4R4R4+ +_+_+_+_12A12A12A12A12A M M M M M N1N1N1N1N4N4N4N4N R+1 3R 2_+3R A12 _+3R A12 _+3R A12 _+4R A12 _+4R A12 _+4R A12 _+4R3A12 _+4A12 _A M M M M M M M M M Leydig 772843 P2023-4023-WO 140 A5N8.0 4A A A8N N N3.0 2A A A2N N N0.1 5A N 08761- 12.29.639877150317.11.5300396432BfnI R S CnI IR S CnI IR:1:01:13: 10101 03 :03030 :1::3 1::3 1:31 0:1 0:1 01 3. :3. :3. :3.0101010 1: .1.1.13:1 3:1 3o os s s s s s sN NoNeYeYeYeYeYeYeY N4R4N44N44N44N44N44+_R A +_R A +_R A +_R A +_R A +_121212121212A M M M M M MN N N N N +31 43 3 4 4N4N N N NR R R R R R R4R3 3 32 _+4A12 _+4+4+4+4+4+4R+4R+4A12 _A12 _A12 _A12 _A12 _A12 _A12 _A12 _A

[0120] M M M M M M M M M M Leydig 772843 P2023-4023-WO 141 A A A3A A A2N40 8N N N1A N N. .0 5N SR A S CnInIReA S CnInIReA S C :1:1:3. 202 2 2: 13:01:0 02: 1:1:1 0: 2 2: 02 2: 02 20210:1 0:1 0:1 0se oNoNoNoNoNo o oY N N N N44N44N44N44N4R_R_R_R R4+ A + A + +_+_121212A12A12A M M M M M N R+3N4N4N4N4N3N3N3N314R 2_+4R A12 _+4R A12 _+4R A12 _+4R A12 _+4R A12 _+4R A12 _+4R A12 _+4A12 _A

[0121] M M M M M M M M M Leydig 772843 P2023-4023-WO 142 A A76.4A A A A A A A N N0N N N N N N N A N 0753198445.06.836171212183.09.4345396247AfnI I R S CnI IR S CnI I303:03030 :22 3. :02 3. :02 3. :02 3.:02:3:.21 3:2:3:.2:25 513:2:3.13:2:3.13 0:01:1seseseses s s so oY Y Y YeYeYeYeY N N N4N4N4N4R4_R4_R4_R4+ + + +_12A12A12A12A M M M M N4N4N N N N N N N NR+1 4R2 _+4R4A12 _+4R4A12 _+4R3R3R3R3R4R4A12 _+4A12 _+4A12 _+4+4+4+4A12 _A12 _A12 _A12 _A

[0122] M M M M M M M M M M Leydig 772843 P2023-4023-WO 14328.0 7A6N8.A51 8N7.A90 1N6.A32 1N6.A 07N 4.430638272347.47.634462162421.17.4340010968saN R S CnI IR S CnI IR S 5 : : : : 053 3 3 :01: 510: 51050: 51050: 51050: 5100:5 3.0:3.03 :3.0:3.0505050o o o o os s s sN N N N NoNeYeYeYeY N4N4N4 4R4_R4_R4N R4+ + +_ _12A12A12A +12A M M M M N4N N N N N N N N NR+1 4R42 _+4R3A12 _+4R3R3R3R4R4R4R4A12 _+4A12 _+4A12 _+4+4+4+4+4A12 _A12 _A12 _A12 _A12 _A

[0123] M M M M M M M M M M Leydig 772843 P2023-4023-WO 144 A A05.7A A A02.7A N N0N N N0N - Vo 2AfBfsaS - NPR -Vo 2AfBfsaS - NPR -Vo 2

[0124] CnInIReA S CnInIReA S C :5:5: ::5:3.13:5:3.51 3:5:3.51 3:5:3.13ses s sYeYeYeY N44N4N4N4R_R4_R4R4+ A + A +_+_121212A12A M M M M N N N NrRererere+314R3R3R32 _+4A12 _+4A12 _+4A12 _A NmaA NmaAmaAmaA RtpRtpN RtpN RtpM M M M A A A A Leydig 772843 P2023-4023-WO 145 A A A A A A A A N N N N N N N N A N 351948A N0.344541248129.06.433221 74 2 35 1 80 8 35 4 9 2 4 545 991 086 682 3 336 4 193 7 755 0 473 2AB saS - RA B saS - fnfInINPeA -Vo 2 fnfnINPeR A -Vo 2R S CIR S C rerer rome eomomomC C C C

