Rodent model for serpina1 gene correction

Abstract

Provided herein are humanized rodent models comprising a human SERPINA1 transgene, optionally wherein the rodents develop Alpha- 1 antitrypsin deficiency (A1ATD). Further provided herein are methods related to the use of the humanized rodent models for screening therapeutic efficacy for A1ATD, for example, for screening the efficacy of any treatment selected from the group consisting of liver transplantation, respiratory agents, purified alpha- 1 antitrypsin (A1AT) protein, and gene therapy.

Description

Attorney Docket No.: 15979-20192.40 RODENT MODEL FOR SERPINA1 GENE CORRECTION CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority benefit of U.S. Provisional Application No. 63 / 703,847, filed October 4, 2024, and U.S. Provisional Application No. 63 / 728,601, filed December 5, 2024, the contents of each which are which is incorporated by reference in their entireties. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (159792019240SEQLIST.xml; Size: 188,865 bytes; and Date of Creation: September 17, 2025) is herein incorporated by reference in its entirety. FIELD OF THE DISCLOSURE

[0003] The present disclosure relates to humanized rodents comprising a human SERPINA1 transgene, optionally wherein the rodents develop Alpha-1 antitrypsin deficiency (A1ATD). In some aspects, the disclosure relates to methods of screening therapeutic efficacy for A1ATD. BACKGROUND

[0004] Alpha-1 antitrypsin deficiency (A1ATD) is an inherited disorder caused by mutations in the SERPINA1 gene that lead to liver and lung disease. A1ATD is frequently underdiagnosed or is misdiagnosed as asthma, chronic obstructive pulmonary disease, or cryptogenic liver disease. Alpha-1 antitrypsin protein (A1AT) is an inhibitor of the serine proteases, of which its main target is neutrophil elastase in the lungs. Elastase breaks down proteins so that they can be removed and used again by the body. If this action is not regulated by A1AT, elastase will also begin to break down and damage lung tissue, which leads to emphysema in A1AT-deficient patients. The most frequently identified A1ATD- associated mutation is the Z allele of SERPINA1 (1096G>A, p.E366K), which accounts for approximately 95% of clinically recognized cases of A1ATD. This mutation causes the accumulation of misfolded A1AT in hepatocytes, which in turn leads to low circulating levels of A1AT. Moreover, A1ATD results in the destruction of the lung tissue and liver disease over time. 1MF-363253604Attorney Docket No.: 15979-20192.40

[0005] Current treatments for A1ATD are (i) liver transplantation when liver failure is life-threatening, and / or (ii) a combination of respiratory agents and augmentation therapy (i.e., infusions of human plasma-derived, purified A1AT) for the treatment of A1ATD-associated lung disease. However, while A1AT protein replacement strategy can sufficiently raise the serum and alveolar epithelial lining fluid (ELF) to the U.S. Food and Drug Administration (FDA) and the European regulatory agencies considered protective levels (over 11 mM and 1.2 mM, respectively), it only does so for about 4.5 days, thus only reducing symptom severity while being costly, limited in supply, variable in purity and activity, and also a burden for patients due to the need for lifetime weekly intravenous (IV) administration to maintain therapeutic concentrations. Moreover, this therapy addresses only AATD-lung manifestations and does not treat the potential liver disease. Currently, there is no clinically available cure for A1ATD. BRIEF SUMMARY

[0006] The disclosure provides a rodent comprising a single copy of a human SERPINA1 transgene. This rodent model stands to markedly improve quality of therapeutic testing for current or novel agents to slow A1ATD disease progression or cure A1ATD. The rodents described herein have wide commercial applicability in the manufacturing and testing of A1ATD pathologies, in particular as relates to the Z allele (“PiZ”).

[0007] In one aspect, the disclosure provides a rodent comprising a single copy of a human SERPINA1 transgene.

[0008] In one embodiment, the rodent comprises a human SERPINA1 transgene comprising the coding sequence of exons 2, 3, 4, and 5 and the non-coding sequence of intron 6 of the human SERPINA1 gene.

[0009] In another embodiment, the rodent comprises the human SERPINA1 transgene comprising the genomic sequence from exon 1 through exon 5 and the sequence of intron 1 through intron 6.

[0010] In some embodiments according to any of the rodents described herein, the human SERPINA1 transgene is mutated. In some embodiments, the mutated human SERPINA1 transgene comprises a mutation in exon 5. In some embodiments, the mutation is a point mutation. In some embodiments, the point mutation occurs at nucleotide position 1096. In some embodiments, the point mutation is the replacement of Guanine at position 1096 of the human SERPINA1 transgene with Adenine (G1096A). 2MF-363253604Attorney Docket No.: 15979-20192.40

[0011] In some embodiments according to any of the rodents described herein, the mutated human SERPINA1 transgene encodes an A1AT protein comprising a substitution at residue 366. In some embodiments, the substitution is the replacement of Glutamic acid at position 366 of the human SERPINA1 protein with Lysine (E366K).

[0012] In some embodiments according to any of the rodents described herein, the human SERPINA1 transgene comprises the sequence of exons 2, 3, 4 and 5, and intron 6 of the human SERPINA1 gene, wherein exon 5 comprises G1096A. In some embodiments, the human SERPINA1 transgene comprises the nucleic acid sequence of SEQ ID NO:2.

[0013] In some embodiments according to any of the rodents described herein, the human SERPINA1 transgene comprises the human SERPINA1 genomic coding sequence of exons 1 through 5 and noncoding sequence of introns 1 through 6, wherein exon 5 comprises the G1096A mutation and about any of 1kb, 2kb, 3kb, 4kb, 5kb, 6 kb, 7kb, 8kb, 9 kb, 10kb, or more of the upstream human SERPINA1 genomic sequence. In some embodiments, the human SERPINA1 transgene comprises the nucleic acid sequence of SEQ ID NO:3.

[0014] In some embodiments according to any of the rodents described herein, the rodent is further characterized by having decreased or no functional endogenous rodent Serpina1 expression. In some embodiments, each endogenous rodent Serpina1 allele is disrupted (e.g., deleted). In some embodiments, each endogenous rodent Serpina1 allele is disrupted (e.g., deleted) from the rodent genome.

[0015] In some embodiments according to any of the rodents described herein, the rodent is further characterized as having alpha-1 antitrypsin deficiency (A1ATD). In some embodiments, the A1ATD is characterized by misfolded alpha-1 antitrypsin protein (A1AT). In some embodiments, the misfolded A1AT accumulates and can form aggregates in hepatocytes.

[0016] In some embodiments according to any of the rodents described herein, the rodent has reduced circulating levels of A1AT compared to a rodent without A1ATD. In some embodiments, the reduced circulating levels of A1AT are decreased by at least about 50% compared to the circulating levels of A1AT in a rodent without A1ATD.

[0017] In some embodiments according to any of the rodents described herein, the rodent has liver dysfunction selected from the group consisting of liver disease, liver damage, liver injury, and hepatocellular carcinoma. In some embodiments, the rodent has lung tissue damage or lung disease. In some embodiments, the lung tissue damage or lung disease is selected from the group consisting of emphysema, asthma, and chronic obstructive pulmonary disease (COPD). 3MF-363253604Attorney Docket No.: 15979-20192.40

[0018] In some embodiments according to any of the rodents described herein, the rodent is a mouse.

[0019] In another aspect, the disclosure provides methods for assessing the efficacy of a treatment for Alpha-1 antitrypsin deficiency (A1ATD), comprising administering to the rodent described herein an effective amount of the treatment. In some embodiments, the treatment is selected from the group consisting of liver transplantation, respiratory agents, purified alpha-1 antitrypsin (A1AT) protein, and gene therapy. In some embodiments, the treatment is gene therapy, wherein the gene therapy comprises editing the human SERPINA1 gene to replace the mutated SERPINA1 gene with the wildtype SERPINA1 gene. In some embodiments, the gene therapy comprises correcting the point mutation at nucleotide position 1096 (e.g., replacing the Adenine with Guanine at position 1096 in the SERPINA1 nucleotide sequence). In some embodiments, the point mutation to be corrected is G1096A, wherein the corrected nucleotide is A1096G. In some embodiments, the edited human SERPINA1 gene encodes a wildtype human A1AT protein. In some embodiments, the wildtype human A1AT protein is set forth in SEQ ID NO:4. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1 shows a schematic representation of the cloning strategy for developing a first humanized mouse model (“PiZ 124”) carrying one copy of a human SERPINA1 transgene with the PiZ allele. This transgene lacks the introns 1-5 and the noncoding exon 1.

[0021] FIG. 2 shows a schematic representation of the cloning strategy for developing a second humanized mouse model (“PiZ 101”) carrying one copy of a human SERPINA1 transgene with the PiZ allele. This transgene comprises all of exons 1-5 and introns 1-6 as well as the 5kb sequence upstream of exon 1 that encompasses known SERPINA1 gene transcriptional regulators.

[0022] FIG. 3 shows the sequence at the position in exon 5 where the PiZ point mutation is introduced (aggctgtgctgaccatcgacgagaaagggactgaagctgct (SEQ ID NO:19); agcagcttcagtccctttctcgtcgatggtcagcacagcct (SEQ ID NO:20); KAVLTIDEKGTEAA (SEQ ID NO:21)).

[0023] FIG. 4 provides genotyping confirmation of the correct integration of the hSERPINA1 transgene from the “PiZ 101” humanized mouse Model into the Rosa26 gene as designed. Flip, primer pair spanning Rosa26 and inserted human SERPINA1 junction; 1 Mut, 4MF-363253604Attorney Docket No.: 15979-20192.40 primer pair spanning a segment of the human SERPINA1 transgene #1 allele; Neo, neomycin cassette.

[0024] FIG. 5 provides genotyping confirmation of the correct integration of the hSERPINA1 transgene from the “PiZ 124” humanized mouse Model into the Rosa26 gene as designed. WT, primer pair for amplifying the Rosa26 gene lacking insertion of the human SERPINA1 transgene; 2 Mut, primer pair spanning a segment of the human SERPINA1 transgene #2 allele.

[0025] FIG. 6 shows the relative quantification of the gene transcription of murine and human SERPINA1 as well as actin levels as a control. Quantification of gene transcription was normalized to the housekeeping gene, GAPDH. mRNA samples were isolated from liver tissue harvested from PiZ 101 and PiZ 124 homozygous humanized mice.

[0026] FIG. 7 shows the human and murine A1AT protein levels as assessed by the Western blot. Protein samples were isolated from liver tissue harvested from homozygous humanized mice from the PiZ 101 and the PiZ 124 models, as well as mA1AT knockout mice and wildtype C57Bl / 6 mice as mA1AT negative and positive controls, respectively. Ponceau staining was used to confirm proper protein loading and transfer to the membrane prior to antibody probing for A1AT protein levels.

[0027] FIGS. 8A-8B show the plasma (FIG. 8A) and liver (FIG. 8B) levels of the human A1AT protein in mice from each of the humanized SERPINA1 PiZ 101 and PiZ 124 mouse models and C57Bl / 6 control mice, as measured by ELISA. N = 8 mice per humanized mouse model and N = 4 mice per C57Bl / 6 control group.

[0028] FIGs. 9A-9B show the plasma (FIG. 9A) and liver (FIG. 9B) levels of the murine A1AT protein in mice from each of the humanized SERPINA1 PiZ 101 and PiZ 124 mouse models and C57Bl / 6 control mice, as measured by ELISA. N = 8 mice per humanized mouse model and N = 4 mice per C57Bl / 6 control group.

[0029] FIG. 10 shows the results from PAS-D staining using formalin-fixed, paraffin- embedded slides using liver samples harvested from mice at 8-10 weeks of age of the humanized mouse model PiZ 101, wildtype control mice, and a known humanized SERPINA1 (“UMass”) mouse model that comprises 5+ copies of the human SERPINA1 gene. Both humanized mouse models lack the murine Serpina1 gene. Results are presented for one representative animal.

[0030] FIG. 11 shows that the disclosed mouse model (“PiZ 124”) carrying one copy of a human SERPINA1 transgene can be used to evaluating editing efficiency of a Cas9 mRNA delivered by a lipid nanoparticle (LNP). 5MF-363253604Attorney Docket No.: 15979-20192.40

[0031] FIGs. 12A and 12B show that that PiZ 124 (FIG. 12A) and PiZ 101 (FIG. 12B), crossed to mSerpina1 KO have stable plasma A1AT levels as the mice are aging.

[0032] FIG. 13 shows a schematic of the neutrophil elastase activity in vivo assay described in Example 5.

[0033] FIG. 14 shows that lung neutrophil elastase activity is elevated in the humanized SERPINA1 PiZ 101 and PiZ 124 mouse models after acute LPS treatment.

[0034] FIGs. 15A-E show measurements of lung volume and lung elasticity using the Flexivent procedure described in Example 6 for mA1AT knockout (KO) mice, the PiZ 101 mice, PiZ 124 mice or the wildtype C57Bl / 6 mice. The results show that that that PiZ mice displayed no significant difference in lung function relative to the control mice. Pulmonary mechanics were determined following a two-hit, 2 weeks LPS challenge. Pulmonary mechanics were determined using a flexiVent, parameters assessed include) pressure–volume (PV) loop (FIG. 15A-C), (B) inspiratory capacity (FIG. 15D), and (C) quasistatic compliance (FIG. 15E) (control (wild type), n = 14; AAT KO (Serpina1a–e knockout mice), n = 19; PiZ 101, n= 11; PiZ 124, n= 15).

[0035] FIG. 16 shows the results of phenotyping for PiZ 101 mice and PiZ 124 mice. DETAILED DESCRIPTION

[0036] Alpha-1 antitrypsin deficiency (A1ATD) is an inherited disorder caused by mutations in SERPINA1, leading to liver and lung disease that often go misdiagnosed. The protein variant with point mutation Glu366Lys (Pi Z) is the most common deficiency allele accounting for approximately 95% of clinically recognized cases of alpha-1 antitrypsin deficiency (A1ATD). Notably, the currently available in vivo models are not physiologically relevant representatives of A1ATD. These mouse models comprise at least 5 copies of a human SERPINA1 PiZ transgene, such that the load of toxic, misfolded PiZ protein aggregates that accumulate within the liver is significantly higher than would be seen in a typical A1ATD patient.

[0037] In some aspects of the present disclosure are provided rodents (e.g., mice) comprising a single copy of a human SERPINA1 transgene. In some embodiments, the human SERPINA1 transgene comprises the coding sequence of exons 2 through 5 and the sequence of intron 6. In other embodiments, the human SERPINA1 transgene comprises the genomic sequence from exon 1 through exon 5 and the sequence of introns 1 through 6. In some embodiments, the human SERPINA1 transgene comprises a mutation in exon 5, e.g., a point 6MF-363253604Attorney Docket No.: 15979-20192.40 mutation, for example, at nucleotide position 1096 (i.e., G1096A). In some embodiments, the rodent is further characterized by having decreased or no functional endogenous rodent Serpina1 expression, for example wherein each endogenous rodent Serpina1 allele is disrupted and / or deleted from the rodent genome. In some embodiments, the rodent is further characterized as having A1ATD (e.g., physiologically relevant A1ATD compared to human A1ATD or symptoms or manifestations thereof).

[0038] Current treatments for A1ATD are largely symptomatic and supportive, and none have been shown to be curative. Therapeutic options are limited to liver transplantation when liver failure is life-threatening, or a combination of respiratory agents and augmentation therapy (i.e., infusions of human plasma-derived, purified A1AT) for the treatment of associated lung disease. While A1ATD-targeted therapeutics are in development, a physiologically relevant in vivo model for testing therapeutic efficacy is not yet available.

[0039] In some aspects, the disclosure provides a rodent model for A1ATD and methods for assessing potential treatments or cures for therapeutic efficacy of A1ATD. Such methods may stand to have a broad therapeutic impact. I. General Techniques

[0040] The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Molecular Cloning: A Laboratory Manual (Sambrook et al., 4thed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 2012); Current Protocols in Molecular Biology (F.M. Ausubel, et al. eds., 2003); Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications (R.I. Freshney, 6thed., J. Wiley and Sons, 2010); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., Academic Press, 1998); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, Plenum Press, 1998); Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., J. Wiley and Sons, 1993-8); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); and Short Protocols in Molecular Biology (Ausubel et al., eds., J. Wiley and Sons, 2002). II. Definitions 7MF-363253604Attorney Docket No.: 15979-20192.40

[0041] A “vector,” as used herein, refers to a recombinant plasmid or virus that comprises a nucleic acid to be delivered into a host cell, either in vitro or in vivo.

[0042] The term “polynucleotide” or “nucleic acid” as used herein refers to a polymeric form of nucleotides of any length, either ribonucleotides or deoxyribonucleotides. Thus, this term includes, but is not limited to, single-, double- or multi-stranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or a polymer comprising purine and pyrimidine bases, or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases. The backbone of the polynucleotide can comprise sugars and phosphate groups (as may typically be found in RNA or DNA), or modified or substituted sugar or phosphate groups. Alternatively, the backbone of the polynucleotide can comprise a polymer of synthetic subunits such as phosphoramidates and thus can be an oligodeoxynucleoside phosphoramidate (P-NH2) or a mixed phosphoramidate- phosphodiester oligomer. In addition, a double-stranded polynucleotide can be obtained from the single stranded polynucleotide product of chemical synthesis either by synthesizing the complementary strand and annealing the strands under appropriate conditions, or by synthesizing the complementary strand de novo using a DNA polymerase with an appropriate primer.

[0043] The terms “polypeptide” and “protein” are used interchangeably to refer to a polymer of amino acid residues, and are not limited to a minimum length. Such polymers of amino acid residues may contain natural or non-natural amino acid residues, and include, but are not limited to, peptides, oligopeptides, dimers, trimers, and multimers of amino acid residues. Both full-length proteins and fragments thereof are encompassed by the definition. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. Furthermore, for purposes of the present disclosure, a “polypeptide” refers to a protein which includes modifications, such as deletions, additions, and substitutions (generally conservative in nature), to the native sequence, as long as the protein maintains the desired activity. These modifications may be deliberate, as through site-directed mutagenesis, or may be accidental, such as through mutations of hosts which produce the proteins or errors due to PCR amplification.

[0044] “Heterologous” means derived from a genotypically distinct entity from that of the rest of the entity to which it is compared or into which it is introduced or incorporated. For example, a polynucleotide introduced by genetic engineering techniques into a different cell type is a heterologous polynucleotide (and, when expressed, can encode a heterologous polypeptide). Similarly, a cellular sequence (e.g., a gene or portion thereof) that is 8MF-363253604Attorney Docket No.: 15979-20192.40 incorporated into a viral vector is a heterologous nucleotide sequence with respect to the vector.

[0045] The term “transgene” refers to a polynucleotide that is introduced into a cell and is capable of being transcribed into RNA and optionally, translated and / or expressed under appropriate conditions. In aspects, it confers a desired property to a cell into which it was introduced, or otherwise leads to a desired therapeutic or diagnostic outcome.

[0046] As used herein, the term “inhibit” may refer to the act of blocking, reducing, eliminating, or otherwise antagonizing the presence, or an activity of, a particular target. Inhibition may refer to partial inhibition or complete inhibition. For example, inhibiting the expression of a gene may refer to any act leading to a blockade, reduction, elimination, or any other antagonism of expression of the gene, including reduction of mRNA abundance (e.g., silencing mRNA transcription), degradation of mRNA, inhibition of mRNA translation, and so forth. In some embodiments, inhibiting the expression of A1AT protein may refer to a blockade, reduction, elimination, or any other antagonism of expression of A1AT protein, including reduction of SERPINA1 mRNA abundance (e.g., silencing SERPINA1 mRNA transcription), degradation of SERPINA1 mRNA, inhibition of SERPINA1 mRNA translation, and so forth. As another example, inhibiting the accumulation of a protein in a cell may refer to any act leading to a blockade, reduction, elimination, or other antagonism of expression of the protein, including reduction of mRNA abundance (e.g., silencing mRNA transcription), degradation of mRNA, inhibition of mRNA translation, degradation of the protein, and so forth. In some embodiments, inhibiting the accumulation of A1AT protein in a cell refers to a blockade, reduction, elimination, or other antagonism of expression of the A1AT protein in a cell, including reduction of SERPINA1 mRNA abundance (e.g., silencing SERPINA1 mRNA transcription), degradation of SERPINA1 mRNA, inhibition of SERPINA1 mRNA translation, degradation of the A1AT protein, and so forth.

[0047] “Percent (%) sequence identity” with respect to a reference polypeptide or nucleic acid sequence is defined as the percentage of amino acid residues or nucleotides in a candidate sequence that are identical with the amino acid residues or nucleotides in the reference polypeptide or nucleic acid sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid or nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software programs, for example, those described in Current Protocols in Molecular Biology 9MF-363253604Attorney Docket No.: 15979-20192.40 (Ausubel et al., eds., 1987), Supp. 30, section 7.7.18, Table 7.7.1, and including BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. A preferred alignment program is ALIGN Plus (Scientific and Educational Software, Pennsylvania). Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X / Y, where X is the number of amino acid residues scored as identical matches by the sequence alignment program in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. For purposes herein, the % nucleic acid sequence identity of a given nucleic acid sequence C to, with, or against a given nucleic acid sequence D (which can alternatively be phrased as a given nucleic acid sequence C that has or comprises a certain % nucleic acid sequence identity to, with, or against a given nucleic acid sequence D) is calculated as follows: 100 times the fraction W / Z, where W is the number of nucleotides scored as identical matches by the sequence alignment program in that program's alignment of C and D, and where Z is the total number of nucleotides in D. It will be appreciated that where the length of nucleic acid sequence C is not equal to the length of nucleic acid sequence D, the % nucleic acid sequence identity of C to D will not equal the % nucleic acid sequence identity of D to C.

[0048] An “isolated” molecule (e.g., nucleic acid or protein) or cell means it has been identified and separated and / or recovered from a component of its natural environment.

[0049] An “effective amount” is an amount sufficient to effect beneficial or desired results, including clinical results (e.g., amelioration of symptoms, achievement of clinical endpoints, and the like). An effective amount can be administered in one or more administrations. In terms of a disease state, an effective amount is an amount sufficient to ameliorate, stabilize, or delay development of a disease.

[0050] An “individual” or “subject” is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In 10MF-363253604Attorney Docket No.: 15979-20192.40 certain embodiments, the individual or subject is a rodent. In some embodiments, the individual or subject is a human.

[0051] As used herein, “treatment” is an approach for obtaining beneficial or desired clinical results. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (e.g., not worsening) state of disease, preventing spread (e.g., metastasis) of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0052] As used herein, the term “prophylactic treatment” refers to treatment, wherein an individual is known or suspected to have or be at risk for having a disorder but has displayed no symptoms or minimal symptoms of the disorder. An individual undergoing prophylactic treatment may be treated prior to onset of symptoms.

[0053] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.”

[0054] As used herein, the singular form of the articles “a,” “an,” and “the” includes plural references unless indicated otherwise.

[0055] It is understood that aspects and embodiments of the disclosure described herein include “comprising,” “consisting,” and / or “consisting essentially of” aspects and embodiments. III. SERPINA1 Rodent Models

[0056] In some aspects, the disclosure provides rodent models wherein the rodents comprise a copy of a human SERPINA1 transgene as disclosed herein. SERPINA1 is also known in the field by the names A1A, A1AT, AAT, PI, PI1, alpha-1-antitrypsin, and alpha1AT. The structure of the SERPINA1 gene is organized into three non-coding exons (exons 1A, 1B and 1C), four coding exons (exons 2, 3, 4 and 5), and six introns. Expression of the SERPINA1 gene is controlled predominantly by two promoters in the 5′ untranslated region (5′UTR) regulatory region. The hepatocyte SERPINA1 promoter is located upstream of the hepatocyte transcription start site, within exon 1C. An alternative promoter region, 11MF-363253604Attorney Docket No.: 15979-20192.40 located upstream of exon 1A, controls SERPINA1 expression in other cells, such as monocytes and macrophages.

[0057] The SERPINA1 gene encodes alpha-1 antitrypsin (A1AT), which is the most abundant protease inhibitor in human serum. A1AT is a 52 kD glycoprotein synthesized mainly by hepatocytes and then secreted into the circulation, through which it reaches the lungs. A1AT acts to inhibit neutrophil elastase (NE) as well as other proteolytic enzymes and pro-inflammatory products, thereby protecting the lungs from excessive proteolytic degradation of interstitial elastin and other connective tissue components. See, e.g., Fereirra et al. (2023), Expert Opin Biol Ther 23(3): 283–291, hereby incorporated by reference.

[0058] In some embodiments, there is provided a rodent comprising a single copy of a human SERPINA1 transgene. In some embodiments, the human SERPINA1 transgene encodes a wild-type A1AT protein comprising the amino acid sequence of SEQ ID NO:4. In some embodiments, the human SERPINA1 transgene encodes a mutated A1AT protein compared to the wild-type A1AT protein sequence (e.g., as set forth in SEQ ID NO:4 or naturally occurring variants thereof that are functionally equivalent). In some embodiments, the human SERPINA1 transgene encodes a mutated A1AT protein comprising a mutation (e.g., a substitution, deletion, or insertion). In some embodiments, the human SERPINA1 transgene encodes a mutated A1AT protein comprising a substitution at residue 366. In some embodiments, the substitution is E366K. In some embodiments, the human SERPINA1 transgene encodes a mutated A1AT protein comprising the amino acid sequence of SEQ ID NO:5. In some embodiments, the rodent is further characterized by having decreased or no functional endogenous rodent Serpina1 expression. In some embodiments, each endogenous rodent Serpina1 allele is disrupted. In some embodiments, each endogenous rodent Serpina1 allele is deleted from the rodent genome. In some embodiments, the rodent is a mouse.

[0059] Thus, in some embodiments, there is provided a rodent comprising a single copy of a human SERPINA1 transgene, wherein the human SERPINA1 transgene comprises the sequence of exons 2, 3, 4 and 5, and intron 6 of the human SERPINA1 gene sequence, wherein exon 5 comprises the point mutation of G1096A. In some embodiments, the human SERPINA1 transgene comprises from 5′ to 3′: (i) a 5′ homology arm genomic sequence (e.g., about 2kb to about 10kb long, for example 5kb long); (ii) a simian virus 40 (SV40) late polyadenylation signal; (iii) a Kozak sequence; (iv) a synthetic duplicated enhancer sequence of α1-microglobulin / bikunin + optimized human SERPINA1 promoter sequence; (v) a human SERPINA1 gene sequence of exon 2; (vi) a human SERPINA1 gene sequence of exon 3; (vii) a human SERPINA1 gene sequence of exon 4; (viii) a human SERPINA1 gene sequence of 12MF-363253604Attorney Docket No.: 15979-20192.40 intron 6; (ix) a human SERPINA1 gene sequence of exon 5; (x) a 3′ untranslated region (UTR); (xi) a bovine growth hormone polyadenylation (polyA) signal; and (xii) a 3′ homology arm genomic sequence. In some embodiments, the human SERPINA1 transgene encodes a wild-type A1AT protein comprising the amino acid sequence of SEQ ID NO:4. In some embodiments, the human SERPINA1 transgene encodes a mutated A1AT protein compared to the wild-type A1AT protein sequence as set forth in SEQ ID NO:4. In some embodiments, the human SERPINA1 transgene encodes a mutated A1AT protein comprising a mutation (e.g., a substitution, deletion, or insertion). In some embodiments, the human SERPINA1 transgene encodes a mutated A1AT protein comprising a substitution at residue 366. In some embodiments, the substitution is E366K. In some embodiments, the human SERPINA1 transgene encodes a mutated A1AT protein comprising the amino acid sequence of SEQ ID NO:5. In some embodiments, the rodent is further characterized by having decreased or no functional endogenous rodent Serpina1 expression. In some embodiments, each endogenous rodent Serpina1 allele is disrupted. In some embodiments, each endogenous rodent Serpina1 allele is deleted from the rodent genome. In some embodiments, the rodent is a mouse.

[0060] Thus, in other embodiments, there is provided a rodent comprising a single copy of a human SERPINA1 transgene, wherein the human SERPINA1 transgene comprises the sequence of exons 1 through 5 and introns 1 through 6 of the human SERPINA1 gene sequence, wherein exon 5 comprises the point mutation of G1096A. In some embodiments, the human SERPINA1 transgene comprises from 5′ to 3′: (i) a 5′ homology arm genomic sequence; (ii) a simian virus 40 (SV40) late polyadenylation signal; (iii) a region of human SERPINA1 gene sequence upstream of exon 1; (iv) a human SERPINA1 gene sequence of exon 1 through exon 5 and introns 1 through 6; and (v) a 3′ homology arm genomic sequence. In some embodiments, the human SERPINA1 transgene encodes a wild-type A1AT protein comprising the amino acid sequence of SEQ ID NO:4. In some embodiments, the human SERPINA1 transgene encodes a mutated A1AT protein compared to the wild-type A1AT protein sequence as set forth in SEQ ID NO:4. In some embodiments, the human SERPINA1 transgene encodes a mutated A1AT protein comprising a mutation (e.g., a substitution, deletion, or insertion). In some embodiments, the human SERPINA1 transgene encodes a mutated A1AT protein comprising a substitution at residue 366. In some embodiments, the substitution is E366K. In some embodiments, the human SERPINA1 transgene encodes a mutated A1AT protein comprising the amino acid sequence of SEQ ID NO:5. In some embodiments, the rodent is further characterized by having decreased or no functional 13MF-363253604Attorney Docket No.: 15979-20192.40 endogenous rodent Serpina1 expression. In some embodiments, each endogenous rodent Serpina1 allele is disrupted. In some embodiments, each endogenous rodent Serpina1 allele is deleted from the rodent genome. In some embodiments, the rodent is a mouse. In some embodiments, there is provided a rodent comprising a single copy of a human SERPINA1 transgene, wherein the human SERPINA1 transgene comprises from 5′ to 3′: (i) a 5′ homology arm genomic sequence comprising the nucleic acid sequence of SEQ ID NO:11; (ii) a 3x SV40 polyA signal comprising the nucleic acid sequence of SEQ ID NO:6; (iii) a Kozak sequence comprising the nucleic acid sequence of GCCACC; (iv) a synthetic duplicated enhancer sequence of α1-microglobulin / bikunin + optimized human SERPINA1 promoter sequence comprising the nucleic acid sequence of SEQ ID NO:7; (v) human SERPINA1 gene sequence of exon 2+exon 3+exon 4+intron 6+exon 5 comprising the nucleic acid sequence of SEQ ID NO:15; (vi) a 3′ untranslated region (UTR) comprising the nucleic acid sequence of SEQ ID NO:16; (vii) a bGH polyA signal comprising the nucleic acid sequence of SEQ ID NO:17; and (xiii) a 3′ homology arm genomic sequence comprising the nucleic acid sequence of SEQ ID NO:12. In some embodiments, the human SERPINA1 transgene comprises the nucleic acid sequence of SEQ ID NO:2. In some embodiments, the nucleic acid construct comprising a human SERPINA1 transgene encodes the nucleic acid sequence of SEQ ID NO:9. In some embodiments, the nucleic acid encoding a human SERPINA1 transgene encodes a polypeptide comprising the amino acid sequence of SEQ ID NO:5. In some embodiments, the rodent is further characterized by having decreased or no functional endogenous rodent Serpina1 expression. In some embodiments, each endogenous rodent Serpina1 allele is disrupted. In some embodiments, each endogenous rodent Serpina1 allele is deleted from the rodent genome. In some embodiments, the rodent is a mouse.

[0061] In other embodiments, there is provided a rodent comprising a single copy of a human SERPINA1 transgene, wherein the human SERPINA1 transgene comprises from 5′ to 3′:(i) a 5′ homology arm genomic sequence comprising the nucleic acid sequence of SEQ ID NO: 11; (ii) a 3x simian virus 40 (SV40) late polyadenylation signal comprising the nucleic acid sequence of SEQ ID NO:6; (iii) region of human SERPINA1 gene sequence upstream of exon 1 comprising the nucleic acid sequence of SEQ ID NO:13; (iv) human SERPINA1 gene sequence of exon 1 through exon 5 and intron 1 through intron 6 comprising the nucleic acid sequence of SEQ ID NO:14; and (v) a 3′ homology arm genomic sequence comprising the nucleic acid sequence of SEQ ID NO: 12. In some embodiments, the human SERPINA1 transgene comprises the nucleic acid sequence of SEQ ID NO:3. In some embodiments, the 14MF-363253604Attorney Docket No.: 15979-20192.40 nucleic acid construct comprising a human SERPINA1 transgene encodes the nucleic acid sequence of SEQ ID NO:10. In some embodiments, the nucleic acid encoding a human SERPINA1 transgene encodes a polypeptide comprising the amino acid sequence of SEQ ID NO:5. In some embodiments, the rodent is further characterized by having decreased or no functional endogenous rodent Serpina1 expression. In some embodiments, each endogenous rodent Serpina1 allele is disrupted. In some embodiments, each endogenous rodent Serpina1 allele is deleted from the rodent genome. In some embodiments, the rodent is a mouse.

[0062] In some embodiments, there is provided a rodent comprising a single copy of a human SERPINA1 transgene, wherein the rodent is further characterized as having alpha-1 antitrypsin deficiency (A1ATD). In some embodiments, the A1ATD is characterized by misfolded alpha-1 antitrypsin protein (A1AT). In some embodiments, the misfolded A1AT accumulates in hepatocytes. In some embodiments, the rodent has reduced circulating levels of A1AT compared to a rodent without A1ATD. In some embodiments, the reduced circulating levels of A1AT are decreased by at least about 50% (for example about any of 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, or more) compared to the circulating levels of A1AT in a rodent without A1ATD. In some embodiments, the rodent has liver dysfunction selected from the group consisting of liver disease, liver damage, liver injury, and hepatocellular carcinoma. In some embodiments, the rodent has lung tissue damage or lung disease. In some embodiments, the lung tissue damage or lung disease is selected from the group consisting of emphysema, asthma, and chronic obstructive pulmonary disease (COPD). In some embodiments, the rodent is a mouse. A. SERPINA1 Constructs and Vectors

[0063] The disclosure provides expression constructs, vectors, and viral particles for expression of the human SERPINA1 transgene described herein to be germline expressed in a rodent model.

[0064] In one aspect, provided herein is a nucleic acid construct encodes a human SERPINA1 transgene comprising the sequence of exons 2, 3, 4, and 5 and intron 6 of the human SERPINA1 gene sequence, wherein exon 5 comprises the point mutation of G1096A. In some embodiments, the nucleic acid construct encoding a human SERPINA1 transgene of the present disclosure comprises from 5′ to 3′: (i) a 5′ homology arm genomic sequence; (ii) a simian virus 40 (SV40) late polyadenylation signal; (iii) a Kozak sequence; (iv) a synthetic duplicated enhancer sequence of α1-microglobulin / bikunin + optimized human SERPINA1 promoter sequence; (v) human SERPINA1 gene sequence of exon 2+exon 3+exon 4+ intron 15MF-363253604Attorney Docket No.: 15979-20192.40 6+exon 5; (vi) a 3′ untranslated region (UTR); (vii) bovine growth hormone polyadenylation (polyA) signal; and (viii) a 3′ homology arm genomic sequence. In some embodiments, the 5′ homology arm genomic sequence is about 1 kb to about 10kb long, for example about any of 1.0 kb, 1.1 kb, 1.2 kb, 1.3 kb, 1.4 kb, 1.5 kb, 1.6 kb, 1.7 kb, 1.8 kb, 1.9 kb, 2.0 kb, 2.2kb, 2.4 kb, 2.6 kb, 2.8 kb, 3.0 kb, 3.5 kb, 4.0 kb, 4.5 kb, 5.0 kb, 5.5 kb, 6.0 kb, 6.5 kb, 7.0 kb, 7.5 kb, 8.0 kb, 8.5 kb, 9.0 kb, 9.5 kb, or 10.0 kb. In some embodiments, the 5′ homology arm genomic sequence is about 1 kb to about 2 kb long. In some embodiments, the 5′ homology arm genomic sequence is about 1.8 kb long. In some embodiments, the 3′ homology arm genomic sequence is about 1 kb to about 10kb long, for example about any of 1.0 kb, 1.1 kb, 1.2 kb, 1.3 kb, 1.4 kb, 1.5 kb, 1.6 kb, 1.7 kb, 1.8 kb, 1.9 kb, 2.0 kb, 2.2kb, 2.4 kb, 2.6 kb, 2.8 kb, 3.0 kb, 3.5 kb, 4.0 kb, 4.5 kb, 5.0 kb, 5.5 kb, 6.0 kb, 6.5 kb, 7.0 kb, 7.5 kb, 8.0 kb, 8.5 kb, 9.0 kb, 9.5 kb, or 10.0 kb. In some embodiments, the 3′ homology arm genomic sequence is about 1 kb to about 2 kb long. In some embodiments, the 3′ homology arm genomic sequence is about 1.8 kb long. In some embodiments, the SV40 late polyadenylation (polyA) signal comprises at least one signal sequence unit, for example about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 SV40 polyA sequence units. In some embodiments, the sv40 polyA sequence comprises 3 sequence units (i.e., “3xSV40 polyA”). In some embodiments, the 3′ untranslated region is about 10 bp to about 1 kb long, for example about any of 10 bp, 20 bp, 30 bp, 40 bp, 50 bp, 60 bp, 70 bp, 80 bp, 90 bp, 100 bp, 200 bp, 300 bp, 400 bp, 500 bp, 600 bp, 700 bp, 800 bp, 900 bp, or 1.0 kb. In some embodiments, the 3′ untranslated region is about 500 bp long. In some embodiments, exon 5 comprises a point mutation, such as a substitution, insertion, or deletion. In some embodiments, exon 5 comprises a substitution at nucleotide position 1096. In some embodiments, exon 5 comprises the point mutation G1096A. In some embodiments, the human SERPINA1 transgene is about 5 kb long.