[0125] NatpNatNatNatT T T T N N N N ApApApA Leydig 772843 P2023-4023-WO 146 R8C78627650 0 7 0 6 0 6 5 8 0Pe dtD5.9.4.7. 187 8 4.6.4.8. 37. 47. 34. 35. 27. 33.ql lC S0 0 0 0 0 0 0 0 0 0 0 0 0 3-cTyoChse n9177987 8 7 1 3 8 8 0 2 1 7R2 5 5 6 1 3 5 2 2 1 9petS-en OMTe miTemirP otnoitiddaetalpmetgniwollofsruoh4taytilibats seeriugtoalroenphcmeet TmA9 9 9 9 9 9 9o N_A_A_A_A_A_A_9_9_9_9_9_9_9_orD 1fd rA A A A A A A A oeteN N N N N N N N N N N N N N m R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R aa1 1 1 1 1 1 1 1 1 1 1 1+ nr t2 2 2 2 2 2 2 2 2 2 21 1oitgaep 2 2 2tA M M M M M M M M M M M M M M ulnaIv(xnoietetetetEit.aaha8Mpha aphphpercilebtfi sosososoasadh'oPhPh hC C 3 M'3' P3' P3'3 3 3 3 3d dT M C C C Cd d Leydig 772843 P2023-4023-WO 147754.0368.23918.185,18120.173,236PesaN R 9 9 9 9 9 9 9 97 7 7 7 7 7 7 7 7_ _ _ _ _ _ _ _9_9_2 2 2 2 2 2 2 2 2A A A A A A A A A A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R R R R R R R R R R R R R R R R1+ + + + + + + + + + + + + + + + R+ R+2121212121212121212121212121212121212M M M M M M M M M M M M M M M M M M M eta eteteha ataph h hTCdCdTdTdTdono o o spspspsin n n ohohohohd dv v v vdnInInInImi i iPamamama' P3' P3' P3'3 3C Leydig 772843 P2023-4023-WO 148138.0043.23175.599,02448.934,48BfnI 727 7 7 7 7 7 7 7 7 7 7 7_2_2_2_2_2_2_2_2_2_2_2_27_27_2_9_9_9 9A A A A A A A A A A A A A A A A A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1+2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 212M M M M M M M M M M M M M M M M M M M T3 3 3CdTdTdTdono o od CdCdCdv v v v inminminmiCC Cd d d dnInInInI a a ama Leydig 772843 P2023-4023-WO 149253.0786.23864.388,16443.795,066AfnI72_AN R+1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2M M M M M M M M M M M M M M M M M M M9_9_9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9A A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R R R R R1 1 1 1 1 1 1 1 1 1 1 1 1 1+ +1+1+1+2 2 2 2 2 2 2 2 2 2 2 2 2 212 2 2 212M M M M M M M M M M M M M M M M M M MsTo o ooshososoCdTdTdTd nininiPhPhPhP3C3C3C3CdC ddC ddC ddv v v vdnInInInImamama Leydig 772843 P2023-4023-WO 150 -S RA S lolrt or1 ntr1r 1r 1r 2r 2r 2r 2rono9_1r 1r 1r 1r 2r 2r 2r 2re e e e e e e eC e C teAe e e e e e e emNmaamamamamamam m t mapt mamamamamama aptptptptptptpl taplpRt+1ptptptptptaptaptpA A A A A A A A meme2A A A A A A A A oo o o o o o oA A A A A A A A T T N N N N N N N N M N N N N N N N N R R R R R R R RoNoN onima Leydig 772843 P2023-4023-WO 151 A N atD. .e e dlC S0 0.0.0.0.0.0.0.0.1.0A At lac ohN Nl ypC shern4 2 4 5 7 2 7 9 9 0 5ha14. 97. 07. 14. 73. 08. 31211198975 2me4 e0 0 0 2 3 2.0. . . .23. 02tT .gMt 3 3 3 3 3 3 3030303033987niC llf0 3r781.3 6.60824tilitPs-re taS2R -NVrR A SoC tririib rra neet bue inminminminminminminminmininimsa cmi5 0 0 5 0 0 5 0 m0 m mlol atM nIT1 2 3 1 2 3 1 2 35102rt orpntaRs s s s s s s s sonofoCohohohohohohohohoshoshohCeCtPt c q- P3P P P P P P P P P Pa el ta _3_3_3_3_3_3 3 3 3 3plap T9pm R_9A_9A_9A_9A_9_ _ _ _ _A_9A_9A_9A_9 9A_A_memifpe rA N N N N N N N N N N TeTot eNonS- R R R R R R R R R R R em+ + + + + + + + + + + NoNoitat 1 1 1 1 1 1 1 1 1 1 1anOp 2 2 2 2 2 2 2 2 2 2 2ulA M M M M M M M M M M M a M vTEe .m9ielTebamiTrP Leydig 772843 P2023-4023-WO 152 57564.0 1.47066. 000.3736319. 454.968, 707,47133 46.292.137,596,2221X M O R A F -S2R -AVoAfS CnI ninmininin n n n n n n nm m mimi imimi imimim0 5 0 m m31 2035102035102035102sohP3_9_ e e e e e e e eAtaNl tal tal tal tal tal tal ta eta eta etap p p p p p plpl l lR+m1elomTrt elor melomelomelomelomelomelpomelpom lpom lon TtrnTtrnTtrnTtrnTtrnTtrnTtrnTt erernTtnTt2 o o o o o o o o o o o o o o o o o o o o on

[0126] M N C N C N C N C N C N C N C N C N C N C NoC Leydig 772843 P2023-4023-WO 153 78 8A332 8.7 3N1.2.01286. 432619.8.A2 103N 62 3 4 22.096. 6325639.4.3.4,94271539,5 5579,0,2,2 1 3314512. 232 75 16 7.7. 3.922.29 1 45, 441, 10,96,212,-37434 525X M OCI 5X A Y O R F V C R -S2 Pe-S2R - VA saR -A So fBfNVCnInIR A SoC nim03etalpmeloTrt2v2 2 2onoTvTvTvT

[0127] N C R R R R Leydig 772843 P2023-4023-WO 154 retsaM R C Pq- T R pdloD et hSSt-seerC nhOTeMlT cnaey emiCh MtT6eC mir ePcn not ecRn seaoi rtleioD tdulD S dFatentiaolppdn nR mE aett.sh6lneaegrneD M i wmoaltlpof ats Aerg ermuN o DaTaN hs6nyotiitlainbiabts mo _ _ _ _ _ _ _ _ _ _ _ercuth2 2 212 2 2 212 2 2 2tiM+M+M+M M M M M M M M a+ + + + + + + +rwsos s s s s s s s s s s s s se ) ho o o o o o o o o o o o o opse h h h h h h h h h h h h h hmeitgP o3P P P P P P P P P P P P P P le _39_3_3_3_3_3_3_3_3_3_3_3_3_3__9_9 9 9 9 9 9 9 9 9 9 9 9 9m onm_ _ _ _ _ _ _ _ _ _ _ _ _ohaA A A A A A A A A A A A A A A orcfeN e N N N N N N N N N N N N N N N l R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R R oTp1 1 1 1 1 1 1 1 1 1 1 1 1+ + noAmitNa 2 2 2 2 2 2 2 2 2 2 2 2 21212S M M M M M M M M M M M M M M M aDuldaevtEar.g0e1tenlI(baxiT M Leydig 772843 P2023-4023-WO 155 61087 76.0 6. 1370.0 6.0672 3.0 3912 6.39 1. 223 5.313493194. 244.16.74271 .026 929508 3133873346818.2 7.18 9124 .3 .537022779379161 3 724-S2 Pe-S R - VA B saR A So fCnfInIN R A S 3_41_4_4_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _2121212 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2M+M M M M M M M M M M M M M M M s+s+s+s+s+s+s+s+s+s+s+s+ + + +M+M+M+o o o o o o o o o os s s s s s sh h h h h h h ho o o o o o o o oP P P P P Ph h h h h h h h h h h33 3 3P P P P P P P P P P P P P _9_ _ _3_3_3_3_3_3_3_3_3_3_3_3_3_3_3__9_9_9_9_9_9_9_9_9_9_9_9_9_9_9 9 9 9A A A A A A A A A A A A A A A_A_A_A_A N N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R 11 1 121+ + + + + + + + + + + + 22 2 21212121212121212121212121212

[0128] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 1563629004 74.60.0 7. 2340.0 4.06677. 171 6. 551 3. 000 6. 86.3 3 32313483 014 28. 83 0. 677 8.57.971.2118022 93234 4304 794605860 434 49. 9.8.1.7 088 09 .5881034 48 9023342 44 83 1 123Pe-PsaS2R- esNaAVoAfBfN R S CnInIR8_81_9_91_91_ _ _ _ _ _ _ _ _ _ _ _ _ _ _212 2 212 2 2 2 2 2 2 2 2 2 2 2 2 2 2M+Ms+M s+M s+M s+M M s+s+M s+M s+M M s+s+M s+M s+M M s+s+M+M+M+M+o o o o o o o o o o o o os s s s sh h h h h h h h h h h ho o o o o oP P P P P P P P P P Ph h h h h h h3 3 3 3 3 3 3 3 3 3P P P P P P P P_ _ _ _ _ _ _ _ _3 3 3 3 3 3 3 3 39 9 9 9 9 9 9 9_ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _9 9 9 9 9 9 9 9 9 9 9A A A A A A A_A_A_A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R R R R R R R R R R R R R R R R1 1+ + + + + + + + + + + + + + + +2 21212121212121212121212121212121212

[0129] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 1575031803 72.3.706080 0.0.0.03809. 492 3. 471 8. 180 3. 22.3 3 3033327 302 7 57.61. 62 9 8. 340. 373.11 05 50263900411722141 52.6538294 7.6.3.37.9 176 225 5 269 4 5 062 76631412 412Pe-S2B s-f aRV AfBnIN R A SoCnfInI313 3 4 4_1_1_1_11 1_ _ _ _ _ _ _ _ _ _ _ _ _ _ _2 2121212 2 2 2 2 2 2 2 2 2 2 2 2 2 2M+M+M M+M+M+M M+M+M+M M+M+M+M M+M+M+Ms s+s s s s+s s s s+s s s+ +o o o o o o o o o o o os s s s s sh h h h h h h h h h ho o o o o o oP P P P P P P P P Ph h h h h h h h3 3 3 3 3 3 3 3 3P P P P P P P P P_ _ _ _ _ _ _ _3 3 3 3 3 3 3 3 3 39 9 9 9 9 9 9_ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _9 9 9 9 9 9 9 9 9 9 9 9A A A A A A A_A_A_A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R R R R R R R R R R R R R R R R1 1+ + + + + + + + + + + + + + + +2 21212121212121212121212121212121212

[0130] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 1587782772041.30.0 3.630.0 2.4862 1. 44 350 8. 6 9 722.9.6.3 31313234830. 6 432 60 6. 5. 70. 78.2246 472095854 305753 266487321.6113 8.2101.0 7.409.29854 61293933 53159411 9Pe-S2A-fB snf aRV AfInIN R A SoCnI8 18 8 8 9_1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 21_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _2121212121212121212121212121212121212M+M M M M M M M M M M M M M M M M M Ms+os+s+s+s+s+s+s+s+s+s+s+s+s+s+s+s+s+shoPhohohohohohohohohohohohohohohohohoh3P_3P3P3P3P3P3P3P3P3P3P3P3P3P3P3P3P3P39__9_9_9_9_9_9_9_9_9_9_9_9_9_9_9_9_9_9A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R R R R R R R R R R R R R R R R R R1+21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 212

[0131] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 159 87701 55.8 6. 3370.0 1.0776 2.9 4876 0.20 0. 133 3.313972872. 478.63.55424 .335 983539 44528370 255.9109.72 301 7 ..6 6 907 2 449 3 837 812 493-S2-Pes-S RV AfBf aR A SoIN CnInR A S 223_23 31_221_221_21 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2M+M M M M M M M M M M M M M s+s+s+s+s+s+s+s+s+s+s+ + +M+M+M+M+M+o o o o o o o o os s s s s s s sh h h h h h ho o o o o o o o o oP P P P Ph h h h h h h h h h h h33 3P P P P P P P P P P P P P P __ _3_3_3_3_3_3_3_3_3_3_3_3_3_3_3_39 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9__ _ _ _ _ _ _ _ _ _ _ _ _ _ _9 9 9A A A A A A A A A A A A A A A_A_A_A_A N N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R 11 1 121+ + + + + + + + + + + + 22 2 21212121212121212121212121212

[0132] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 1607545599 73.30.0 6. 3230.0 2.01582. 851 5. 011 7. 120 4. 72.3 3 3331393 48.6 298 124.62 02.46.361.20 50 1 81 3125 58 236924940762 772.1 9.5.609.73 .048 253 14 37196 530643101 2 614Pes-aS2 PeR -N AVoA sfBanfnN R S CI IR727 82828_2_ _21_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _212121212 2 2 2 2 2 2 2 2 2 2 2 2 2 2M+M M+M+M+M M+M+M+M M+M+M+M M+M+M+M Ms+s s s s+s s s s+s s s+ + +o o o o o o o o o o os s s s s s sh h h h h h h h h ho o o o o o o oP P P P P P P P Ph h h h h h h h h3 3 3 3 3 3 3 3P P P P P P P P P P_ _ _ _ _ _ _3 3 3 3 3 3 3 3 3 3 39 9 9 9 9 9_ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _9 9 9 9 9 9 9 9 9 9 9 9 9A A A A A A_A_A_A_A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R R R R R R R R R R R R R R R R1 1+ + + + + + + + + + + + + + + +2 21212121212121212121212121212121212

[0133] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 1614460578 61.3.782630 0.0.0.03261. 123 5. 601 5. 251 7. 25.3 3 3032363 4 236 33.443. 84 2 3.11.135.95 35 5136 48 51291 81169 25 18 73 83.55. 2.32.68.9 630875319 35461 34 039 20 814PeB s-S2-f aRV AnfBfIN R A SoCnInI232 2 3 3_31_31_3_31_ _ _ _ _ _ _ _ _ _ _ _ _ _ _2 212 212 2 2 2 2 2 2 2 2 2 2 2 2 2 2M+M+M+M+M+M+M M+M+M+M M+M+M+M M+M+M+Ms s s s s s+s s s s+s s s s+ +o o o o o o o o o o o o os s s s sh h h h h h h h h h h ho o o o o oP P P P P P P P P P Ph h h h h h h3 3 3 3 3 3 3 3 3 3P P P P P P P P_ _ _ _ _ _ _ _ _3 3 3 3 3 3 3 3 39 9 9 9 9 9 9 9_ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _9 9 9 9 9 9 9 9 9 9 9A A A A A A A_A_A_A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R R R R R R R R R R R R R R R R1 1+ + + + + + + + + + + + + + + +2 21212121212121212121212121212121212

[0134] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 1622534. 779147440.0 4.40.0 6.0048 5 2. 7 3490 8.2 5. 0 319.3.3 3 30303792 97.3 6068 1. 15. 8.28.92 2427 33 250228417 717 351412597.64 23 5.1037.9 99.7 2.3364 304112853 8738763 121Pe-S2A saR -fBfV AnInIN R A So fCnI7 7 7 7 8 3_3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 41_21_21_21_21_21_21_21_21_21_21_21_21_21_21_21_21_21_212M+M M M M M M M M M M M M M M M M M Ms+os+s+s+s+s+s+s+s+s+s+s+s+s+s+s+s+s+shoPhohohohohohohohohohohohohohohohohoh3P_3P3P3P3P3P3P3P3P3P3P3P3P3P3P3P3P3P39__9_9_9_9_9_9_9_9_9_9_9_9_9_9_9_9_9_9A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R R R R R R R R R R R R R R R R R R1+21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 212