[0065] In other embodiments, the nucleic acid construct encodes a human SERPINA1 transgene comprising the sequence of exons 1 through 5 and introns 1 through 6 of the human SERPINA1 gene sequence, wherein exon 5 comprises the point mutation of G1096A. In some embodiments, the nucleic acid construct encoding a human SERPINA1 transgene of the present disclosure comprises from 5′ to 3′: (i) a 5′ homology arm genomic sequence; (ii) a simian virus 40 (SV40) late polyadenylation signal; (iii) a region of human SERPINA1 gene sequence upstream of exon 1; (iv) human SERPINA1 gene sequence of exon 1 through exon 5 and intron 1 through intron 6; and (v) a 3′ homology arm genomic sequence. In some embodiments, the 5′ homology arm genomic sequence is about 1 kb to about 10kb long, for example about any of 1.0 kb, 1.1 kb, 1.2 kb, 1.3 kb, 1.4 kb, 1.5 kb, 1.6 kb, 1.7 kb, 1.8 kb, 1.9 16MF-363253604Attorney Docket No.: 15979-20192.40 kb, 2.0 kb, 2.2kb, 2.4 kb, 2.6 kb, 2.8 kb, 3.0 kb, 3.5 kb, 4.0 kb, 4.5 kb, 5.0 kb, 5.5 kb, 6.0 kb, 6.5 kb, 7.0 kb, 7.5 kb, 8.0 kb, 8.5 kb, 9.0 kb, 9.5 kb, or 10.0 kb. In some embodiments, the 5′ homology arm genomic sequence is about 1 kb to about 2 kb long. In some embodiments, the 5′ homology arm genomic sequence is about 1.8 kb long. In some embodiments, the 3′ homology arm genomic sequence is about 1 kb to about 10kb long, for example about any of 1.0 kb, 1.1 kb, 1.2 kb, 1.3 kb, 1.4 kb, 1.5 kb, 1.6 kb, 1.7 kb, 1.8 kb, 1.9 kb, 2.0 kb, 2.2kb, 2.4 kb, 2.6 kb, 2.8 kb, 3.0 kb, 3.5 kb, 4.0 kb, 4.5 kb, 5.0 kb, 5.5 kb, 6.0 kb, 6.5 kb, 7.0 kb, 7.5 kb, 8.0 kb, 8.5 kb, 9.0 kb, 9.5 kb, or 10.0 kb. In some embodiments, the 3′ homology arm genomic sequence is about 1 kb to about 2 kb long. In some embodiments, the 3′ homology arm genomic sequence is about 1.8 kb long. In some embodiments, the SV40 late polyadenylation (polyA) signal comprises at least one signal sequence unit, for example about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 SV40 polyA sequence units. In some embodiments, the sv40 polyA sequence comprises 3 sequence units (i.e., “3xSV40 polyA”). In some embodiments, the region of human SERPINA1 gene sequence upstream of exon 1 is about 1 kb to about 10kb long, for example about any of 1.0 kb, 1.1 kb, 1.2 kb, 1.3 kb, 1.4 kb, 1.5 kb, 1.6 kb, 1.7 kb, 1.8 kb, 1.9 kb, 2.0 kb, 2.2kb, 2.4 kb, 2.6 kb, 2.8 kb, 3.0 kb, 3.5 kb, 4.0 kb, 4.5 kb, 5.0 kb, 5.5 kb, 6.0 kb, 6.5 kb, 7.0 kb, 7.5 kb, 8.0 kb, 8.5 kb, 9.0 kb, 9.5 kb, or 10.0 kb. In some embodiments, the region of human SERPINA1 gene sequence upstream of exon 1 is about 1 kb to about 5 kb long. In some embodiments, the region of human SERPINA1 gene sequence upstream of exon 1 is about 5 kb. In some embodiments, exon 5 comprises a point mutation, such as a substitution, insertion, or deletion. In some embodiments, exon 5 comprises a substitution at nucleotide position 1096. In some embodiments, exon 5 comprises the point mutation G1096A. In some embodiments, the human SERPINA1 transgene is about 16 kb long. In some embodiments, the nucleic acid construct encoding a human SERPINA1 transgene of the present disclosure comprises from 5′ to 3′: (i) a 5′ homology arm genomic sequence comprising the nucleic acid sequence of SEQ ID NO:11; (ii) a 3x SV40 polyA signal comprising the nucleic acid sequence of SEQ ID NO: 6; (iii) a Kozak sequence comprising the nucleic acid sequence of GCCACC; (iv) a synthetic duplicated enhancer sequence of α1- microglobulin / bikunin + optimized human SERPINA1 promoter sequence comprising the nucleic acid sequence of SEQ ID NO:7; (v) a human SERPINA1 gene sequence of exon 2+exon 3+exon 4+ intron 6+exon 5 comprising the nucleic acid sequence of SEQ ID NO:15; (vi) a 3′ untranslated region (UTR) comprising the nucleic acid sequence of SEQ ID NO:16; (vii) a bGH polyA signal comprising the nucleic acid sequence of SEQ ID NO:17; and (viii) a 17MF-363253604Attorney Docket No.: 15979-20192.40 3′ homology arm genomic sequence comprising the nucleic acid sequence of SEQ ID NO:12. In some embodiments, the human SERPINA1 transgene comprises the nucleic acid sequence of SEQ ID NO:2. In some embodiments, the nucleic acid construct comprising a human SERPINA1 transgene encodes the nucleic acid sequence of SEQ ID NO:9. In some embodiments, the nucleic acid construct encoding a human SERPINA1 transgene encodes a polypeptide comprising the amino acid sequence of SEQ ID NO:5.

[0066] In some embodiments, the nucleic acid construct encoding a human SERPINA1 transgene of the present disclosure comprises from 5′ to 3′: (i) a 5′ homology arm genomic sequence comprising the nucleic acid sequence of SEQ ID NO:11; (ii) a 3x simian virus 40 (SV40) late polyadenylation signal comprising the nucleic acid sequence of SEQ ID NO:6; (iii) a region of human SERPINA1 gene sequence upstream of exon 1 comprising the nucleic acid sequence of SEQ ID NO:13; (iv) a human SERPINA1 gene sequence of exon 1 through exon 5 and intron 1 through intron 6 comprising the nucleic acid sequence of SEQ ID NO:14; and (v) a 3′ homology arm genomic sequence comprising the nucleic acid sequence of SEQ ID NO:12. In some embodiments, the human SERPINA1 transgene comprises the nucleic acid sequence of SEQ ID NO:3. In some embodiments, the nucleic acid construct comprising a human SERPINA1 transgene encodes the nucleic acid sequence of SEQ ID NO:10. In some embodiments, the nucleic acid construct encoding a human SERPINA1 transgene encodes a polypeptide comprising the amino acid sequence of SEQ ID NO:5.

[0067] In some embodiments, the transgene (e.g., a human SERPINA1 transgene of the present disclosure) is operably linked to a promoter. Exemplary promoters include, but are not limited to, the human SERPINA1 promoter, an optimized human SERPINA1 promoter or functionally active fragment thereof, the cytomegalovirus (CMV) immediate early promoter, the RSV LTR, the MoMLV LTR, the phosphoglycerate kinase- 1 (PGK) promoter, a simian virus 40 (SV40) promoter and a CK6 promoter, a transthyretin promoter (TTR), a TK promoter, a tetracycline responsive promoter (TRE), an HBV promoter, an hAAT promoter, an LSP promoter, chimeric liver-specific promoters (LSPs), the E2F promoter, the telomerase (hTERT) promoter; the cytomegalovirus enhancer / chicken beta-actin / Rabbit β-globin promoter (CAG promoter; Niwa et al., Gene, 1991, 108(2):193-9) and the elongation factor 1-alpha promoter (EFl-alpha) promoter (Kim et al., Gene, 1990, 91(2):217-23 and Guo et al., Gene Ther., 1996, 3(9):802-10). In some embodiments, the promoter comprises a human β- glucuronidase promoter or a cytomegalovirus enhancer linked to a chicken β-actin (CBA) promoter. The promoter can be a constitutive, inducible, or repressible promoter. In some 18MF-363253604Attorney Docket No.: 15979-20192.40 embodiments, the disclosure provides a recombinant vector comprising the nucleic acid construct encoding a human SERPINA1 transgene of the present disclosure operably linked to a CBA promoter. Exemplary promoters and descriptions may be found, e.g., in U.S. PG Pub. 20140335054. In some embodiments, the promoter is a CBA promoter, a minimum CBA promoter, a CMV promoter or a GUSB promoter. In some embodiments, the promoter is a hEF1a promoter. In some embodiments, the promoter is a synthetic duplicated enhancer sequence of α1-microglobulin / bikunin + optimized human SERPINA1 promoter sequence.

[0068] Examples of constitutive promoters include, without limitation, the retroviral Rous sarcoma virus (RSV) LTR promoter (optionally with the RSV enhancer), the cytomegalovirus (CMV) promoter (optionally with the CMV enhancer) [see, e.g., Boshart et al, Cell, 41:521-530 (1985)], the SV40 promoter, the dihydrofolate reductase promoter, the 13-actin promoter, the phosphoglycerol kinase (PGK) promoter, and the EFla promoter [Invitrogen].

[0069] Inducible promoters allow regulation of gene expression and can be regulated by exogenously supplied compounds, environmental factors such as temperature, or the presence of a specific physiological state, e.g., acute phase, a particular differentiation state of the cell, or in replicating cells only. Inducible promoters and inducible systems are available from a variety of commercial sources, including, without limitation, Invitrogen, Clontech, and Ariad. Many other systems have been described and can be readily selected by one of skill in the art. Examples of inducible promoters regulated by exogenously supplied promoters include the zinc-inducible sheep metallothionine (MT) promoter, the dexamethasone (Dex)-inducible mouse mammary tumor virus (MMTV) promoter, the T7 polymerase promoter system (WO 98 / 10088); the ecdysone insect promoter (No et al, Proc. Natl. Acad. Sci. USA, 93:3346-3351 (1996)), the tetracycline-repressible system (Gossen et al, Proc. Natl. Acad. Sci. USA, 89:5547-5551 (1992)), the tetracycline-inducible system (Gossen et al, Science, 268:1766- 1769 (1995), see also Harvey et al, Curr. Opin. Chem. Biol., 2:512-518 (1998)), the RU486- inducible system (Wang et al, Nat. Biotech., 15:239-243 (1997) and Wang et al, Gene Ther., 4:432-441 (1997)) and the rapamycin-inducible system (Magari et al, J. Clin. Invest., 100:2865-2872 (1997)). Still other types of inducible promoters which may be useful in this context are those which are regulated by a specific physiological state, e.g., temperature, acute phase, a particular differentiation state of the cell, or in replicating cells only.

[0070] In another embodiment, the native promoter, or fragment thereof, for the transgene is used. The native promoter may be preferred when it is desired that expression of the transgene should mimic the native expression. The native promoter may be used when 19MF-363253604Attorney Docket No.: 15979-20192.40 expression of the transgene must be regulated temporally or developmentally, or in a tissue- specific manner, or in response to specific transcriptional stimuli. In a further embodiment, other native expression control elements, such as enhancer elements, polyadenylation sites, or Kozak consensus sequences may also be used to mimic the native expression.

[0071] In some embodiments, the regulatory sequences impart tissue-specific gene expression capabilities. In some cases, the tissue-specific regulatory sequences bind tissue- specific transcription factors that induce transcription in a tissue specific manner. Such tissue- specific regulatory sequences (e.g., promoters, enhancers, etc.) are well known in the art. Exemplary liver tissue-specific regulatory sequences include, but are not limited to the following tissue specific promoters: a transthyretin promoter (TTR), a thyroxine binding globulin promoter (TBG), minimal TTR promotor (TTRm), an AAT promoter, an albumin (ALB) promotor or minimal promoter, an apolipoprotein A1 (APOA1) promoter or minimal promoter, a complement factor B (CFB) promoter, a ketohexokinase (KHK) promoter, a hemopexin (HPX) promoter or minimal promoter, a nicotinamide N-methyltransferase (NNMT) promoter or minimal promoter, a carboxylesterase 1 (CES1) promoter or minimal promoter, a protein C (PROC) promoter or minimal promoter, an apolipoprotein C3 (APOC3) promoter or minimal promoter, a mannan-binding lectin serine protease 2 (MASP2) promoter or minimal promoter, a hepcidin antimicrobial peptide (HAMP) promoter or minimal promoter, and a serpin peptidase inhibitor, clade C (antithrombin), or member 1 (SERPINC1) promoter or minimal promoter.

[0072] In some embodiments, the promoter expresses the nucleic acid construct in a cell of the liver (e.g., hepatocyte). In some embodiments, the promoter expresses the nucleic acid construct in a liver cell. A liver cell may refer to any liver cell known in the art, including without limitation a hepatocyte, a stellate cell, a Kupffer cell, and / or a liver sinusoidal endothelial cell. In some embodiments, the promoter expresses the nucleic acid construct in a hepatocyte.

[0073] Various promoters that express transcripts (e.g., a human SERPINA1 transgene) in liver cells (e.g., hepatocytes) are known in the art. Such promoters can comprise control sequences normally associated with the selected gene or heterologous control sequences. Often, useful heterologous control sequences include those derived from sequences encoding mammalian or viral genes. Examples include, without limitation, the SV40 early promoter, mouse mammary tumor virus LTR promoter, adenovirus major late promoter (Ad MLP), a herpes simplex virus (HSV) promoter, a cytomegalovirus (CMV) promoter such as the CMV immediate early promoter region (CMVIE), a rous sarcoma virus (RSV) promoter, synthetic 20MF-363253604Attorney Docket No.: 15979-20192.40 promoters, hybrid promoters, and the like. In addition, sequences derived from nonviral genes, such as the murine metallothionein gene, may also be used. Such promoter sequences are commercially available from, e.g., Stratagene (San Diego, CA). Liver-specific promoters and inducible promoters may be used. Examples of liver-specific promoters include without limitation those isolated from liver-specific genes, such as a transthyretin promoter (TTR), a thyroxine binding globulin promoter (TBG), minimal TTR promotor (TTRm), an AAT promoter, an albumin (ALB) promotor or minimal promoter, an apolipoprotein A1 (APOA1) promoter or minimal promoter, a complement factor B (CFB) promoter, a ketohexokinase (KHK) promoter, a hemopexin (HPX) promoter or minimal promoter, a nicotinamide N- methyltransferase (NNMT) promoter or minimal promoter, a carboxylesterase 1 (CES1) promoter or minimal promoter, a protein C (PROC) promoter or minimal promoter, an apolipoprotein C3 (APOC3) promoter or minimal promoter, a mannan-binding lectin serine protease 2 (MASP2) promoter or minimal promoter, a hepcidin antimicrobial peptide (HAMP) promoter or minimal promoter, and a serpin peptidase inhibitor, clade C (antithrombin), member 1 (SERPINC1) promoter or minimal promoter; viral promoters such as hepatitis B, C, or E promoters; and any liver-specific promoters disclosed in, e.g., WO2020104424; WO2023044059; CN116555266; WO2014204726; WO2011005968; and Lee et al., Sci Rep. 2019; 9: 1616; each hereby incorporated by reference in its entirety. Examples of inducible promoters include DNA responsive elements for ecdysone, tetracycline, metallothionein, and hypoxia, inter alia.

[0074] Also provided herein are vectors encoding any of the nucleic acid constructs described herein. The vectors can be any one of a plasmid, a phagemid, a cosmid, a transposon, or a viral vector. In some embodiments, the vector is selected from the group consisting of adenovirus, Chimpanzee adenovirus, lentivirus, alphavirus, retrovirus, poxvirus, flavivirus, adeno-associated virus, rhabdoviridae, herpes simplex virus, chimeric virus, arenavirus, fowlpox virus, vesicular stomatitis virus, vaccinia virus, modified vaccinia virus Ankara, human cytomegalovirus, Sendai virus, measles virus, and Newcastle disease virus. For example, in some embodiments, the vector is a retroviral vector. In some embodiments, the retroviral vector is a lentiviral vector. In some embodiments, the vector is an AAV vector.

[0075] While not necessary for expression of a transgene encoded by a vector, a selectable marker can help identify and / or select for cells expressing the vector. Selectable markers may include antibiotic resistance genes, fluorescent proteins, toxins, etc. Selectable markers can permit positive selection (i.e., cells comprising the selectable marker are not killed) or negative selection (i.e., cells comprising the selectable marker are killed). Non- 21MF-363253604Attorney Docket No.: 15979-20192.40 limiting examples of antibiotic resistance selectable markers known to those skill in the art include, for example, ampicillin, blasticidin, carbenicillin, chloramphenicol, hygromycin B, kanamycin, puromycin, spectinomycin, tetracycline, and zeocin.

[0076] The present disclosure provides vectors in which any of the human SERPINA1 transgenes disclosed herein can be inserted by (e.g.) the Gibson Assembly method into a specific location within or section of the vector nucleotide sequence, which is known in the art. The Gibson Assembly method is a cloning method that typically does not require restriction enzyme digestion. Briefly, the 5' end of one or more blunt end, double-stranded DNA is digested, cleaved, or otherwise pared back using a T5 exonuclease. A Phusion DNA polymerase and Taq DNA ligase are used to fill in the gaps in the plasmid and seal the nicks in the DNA backbone, respectively. See, Gibson et al. (2009) Nat Methods. 6(5):343-5, which is incorporated by reference.

[0077] Additional methods of inserting a transgene into a vector provided herein include recombineering, homologous recombination, standard restriction enzyme cloning, CRISPR systems, zinc-finger nuclease (ZFN) systems, TALENS, etc., as is known by one skilled in the art.

[0078] In some embodiments, a vector of the present disclosure comprises one or more sequences encoding one or more selection markers. In some embodiments, the one or more selection markers comprise a fluorescent protein. In some embodiments, the fluorescent protein is selected from green fluorescent protein (GFP), enhanced green fluorescent protein (EGFP), yellow fluorescent protein (YFP), enhanced yellow fluorescent protein (EYFP), blue fluorescent protein (BFP), enhanced blue fluorescent protein (EBFP), cyan fluorescent protein (CFP), enhanced cyan fluorescent protein (ECFP), superfolder GFP, superfolder YFP, orange fluorescent protein, red fluorescent protein, small ultrared fluorescent protein, FMN- binding fluorescent protein, dsRed, qFP611, Dronpa, TagRFP, KFP, EosFP, IrisFP, Dendra, Kaede, KikGr1, emerald fluorescent protein, Azami Green, mWasabi, TagGFP, TurboGFP, AcGFP, ZsGreen, or T-Sapphire, or any suitable fluorescent protein known in the art. In some embodiments, fluorescent protein selection markers are screened using flow cytometry to select engineered cells or populations of cells (e.g., engineered oocytes or blastocysts for embryo injection into a sham-pregnant rodent) by confirming expression of selection marker in the cell. In other embodiments, fluorescent protein selection markers are screened using spectral imaging to select for the rodent model(s).

[0079] In some embodiments, a vector of the present disclosure comprises one or more sequences encoding one or more selection proteins. In some embodiments, the one or more 22MF-363253604Attorney Docket No.: 15979-20192.40 selection proteins are selected from a membrane-bound selection molecule, a blasticidin selection protein, a hygromycin selection protein, a puromycin selection protein, a zeocin selection protein, a neomycin selection protein, a ganciclovir selection protein, a 5′- fluorocytosine selection protein, a G418 (geneticin) selection protein, or a cytosine deaminase selection protein, or any other suitable selection protein known in the art. In some embodiments, antibiotic resistance screening is used to select for engineered cells or population of cells. In some embodiments, membrane-bound selection molecules can include, for example, membrane-bound biotin mimetic peptides (BMPs) or biotin acceptor peptides (BAPs) (see, e.g., WO2012085911, hereby incorporated by reference in its entirety, for a list of BMPs and BAPs). In some embodiments, the membrane-bound selection molecule can include membrane peptides with mutated posttranslational modifications, for example glycosylation, acetylation, phosphorylation, nitrosylation, methylation, lipidation, etc. In some embodiments, membrane-bound selection molecules may include, for example, extracellular domain peptides of exogenous receptors, extracellular and transmembrane domain peptides of exogenous receptors, and / or full-length peptides of exogenous receptors that are not otherwise produced by the rodent model as described herein. In some embodiments, membrane-bound selection molecules are screened using flow cytometry to select for engineered cells or populations of cells (e.g., engineered oocytes or blastocysts for embryo injection into a sham-pregnant rodent). In some embodiments, membrane-bound selection molecules are screened using cytometry by time of flight (i.e., CyTOF) to select for engineered cells or populations of cells. In some embodiments, membrane-bound selection molecules are screened using spectral imaging to select for engineered cells or populations of cells. In some embodiments, the engineered cell or population of cells as described herein is sorted or selected by flow cytometry, CyTOF, or spectral imaging using antibodies that bind to membrane-bound selection molecules.

[0080] Also provided are methods of making any of the rodent models described herein comprising introducing into a rodent any of the nucleic acid constructs or vectors comprising the nucleic acid constructs of the present disclosure. In some embodiments, the method further comprises disrupting and / or deleting each endogenous rodent Serpina1 allele in the rodent genome, for example using any standard gene editing techniques known in the field. In some embodiments, the disrupting and / or deleting may involve cross-breeding of any of the rodent models described herein to a commercially available rodent model of the same species, wherein the commercially available rodent model has disrupted and / or deleted endogenous rodent Serpina1 allele in the rodent genome. 23MF-363253604Attorney Docket No.: 15979-20192.40

[0081] In some embodiments, the method of making comprises introducing any of the nucleic acid constructs or vectors comprising thereof described herein into a cell or a population of cells, such as a rodent oocyte, spermatocyte, sperm, embryonic stem cell, blastocyst, or embryo, that can be injected into a sham-pregnant rodent and develop normally into a fetus. Methods for the insertion or introduction of the nucleic acid constructs or vectors comprising thereof of the present disclosure into said cells are well-known to those of skill in the art and include, but are not limited to, lipid-mediated transfer (e.g., liposomes, including neutral and cationic lipids), electroporation, direct injection, cell fusion, particle bombardment, calcium phosphate co-precipitation, DEAE-dextran-mediated transfer, and viral vector-mediated transfer. In some embodiments, the introducing any of the nucleic acid constructs or vectors comprising thereof into a cell or a population of cells (e.g., embryonic stem (ES) cell) is performed using electroporation.

[0082] After the introducing any of the nucleic acid constructs or vectors comprising thereof into a cell or a population of cells is performed, the cell or population of cells (e.g., ES cell) is screened for germline insertion, for example using standard techniques such as Southern blotting, PCR analysis, and / or DNA sequencing. Once proper insertion into the ES cell genome has been confirmed, ES cells can then be injected, e.g., via microinjection, into a rodent blastocyst that is then transferred into a sham-pregnant female rodent of the same species in order to generate rodent chimeras. These chimeras then are bred to other rodents of the same species in order to identify rodents wherein the human SERPINA1 transgene has been inserted into the germline genome for transmission to future generations. In some embodiments, the method of making further comprises disrupting and / or deleting an endogenous rodent Serpina1 allele by cross-breeding of any of the rodent models described herein to a commercially available rodent model of the same species, wherein the commercially available rodent model has a disrupted and / or deleted endogenous rodent Serpina1 allele in the rodent genome. These germline rodents can then be used as described herein, e.g., for assessing the efficacy of A1ATD treatments. V. Methods of Assessing Treatment Efficacy

[0083] The disclosure provides, inter alia, methods of assessing various treatments of A1ATD for therapeutic efficacy in an individual; i.e., a mammal; e.g., a rodent such as a mouse. Non-limiting examples of possible treatments include augmentation therapy, lung 24MF-363253604Attorney Docket No.: 15979-20192.40 surgery or transplantation, oxygen therapy, pulmonary rehabilitation, liver transplantation, respiratory agent(s), cell therapy, and gene therapy.

[0084] The methods of assessing treatments for therapeutic efficacy as described herein use any of the rodent models described herein. In some embodiments, the rodent models described herein are characterized as having Alpha-1 antitrypsin deficiency (A1ATD). In some embodiments, the A1ATD is characterized by misfolded alpha-1 antitrypsin protein (A1AT). In some embodiments, the misfolded A1AT accumulates in hepatocytes. In some embodiments, the rodent has reduced circulating levels of A1AT (e.g., decreased by at least about 50%, such as about any of 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, or more) compared to a rodent without A1ATD. In some embodiments, the rodent has liver dysfunction selected from the group consisting of liver disease, liver damage, liver injury, and hepatocellular carcinoma. In some embodiments, the rodent has lung tissue damage or lung disease. In some embodiments, the lung tissue damage or lung disease is selected from the group consisting of emphysema, asthma, and chronic obstructive pulmonary disease (COPD). In some embodiments, the rodent is a mouse.

[0085] Evaluation of the therapeutic efficacy of the treatments described below can include, e.g., evaluating the degree of A1AT accumulation in hepatocytes; evaluating the progression and / or degree of liver disease, liver damage, liver injury, and / or hepatocellular carcinoma; evaluating the progression and / or degree of lung tissue damage or lung disease; evaluating the delay in onset of liver or lung damage; evaluating the reversal of liver or lung damage; etc. For example, such evaluation can identify a therapy’s ability to act as a treatment, a cure, and / or a prophylaxis, including to identify successful dosing regimens and / or dosing schedules, including, for example, combination therapies. Impact on quality of life can be assessed, e.g., through analysis of murine activity levels, food intake, body weight, etc. Accumulation of misfolded A1AT protein aggregates in hepatocytes can be assessed via histology (e.g., PAS-D staining of the liver or A1AT immunostaining of the liver) or via protein isolation and quantification (e.g., Western blotting, ELISA, or mass spectrometry of protein samples isolated from hepatocytes). The progression, delay, and / or reversal of liver disease, liver damage, liver injury, and / or hepatocellular carcinoma and / or of lung tissue damage or lung disease can be assessed by histology, quantitative PCR, protein analysis, analysis of overall survival, etc. as part of a time course. In order to obtain liver or lung samples at various time points throughout development and ageing, murine liver or lung biopsies or euthanasia followed by liver or lung tissue harvesting can be utilized. 25MF-363253604Attorney Docket No.: 15979-20192.40

[0086] In humans, evaluating therapeutic efficacy on lung improvement can include, e.g., spirometry to calculate forced expiratory volume (FEV1) and forced vital capacity (FVC), computed tomography (CT) densitometry, magnetic resonance imaging (MRI) of the chest, lung volume, lung diffusion capacity (DLCO), chest X-ray, positron emission tomography (PET) scan of the chest, exercise tests, etc. Spirometry can be used to evaluate the degree of airflow limitation and is used to calculate FEV1, FVC, and the FEV1 / FVC ratio. FEV1 is a clinical parameter that evaluates lung function progression and severity of lung disease, wherein the FEV1 / FVC ratio and % FEV1 denote the severity of lung damage (e.g., COPD severity, emphysema severity). Computed tomography (CT) densitometry, magnetic resonance imaging (MRI), positron emission tomography (PET) scan, and / or X-ray of the chest can be used to evaluate the decrease in lung density over time and development of emphysema. Diffusing capacity of the lungs for carbon monoxide (DLCO) is also known as the transfer factor and is a measurement to assess the lungs' ability to transfer gas from inspired air to the bloodstream. The volume in the lung can be divided into four units: tidal volume, expiratory reserve volume, inspiratory reserve volume, and residual volume; lung volume measurement can be performed using, e.g., body plethysmography. Exercise tests (i.e., cardiopulmonary exercise testing) can be utilized to identify decreases in oxygen consumption.

[0087] Furthermore, assessing therapeutic efficacy on liver improvement can include, e.g., blood tests to assess the levels of markers of liver function such as alanine transaminase (ALT) and aspartate transaminase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), serum bilirubin, prothrombin time (PT), the international normalized ratio (INR), total protein, and albumin; liver scan; liver ultrasonography (US); liver computed tomography (CT) scan; liver magnetic resonance imaging (MRI) scan; liver biopsy; etc. Serum A1AT Augmentation Therapy

[0088] The disclosure provides methods of assessing serum A1AT augmentation therapy for therapeutic efficacy using any of the rodent models described herein. Augmentation therapy with purified human A1AT increases serum and pulmonary epithelial A1AT levels, restores anti-elastase capacity, and decreases inflammatory mediators in the lung. Augmentation therapy reduces the loss of lung density over time, thus slowing progression of the disease. Augmentation therapy with intravenous purified A1AT is the only specific, approved treatment for A1ATD. This therapy is aimed at increasing patient survival and 26MF-363253604Attorney Docket No.: 15979-20192.40 symptom control, and at preventing the progression of A1ATD-related pulmonary emphysema. A1AT augmentation therapy is also indicated for patients with necrotizing panniculitis. See, e.g., Feitosa (2023), Drugs Context. 12: 2023-3-1, hereby incorporated by reference in its entirety.

[0089] The only approved regimen for patients with A1ATD is weekly intravenous infusions of A1AT at 60 mg / kg. This regimen maintains serum trough A1AT levels above the protective threshold during the week and long term. Serum A1AT levels are more consistently above the protective threshold with weekly infusions than with biweekly or monthly therapy. Studies are ongoing to review the therapeutic efficacy of high-dose A1AT augmentation therapy.

[0090] Thus, in some embodiments, there is provided a method of assessing serum A1AT augmentation therapy for therapeutic efficacy using the rodent models described herein, wherein purified A1AT is administered at least about every week at a dose of at least about 60 mg / kg. In some embodiments, purified A1AT is administered parenterally, e.g., intravenously, intramuscularly, intraperitoneally, subcutaneously, etc. In some embodiments, purified A1AT is administered at least about once every week, for example at least about once every 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or more. In some embodiments, purified A1AT is administered at a dose of at least about any of 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, 105 mg / kg, 110 mg / kg, 115 mg / kg, 120 mg / kg, 125 mg / kg, 130 mg / kg, 135 mg / kg, 140 mg / kg, 145 mg / kg, 150 mg / kg, 155 mg / kg, 160 mg / kg, 165 mg / kg, 170 mg / kg, 175 mg / kg, 180 mg / kg, 185 mg / kg, 190 mg / kg, 195 mg / kg, 200 mg / kg, or more. Lung Surgery or Transplantation

[0091] The disclosure provides methods of assessing lung surgery or transplantation for therapeutic efficacy using any of the rodent models described herein. For individuals with severe airflow obstruction, an effective therapy may be lung surgery or transplantation. Despite a possible increased risk for infectious complications, lung transplantation remains a viable option for these individuals. Given limited donor availability, however, lung volume reduction surgery (LVRS) is considered, often as a bridge to transplantation. LVRS for 27MF-363253604Attorney Docket No.: 15979-20192.40 individuals who have A1ATD remains relatively uncommon despite a general perception that it remains a surgical option.

[0092] Short-term complications following lung surgery or lung transplantation have been identified for individuals with A1ATD, e.g., airway, wound, reoperation for bleeding, gastrointestinal (GI) complications. For example, GI complications occur in up to 50% of recipients following lung transplantation. GI complications can include, e.g., any documented pathologic diagnosis related to the hepatopancreatobiliary (HPB) complex (e.g., cirrhosis, steatosis, ascites, gallstone disease, cholangitis, pancreatitis), mechanical alimentary function (e.g., bowel obstruction, diverticulitis), or GI bleeding from any source and sequelae of peptic ulcer disease. See, e.g., Spratt et al (2019), J. Thorac Dis. 11(4):1130-114, hereby incorporated by reference in its entirety.

[0093] Therefore, in some embodiments, provided herein are methods of assessing lung surgery or transplantation for therapeutic efficacy using any of the rodent models described herein, wherein the method further comprises assessing for therapeutic efficacy of treatments for complications or secondary diseases, disorders, symptoms, etc. Oxygen Therapy

[0094] The disclosure provides methods of assessing oxygen therapy for therapeutic efficacy using any of the rodent models described herein. Oxygen therapy, or supplemental oxygen is indicated when the oxygen saturation falls below 89%, or the arterial oxygen pressure falls below 60 mmHg. Oxygen therapy (e.g., long-term oxygen therapy (LTOT)) can include liquid oxygen, mobile oxygen, home oxygen therapy, hyperbaric oxygen therapy, oxygen as-needed, oxygen for more than 15 hours per day, oxygen for less than 15 hours per day, etc. With regard to oxygen treatment, individuals with A1ATD had higher oxygen flow prescribed, and were more often prescribed liquid oxygen and portable oxygen devices compared to individuals without A1ATD. See, e.g., Ringbaek, et al. (2014) Resp Med. 108(8): 1189-1194, hereby incorporated by reference in its entirety. In some embodiments, LTOT is terminated after lung surgery or lung transplantation. Pulmonary Rehabilitation

[0095] The disclosure provides methods of assessing pulmonary rehabilitation for therapeutic efficacy using any of the rodent models described herein. Pulmonary 28MF-363253604Attorney Docket No.: 15979-20192.40 rehabilitation (PR) programs are a multifaceted health care service that includes exercise therapy and educational sessions. Studies reviewing the efficacy of PR for individuals with A1ATD demonstrated improvement in the 6-minute walk test, although to a lower degree than individuals with COPD without A1ATD, as well as improvement in Quality of Life (QoL) scores. In some embodiments, inpatient PR programs for individuals with A1ATD are shorter in duration (3–5 weeks) but higher in frequency (daily exercise) than inpatient PR programs for individuals without A1ATD. See, e.g., Alwadani et al. (2023), J COPD Foundation 11(1): 121-132, hereby incorporated by reference in its entirety. 29MF-363253604Attorney Docket No.: 15979-20192.40 Liver Transplantation

[0096] The disclosure provides methods of assessing liver transplantation for therapeutic efficacy using any of the rodent models described herein. Liver transplantation (LT) is the therapeutic option for end-stage liver disease associated with A1ATD. Only about 10% of individuals with A1ATD present with liver damage so severe that liver transplantation is required for survival. LT can cure cirrhosis caused by A1AT deficiency and may restore the normal production of A1AT. In some cases, liver transplantations are provided for children with severe A1ATD-associated infantile hepatitis. While long-term survival rates for A1ATD patients who receive liver transplants is good, and although the A1AT levels normalize for most patients after transplantation, FEV1 continues to decline unexpectedly in some individuals with A1ATD. Respiratory Agent(s)

[0097] The disclosure provides methods of assessing respiratory agent(s) for therapeutic efficacy using any of the rodent models described herein. Such respiratory agents may include bronchodilators, inhaled steroids for patients with exacerbations, antibiotics, and oral corticosteroids during flare-ups, etc. Bronchodilators can make breathing easier by relaxing the muscles in the lungs and widening the airways (bronchi) and can be short-acting or long- acting. Bronchodilators can include, e.g., beta-2 agonists (e.g., salbutamol, salmeterol, formoterol, and vilanterol), anticholinergics (e.g., ipratropium, tiotropium, aclidinium, and glycopyrronium), and theophylline. Inhaled corticosteroids have potent glucocorticoid activity and work directly at the cellular level by reversing capillary permeability and lysosomal stabilization to reduce inflammation. Examples of commonly prescribed inhaled corticosteroids include, e.g., Alvesco® (ciclesonide), Flovent® (fluticasone), Pulmicort® (budesonide), and Qvar® (beclomethasone HFA). Antibiotics or inhaled corticosteroids may be recommended to control symptoms of flare-ups, infections, or exacerbations. These oral and / or nasal treatments can also be paired with influenza vaccination, antipneumococcal vaccination, etc., in order to decrease the risk of developing severe infections that can lead to lung damage. In some embodiments, respiratory agents are used in combination with one or more additional therapies. 30MF-363253604Attorney Docket No.: 15979-20192.40 Cell Therapy

[0098] The disclosure provides methods of assessing cell therapy for therapeutic efficacy using any of the rodent models described herein. Cell therapy can be used, e.g., to introduce cells capable of producing and secreting wild-type, functional A1AT protein. As such, the cell therapy could involve transplantation of donor-matched or autologous-derived hepatocytes capable of producing and secreting wild-type, functional A1AT protein. The cell therapy also could involve transplantation, infusion, or engraftment of donor-matched or autologous-derived cells capable of producing and secreting wild-type, functional A1AT protein that do not typically produce A1AT (e.g., engineered immune cells).

[0099] For example, in some embodiments, the cell therapy comprises transplantation of hepatic-specified cells derived from human-induced pluripotent stem cells to the liver of an individual with A1ATD. In some embodiments, the cell therapy comprises transplantation or infusion of a human cell capable of producing and secreting exogenous wild-type A1AT. In some embodiments, the cell therapy rescues circulating A1AT levels, thereby treating A1ATD-associated lung damage, lung injury, or lung disease. In some embodiments, the cell therapy is allogeneic. In some embodiments, the cells of the cell therapy are HLA-matched. In some embodiments, the cell therapy is autologous and further comprises gene correction of a variant SERPINA1 allele to the wild-type SERPINA1 allele. In some embodiments, the cells of the cell therapy do not induce Graft versus Host Disease (GvHD). In some embodiments, the cell therapy is administered once. In some embodiments, the cell therapy is administered more than once, such as at least two times, three times, four times, five times, or more. In some embodiments, the cell therapy is administered more than once with at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 1 year, 2 years, 3 years, 4 years, 5 years or more between the first dose and subsequent doses or between any dose and its subsequent dose. 31MF-363253604Attorney Docket No.: 15979-20192.40 Gene Therapy

[0100] The disclosure provides methods of assessing gene therapies for therapeutic efficacy using any of the rodent models described herein. In some embodiments, the gene therapy comprises editing the human SERPINA1 gene to correct a point mutation at nucleotide position 1096. In some embodiments, the point mutation to be corrected is G1096A, wherein the corrected nucleotide is A1096G. In some embodiments, the edited human SERPINA1 gene encodes a wildtype human A1AT protein, e.g., as set forth in SEQ ID NO:4.

[0101] Gene therapy for A1ATD could allow for continuous, long-term expression of the gene under its normal regulatory mechanisms, e.g., to prevent the development of the disease, to slow the development of disease, and / or to cure the disease. Such therapeutic action could also alleviate additional symptoms of A1ATD, such as dermatitis and connective tissue defects.

[0102] In some embodiments, the gene therapy comprises a viral vector, a zinc finger nuclease (ZFN), a TAL-effector nuclease (TALEN), meganucleases, transposases, and / or an RNA-guided nuclease (e.g., clustered regularly interspaced short palindromic repeat (CRISPR)) that specifically binds to, recognizes, or hybridizes to the target PiZ A1AT allele. Virus

[0103] In some embodiments, the gene therapy comprises a vector encoding a human SERPINA1 transgene, such as an expression vector, a viral vector, or a cloning vector. The expression vectors may contain a variety of elements for controlling expression, including without limitation, promoter sequences, transcription initiation sequences, enhancer sequences, selectable markers, and signal sequences. These elements may be selected as appropriate by a person of ordinary skill in the art. Promoter sequences may be selected to promote the transcription of a gene therapy (e.g., nucleic acid) encoded by the vector, for example tissue-specific or cell-specific promoters can be selected to ensure targeted production of the gene therapy within the cell type of interest or therapeutic value. Enhancer sequences may be selected to enhance the transcription of the nucleic acids. Selectable markers may be selected to allow selection of the host cells inserted with the vector from those not, for example, the selectable markers may be genes that confer antibiotic resistance. Signal sequences may be selected to allow for transport outside of the host cell. 32MF-363253604Attorney Docket No.: 15979-20192.40

[0104] Suitable vectors include, but are not limited to, nucleic acid molecules that are single-stranded, double-stranded, or partially double-stranded; nucleic acid molecules that comprise one or more free ends, no free ends (e.g., circular); nucleic acid molecules that comprise DNA, RNA, or both; and other varieties of polynucleotides known in the art. One type of vector is a “plasmid,” which refers to a circular double stranded DNA loop into which additional DNA segments can be inserted, such as by standard molecular cloning techniques. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the transcription or expression of coding nucleotide sequences to which they are operatively linked. Such vectors are referred to herein as “expression vectors”.