[0135] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 163 82345 97.4 5. 1172.1 3.0939 2.3 4439 5.29 9. 722 4.313119 2 25. 598. 10. 68.62 9 228 1 11476 53 191722207 601 5 24 5.8.17 .92.246434292346121 3 593-S2 Pe-S R - VA B saR A So fCnfInIN R A S 142 2_41_4221_421_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _212 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2M+M M M M M M M M M M M M s+s+s+s+s+s+s+s+s+s+ + +M+M+M+M+M+M+o o o o o o o os s s s s s s s sh h h h h ho o o o o o o o o o oP P P Ph h h h h h h h h h h h h33P P P P P P P P P P P P P P P __3_3_3_3_3_3_3_3_3_3_3_3_3_3_3_3 39 9 9 9 9 9 9 9 9 9 9 9 9 9 9_ __ _ _ _ _ _ _ _ _ _ _ _ _ _9 9 9 9A A A A A A A A A A A A A A_A_A_A_A_A N N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R 11 1 121+ + + + + + + + + + + + 22 2 21212121212121212121212121212

[0136] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 1649175077 01.30.0 3. 2250.0 2.05826. 181 6. 531 2. 640 1. 91.3 3 3231377487 7 76.9 2. 351 3. 530. 893.3920341404 1 673 1 1812225635580940. 6.3.0.6 407 65 .1708142 18 5307452 65 04 1 134Pe-PsaS2R- esNaAVoAfBfN R S CnInIR646 7 7 7_4 4 4 41_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _212121212 2 2 2 2 2 2 2 2 2 2 2 2 2 2M+M M+M+M+M M+M+M+M M+M+M+M M+M+M M Ms+s s s s+s s s s+s s+ + + +o o o o o o o o o os s s s s s s sh h h h h h h h ho o o o o o o o oP P P P P P P P Ph h h h h h h h h h3 3 3 3 3 3 3 3P P P P P P P P P P_ _ _ _ _ _ _3 3 3 3 3 3 3 3 3 3 39 9 9 9 9 9_ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _9 9 9 9 9 9 9 9 9 9 9 9 9A A A A A A_A_A_A_A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R R R R R R R R R R R R R R R R1 1+ + + + + + + + + + + + + + + +2 21212121212121212121212121212121212

[0137] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 1652571329 24.3.765800 0.0.0.01019. 742 4. 381 1. 122 3. 10.3 3 30333270 8 4975.67 6. 427 2. 973.43.65779848 8210 533103 106 07.0900. 4138 8.5.00.8 894 8487 49 045 32 170041525 614Pe-S2B s-f aRV AfBnIN R A SoCnfInI1_1 1 2 2A_A_A_A_AN N N N N R+ R+ R R R1+ + + 212121212 2 2 2 2 2 2 2 2 2 2 2 2 2 2M+M+M M+M+M+M M+M+M+M M+M+M+M M+M+M Ms s+s s s s+s s s s+s s+ + +o o o o o o o o o o os s s s s s sh h h h h h h h h ho o o o o o o oP P P P P P P P Ph h h h h h h h h3 3 3 3 3 3 3P3P P P P P P P P P_ _3_ _ _ _3_3 3 3 3 3 3 3 3 39 9 9 9 9 9_ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _9 9 9 9 9 9 9 9 9 9 9 9 9A A A A A A_A_A_A_A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R R R R R R R R R R R R R R R R1 1+ + + + + + + + + + + + + + + +2 21212121212121212121212121212121212

[0138] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 1660789. 553309110.10.70.0 3.0263 3 5. 5 4 0770 7.2 7.1 7. 719.3 3 3 303309110. 69 4.63985687.3 0..25974 657939351 6025214 29616369.504.42.4 5.6 8.637 0767413224 92598 61 34121PeA s-fBnf aS2InIN R - R AVSoAfCnI6_6A_6A_6A_7A_AN N N N N R+ R+ R+ R+ R+ R+ R+ R+ R+ R R R R R R R R R R1 1 1 1 1 1 1+1+1+ +1+ + + + + +2 2 212 2 2 212 2 2 212 2121212121212M+M+M+M M+M+M+M M+M+M+M M+M+M M M M Ms s s+s s s s+s s s s+s+ + + + +o o o o o o o o o o o os s s s s s sh h h h h h h h h h h hoho o o o o oP P P P P P P P P P P P Ph h h h h h3 3 3 3 3 3 3 3 3 3P3P3P P3P3P_ _ _3_ _ _ _3_ _ _ _3_ _ _3 39 9 9 9 9 9 9 9 9 9 9 9 9 9_9_ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _9 9 9 9A A A A A A A A A A A A A A A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R R1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1+1+2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 212

[0139] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 167 69141 12.2. 07130 0.0.0443 0.6 6871 3.30 5. 132 5.313172 010. 980. 55 83.47.7986 7648 4334161 50329611.5 6.09 2084 .9 .6639585327078151 583-S2-Pe-S RV A sfBaR Ao fI IN S Cn nR A S 910 0 0_1 1 1A_A_A_A N N N N R+ R 1 + R R 21+ 21+ 212 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2M+M M M M M M M M M M M M s+s+s+s+s+s+s+s+s+s+ + +M+M+M+M+M+M+o o o o o o o os s s s s s s s sh h h h h ho o o o o o o o o o oP P P Ph h h h h h h h h h h h h33P P P P P P P P P P P P P P P __3_3_3_3_3_3_3_3_3_3_3_3_3_3_3_3 39 9 9 9 9 9 9 9 9 9 9 9 9 9 9_ __ _ _ _ _ _ _ _ _ _ _ _ _ _9 9 9 9A A A A A A A A A A A A A A_A_A_A_A_A N N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R 11 1 121+ + + + + + + + + + + + 22 2 21212121212121212121212121212

[0140] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 1684408530 52.3.362730 0.0.0.06257. 081 9. 194. 211. 44.3130333137526. 24 3 130 9. 735. 21.6.9 58 2 303 0 311 9 0 02533102137676. 986 93 449.6.065.62 .7817 53 7765 08450 62134121 263Pes-aS2 PeN R - VAfB sfaN R A SoCnInIR414 5 5_1_1_15_1A A A A_AN N N N N R+ R+ R R R1 1+1+1+1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2M+M M+M+M+M M+M+M+M M+M+M M M M M M Ms+s s s s+s s s+ + + + + + + +o o o o o o os s s s s s s s s s sh h h h h ho o o o o o o o o o o oP P P P P Ph h h h h h h h h h h h h3 3 3 3P3P P P P P P P P P P P P_3_ _ _ _3 3 3 3 3 3 3 3 3 3 3 3 39 9 9 9_ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _9 9 9 9 9 9 9 9 9 9 9 9 9 9 9A A A A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R R R R R R R R R R R R R R R R R1+ + + + + + + + + + + + + + + + +2121212121212121212121212121212121212