[0105] In some embodiments, the vector is selected from the group consisting of a viral vector, a bacterial vector, and a mammalian cell vector. Viral vector technology is well known in the art and is described, for example, in Sambrook et al. (2012), and in Ausubel et al. (1999), and in other virology and molecular biology manuals. Viruses, which are useful as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses (AAV), herpes viruses, and lentiviruses. In some embodiments, a murine stem cell virus (MSCV) vector is used to express a desired nucleic acid. MSCV vectors have been demonstrated to efficiently express desired nucleic acids in cells. Other examples of viral vectors are those based upon Moloney Murine Leukemia Virus (MoMuLV) and human immunodeficiency virus (HIV). In some embodiments, a suitable vector contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endonuclease sites, and one or more selectable markers. (See, e.g., WO 01 / 96584; WO 01 / 29058; and U.S. Pat. No. 6,326,193). EXAMPLES

[0106] The disclosure will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the disclosure. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. 33MF-363253604Attorney Docket No.: 15979-20192.40 General Methods Animal use and care

[0107] All procedures were performed according to a protocol approved by the Institutional Animal Care and Use Committee (IACUC) at Sanofi, as per guidelines specified by the Guide for the Care and Use of Laboratory Animals, NIH. Adult animals were group housed and maintained on a 12-hour light / dark cycle with food and water available ad libitum. Each animal was identified with a unique ear tag. Tissue processing and SERPINA1 mRNA quantification by RT-qPCR

[0108] Following euthanasia, hSERPINA1 mice were dissected, and liver and / or tail and / or lung tissue samples harvested, flash frozen in liquid nitrogen, and stored at -80℃. Tissue was bead homogenized at 4℃ in TRIzol reagent (Invitrogen) using the TissueLyser II (QIAGEN) for 3 minutes at 30 Hz, followed by aqueous phase separation according to manufacturer’s instructions. RNA was isolated from the aqueous phase using the miRNeasy Mini Kit (QIAGEN) according to manufacturer’s instructions with on-column DNase treatment using the RNase-free DNase Set (QIAGEN). RNA concentration and purity were assessed by measuring absorbance at A260 / 280 on a NanoDrop spectrophotometer (Thermo Scientific). A nine-step process was performed to extract RNA from tissues, and a six-step process was performed cDNA synthesis. RNA and cDNA were diluted to a final working concentration of 100ng / μl for qPCR.

[0109] mRNA expression was quantified by qPCR using the TaqMan Fast Virus 1-Step Master Mix (Applied Biosystems) with pre-validated Taqman probes targeting human SERPINA1 and mouse Serpina1 on the Quantstudio 6 (Applied Biosystems). Samples were run in triplicate wells on the same plate with 100 nanograms RNA input per well. Relative levels of SERPINA1 mRNA were quantified in the hSERPINA1 animals versus control animals by the 2^ΔΔCt method with Actin and / or Gapdh expression as housekeeping control using VIAA7 software (VIAA7, Applied Biosystems). 34MF-363253604Attorney Docket No.: 15979-20192.40 Tissue homogenization and SERPINA1 protein quantification by Western blotting

[0110] Following euthanasia, hSERPINA1 mice were dissected, and liver and / or tail and / or lung tissue samples harvested, flash frozen in liquid nitrogen, and stored at -80℃. Tissue was bead homogenized at 4℃ in T-PER buffer (Thermofisher) using the TissueLyser II (QIAGEN) for 3 minutes at 30 Hz, aliquoted, and stored at -80℃ until further use. T-PER homogenates were thawed on ice and 2x RIPA lysis buffer (Boston BioProducts) was added to a final concentration of 1x with added 1x Halt Protease Inhibitor Cocktail (Thermo Scientific). Samples were incubated on ice for 30 minutes and centrifuged at 14,000 RCF for 15 minutes at 4℃. Soluble protein concentration was quantified in the supernatant using Micro BCA Protein Assay Kit (Thermofisher) according to manufacturer’s instructions. For each sample loaded into the gel for Western blot analysis, 10μg protein was loaded per well on 4%-12% Bis-Tris gels. After transfer to PVDF membrane, the membranes were stained with Ponceau and imaged, and then the Ponceau washed out per standard methods. Then the membranes were blocked and then probed with either a recombinant Rabbit monoclonal Anti-human alpha 1 Antitrypsin antibody [EPR17087-50] (Abcam ab207303) at a dilution of 1:10,000 overnight, or recombinant Rabbit monoclonal Anti-mouse alpha 1 Antitrypsin antibody (Abcam ab231093) at a dilution of 1:10,000 overnight. Secondary antibody (goat anti-rabbit IgG H&L:HRP) was diluted at 1:5,000 and incubated for 1 hr at room temperature. After washing off excess secondary antibody, the PVDF membranes were then incubated for 1 min with BioRad Clarity ECL before being imaged using a BioRad ChemiDoc. Plasma and Liver A1AT protein quantification by ELISA

[0111] A1AT levels in serum and liver samples were quantified by direct ELISA as described by the manufacturer (R&D SYSTEMS; DY1268). Briefly, serum and liver proteins were captured in each well using a goat anti-human A1AT antibody: A1AT was detected by incubating with a biotinylated polyclonal goat anti-human A1AT antibody, followed by incubation with streptavidin-HRP and substrate solution. OD450nm was read and a four- parameter logistic model was fit to the standard curve; subsequently, A1AT concentration of the unknown samples was derived. Samples were run in technical triplicates. 35MF-363253604Attorney Docket No.: 15979-20192.40 Liver PAS-D staining

[0112] Mouse livers were collected in 10% neutral buffered formalin, embedded in paraffin, sectioned, and manually stained using the Periodic Acid Schiff (PAS) Diastase protocol. Stained whole liver sections were analyzed for PAS (+) Diastase resistant area using the corresponding Indica Labs HALO software algorithm (v.2.1.11). Example 1: Generation of exemplary hSERPINA1 murine models

[0113] Two exemplary murine models were generated wherein the mice of each model comprise a single copy of a human SERPINA1 transgene as described below. The two exemplary murine model designs are based on transcript-202 (NM_000295.5), which encodes a 418 aa protein and has 5 exons. The START codon is located on exon 2, and the STOP codon is on exon 5. Both models described below display the PiZ allele, which includes a G1096A point mutation (see, e.g., FIG. 3). Model 1: Synthesized hSERPINA1 transgene

[0114] As shown in FIG. 1, transgenic mice were generated wherein a single copy of a human SERPINA1 transgene with the PiZ point mutation in exon 5 was inserted into the Rosa26 transgene. This first transgene lacks SERPINA1 exon 1 and introns 1-3; instead, the transgene cassette comprises the following components: splicing acceptor – 3XSV40 polyA – duplicated enhancer sequence of α1-microglobulin / bikunin and optimized human SERPINA1 promoter sequence - human SERPINA1 exon 2 coding sequence – exon 3 coding sequence – exon 4 coding sequence – intron 6 noncoding sequence – exon 5 coding sequence (which includes a G1096A point mutation) – [approximately 500bp] 3′ UTR – bGH polyA. This transgene sequence was then inserted into introns 1-2 of the mouse Rosa26 gene, as indicated in FIG. 1. The inserted fragment was about 5 kb in length. The 3XSV40 PolyA sequence was inserted upstream of the SERPINA1 promoter in order to block endogenous Rosa26 promoter activity such that the human SERPINA1 gene expression would be controlled only by its associated optimized SERPINA1 promoter / enhancer (i.e., a duplicated sequence of α1- microglobulin / bikunin enhancer that is associated to an optimized, functional fraction of the human SERPINA1 promoter). This mouse model was further crossed to a mouse that lacks any murine Serpina1 (Strain #:000664). 36MF-363253604Attorney Docket No.: 15979-20192.40 Model 2: Native hSERPINA1 transgene

[0115] As shown in FIG. 2, transgenic mice were generated wherein a single copy of a human SERPINA1 transgene with the PiZ point mutation in exon 5 was inserted into the Rosa26 gene. The transgene cassette comprises the following components: splicing acceptor – 3XSV40 polyA – human SERPINA1 genome (including ~5 kb upstream genome sequence) that included 5kb upstream+exon 1+exon 2+exon 3+exon 4+intron 6+exon 5, wherein exon 5 included the G1096A point mutation. This transgene sequence was then inserted into introns 1-2 of the mouse Rosa26 gene, as indicated in FIG. 2. The inserted fragment was about 16 kb in length. The 3XSV40 PolyA sequence was inserted upstream of the SERPINA1 promoter in order to block endogenous Rosa26 promoter activity such that the human SERPINA1 gene expression would be controlled only by its associated SERPINA1 promoter. This mouse model was further crossed to a mouse lacking murine Serpina1 (Strain #:000664).

[0116] Plasmids comprising either of the transgene cassettes described herein were linearized and injected into murine blastocysts. ES cell lysate was collected to test for correct transgene insertion into the Rosa26 allele. Blastocysts showing correct insertion were then selected for transfer to sham-pregnant female mice to generate founding chimeras, which were then backcrossed to generate germline transmission of the hSERPINA1 transgene and genotype and select for these mice.

[0117] FIG. 4 provides genotyping confirmation of the correct integration of the hSERPINA1 transgene from Model 2 (i.e., “PiZ 101”) into the Rosa26 gene as designed. FIG. 5 provides genotyping confirmation of the correct integration of the hSERPINA1 transgene from Model 1 (i.e., “PiZ 124”) into the Rosa26 gene as designed.

[0118] Two rounds of RT-PCR were performed on mRNA samples isolated from the liver or tail as described herein. As shown in FIG. 6, the semi-quantification results from normalizing the CT values to the housekeeping gene, GAPDH, demonstrated the liver expression profile for human, but not murine, SERPINA1 in both the PiZ 101 and PiZ 124 mouse models.

[0119] As shown qualitatively in FIG. 7, Western blotting analysis confirmed the production of human A1AT protein in homozygous mice from both Models PiZ 101 and PiZ 124, but not from control mice that lack the hSERPINA1 transgene. As expected, murine A1AT protein was only produced in C57Bl / 6 mice (“C57”). In conjunction with the RT-PCR 37MF-363253604Attorney Docket No.: 15979-20192.40 data described herein, these results confirm that the human SERPINA1 gene is being effectively expressed and translated into A1AT protein. Example 2: Characterization of exemplary hSERPINA1 murine models

[0120] Mice from both Model PiZ 101 and PiZ 124, as well as C57 / Bl6 mice, were tested for plasma A1AT levels and accumulation of misfolded A1AT protein in the liver at 5 weeks of age. Plasma levels of A1AT from mice of both models was measured around 100 µg / mL by ELISA (see FIG. 8A), with the plasma levels being slightly higher in PiZ 124 mice. Analysis of human A1AT levels in the liver using ELISA showed about 100 ng / mg hA1AT in the PiZ 101 model and about 200 ng / mg hA1AT protein in the PiZ 124 model. As shown in FIGs. 9A-9B, neither the PiZ 101 mice nor the PiZ 124 mice produced any circulating plasma murine A1AT (FIG. 9A) nor liver murine A1AT (FIG. 9B), whereas C57Bl / 6 wildtype mice produced both circulating plasma and liver murine A1AT.

[0121] Moreover, an accumulation of PiZ A1AT protein in the liver was not observed in liver samples harvested from five-week-old Model PiZ 101 or Model PiZ 124 mice expressing a single copy of the hSERPINA1 transgene in comparison to the UMass PiZ mouse model that expresses at least five copies of a hSERPINA1 transgene, as seen by PAS- D staining (see FIG. 10). The UMass PiZ mice expressed at least five copies of the hSERPINA1 transgene (denoted “UMass mice” in FIG. 10; see, e.g., Carlson et al. (1989), J Clin Invest. 83(4):1183-90, hereby incorporated by reference in its entirety). Example 3: hSERPINA1 murine model used to assess editing efficacy of PiZ gene

[0122] PiZ 124 mice were treated using a lipid nanoparticle (LNP) encapsulating Cas9 mRNA (CleanCap Cas9 N1-methyl-PseudoU modified mRNA from Trilink) and guide RNA targeting SERPINA1 (gRNA seq; GAGGAACAGGCCATTGCCGG (SEQ ID NO: 22), targeting SERPINA1 exon 2). LNPs were administered in the adult mouse by tail vein injection at 0.5 mpk.

[0123] Lipid nanoparticle formulations: Cas9 mRNA and guide RNA were co- encapsulated at a 1:1 weight ratio in lipid nanoparticles. The LNPs were generated by rapidly mixing an aqueous solution of the RNA at a pH of 4.5 with an ethanol solution containing four lipid components: an ionizable lipid, helper lipid, cholesterol, and a lipid anchored PEG. 38MF-363253604Attorney Docket No.: 15979-20192.40 The two solutions were mixed using multichannel high throughput device. Post mixing, the formulations were dialyzed and buffer exchanged by Ambr crossflow at room temperature against our treatment buffer. The total RNA concentration was determined using Quant-iT Ribogreen (ThermoFisher Scientific). Mice were euthanized 10d post-treatment and tissue were collected by ELISA and next generation sequencing (NGS [PMID; 36522432 and 30809026]).

[0124] Editing efficacy measured by ELISA and NGS. As shown in FIG. 11, 40% indels were measured associated to 80% decrease of plasmatic PiZ protein (control (wild type), n = 3; treated PiZ 124, n= 3). Statistical significance was determined by two-tailed unpaired t test. Example 4: Evaluating plasma A1AT levels of aging mice using different mouse models Plasma collection

[0125] Blood from PiZ 101 and PiZ 124 mice were collected in EDTA tubes, placed on ice, spun and plasma removed to fresh tube. Plasma samples were stored at -80C. hA1AT ELISA

[0126] R&D Systems DuoSet kit were used to quantify human A1AT (Human A1AT ELISA, catalog #DY1268). Briefly, 96 well plates were coated with 100 µL / well Goat anti- Human A1AT capture antibody overnight. Plates were washed, blocked with 300 µL / well reagent diluent for 1- 1.5 hrs at RT and washed again. 100 µL / well standard (recombinant human A1AT, supplied with kit) and 1:100,000 plasma dilutions were added to plate and incubated 2h at room temperature. Plates were washed and 100 µL / well Streptavidin-HRP was added and incubation for 20 min in dark. Plates were washed before addition of 100 µL TMB substrate for 10-15 min in dark. Reaction was stopped with 50 µL stop solution and plates were read on Molecular Devices Spectamax PLUS 384, wavelength set to 450 nm with correction set to 540 nm. Four parameter curve-fit using SoftMax to determine human A1AT concentrations.

[0127] FIGs. 12A and 12B show that that PiZ 124 (FIG. 12A) and PiZ 101 (FIG. 12B), crossed to mSerpina1 KO have stable plasma A1AT levels as the mice are aging. The diamond shapes associated with each bar of the bar graphs indicate individual mice that were assessed for plasma A1AT levels. Plasma levels of A1AT measured are around 130 µg / mL 39MF-363253604Attorney Docket No.: 15979-20192.40 and around 100 µg / mL from PiZ 124 and PiZ 101 mice, respectively, as measured by ELISA. These results indicated that the different promoter regions utilized in PiZ 124 and PiZ 101 did not lead to a substantial difference in circulating A1AT protein levels. Moreover, no difference of A1AT levels between male and female mice was noticed. Example 5: Neutrophil elastase activity in vivo assay

[0128] Acute Lung Injury Mouse Model. Acute lung inflammation was induced in mice according to published protocols with slight modifications (Kossodo, S. et al. Noninvasive In Vivo Quantification of Neutrophil Elastase Activity in Acute Experimental Mouse Lung Injury. Int. J. Mol. Imaging 2011, 581406 (2011)). A schematic of the protocol is depicted in FIG. 13. Specifically, 8-12 week-old C57BL6 mice (Charles River) were housed in Alpha- dri® bedding and housed in a 12 hour light / dark cycle. All animal experimental procedures were approved by the Sanofi Institutional Animal Care and Use Committee and were in accordance with veterinarian requirements. Briefly, IVISense™ Neutrophil Elastase 680 FAST probe, also referred to as NE680, is a near-infrared fluorescent (NIRF) contrast agent used in animal models for in vivo imaging and quantification of neutrophil elastase (NE) activity. First, mice were challenged, via oropharyngeal instillation, with 30 μg of LPS (serotype 055:B5 Escherichia coli LPS, L2880; Sigma-Aldrich) solubilized in 40 μL PBS. Eighteen hours later, mice received an oropharyngeal instillation of the chemotactic peptide N-formylmet-leu-phe (f3506, Sigma-Aldrich) at 200nM in 40 μL PBS together with 4 nmol of NE680 (NEV11169 from Revvity). Six hour later, lung tissues from different mouse stains were collected quickly after euthanasia and fluorescence signals were measured and compared to each other’s.

[0129] FIG. 14 shows that lung neutrophil elastase activity is elevated in the humanized SERPINA1 PiZ 101 and PiZ 124 mouse models after acute LPS treatment. The increase in lung neutrophil elastase activity is comparable to the mA1AT knockout (KO) mice but significantly greater than the wildtype C57Bl / 6 mice. Statistical significance was determined by two-tailed unpaired t test. Example 6: Lung functional differences observed in hSERPINA1 murine models

[0130] The LPS challenge protocol for flexivent was adopted from Borel et al. with slight modification. See Borel, F. et al. Editing out five Serpina1 paralogs to create a mouse model 40MF-363253604Attorney Docket No.: 15979-20192.40 of genetic emphysema. Proc. Natl. Acad. Sci. 115, 2788–2793 (2018). Mice were housed with 12-h light / dark cycles on alpha-dri® (Shephard) bedding and fed a standard laboratory diet. Lipopolysaccharide (LPS) challenge was as follows: male and female mice from the three lines (age 10–23 wk) received two sequential oropharyngeal doses of LPS, 1 μg on day1 and 0.5 μg on day 12 (serotype 055:B5 Escherichia coli LPS, L2880; Sigma-Aldrich) in 30 μL PBS. The mice were anesthetized with 3-5% isoflurane in oxygen flowing at 1l / min to sustain a surgical plane of anesthesia during the procedure. Animal were placed in dorsal recumbency on a rodent workstand (Braintree Scientific) and dosed. During the course of the challenge, the animals treated with LPS lost weight for 3 days in response to the two doses and appeared slightly lethargic and with unkempt coats. Flexivent Procedure

[0131] Forced oscillometry was performed in intubated and anesthetized mice. Mice were anesthetized with an i.p. injection of a nembutol / xylazine mixture (80 mg / kg of nembutol and 8 mg / kg of xylazine). Following an adequate plane of anesthesia (loss of withdrawal to toe pinch), tracheotomy was performed, and a precalibrated cannula was introduced into the trachea. The mouse was then placed on a computer-controlled piston-ventilator Flexivent system (SCIREQ) and ventilated at a tidal volume of 10 mL / kg, rate of 150 breaths per minute and a positive end expiratory pressure of 3 mmHg. In brief, measurements were obtained by analyzing pressure and volume signals acquired in reaction to predefined, small amplitude, oscillatory airflow waveforms (perturbations) applied to the subject’s airways. First a “snapshot perturbation” maneuver was imposed to measure resistance (R), compliance (C), and elastance (E) of the whole respiratory system (airways, lung, and chest wall). Forced oscillation perturbation (“primewave-8”) was consequently applied, and resulted in Rn, inertia of the air, tissue damping (resistance, G), H, and tissue hysteresivity {tissue damping [G] / H}. Next, maximal PV loops were generated to obtain maximal vital (total) lung capacity (TLC), inspiratory capacity (IC) from zero pressure, form of deflating PV loop (K), static C (Cst), static elastance (Est), and hysteresis (area between inflating and deflating part of the loop). All maneuvers and perturbations were performed until three correct measurements were achieved. For flexiVent perturbations, a coefficient of determination of 0.95 was the lower limit for accepting a measurement. For each parameter, a total of three accepted measurements were calculated, and the average of the three technical replicates is used in data representation 41MF-363253604Attorney Docket No.: 15979-20192.40

[0132] FIGs. 15A-E show PV-loops, measurements (FIGS. 15A-C) of lung volume (FIG. 15D) and lung elasticity (FIG. 15E), using the Flexivent procedure discussed above for mA1AT knockout (KO) mice, the PiZ 101 mice, PiZ 124 mice or the wildtype C57Bl / 6 mice. The extent of lung injury was greater in the mA1AT knockout (Serpina1a–e knockout mice) mice than in the PiZ 101 mice, PiZ 124 mice or the wildtype C57Bl / 6 mice. LPS induced emphysema was observed only in the mA1AT knockout (Serpina1a–e knockout mice) mice. From an initial experiment, PiZ 124 mice displayed differences in lung function relative to the control mice and Serpina1a–e knockout mice but this effect was reassessed in follow up experiments using similar experimental conditions. The amount of A1AT protein is hypothesized to be sufficient to prevent lung damage associated with the moderate LPS challenge. Further characterization and optimization of the stress regimen maybe required to hypothetically induce lung disease in the PiZ mouse models. Statistical significance was determined by two-way ANOVA for PV-loops and by two-tailed unpaired t test for inspiratory capacity and quasi-static compliance. Example 7: Tissue phenotyping

[0133] The tissues of PiZ 101 and PiZ 124 including liver and lung were collected and fixed in 10% neutral buffered formalin (NBF), routinely processed, embedded in paraffin, and sectioned. Tissue sections were stained with hematoxylin and eosin (H&E) to evaluate the nature and degree of inflammatory cell infiltration. Serial sections of liver were submitted to Periodic acid–Schiff with diastase (PAS-D) staining to investigate mutant protein accumulation. Stained slides were evaluated by a board-certified veterinary pathologist

[0134] The findings of this study are depicted in the Table of FIG. 16. Compared to wild- type mice, Piz 101 and Piz 124 mice had increased frequency of chronic immune cell infiltrates and lymphoproliferation in multiple tissues including liver, lung, lymph node, pleura, kidney, and spleen. Intrahepatocytic PAS-D+ globules were present in only one PiZ 124 mouse and not present in PiZ 101 mice. PiZ 101 and PiZ 124 mice had a slightly increased frequency of lymphoproliferation and mononuclear infiltrates in multiple tissues compared to C57BL / 6 mice. 42MF-363253604Attorney Docket No.: 15979-20192.40 SEQUENCE LISTING SEQ ID NO:1 (wildtype human SERPINA1 transgene, nucleic acid) TCAGAGTCCTGAGCTGAACCAAGAAGGAGGAGGGGGTCGGGCCTCCGAGGAAG GCCTAGCCGCTGCTGCTGCCAGGAATTCCAGGTTGGAGGGGCGGCAACCTCCTG CCAGCCTTCAGGCCACTCTCCTGTGCCTGCCAGAAGAGACAGAGCTTGAGGAGA GCTTGAGGAGAGCAGGAAAGgtgggacattgctgctgctgctcactcagttccacaggtgggagggacagcagg gcttagagtgggggtcattgtgcagatgggaaaacaaaggcccagagaggggaagaaatgcccaggagctaccgagggcaggcg acctcaaccacagcccagtgctggagctgtgagtggatgtagagcagcggaatatccattcagccagctcaggggaaggacaggg gccctgaagccaggggatggagctgcagggaagggagctcagagagaaggggaggggagtctgagctcagtttcccgctgcctg aaaggagggtggtacctactcccttcacagggtaactgaatgagagactgcctggaggaaagctcttcaagtgtggcccaccccacc ccagtgacaccagcccctgacacgggggagggagggcagcatcaggaggggctttctgggcacacccagtacccgtctctgagct 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gctaaaggccaagtggatagtgatggccctgccagggctagaagccacaacctctggccctgaggccactcagcatatttagtgtccc caccctgcagaggcccaactccctcctgaccactgagccctgtaatgatgggggaatttccataagccatgaaggactgcacaaagtt cagttgggaagtgaaagagaaattaaagggagatggaaatatacagcactaattttagcaccgtctttagttctaacaacactagctagc 44MF-363253604Attorney Docket No.: 15979-20192.40 tgaagaaaaatacaaacatgtattatgtaatgtgtggtctgttccatttggattacttagaggcacgagggccaggagaaaggtggtgga gagaaaccagctttgcacttcatttgttgctttattggaaggaaacttttaaaagtccaagggggttgaagaatctcaatatttgttatttcca gctttttttctccagtttttcatttcccaaattcaaggacacctttttctttgtattttgttaagatgatggttttggttttgtgactagtagttaacaat gtggctgccgggcatattctcctcagctaggacctcagttttcccatctgtgaagacggcaggttctacctagggggctgcaggctggt ggtccgaagcctgggcatatctggagtagaaggatcactgtggggcagggcaggttctgtgttgctgtggatgacgttgactttgacca ttgctcggcagagcctgctctcgctggttcagccacaggccccaccactccctattgtctcagccccgggtatgaaacatgtattcctca ctggcctatcacctgaagcctttgaatttgcaacacctgccaacccctccctcaaaagagttgccctctcagatccttttgatgtaaggttt ggtgttgagacttatttcactaaattctcatacataaacatcactttatgtatgaggcaaaatgaggaccagggagatgaatgacttgtcct ggctcatacacctggaaagtgacagagtcagattagatcccaggtctatctgaagttaaaagaggtgtcttttcacttcccacctcctcca tctactttaaagcagcacaaacccctgctttcaaggagagatgagcgtctctaaagcccctgacagcaagagcccagaactgggaca ccattagtgacccagacggcaggtaagctgactgcaggagcatcagcctattcttgtgtctgggaccacagagcattgtggggacagc cccgtctcttgggaaaaaaaccctaagggctgaggatccttgtgagtgttgggtgggaacagctcccaggaggtttaatcacagcccc tccatgctctctagctgttgccattgtgcaagatgcatttcccttctgtgcagcagtttccctggccactaaatagtgggattagatagaag ccctccaagggcttccagcttgacatgattcttgattctgatctggcccgattcctggataatcgtgggcaggcccattcctcttcttgtgc ctcattttcttcttttgtaaaacaatggctgtaccatttgcatcttagggtcattgcagatgtaagtgttgctgtccagagcctgggtgcagga cctagatgtaggattctggttctgctacttcctcagtgacattgaatagctgacctaatctctctggctttggtttcttcatctgtaaaagaag gatattagcattagcacctcacgggattgttacaagaaagcaatgaattaacacatgtgagcacggagaacagtgcttggcatatggta agcactacgtacattttgctattcttctgattctttcagtgttactgatgtcggcaagtacttggcacaggctggtttaataatccctaggcact tccacgtggtgtcaatccctgatcactgggagtcatcatgtgccttgactcggggcctggcccccccatctctgtcttgcagGACAA TGCCGTCTTCTGTCTCGTGGGGCATCCTCCTGCTGGCAGGCCTGTGCTGCCTGGTC CCTGTCTCCCTGGCTGAGGATCCCCAGGGAGATGCTGCCCAGAAGACAGATACA TCCCACCATGATCAGGATCACCCAACCTTCAACAAGATCACCCCCAACCTGGCTG AGTTCGCCTTCAGCCTATACCGCCAGCTGGCACACCAGTCCAACAGCACCAATAT CTTCTTCTCCCCAGTGAGCATCGCTACAGCCTTTGCAATGCTCTCCCTGGGGACC AAGGCTGACACTCACGATGAAATCCTGGAGGGCCTGAATTTCAACCTCACGGAG ATTCCGGAGGCTCAGATCCATGAAGGCTTCCAGGAACTCCTCCGTACCCTCAACC AGCCAGACAGCCAGCTCCAGCTGACCACCGGCAATGGCCTGTTCCTCAGCGAGG GCCTGAAGCTAGTGGATAAGTTTTTGGAGGATGTTAAAAAGTTGTACCACTCAGA AGCCTTCACTGTCAACTTCGGGGACACCGAAGAGGCCAAGAAACAGATCAACGA TTACGTGGAGAAGGGTACTCAAGGGAAAATTGTGGATTTGGTCAAGGAGCTTGA CAGAGACACAGTTTTTGCTCTGGTGAATTACATCTTCTTTAAAGgtaaggttgctcaaccagc ctgagctgttcccatagaaacaagcaaaaatattctcaaaccatcagttcttgaactctccttggcaatgcattatgggccatagcaatgct tttcagcgtggattcttcagttttctacacacaaacactaaaatgttttccatcattgagtaatttgaggaaataatagattaaactgtcaaaac tactgacagctctgcagaacttttcagagcctttaatgtccttgtgtatactgtatatgtagaatatataatgcttagaactatagaacaaattg 45MF-363253604Attorney Docket No.: 15979-20192.40 taatacactgcataaagggatagtttcatggaacatactttacacgactctagtgtcccagaatcagtatcagttttgcaatctgaaagacc tgggttcaaatcctgcctctaacacaattagcttttgacaaaaacaatgcattctacctctttgaggtgctaatttctcatcttagcatggaca aaataccattcttgctgtcaggtttttttaggattaaacaaatgacaaagactgtggggatggtgtgtggcatacagcaggtgatggactct tctgtatctcaggctgccttcctgcccctgaggggttaaaatgccagggtcctgggggccccagggcattctaagccagctcccactgt cccaggaaaacagcataggggaggggaggtgggaggcaaggccaggggctgcttcctccactctgaggctcccttgctcttgagg caaaggagggcagtggagagcagccaggctgcagtcagcacagctaaagtcctggctctgctgtggccttagtgggggcccaggt ccctctccagccccagtctcctccttctgtccaatgagaaagctgggatcaggggtccctgaggcccctgtccactctgcatgcctcgat ggtgaagctctgttggtatggcagaggggaggctgctcaggcatctgcatttcccctgccaatctagaggatgaggaaagctctcagg aatagtaagcagaatgtttgccctggatgaataactgagctgccaattaacaaggggcagggagccttagacagaaggtaccaaatat gcctgatgctccaacattttatttgtaatatccaagacaccctcaaataaacatatgattccaataaaaatgcacagccacgatggcatctc ttagcctgacatcgccacgatgtagaaattctgcatcttcctctagttttgaattatccccacacaatctttttcggcagcttggatggtcagt ttcagcaccttttacagatgatgaagctgagcctcgagggatgtgtgtcgtcaagggggctcagggcttctcagggaggggactcatg gtttctttattctgctacactcttccaaaccttcactcacccctggtgatgcccaccttcccctctctccagGCAAATGGGAGAG ACCCTTTGAAGTCAAGGACACCGAGGAAGAGGACTTCCACGTGGACCAGGTGAC CACCGTGAAGGTGCCTATGATGAAGCGTTTAGGCATGTTTAACATCCAGCACTGT AAGAAGCTGTCCAGCTGGGTGCTGCTGATGAAATACCTGGGCAATGCCACCGCC ATCTTCTTCCTGCCTGATGAGGGGAAACTACAGCACCTGGAAAATGAACTCACCC ACGATATCATCACCAAGTTCCTGGAAAATGAAGACAGAAGgtgattccccaacctgagggtga ccaagaagctgcccacacctcttagccatgttgggactgaggcccatcaggactggccagagggctgaggagggtgaaccccacat ccctgggtcactgctactctgtataaacttggcttccagaatgaggccaccactgagttcaggcagcgccatccatgctccatgaggag gacagtacccaggggtgaggaggtaaaggtctcgtccctggggacttcccactccagtgtggacactgtcccttcccaatatccagtg cccagggcagggacagcagcaccaccacacgttctggcagaaccaaaaaggaacagatgggcttcctggcaaaggcagcagtgg agtgtggagttcaagggtagaatgtccctggggggacgggggaagagcctgtgtggcaaggcccagaaaagcaaggttcggaatt ggaacagccaggccatgttcgcagaaggcttgcgtttctctgtcactttatcggtgctgttagattgggtgtcctgtagtaagtgatactta aacatgagccacacattagtgtatgtgtgtgcattcgtgattatgcccatgccctgctgatctagttcgttttgtacactgtaaaaccaagat gaaaatacaaaaggtgtcgggttcataataggaatcgaggctggaatttctctgttccatgccagcacctcctgaggtctctgctccagg ggttgagaaagaacaaagaggctgagagggtaacggatcagagagcccagagccaagctgcccgctcacaccagaccctgctca gggtggcattgtctccccatggaaaaccagagaggagcactcagcctggtgtggtcactcttctcttatccactaaacggttgtcactgg gcactgccaccagccccgtgtttctctgggtgtagggccctggggatgttacaggctgggggccaggtgacccaacactacagggc aagatgagacaggcttccaggacacctagaatatcagaggaggtggcatttcaagcttttgtgattcattcgatgttaacattctttgactc aatgtagaagagctaaaagtagaacaaaccaaagccgagttcccatcttagtgtgggtggaggacacaggagtaagtggcagaaata atcagaaaagaaaacacttgcactgtggtgggtcccagaagaacaagaggaatgctgtgccatgccttgaatttcttttctgcacgaca gGTCTGCCAGCTTACATTTACCCAAACTGTCCATTACTGGAACCTATGATCTGAA GAGCGTCCTGGGTCAACTGGGCATCACTAAGGTCTTCAGCAATGGGGCTGACCTC 46MF-363253604Attorney Docket No.: 15979-20192.40 TCCGGGGTCACAGAGGAGGCACCCCTGAAGCTCTCCAAGgtgagatcaccctgacgaccttgtt gcaccctggtatctgtagggaagaatgtgtgggggctgcagctctgtcctgaggctgaggaaggggccgagggaaacaaatgaaga cccaggctgagctcctgaagatgcccgtgattcactgacacgggacgtggtcaaacagcaaagccaggcaggggactgctgtgcag ctggcactttcggggcctcccttgaggttgtgtcactgaccctgaatttcaactttgcccaagaccttctagacattgggccttgatttatcc atactgacacagaaaggtttgggctaagttgtttcaaaggaatttctgactccttcgatctgtgagatttggtgtctgaattaatgaatgattt cagctaaagatgacacttattttggaaaactaaaggcgaccaatgaacaactgcagttccatgaatggctgcattatcttggggtctggg cactgtgaaggtcactgccagggtccgtgtcctcaaggagcttcaagccgtgtactagaaaggagagagccctggaggcagacgtg gagtgacgatgctcttccctgttctgagttgtgggtgcacctgagcagggggagaggcgcttgtcaggaagatggacagaggggag ccagccccatcagccaaagccttgaggaggagcaaggcctatgtgacagggagggagaggatgtgcagggccagggccgtccag ggggagtgagcgcttcctgggaggtgtccacgtgagccttgctcgaggcctgggatcagccttacaacgtgtctctgcttctctcccct ccagGCCGTGCATAAGGCTGTGCTGACCATCGACGAGAAAGGGACTGAAGCTGCT GGGGCCATGTTTTTAGAGGCCATACCCATGTCTATCCCCCCCGAGGTCAAGTTCA ACAAACCCTTTGTCTTCTTAATGATTGAACAAAATACCAAGTCTCCCCTCTTCATG GGAAAAGTGGTGAATCCCACCCAAAAATAACTGCCTCTCGCTCCTCAACCCCTCC CCTCCATCCCTGGCCCCCTCCCTGGATGACATTAAAGAAGGGTTGAGCTGGTCCC TGCCTGCATGTGACTGTAAATCCCTCCCATGTTTTCTCTGAGTCTCCCTTTGCCTG CTGAGGCTGTATGTGGGCTCCAGGTAACAGTGCTGTCTTCGGGCCCCCTGAACTG TGTTCATGGAGCATCTGGCTGGGTAGGCACATGCTGGGCTTGAATCCAGGGGGG ACTGAATCCTCAGCTTACGGACCTGGGCCCATCTGTTTCTGGAGGGCTCCAGTCT TCCTTGTCCTGTCTTGGAGTCCCCAAGAAGGAATCACAGGGGAGGAACCAGATA CCAGCCATGACCCCAGGCTCCACCAAGCATCTTCATGTCCCCCTGCTCATCCCCC ACTCCCCCCCACCCAGAGTTGCTCATCCTGCCAGGGCTGGCTGTGCCCACCCCAA GGCTGCCCTCCTGGGGGCCCCAGAACTGCCTGATCGTGCCGTGGCCCAGTTTTGT GGCATCTGCAGCAACACAAGAGAGAGGACAATGTCCTCCTCTTGACCCGCTGTC ACCTAACCAGACTCGGGCCCTGCACCTCTCAGGCACTTCTGGAAAATGACTGAG GCAGATTCTTCCTGAAGCCCATTCTCCATGGGGCAACAAGGACACCTATTCTGTC CTTGTCCTTCCATCGCTGCCCCAGAAAGCCTCACATATCTCCGTTTAGAATCAGG TCCCTTCTCCCCAGATGAAGAGGAGGGTCTCTGCTTTGTTTTCTCTATCTCCTCCT CAGACTTGACCAGGCCCAGCAGGCCCCAGAAGACCATTACCCTATATCCCTTCTC CTCCCTAGTCACATGGCCATAGGCCTGCTGATGGCTCAGGAAGGCCATTGCAAG GACTCCTCAGCTATGGGAGAGGAAGCACATCACCCATTGACCCCCGCAACCCCT CCCTTTCCTCCTCTGAGTCCCGACTGGGGCCACATGCAGCCTGACTTCTTTGTGCC TGTTGCTGTCCCTGCAGTCTTCAGAGGGCCACCGCAGCTCCAGTGCCACGGCAGG AGGCTGTTCCTGAATAGCCCCTGTGGTAAGGGCCAGGAGAGTCCTTCCATCCTCC 47MF-363253604Attorney Docket No.: 15979-20192.40 AAGGCCCTGCTAAAGGACACAGCAGCCAGGAAGTCCCCTGGGCCCCTAGCTGAA GGACAGCCTGCTCCCTCCGTCTCTACCAGGAATGGCCTTGTCCTATGGAAGGCAC TGCCCCATCCCAAACTAATCTAGGAATCACTGTCTAACCACTCACTGTCATGAAT GTGTACTTAAAGGATGAGGTTGAGTCATACCAAATAGTGATTTCGATAGTTCAAA ATGGTGAAATTAGCAATTCTACATGATTCAGTCTAATCAATGGATACCGACTGTT TCCCACACAAGTCTCCTGTTCTCTTAAGCTTACTCACTGACAGCCTTTCACTCTCC ACAAATACATTAAAGATATGGCCATCACCAAGCCCCCTAGGATGACACCAGACC TGAGAGTCTGAAGACCTGGATCCAAGTTCTGACTTTTCCCCCTGACAGCTGTGTG ACCTTCGTGAAGTCGCCAAACCTCTCTGAGCCCCAGTCATTGCTAGTAAGACCTG CCTTTGAGTTGGTATGATGTTCAAGTTAGATAACAAAATGTTTATACCCATTAGA ACAGAGAATAAATAGAACTACATTTCTTGCA SEQ ID NO:2 (human SERPINA1 transgene #1, nucleic acid) TCAGAGTCCTGAGCTGAACCAAGAAGGAGGAGGGGGTCGGGCCTCCGAGGAAG GCCTAGCCGCTGCTGCTGCCAGGAATTCCAGGTTGGAGGGGCGGCAACCTCCTG CCAGCCTTCAGGCCACTCTCCTGTGCCTGCCAGAAGAGACAGAGCTTGAGGAGA GCTTGAGGAGAGCAGGAAAGgtgggacattgctgctgctgctcactcagttccacaggtgggagggacagcagg gcttagagtgggggtcattgtgcagatgggaaaacaaaggcccagagaggggaagaaatgcccaggagctaccgagggcaggcg acctcaaccacagcccagtgctggagctgtgagtggatgtagagcagcggaatatccattcagccagctcaggggaaggacaggg gccctgaagccaggggatggagctgcagggaagggagctcagagagaaggggaggggagtctgagctcagtttcccgctgcctg aaaggagggtggtacctactcccttcacagggtaactgaatgagagactgcctggaggaaagctcttcaagtgtggcccaccccacc ccagtgacaccagcccctgacacgggggagggagggcagcatcaggaggggctttctgggcacacccagtacccgtctctgagct ttccttgaactgttgcattttaatcctcacagcagctcaacaaggtacataccgtcaccatccccattttacagatagggaaattgaggctc ggagcggttaaacaactcacctgaggcctcacagccagtaagtgggttccctggtctgaatgtgtgtgctggaggatcctgtgggtca ctcgcctggtagagccccaaggtggaggcataaatgggactggtgaatgacagaaggggcaaaaatgcactcatccattcactctgc aagtatctacggcacgtacgccagctcccaagcaggtttgcgggttgcacagcgggcgatgcaatctgatttaggcttttaaagggatt gcaatcaagtggggccccactagcctcaaccctgtacctcccctcccctccacccccagcagtctccaaaggcctccaacaacccca gagtgggggccatgtatccaaagaaactccaagctgtatacggatcacactggttttccaggagcaaaaacagaaacaggcctgagg ctggtcaaaattgaacctcctcctgctctgagcagcctggggggcagactaagcagagggctgtgcagacccacataaagagcctac tgtgtgccaggcacttcacccgaggcacttcacaagcatgcttgggaatgaaacttccaactctttgggatgcaggtgaaacagttcctg gttcagagaggtgaagcggcctgcctgaggcagcacagctcttctttacagatgtgcttccccacctctaccctgtctcacggcccccc atgccagcctgacggttgtgtctgcctcagtcatgctccatttttccatcgggaccatcaagagggtgtttgtgtctaaggctgactgggt aactttggatgagcggtctctccgctctgagcctgtttcctcatctgtcaaatgggctctaacccactctgatctcccagggcggcagtaa gtcttcagcatcaggcattttggggtgactcagtaaatggtagatcttgctaccagtggaacagccactaaggattctgcagtgagagca 48MF-363253604Attorney Docket No.: 15979-20192.40 gagggccagctaagtggtactctcccagagactgtctgactcacgccaccccctccaccttggacacaggacgctgtggtttctgagc caggtacaatgactcctttcggtaagtgcagtggaagctgtacactgcccaggcaaagcgtccgggcagcgtaggcgggcgactca gatcccagccagtggacttagcccctgtttgctcctccgataactggggtgaccttggttaatattcaccagcagcctcccccgttgccc ctctggatccactgcttaaatacggacgaggacagggccctgtctcctcagcttcaggcaccaccactgacctgggacagtgaatcgt aagtatgcctttcactgcgagaggttctggagaggcttctgagctccccatggcccaggcaggcagcaggtctggggcaggagggg ggttgtggagtgggtatccgcctgctgaggtgcagggcagatggagaggctgcagctgagctcctattttcataataacagcagccat gagggttgtgtcctgtttcccagtcctgcccggtcccccctcggtacctcctggtggatacactggttcctgtaagcagaagtggatgag ggtgtctaggtctgcagtcctggcaccccaggatgggggacaccagccaagatacagcaacagcaacaaagcgcagccatttctttc tgtttgcacagctcctctgtctgtcgggggctcctgtctgttgtctcctataagcctcaccacctctcctactgcttgggcatgcatctttctc cccttctatagatgaggaggttaaggtccagagaggggtggggaggaacgccggctcacattctccatcccctccagatatgaccag gaacagacctgtgccaggcctcagccttacatcaaaatgggcctccccatgcaccgtggacctctgggccctcctgtcccagtggag gacaggaagctgtgaggggcactgtcacccagggctcaagctggcattcctgaataatcgctctgcaccaggccacggctaagctca gtgcgtgattaagcctcataaccctccaaggcagttactagtgtgattcccattttacagatgaggaagatggggacagagaggtgaat aactggccccaaatcacacaccatccataattcgggctcaggcacctggctccagtccccaaactcttgaacctggccctagtgtcact gtttctcttgggtctcaggcgctggatggggaacaggaaacctgggctggacttgaggcctctctgatgctcggtgacttcagacagtt gctcaacctctctgttctcttgggcaaaacatgataacctttgacttctgtcccctcccctcaccccacccgaccttgatctctgaagtgttg gaaggatttaatttttcctgcactgagttttggagacaggtcaaaaagatgaccaaggccaaggtggccagtttcctatagaacgcctct aaaagacctgcagcaatagcagcaagaactggtattctcgagaacttgctgcgcagcaggcacttcttggcattttatgtgtatttaatttc acaatagctctatgacaaagtccacctttctcatctccaggaaactgaggttcagagaggttaagtaacttgtccaaggtcacacagcta atagcaagttgacgtggagcaatctggcctcagagcctttaattttagccacagactgatgctcccctcttcatttagccaggctgcctct gaagttttctgattcaagacttctggcttcagctttgtacacagagatgattcaatgtcaggttttggagtgaaatctgtttaatcccagacaa aacatttaggattacatctcagttttgtaagcaagtagctctgtgatttttagtgagttatttaatgctctttggggctcaatttttctatctataaa atagggctaataatttgcaccttatagggtaagctttgaggacagattagatgatacggtgcctgtaaaacaccaggtgttagtaagtgtg gcaatgatggtgacgctgaggctgatgtttgcttagcatagggttaggcagctggcaggcagtaaacagttggataatttaatggaaaat ttgccaaactcagatgctgttcactgctgagcaggagccccttcctgctgaaatggtcctggggagtgcagcaggctctccgggaaga aatctaccatctctcgggcaggagctcaacctgtgtgcaggtacagggagggcttcctcacctggtgcccactcatgcattacgtcagtt attcctcatccctgtccaaaggattcttttctccattgtacagctatgaagctagtgctcaaagaagtgaagtcatttaccccaggccccct gccagtaagtgacagggcctggtcacacttgggtttatttattgcccagttcaacaggttgtttgaccataggcgagattctcttccctgca ccctgccgggttgctcttggtcccttattttatgctcccgggtagaaatggtgtgagattaggcagggagtggctcgcttccctgtccctg gccccgcaaagagtgctcccacctgccccgatcccagaaatgtcaccatgaagccttcattcttttggtttaaagcttggcctcagtgtcc gtacaccatggggtacttggccagatggcgactttctcctctccagtcgccctcccaggcactagcttttaggagtgcagggtgctgcct ctgatagaagggccaggagagagcaggttttggagtcctgatgttataaggaacagcttgggaggcataatgaacccaacatgatgct tgagaccaatgtcacagcccaattctgacattcatcatctgagatctgaggacacagctgtctcagttcatgatctgagtgctgggaaag ccaagacttgttccagctttgtcactgacttgctgtatagcctcaacaaggccctgaccctctctgggcttcaaactcttcactgtgaaagg 49MF-363253604Attorney Docket No.: 15979-20192.40 aggaaaccagagtaggtgatgtgacaccaggaaagatggatgggtgtgggggaatgtgctcctcccagctgtcaccccctcgccac cctccctgcaccagcctctccacctcctttgagcccagaattcccctgtctaggagggcacctgtctcatgcctagccatgggaattctc catctgttttgctacattgaacccagatgccattctaaccaagaatcctggctgggtgcaggggctctcgcctgtaaccccagcactttgg gaggccaaggcaggcggatcaagaggtcaggagttcaagacctgcctggccaacacggtgaaacctcagctctactaaaaatacaa aaattagccaggcgtggtggcacacgcctgtaatcccagctatttgggaagctgagacagaagaatttcttgaacccgggaggtgga ggtttcagtgagccgagatcacgccactgcactccaccctggcagataaagcgagactctgtctcaaaaaaaacccaaaaacctatgt tagtgtacagagggccccagtgaagtcttctcccagccccactttgcacaactggggagagtgaggccccaggaccagaggattctt gctaaaggccaagtggatagtgatggccctgccagggctagaagccacaacctctggccctgaggccactcagcatatttagtgtccc caccctgcagaggcccaactccctcctgaccactgagccctgtaatgatgggggaatttccataagccatgaaggactgcacaaagtt cagttgggaagtgaaagagaaattaaagggagatggaaatatacagcactaattttagcaccgtctttagttctaacaacactagctagc tgaagaaaaatacaaacatgtattatgtaatgtgtggtctgttccatttggattacttagaggcacgagggccaggagaaaggtggtgga gagaaaccagctttgcacttcatttgttgctttattggaaggaaacttttaaaagtccaagggggttgaagaatctcaatatttgttatttcca gctttttttctccagtttttcatttcccaaattcaaggacacctttttctttgtattttgttaagatgatggttttggttttgtgactagtagttaacaat gtggctgccgggcatattctcctcagctaggacctcagttttcccatctgtgaagacggcaggttctacctagggggctgcaggctggt ggtccgaagcctgggcatatctggagtagaaggatcactgtggggcagggcaggttctgtgttgctgtggatgacgttgactttgacca ttgctcggcagagcctgctctcgctggttcagccacaggccccaccactccctattgtctcagccccgggtatgaaacatgtattcctca ctggcctatcacctgaagcctttgaatttgcaacacctgccaacccctccctcaaaagagttgccctctcagatccttttgatgtaaggttt ggtgttgagacttatttcactaaattctcatacataaacatcactttatgtatgaggcaaaatgaggaccagggagatgaatgacttgtcct ggctcatacacctggaaagtgacagagtcagattagatcccaggtctatctgaagttaaaagaggtgtcttttcacttcccacctcctcca tctactttaaagcagcacaaacccctgctttcaaggagagatgagcgtctctaaagcccctgacagcaagagcccagaactgggaca ccattagtgacccagacggcaggtaagctgactgcaggagcatcagcctattcttgtgtctgggaccacagagcattgtggggacagc cccgtctcttgggaaaaaaaccctaagggctgaggatccttgtgagtgttgggtgggaacagctcccaggaggtttaatcacagcccc tccatgctctctagctgttgccattgtgcaagatgcatttcccttctgtgcagcagtttccctggccactaaatagtgggattagatagaag ccctccaagggcttccagcttgacatgattcttgattctgatctggcccgattcctggataatcgtgggcaggcccattcctcttcttgtgc ctcattttcttcttttgtaaaacaatggctgtaccatttgcatcttagggtcattgcagatgtaagtgttgctgtccagagcctgggtgcagga cctagatgtaggattctggttctgctacttcctcagtgacattgaatagctgacctaatctctctggctttggtttcttcatctgtaaaagaag gatattagcattagcacctcacgggattgttacaagaaagcaatgaattaacacatgtgagcacggagaacagtgcttggcatatggta agcactacgtacattttgctattcttctgattctttcagtgttactgatgtcggcaagtacttggcacaggctggtttaataatccctaggcact tccacgtggtgtcaatccctgatcactgggagtcatcatgtgccttgactcggggcctggcccccccatctctgtcttgcagGACAA TGCCGTCTTCTGTCTCGTGGGGCATCCTCCTGCTGGCAGGCCTGTGCTGCCTGGTC CCTGTCTCCCTGGCTGAGGATCCCCAGGGAGATGCTGCCCAGAAGACAGATACA TCCCACCATGATCAGGATCACCCAACCTTCAACAAGATCACCCCCAACCTGGCTG AGTTCGCCTTCAGCCTATACCGCCAGCTGGCACACCAGTCCAACAGCACCAATAT CTTCTTCTCCCCAGTGAGCATCGCTACAGCCTTTGCAATGCTCTCCCTGGGGACC 50MF-363253604Attorney Docket No.: 15979-20192.40 AAGGCTGACACTCACGATGAAATCCTGGAGGGCCTGAATTTCAACCTCACGGAG ATTCCGGAGGCTCAGATCCATGAAGGCTTCCAGGAACTCCTCCGTACCCTCAACC AGCCAGACAGCCAGCTCCAGCTGACCACCGGCAATGGCCTGTTCCTCAGCGAGG GCCTGAAGCTAGTGGATAAGTTTTTGGAGGATGTTAAAAAGTTGTACCACTCAGA AGCCTTCACTGTCAACTTCGGGGACACCGAAGAGGCCAAGAAACAGATCAACGA TTACGTGGAGAAGGGTACTCAAGGGAAAATTGTGGATTTGGTCAAGGAGCTTGA CAGAGACACAGTTTTTGCTCTGGTGAATTACATCTTCTTTAAAGgtaaggttgctcaaccagc ctgagctgttcccatagaaacaagcaaaaatattctcaaaccatcagttcttgaactctccttggcaatgcattatgggccatagcaatgct tttcagcgtggattcttcagttttctacacacaaacactaaaatgttttccatcattgagtaatttgaggaaataatagattaaactgtcaaaac tactgacagctctgcagaacttttcagagcctttaatgtccttgtgtatactgtatatgtagaatatataatgcttagaactatagaacaaattg taatacactgcataaagggatagtttcatggaacatactttacacgactctagtgtcccagaatcagtatcagttttgcaatctgaaagacc tgggttcaaatcctgcctctaacacaattagcttttgacaaaaacaatgcattctacctctttgaggtgctaatttctcatcttagcatggaca aaataccattcttgctgtcaggtttttttaggattaaacaaatgacaaagactgtggggatggtgtgtggcatacagcaggtgatggactct tctgtatctcaggctgccttcctgcccctgaggggttaaaatgccagggtcctgggggccccagggcattctaagccagctcccactgt cccaggaaaacagcataggggaggggaggtgggaggcaaggccaggggctgcttcctccactctgaggctcccttgctcttgagg caaaggagggcagtggagagcagccaggctgcagtcagcacagctaaagtcctggctctgctgtggccttagtgggggcccaggt ccctctccagccccagtctcctccttctgtccaatgagaaagctgggatcaggggtccctgaggcccctgtccactctgcatgcctcgat ggtgaagctctgttggtatggcagaggggaggctgctcaggcatctgcatttcccctgccaatctagaggatgaggaaagctctcagg aatagtaagcagaatgtttgccctggatgaataactgagctgccaattaacaaggggcagggagccttagacagaaggtaccaaatat gcctgatgctccaacattttatttgtaatatccaagacaccctcaaataaacatatgattccaataaaaatgcacagccacgatggcatctc ttagcctgacatcgccacgatgtagaaattctgcatcttcctctagttttgaattatccccacacaatctttttcggcagcttggatggtcagt ttcagcaccttttacagatgatgaagctgagcctcgagggatgtgtgtcgtcaagggggctcagggcttctcagggaggggactcatg gtttctttattctgctacactcttccaaaccttcactcacccctggtgatgcccaccttcccctctctccagGCAAATGGGAGAG ACCCTTTGAAGTCAAGGACACCGAGGAAGAGGACTTCCACGTGGACCAGGTGAC CACCGTGAAGGTGCCTATGATGAAGCGTTTAGGCATGTTTAACATCCAGCACTGT AAGAAGCTGTCCAGCTGGGTGCTGCTGATGAAATACCTGGGCAATGCCACCGCC ATCTTCTTCCTGCCTGATGAGGGGAAACTACAGCACCTGGAAAATGAACTCACCC ACGATATCATCACCAAGTTCCTGGAAAATGAAGACAGAAGgtgattccccaacctgagggtga ccaagaagctgcccacacctcttagccatgttgggactgaggcccatcaggactggccagagggctgaggagggtgaaccccacat ccctgggtcactgctactctgtataaacttggcttccagaatgaggccaccactgagttcaggcagcgccatccatgctccatgaggag gacagtacccaggggtgaggaggtaaaggtctcgtccctggggacttcccactccagtgtggacactgtcccttcccaatatccagtg cccagggcagggacagcagcaccaccacacgttctggcagaaccaaaaaggaacagatgggcttcctggcaaaggcagcagtgg agtgtggagttcaagggtagaatgtccctggggggacgggggaagagcctgtgtggcaaggcccagaaaagcaaggttcggaatt ggaacagccaggccatgttcgcagaaggcttgcgtttctctgtcactttatcggtgctgttagattgggtgtcctgtagtaagtgatactta 51MF-363253604Attorney Docket No.: 15979-20192.40 aacatgagccacacattagtgtatgtgtgtgcattcgtgattatgcccatgccctgctgatctagttcgttttgtacactgtaaaaccaagat gaaaatacaaaaggtgtcgggttcataataggaatcgaggctggaatttctctgttccatgccagcacctcctgaggtctctgctccagg ggttgagaaagaacaaagaggctgagagggtaacggatcagagagcccagagccaagctgcccgctcacaccagaccctgctca gggtggcattgtctccccatggaaaaccagagaggagcactcagcctggtgtggtcactcttctcttatccactaaacggttgtcactgg gcactgccaccagccccgtgtttctctgggtgtagggccctggggatgttacaggctgggggccaggtgacccaacactacagggc aagatgagacaggcttccaggacacctagaatatcagaggaggtggcatttcaagcttttgtgattcattcgatgttaacattctttgactc aatgtagaagagctaaaagtagaacaaaccaaagccgagttcccatcttagtgtgggtggaggacacaggagtaagtggcagaaata atcagaaaagaaaacacttgcactgtggtgggtcccagaagaacaagaggaatgctgtgccatgccttgaatttcttttctgcacgaca gGTCTGCCAGCTTACATTTACCCAAACTGTCCATTACTGGAACCTATGATCTGAA GAGCGTCCTGGGTCAACTGGGCATCACTAAGGTCTTCAGCAATGGGGCTGACCTC TCCGGGGTCACAGAGGAGGCACCCCTGAAGCTCTCCAAGgtgagatcaccctgacgaccttgtt gcaccctggtatctgtagggaagaatgtgtgggggctgcagctctgtcctgaggctgaggaaggggccgagggaaacaaatgaaga cccaggctgagctcctgaagatgcccgtgattcactgacacgggacgtggtcaaacagcaaagccaggcaggggactgctgtgcag ctggcactttcggggcctcccttgaggttgtgtcactgaccctgaatttcaactttgcccaagaccttctagacattgggccttgatttatcc atactgacacagaaaggtttgggctaagttgtttcaaaggaatttctgactccttcgatctgtgagatttggtgtctgaattaatgaatgattt cagctaaagatgacacttattttggaaaactaaaggcgaccaatgaacaactgcagttccatgaatggctgcattatcttggggtctggg cactgtgaaggtcactgccagggtccgtgtcctcaaggagcttcaagccgtgtactagaaaggagagagccctggaggcagacgtg gagtgacgatgctcttccctgttctgagttgtgggtgcacctgagcagggggagaggcgcttgtcaggaagatggacagaggggag ccagccccatcagccaaagccttgaggaggagcaaggcctatgtgacagggagggagaggatgtgcagggccagggccgtccag ggggagtgagcgcttcctgggaggtgtccacgtgagccttgctcgaggcctgggatcagccttacaacgtgtctctgcttctctcccct ccagGCCGTGCATAAGGCTGTGCTGACCATCGACAAGAAAGGGACTGAAGCTGCT GGGGCCATGTTTTTAGAGGCCATACCCATGTCTATCCCCCCCGAGGTCAAGTTCA