[0141] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 1699220588 42.1.606200 0.0.0.16490. 373 9. 879. 648. 58.30303032343 20 37 8 27.21. 6.59129 66 .7.59 82 9 907 97781 7340290 16.2915. 5781 7.9.22.8 770398 047 8 493981357956141 5PeB s-f aS2-nIN RV AfBfR A SoCnInI02020 1 1_ _2 2 2A A_A_A_AN N N N N R+ R1+ R 1 + R+ R 1 + 2 212 212 2 2 2 2 2 2 2 2 2 2 2 2 2 2M+M+M M+M+M+M M+M+M+M M+M+M+M M M M Ms s+s s s s+s s s s+ + + + + +o o o o o o o o os s s s s s s s sh h h h h h h ho o o o o o o o o oP P P P P P P Ph h h h h h h h h h h3 3 3 3 3 3P3P P P P P P P P P P_ _3_ _ _ _3 3 3 3 3 3 3 3 3 3 39 9 9 9 9_ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _9 9 9 9 9 9 9 9 9 9 9 9 9 9A A A A A_A_A_A_A_A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R R R R R R R R R R R R R R R R R1+ + + + + + + + + + + + + + + + +2121212121212121212121212121212121212

[0142] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 1702597. 89 3 037 6 70.10.20.1 2.0577 5 7 56. 10 5. 232 2. 731 6. 431 5.303219 1 92. 16 76 1.4 8. 160.620.29421 9346 233014 6375 193 94.2 65807051. 6.2.8.2 77 8 5559931 81 57588165 721 4 191Pe-S2A saR -fBfV AnN Ao fInIR S CnI525 5 5 6_2 2 2 2A_A_A_A_AN N N N N R+ R+ R+ R+ R+ R R R R R R R R R R R R R R1 1 1 1+1+1+ + + + + + + + + + + +2 2 212 2 2 2121212121212121212121212M+M+M+M M+M+M+M M+M+M M M M M M M M Ms s s+s s s s+s s+ + + + + + + + +o o o o o o o o os s s s s s s s s sh h h h h h h h hoho o o o o o o o oP P P P P P P P P Ph h h h h h h h h3 3 3 3 3 3 3 3P3P P3P3P P P P P_ _ _3_ _ _ _3_ _ _ _3_3 3 3 3 39 9 9 9 9 9 9 9 9 9 9 9_9_ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _9 9 9 9 9 9A A A A A A A A A A A A A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R R R1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1+1+ +2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 21212

[0143] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 171 00356 37.5. 63940 0.0.0249 7.8 1802 2.30 7. 632 4.31354 8 788.6072.5 6246..224518556666 5852208646.6 7.71.98.953895632709 15536 51554-S2-Pes-S RV AfBf aR A SoIN CnInR A S 920_30303A_A_A_A N N N N R+ R 1 + R R 21+ 21+ 212 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2M+M M M M M M M M M M M M s+s+s+s+s+s+s+s+s+s+ + +M+M+M+M+M+M+o o o o o o o os s s s s s s s sh h h h h ho o o o o o o o o o oP P P Ph h h h h h h h h h h h h33P P P P P P P P P P P P P P P __3_3_3_3_3_3_3_3_3_3_3_3_3_3_3_3 39 9 9 9 9 9 9 9 9 9 9 9 9 9 9_ __ _ _ _ _ _ _ _ _ _ _ _ _ _9 9 9 9A A A A A A A A A A A A A A_A_A_A_A_A N N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R 11 1 121+ + + + + + + + + + + + 22 2 21212121212121212121212121212

[0144] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 1726813428 84.0.546360 1.0.0.00852. 261 7. 796. 484. 84.3130323138630. 41 7 758 1. 040. 99.7.2 35 1 615 9 068 6 0 45912351063178. 624 84 538.7.745.48 .0314 29 2475 42342 16843121 553Pes-aS2 PeN R - VAfB sfaN R A SoCnInIR434 5 5_3_3_35_3A A A A_AN N N N N R+ R+ R R R1 1+1+1+1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2M+M M+M+M+M M+M+M+M M+M+M M M M M M Ms+s s s s+s s s+ + + + + + + +o o o o o o os s s s s s s s s s sh h h h h ho o o o o o o o o o o oP P P P P Ph h h h h h h h h h h h h3 3 3 3P3P P P P P P P P P P P P_3_ _ _ _3 3 3 3 3 3 3 3 3 3 3 3 39 9 9 9_ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _9 9 9 9 9 9 9 9 9 9 9 9 9 9 9A A A A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R R R R R R R R R R R R R R R R R1+ + + + + + + + + + + + + + + + +2121212121212121212121212121212121212

[0145] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 1733065030 63.5.185750 0.0.0.04765. 882 1. 806. 587. 47.31313032381 49367 10.91.386809 1.0.6.82 08 21150382932435133 059502 03.32.8.8.520 2 .018524 892 286 72526 0846151 5PeB s-S2-f aRV AnfBfIN R A SoCnInI939 9 0 0_3 3 4 4A_A_A_A_AN N N N N R+ R+ R+ R+ R1 1+ 2 2121212 2 2 2 2 2 2 2 2 2 2 2 2 2 2M+M+M M+M+M+M M+M+M+M M+M+M+M M M M Ms s+s s s s+s s s s+ + + + + +o o o o o o o o os s s s s s s s sh h h h h h h ho o o o o o o o o oP P P P P P P Ph h h h h h h h h h h3 3 3 3 3 3P3P P P P P P P P P P_ _3_ _ _ _3 3 3 3 3 3 3 3 3 3 39 9 9 9 9_ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _9 9 9 9 9 9 9 9 9 9 9 9 9 9A A A A A_A_A_A_A_A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R R R R R R R R R R R R R R R R R1+ + + + + + + + + + + + + + + + +2121212121212121212121212121212121212

[0146] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 174267 2 1 11. 134 5 50.10.30.0 3.0502 5 8 07. 81 4. 332 5. 831 0. 732 5.3035546 642.4 9.1 430. 157.356.7317 5 5162 97 25 7291 4048845.912915 6. 1.5.7.94014621599587 2607485549141Pe-AfB saS2R - VnfInIN R A SoAfCnI4444444 5_ _ _4 4A A A_A_AN N N N N R+ R+ R+ R+ R+ R+ R+ R R R R R R R R R R R R1 1 1 1 1 1+ +1+1+ + + + + + + + +2 2 212 2 2 212 2 2121212121212121212M+M+M+M M+M+M+M M+M+M+M M+M M M M M Ms s s+s s s s+s s s s+ + + + + + +o o o o o o o o o o os s s s s s s sh h h h h h h h h h hoho o o o o o oP P P P P P P P P P P Ph h h h h h h3 3 3 3 3 3 3 3 3P3P3P3P P3P P_ _ _3_ _ _ _3_ _ _ _3_ _3 3 39 9 9 9 9 9 9 9 9 9 9 9 9_9_ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _9 9 9 9 9A A A A A A A A A A A A A A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R R R1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1+1+ +2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 21212

[0147] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 175 886 8 64. 7 55500 7.0.0.0668 4 46. 613. 409. 78.3 323132680. 0156123.8.1.27 0 34187320649301031103392.6 3.31.243.13507 1083 7092 04251 573-S2-Pes-S RVaR A SoAfBfIN CnInR A S 849 9 9_4_4 4 A A_A_A_A_A_A_A_A N N N N N N N N N R+ R+ R+ R+ R+ R+ R R R 12121212121+ 21+ 21+ 212M+M M M M s+ + + +M+M+M+M+ososososos s s sh h ho o o oPh h h h h h3 P3P3P3P P3P P P __ _3 3 3 39_ _ _ _ _ __9_9_9_9_9 9 9 9A A A A A_A_A_A_A N N N N N N N N N R+ R 1 + R+ R+ R+ R+ R+ R+ R+ 212121212121212122v2Tv2Tv2TvC C C C T T T T T