ACAAACCCTTTGTCTTCTTAATGATTGAACAAAATACCAAGTCTCCCCTCTTCATG GGAAAAGTGGTGAATCCCACCCAAAAATAACTGCCTCTCGCTCCTCAACCCCTCC CCTCCATCCCTGGCCCCCTCCCTGGATGACATTAAAGAAGGGTTGAGCTGGTCCC TGCCTGCATGTGACTGTAAATCCCTCCCATGTTTTCTCTGAGTCTCCCTTTGCCTG CTGAGGCTGTATGTGGGCTCCAGGTAACAGTGCTGTCTTCGGGCCCCCTGAACTG TGTTCATGGAGCATCTGGCTGGGTAGGCACATGCTGGGCTTGAATCCAGGGGGG ACTGAATCCTCAGCTTACGGACCTGGGCCCATCTGTTTCTGGAGGGCTCCAGTCT TCCTTGTCCTGTCTTGGAGTCCCCAAGAAGGAATCACAGGGGAGGAACCAGATA CCAGCCATGACCCCAGGCTCCACCAAGCATCTTCATGTCCCCCTGCTCATCCCCC ACTCCCCCCCACCCAGAGTTGCTCATCCTGCCAGGGCTGGCTGTGCCCACCCCAA GGCTGCCCTCCTGGGGGCCCCAGAACTGCCTGATCGTGCCGTGGCCCAGTTTTGT GGCATCTGCAGCAACACAAGAGAGAGGACAATGTCCTCCTCTTGACCCGCTGTC 52MF-363253604Attorney Docket No.: 15979-20192.40 ACCTAACCAGACTCGGGCCCTGCACCTCTCAGGCACTTCTGGAAAATGACTGAG GCAGATTCTTCCTGAAGCCCATTCTCCATGGGGCAACAAGGACACCTATTCTGTC CTTGTCCTTCCATCGCTGCCCCAGAAAGCCTCACATATCTCCGTTTAGAATCAGG TCCCTTCTCCCCAGATGAAGAGGAGGGTCTCTGCTTTGTTTTCTCTATCTCCTCCT CAGACTTGACCAGGCCCAGCAGGCCCCAGAAGACCATTACCCTATATCCCTTCTC CTCCCTAGTCACATGGCCATAGGCCTGCTGATGGCTCAGGAAGGCCATTGCAAG GACTCCTCAGCTATGGGAGAGGAAGCACATCACCCATTGACCCCCGCAACCCCT CCCTTTCCTCCTCTGAGTCCCGACTGGGGCCACATGCAGCCTGACTTCTTTGTGCC TGTTGCTGTCCCTGCAGTCTTCAGAGGGCCACCGCAGCTCCAGTGCCACGGCAGG AGGCTGTTCCTGAATAGCCCCTGTGGTAAGGGCCAGGAGAGTCCTTCCATCCTCC AAGGCCCTGCTAAAGGACACAGCAGCCAGGAAGTCCCCTGGGCCCCTAGCTGAA GGACAGCCTGCTCCCTCCGTCTCTACCAGGAATGGCCTTGTCCTATGGAAGGCAC TGCCCCATCCCAAACTAATCTAGGAATCACTGTCTAACCACTCACTGTCATGAAT GTGTACTTAAAGGATGAGGTTGAGTCATACCAAATAGTGATTTCGATAGTTCAAA ATGGTGAAATTAGCAATTCTACATGATTCAGTCTAATCAATGGATACCGACTGTT TCCCACACAAGTCTCCTGTTCTCTTAAGCTTACTCACTGACAGCCTTTCACTCTCC ACAAATACATTAAAGATATGGCCATCACCAAGCCCCCTAGGATGACACCAGACC TGAGAGTCTGAAGACCTGGATCCAAGTTCTGACTTTTCCCCCTGACAGCTGTGTG ACCTTCGTGAAGTCGCCAAACCTCTCTGAGCCCCAGTCATTGCTAGTAAGACCTG CCTTTGAGTTGGTATGATGTTCAAGTTAGATAACAAAATGTTTATACCCATTAGA ACAGAGAATAAATAGAACTACATTTCTTGCA SEQ ID NO:3 (human SERPINA1 transgene #2, nucleic acid) atgccgtcttctgtctcgtggggcatcctcctgctggcaggcctgtgctgcctggtccctgtctccctggctgaggatccccagggagat gctgcccagaagacagatacatcccaccatgatcaggatcacccaaccttcaacaagatcacccccaacctggctgagttcgccttca gcctataccgccagctggcacaccagtccaacagcaccaatatcttcttctccccagtgagcatcgctacagcctttgcaatgctctccc tggggaccaaggctgacactcacgatgaaatcctggagggcctgaatttcaacctcacggagattccggaggctcagatccatgaag gcttccaggaactcctccgtaccctcaaccagccagacagccagctccagctgaccaccggcaatggcctgttcctcagcgagggcc tgaagctagtggataagtttttggaggatgttaaaaagttgtaccactcagaagccttcactgtcaacttcggggacaccgaagaggcc aagaaacagatcaacgattacgtggagaagggtactcaagggaaaattgtggatttggtcaaggagcttgacagagacacagtttttg ctctggtgaattacatcttctttaaaggcaaatgggagagaccctttgaagtcaaggacaccgaggaagaggacttccacgtggacca ggtgaccaccgtgaaggtgcctatgatgaagcgtttaggcatgtttaacatccagcactgtaagaagctgtccagctgggtgctgctga tgaaatacctgggcaatgccaccgccatcttcttcctgcctgatgaggggaaactacagcacctggaaaatgaactcacccacgatatc atcaccaagttcctggaaaatgaagacagaaggtctgccagcttacatttacccaaactgtccattactggaacctatgatctgaagagc 53MF-363253604Attorney Docket No.: 15979-20192.40 gtcctgggtcaactgggcatcactaaggtcttcagcaatggggctgacctctccggggtcacagaggaggcacccctgaagctctcc aaggtgagatcaccctgacgaccttgttgcaccctggtatctgtagggaagaatgtgtgggggctgcagctctgtcctgaggctgagg aaggggccgagggaaacaaatgaagacccaggctgagctcctgaagatgcccgtgattcactgacacgggacgtggtcaaacagc aaagccaggcaggggactgctgtgcagctggcactttcggggcctcccttgaggttgtgtcactgaccctgaatttcaactttgcccaa gaccttctagacattgggccttgatttatccatactgacacagaaaggtttgggctaagttgtttcaaaggaatttctgactccttcgatctgt gagatttggtgtctgaattaatgaatgatttcagctaaagatgacacttattttggaaaactaaaggcgaccaatgaacaactgcagttcca tgaatggctgcattatcttggggtctgggcactgtgaaggtcactgccagggtccgtgtcctcaaggagcttcaagccgtgtactagaa aggagagagccctggaggcagacgtggagtgacgatgctcttccctgttctgagttgtgggtgcacctgagcagggggagaggcgc ttgtcaggaagatggacagaggggagccagccccatcagccaaagccttgaggaggagcaaggcctatgtgacagggagggaga ggatgtgcagggccagggccgtccagggggagtgagcgcttcctgggaggtgtccacgtgagccttgctcgaggcctgggatcag ccttacaacgtgtctctgcttctctcccctccaggccgtgcataaggctgtgctgaccatcgacAagaaagggactgaagctgctggg gccatgtttttagaggccatacccatgtctatcccccccgaggtcaagttcaacaaaccctttgtcttcttaatgattgaacaaaataccaa gtctcccctcttcatgggaaaagtggtgaatcccacccaaaaataactgcctctcgctcctcaacccctcccctccatccctggccccct ccctggatgacattaaagaagggttgagctggtccctgcctgcatgtgactgtaaatccctcccatgttttctctgagtctccctttgcctg ctgaggctgtatgtgggctccaggtaacagtgctgtcttcgggccccctgaactgtgttcatggagcatctggctgggtaggcacatgc tgggcttgaatccaggggggactgaatcctcagcttacggacctgggcccatctgtttctggagggctccagtcttccttgtcctgtcttg gagtccccaagaaggaatcacaggggaggaaccagataccagccatgaccccaggctccaccaagcatcttcatgtccccctgctc atcccccactcccccccacccagagttgctcatcctgccagggctggctgtgcccaccccaaggctgccctcctgggggccccagaa ctgcctgatcgtgccgtggcccagttttgtggcatctgcagcaacacaagagagaggacaatgtcctcctcttgacccgctgtcaccta accagactcgggccctgcacctctcaggcacttctggaaaatgactgaggcagattcttcctgaagcccattctccatggggcaacaa ggacacctattctgtccttgtccttccatcgctgccccagaaagcctcacatatctccgtttagaatcaggtcccttctccccagatgaaga ggagggtctctgctttgttttctctatctcctcctcagacttgaccaggcccagcaggccccagaagaccattaccctatatcccttctcct ccctagtcacatggccataggcctgctgatggctcaggaaggccattgcaaggactcctcagctatgggagaggaagcacatcaccc attgacccccgcaacccctccctttcctcctctgagtcccgactggggccacatgcagcctgacttctttgtgcctgttgctgtccctgca gtcttcagagggccaccgcagctccagtgccacggcaggaggctgttcctgaatagcccctgtggtaagggccaggagagtccttcc atcctccaaggccctgctaaaggacacagcagccaggaagtcccctgggcccctagctgaaggacagcctgctccctccgtctctac caggaatggccttgtcctatggaaggcactgccccatcccaaactaatctaggaatcactgtctaaccactcactgtcatgaatgtgtact taaaggatgaggttgagtcataccaaatagtgatttcgatagttcaaaatggtgaaattagcaattctacatgattcagtctaatcaatggat accgactgtttcccacacaagtctcctgttctcttaagcttactcactgacagcctttcactctccacaaatacattaaagatatggccatca ccaagccccctaggatgacaccagacctgagagtctgaagacctggatccaagttctgacttttccccctgacagctgtgtgaccttcgt gaagtcgccaaacctctctgagccccagtcattgctagtaagacctgcctttgagttggtatgatgttcaagttagataacaaaatgtttat acccattagaacagagaataaatagaactacatttcttgca SEQ ID NO:4 (wildtype human alpha-1 antitrypsin (A1AT) protein, amino acid) 54MF-363253604Attorney Docket No.: 15979-20192.40 MPSSVSWGILLLAGLCCLVPVSLAEDPQGDAAQKTDTSHHDQDHPTFNKITPNLAEF AFSLYRQLAHQSNSTNIFFSPVSIATAFAMLSLGTKADTHDEILEGLNFNLTEIPEAQIH EGFQELLRTLNQPDSQLQLTTGNGLFLSEGLKLVDKFLEDVKKLYHSEAFTVNFGDT EEAKKQINDYVEKGTQGKIVDLVKELDRDTVFALVNYIFFKGKWERPFEVKDTEEED FHVDQVTTVKVPMMKRLGMFNIQHCKKLSSWVLLMKYLGNATAIFFLPDEGKLQH LENELTHDIITKFLENEDRRSASLHLPKLSITGTYDLKSVLGQLGITKVFSNGADLSGV TEEAPLKLSKAVHKAVLTIDEKGTEAAGAMFLEAIPMSIPPEVKFNKPFVFLMIEQNT KSPLFMGKVVNPTQK SEQ ID NO:5 (human SERPINA1 PiZ, amino acid) MPSSVSWGILLLAGLCCLVPVSLAEDPQGDAAQKTDTSHHDQDHPTFNKITPNLAEF AFSLYRQLAHQSNSTNIFFSPVSIATAFAMLSLGTKADTHDEILEGLNFNLTEIPEAQIH EGFQELLRTLNQPDSQLQLTTGNGLFLSEGLKLVDKFLEDVKKLYHSEAFTVNFGDT EEAKKQINDYVEKGTQGKIVDLVKELDRDTVFALVNYIFFKGKWERPFEVKDTEEED FHVDQVTTVKVPMMKRLGMFNIQHCKKLSSWVLLMKYLGNATAIFFLPDEGKLQH LENELTHDIITKFLENEDRRSASLHLPKLSITGTYDLKSVLGQLGITKVFSNGADLSGV TEEAPLKLSKAVHKAVLTIDKKGTEAAGAMFLEAIPMSIPPEVKFNKPFVFLMIEQNT KSPLFMGKVVNPTQK SEQ ID NO:6 (3XSV40 polyA, nucleic acid) TCGCGATGAATAAATGAAAGCTTGCAGATCTGCGACTCTAGAGGATCTGCGACT CTAGAGGATCATAATCAGCCATACCACATTTGTAGAGGTTTTACTTGCTTTAAAA AACCTCCCACACCTCCCCCTGAACCTGAAACATAAAATGAATGCAATTGTTGTTG TTAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAA TTTCACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTGGTTTGTCCAAACTCA TCAATGTATCTTATCATGTCTGGATCTGCGACTCTAGAGGATCATAATCAGCCAT ACCACATTTGTAGAGGTTTTACTTGCTTTAAAAAACCTCCCACACCTCCCCCTGA ACCTGAAACATAAAATGAATGCAATTGTTGTTGTTAACTTGTTTATTGCAGCTTAT AATGGTTACAAATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTTTTTT CACTGCATTCTAGTTGTGGTTTGTCCAAACTCATCAATGTATCTTATCATGTCTGG ATCTGCGACTCTAGAGGATCATAATCAGCCATACCACATTTGTAGAGGTTTTACT TGCTTTAAAAAACCTCCCACACCTCCCCCTGAACCTGAAACATAAAATGAATGCA ATTGTTGTTGTTAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAG CATCACAAATTTCACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTGGTTTGT 55MF-363253604Attorney Docket No.: 15979-20192.40 CCAAACTCATCAATGTATCTTATCATGTCTGGATCCCCATCAAGCTGATCCGGAA CCCTTAAT SEQ ID NO:7 (α1-microglobulin / bikrunin enhancer and optimized human SERPINA1 promoter region, nucleic acid) ATCGATGGCCCCAGGTTAATTTTTAAAAAGCAGTCAAAAGTCCAAGTGGCCCTTG GCAGCATTTACTCTCTCTGTTTGCTCTGGTTAATAATCTCAGGAGCACAAACATTC CTGGAGGCAGGAGAAGAAATCAACATCCTGGACTTATCCTCTGGGCCTCTCCCCA CCTTCGATGGCCCCAGGTTAATTTTTAAAAAGCAGTCAAAAGTCCAAGTGGCCCT TGGCAGCATTTACTCTCTCTGTTTGCTCTGGTTAATAATCTCAGGAGCACAAACA TTCCTGGAGGCAGGAGAAGAAATCAACATCCTGGACTTATCCTCTGGGCCTCTCC CCACCTTCGAACTAGCCACTAGCCTGAGGCTGGTCAAAATTGAACCTCCTCCTGC TCTGAGCAGCCTGGGGGGCAGACTAAGCAGAGGGCTGTGCAGACCCACATAAAG AGCCTACTGTGTGCCAGGCACTTCACCCGAGGCACTTCACAAGCATGCTTGGGAA TGAAACTTCCAACTCTTTGGGATGCAGGTGAAACAGTTCCTGGTTCAGAGAGGTG AAGCGGCCTGCCTGAGGCAGCACAGCTCTTCTTTACAGATGTGCTTCCCCACCTC TACCCTGTCTCACGGCCCCCCATGCCAGCCTGACGGTTGTGTCTGCCTCAGTCAT GCTCCATTTTTCCATCGGGACCATCAAGAGGGTGTTTGTGTCTAAGGCTGACTGG GTAACTTTGGATGAGCGGTCTCTCCGCTCTGAGCCTGTTTCCTCATCTGTCAAATG GGCTCTAACCCACTCTGATCTCCCAGGGCGGCAGTAAGTCTTCAGCATCAGGCAT TTTGGGGTGACTCAGTAAATGGTAGATCTTGCTACCAGTGGAACAGCCACTAAG GATTCTGCAGTGAGAGCAGAGGGCCAGCTAAGTGGTACTCTCCCAGAGACTGTC TGACTCACGCCACCCCCTCCACCTTGGACACAGGACGCTGTGGTTTCTGAGCCAG GTACAATGACTCCTTTCGGTAAGTGCAGTGGAAGCTGTACACTGCCCAGGCAAA GCGTCCGGGCAGCGTAGGCGGGCGACTCAGATCCCAGCCAGTGGACTTAGCCCC TGTTTGCTCCTCCGATAACTGGGGTGACCTTGGTTAATATTCACCAGCAGCCTCC CCCGTTGCCCCTCTGGATCCACTGCTTAAATACGGACGAGGACAGGGCCCTGTCT CCTCAGCTTCAGGCACCACCACTGACCTGGGACAG SEQ ID NO:9 (full human SERPINA1 transgene #1 construct, nucleic acid) TCCATCAACTTACTATATCCCCAAAAGGAAAGGAAAATAGAGAACCTATTAAAT TTGGGGAAAGAGAATGAAGAAAGGGAAGAGTAGGTGATCAGAATTTCTTAAATT CATGTTTTTATTTCACAAAGTCAAATATAGTACTGACCAAAATGAGCTCTCAATA TCCAAAATAATAACAGGTCATAAACATGGAAGAAAGCTGTTCACAAGTCACCAT 56MF-363253604Attorney Docket No.: 15979-20192.40 CCATTAGAAGGCATGCCCTTTACATTTATGTGTGTGGGTGTGGGCGTGCGCATGT TTCCAATTTTTAAAAATCTGGAAAACAAAGTAATCTTTAGAAAAATATTTTCAAA AGTATATTCACAATTTTGAAGTGAAAAAAAAAAAGGTTTGAAGGTGACAGTAAA AAGAAGAAATAAAATAGTCAAGTATTCAGCAGCAGCAAGTAAGAGGAAGGACA GAGGCAAAGTAAAAATATAGTTTCACTCTGCCATCAATTATCAACCCACCAGATC TACAAAATACCGGATCCACTAACAAACCCAGCCTGTCTTCCAATACTGAGCACTC TTTTGAGAGTTACCATTTATATGTAGTTTCTAGACTTTTAAGATTTCAGAAGAAAT GTATCAGACAGGTGAGGCGGAAGCAGCTGGGAGACAAGAGACCAGTAAACAGT CAACCCAATGAAAGAAACGCACAAGTCAGCTTTAGCAATCCTGTGAAGAGGACT GGCAGGAAGAAGAGTGCAGCTTTAGAAAGAGAACAGGCCTCGTATGCTTCAGAC AGTCTTTGTACTGAGGCTGTGGACCTTGGCCACTCTCCCAGAGATGATGCAATCC TGATGAACAAGATCTGCTGCCAGACAAGCGATTGTTAGCAGCCTTTGCAGACAG CAACTCAGCCAAGAAGCAATCTCTGAGCAGCTCCCCATAAGCCACCAGAATGTC AAATTTCTTCCATTTCAGTCTCTGATAAAATAAAGGGAATATCCCTACCCCACGC ATCCCAAGCCCTTTTCTTAGAGAGCCCTTTGTCTTCCCTGCTTTCCTTTAACTGTG TTTAAAGTCTCCACCACTCATAATTATATTTCAAATGAAACACCAAAAATATTTTT ACTCTGATGAGCAGAATTCTCTAAACATATTAACGATAAGGCCTTTACAGTAAAA ATTTATACTAATTTTCCTCAGTTTCCCAAGAAAAACCTGGGACACAATAGTTTCTT GTATAAAAACTGTTATGAAATCTGATACTCAATTATGACTCACAAAAATAAAGAT AAATATTTAGACTAATCTAGGGTCAGAGAGGTATATTTTGAATTCTGAAATTACA TGGAACTCAGTACATAAAACAATGTCATCTAGGAGAGAAAAAAGAAAATCTACT CTAGCTTAGGTCAAGATAAACATTAACAAAGTGTCTTTACAATGTTAGGTACAAC GCCTCCTTTTCTAGGGGCAGCATGACTTCAGATCTTACTAGAGTTAATGATTATA ATCCATTTACTTAGACTCCAGCTTAAATATACATTCAATTTAAAAATCTTCCCTAG AATTGTCATCATAGGCCCAATTTCTTTTCAGTTTAGGTACTGGGTTTTTCATATAC AATATTGTTTCTCACCTTGTTAAAGACTTAGGTTAGGGAACTTCAACTACAGGAA GCCTCAAACCAAATTTCTTTTTAAAACCACCATCCTTAAACTGGGACACAATTCA AGATTCAGGTTTCTTACACATATATATTACTGAAAGCATTATGTTCAACCCTGTAT TTAGATAATGGAAATTAACACATATAGCACAGCTCTGAAAATTCTTTAGTAGGCT AATGAGTAACTGAATTAAGAGAGAAAATTTGTACAAAGAGATAATTTGGTAGGG TACTTGCCTGGCACCACAAAGCCCTGAGTTTTCTTAGCCTTGCACAAATTTGGCA TGGTGTTATGAGGCTATCTATAATCCTAGGACTTTGGAGGTACAGGTAGAATTAT CAGAATTCCAGGTTATTCTGGGTTACATATAGCAAATTTTGGGCAAATTTGGGAT ATGTGAGCCCTGTCTTAAAAAACAAAACAAAACAAAAACCCTTCAAAAAAATTG 57MF-363253604Attorney Docket No.: 15979-20192.40 CAAAGGGGTTGGGGGAAAAATTGCAATTTTATGATTGGATCTTTCCGTCTGCATG TGAGTTGAATTTTCTCTTAAATCAGTTTTTCTTATGACTATAAAATTTAAAAGGGG GGATTGAGAGAGTAGGGCTGGGAGGAGAAGAGGGGAGGAAAAATAAATTAATG AAAAACTTTTTTTTTTTTTTTTAACAAAGTGGGAACTCTTATGAGGACTTTAAAAT GATAAAGTCTTGCAGGGCGTGGTGGCACAGGCCTTTAATCCCAGCACTCCAGAG GCAGAGGCAGGCAGATCTCTGAGTTCGAGGCCACCCTGGTCTACAAAGTGAGTT CCAGGACAGTCAGGGCTACACAGGGAAAACGTGTCTTGAAAAAACAACAACAA AAACAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGA AAGAAAGAAAGAACGAAAAAGAAAAAAATATGTAGTTTCACTTTCCCATCAATG AACAACCTACCAGATCTACAGAATACTGGATCCACTAGCAAACCCAGCTTGTCCT GCTTTACTCCTTTTTATTTTCTTTTGATTTTTCAAGACGGTTTTTCTGTGTAGCCCC GGCTGTCCTGGAACTCACTTTGTAGGCCAGGCTGGCCTTGAATTGAGTAATCTGC CTGTCTCCGCCTCCCAAGTGCTGGAATTAAAGGCGTGCTCCACCACGGCTTTACT CCTCCTTTTACTACACACACACACACACACACACACACACACACACACACACACC AGTTCAAAATGTGGGTTTTTAATGCATACAATCAGCTTTCTGCAGAACTCATGTA CCATCTGAATTATATGCTTATCCATTTCTAGCCAAAACCCAACTATCCCAAGGGA AAAAAAACTAGCAGTACTACTTTTTTTTGCTTTGGGAGAAAAGGATATTAGGAAA AATGATTACATAAGGAGCTAGAAATTTTGTGATATAGCCCACAATTTAGCTCAAT GACTCCAGAAACATTGTATTACACAGATGACTTTTTTTTTTTTTGGTTGTTTTAGA TGACTTCTAAATGTATCAATATAAAATAGTTATTTTCTTTTTTCCTGCTTCATATTT TCTGTGAATCCTCAACTTGCTTGGCAATTTATGTCTCAAGTAGGTACAACAGAAA GAATACTGTCCCGCTCTAAGAAACACATGGAGAAGAATCTGCAGTAGGATATTT ATGAAGCTTGTAGAATTAGAAGAATCTACAAAGAAAGAAGTGCCACACTAATAA CTTGAATGTGGCTAAAAATAGCTTCCGCCTTTCCACACCCAAAAAGTATAGGAAG AGGAAATGGGAAAAATATGACAAAGAAGTAAAAAACCCCACAATAAAACCCAA ACAAAAACCCAAAAGATATAGGCTGGGTGTGGTGGTAAAAGCCTTTAGTCTCAG TCCTAGAAAGGCAATCCCTGTGAGTTCCAGGTCAAGGTGGGCACACAGTGAGAC CGTCTCAAAATAAAAACCAACAAACCAAACAGTAAAAGGGAGAGAAAGGATAA ATACTACAGGAGTATTTATAAATATTCAGAGATCTGGTGAGAAGCTCACCTAATT TACACAATAGTAAATTGGGCTTAACTGTGAAGATAGTGAATACAGGAAATAGAT CCAGGAGTTGTAGAAAAAAGAAAGAAAGAGAAACAGATTGGCATAATCTGAAA TATGTGACTTAACAATTCAAGCCAAGATAAAATTTCCTTTTCTTCTAACTCTTGTT TATCCTTTGGTTTCTTAAAATTTACATTCTCTCTAGGGGATTCTGGAACTGGTAAA ATGTCTGTAAAGCTTCGCTTACTATGAAGCAATTTTAAGACCAATTAAAAAGAAA 58MF-363253604Attorney Docket No.: 15979-20192.40 GTCCTACTTATAATGGCTATGATAGAGGTCAAGGCGTACATTTACCTTTCCTAGA TAGTTATTTACATGTACTAGGAGGCATACCTCATAATTGTACTGGCTTAAATAAA TTCAACTTCATAAAAATAGTTTTAGGACTTAGAAGATGGTTTTTAAAAACCTCTG TGTGAACACACAAGTATGCAGGTCAGAGGAAGACTGATACCTGAAGTTATCAGG CGATTCTGGTGACTTTCCTGTCTGGACTCTCTTACAGGCTGGAATAACAGACCTG TACAGTTTTGCATGGGTTTACTCAAACCCAGCTCTCATGCTTGTGAGGCAAGTAC TTTTAATCACTGAGACATCGCCAAACCTTGATTATTTTACAGACAAAAACATAAT TAGAAAAAGATTAACTCAGGGAACTGAAGGTATAGCTGAGTGGTAGAGTGCTTG CCTAGCATTCAATAAGCTCTGGGTTGTATGAGTAACAATGAAAGGGGGAATTTAC TCACAAGAAAGTCACAAATACAGCAGATTTCAAAAGAAAATTAAGATTTTAACA CGTAGCTTTTATTTATTAAACTAATTACGTTGGGTAGCAATATCTAAATTAAAAG TGTGTTTATTAACAAGTCCAGAATCTTCCAGCTCTCTGGGGGAATTTATATTATGT AGCTTTACCTTGAGTTTTATATATGCAGATTTCCCACTTCTCCCTTTATCAATGAC AACAAACAATTACTATGAACATAAAAGCTATCTGAAGGTGTGTCTTCCATCTTAG GTACTCTGTAGGCTGATTTCAAACTCCAATTCACCTGCCTCTACCTCCTGCATGCT AATAATAGGGATGTACCAAAACACCTAGAGTTTTATATGGTGATAGGAATCAAG TCTAGAGCTGTTTGCATGGTAGGCAAGCACTTTTACCAACTAAGCCACATTATCA GCCCTGAAGCCGCCTTCTTCTTCTTTTTTTTTTTTTTGAGACACTTGGTCTCACTAT ATTGTTCTGGCTGGCCTAGAACTCCTCAAACTTAAAAGATCCTGCCTCCTCCACC CAAATGCTGGATTTAGGATGTGGAATCATCACCTCACCCTGTCCTTGAATATGTT TAACTCTTTAGGTTTACTCATGTGACAAGAATTACATGTTGACAACCACTTACAA GAAAAACAAAAATCATACCAAACCAAAAATACCTCTTAACTATGTTTCTTCCTAT AACTGAGTCAAATTCTGAAGGGAAAGTAACCCTCCTGTCTGCTTAAAAGCCAATC CACTGCATTGTTTACCAGGGGAGTTTCTTGTGTAAGTAGCTTGTTGTTTAGAAAA CACAAACTTTTTCTTACCGTAATAAAGGAAAATATGATAGAAGATTTCTCAAATG ACAGCTAAGGACAGTAACACCAAAGAAACCTTAAGCATAATACTCTGATGTGTA CAAGAGGCCTCCTCACTGCAGTGGTCCGGCTCTATTACAAAGATGCTTATAAAGT ATACAATCATAACTGGGTGTGCTGGGCAAATGGCAGGAATTCTACAACATGAAG AGACAAAGACTTTTTCTAAGTTTAAGGTTAGTCTACATACCAAGTTTCAGGCTGA CTAGAGCCACACAGTGATACTATATATTGCAAACAAACAAACAAACAAAAAACC TATCATTAGAAGAACATAAAAAACAGAAGTAAAATTCTCGTGTATCCTCTTAAAA GAGAAAAGGAATAGTCTGACTGGTTTTGTAAACTGGTTTTGATATTTAACGTGAC CATATTTAAATATGTACTTCTTCAATGATACTGTAGCACTGTTCTATTGATTCATT ATAATTTAAATGATTCTTCAGCAGGCAGATACTCATTTTTGGTACTCTGCAGTGTT 59MF-363253604Attorney Docket No.: 15979-20192.40 GCACTGAACATCCATTCATGTACTGAGAACTTTGTTTACACTATATATACAAGTC TTTACTCAGACAAGAACTGCTTCATAGGTGGGCTTCATAATAGTTTGTTACCCTTT TCAGACCAAAAAATTAGCTGAATCTGGTATATGTTGCTTTCTTAAACAAATTCTA GGATATCTGTAGTTCTTATACTTTTCATATAATCAATGGAATAATGAAAAACAGG TGCTGTTAAGGAGTGGTCATTGATATCCATAATAACCTGATAAAGACCATACAAC TTTTCCTCAAAAACAAAAACAAACAAAAAAATCAAAATATGATCTAAAGTATCC AGAAACCCAAGTTTTTGCTCTATATATATATCTTCTGAACTGCAACTAGTCTGGA ATAAAGGAGGCTCAAAAGCAACTTATGGTATACAGATATCTGGAAGCTTTGCCT CCCATTACCAGGAAATAAGAATTTGCAATCACTATAATAAGGGATAACTCTCAAT AACTTCCCATTTATTTCCTCTTCTGACAAAGCAGCCTGAAGGAAAAAAAACTCAA AATATATCTAAACAACAAATGGAAGAAAGTGAAGATTTTAACAGCACAGTCAAA GGTTCCTGAAATCAGAAGAGTGACATGGTATAATGAAAAGATCTTGAAATCGAC AGATTTGATATACCATATTATTTAGCTGTGTGGTCATTCTAATTAAATCTGTTATA ATTCACCTAAGTGCATGGTTCTAAGAACTTAGCACATTACAAATTTTGATATACA GCTTTCCAATACAAAAGGAATAGAATAGGAACTAAGATGAAAACAAACAAGGA ACTCCTTCTTCTAAGGCAACCGTTTCAAGTGAAGTTGAGGAATGGACAGTTTTGT TCCATGTCACTAGTGATGCTAAGGCCTGAGTAGTAAACAGGCTTATTTAAATACC AGGTCAGATTTCTTTGGTAAAGCTTCAGTATTTGGCATAAATCTGGTATTTATGA GATGCTTCACCAAAAATTCAGCCAACTCAAAGATCTACTATATACTGAACATATT AATAATTAACAAATTTACCTCCTCAATCTTCCAGTCAAGAAGGCTTTCCAAACTT TGTAGACTTCTTTAAAATTTTAAAAATTGTGATATATCTCAGTCTGGTCTATAAAG GAAGTTCCAGGGCAACCAAGGCTACACCCTGTCTCAAAACAAAACCAGAAAAAC AAACAAACAAAAAATCCCTACTCTATATAGGCCACTATATTTTTATTGAGCCACT CCATTTCGTTGTTGACTGGAAATATGTGATGGTCAGGAGATGAACTTGGCTCATA GTACATACAGTAAACAACAGGGAGAAACCAAACCATCTGGTTCTGTTTGGAGTT TTGTTTTTATTTTGAGATTGGACCCTATTCTGAAGCCCAGGCTGGCTTCCAACTCT AAACGAGTCTGTCTTACCTACACCAACAAGTATTCAGATTACAGGTATACCCGCT GATTCTGCTATTGTAGTCTGCTTGACCAGGTCCCACTATGGTCAACTTTTACTCTA AATTTAAAATGTTTTATAAGGAAGATTTTTAAATAGGCACAAAACTGAAATAATT CTAGTTCATATAGTCATTAGCCAGTTTTACAAATCCTACAACTGATTTTCATTCCA AAGCAAATCACAGATAGCCTATCATAAGCAATACTTCAGCATGTATATACAAAT AATAGCTGTCTTCAGACAGACCAGAAGAGGGTATCAGATCCTATTACAGATGGT TGTGTGCCACCATGTGGTTGCTGGGAATTGAACTCAGAACCTCTGGAAGACTGAG ACAGTGTTCTTTATTGCTGAGCTATCTCTCTAGGCCCCATGGGACAATCTTTTGGG 60MF-363253604Attorney Docket No.: 15979-20192.40 AGCTGGTGCTCTCCTTCCAACTTTAAGTGAGATCTAGAGACTGATCTCTAGTTGG ACAGCACAGCAAGAATTTTTAACCTGATTACATTTCTGAAGTAAACACTGGCATA TTTATAAAATGAGAGACCTGCCTAGTATGATAATGAAAACATGTAGTGAAACTTA GGTGTTGGAGGCAGTCAGATTCACAAGTTCAATGTCAACCTGGGCTACAAAGAC TTAAAGGAAGAGGGACTGGGAATATAGCTCTGTGGCAAAACACTGCTAAGTACA GGCAAAGCTCTCAGAAGCTTCAAATTTCAGCTAAGTACCAATTACTCCTTTTTAA AAAAAACAATTAGTTATTTTCATATAATCAATGGAATAATAAAAATCAGGTGCTA TTTACAAAATTATGAACATAACCCTAAGTAAGGTTGAAGTTTAAAAACTAATCAG ATACGCACAGCAGAATACCAACTTTCAAATTAAAAGCTACCTTTTACTGATTATT CTGTACCAGAAAGTTTTTCTATATTCCATTTCCATGTAACATTTATAATAACAACT CTATGAGGAAGGCACTATTTCTATTAGGGCAAATTAAATTTGCCAAGACACTTGA ATCAGGCTGGGCAGTGGTGGCGCACGCCTTTAATCTCAGCTCTTGGGAGGCAGA GGCAGGTGGATCTCTGAGTTTCAGGACAGCCAAGGATACACAGAGAAATCCTGT CTTGGAAAAAAACAAACTAGAATCTGGGTCTGAAGAGATGGCTCAGCAGTTAAT AGAGTGCATACTGCTCTTGCAAAAGAAGTAAGTTCAATTCCCAGCACAAATGTTG GACTGCTCACAAATACTTAATTCCATCTCTAGGAGATCCTGCACCACCTTCTTGC CTTCAAGTACCTGATTTTTTATTTTATTAACGTGTGCACACACATTAACAGAAGCA CCAGAACATGAATTAAAGTCTATACAATTTCAGAGCTCCCATATAGTTTTGTGTG GGCTGAAGTGGGGACAACTCAAAGTGTACCTATTTGCTTTCTTTTTAATTTAAATT TATATACAAAAATACACACCATATATTTTTCCCTTTTAGAACCTTCACATCCTTGT AATCACTATTTCTTCACTGACTCACCTGTTGTGAGTTTAATAATGTTAGTCTACTT ATTACAACTTGATAGTGTTAAAATGTGAAACTGTAACTCTTAGGATATCTCAGTT AGCAAGAATAAAACATTTAACTCATTTTTAAAACACCTGAATTCATCTGAAATGG TACTTTTTATAAACATTCATGAAATGTCTGCTAGCCGGGTGTGGTGGTGCAGGCC TTTAATCCCAGCACTTGGGAGGCGGAGGCAGGCAAATTTCTGAGTTAAGATACA CAGAGAAACCCTGTCTCGAAGAAAAAAAAAAAAAAAAAGGAATGTCTGCTGAG GAGCTACTGCAGCAGTGGCGTCCACCAGGAACAAACATGACCTAGCATTTCAAC ACACATTTTTAGAAGAAAAAGGCGTATTTCTACCCCAATAAATTATACTAAGTCA AGAAATCCTGGTTTCTAAGAAACTCTATGCCACTACTTTTATGGTATAAAACTAT CTATTGAAAAATTATTGAAAATCTAAAATGAGATAGTTTGTATTAACTTACTTTTT AGACACTTAAAACAGAAGTATCCTGAGAAAATACCACTGTGAGTTAGCAAGATG GTTCACATTTGATCCCCAGAATACATATGCCAAGAAAACTAACTCACGAGTTAAC TTCTGACTTCAGGCATGTAAATGTGCATGCCTCCCCAAAAATAAATGTAAATGCA AAAAAATACACCTCTTCTTTATAAACATATATTCTTTATTAAACAGTATGTTTAAT 61MF-363253604Attorney Docket No.: 15979-20192.40 AAAGAATAGGTGAAGTCTGAGTGTGTGACAGAAAGAGAACAGGGATGAAGTCCT CAGGGCTAAAAGCAGGATTTTTTTTTATCATACTTAGCTTTCTATATTTTACATAA TAACTAGAAAAATATTTTATTTACTTGCAAAGCAAAAGGTAATCCCTGAAAAATC TGAAAGTGAAATAAAAATTACTTCACTAAGTTTCTAGCTGGTGGTATAATCAGAG CACACACCAAAAAATTTAAAATGCTGTAATTTAGATGACTATATTCGAAGGGATA TGTTTTAAAGAAAAGTAAACAGAATAAAGCAAACCATTCAACTTTTAGTAATCAT ATTGTTCTACTAATCTGAAACTGTTTCAAGTATACTGTGGCAAAAATAAAGTGAA GAAATATGTTGGTGTCACTGGAAATTGGGAGTTGTGCACAGAAAAAAAGATCAG TTTACATTAACTATGTGGTACTGAATTTGAAATATAAGTAGTCGGGTGTTTTAAA AAAAATCATTTTTAAAGCTTTGCTTATTTAAAAGATCTAGAAACAGATCAATTAA AGACCAATGAACATTCCTTGTCTCTAAGGATCATTTACCATTAAAACAAACCAAG ACTGTGTGAGACAACCAAAGTAGAAAGGAAGACCTGAGGTTCTAGGGCAAGCCT GTGCCCAAGACCCTGTCACAAAAGGAAAATGAAACACCCTCACTCCACACATGC ACAACCACACAACCCAGCAACTGTTTGGGGTGAAAAATGGTAAAAATGATCCTA AAACATTGGGTTATAATAGAACACAAGAACTAGAGAGCAATGAAACAAGCAAG GAAGCTACTAAGATGAATTTAAAGGATTTATTTAGCTAACAGCTAAAGGCAGTAT AATCTGAATATGTCAAAAATACAGCAGAATGCTAACACATTAAACATATTCAAA ACCATGAGCACAAAACAGTAGTATTTCACTGCTAGACTCCCTCAAGGGGCACCCT GAGTTTCCTATTTTCTGACTGTATATCCATGAGTATATGGATATCCTGTTTTCAGC TGATTGTGAAAATTAAAGAAGCAGTTTTGAAAACACAGCTGTCTTCTATTAAGAT ACTAAAGAGATTTGCAAAATTGTAAAATAATGTAATTAAAAAAATAGAAAGTTA TTGTTCATATCAAGCTGGGTGGTGGTTGTGAAAGCCTTTAATACCAGCATTCAGG AGGCAGAGGCAGGCAGATCTCTGTAAACTAGGTGCCAACCTGGTCTACAGAGTG AGTTCCAGAACAGCCAGGGCTACACAGAGAAACCCTGTCTCAAAACAAACAAAC AAACAAACAAACAAACAGGCATGTCAACAATACTCCTTGTTTTTAAAAGCCTTGT TAGTGGGCTGGAAAGATGGCTCAGAGGTTAAGAGCACTGGTTGCTCTTCCAGAG ATCCTGAGTTCAATTCCCACAAACCACATAGTGGCTCACAACCATCTATAATGAA ATCTGATGCCCTCTTCTGGCCTGCAGGCATACATGCAGGCAGAATGCTGTATATG TAATAAATAAGTCTTTTTTAAAAATTCCTATTAGTAATTAAAAACTTTAAGGATTT ATCTCTCTTTTTTTAAAGATTTATTTATTTATTATAATAAATAAGTACACTGTAGC TGTCTTCGGACACACCAGAAGAGAGCATCAGATCTCATTACAGATGGTTGTGAG CCACCATGTGGTTGCTGGGATTTGAACTCGGGACCTTCGGAAGAGCAGTCAGTGC TCTTACCCATTGAGCCATCTCGACAGCCCAGGATTTATCTCTTAAGTGTACAAGT GTGCATGCCAAGGAGGCTAGATGAAGGCACTTGTGAGCTACCTGCATGAGTGCC 62MF-363253604Attorney Docket No.: 15979-20192.40 TGAAACTGAACTCTTTCTCTGGAAGAGCAGCATATGTTCTGGATCACTAAGCCAT TGCTCCAGAATTATTCTGGTTTTAACTTCAAGTACTAAATCTTAGTGTAGAGAAC CACTCAAACACTAATTCTTTGGGAACTCATGGGAACTCATGTTTAATACTTTAAA GTGTGAGGGTAGTTGATCTAGGCCACCAATATCAACAGTTGTTTAATATCATAAT TAGGCAAATACTATGAAATTCAACAAAGTACATACTACCATTATAAAGTATCCCT GCAATCTAACTCATCACCAATTCATATGAAATATAGGTATAAGGATATCTCTCAG TAAAATGTACTAATGACAATCTAGCCTTTAAACCCAAAAAATTAGAAACTGTAA AACAGCATTTAAAAAAATATACACAGGACACAAAAGAAAAGGAGGTAAAACCT ACAGACTCAAACCAATAAAGCCCAATATATTGACCTTACCTTAAAAAGTGATTTC TCCCGGGGCCTAGCAAACACAGAAGTGGATGCTCACAGTCAGCTATTGGATGGG TCACACGGCCCCCAATGGAGGAGCTAGAAAAATTCCCCAAGGAGCTAAAGGGAA CTGCAACCCTATAGGTGGAACAACAATATGAACTAACCAGTACCCGGGAGCTCT TGTCTCTAGCTGCATATGTATCAGAAGATGGCCTAGTCGGCCATCAGTGGAAAGA GAGGCCCATTGGTCTTGCAAACTTTATATGCCCCAGTACAGGGGAACGCCAGGG CCAAAAAGGGGGAGTGGGTGGGTAGGGGATTGGGGGGGGTGGGTATGGGGGGA ATTTTGGGATAGCATTGAAAATGTAAACGAGGAAAATACCTAATAAAAAAATAA ATTAATTAAAAAAAGTGATTTCTCTCTACATGGGGTGTTCTGCCTGTATTTATGTG TCAGAACCACAGGTGTGCCTGATGACTGTGGAAGCCAGAAGAGGGTGTCAGATT CCCTGGAACTAGAGTTACAGAGGGTTGTAAGCTACCTTCTGGATGTTGAGACCCC AACCTGGATCCTCTATAAAAGCAGCAAGTGCTCTTAACTGCTGAGCCATTTCTCC AGTCCCATTATGGCCCTTAACCAAGTGAATTTGAGTAGGGTGTGGTAGGAGAATC TAGGGCTTATACCACCTTCCCTGCTCTAAATAAGGTATTTTAAACTAACAATTTTA TAAAGTCCAAAGGAAATACATTTTTCCTAATCTAATCTCTAGCTACTTCTTGCCAT ACTATTAAATAAAAAAAAAATACATTCTAAAAATTGCTTACAGGGGAGAATAAA AGACCAACAGACAAATTCTAGCACAGAATCAGAACTCTACAAAGAAAACTGGTT TGCTAGGTAGGGACTAAGAGTTTCCTCCAGTTGATGGTCTGTTCTAGGGAAACTC ATGGTCCCTCCTCATAAAAGATTAAGAAAAATAATTTTGGGTCTAGGGTGTAGTG ATAGAACACTTGCTTCCCCCCCCCCCCATTGTTCTCAAAAAGACAATCATCTGAG GTGCTGGAGAGGACCAGAGTTCAATTCCTAGAACTCAAATGGTGGCTTATAACC ATCTGTAAATTCAATACTAGAGGATCTGGCACCTTTGTCTGGCCTCTACAGGTTA TCATGCAAAATCATGATGCACAAACACAGATGCAGACAAAACACCCATAACTAG AAAATAAACAGAACTTTAAAAAATGTAGTTGAATCCTTTGCACAATTACCTGCAA TAGAAATGTATTACTATTATTACACATTTAGGCAAAACTAACTCATTCCACAAAA AATTACTTTTCACCTCTCTTGTTTAGAACATTGCAACTTTTGTGAAAGATTTATTT 63MF-363253604Attorney Docket No.: 15979-20192.40 TTAAATTGTTTGCATATGAATGTGGTTCCCTTATTTTTAAATTGTATGCATATGAA TGTGGTTCCCTTGACGGCCAGAAGAGACCATCAGCTCCCCTTAAGCTTGAGTGTG CTAGGCACCAAACTTGGATCCTGATCCTCTATACAGTGGTTTTCAACATGTTGGT TGTGACTCCCTCAGGTAGCCTTCAAGACCATCAGAAAACACGGATACTTACAATT CATAATAGTAGCAAAATTACAGTTATGAAGCAGCAATGAAAATAACCTTATGGC TGGTGGGTCACCACATAAAGAACTGTACTAAAGAATCGCAGCATTAGGACCCTA CTGCAGAAGGCCACTACAGCAGATCAGGAAGTTCTCTTAATCCTGAGCTATCCAG CTCCCACACTATTTTATAGAGTATGCCTACTTCTTGTTGCTTTGTATACTATGCAA ATTTCCAGCCATTCTTTTTCATACTAACAGTTCATAATAAACTACAAAGGAAAGT TACACCAATCCAGAGTCATGTTTCTCAAAAAAAAAAAAAAAAAAAAAGACTAGA TTTCTACTCAAATCATGAACTGATCCATTAGGACTAGCAATACTGTGAAGCCTAA TGACCTAAGCACCAAGTATGAGTAAAATAAAAACATTTGGTTTAAGTCAATTAA GCCCAAGATCCCAAAGTAAAAGTACCTTGGAGTTAGCTTTCTTATTTACTTGTTCT AATACTTATATAGCAACACTAACTTCTGAGCAATATACCTGATGCTAGCAATGTT TACTTGTTTTGATTCTTTGATACTTCTGCTTATTTACTGTGCAGTCAATAAAGTGA TTGTTAACCTGGGAAGATTTTGTTTTAAAGATTTTTAAACATTGACACTCTCTCAA TAAAAGTAGCCTAAACACAAACATCCTAACAATTTCATATATTTTTAGCTTCATC TTAAGATGTTCTTTGACATAACCAACCTGACCTGGTTTTGTACTTTTGCTGGGTCA TGAATTAAAAGTTTTATCTGGTATAAATAAAAGTAAATTTGTCTAGAAAGAACGG AACTATTTTAAAAGAGCCTACAATTTTAGACTTGCTCCTACATTTTTTCTAGATTT GTTCTTAAAAAAAAATCTAGCTAACATTTTCAGGCTGTGGGCACAGAAACACAC CTATTTCCATGGCTGTAGTTGTTTGTGCCACAGAATTGAAAAATAAAATTTATGT GTTCGTACAGCAATTTAATGTTACATTCACCCTGTGGTCAATCTCACTGCCTCAA AAACCTATCTTTGTTCTGCATTAGGTGGTTAAATACTTGTTTTAAGTATCCTTCTG GGCTCACATATATATAGCACTTACCAATACATGCAAGGTCCTGGGTTCAAGACTC AAAAACGACAAAAAAGCACTCTTTTGAGTCTATCTCAAATGTCACAATAACCAC ATTTATTTTAAGAATAAATATAACTACCCCCTAAAAACAAGCCAATTCTCAACAG TCCATTGGAAAAAGAAAAAAAAAAAAATAAATGAAGAAAAATGTAATACAAAT AAATGCAGAGGAAAACTAATTGCTAAAATATCCTTTAAGGTTCTTTTTCCTAAGT AAAACCTTGCTTGGATACCAAGAGTGTTCAGTTGATTGTTAGCTGTAGATTGCAT TGCACTCCTTCACAGAAGACATGAAGGCACAAAAGTATATGCTATGGTTGGTGA TAGGAAATAGAATTTTTCAGTATGGGATAAAAATCAGAACAAGACAAGAATAAA TTTTTTTAAAGAGTTATATACATTGGGAGAGAAAACAATAACTTCCTAATACAAA TCAACAATAAATGTAAACATAAAATAATGAAATCCCTGTGGATTGATTTGAGCAC 64MF-363253604Attorney Docket No.: 15979-20192.40 AAACCTAGAAAATTCTAACCAGATCATAATGTCTAAGAATTACAAAGTTTCCACT CTTACTATAATAGTAGCACACATGTACCATATGAATTATTGGGGGTAGGGGTGGG GTCCAAGTCTCCACATTTCAGGAGTGAAGAGGGAGAAAATCTGAGCACCAAAAT ACAACAAAAATGGCAAAAAATAAAAATTTCAGTTTGAGTAATGTTGGAAAAGAA AGTTTAAAATAATTCAGGCATGAAATTTTCATATTCAATCGACTATTTAATTGTTA GAGAGGTATATATCTTTATCTAACTATCTATAGGTAGATAGATAGGTTTAATGTT AAAAATCTCAATTCTAGTCATAGACCCAAGCTGCAAAATAAAAACTACAAATAG AGAATGGATTTCACCTTATAATACAATGGCATCTGGTAGTGGTAATTATTATAAA CAGCCAATGATATTACATGCTTTAAAAATCTTTCTGTAAGCTCAGAATCTGAAAC AGTGTACCAAGAGTGGAAGATATAAAAGTTATTTGTCACTAGCCTTTAAAGTACT AGCTTTAGAACATATAAACAAATCCACAACCTAACATAAGCTATAAACTACAGC AGCCCATTCAATTTCCCCCTTTGTCCTAGTTTCTTTTTTTGCTGGGAAGAGGCGTA GTGGGATAATAATAGCAGGAAGTAAGGTGGAGCAGCTGCACACCAAGATGAGG TGCTGTGTGTGCTTCACCTCCATGCTGGCCTACTGCTGCCTCGATCTTACAAAAAT GAAATTAGCTATTTGGGAAGCTACAAGTTATAAATATTACTGGAATCAAGATGTA ATCTCCTACTTTCTCACGTTTGTCAGAATCTGTTTTAGGTCTCTAGTTTGATTCGGT TGAAGCAATAAAAGCTACATTTCTAGTATTTTTTGCAAGGGAACCCTAATGCTAG CAATAGATATTTGATAGAGACACTGGAGCTAGAAAAACCAGCTTCCTTTTAGTTC CCACAAATTTATGGGAATAATCCATGTTAACAGACTATAAAAAGAAGAAAAGAC CATCTAAATTTCTATTGTAATGTATAATGAGGTATCACTAGAGTTCACATTAAAA TTGTTGCTATTTTGCTGATGAGAAATGTTTCCCAGCAGTGATAATAACACAAATG TACTTTCTTGTTTGGGCATGTGTGAACAAGGGTATGCATGTTCAGGCCAGAGGAC AACCTCATTTCATTTTTCAGGAATTCTTTCCCCACAACTCAGACAGGGTCTCTTAC TAGCCTAAACTGGACAAGTAGGCCAGGCTGACCAGTGAGTAAGCCCTAGAGACC TGGCATCTCTGTCTGCCCAGGGCTGGGATTACAAGCAGCACACACAATTTTACGT GAGTTTGAGAAACTGAACTCAAGTACTCTTTTTACAAATACCTGACCAACTGAGC CTTCGACCAGTCTTTTAATTTTTTTTCAGATCAAAATATTTTGTGTACTGTAACTG CCAAGACTGCCATACTTAAAATAAAATGTTACATGGGTAACATGCTGTACTTCTT TTTACAAAAGAGAGAAATGATGCAAAACAAAACAACAAAAACTCGATCAATGTA CATTACATGCAGCATTCTGGTTATGTTCGTCTACAACAATGTCTTCTTTGCTACAC AAAGTAATCATCATTCCGATTCTCTATCTCACTCAAGCAACAGATGTGCTCTTGG AAAAACAGTTCAAGGATTTCTAAAAATTAATTCTCTTAAAGCAAAACATTCGTTC GTGGAAATGTGCTGTCATATACTACTCTATAAGGAAGAACTTTTGTAATCTAAAT AACTACTGTCTAATTTGTGAGTGTAATTTTTAAAATGAACTAGCATACATGTAAC 65MF-363253604Attorney Docket No.: 15979-20192.40 ATTTGACATTTCCTTTAAAGTACCTGAAATGATTCAGGATAGAGTCTTTAACATTT TAATAACACCTTCAACAGGAACCTAATTTTGGCAGTATCTCTCATGGCTTTGCCT ATAAGAGATACAACTTACACACCTCTAACACCATAATTTTCATTAAGTAATAAGC TAGATGCAATCACCTTTTGCTGAGAGTCAAGCACAAACTAATAGAATTAAGCCTA AACTAAAAGATGGGGACAGGTAGTAATCTCCAGAGCATATCAGATTCTGCAGGA AGTAGGAGGAAGACTGAAACAATAAGGTAAGCTCTCCTTATGTGTTTGGGGGTG GGGAGGAAGGGGGTTCCTGTATGTTTGTTTGTTGATACAAGAGTCTTATTCTTTTT TTTTGTTTTTTTTTGTTTTTGTTTTTGTTTTTTGTTTTTTGAGACAGGGTTTCTCTGT GTAGCCCTGGCTGTCCTGGAACTCACTCTGTAGACCAGGCTGGCCTCGAACTCAG AAATTCACCTGTCTCTACCTCCCAAGTGCTGGGATTAAAGGCGTGCGCCACCACA CCCGGCAGAGTCTTATTTTATAGTTTGGCTGGCATCAGTCTTTGGCTCAGTCTCTT GAGTCAGTTTCCTGAGTACAGAACATACAGATGTAAGCTAAAAGGCCCTTATAA AAATCCTTTTTCAGTTCACATTTTACATAATGATCAAACATATAAATATTGCACA AAGGAAAACAGTACACCTTGTCAAATCTAAACCCAACTAAACATACTGCATATA CTGAAATACAAATTTACTTTACACAGAATAGGTCATTCCAATCATTACTAAAACC TAGATGCTCTAGACCTGGTCCACTAAGGAGGCAACTTACATTTATAAGGACAGG GAACATGGAACTCACTTTAATCCATACAAAGCTTTGGGGCCTCCCCACTCCTCAG AAGATAGGATAGGTTCTTTCTGATTTCTAGACCGTATGAAATTTGGGTTTTAAAA GTATGTGCTTGACATAAATTAAAGGCGTAAGTGAAAACTAAAAACAGTTTCTTTA ATTGTAAACCAAAGTGAATACTCTCCTAGGGGGAAAAAAAAATCTCTTTCCTTCC CTACCTCCGGCCCCTCCCCCACCAACACTGCCTCCCTGCTGTGCAAAGAGCCCTT TGTCCTGCCCCGCACTTATCTAGCTGTTTGGCCATATTGACAGGCCTACTGGAGG CATAATAAGGGAGTCAGTCTGACATAAGCAGCTGGCGATTTCAAACAAAAATCT TCCTTTTCTACTCACACAAAATCCTGCTGCAGAGGTCTGTGGCTCCTCCCATACTT CCACCTAGTTCTCAAATAGAGCAGCAAGGAACTGGCATTTCCCCTCGATTCCGTA GTATAAATCAAAAACTTGATTCTCTAGCCAGAATTCTTATAGCCACTGATTTGTT GCTGTTTTGTGTTGTAATCCCTAAATTAGGTTTCTTCATCTCTGGTATATACATGT ATGATTATCACTTCAATGTGCCATGAAAACTCTGGGAAGCCTCATACTACAAGAC AGAAGAGACATGGAAGTGGCAAACACACACACCACAAACAAAACTGAGCAATA CTCTTAGGGTTTTGAGAATACCAATGATTTTTAAAAGATTAAAAAAAAAAATCAC TTTCCTGACACCAAAGATACTTTATGGAAATTTACATTCAGGCATTTCCCTAGAT ACTCTGAAAAAAAGAAAGAAAGAAAGAAAGAAAGGAAGGAAGGAAGGAAGGA AGGAAGGAAGGAAGGAAGGAAGGAAACAGTAATGGAAGGAAGGGGTTGGGGTT TGAGAACCCTTACTCATAAGAAAAACATAGACTGTACTTTTGTGTACCTCACAGC 66MF-363253604Attorney Docket No.: 15979-20192.40 TCCTTTCTTCAAGTACTGAGTAAGAACTCGTCCAAGGGATGCTTTCTAACAGAAC CAACTCTCAGGGTTACTGGCATGTCTACCCAGTTTATAACTTAATACACAACAAG ACAATTTCACTATACGTATCGTTAAGTGAAAGAAAGGCTACTCCTTTTACCTTTTG CAATTTCCCTGAATTCCAGCCACTAGAGAAACGAATCACAATACCAAATGAAGG TCATGCCATTTACTAGATGTGTTAGAATATCTGGGCTCCAAGACTTATCTACCTC ATAGGTGCATTGCTCTTCTTTTCTAAGTCTATCTGAAAGGACACTTTAAACCAAAT TATAAATGACTACCAGTTTAAAAAAAATGACTACCAGTTGAACTATTATACGCAT ATTATACGCATATTTCAGTCTAAGTTCACCACTAGTCAGGCCTCCTAATTTCAAAT TAAACTGAAAAAAAAAAAAAAAAACTAGTTTAGCCAAAAGTTGTAATAAAATTT TATTTTACTTATGATCTAATTTATTGTAGATATGTACTCAATAATTACTGACTACT ATTGCCTTATGTTTCAAAGTTCCACCTTCATCAAAAGGGTCAGAATAATTTCTAA AGTATACAGGCTTCTAGATACTAAGCAGTATCAAGATGTAGGCATTTTTAAGTGT GTCAGTTCAAGTAATCCTTCTAAGAAAAAAGCCTCTTGATCTTCCAGAGATTACT GTAAGACCACAATCAGATCCAAAAAAACAGGAAATAAAAGTGGTAGTCATTATT TTCTAAGGGAACTTGTATATTATAATTAAGCTCAAAACACTTGCACCTTAACTGT AAATACCTTGAACTGTAATATCAGTATGAGTGATATCATACTTATGGGATACAGC ACCTAATCTACGTAACAAAAATATTATTACAACCATCTAAAACAATCATTAACAG AGTTTTGTTTTATGGACTTGCTTTTAGCACTGGAAAAACAATATGAACTACATTTG TGAATTCAAAATACTCTACAATGTTTCTTCATTTTTTGCTACAAATTCTAGAACCA TTACATTTATGGGATCTAAATAAATTTGTACAAAATTAAACAGACTCCCGAAGGA AAAGGCATTGGTTGCAGTAATAATCCTAGGGAGGAAAAACCCTACGATTTTATGT GCTGCACATGCCTGGGTGATGGTTCAGTTTCAAATATTCCTTGCCAGACAAACTA CTTAAAAAGGCTTAATCAAAGATCACCCTGGTTCTATTTGGTTAGGGGTAGGGTG GGCTTAGAATGGACTCTTGCTGCCTTCTTAGTATCTTGAACTAAACTTACTCAATT TCTGAATATTCCTTCTGTGTCTCTGATGGATTACTGCCAAAACACATCTTTGTTCG GTGGAAAGTCTATAATCCAACACATACACGATTAATCCAATTTATAGGTCAGATA TCAGTAAGTATATCTAATCTGGAGAGGTCTACAGATTAATTTAGAATTAACAACA AACCAAGCATTAATCCAAAAGCAGCTCTTTTTAGTTTAGGCATCCAAATATATAG TAAGATGTTTCAAAGAACATCAATCTATTCACAAAGGTAAATACGGCCTAATAC GGAGAGACAAATACAAATCTGAAATGACTCAAGCAATTAAAAGATGGAGGAATT CATGTCACTTGCACTGGGAAAACAAAACAAAGATCCTCCTCACCCTATTACCCAC ATTACTATTTTTAGGTTTTTTAGGGGTTAAAAAAGATCAAAACACTAATGAACTT TAAGTCCTGTGAAGGGTAAAACCTCAGATAGTAACAAAAAGCTTCCAACCCCTC CTCAAACAAAAAACCCCAAGTCTTTAACTTTGATCCAGTTTTCAGATGCTGATAT 67MF-363253604Attorney Docket No.: 15979-20192.40 CCATAAATGGATACAGTTATGAATTGCTAATTCTGGTCTCTTCACTAGCAAAAAG CAAAGCAGCTCAGCAGTACAATTTCCCAGGAAAGCAAGCAAGGTTTCTTTCCAG CCTGAGCAGCCATCACTAAGTGCAGTTCCCTGCAGCCAACAGCATTAATGGACG CTGCACTGCTGTCCTTCCCTGGAGACAGCAGCCAGCACTACTCAAGCTTCTCACG TAGCAACCAGAGCTCCAGAGCCAGCAGCTGCTGCCGCCTTGTATACTCACTCCTG TGATCCAACACAGGAGCAACCTTTTCTTTACCCCACCCCCACTTCTTAACACACTT TTTTTTGGGGGGGGGGGGGAACAAGTGCTCCATGCTGGAAGGATTGGAACTATG CTTTTAGAAAGGAACAATCCTAAGGTCACTTTTAAATTGAGGTCTTTGATTTGAA AATCAACAAATACCAAATTCCAAATATTCGTTTTAATTAAACCAGCAATGTGGAT ATAAGCATTAAGTTTTAGTTTTAAAAAGGTCAATTTTCCAAACATTCAGCAATCA TATTTAAATTTACAGCTAGGAACAAGAGCCTTGGGTCATGTCCTACCAAAGAACA TAACTCAATATTCTACACATGACAATCTGAATAACCTTAAAGCCTCTAATCCCAT AACAGGCCACAAATTTTGGACAGAGAACTAATGATCCTCCTGAGAAAACTGGAA GAAATCCAGGGAAAAGAAATTCCTGTGTCCTCCAAACTCAGAAATCTCTAATTAT GTCAGTATTCTCTGCTTTAGTCCTAGGTCAGATTGCACACATCTAAAATAACCTCT TAAAGTTTTCCTCCTAGCGACCTAAACCATTATTAATATCAAATTAACCATCAAA ACACTTTCCTCTCAATATGCTGCACACAAACCTCCTCCTGGAACCTCCTCCATCTG GATCCTCCCCAATCAAAAGTATAGGTATTTAACATATAAGCAAGGAAGTAATGT AAACATGACCTTGGTCACAAATATGTCATCTAAAAACAATTTAGTCAAGGTATGG AGGAAATTCGAGAACCTGAATCTTTTTAAGTATTTTGAGCACAGGAACAATTGGC AAAAGGAATCCAGGTATAGACAAAACCCAGAGCCCAGAGCTCTGGGCGAAAAA TGAGTTGCTGGTGAAGACGTTACACAAGTAACATGAGAAAGCAGAAAATGCAGG TCATCCACGCACCCCTGACCCAGGCCAGCAGGGCGGGCTGCAGCATCAGTACAC AGGAGAAAGATCCTTATTCCTAAGAATGAGAAAGGCAAAGGCGCCCGATAGAAT AAATTAGCATAGAAGGGGCTTTCCCAGGAGTTAAAACTTTCCTTCTGAGCGATTA CCTACTAAAACCAGGGCTTTTGCCCACTACCATTTACCTAGGATCTTGGCTTGCA CGGATTCATAGGGGCATATCCCTCCCCCTCTTCTTTAGAGTCGTTCTTAAAAGATC GCTCTCCACGCCCTAGGCAGGGAAAACGACAAAATCTGGCTCAATTCCAGGCTA GAACCCTACAAATTCAACAGGGATATCGCAAGGATACTGGGGCATACGCCACAG GGAGTCCAAGAATGTGAGGTGGGGGTGGCGAAGGTAATGTCTTTGGTGTGGGAA AAGCAGCAGCCATCTGAGATAGGAACTGGAAAACCAGAGGAGAGGCGTTCAGG AAGATTATGGAGGGGAGGACTGGGCCCCCACGAGCGACCAGAGTTGTCACAAGG CCGCAAGAACAGGGGAGGTGGGGGGCTCAGGGACAGAAAAAAAAGTATGTGTA TTTTGAGAGCAGGGTTGGGAGGCCTCTCCTGAAAAGGGTATAAACGTGGAGTAG 68MF-363253604Attorney Docket No.: 15979-20192.40 GCAATACCCAGGCAAAAAGGGGAGACCAGAGTAGGGGGAGGGGAAGAGTCCTG ACCCAGGGAAGACATTAAAAAGGTAGTGGGGTCGACTAGATGAAGGAGAGCCTT TCTCTCTGGGCAAGAGCGGTGCAATGGTGTGTAAAGGTAGCTGAGAAGACGAAA AGGGCAAGCATCTTCCTGCTACCAGGCTGGGGAGGCCCAGGCCCACGACCCCGA GGAGAGGGAACGCAGGGAGACTGAGGTGACCCTTCTTTCCCCCGGGGCCCGGTC GTGTGGTTCGGTGTCTCTTTTCTGTTGGACCCTTACCTTGACCCAGGCGCTGCCGG GGCCTGGGCCCGGGCTGCGGCGCACGGCACTCCCGGGAGGCAGCGAGACTCGAG TTAGGCCCAACGCGGCGCCACGGCGTTTCCTGGCCGGGAATGGCCCGTACCCGT GAGGTGGGGGTGGGGGGCAGAAAAGGCGGAGCGAGCCCGAGGCGGGGAGGGG GAGGGCCAGGGGCGGAGGGGGCCGGCACTACTGTGTTGGCGGACTGGCGGGACT AGGGCTGCGTGAGTCTCTGAGCGCAGGCGGGCGGCGGCCGCCCCTCCCCCGGCG GCGGCAGCGGCGGCAGCGGCGGCAGCTCACTCAGCCCGCTGCCCGAGCGGAAAC GCCACTGACCGCACGGGGATTCCCAGTGCCGGCGCCAGGGGCACGCGGGACACG CCCCCTCCCGCCGCGCCATTGGCCTCTCCGCCCACCGCCCCACACTTATTGGCCG GTGCGCCGCCAATCAGCGGAGGCTGCCGGGGCCGCCTAAAGAAGAGGCTGTGCT TTGGGGCTCCGGCTCCTCAGAGAGCCTCGGCTAGGTAGGGGATCGGGACTCTGG CGGGAGGGCGGCTTGGTGCGTTTGCGGGGATGGGCGGCCGCGGCAGGCCCTCCG AGCGTGGTGGAGCCGTTCTGTGAGACAGCCGGGTACGAGTCGTGACGCTGGAAG GGGCAAGCGGGTGGTGGGCAGGAATGCGGTCCGCCCTGCAGCAACCGGAGGGG GAGGGAGAAGGGAGCGGAAAAGTCTCCACCGGACGCGGCCATGGCTCGGGGGG GGGGGGGCAGCGGAGGAGCGCTTCCGGCCGACGTCTCGTCGCTGATTGGCTTCTT TTCCTCCCGCCGTGTGTGAAAACACAAATGGCGTGTTTTGGTTGGCGTAAGGCGC CTGTCAGTTAACGGCAGCCGGAGTGCGCAGCCGCCGGCAGCCTCGCTCTGCCCA CTGGGTGGGGCGGGAGGTAGGTGGGGTGAGGCGAGCTGGACGTGCGGGCGCGG TCGGCCTCTGGCGGGGCGGGGGAGGGGAGGGAGGGTCAGCGAAAGTAGCTCGC GCGCGAGCGGCCGCCCACCCTCCCCTTCCTCTGGGGGAGTCGTTTTACCCGCCGC CGGCCGGGCCTCGTCGTCTGATTGGCTCTCGGGGCCCAGAAAACTGGCCCTTGCC ATTGGCTCGTGTTCGTGCAAGTTGAGTCCATCCGCCGGCCAGCGGGGGCGGCGA GGAGGCGCTCCCAGGTTCCGGCCCTCCCCTCGGCCCCGCGCCGCAGAGTCTGGCC GCGCGCCCCTGCGCAACGTGGCAGGAAGCGCGCGCTGGGGGCGGGGACGGGCA GTAGGGCTGAGCGGCTGCGGGGCGGGTGCAAGCACGTTTCCGACTTGAGTTGCC TCAAGAGGGGCGTGCTGAGCCAGACCTCCATCGCGCACTCCGGGGAGTGGAGGG AAGGAGCGAGGGCTCAGTTGGGCTGTTTTGGAGGCAGGAAGCACTTGCTCTCCC AAAGTCGCTCTGAGTTGTTATCAGTAAGGGAGCTGCAGTGGAGTAGGCGGGGAG 69MF-363253604Attorney Docket No.: 15979-20192.40 AAGGCCGCACCCTTCTCTTAATtaagtgacctgcacgtctagggcgcagtagtccagggtttccttgatgatgtcat acttatcctgtcccttttttttccacagctcgcggttgaggacaaactcttcgcggtctttccagtatttGCTGGCGCGCCTCGC GATGAATAAATGAAAGCTTGCAGATCTGCGACTCTAGAGGATCTGCGACTCTAG AGGATCATAATCAGCCATACCACATTTGTAGAGGTTTTACTTGCTTTAAAAAACC TCCCACACCTCCCCCTGAACCTGAAACATAAAATGAATGCAATTGTTGTTGTTAA CTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAATTTC ACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTGGTTTGTCCAAACTCATCAA TGTATCTTATCATGTCTGGATCTGCGACTCTAGAGGATCATAATCAGCCATACCA CATTTGTAGAGGTTTTACTTGCTTTAAAAAACCTCCCACACCTCCCCCTGAACCTG AAACATAAAATGAATGCAATTGTTGTTGTTAACTTGTTTATTGCAGCTTATAATG GTTACAAATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTTTTTTCACT GCATTCTAGTTGTGGTTTGTCCAAACTCATCAATGTATCTTATCATGTCTGGATCT GCGACTCTAGAGGATCATAATCAGCCATACCACATTTGTAGAGGTTTTACTTGCT TTAAAAAACCTCCCACACCTCCCCCTGAACCTGAAACATAAAATGAATGCAATTG TTGTTGTTAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATC ACAAATTTCACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTGGTTTGTCCAA ACTCATCAATGTATCTTATCATGTCTGGATCCCCATCAAGCTGATCCGGAACCCT TAATGCGATCGCtctcccatagtccccacgcaagggtgagtcttgcacgctcagccctgcctgtggttcccagaaggcctct gtcactgcgtgcttgctttctctcccagggaagataccccagtgccatgtcttggggcaagagaaaatgaagacagacctggaacatg aacatggtggccttgccagaaagcaagtgtgtgttgctgaaacatcagcagagattgtcaaagggataaagagataacttaaaagggtt cctattgaccaaaatgcgacaagttgaccatctaaaatcaaatcataattatagttcaataggacacattgagtctcttaaaagcttccaatc cgtaatgaccatcaaggcccataacctcaaaagagtaaagttaaaataaagttcagaaaaggttagctgcaataaaacatgagttttagt aattttaacaagaaggggatgaagctatagatgcatttttattccttcttttaactatgttgccccttataatgtatagctttgccttatttttctct gtctgagtaaggataaagagtaaaggccaggcacagtggctcacacctgtaattccagcactttgggaggccgaggcgggcagata acttgaggccaggagtttgagaccagcctggccaacatggtgaaaccctgtcactactaaaaatacaaaaattaactggaattggtagc acatgcctgtaatgccagctactctggaggctgaggcacgagaatcgctcgtaattccagaattcgagaggtggagtttgcagtaagc caagattgcgccactgtactccagcctgggtgactgagtgagactctgtctcaaaaaaaaaaaaaaaaagaagaagctgtgagtagg ccacatagttccagaaaatgcagaaatcccccctcccctccccaacacacaggaagtggctcaggagattacacacagaaggaaagt gtgtctgctggggttttgcaagttggctaatttgaaaggtgactggaggaggtgaaaaaatggtgcaaacttcattcattcattaaatgagt tataagaagacagacacaagtgtccattatgctaacagagctctgtgttaaacaccccaccagcatcgcctcatctaagcctcagaaga gctatgtgggaaagaaacttttatccctattttatagatgaggaaaccaaggctcagagaactgagggcctcccccggatccaagtcca cctagctgcagtcaccccacatcctctgcatgtcacaggtgctcagaaagatgctgaaggcacctggcccttcaccttcggaaagcca aaatgagcacggcccctaaagaggggattgacagccttttctggaaaaaatggaagtttgaatctgaggaggtgtccctcaacaacag gtgctgctccccaaatctggggccaaacgcagcagttgttcccccacttagacccctgagacccatctatatggtttttcagagccagga 70MF-363253604Attorney Docket No.: 15979-20192.40 cacatccccaaaggtcatggcctttggtggttagcattgacttggggcccatcacatgccagaggctgcccgaagtgcttaaatgttatt atctcattcgatcttcacagtcctgatggaagtgactcttcttagagtcttcctatctcacagatgaggaaaccgaggcacagagaggtta agtggcttgtctaagagctcacaaaaagagcgatggagctaaggcttggccccagatattagatcccgaacccacgccttaaccagtg acctgcactgactctcaaagaaggaagctggtgcctgggaaggagggtgcatagtgagggtgtgcatggggtgtgtgtgtttgtggg gtggccagcactctccgggggcactttgccaatgagttcagctcccatgaagtccactgttgttctcctgaccagccactcagtcttgatt tacttggcccagggccactggcacacctcacccccttacccgattccttgctgcagaccccaaatctcgactctcacatccctatccagc ccataccacgaggctcccatctccaggcagggccctgtggtggggcagggcctcccccagatgccccttactcatgaccagctcaca ggatcttcccatgatgcatttcctctggggggatcagcccagatgctgcaatagacaattgtggaagtaaccaggtggacaagactttc cccctcatgtcctggggttcctgggggcacagtatccttgtgaatggccactgagtactcccacccctcccaccacaacccccgggatt ttgtcctggtgcgtttttccagattatcctagcccttcctcccaggatggatgtccagagcagggcgggggctgagcctagagccctgc caaaagagcaggaccccaaattctgagccccttacttgcctcacctgctcccacccatgctttcttcattcctcctccaaaagccccagct ccccactgcaatcccttctgcacccagccaggtcctatgacacacacctccccagtgcacacagacctgcccaactgtggggctgcc cactgggcatttcataggtggctcagtcctcttccctctgcagctggccccagaaacctgccagttattggtgccaggtctgtgccagga gggcgaggcctgtcatttctagtaatcctctgggcagtgtgactgtacctcttgcggcaactcaaagggagagggtgacttgtcccggg tcacagagctgaaagggcaggtacaacaggtgacatgccgggctgtctgagtttatgagggcccagtcttgtgtctgccgggcaatga gcaaggctccttcctgtccaagctccccgcccctccccagcctactgcctccacccgaagtctacttcctgggtgggcaggaactggg cactgtgcccagggcatgcactgcctccacgcagcaaccctcagagtcctgagctgaaccaagaaggaggagggggtcgggcctc cgaggaaggcctagccgctgctgctgccaggaattccaggttggaggggcggcaacctcctgccagccttcaggccactctcctgtg cctgccagaagagacagagcttgaggagagcttgaggagagcaggaaaggtgggacattgctgctgctgctcactcagttccacag gtgggagggacagcagggcttagagtgggggtcattgtgcagatgggaaaacaaaggcccagagaggggaagaaatgcccagg agctaccgagggcaggcgacctcaaccacagcccagtgctggagctgtgagtggatgtagagcagcggaatatccattcagccagc tcaggggaaggacaggggccctgaagccaggggatggagctgcagggaagggagctcagagagaaggggaggggagtctgag ctcagtttcccgctgcctgaaaggagggtggtacctactcccttcacagggtaactgaatgagagactgcctggaggaaagctcttcaa gtgtggcccaccccaccccagtgacaccagcccctgacacgggggagggagggcagcatcaggaggggctttctgggcacaccc agtacccgtctctgagctttccttgaactgttgcattttaatcctcacagcagctcaacaaggtacataccgtcaccatccccattttacaga tagggaaattgaggctcggagcggttaaacaactcacctgaggcctcacagccagtaagtgggttccctggtctgaatgtgtgtgctg gaggatcctgtgggtcactcgcctggtagagccccaaggtggaggcataaatgggactggtgaatgacagaaggggcaaaaatgca ctcatccattcactctgcaagtatctacggcacgtacgccagctcccaagcaggtttgcgggttgcacagcgggcgatgcaatctgattt aggcttttaaagggattgcaatcaagtggggccccactagcctcaaccctgtacctcccctcccctccacccccagcagtctccaaag gcctccaacaaccccagagtgggggccatgtatccaaagaaactccaagctgtatacggatcacactggttttccaggagcaaaaac agaaacaggcctgaggctggtcaaaattgaacctcctcctgctctgagcagcctggggggcagactaagcagagggctgtgcagac ccacataaagagcctactgtgtgccaggcacttcacccgaggcacttcacaagcatgcttgggaatgaaacttccaactctttgggatg caggtgaaacagttcctggttcagagaggtgaagcggcctgcctgaggcagcacagctcttctttacagatgtgcttccccacctctac cctgtctcacggccccccatgccagcctgacggttgtgtctgcctcagtcatgctccatttttccatcgggaccatcaagagggtgtttgt 71MF-363253604Attorney Docket No.: 15979-20192.40 gtctaaggctgactgggtaactttggatgagcggtctctccgctctgagcctgtttcctcatctgtcaaatgggctctaacccactctgatc tcccagggcggcagtaagtcttcagcatcaggcattttggggtgactcagtaaatggtagatcttgctaccagtggaacagccactaag gattctgcagtgagagcagagggccagctaagtggtactctcccagagactgtctgactcacgccaccccctccaccttggacacag gacgctgtggtttctgagccaggtacaatgactcctttcggtaagtgcagtggaagctgtacactgcccaggcaaagcgtccgggcag cgtaggcgggcgactcagatcccagccagtggacttagcccctgtttgctcctccgataactggggtgaccttggttaatattcaccag cagcctcccccgttgcccctctggatccactgcttaaatacggacgaggacagggccctgtctcctcagcttcaggcaccaccactga cctgggacagtgaatcgtaagtatgcctttcactgcgagaggttctggagaggcttctgagctccccatggcccaggcaggcagcag gtctggggcaggaggggggttgtggagtgggtatccgcctgctgaggtgcagggcagatggagaggctgcagctgagctcctatttt cataataacagcagccatgagggttgtgtcctgtttcccagtcctgcccggtcccccctcggtacctcctggtggatacactggttcctgt aagcagaagtggatgagggtgtctaggtctgcagtcctggcaccccaggatgggggacaccagccaagatacagcaacagcaaca aagcgcagccatttctttctgtttgcacagctcctctgtctgtcgggggctcctgtctgttgtctcctataagcctcaccacctctcctactgc ttgggcatgcatctttctccccttctatagatgaggaggttaaggtccagagaggggtggggaggaacgccggctcacattctccatcc cctccagatatgaccaggaacagacctgtgccaggcctcagccttacatcaaaatgggcctccccatgcaccgtggacctctgggcc ctcctgtcccagtggaggacaggaagctgtgaggggcactgtcacccagggctcaagctggcattcctgaataatcgctctgcacca ggccacggctaagctcagtgcgtgattaagcctcataaccctccaaggcagttactagtgtgattcccattttacagatgaggaagatgg ggacagagaggtgaataactggccccaaatcacacaccatccataattcgggctcaggcacctggctccagtccccaaactcttgaac ctggccctagtgtcactgtttctcttgggtctcaggcgctggatggggaacaggaaacctgggctggacttgaggcctctctgatgctc ggtgacttcagacagttgctcaacctctctgttctcttgggcaaaacatgataacctttgacttctgtcccctcccctcaccccacccgacc ttgatctctgaagtgttggaaggatttaatttttcctgcactgagttttggagacaggtcaaaaagatgaccaaggccaaggtggccagttt cctatagaacgcctctaaaagacctgcagcaatagcagcaagaactggtattctcgagaacttgctgcgcagcaggcacttcttggcat tttatgtgtatttaatttcacaatagctctatgacaaagtccacctttctcatctccaggaaactgaggttcagagaggttaagtaacttgtcc aaggtcacacagctaatagcaagttgacgtggagcaatctggcctcagagcctttaattttagccacagactgatgctcccctcttcattt agccaggctgcctctgaagttttctgattcaagacttctggcttcagctttgtacacagagatgattcaatgtcaggttttggagtgaaatct gtttaatcccagacaaaacatttaggattacatctcagttttgtaagcaagtagctctgtgatttttagtgagttatttaatgctctttggggctc aatttttctatctataaaatagggctaataatttgcaccttatagggtaagctttgaggacagattagatgatacggtgcctgtaaaacacca ggtgttagtaagtgtggcaatgatggtgacgctgaggctgatgtttgcttagcatagggttaggcagctggcaggcagtaaacagttgg ataatttaatggaaaatttgccaaactcagatgctgttcactgctgagcaggagccccttcctgctgaaatggtcctggggagtgcagca ggctctccgggaagaaatctaccatctctcgggcaggagctcaacctgtgtgcaggtacagggagggcttcctcacctggtgcccact catgcattacgtcagttattcctcatccctgtccaaaggattcttttctccattgtacagctatgaagctagtgctcaaagaagtgaagtcatt taccccaggccccctgccagtaagtgacagggcctggtcacacttgggtttatttattgcccagttcaacaggttgtttgaccataggcg agattctcttccctgcaccctgccgggttgctcttggtcccttattttatgctcccgggtagaaatggtgtgagattaggcagggagtggct cgcttccctgtccctggccccgcaaagagtgctcccacctgccccgatcccagaaatgtcaccatgaagccttcattcttttggtttaaag cttggcctcagtgtccgtacaccatggggtacttggccagatggcgactttctcctctccagtcgccctcccaggcactagcttttagga gtgcagggtgctgcctctgatagaagggccaggagagagcaggttttggagtcctgatgttataaggaacagcttgggaggcataatg 72MF-363253604Attorney Docket No.: 15979-20192.40 aacccaacatgatgcttgagaccaatgtcacagcccaattctgacattcatcatctgagatctgaggacacagctgtctcagttcatgatc tgagtgctgggaaagccaagacttgttccagctttgtcactgacttgctgtatagcctcaacaaggccctgaccctctctgggcttcaaac tcttcactgtgaaaggaggaaaccagagtaggtgatgtgacaccaggaaagatggatgggtgtgggggaatgtgctcctcccagctg tcaccccctcgccaccctccctgcaccagcctctccacctcctttgagcccagaattcccctgtctaggagggcacctgtctcatgccta gccatgggaattctccatctgttttgctacattgaacccagatgccattctaaccaagaatcctggctgggtgcaggggctctcgcctgta accccagcactttgggaggccaaggcaggcggatcaagaggtcaggagttcaagacctgcctggccaacacggtgaaacctcagc tctactaaaaatacaaaaattagccaggcgtggtggcacacgcctgtaatcccagctatttgggaagctgagacagaagaatttcttgaa cccgggaggtggaggtttcagtgagccgagatcacgccactgcactccaccctggcagataaagcgagactctgtctcaaaaaaaac ccaaaaacctatgttagtgtacagagggccccagtgaagtcttctcccagccccactttgcacaactggggagagtgaggccccagg accagaggattcttgctaaaggccaagtggatagtgatggccctgccagggctagaagccacaacctctggccctgaggccactcag catatttagtgtccccaccctgcagaggcccaactccctcctgaccactgagccctgtaatgatgggggaatttccataagccatgaag gactgcacaaagttcagttgggaagtgaaagagaaattaaagggagatggaaatatacagcactaattttagcaccgtctttagttctaa caacactagctagctgaagaaaaatacaaacatgtattatgtaatgtgtggtctgttccatttggattacttagaggcacgagggccagg agaaaggtggtggagagaaaccagctttgcacttcatttgttgctttattggaaggaaacttttaaaagtccaagggggttgaagaatctc aatatttgttatttccagctttttttctccagtttttcatttcccaaattcaaggacacctttttctttgtattttgttaagatgatggttttggttttgtg actagtagttaacaatgtggctgccgggcatattctcctcagctaggacctcagttttcccatctgtgaagacggcaggttctacctaggg ggctgcaggctggtggtccgaagcctgggcatatctggagtagaaggatcactgtggggcagggcaggttctgtgttgctgtggatg acgttgactttgaccattgctcggcagagcctgctctcgctggttcagccacaggccccaccactccctattgtctcagccccgggtatg aaacatgtattcctcactggcctatcacctgaagcctttgaatttgcaacacctgccaacccctccctcaaaagagttgccctctcagatc