[0148] M M M M M M M M M R R R R N N N N Leydig 772843 P2023-4023-WO 176 retsaM R C219414374375249246650 4 6Pq-e dl tD2.4 4 6 3 2 5 6 8 58317461.0. . . . . . . . . . .TloCS 0 0 0 0 0 0 0 0 0 0 0Rcy hps 1 7 1 7 9 8 2 3 6 1 6 8 5etS-en OMTe m.isn TeoitmiarrtP n oetcnnooi cti foddtaneeit d al arpgmaetssgonricwaol slroef m sratu p oah6A y N tiD lifboatssriea rp_A_A_A_A_A_A_A_A_A_A_A_A_A uth N N N atiN N N N N N N N N N rew R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R p)me1 1 1 1 1+ s ei2 2 2 2 21212121212121212gM+M+M+M+M+M+M+M+M+M M M M tol s s s s s s s s s+s+s+s+smoonohhoPhoPhoPho o o o o o o o oPhPhPhPhPhPh h h hocfeoTe3_3 3 3P P P P r3 3 3 3 3 3 3 3 39__9__9__9_ _ _ _ _ _ _ _ __9_9_9_9_9 9 9 9 9n AmaA A A A A A A A_A_A_A_ _oitN N A A N N N N N N N N N N N N N aDueldelpR+ R R 1 +1+ R R R R 1 +1+1+ + R+ R+ R+ R+ R+ R+ at m2 2 2 2 2121212121 1 1 1v Eara 2 2 2 2gS M M M M M M M M M M M M M .1e1tenlI(baxiT M Leydig 772843 P2023-4023-WO 1771863. 962. 520 0.17878503.2 1.1 1.3 3236363. 873007. .03595233922 56918 03.7368. 79.7 83 126 0589 911422- VPoeCs-f aSBRnIN R A S26:6:66::61:6:_1 1s_ _os shohoP3Ph_3P1_3_1111_A_1A_ A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R R R R R R R R R R R R R R R R R1 1+1+ + + + + + + + + + + + + + + +2 2 212121212121212121212121212121212M+M+M+M+M+M M M M M M M M M M M M M Ms s s s s+s+ + + + + + + + + + + + +o o o o o osos s s s s s s s s s s sh h h h h h hoho o o o o o o o o o oP P P P P P P PhPh h h h h h h h h h3 3 3 3 3 3 3 3 3P3P P P P P P P P P_ _ _ _ _ _ _ _ _ _3_3 3 3 3 3 3 3 39 9 9 9 9 9 9 9 9 9 9_9_ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _9 9 9 9 9 9 9A A A A A A A A A A A A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N N N N N R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R+ R R R+ R1 1 1 1 1 1 1 1 1 1 1 1 1 1 1+1+1+2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 21212

[0149] M M M M M M M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 178589. 963 1. 810 0.00685140 76. .2 8.3 30365 7.0 0955.66.2 18 9 556 03 8 72324 692.89 487 .2 .95 8 87 9 582 32 9 684- VPoeC-SA sfBnf aInIN R R A S6:6 66: ::6:61_1:1s_s_ohosoPhPh3_3P7_3_ _474747_47_ _4747_7_A_A_A_A_A_4 4A_A_AN N N N N N N N C C C CR T T T T + R1+ R+ R+ R+ R+ R+ R N N N N212121+ 212121212 - - - -M4:4:4:4:4:4:4:4+M M M M M M M1 1 1 1 1 1 1:1s+s+ + + + + + _ _ _ _ _ _ _ _o ososos s s s s s s s s s s sh h h hohoho o o o o o o o o oP P P P P PhPh h h h h h h h h3 3 3 3 3 3 3P3P3P P P P P P P_9_9_9_9_9_9_9_9_39_39_3 39_9_3 39_ _3__ _ _ _ _ _ _ _ _ _ _ _ _9_9 9A A A A A A A A A A A A A A_A_AN N N N N N N N N N N N N N N N R+ R R1+ + R R+ R R+ R R+ R R R R R R R2121+ 2121+ 2121+ 2121+ 21+ 21+ 21+ 21+ 21+ 21+ 2122v2Tv2TvT

[0150] M M M M M M M M M M M M M M M M R R R Leydig 772843 P2023-4023-WO 179 070. 2 915.92526.17931015.97735-VoC-S RA S22vT

[0151] R Leydig 772843 P2023-4023-WO 180 retd 3sl 77 8 1 9 3 8 7 2 5 9 93aoh9120395090415155 4 8 157s D5 1 5 4 8 6 6 0875386357MeRr S 1ht 5. 36. 45. 15. 98. 91. 95. 16. 37. 74. 52. 80.5.0T C0 0 0 1 0 1 0 0 0 0 0 1C Peql n8-c948 77 5716459411 58 45887698TyaCe58928 271 6. 78 7 5 585 2 0 6419675877 3. 40657 1R.sh Mt .0.3 03 .0.9.3.0.1 03 .3.0 6.1 9.0MTi iiilillilits c _es_s_s_s_s_s_s_s+sra o o o o o o o o outhh h h h h h h h hatiP P P P P P P P Prew3 3 3 3 3 3 3 3 3p)_s1_ _ _ _ _ _ _ _e11 1 1 7 7 7 7 1_1 1 1 4 4 4 4 1m ig _ _ _ _ _ _ _ _et olA A A A A A A A A o N N N N N N N N N mnR R R R R R R R R o h + r1+ + + + + + + + ocfe 4:4:4:4:21212121212121212oT1n_1 1 1M M M M M M M M M o As_s_s_s+s+s+s+s+s+s+s+ +itNoDhoPhoPhoPho o o o o o ososoPhPhPhPhPhPhPh hPhalae e3 3 3 3 3 3 3 3P P ud_vt 9_9_9_3 3 3 3 39_9_9_9_9_9_9_9_ _Ear m.g2ea _N A_A_A_A_A_A_A_A_A_A_9A_9A_A N N N N N N 1t eN N N N N N N R R R R R R R R R R R R R enlIl(p+ b1+1+1+ + + + + + + + + + axima 2 2 212121212121212121212T M S M M M M M M M M M M M M M Leydig 772843 P2023-4023-WO 18194937832954091468250429 9 2 3 52 4 6 9 1 5 0 0 9 6 69890581 4916 4 4 9 7 0 3 6 2 9 9 2 277541.181959.336.8114364.63527BfnI4:4:4:1_sohP3_74_AN R+12M+s ohohohohohoho o o o oP P P Ph h h h h3 3 3P P P P P P P_1_ _3_3_3_3_3_3_3_3_1111111111111111 1 1_ _ _ _ _A_1 1 1A A A A A_A_A_A_A_AN N N N N N N N N N N C C C C R+ R R R R R R R R R R T T T T1+ + + + + + + + + + N212121212121212121212 -N- N- N-M M M M M M M M4:4:4:4:+ + + + + + + +M+M+M+1_1 1 1sos s s s s s s s s s s_s_s_shohohoho o o o o o o o o o oP3P P Ph h h h h h h hPhPhPhP_3 3 3P3P3P3P3P3P3P3 39_ _ _ _ _ _ _ _ _ _ _3_3_3__9_9_9_9 9 9 9 9 9 9 9 9 9 9A A A A_A_A_A_A_A_A_A_A_A_A_AN N N N N N N N N N N N N N N R+ R R R R R R R R R R R R R R1+21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 21+ 2122v2Tv2Tv2Tv+ T1+ 21+ 21+ 212MM M M M M M M M M M R R R R M M M M Leydig 772843 P2023-4023-WO 182 All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein. The use of the terms “a” and “an” and “the” and “at least one” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. Preferred aspects of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred aspects may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof Leydig 772843 P2023-4023-WO 183 is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of biochemistry, molecular biology, immunology, microbiology, genetics, cell and tissue culture, and protein and nucleic acid chemistry described herein are well known and commonly used in the art. In case of conflict, the present disclosure, including definitions, will control. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the embodiments and aspects described herein. As used herein, the terms “amino acid,” “nucleotide,” “polynucleotide,” “vector,” “polypeptide,” and “protein” have their common meanings as would be understood by a biochemist of ordinary skill in the art. Standard single letter nucleotides (A, C, G, T, U) and standard single letter amino acids (A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y) are used herein. As used herein, the terms such as “include,” “including,” “contain,” “containing,” “having,” and the like mean “comprising.” The present disclosure also contemplates other embodiments “comprising,” “consisting of,” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not. As used herein, the term “or” can be conjunctive or disjunctive. As used herein, the term “substantially” means to a great or significant extent, but not completely. As used herein, the term “about” or “approximately” as applied to one or more values of interest, refers to a value that is similar to a stated reference value, or within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, such as the limitations of the measurement system. In one aspect, the term “about” refers to any values, including both integers and fractional components that are within a variation of up to ± 10% of the value modified by the term “about.” Alternatively, “about” can mean within 3 or more standard deviations, per the practice in the art. Alternatively, such as with respect to biological systems or processes, the term “about” can mean within an order of magnitude, in some embodiments within 5-fold, and in some embodiments within 2-fold, of a value. As used herein, the symbol “~”means “about” or “approximately.” Leydig 772843 P2023-4023-WO 184 All ranges disclosed herein include both end points as discrete values as well as all integers and fractions specified within the range. For example, a range of 0.1-2.0 includes 0.1, 0.2, 0.3, 0.4...2.0. If the end points are modified by the term “about,” the range specified is expanded by a variation of up to ± 10% of any value within the range or within 3 or more standard deviations, including the end points. As used herein, the term “hybridization” refers to the process of combining two complementary single-stranded nucleic acid molecules and allowing them to form a single double-stranded hybrid molecule through base pairing. As used herein, the term “target enrichment” with respect to a nucleic acid is intended to refer to increasing the relative concentration of particular nucleic acid species in the sample. As used herein, the term “nucleic acid” may refer to DNA, RNA, dsDNA, dsRNA, ssDNA, ssRNA, or hybrids of DNA / RNA complexes or sequences obtained from any source, containing target and non-target sequences. For example, a nucleic acid sample can be obtained from artificial sources or by chemical synthesis, or from viruses, prokaryotic cells including microbes, or eukaryotic cells. Biological samples may be vertebrate, including human or excluding humans, invertebrates, plants, microbes, viruses, mycoplasma, fungi, or Archaea. A nucleic acid sample may comprise whole genomic sequences, portions of the genomic sequence, chromosomal sequences, mitochondrial sequences, PCR products, whole genome amplification products or products of other amplification protocol, such as but not limited to, cDNA sequences, mRNA sequences, whole transcriptome sequences, exons, or intronic. These examples are not to be construed as limiting the sample types applicable to aspects described herein. By a polynucleotide having a nucleotide sequence at least, for example, 90-99% “identical” to a reference nucleotide sequence (e.g., SEQ ID NO: 2) is intended that the nucleotide sequence of the polynucleotide be identical to the reference sequence except that the polynucleotide sequence can include up to about 10 to 1 point mutations, additions, or deletions per each 100 nucleotides of the reference nucleotide sequence without affecting the function or activity of the polynucleotide sequence. In other words, to obtain a polynucleotide having a nucleotide sequence about at least 90-99% identical to a reference nucleotide sequence, up to 10% of the nucleotides in the reference sequence can be deleted, added, or substituted, with another nucleotide, or a number of nucleotides up to 10% of the total nucleotides in the reference sequence can be Leydig 772843 P2023-4023-WO 185 inserted into the reference sequence. These mutations of the reference sequence can occur at the 5'- or 3'- terminal positions of the reference nucleotide sequence or anywhere between those terminal positions, interspersed either individually among nucleotides in the reference sequence or in one or more contiguous groups within the reference sequence. As noted above, two or more polynucleotide sequences can be compared by determining their percent identity. The percent identity of two sequences is generally described as the number of exact matches between two aligned sequences divided by the length of the shorter sequence and multiplied by 100. An approximate alignment for nucleic acid sequences is provided by the local homology algorithm of Smith and Waterman, Advances in Applied Mathematics, 2(4): 82-489 (1981). The polynucleotides described herein include those comprising mutations, variations, substitutions, additions, deletions, and particular examples of the polynucleotides described herein. In addition, the polynucleotides can be ribonucleotides (RNA), deoxyribonucleotides (DNA), or combinations thereof, where the sequence comprise one or more ribonucleotides, or deoxyribonucleotides. The sequences can comprise ribonucleotides with for example ribothymidine nucleotides instead of uridine nucleotides to maintain consonance with the analogous DNA sequence. It will be apparent to one of ordinary skill in the relevant art that suitable modifications and adaptations to the compositions, formulations, methods, processes, and applications described herein can be made without departing from the scope of any embodiments or aspects thereof. The compositions and methods provided are exemplary and are not intended to limit the scope of any of the specified embodiments. All of the various embodiments, aspects, and options disclosed herein can be combined in any variations or iterations. The scope of the compositions, formulations, methods, and processes described herein include all actual or potential combinations of embodiments, aspects, options, examples, and preferences herein described. The exemplary compositions and formulations described herein may omit any component, substitute any component disclosed herein, or include any component disclosed elsewhere herein. The ratios of the mass of any component of any of the compositions or formulations disclosed herein to the mass of any other component in the formulation or to the total mass of the other components in the formulation are hereby disclosed as if they were expressly disclosed. Should the meaning of any terms in any of the patents or publications incorporated by reference conflict with the meaning of the terms used in this disclosure, the meanings of the terms or phrases in this disclosure are Leydig 772843 P2023-4023-WO 186 controlling. Furthermore, the foregoing discussion discloses and describes merely exemplary embodiments.