cttttgatgtaaggtttggtgttgagacttatttcactaaattctcatacataaacatcactttatgtatgaggcaaaatgaggaccagggag atgaatgacttgtcctggctcatacacctggaaagtgacagagtcagattagatcccaggtctatctgaagttaaaagaggtgtcttttca cttcccacctcctccatctactttaaagcagcacaaacccctgctttcaaggagagatgagcgtctctaaagcccctgacagcaagagc ccagaactgggacaccattagtgacccagacggcaggtaagctgactgcaggagcatcagcctattcttgtgtctgggaccacagag cattgtggggacagccccgtctcttgggaaaaaaaccctaagggctgaggatccttgtgagtgttgggtgggaacagctcccaggag gtttaatcacagcccctccatgctctctagctgttgccattgtgcaagatgcatttcccttctgtgcagcagtttccctggccactaaatagt gggattagatagaagccctccaagggcttccagcttgacatgattcttgattctgatctggcccgattcctggataatcgtgggcaggcc cattcctcttcttgtgcctcattttcttcttttgtaaaacaatggctgtaccatttgcatcttagggtcattgcagatgtaagtgttgctgtccaga gcctgggtgcaggacctagatgtaggattctggttctgctacttcctcagtgacattgaatagctgacctaatctctctggctttggtttcttc atctgtaaaagaaggatattagcattagcacctcacgggattgttacaagaaagcaatgaattaacacatgtgagcacggagaacagtg cttggcatatggtaagcactacgtacattttgctattcttctgattctttcagtgttactgatgtcggcaagtacttggcacaggctggtttaat aatccctaggcacttccacgtggtgtcaatccctgatcactgggagtcatcatgtgccttgactcggggcctggcccccccatctctgtct tgcaggacaatgccgtcttctgtctcgtggggcatcctcctgctggcaggcctgtgctgcctggtccctgtctccctggctgaggatccc cagggagatgctgcccagaagacagatacatcccaccatgatcaggatcacccaaccttcaacaagatcacccccaacctggctgag ttcgccttcagcctataccgccagctggcacaccagtccaacagcaccaatatcttcttctccccagtgagcatcgctacagcctttgca 73MF-363253604Attorney Docket No.: 15979-20192.40 atgctctccctggggaccaaggctgacactcacgatgaaatcctggagggcctgaatttcaacctcacggagattccggaggctcaga tccatgaaggcttccaggaactcctccgtaccctcaaccagccagacagccagctccagctgaccaccggcaatggcctgttcctcag cgagggcctgaagctagtggataagtttttggaggatgttaaaaagttgtaccactcagaagccttcactgtcaacttcggggacaccg aagaggccaagaaacagatcaacgattacgtggagaagggtactcaagggaaaattgtggatttggtcaaggagcttgacagagac acagtttttgctctggtgaattacatcttctttaaaggtaaggttgctcaaccagcctgagctgttcccatagaaacaagcaaaaatattctc aaaccatcagttcttgaactctccttggcaatgcattatgggccatagcaatgcttttcagcgtggattcttcagttttctacacacaaacact aaaatgttttccatcattgagtaatttgaggaaataatagattaaactgtcaaaactactgacagctctgcagaacttttcagagcctttaatg tccttgtgtatactgtatatgtagaatatataatgcttagaactatagaacaaattgtaatacactgcataaagggatagtttcatggaacata ctttacacgactctagtgtcccagaatcagtatcagttttgcaatctgaaagacctgggttcaaatcctgcctctaacacaattagcttttga caaaaacaatgcattctacctctttgaggtgctaatttctcatcttagcatggacaaaataccattcttgctgtcaggtttttttaggattaaac aaatgacaaagactgtggggatggtgtgtggcatacagcaggtgatggactcttctgtatctcaggctgccttcctgcccctgaggggtt aaaatgccagggtcctgggggccccagggcattctaagccagctcccactgtcccaggaaaacagcataggggaggggaggtgg gaggcaaggccaggggctgcttcctccactctgaggctcccttgctcttgaggcaaaggagggcagtggagagcagccaggctgca gtcagcacagctaaagtcctggctctgctgtggccttagtgggggcccaggtccctctccagccccagtctcctccttctgtccaatgag aaagctgggatcaggggtccctgaggcccctgtccactctgcatgcctcgatggtgaagctctgttggtatggcagaggggaggctg ctcaggcatctgcatttcccctgccaatctagaggatgaggaaagctctcaggaatagtaagcagaatgtttgccctggatgaataactg agctgccaattaacaaggggcagggagccttagacagaaggtaccaaatatgcctgatgctccaacattttatttgtaatatccaagaca ccctcaaataaacatatgattccaataaaaatgcacagccacgatggcatctcttagcctgacatcgccacgatgtagaaattctgcatct tcctctagttttgaattatccccacacaatctttttcggcagcttggatggtcagtttcagcaccttttacagatgatgaagctgagcctcga gggatgtgtgtcgtcaagggggctcagggcttctcagggaggggactcatggtttctttattctgctacactcttccaaaccttcactcac ccctggtgatgcccaccttcccctctctccaggcaaatgggagagaccctttgaagtcaaggacaccgaggaagaggacttccacgt ggaccaggtgaccaccgtgaaggtgcctatgatgaagcgtttaggcatgtttaacatccagcactgtaagaagctgtccagctgggtg ctgctgatgaaatacctgggcaatgccaccgccatcttcttcctgcctgatgaggggaaactacagcacctggaaaatgaactcaccca cgatatcatcaccaagttcctggaaaatgaagacagaaggtgattccccaacctgagggtgaccaagaagctgcccacacctcttagc catgttgggactgaggcccatcaggactggccagagggctgaggagggtgaaccccacatccctgggtcactgctactctgtataaa cttggcttccagaatgaggccaccactgagttcaggcagcgccatccatgctccatgaggaggacagtacccaggggtgaggaggt aaaggtctcgtccctggggacttcccactccagtgtggacactgtcccttcccaatatccagtgcccagggcagggacagcagcacc accacacgttctggcagaaccaaaaaggaacagatgggcttcctggcaaaggcagcagtggagtgtggagttcaagggtagaatgt ccctggggggacgggggaagagcctgtgtggcaaggcccagaaaagcaaggttcggaattggaacagccaggccatgttcgcag aaggcttgcgtttctctgtcactttatcggtgctgttagattgggtgtcctgtagtaagtgatacttaaacatgagccacacattagtgtatgt gtgtgcattcgtgattatgcccatgccctgctgatctagttcgttttgtacactgtaaaaccaagatgaaaatacaaaaggtgtcgggttca taataggaatcgaggctggaatttctctgttccatgccagcacctcctgaggtctctgctccaggggttgagaaagaacaaagaggctg agagggtaacggatcagagagcccagagccaagctgcccgctcacaccagaccctgctcagggtggcattgtctccccatggaaaa ccagagaggagcactcagcctggtgtggtcactcttctcttatccactaaacggttgtcactgggcactgccaccagccccgtgtttctct 74MF-363253604Attorney Docket No.: 15979-20192.40 gggtgtagggccctggggatgttacaggctgggggccaggtgacccaacactacagggcaagatgagacaggcttccaggacacc tagaatatcagaggaggtggcatttcaagcttttgtgattcattcgatgttaacattctttgactcaatgtagaagagctaaaagtagaacaa accaaagccgagttcccatcttagtgtgggtggaggacacaggagtaagtggcagaaataatcagaaaagaaaacacttgcactgtg gtgggtcccagaagaacaagaggaatgctgtgccatgccttgaatttcttttctgcacgacaggtctgccagcttacatttacccaaactg tccattactggaacctatgatctgaagagcgtcctgggtcaactgggcatcactaaggtcttcagcaatggggctgacctctccggggt cacagaggaggcacccctgaagctctccaaggtgagatcaccctgacgaccttgttgcaccctggtatctgtagggaagaatgtgtgg gggctgcagctctgtcctgaggctgaggaaggggccgagggaaacaaatgaagacccaggctgagctcctgaagatgcccgtgatt cactgacacgggacgtggtcaaacagcaaagccaggcaggggactgctgtgcagctggcactttcggggcctcccttgaggttgtgt cactgaccctgaatttcaactttgcccaagaccttctagacattgggccttgatttatccatactgacacagaaaggtttgggctaagttgtt tcaaaggaatttctgactccttcgatctgtgagatttggtgtctgaattaatgaatgatttcagctaaagatgacacttattttggaaaactaa aggcgaccaatgaacaactgcagttccatgaatggctgcattatcttggggtctgggcactgtgaaggtcactgccagggtccgtgtcc tcaaggagcttcaagccgtgtactagaaaggagagagccctggaggcagacgtggagtgacgatgctcttccctgttctgagttgtgg gtgcacctgagcagggggagaggcgcttgtcaggaagatggacagaggggagccagccccatcagccaaagccttgaggagga gcaaggcctatgtgacagggagggagaggatgtgcagggccagggccgtccagggggagtgagcgcttcctgggaggtgtccac gtgagccttgctcgaggcctgggatcagccttacaacgtgtctctgcttctctcccctccaggccgtgcataaggctgtgctgaccatcg acAagaaagggactgaagctgctggggccatgtttttagaggccatacccatgtctatcccccccgaggtcaagttcaacaaacccttt gtcttcttaatgattgaacaaaataccaagtctcccctcttcatgggaaaagtggtgaatcccacccaaaaataactgcctctcgctcctca acccctcccctccatccctggccccctccctggatgacattaaagaagggttgagctggtccctgcctgcatgtgactgtaaatccctcc catgttttctctgagtctccctttgcctgctgaggctgtatgtgggctccaggtaacagtgctgtcttcgggccccctgaactgtgttcatgg agcatctggctgggtaggcacatgctgggcttgaatccaggggggactgaatcctcagcttacggacctgggcccatctgtttctgga gggctccagtcttccttgtcctgtcttggagtccccaagaaggaatcacaggggaggaaccagataccagccatgaccccaggctcc accaagcatcttcatgtccccctgctcatcccccactcccccccacccagagttgctcatcctgccagggctggctgtgcccaccccaa ggctgccctcctgggggccccagaactgcctgatcgtgccgtggcccagttttgtggcatctgcagcaacacaagagagaggacaat gtcctcctcttgacccgctgtcacctaaccagactcgggccctgcacctctcaggcacttctggaaaatgactgaggcagattcttcctg aagcccattctccatggggcaacaaggacacctattctgtccttgtccttccatcgctgccccagaaagcctcacatatctccgtttagaa tcaggtcccttctccccagatgaagaggagggtctctgctttgttttctctatctcctcctcagacttgaccaggcccagcaggccccaga agaccattaccctatatcccttctcctccctagtcacatggccataggcctgctgatggctcaggaaggccattgcaaggactcctcagc tatgggagaggaagcacatcacccattgacccccgcaacccctccctttcctcctctgagtcccgactggggccacatgcagcctgac ttctttgtgcctgttgctgtccctgcagtcttcagagggccaccgcagctccagtgccacggcaggaggctgttcctgaatagcccctgt ggtaagggccaggagagtccttccatcctccaaggccctgctaaaggacacagcagccaggaagtcccctgggcccctagctgaag gacagcctgctccctccgtctctaccaggaatggccttgtcctatggaaggcactgccccatcccaaactaatctaggaatcactgtcta accactcactgtcatgaatgtgtacttaaaggatgaggttgagtcataccaaatagtgatttcgatagttcaaaatggtgaaattagcaatt ctacatgattcagtctaatcaatggataccgactgtttcccacacaagtctcctgttctcttaagcttactcactgacagcctttcactctcca caaatacattaaagatatggccatcaccaagccccctaggatgacaccagacctgagagtctgaagacctggatccaagttctgactttt 75MF-363253604Attorney Docket No.: 15979-20192.40 ccccctgacagctgtgtgaccttcgtgaagtcgccaaacctctctgagccccagtcattgctagtaagacctgcctttgagttggtatgat gttcaagttagataacaaaatgtttatacccattagaacagagaataaatagaactacatttcttgcacttatgagctttctgtgaatcagac atccctatgaagtacctcccctggctgtttctcatttactcactgtagcagcactgcgatgtgtgagtatatctgctgtgctcttaaactccaa atctgaggaaactgaggctcagagaggctactggtctcccacaatgtcacacagctcataagtggcaaagctggcttgatgggctactt gttcctctgaaccataccacctcaccacactctccccttcgagggtcacgctaaacttctgcagaggtaattcctccttaaaccagaagg gtGAATTCCGAAGTTCCTATTCTCTAGAAAGTATAGGAACTTCAGGTCTGAAGAG GAGTTTACGTCCAGCCAAGCTAGCTTGGCTGCAGGTCGTCGAAATTCTACCGGGT AGGGGAGGCGCTTTTCCCAAGGCAGTCTGGAGCATGCGCTTTAGCAGCCCCGCT GGGCACTTGGCGCTACACAAGTGGCCTCTGGCCTCGCACACATTCCACATCCACC GGTAGGCGCCAACCGGCTCCGTTCTTTGGTGGCCCCTTCGCGCCACCTTCTACTC CTCCCCTAGTCAGGAAGTTCCCCCCCGCCCCGCAGCTCGCGTCGTGCAGGACGTG ACAAATGGAAGTAGCACGTCTCACTAGTCTCGTGCAGATGGACAGCACCGCTGA GCAATGGAAGCGGGTAGGCCTTTGGGGCAGCGGCCAATAGCAGCTTTGCTCCTT CGCTTTCTGGGCTCAGAGGCTGGGAAGGGGTGGGTCCGGGGGCGGGCTCAGGGG CGGGCTCAGGGGCGGGGCGGGCGCCCGAAGGTCCTCCGGAGGCCCGGCATTCTG CACGCTTCAAAAGCGCACGTCTGCCGCGCTGTTCTCCTCTTCCTCATCTCCGGGCC TTTCGACCTGCAGCCTGTTGACAATTAATCATCGGCATAGTATATCGGCATAGTA TAATACGACAAGGTGAGGAACTAAACCATGGGATCGGCCATTGAACAAGATGGA TTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGG CACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGG GGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCA GGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGC TGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGT GCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATC ATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCG ACCACCAAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTC TTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAAC TGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGATGATCTCGTCGTGACCCA TGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTC ATCGACTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCT ACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGC TTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGAC GAGTTCTTCTGAGGGGATCAATTCTCTAGAGCTCGCTGATCAGCCTCGACTGTGC CTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTG 76MF-363253604Attorney Docket No.: 15979-20192.40 GAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATT GTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGG GGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTATGG CTTCTGAGGCGGAAAGAACCAGCTGGGGCTCGACTAGAGCTTGCGGAACCCTTC GAAGTTCCTATTCTCTAGAAAGTATAGGAACTTCATCAGTCAGGTACATAATGGT GGATCCCGGAGGGGGGAGGGGAGTGTTGCAATACCTTTCTGGGAGTTCTCTGCT GCCTCCTGGCTTCTGAGGACCGCCCTGGGCCTGGGAGAATCCCTTCCCCCTCTTC CCTCGTGATCTGCAACTCCAGTCTTTCTAGAAGATGGGCGGGAGTCTTCTGGGCA GGCTTAAAGGCTAACCTGGTGTGTGGGCGTTGTCCTGCAGGGGAATTGAACAGG TGTAAAATTGGAGGGACAAGACTTCCCACAGATTTTCGGTTTTGTCGGGAAGTTT TTTAATAGGGGCAAATAAGGAAAATGGGAGGATAGGTAGTCATCTGGGGTTTTA TGCAGCAAAACTACAGGTTATTATTGCTTGTGATCCGCCTCGGAGTATTTTCCAT CGAGGTAGATTAAAGACATGCTCACCCGAGTTTTATACTCTCCTGCTTGAGATCC TTACTACAGTATGAAATTACAGTGTCGCGAGTTAGACTATGTAAGCAGAATTTTA ATCATTTTTAAAGAGCCCAGTACTTCATATCCATTTCTCCCGCTCCTTCTGCAGCC TTATCAAAAGGTATTTTAGAACACTCATTTTAGCCCCATTTTCATTTATTATACTG GCTTATCCAACCCCTAGACAGAGCATTGGCATTTTCCCTTTCCTGATCTTAGAAGT CTGATGACTCATGAAACCAGACAGATTAGTTACATACACCACAAATCGAGGCTG TAGCTGGGGCCTCAACACTGCAGTTCTTTTATAACTCCTTAGTACACTTTTTGTTG ATCCTTTGCCTTGATCCTTAATTTTCAGTGTCTATCACCTCTCCCGTCAGGTGGTG TTCCACATTTGGGCCTATTCTCAGTCCAGGGAGTTTTACAACAATAGATGTATTG AGAATCCAACCTAAAGCTTAACTTTCCACTCCCATGAATGCCTCTCTCCTTTTTCT CCATTTATAAACTGAGCTATTAACCATTAATGGTTTCCAGGTGGATGTCTCCTCCC CCAATATTACCTGATGTATCTTACATATTGCCAGGCTGATATTTTAAGACATTAA AAGGTATATTTCATTATTGAGCCACATGGTATTGATTACTGCTTACTAAAATTTTG TCATTGTACACATCTGTAAAAGGTGGTTCCTTTTGGAATGCAAAGTTCAGGTGTT TGTTGTCTTTCCTGACCTAAGGTCTTGTGAGCTTGTATTTTTTCTATTTAAGCAGT GCTTTCTCTTGGACTGGCTTGACTCATGGCATTCTACACGTTATTGCTGGTCTAAA TGTGATTTTGCCAAGCTTCTTCAGGACCTATAATTTTGCTTGACTTGTAGCCAAAC ACAAGTAAAATGATTAAGCAACAAATGTATTTGTGAAGCTTGGTTTTTAGGTTGT TGTGTTGTGTGTGCTTGTGCTCTATAATAATACTATCCAGGGGCTGGAGAGGTGG CTCGGAGTTCAAGAGCACAGACTGCTCTTCCAGAAGTCCTGAGTTCAATTCCCAG CAACCACATGGTGGCTCACAACCATCTGTAATGGGATCTGATGCCCTCTTCTGGT GTGTCTGAAGACCACAAGTGTATTCACATTAAATAAATAAATCCTCCTTCTTCTT 77MF-363253604Attorney Docket No.: 15979-20192.40 CTTTTTTTTTTTTTTAAAGAGAATACTGTCTCCAGTAGAATTTACTGAAGTAATGA AATACTTTGTGTTTGTTCCAATATGGTAGCCAATAATCAAATTACTCTTTAAGCAC TGGAAATGTTACCAAGGAACTAATTTTTATTTGAAGTGTAACTGTGGACAGAGGA GCCATAACTGCAGACTTGTGGGATACAGAAGACCAATGCAGACTTTAATGTCTTT TCTCTTACACTAAGCAATAAAGAAATAAAAATTGAACTTCTAGTATCCTATTTGT TTAAACTGCTAGCTTTACTTAACTTTTGTGCTTCATCTATACAAAGCTGAAAGCTA AGTCTGCAGCCATTACTAAACATGAAAGCAAGTAATGATAATTTTGGATTTCAAA AATGTAGGGCCAGAGTTTAGCCAGCCAGTGGTGGTGCTTGCCTTTATGCCTTTAA TCCCAGCACTCTGGAGGCAGAGACAGGCAGATCTCTGAGTTTGAGCCCAGCCTG GTCTACACATCAAGTTCTATCTAGGATAGCCAGGAATACACACAGAAACCCTGTT GGGGAGGGGGGCTCTGAGATTTCATAAAATTATAATTGAAGCATTCCCTAATGA GCCACTATGGATGTGGCTAAATCCGTCTACCTTTCTGATGAGATTTGGGTATTATT TTTTCTGTCTCTGCTGTTGGTTGGGTCTTTTGACACTGTGGGCTTTCTTTAAAGCCT CCTTCCTGCCATGTGGTCTCTTGTTTGCTACTAACTTCCCATGGCTTAAATGGCAT GGCTTTTTGCCTTCTAAGGGCAGCTGCTGAGATTTGCAGCCTGATTTCCAGGGTG GGGTTGGGAAATCTTTCAAACACTAAAATTGTCCTTTAATTTTTTTTTTAAAAAAT GGGTTATATAATAAACCTCATAAAATAGTTATGAGGAGTGAGGTGGACTAATATT AAATGAGTCCCTCCCCTATAAAAGAGCTATTAAGGCTTTTTGTCTTATACTTAACT TTTTTTTTAAATGTGGTATCTTTAGAACCAAGGGTCTTAGAGTTTTAGTATACAGA AACTGTTGCATCGCTTAATCAGATTTTCTAGTTTCAAATCCAGAGAATCCAAATT CTTCACAGCCAAAGTCAAATTAAGAATTTCTGACTTTTAATGTTAATTTGCTTACT GTGAATATAAAAATGATAGCTTTTCCTGAGGCAGGGTCTCACTATGTATCTCTGC CTGATCTGCAACAAGATATGTAGACTAAAGTTCTGCCTGCTTTTGTCTCCTGAAT ACTAAGGTTAAAATGTAGTAATACTTTTGGAACTTGCAGGTCAGATTCTTTTATA GGGGACACACTAAGGGAGCTTGGGTGATAGTTGGTAAAATGTGTTTCAAGTGAT GAAAACTTGAATTATTATCACCGCAACCTACTTTTTAAAAAAAAAAGCCAGGCCT GTTAGAGCATGCTTAAGGGATCCCTAGGACTTGCTGAGCACACAAGAGTAGTTA CTTGGCAGGCTCCTGGTGAGAGCATATTTCAAAAAACAAGGCAGACAACCAAGA AACTACAGTTAAGGTTACCTGTCTTTAAACCATCTGCATATACACAGGGATATTA AAATATTCCAAATAATATTTCATTCAAGTTTTCCCCCATCAAATTGGGACATGGA TTTCTCCGGTGAATAGGCAGAGTTGGAAACTAAACAAATGTTGGTTTTGTGATTT GTGAAATTGTTTTCAAGTGATAGTTAAAGCCCATGAGATACAGAACAAAGCTGCT ATTTCGAGGTCTCTTGGTTTATACTCAGAAGCACTTCTTTGGGTTTCCCTGCACTA TCCTGATCATGTGCTAGGCCTACCTTAGGCTGATTGTTGTTCAAATAAACTTAAGT 78MF-363253604Attorney Docket No.: 15979-20192.40 TTCCTGTCAGGTGATGTCATATGATTTCATATATCAAGGCAAAACATGTTATATA TGTTAAACATTTGTACTTAATGTGAAAGTTAGGTCTTTGTGGGTTTGATTTTTAAT TTTCAAAACCTGAGCTAAATAAGTCATTTTTACATGTCTTACATTTGGTGGAATTG TATAATTGTGGTTTGCAGGCAAGACTCTCTGACCTAGTAACCCTACCTATAGAGC ACTTTGCTGGGTCACAAGTCTAGGAGTCAAGCATTTCACCTTGAAGTTGAGACGT TTTGTTAGTGTATACTAGTTTATATGTTGGAGGACATGTTTATCCAGAAGATATTC AGGACTATTTTTGACTGGGCTAAGGAATTGATTCTGATTAGCACTGTTAGTGAGC ATTGAGTGGCCTTTAGGCTTGAATTGGAGTCACTTGTATATCTCAAATAATGCTG GCCTTTTTTAAAAAGCCCTTGTTCTTTATCACCCTGTTTTCTACATAATTTTTGTTC AAAGAAATACTTGTTTGGATCTCCTTTTGACAACAATAGCATGTTTTCAAGCCAT ATTTTTTTTCCTTTTTTTTTTTTTTTTTGGTTTTTCGAGACAGGGTTTCTCTGTATAG CCCTGGCTGTCCTGGAACTCACTTTGTAGACCAGGCTGGCCTCGAACTCAGAAAT CCGCCTGCCTCTGCCTCCTGAGTGCCGGGATTAAAGGCGTGCACCACCACGCCTG GCTAAGTTGGATATTTTGTTATATAACTATAACCAATACTAACTCCACTGGGTGG ATTTTTAATTCAGTCAGTAGTCTTAAGTGGTCTTTATTGGCCCTTCATTAAAATCT ACTGTTCACTCTAACAGAGGCTGTTGGTACTAGTGGCACTTAAGCAACTTCCTAC GGATATACTAGCAGATTAAGGGTCAGGGATAGAAACTAGTCTAGCGTTTTGTATA CCTACCAGCTTTATACTACCTTGTTCTGATAGAAATATTTCAGGACATCTAGAGT GTACTATAAGGTTGATGGTAAGCTTATAAGGAACTTGAAAGTGGAGTAACTACTC CATTTCTCTGAGGGGAGAATTAAAATTTTTGACCAAGTGTTGTTGAGCCACTGAG AATGGTCTCAGAACATAACTTCTTAAGGAACCTTCCCAGATTGCCCTCAACACTG CACCACATTTGGTCCTGCTTGAACATTGCCATGGCTCTTAAAGTCTTAATTAAGA ATATTAATTGTGTAATTATTGTTTTTCCTCCTTTAGATCATTCCTTGAGGACAGGA CAGTGCTTGTTTAAGGCTATATTTCTGCTGTCTGAGCAGCAACAGGTCTTCGAGA TCAACATGATGTTCATAATCCCAAGATGTTGCCATTTATGTTCTCAGAAGCAAGC AGAGGCATGATGGTCAGTGACAGTAATGTCACTGTGTTAAATGTTGCTATGCAGT TTGGATTTTTCTAATGTAGTGTAGGTAGAACATATGTGTTCTGTATGAATTAAACT CTTAAGTTACACCTTGTATAATCCATGCAATGTGTTATGCAATTACCATTTTAAGT ATTGTAGCTTTCTTTGTATGTGAGGATAAAGGTGTTTGTCATAAAATGTTTTGAAC ATTTCCCCAAAGTTCCAAATTATAAAACCACAACGTTAGAACTTATTTATGAACA ATGGTTGTAGTTTCATGCTTTTAAAATGCTTAATTATTCAATTAACACCGTTTGTG TTATAATATATATAAAACTGACATGTAGAAGTGTTTGTCCAGAACATTTCTTAAA TGTATACTGTCTTTAGAGAGTTTAATATAGCATGTCTTTTGCAACATACTAACTTT TGTGTTGGTGCGAGCAATATTGTGTAGTCATTTTGAAAGGAGTCATTTCAATGAG 79MF-363253604Attorney Docket No.: 15979-20192.40 TGTCAGATTGTTTTGAATGTTATTGAACATTTTAAATGCAGACTTGTTCGTGTTTT AGAAAGCAAAACTGTCAGAAGCTTTGAACTAGAAATTAAAAAGCTGAAGTATTT CAGAAGGGAAATAAGCTACTTGCTGTATTAGTTGAAGGAAAGTGTAATAGCTTA GAAAATTTAAAACCATATAGTTGTCATTGCTGAATATCTGGCAGATGAAAAGAA ATACTCAGTGGTTCTTTTGAGCAATATAACAGCTTGTTATATTAAAAATTTTCCCC ACAGATATAAACTCTAATCTATAACTCATAAATGTTACAAATGGATGAAGCTTAC AAATGTGGCTTGACTTGTCACTGTGCTTGTTTTAGTTATGTGAAAGTTTGGCAATA AACCTATGTCCTAAATAGTCAAACTGTGGAATGACTTTTTAATCTATTGGTTTGTC TAGAACAGTTATGTTGCCATTTGCCCTAATGGTGAAAGAAAAAGTGGGGAGTGC CTTGGCACTGTTCATTTGTGGTGTGAACCAAAGAGGGGGGCATGCACTTACACTT CAAACATCCTTTTGAAAGACTGACAAGTTTGGGTCTTCACAGTTGGAATTGGGCA TCCCTTTTGTCAGGGAGGGAGGGAGGGAGGGAGGCTGGCTTGTTATGCTGACAA GTGTGATTAAATTCAAACTTTGAGGTAAGTTGGAGGAACTTGTACATTGTTAGGA GTGTGACAATTTGGACTCTTAATGATTTGGTCATACAAAATGAACCTAGACCAAC TTCTGGAAGATGTATATAATAACTCCATGTTACATTGATTTCACCTGACTAATACT TATCCCTTATCAATTAAATACAGAAGATGCCAGCCATCTGGGCCTTTTAACCCAG AAATTTAGTTTCAAACTCCTAGGTTAGTGTTCTCACTGAGCTACATCCTGATCTAG TCCTGAAAATAGGACCACCATCACCCCCAAAAAAATCTCAAATAAGATTTATGCT AGTGTTTCAAAATTTTAGGAATAGGTAAGATTAGAAAGTTTTAAATTTTGAGAAA TGGCTTCTCTAGAAAGATGTACATAGTGAACACTGAATGGCTCCTAAAGAGCCTA GAAAACTGGTACTGAGCACACAGGACTGAGAGGTCTTTCTTGAAAAGCATGTAT TGCTTTACGTGGGTCACAGAAGGCAGGCAGGAAGAACTTGGGCTGAAACTGGTG TCTTAAGTGGCTAACATCTTCACAACTGATGAGCAAGAACTTTATCCTGATGCAA AAACCATCCAAACAAACTAAGTGAAAGGTGGCAATGGATCCCAGGCTGCTCTAG AGGAGGACTTGACTTCTCATCCCATCACCCACACCAGATAGCTCATAGACTGCCA ATTAACACCAGCTTCTAGCCTCCACAGGCACCTGCACTGGTACACATAATTTCAC ACAAACACAGTAAGAAGCCTTCCACCTGGCATGGTATTGCTTATCTTTAGTTCCC AACACTTGGGAGGCAGAGGCCAGCCAGGGCTATGTGACAAAAACCTTGTCTAGA GGAGAAACTTCATAGCTTATTTCCTATTCACGTAACCAGGTTAGCAAAATTTACC AGCCAGAGATGAAGCTAACAGTGTCCACTATATTTGTAGTGTTTTAAGTCAATTT TTTAAATATACTTAATAGAATTAAAGCTATGGTGAACCAAGTACAAACCTGGTGT ATTAACTTGAGAACTTAGCATAAAAAGTAGTTCATTTGTTCAGTAAATATTAAAT GCTTACTGGCAAAGATTATGTCAGGAACTTGGTAAATGGTGATGAAACAATCAT AGTTGTACATCTTGGTTCTGTGATCACCTTGGTTTGAGGTAAAAGTGGTTCCTTTG 80MF-363253604Attorney Docket No.: 15979-20192.40 ATCAAGGATGGAATTTTAAGTTTATATTCAATCAATAATGTATTATTTTGTGATTG CAAAATTGCCTATCTAGGGTATAAAACCTTTAAAAATTTCATAATACCAGTTCAT TCTCCAGTTACTAATTCCAAAAAGCCACTGACTATGGTGCCAATGTGGATTCTGT TCTCAAAGGAAGGATTGTCTGTGCCCTTTATTCTAATAGAAACATCACACTGAAA ATCTAAGCTGAAAGAAGCCAGACTTTCCTAAATAAATAACTTTCCATAAAGCTCA AACAAGGATTACTTTTAGGAGGCACTGTTAAGGAACTGATAAGTAATGAGGTTA CTTATATAATGATAGTCCCACAAGACTATCTGAGGAAAAATCAGTACAACTCGA AAACAGAACAACCAGCTAGGCAGGAATAACAGGGCTCCCAAGTCAGGAGGTCT ATCCAACACCCTTTTCTGTTGAGGGCCCCAGACCTACATATTGTATACAAACAGG GAGGTGGGTGATTTTAACTCTCCTGAGGTACCTTGGTAAATCTTTGTCCTGAGTA AGCAGTACAGTGTACAGTTTACATTTTCATTTAAAGATACATTAGCTCCCTCTAC CCCCTAAGACTGACAGGCACTTTGGGGGTGGGGAGGGCTTTGGAAAATAACGCT TCCATACACTAAAAGAGAAATTTCTTTAATTAGGCTTGTTGGTTCCATACATCTAC TGGTGTTTCTACTACTTAGTAATATTATAATAGTCACACAAGCATCTTTGCTCTGT TTAGGTTGTATATTTATTTTAAGGCAGATGATAAAACTGTAGATCTTAAGGGATG CTTCTGCTTCTGAGATGATACAAAGAATTTAGACCATAAAACAGTAGGTTGCACA AGCAATAGAATATGGCCTAAAGTGTTCTGACACTTAGAAGCCAAGCAGTGTAGG CTTCTTAAGAAATACCATTACAATCACCTTGCTAGAAATCAAGCATTCTGGAGTG GTCAAGCAGTGTAACCTGTACTGTAAGTTACTTTTCTGCTATTTTTCTCCCAAAGC AAGTTCTTTATGCTGATATTTCCAGTGTTAGGAACTACAAATATTAATAAGTTGTC TTCACTCTTTTCTTTACCAAGGAGGGTCTCTTCCTTCATCTTGATCTGAAGGATGA ACAAAGGCTTGAGCAGTGCGCTTTAGAAGATAAACTGCAGCATGAAGGCCCCCG ATGTTCACCCAGACTACATGGACCTTTCGCCACACATGTCCCATTCCAGATAAGG CCTGGCACACACAAAAAACATAAGTCATTAGGCTACCAGTCTGATTCTAAAACA ACCTAAAATCTTCCCACTTAAATGCTATGGGTGGTGGGTTGGAAAGTTGACTCAG AAAATCACTTGCTGTTTTTAGAGAGGATCTGGGTTCAGTTTCTGATACATTGTGG CTTACAACTATAACTCCAGTTCTAGGGGGTCCATCCAACATCCTCTTCTGTTGAG GGCACCAAATAAATGTATTGTGTACAAACAGGGAGGTGAGTGATTTAACTCTCGT GTATAGTACCTTGGTAAAACATTTCTTGTCCTGAGTAAGCAGTACAGCTCTGCCT GTCCCTGGTCTACAGACACGGCTCATTTCCCGAAGGCAAGCTGGATAGAGATTCC AATTTCTCTTCTTGGATCCCATCCTATAAAAGAAGGTCAAGTTTAATCTATTGCAA AAGGTAAATAGGTAGTTTCTTACATGAGACAAGAACAAATCTTAGGTGTGAAGC AGTCATCTTTTACAGGCCAGAGCCTCTATTCTATGCCAATGAAGGAAACTGTTAG TCCAGTGTTATAGAGTTAGTCCAGTGTATAGTTTTCTATCAGAACACTTTTTTTTT 81MF-363253604Attorney Docket No.: 15979-20192.40 AAACAACTGCAACTTAGCTTATTGAAGACAAACCACGAGTAGAAATCTGTCCAA GAAGCAAGTGCTTCTCAGCCTACAATGTGGAATAGGACCATGTAATGGTACAGT GAGTGAAATGAATTATGGCATGTTTTTCTGACTGAGAAGACAGTACAATAAAAG GTAAACTCATGGTATTTATTTAAAAAGAATCCAATTTCTACCTTTTTCCAAATGGC ATATCTGTTACAATAATATCCACAGAAGCAGTTCTCAGTGGGAGGTTGCAGATAT CCCACTGAACAGCATCAATGGGCAAACCCCAGGTTGTTTTTCTGTGGAGACAAA GGTAAGATATTTCAATATATTTTCCCAAGCTAATGAGATGGCTCAGCAAATAATG GTACTGGCCATTAAGTCTCATGACCTGAGCTTGATCCTCAGGGACCATGTGGTAC AAGGAGAGACCTAAATCCTTCAGTTGGACTTCAATCTTCTACCCTCATGTCCACA CACAAATAAATACAATAAAAAACATTCTGCAGTCTGAATTTCTAAAGGTTGTTTT TCTAAAAAGAAATGTTAAAGTAACATAGGAAGAAATATGTCCATAACTGAAATA CAAGTTTTTTAAATGGTTAAGACTGGTTTTCAAAGGATGTATGGTTAAGAAAATA CCAGGGAAAATGAGCTTACATGTAAAAAAGTGTCTAAAAGGCCAGAGAAATGAC CCAGCTGGCAAAGGTGTCTGCCCTAAGCCAGACAAAAGGAATTTGATTCACAGG AAGAAGAGACCCAACTCTCACTAGTTATCCTCTGACTTCCACACCATGACACAGC TCCATGGCACTCTCAGGCCCCCACACATATACAGATATAAACAGAAACCTAATCC ACCAGCCTTCAGAAGCAAAGCAATTGGAGGATTTAAACAGGCCATGGCTACTAA TAGAGATAACTGGTAGTTTAAAAGTTATGGTAATGACTTTCATGCTTCTTTCAACT CATATTGTTCTAAATAATTAATTTGGTTTTTCAAGGCAGGGTTTCTCTGTGTAGTT CTGGCTGTCCTGGAACTCACTCTGTAGACCAGGCTGGCCTTGAACTCAGATCCAT CTGCCTCTGGAATAAGGGCACGTGCGTGCCTTTTCTACATAACAAAACCTATACT ATAACAAAACCTATACCATACTGTACCGTTTTGGGAAAAGACAAAAAATAATGA ACAAAAAAGGAGAAATAACATTCCAATAAAGTATGGAAATGGTAGTTAAATTAA TTACAAATGTTTTTCAGTAAATTAGATGTGACTTCTCATACTGTTCATTTGGCTAT AATGATACCACAAAGCACTGGGGGTGAATAATAATTCCAAGTCAGTAGGGAGAG AGACTTGAAAAGATGCAATGCAATCATTGAAGTTAAACTTACCCATCTTTAATCT GGCTCTTAGTCAATAGAGATGAGATGTTATTTGCTGCTCTGTTCACTGCCAGTGG GTTATTGTCCCCAGCAATATGGTAACAGTGAGACCACTCAGTAGCCCCCTATGAG ACAGGAGTGTTGGTTAAACATGCCACAAGAGAAAAGGGAAAAGTCACTATGGCC AACTCTCAGTAACATGGCAATCCGTGCCATTCATTTCCTTGCCAGAAATGTCTTC CCTGTTCTTCTGCCTACTGAACTTTCACCCACTAGAAATGTGGCTCCAATGTCATC CACTATGACATCAATGTCAGCGCTAGAAGCACTTTGCACACCTCTGTTGCTGACT TAGCCCATTTGAAACTATGTCTATCACCTCTGCCTAAGTAATCCAGCAATTCCTTC CAGATAGGTCTAGTATTTTCTTTCTACCCGGCAATGGCTGGCACATATAAGGGAC 82MF-363253604Attorney Docket No.: 15979-20192.40 TGCATTCTCTTAATTAACATGATTTTTAAAAATTTACCTAACTAACCAGACCTATG CTGTCTTGGATTGTGAGTTTAGCTTTTAAAAGATAACCACATTTCTGAAAAGATTT TGTAGTTAAGTAAAAAATGTCAGCAGCATATAAATGCCAAGCAGTGACATATTT GTGAAACAAAGTGACATACTATGGTACTGTTTCTGCCACAAAGACATGCATGCAT GAATACAGCACTTCATAACTATTTTGCCCAGACCCTTTAGGATGATGACATTCTG GTCTATTATTCTATAATGACAGCAAACAAGAGGAATGTTCAAGTATGCCATAAAC TGGGTGTGCAGGGATACAGGAAGAACTCACAGGTGTGATCTGTGCTTGCCAACC TTTTTATTTTTTTTAATTATTATTTTAATGTTTAATCCAGGATGGATTTCCTACCTT GGGCTACATTTACAGTACTTCTAAATCTCAGTGTCTTCTAGGACAGGTATTAGAT AATTTAATGGGCACATCTGTACACAGACCCTTCAGTTTCCATCATGACTCAGCTG AAGTTTCCACGTAGGTACTCTCTCTCATGCCTACTTTTACGTGGAAATGGCTTAAT CTGGTTTTCCCACCCCACCCCTTTTATTCTGATGTCTACTTTGATTGTGTGTTTCTT CATCATGGTCAGTTTACCTGCCATTTCGCAGATAAGTCATGGTTTAATGATGGAG AACTACAGTTTGGTTTCCAGAATTCTTGACTATAATAATTCAGCTCCTGTTCAGAT CTCAAGAAGTAGTCACTCACTAGCCACCACCAGTGGAACATTCAAACTAGGTGC ATTTTCCTCTTGGATTTTAACTCCCAATCAAAGTCAGACCAGAGATTTCCTAATTA TACTAGATTATTTTTCCCTTTGTGGGTTGCTTTGGGCTTGCTCATCTGTCCAATTTC TGCCCGCTCAACACAACCTGTGGTACCATGAATTCAAGGTGAGCCTGTGCTACAT ACCAAGACCTTGCCTCAAAAGGATTAAAAAAAAGAAAGAAAGAAAACATCTTCC CATTTCTTACTTTGCCTTCTGTAATGTTTTGTTTTGTTTTTGTTTTTGTGACTGGCTT TCTCTGTGCAGCTCTGACTGTCCTGGAACTCACAAGAGATCTGCCTGCCTCTGCC