Claims

Leydig 772843 P2023-4023-WO 187CLAIM(S):

1. A DNA aptamer comprising a nucleotide sequence that has at least 95% sequence identity to at least one of SEQ ID NOs: 2-101.

2. The DNA aptamer of claim 1, wherein the DNA aptamer consists of from about 50 to about 90 nucleotides.

3. The DNA aptamer of claim 1 or 2, comprising a nucleotide sequence that has at least 95% sequence identity to at least one of SEQ ID NOs: 29 (M21_28), 45 (M21_44), 60 (M21+RNA_9), 72 (M21+RNA_21), 76 (M21+RNA_25), 78 (M21+RNA_27), 79 (M21+RNA_28), 81 (M21+RNA_30), 82 (M21+RNA_31), 83 (M21+RNA_32), 90 (M21+RNA_39), 91 (M21+RNA_40), 93 (M21+RNA_42), 94 (M21+RNA_43), 95 (M21+RNA_44), 121 (M21+RNA_9_3Phos), 134 (M21+RNA_11_3Phos), and 135 (M21+RNA_47_3Phos).

4. The DNA aptamer of any one of claims 1-3, comprising a nucleotide sequence that has at least 95% sequence identity to at least one of SEQ ID NOs: 121 (M21+RNA_9_3Phos), 134 (M21+RNA_11_3Phos), and 135 (M21+RNA_47_3Phos).

5. The DNA aptamer of any one of claims 1-4, wherein the DNA aptamer comprises at least one 1-20 bp truncation.

6. The DNA aptamer of claim 1 or 2, wherein the DNA aptamer comprises 3’- phosphorylation.

7. The DNA aptamer of any one of claims 1-5, wherein the DNA aptamer has binding affinity for a reverse transcriptase.

8. The DNA aptamer of any one of claims 1-7, wherein the DNA aptamer inhibits a reverse transcriptase at from about 20 ℃ to about 30 ℃.

9. The DNA aptamer of any one of claims 1-8, wherein the DNA aptamer fails to inhibit a reverse transcriptase at from about 45 ℃ to about 55 ℃.Leydig 772843 P2023-4023-WO 18810. The DNA aptamer of any one of claims 7-9, wherein the reverse transcriptase is derived from Moloney murine leukemia virus (MMLV), avian myeloblastosis virus (AMV), or human immunodeficiency virus type 1 (HIV-1).

11. The DNA aptamer of any one of claims 7-10, wherein the reverse transcriptase comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO:

132.

12. A composition comprising at least one DNA aptamer of any one of claims 1-11.

13. The composition of claim 12, wherein the at least one DNA aptamer is polyacrylamide gel electrophoresis (PAGE)-purified.

14. The composition of claim 12 or 13, wherein the composition further comprises a reverse transcriptase.

15. The composition of any one of claims 12-14, wherein the composition further comprises deoxynucleotide triphosphates (dNTPs), a buffer, or a combination thereof.

16. The composition of any one of claims 12-15, wherein the DNA aptamer is present in the composition at a reverse transcriptase:aptamer ratio of from about 1:2 to about 1:

8.

17. The composition of any one of claims 12-15, wherein the composition comprises a first DNA aptamer (aptamer1), a second DNA aptamer (aptamer2), and optionally a third DNA aptamer (aptamer3).

18. The composition of claim 17, wherein the composition comprises a reverse transcriptase:aptamer1:aptamer2 ratio of from about 1:2:2 to about 1:8:

8.

19. The composition of claim 17, wherein the first DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 121 (M21+RNA_9_3Phos), the second DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 134 (M21+RNA_11_3Phos), and the third DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 135 (M21+RNA_47_3Phos).Leydig 772843 P2023-4023-WO 18920. The composition of claim 17, wherein the first DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 121 (M21+RNA_9_3Phos), the second DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 134 (M21+RNA_11_3Phos), and the third DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 135 (M21+RNA_47_3Phos), and wherein the composition comprises a reverse transcriptase:aptamer1:aptamer2:aptamer3 ratio of from about 1:2:2:2 to about 1:8:8:

8.

21. The composition of claim 17, wherein first DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 121 (M21+RNA_9_3Phos), the second DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 134 (M21+RNA_11_3Phos), and the third DNA aptamer comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 135 (M21+RNA_47_3Phos), and wherein the composition comprises a reverse transcriptase:aptamer1:aptamer2:aptamer3 ratio of about 1:6:6:

6.

22. The composition of any one of claims 12-20, further comprising a RNA aptamer, optionally wherein the RNA aptamer comprises a sequence that has at least 95% sequence identity to SEQ ID NO:

1.

23. A kit comprising the DNA aptamers of any one of claims 1-11, or the composition of any one of claims 12-22.

24. A method for amplifying a target DNA sequence, the method comprising: a. providing a composition of any one of claims 12-22, the composition further comprising at least one oligonucleotide primer, and at least one sample comprising at least one target DNA sequence, wherein the composition is at a temperature of from about 20 ℃ to about 30 ℃, and wherein the reverse transcriptase is bound to the at least one DNA aptamer; b. elevating the temperature of the composition to release the reverse transcriptase from the at least one DNA aptamer;Leydig 772843 P2023-4023-WO 190 c. hybridizing the at least one oligonucleotide primer to the at least one sample comprising at least one target DNA sequence; and d. initiating DNA polymerase activity and extending the primer with the DNA polymerase to provide additional target DNA sequences.

25. The method of claim 24, wherein the composition is at a temperature of from about 20 ℃ to about 30 ℃ for at least 4 hours in step (a).

26. The method of claim 24, wherein the composition is at a temperature of from about 20 ℃ to about 30 ℃ for at least 12 hours in step (a).

27. The method of claim 24, wherein the composition is elevated to a temperature of from about 45 ℃ to about 55 ℃ in step (b).

28. A method for identifying at least one DNA aptamer that inhibits at least one reverse transcriptase, the method comprising: a. providing a DNA aptamer pool comprising DNA aptamers; b. allowing the DNA aptamers to be in proximity to the at least one reverse transcriptase in the presence of a RNA aptamer; c. separating DNA aptamers with high affinity for the at least one reverse transcriptase from the DNA aptamers with low affinity for the at least one reverse transcriptase; and d. amplifying the DNA aptamers with high affinity for the at least one reverse transcriptase to obtain an enriched DNA aptamer pool, wherein the at least one DNA aptamer that inhibits at least one reverse transcriptase may be identified from the enriched DNA aptamer pool.

29. The method of claim 28, wherein the RNA aptamer comprises a sequence that has at least 95% sequence identity to SEQ ID NO:

1.

30. The method of claim 28 or 29, wherein the reverse transcriptase comprises a nucleotide sequence that has at least 95% sequence identity to SEQ ID NO: 132.

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