TCTTGAGTACTGGGATAAATGTATATGCCACCACCACCACCTAGTACCTTCTGTA GTTTTTTGAGTGTTGTAGCAATTCTGAAAATTATTGATGGTCACTGGGTATGTAGC CTTGTCAGATTTCCTAAAATACGTTTTTTTTTTAAAAAAAAGGTCAAACGGCCAG GTAGTTTGTGCCCTAGAGGAGATGGGTGAATCCCTGTGAGTTTGAGGACAGCCA GGGCTACATAATAAGACCCCCATCTCAAAACAAACATAAAGAATACTTATAGGT ATTCTTTTTTTTTTTCCGAGACAGGGTTTCCTCTGTATAGCCCTGGCTGTCCTGGA ACTCACTTTGTAGACCAGGCTGGCCTCGAACTCAGAAATCCGCCTGCCTCTGCCT CCTGAGTGCTGAGATTAAGGGTGTGCGCCACCACGCCCGGCAATTTAGGTATTCT TATGGGTTTGTTTTGCAGTGCTGGAGATCAAGCCCAGAACACCTGTTTTGCATGC AGATGCCCTGGCACTGAGCTGCAATGCTGTGGTTTCTCCTTCCCACTTATTCACTC CAGGAAGCTCTAATTATGTGGACGTTTATGACCCCCTCAGTTATCCTCTGCTGTTC AACCTAGTGCCTCGTCCATTCATTACAGGGAAAAAGGCTTATCAGTTTGCCGTTC TCAGCTCGCTTCTCTACCACTTCAGCTTTCACCATCTAACCACACGGTACTTGGCT 83MF-363253604Attorney Docket No.: 15979-20192.40 GTGTGAAATCAATGCTTACAATGCTTTAACAGAACTTTTACCCTGACTATGAGAA GTTTTTTCAAACTTTTGGGGTTTTTCTCATTGGATCCAATTTGCCCACCATTTTGA ATAGATCACTTGCTTATGTAAAAATAAAAAGCTGTTATTACCTCTATTGGTATTG CCCCTGTTCCACACATTGGGTCCACTATTACATCAGTAGGCTTAGGTTCACAGAG CCTGGAGGGAGAAAACAATCCAGCACATGTGAAAACCAACCAAAAACTAAGAC TGGGATCTACTACTGGCATAGGATCTGCACACCAGCGTGAAGGATCAGCAATTT ATGGTTTGAAAGTCAGCCTGGGGTTGACACTCAGTAGCAGCCCTCGCCTATGCGT ACAATGCTTCTGGTGGTAGGGGAGAGAGCGAGAGATACTGATTTGTTATCCTAGC ACTCAGGAAGCTGAGGCAGGGAGATTTTTAGTGGGCATTTGCTGACAACCAGAC ATTCAGTCTCCTTTCATTTTGGATTTAACTATGGAGATACAGTCCTTAACATAAAA TAACTGCTTTAACTTTATACACTTGAAATTCTTTAAACAACCCTATTACCATTTAA CAGACAAAATGATCCAAAGAAACATTTTTCCTAGGACACAAAATAAGGAGTCAA GACTACATGTGACTAGCTTTAAATGTTACTTACCAGTCCTCAGGTTACTAAGTTTT ATCTGATTTTTCTATTCTGTTTGAGACCTTGCATCATGCATGTTAATGATCTCCCT CATAAGACGGATTCTTGGGCAAGCCTGTAATGCCAGTCATTGTTAATGGGCCAGA ATTGGGCACTTGATCAAATTATGTCACTCAAATCCTCTTAGGAATGTGGAATAAA GAGCAAGTAACCCTGGGTCGTTTGAGCCAGTCATGTGCAACTGGAGGACAGGCA GTCAAGTGCACAGGCGAGCTAAGCCAGAACACACAAGCTTTTAGAAGACAGGAA AGCAGTCCTTTGCATTTTCTACTATCTAGTTTCTGCACCTCTTAATTTTTAGCCTTT ATGTCTATGGATATATTGCTGTCATGTATATCTGTATCACATGTGAGCACTGCCTG TCAAATCAAAAAGAGGGCATCTGACCCCTTGAGGCAAGTTATTAACCATTATGA GCCACCATGTCAGTGCTAGGAATTGAACCCAGGTTCTCTGGAACAGCCATCTGTC TAGCCCTGTAGTTTCTGCCTTTCTTGAGAATCGCCCAAGGGTTTTTTGTGGATCTG GTATAATCTTTGCTCATCTCTCCAACCACCGCAATCCTCAGCATAATTATCACTTC ATGTGTCTGTACACTTGTGTTTGCCACATGCACATGAAAGCCAAAAATAGAAATC AAGATCTGGCATCCCAATCCACCACCCTGCTTGCCTCTTGTTTTGGTTTTTTTGAG AGAGGGTCTCTACAGAGCCCTGGCTGTCCTGGAACTATGTAGGCCAAGCCCAAG CTGGCCTTGAGTTCACAGAAATCTATCTGCCTCAGCCTCCTAAGTGCTGAGATTA AAGGTATGTGCCACTGCACTCAGCTGGGCACCTTTCTCAATTGCTCTTTACCTCAC AACCTAGAGCTCACAAATTCAGTTAGAGTGGCTGGCCAGAAAGCCTGGGGTATC CTCCTGTCTCAGCCTCCTCAATGCTAGGATTATTGACAATAGCGATGCTGTGAGG CTGGGGTTAGGCTTGTGCGGAGAGTGCACCAGGCTGTCTCCTCAGCCCAATCATT ACTTTTTTATTCTATTTAGTTTTTAATACCAGCACTCAACTCTGTATGCTGGTTTCT ATAATCATGGTTGGAGGCAGATAGTAAATATCTGTTTAGTGAAAGAAGCTTAGG 84MF-363253604Attorney Docket No.: 15979-20192.40 AGTGTTTCTCTTAAGTTTTCTGTTACTAACTTAATGTGTTCCAGTTGTGAGGAACT GTGACCATGACAAAAGAGGAAGCAAAAATTGAAAAGGAAGAAAATGTAATTAT GTAACTCACTAGATCATGCCAGGAACTGTACAGAATAAGATAATCTGACTATGTT TCTGCATTTAATCCTTATGAACAAAATTTTTTAATAAATATTTTCACATTTTATTT ATACATGTGTGTTAGTACCTCTGTGTGTGTACCCAAAGACCAGAAGAGGATATTG GAAGAGAGTATGGAGCTGGAATTAAAGACTGTTGTAAGCTGCCAGGCATGGAAG TCTAGAACTGAGCTCTGGTCATATGGAAAACCAGCATCAACATTAACTGTTGAGC CATCTCTCTAGCCCTAAAGTCAGTCACCACGTTTTTTTTTTTAAGTATGCATATGT GTGGGTGGGATTTTTAAAGTATGTATGTGCTGGTGCCTACAGAAGACAGGTGTTG AATCCCCTGGAGCTGAAGTTGCAGGTTGTTGTTATCTACCAACCTGAATGTTAGG AACCAAACTTAGGTCCTCTGCAAGAGCAGCAGACATTCTTAAAGCTCTGAGCCAT CTCTCCAGCATGAGTAAACCTTTTCTTCTTTTTCTTTTTCTTTTCATATAGAACACT TCACAAATCTGTCTGTCATCTTTATGCAGGGGCCATACTAATCTTCTCTATATTGC TTTAGTTGAGTGTATGTGCTGCCAAGTTGAGCACATGAATAATCTTTGGCATCCC ATGTCAAGCCCATTTTGCAGTACTGAAATCTCAAGTGTAGGGGGGAAAAAGACT TATTTGAGAAAGAAAACACCAAGAACGTAAGACTGACAACAGAGGCAGGCTGCT TGTCTTGCACTTGTCAAAGTCCCAACACGATCCCTAGGTTACAGCCAGTGTAACA TTTAAAACTATGAGTAAATGGGGTGTGGTGATATGTACCATGATCCCAGCACTCA GGCTACCAAGCTGCATGCCAGCACTGTCACTCAACAGACAAGGTCTGTACTCACT CACACATCACAAGGATCTCCTCTGCTTCACTCTATTGCCTAAAGCAGCACAGCCT CTCTCGACAGAAGCAGCTCCTCGCTGAAGACACACAACACCACTCTCACATGTAT AACCAAGAATACTAATAAACCATCCACGTGGTGTTTTCTGCATCAAAAACTGACA ACAGTAAATACTGAAGAGAAAATAGGTACTTTGTAATTCTAACTAAGAAAATGG TTTTGGGAGTTTTTGTTTTGTTTTTTTTTAGAAAATGAGTGATTTAATTCAGAGCA AAGTGTTCATTACAATATGGACAGCAAAATCCCCTTCTGTTACCTGAGCATCCCA TAGGCAAGAGTTGACCTAAGAGTTGTAGGTCCAAAATGTGTAATATTTCTGCGAT GGAGACTCTCTTCTGTCAGTGCAATAGCAACAATGACTTCATTATCATGGATGTT CAGGAGAACCTACATCAAATTAGAGACAAACGAGAAAGTCAACAGTCTTCGAAC TGTACCTACTAACAAGACCCTTAAAAACAATCCAGGGCCTTATCTGGCTGTGGTA CTACCTCCCAAGTGCTCTAACTAATCCCAGCACTTAGAAGGCAGAGGCAGGCGG ATCTCTGTAAGTTCAAGGCCAACCAGGTCTACACAGTGAGTTCCAGGGCAGCCA GGACTAGATAGAAAGACTGTCTCAAACAAACAACAACAAAATAAATAAATAAAT AAATTTAAAAGAGTAAAATAAACAGAGCCTTGAAGCCAAAATTGGCTTGAATTC TTAGATAGGCTAGCTGGACTGAAACTCAAAATCCTCTTGCCTCTGCCTCATAAAT 85MF-363253604Attorney Docket No.: 15979-20192.40 GCTGTGATCACAAGAAAGAGATACATGTCTTCCTTATTAAGACTTTTTGAATTAA GATAAAAACAACAAAACCAGGGCTAGGTCTGAGGTGAGCCAATGGGAAGAGTA CTTGCTTGGCAAGTATGAAGATCTGAGTTTATCCCTGGAACCCAAGTAAAAGCCA AGCATGGCTTATACATACATAACAGCCACAACACAGAGAACTTTCTTTTCAGAAC ATTTTAAATTTTTATTCTATGTGCACAAATGTTTTGCCTGAATGTATATCTGTGCA CCACATGCACACTTGGTGCCCATGGAAGCTAGAAAGAGGTGTGTGATCCCTTGG AACTAGAGTTACAGCTACCTACCGTATGGGTGCTGGGAATTAAACTTGTATCCTC TGAAAGAGCAGACAATTCTTTTAACTGCTAAGCTATCTTGCCAGCCTATACAAAC TTTCTGATTGAATTATACTTTACAGGTTTACTATACAGTACATAAAATTCAGTTAT TTGCGTATTTATTTGTGTTTGTGTATGGATTGGGTTTGGGGATCAGAGGACAACTT CTACCATGCATCCTAGGAACTGAACTCAGGTCAGCAACCTTAGTGGTAAATCTGC CTACCTAGTGAGCCCAGAGGTGTAAGCCTTCTGCATATACATTTCAGTGAGCTCT GACCTATACTCAGTACCCTTTACAAAGTTCTCTTTTGTCTCTTTCCTGGGTGATCA TTAATCTAACCACTATTATTATAAGTTAGTTGTATCAGTTTTTGGAGTTAACAAAA ATGAAATAGTATATGTACTATTTTCATTTAATTTTAAAACATTTTATTCTTTTTACT CCCCCCACACACAGGCTATTAATAAGTTATCTCCCAGTTTTTATTATATGAACAT ATTTTGATGGTATAGATTTAAAATATGTATGTATGTTTTGGGTTTTTTTTTTTTCTA CCACCTTTTATTTTCTCAATACAGGCTTCTCTGTGTAACTTTGGCTGTCTTGGAAC TCACTCTATAGACCAGGCTGGCCTCAACTCAGAGATTCATCTGCCTCTGTCTCCC AAATGCTGGGATTAAAGGTGTGTACAACCACTGCCTGGGTGTGTGTGTGTGTTTC ACTGTGCCCTTTGGCTGGCATGGAAGTCACTATGGAGACCAGGCTGGCCTTAAAA TTAGAGATCTGACAGTCTCTGTCTCCTGAGTCTGGGATCCAAGGCATGTGCCACC ACATTTGGTCTACATATATTTTTTAAATTACTACGTGTTTTTGAAGAACACTTCAA ACACTTTAACGGTGGCCTCTCAAAACATACCCTTTATCCAAAGCTGACACCACGT CATGTTTGCTTTTATTTTGTTTTCCTAGTAGTTTGTCTTTCTTTCTTTCTTTTTTTTTT TTTTTTTTTTTTTTTTTTTTTTTTTGAGACAGGGTTTTTCTGTGTAGCCTTGGCTGTC CTGGAACTCACTCTGTAGACCAGGTTGACCTCAAACTCAGAAATCTGCCTGCCTC TGCCTCCCAAGTGCTGGGATCACAGGCGTGCACCACCACGCCCAGCTCCTGGTAG TTTTATAACAATGTCTGATTATGACTACCTTTGTCCTAGTTTTCCTAACTCACAAA CATTCTAAGAAGATAAAATGTTCCCCAGTATTCCCCCTAAAATGTCCTCATCATG GCCTTACCAAAGGCAGAGGTCTAGAGCTAACACTCTAACATGCAAGGCCCTGTC CTACATATCTTATTCACATGGCCTCATTTCCTAGGAAGCCCTCTGAGCCTGGGAC ACAGAGACACCAGTTCATACAGGATTTGTCTTCTGTGCTACCTTGGAGACTTCTG GACATGGCCTTTGTTAGCCTCTTTGTTCTTACAGCTGTGTAAGAAAATATAGAAT 86MF-363253604Attorney Docket No.: 15979-20192.40 GGAGAATTGTTCTTGTCTGACATTAAAAAAAAAAAAAAAGTTACAAAGAGAGTG ATATGCCCCAGGCTTGAGTATCCCAAATGAAACAAAAATTGACTTCTTGGTAAAA ATGTCAACTGCTAAGGACCTACATAAACCATCAGAAATTTAAAGAACTCCAATT ACCATTATCAACAAAAGTCACCCAGTAGTCACAAGGATACTCAAGCTAACAGGA GGCATTTGGTTTTAAGAACCTAGCTGACTTTAAAAAGAACAAAGCTGGCTCTAGA TGAAGATTAGCTCTAAAACCCTGATAGAAGGTTCTGAAAACTATATTCTATTATT GTTTAGTAGCAGAATTTCCAACTAAGGTAGAAGTAAGTTTATTTTAGGTTAAGTT ACAATCTAGAAATCCATATAATGTAGAAAAATACTAGATTAGAAATAAGAAGAC TGGGGCTGGTGA SEQ ID NO:10 (full human SERPINA1 transgene #2 construct, nucleic acid) TCCATCAACTTACTATATCCCCAAAAGGAAAGGAAAATAGAGAACCTATTAAAT TTGGGGAAAGAGAATGAAGAAAGGGAAGAGTAGGTGATCAGAATTTCTTAAATT CATGTTTTTATTTCACAAAGTCAAATATAGTACTGACCAAAATGAGCTCTCAATA TCCAAAATAATAACAGGTCATAAACATGGAAGAAAGCTGTTCACAAGTCACCAT CCATTAGAAGGCATGCCCTTTACATTTATGTGTGTGGGTGTGGGCGTGCGCATGT TTCCAATTTTTAAAAATCTGGAAAACAAAGTAATCTTTAGAAAAATATTTTCAAA AGTATATTCACAATTTTGAAGTGAAAAAAAAAAAGGTTTGAAGGTGACAGTAAA AAGAAGAAATAAAATAGTCAAGTATTCAGCAGCAGCAAGTAAGAGGAAGGACA GAGGCAAAGTAAAAATATAGTTTCACTCTGCCATCAATTATCAACCCACCAGATC TACAAAATACCGGATCCACTAACAAACCCAGCCTGTCTTCCAATACTGAGCACTC TTTTGAGAGTTACCATTTATATGTAGTTTCTAGACTTTTAAGATTTCAGAAGAAAT GTATCAGACAGGTGAGGCGGAAGCAGCTGGGAGACAAGAGACCAGTAAACAGT CAACCCAATGAAAGAAACGCACAAGTCAGCTTTAGCAATCCTGTGAAGAGGACT GGCAGGAAGAAGAGTGCAGCTTTAGAAAGAGAACAGGCCTCGTATGCTTCAGAC AGTCTTTGTACTGAGGCTGTGGACCTTGGCCACTCTCCCAGAGATGATGCAATCC TGATGAACAAGATCTGCTGCCAGACAAGCGATTGTTAGCAGCCTTTGCAGACAG CAACTCAGCCAAGAAGCAATCTCTGAGCAGCTCCCCATAAGCCACCAGAATGTC AAATTTCTTCCATTTCAGTCTCTGATAAAATAAAGGGAATATCCCTACCCCACGC ATCCCAAGCCCTTTTCTTAGAGAGCCCTTTGTCTTCCCTGCTTTCCTTTAACTGTG TTTAAAGTCTCCACCACTCATAATTATATTTCAAATGAAACACCAAAAATATTTTT ACTCTGATGAGCAGAATTCTCTAAACATATTAACGATAAGGCCTTTACAGTAAAA ATTTATACTAATTTTCCTCAGTTTCCCAAGAAAAACCTGGGACACAATAGTTTCTT GTATAAAAACTGTTATGAAATCTGATACTCAATTATGACTCACAAAAATAAAGAT 87MF-363253604Attorney Docket No.: 15979-20192.40 AAATATTTAGACTAATCTAGGGTCAGAGAGGTATATTTTGAATTCTGAAATTACA TGGAACTCAGTACATAAAACAATGTCATCTAGGAGAGAAAAAAGAAAATCTACT CTAGCTTAGGTCAAGATAAACATTAACAAAGTGTCTTTACAATGTTAGGTACAAC GCCTCCTTTTCTAGGGGCAGCATGACTTCAGATCTTACTAGAGTTAATGATTATA ATCCATTTACTTAGACTCCAGCTTAAATATACATTCAATTTAAAAATCTTCCCTAG AATTGTCATCATAGGCCCAATTTCTTTTCAGTTTAGGTACTGGGTTTTTCATATAC AATATTGTTTCTCACCTTGTTAAAGACTTAGGTTAGGGAACTTCAACTACAGGAA GCCTCAAACCAAATTTCTTTTTAAAACCACCATCCTTAAACTGGGACACAATTCA AGATTCAGGTTTCTTACACATATATATTACTGAAAGCATTATGTTCAACCCTGTAT TTAGATAATGGAAATTAACACATATAGCACAGCTCTGAAAATTCTTTAGTAGGCT AATGAGTAACTGAATTAAGAGAGAAAATTTGTACAAAGAGATAATTTGGTAGGG TACTTGCCTGGCACCACAAAGCCCTGAGTTTTCTTAGCCTTGCACAAATTTGGCA TGGTGTTATGAGGCTATCTATAATCCTAGGACTTTGGAGGTACAGGTAGAATTAT CAGAATTCCAGGTTATTCTGGGTTACATATAGCAAATTTTGGGCAAATTTGGGAT ATGTGAGCCCTGTCTTAAAAAACAAAACAAAACAAAAACCCTTCAAAAAAATTG CAAAGGGGTTGGGGGAAAAATTGCAATTTTATGATTGGATCTTTCCGTCTGCATG TGAGTTGAATTTTCTCTTAAATCAGTTTTTCTTATGACTATAAAATTTAAAAGGGG GGATTGAGAGAGTAGGGCTGGGAGGAGAAGAGGGGAGGAAAAATAAATTAATG AAAAACTTTTTTTTTTTTTTTTAACAAAGTGGGAACTCTTATGAGGACTTTAAAAT GATAAAGTCTTGCAGGGCGTGGTGGCACAGGCCTTTAATCCCAGCACTCCAGAG GCAGAGGCAGGCAGATCTCTGAGTTCGAGGCCACCCTGGTCTACAAAGTGAGTT CCAGGACAGTCAGGGCTACACAGGGAAAACGTGTCTTGAAAAAACAACAACAA AAACAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGAAAGA AAGAAAGAAAGAACGAAAAAGAAAAAAATATGTAGTTTCACTTTCCCATCAATG AACAACCTACCAGATCTACAGAATACTGGATCCACTAGCAAACCCAGCTTGTCCT GCTTTACTCCTTTTTATTTTCTTTTGATTTTTCAAGACGGTTTTTCTGTGTAGCCCC GGCTGTCCTGGAACTCACTTTGTAGGCCAGGCTGGCCTTGAATTGAGTAATCTGC CTGTCTCCGCCTCCCAAGTGCTGGAATTAAAGGCGTGCTCCACCACGGCTTTACT CCTCCTTTTACTACACACACACACACACACACACACACACACACACACACACACC AGTTCAAAATGTGGGTTTTTAATGCATACAATCAGCTTTCTGCAGAACTCATGTA CCATCTGAATTATATGCTTATCCATTTCTAGCCAAAACCCAACTATCCCAAGGGA AAAAAAACTAGCAGTACTACTTTTTTTTGCTTTGGGAGAAAAGGATATTAGGAAA AATGATTACATAAGGAGCTAGAAATTTTGTGATATAGCCCACAATTTAGCTCAAT GACTCCAGAAACATTGTATTACACAGATGACTTTTTTTTTTTTTGGTTGTTTTAGA 88MF-363253604Attorney Docket No.: 15979-20192.40 TGACTTCTAAATGTATCAATATAAAATAGTTATTTTCTTTTTTCCTGCTTCATATTT TCTGTGAATCCTCAACTTGCTTGGCAATTTATGTCTCAAGTAGGTACAACAGAAA GAATACTGTCCCGCTCTAAGAAACACATGGAGAAGAATCTGCAGTAGGATATTT ATGAAGCTTGTAGAATTAGAAGAATCTACAAAGAAAGAAGTGCCACACTAATAA CTTGAATGTGGCTAAAAATAGCTTCCGCCTTTCCACACCCAAAAAGTATAGGAAG AGGAAATGGGAAAAATATGACAAAGAAGTAAAAAACCCCACAATAAAACCCAA ACAAAAACCCAAAAGATATAGGCTGGGTGTGGTGGTAAAAGCCTTTAGTCTCAG TCCTAGAAAGGCAATCCCTGTGAGTTCCAGGTCAAGGTGGGCACACAGTGAGAC CGTCTCAAAATAAAAACCAACAAACCAAACAGTAAAAGGGAGAGAAAGGATAA ATACTACAGGAGTATTTATAAATATTCAGAGATCTGGTGAGAAGCTCACCTAATT TACACAATAGTAAATTGGGCTTAACTGTGAAGATAGTGAATACAGGAAATAGAT CCAGGAGTTGTAGAAAAAAGAAAGAAAGAGAAACAGATTGGCATAATCTGAAA TATGTGACTTAACAATTCAAGCCAAGATAAAATTTCCTTTTCTTCTAACTCTTGTT TATCCTTTGGTTTCTTAAAATTTACATTCTCTCTAGGGGATTCTGGAACTGGTAAA ATGTCTGTAAAGCTTCGCTTACTATGAAGCAATTTTAAGACCAATTAAAAAGAAA GTCCTACTTATAATGGCTATGATAGAGGTCAAGGCGTACATTTACCTTTCCTAGA TAGTTATTTACATGTACTAGGAGGCATACCTCATAATTGTACTGGCTTAAATAAA TTCAACTTCATAAAAATAGTTTTAGGACTTAGAAGATGGTTTTTAAAAACCTCTG TGTGAACACACAAGTATGCAGGTCAGAGGAAGACTGATACCTGAAGTTATCAGG CGATTCTGGTGACTTTCCTGTCTGGACTCTCTTACAGGCTGGAATAACAGACCTG TACAGTTTTGCATGGGTTTACTCAAACCCAGCTCTCATGCTTGTGAGGCAAGTAC TTTTAATCACTGAGACATCGCCAAACCTTGATTATTTTACAGACAAAAACATAAT TAGAAAAAGATTAACTCAGGGAACTGAAGGTATAGCTGAGTGGTAGAGTGCTTG CCTAGCATTCAATAAGCTCTGGGTTGTATGAGTAACAATGAAAGGGGGAATTTAC TCACAAGAAAGTCACAAATACAGCAGATTTCAAAAGAAAATTAAGATTTTAACA CGTAGCTTTTATTTATTAAACTAATTACGTTGGGTAGCAATATCTAAATTAAAAG TGTGTTTATTAACAAGTCCAGAATCTTCCAGCTCTCTGGGGGAATTTATATTATGT AGCTTTACCTTGAGTTTTATATATGCAGATTTCCCACTTCTCCCTTTATCAATGAC AACAAACAATTACTATGAACATAAAAGCTATCTGAAGGTGTGTCTTCCATCTTAG GTACTCTGTAGGCTGATTTCAAACTCCAATTCACCTGCCTCTACCTCCTGCATGCT AATAATAGGGATGTACCAAAACACCTAGAGTTTTATATGGTGATAGGAATCAAG TCTAGAGCTGTTTGCATGGTAGGCAAGCACTTTTACCAACTAAGCCACATTATCA GCCCTGAAGCCGCCTTCTTCTTCTTTTTTTTTTTTTTGAGACACTTGGTCTCACTAT ATTGTTCTGGCTGGCCTAGAACTCCTCAAACTTAAAAGATCCTGCCTCCTCCACC 89MF-363253604Attorney Docket No.: 15979-20192.40 CAAATGCTGGATTTAGGATGTGGAATCATCACCTCACCCTGTCCTTGAATATGTT TAACTCTTTAGGTTTACTCATGTGACAAGAATTACATGTTGACAACCACTTACAA GAAAAACAAAAATCATACCAAACCAAAAATACCTCTTAACTATGTTTCTTCCTAT AACTGAGTCAAATTCTGAAGGGAAAGTAACCCTCCTGTCTGCTTAAAAGCCAATC CACTGCATTGTTTACCAGGGGAGTTTCTTGTGTAAGTAGCTTGTTGTTTAGAAAA CACAAACTTTTTCTTACCGTAATAAAGGAAAATATGATAGAAGATTTCTCAAATG ACAGCTAAGGACAGTAACACCAAAGAAACCTTAAGCATAATACTCTGATGTGTA CAAGAGGCCTCCTCACTGCAGTGGTCCGGCTCTATTACAAAGATGCTTATAAAGT ATACAATCATAACTGGGTGTGCTGGGCAAATGGCAGGAATTCTACAACATGAAG AGACAAAGACTTTTTCTAAGTTTAAGGTTAGTCTACATACCAAGTTTCAGGCTGA CTAGAGCCACACAGTGATACTATATATTGCAAACAAACAAACAAACAAAAAACC TATCATTAGAAGAACATAAAAAACAGAAGTAAAATTCTCGTGTATCCTCTTAAAA GAGAAAAGGAATAGTCTGACTGGTTTTGTAAACTGGTTTTGATATTTAACGTGAC CATATTTAAATATGTACTTCTTCAATGATACTGTAGCACTGTTCTATTGATTCATT ATAATTTAAATGATTCTTCAGCAGGCAGATACTCATTTTTGGTACTCTGCAGTGTT GCACTGAACATCCATTCATGTACTGAGAACTTTGTTTACACTATATATACAAGTC TTTACTCAGACAAGAACTGCTTCATAGGTGGGCTTCATAATAGTTTGTTACCCTTT TCAGACCAAAAAATTAGCTGAATCTGGTATATGTTGCTTTCTTAAACAAATTCTA GGATATCTGTAGTTCTTATACTTTTCATATAATCAATGGAATAATGAAAAACAGG TGCTGTTAAGGAGTGGTCATTGATATCCATAATAACCTGATAAAGACCATACAAC TTTTCCTCAAAAACAAAAACAAACAAAAAAATCAAAATATGATCTAAAGTATCC AGAAACCCAAGTTTTTGCTCTATATATATATCTTCTGAACTGCAACTAGTCTGGA ATAAAGGAGGCTCAAAAGCAACTTATGGTATACAGATATCTGGAAGCTTTGCCT CCCATTACCAGGAAATAAGAATTTGCAATCACTATAATAAGGGATAACTCTCAAT AACTTCCCATTTATTTCCTCTTCTGACAAAGCAGCCTGAAGGAAAAAAAACTCAA AATATATCTAAACAACAAATGGAAGAAAGTGAAGATTTTAACAGCACAGTCAAA GGTTCCTGAAATCAGAAGAGTGACATGGTATAATGAAAAGATCTTGAAATCGAC AGATTTGATATACCATATTATTTAGCTGTGTGGTCATTCTAATTAAATCTGTTATA ATTCACCTAAGTGCATGGTTCTAAGAACTTAGCACATTACAAATTTTGATATACA GCTTTCCAATACAAAAGGAATAGAATAGGAACTAAGATGAAAACAAACAAGGA ACTCCTTCTTCTAAGGCAACCGTTTCAAGTGAAGTTGAGGAATGGACAGTTTTGT TCCATGTCACTAGTGATGCTAAGGCCTGAGTAGTAAACAGGCTTATTTAAATACC AGGTCAGATTTCTTTGGTAAAGCTTCAGTATTTGGCATAAATCTGGTATTTATGA GATGCTTCACCAAAAATTCAGCCAACTCAAAGATCTACTATATACTGAACATATT 90MF-363253604Attorney Docket No.: 15979-20192.40 AATAATTAACAAATTTACCTCCTCAATCTTCCAGTCAAGAAGGCTTTCCAAACTT TGTAGACTTCTTTAAAATTTTAAAAATTGTGATATATCTCAGTCTGGTCTATAAAG GAAGTTCCAGGGCAACCAAGGCTACACCCTGTCTCAAAACAAAACCAGAAAAAC AAACAAACAAAAAATCCCTACTCTATATAGGCCACTATATTTTTATTGAGCCACT CCATTTCGTTGTTGACTGGAAATATGTGATGGTCAGGAGATGAACTTGGCTCATA GTACATACAGTAAACAACAGGGAGAAACCAAACCATCTGGTTCTGTTTGGAGTT TTGTTTTTATTTTGAGATTGGACCCTATTCTGAAGCCCAGGCTGGCTTCCAACTCT AAACGAGTCTGTCTTACCTACACCAACAAGTATTCAGATTACAGGTATACCCGCT GATTCTGCTATTGTAGTCTGCTTGACCAGGTCCCACTATGGTCAACTTTTACTCTA AATTTAAAATGTTTTATAAGGAAGATTTTTAAATAGGCACAAAACTGAAATAATT CTAGTTCATATAGTCATTAGCCAGTTTTACAAATCCTACAACTGATTTTCATTCCA AAGCAAATCACAGATAGCCTATCATAAGCAATACTTCAGCATGTATATACAAAT AATAGCTGTCTTCAGACAGACCAGAAGAGGGTATCAGATCCTATTACAGATGGT TGTGTGCCACCATGTGGTTGCTGGGAATTGAACTCAGAACCTCTGGAAGACTGAG ACAGTGTTCTTTATTGCTGAGCTATCTCTCTAGGCCCCATGGGACAATCTTTTGGG AGCTGGTGCTCTCCTTCCAACTTTAAGTGAGATCTAGAGACTGATCTCTAGTTGG ACAGCACAGCAAGAATTTTTAACCTGATTACATTTCTGAAGTAAACACTGGCATA TTTATAAAATGAGAGACCTGCCTAGTATGATAATGAAAACATGTAGTGAAACTTA GGTGTTGGAGGCAGTCAGATTCACAAGTTCAATGTCAACCTGGGCTACAAAGAC TTAAAGGAAGAGGGACTGGGAATATAGCTCTGTGGCAAAACACTGCTAAGTACA GGCAAAGCTCTCAGAAGCTTCAAATTTCAGCTAAGTACCAATTACTCCTTTTTAA AAAAAACAATTAGTTATTTTCATATAATCAATGGAATAATAAAAATCAGGTGCTA TTTACAAAATTATGAACATAACCCTAAGTAAGGTTGAAGTTTAAAAACTAATCAG ATACGCACAGCAGAATACCAACTTTCAAATTAAAAGCTACCTTTTACTGATTATT CTGTACCAGAAAGTTTTTCTATATTCCATTTCCATGTAACATTTATAATAACAACT CTATGAGGAAGGCACTATTTCTATTAGGGCAAATTAAATTTGCCAAGACACTTGA ATCAGGCTGGGCAGTGGTGGCGCACGCCTTTAATCTCAGCTCTTGGGAGGCAGA GGCAGGTGGATCTCTGAGTTTCAGGACAGCCAAGGATACACAGAGAAATCCTGT CTTGGAAAAAAACAAACTAGAATCTGGGTCTGAAGAGATGGCTCAGCAGTTAAT AGAGTGCATACTGCTCTTGCAAAAGAAGTAAGTTCAATTCCCAGCACAAATGTTG GACTGCTCACAAATACTTAATTCCATCTCTAGGAGATCCTGCACCACCTTCTTGC CTTCAAGTACCTGATTTTTTATTTTATTAACGTGTGCACACACATTAACAGAAGCA CCAGAACATGAATTAAAGTCTATACAATTTCAGAGCTCCCATATAGTTTTGTGTG GGCTGAAGTGGGGACAACTCAAAGTGTACCTATTTGCTTTCTTTTTAATTTAAATT 91MF-363253604Attorney Docket No.: 15979-20192.40 TATATACAAAAATACACACCATATATTTTTCCCTTTTAGAACCTTCACATCCTTGT AATCACTATTTCTTCACTGACTCACCTGTTGTGAGTTTAATAATGTTAGTCTACTT ATTACAACTTGATAGTGTTAAAATGTGAAACTGTAACTCTTAGGATATCTCAGTT AGCAAGAATAAAACATTTAACTCATTTTTAAAACACCTGAATTCATCTGAAATGG TACTTTTTATAAACATTCATGAAATGTCTGCTAGCCGGGTGTGGTGGTGCAGGCC TTTAATCCCAGCACTTGGGAGGCGGAGGCAGGCAAATTTCTGAGTTAAGATACA CAGAGAAACCCTGTCTCGAAGAAAAAAAAAAAAAAAAAGGAATGTCTGCTGAG GAGCTACTGCAGCAGTGGCGTCCACCAGGAACAAACATGACCTAGCATTTCAAC ACACATTTTTAGAAGAAAAAGGCGTATTTCTACCCCAATAAATTATACTAAGTCA AGAAATCCTGGTTTCTAAGAAACTCTATGCCACTACTTTTATGGTATAAAACTAT CTATTGAAAAATTATTGAAAATCTAAAATGAGATAGTTTGTATTAACTTACTTTTT AGACACTTAAAACAGAAGTATCCTGAGAAAATACCACTGTGAGTTAGCAAGATG GTTCACATTTGATCCCCAGAATACATATGCCAAGAAAACTAACTCACGAGTTAAC TTCTGACTTCAGGCATGTAAATGTGCATGCCTCCCCAAAAATAAATGTAAATGCA AAAAAATACACCTCTTCTTTATAAACATATATTCTTTATTAAACAGTATGTTTAAT AAAGAATAGGTGAAGTCTGAGTGTGTGACAGAAAGAGAACAGGGATGAAGTCCT CAGGGCTAAAAGCAGGATTTTTTTTTATCATACTTAGCTTTCTATATTTTACATAA TAACTAGAAAAATATTTTATTTACTTGCAAAGCAAAAGGTAATCCCTGAAAAATC TGAAAGTGAAATAAAAATTACTTCACTAAGTTTCTAGCTGGTGGTATAATCAGAG CACACACCAAAAAATTTAAAATGCTGTAATTTAGATGACTATATTCGAAGGGATA TGTTTTAAAGAAAAGTAAACAGAATAAAGCAAACCATTCAACTTTTAGTAATCAT ATTGTTCTACTAATCTGAAACTGTTTCAAGTATACTGTGGCAAAAATAAAGTGAA GAAATATGTTGGTGTCACTGGAAATTGGGAGTTGTGCACAGAAAAAAAGATCAG TTTACATTAACTATGTGGTACTGAATTTGAAATATAAGTAGTCGGGTGTTTTAAA AAAAATCATTTTTAAAGCTTTGCTTATTTAAAAGATCTAGAAACAGATCAATTAA AGACCAATGAACATTCCTTGTCTCTAAGGATCATTTACCATTAAAACAAACCAAG ACTGTGTGAGACAACCAAAGTAGAAAGGAAGACCTGAGGTTCTAGGGCAAGCCT GTGCCCAAGACCCTGTCACAAAAGGAAAATGAAACACCCTCACTCCACACATGC ACAACCACACAACCCAGCAACTGTTTGGGGTGAAAAATGGTAAAAATGATCCTA AAACATTGGGTTATAATAGAACACAAGAACTAGAGAGCAATGAAACAAGCAAG GAAGCTACTAAGATGAATTTAAAGGATTTATTTAGCTAACAGCTAAAGGCAGTAT AATCTGAATATGTCAAAAATACAGCAGAATGCTAACACATTAAACATATTCAAA ACCATGAGCACAAAACAGTAGTATTTCACTGCTAGACTCCCTCAAGGGGCACCCT GAGTTTCCTATTTTCTGACTGTATATCCATGAGTATATGGATATCCTGTTTTCAGC 92MF-363253604Attorney Docket No.: 15979-20192.40 TGATTGTGAAAATTAAAGAAGCAGTTTTGAAAACACAGCTGTCTTCTATTAAGAT ACTAAAGAGATTTGCAAAATTGTAAAATAATGTAATTAAAAAAATAGAAAGTTA TTGTTCATATCAAGCTGGGTGGTGGTTGTGAAAGCCTTTAATACCAGCATTCAGG AGGCAGAGGCAGGCAGATCTCTGTAAACTAGGTGCCAACCTGGTCTACAGAGTG AGTTCCAGAACAGCCAGGGCTACACAGAGAAACCCTGTCTCAAAACAAACAAAC AAACAAACAAACAAACAGGCATGTCAACAATACTCCTTGTTTTTAAAAGCCTTGT TAGTGGGCTGGAAAGATGGCTCAGAGGTTAAGAGCACTGGTTGCTCTTCCAGAG ATCCTGAGTTCAATTCCCACAAACCACATAGTGGCTCACAACCATCTATAATGAA ATCTGATGCCCTCTTCTGGCCTGCAGGCATACATGCAGGCAGAATGCTGTATATG TAATAAATAAGTCTTTTTTAAAAATTCCTATTAGTAATTAAAAACTTTAAGGATTT ATCTCTCTTTTTTTAAAGATTTATTTATTTATTATAATAAATAAGTACACTGTAGC TGTCTTCGGACACACCAGAAGAGAGCATCAGATCTCATTACAGATGGTTGTGAG CCACCATGTGGTTGCTGGGATTTGAACTCGGGACCTTCGGAAGAGCAGTCAGTGC TCTTACCCATTGAGCCATCTCGACAGCCCAGGATTTATCTCTTAAGTGTACAAGT GTGCATGCCAAGGAGGCTAGATGAAGGCACTTGTGAGCTACCTGCATGAGTGCC TGAAACTGAACTCTTTCTCTGGAAGAGCAGCATATGTTCTGGATCACTAAGCCAT TGCTCCAGAATTATTCTGGTTTTAACTTCAAGTACTAAATCTTAGTGTAGAGAAC CACTCAAACACTAATTCTTTGGGAACTCATGGGAACTCATGTTTAATACTTTAAA GTGTGAGGGTAGTTGATCTAGGCCACCAATATCAACAGTTGTTTAATATCATAAT TAGGCAAATACTATGAAATTCAACAAAGTACATACTACCATTATAAAGTATCCCT GCAATCTAACTCATCACCAATTCATATGAAATATAGGTATAAGGATATCTCTCAG TAAAATGTACTAATGACAATCTAGCCTTTAAACCCAAAAAATTAGAAACTGTAA AACAGCATTTAAAAAAATATACACAGGACACAAAAGAAAAGGAGGTAAAACCT ACAGACTCAAACCAATAAAGCCCAATATATTGACCTTACCTTAAAAAGTGATTTC TCCCGGGGCCTAGCAAACACAGAAGTGGATGCTCACAGTCAGCTATTGGATGGG TCACACGGCCCCCAATGGAGGAGCTAGAAAAATTCCCCAAGGAGCTAAAGGGAA CTGCAACCCTATAGGTGGAACAACAATATGAACTAACCAGTACCCGGGAGCTCT TGTCTCTAGCTGCATATGTATCAGAAGATGGCCTAGTCGGCCATCAGTGGAAAGA GAGGCCCATTGGTCTTGCAAACTTTATATGCCCCAGTACAGGGGAACGCCAGGG CCAAAAAGGGGGAGTGGGTGGGTAGGGGATTGGGGGGGGTGGGTATGGGGGGA ATTTTGGGATAGCATTGAAAATGTAAACGAGGAAAATACCTAATAAAAAAATAA ATTAATTAAAAAAAGTGATTTCTCTCTACATGGGGTGTTCTGCCTGTATTTATGTG TCAGAACCACAGGTGTGCCTGATGACTGTGGAAGCCAGAAGAGGGTGTCAGATT CCCTGGAACTAGAGTTACAGAGGGTTGTAAGCTACCTTCTGGATGTTGAGACCCC 93MF-363253604Attorney Docket No.: 15979-20192.40 AACCTGGATCCTCTATAAAAGCAGCAAGTGCTCTTAACTGCTGAGCCATTTCTCC AGTCCCATTATGGCCCTTAACCAAGTGAATTTGAGTAGGGTGTGGTAGGAGAATC TAGGGCTTATACCACCTTCCCTGCTCTAAATAAGGTATTTTAAACTAACAATTTTA TAAAGTCCAAAGGAAATACATTTTTCCTAATCTAATCTCTAGCTACTTCTTGCCAT ACTATTAAATAAAAAAAAAATACATTCTAAAAATTGCTTACAGGGGAGAATAAA AGACCAACAGACAAATTCTAGCACAGAATCAGAACTCTACAAAGAAAACTGGTT TGCTAGGTAGGGACTAAGAGTTTCCTCCAGTTGATGGTCTGTTCTAGGGAAACTC ATGGTCCCTCCTCATAAAAGATTAAGAAAAATAATTTTGGGTCTAGGGTGTAGTG ATAGAACACTTGCTTCCCCCCCCCCCCATTGTTCTCAAAAAGACAATCATCTGAG GTGCTGGAGAGGACCAGAGTTCAATTCCTAGAACTCAAATGGTGGCTTATAACC ATCTGTAAATTCAATACTAGAGGATCTGGCACCTTTGTCTGGCCTCTACAGGTTA TCATGCAAAATCATGATGCACAAACACAGATGCAGACAAAACACCCATAACTAG AAAATAAACAGAACTTTAAAAAATGTAGTTGAATCCTTTGCACAATTACCTGCAA TAGAAATGTATTACTATTATTACACATTTAGGCAAAACTAACTCATTCCACAAAA AATTACTTTTCACCTCTCTTGTTTAGAACATTGCAACTTTTGTGAAAGATTTATTT TTAAATTGTTTGCATATGAATGTGGTTCCCTTATTTTTAAATTGTATGCATATGAA TGTGGTTCCCTTGACGGCCAGAAGAGACCATCAGCTCCCCTTAAGCTTGAGTGTG CTAGGCACCAAACTTGGATCCTGATCCTCTATACAGTGGTTTTCAACATGTTGGT TGTGACTCCCTCAGGTAGCCTTCAAGACCATCAGAAAACACGGATACTTACAATT CATAATAGTAGCAAAATTACAGTTATGAAGCAGCAATGAAAATAACCTTATGGC TGGTGGGTCACCACATAAAGAACTGTACTAAAGAATCGCAGCATTAGGACCCTA CTGCAGAAGGCCACTACAGCAGATCAGGAAGTTCTCTTAATCCTGAGCTATCCAG CTCCCACACTATTTTATAGAGTATGCCTACTTCTTGTTGCTTTGTATACTATGCAA ATTTCCAGCCATTCTTTTTCATACTAACAGTTCATAATAAACTACAAAGGAAAGT TACACCAATCCAGAGTCATGTTTCTCAAAAAAAAAAAAAAAAAAAAAGACTAGA TTTCTACTCAAATCATGAACTGATCCATTAGGACTAGCAATACTGTGAAGCCTAA TGACCTAAGCACCAAGTATGAGTAAAATAAAAACATTTGGTTTAAGTCAATTAA GCCCAAGATCCCAAAGTAAAAGTACCTTGGAGTTAGCTTTCTTATTTACTTGTTCT AATACTTATATAGCAACACTAACTTCTGAGCAATATACCTGATGCTAGCAATGTT TACTTGTTTTGATTCTTTGATACTTCTGCTTATTTACTGTGCAGTCAATAAAGTGA TTGTTAACCTGGGAAGATTTTGTTTTAAAGATTTTTAAACATTGACACTCTCTCAA TAAAAGTAGCCTAAACACAAACATCCTAACAATTTCATATATTTTTAGCTTCATC TTAAGATGTTCTTTGACATAACCAACCTGACCTGGTTTTGTACTTTTGCTGGGTCA TGAATTAAAAGTTTTATCTGGTATAAATAAAAGTAAATTTGTCTAGAAAGAACGG 94MF-363253604Attorney Docket No.: 15979-20192.40 AACTATTTTAAAAGAGCCTACAATTTTAGACTTGCTCCTACATTTTTTCTAGATTT GTTCTTAAAAAAAAATCTAGCTAACATTTTCAGGCTGTGGGCACAGAAACACAC CTATTTCCATGGCTGTAGTTGTTTGTGCCACAGAATTGAAAAATAAAATTTATGT GTTCGTACAGCAATTTAATGTTACATTCACCCTGTGGTCAATCTCACTGCCTCAA AAACCTATCTTTGTTCTGCATTAGGTGGTTAAATACTTGTTTTAAGTATCCTTCTG GGCTCACATATATATAGCACTTACCAATACATGCAAGGTCCTGGGTTCAAGACTC AAAAACGACAAAAAAGCACTCTTTTGAGTCTATCTCAAATGTCACAATAACCAC ATTTATTTTAAGAATAAATATAACTACCCCCTAAAAACAAGCCAATTCTCAACAG TCCATTGGAAAAAGAAAAAAAAAAAAATAAATGAAGAAAAATGTAATACAAAT AAATGCAGAGGAAAACTAATTGCTAAAATATCCTTTAAGGTTCTTTTTCCTAAGT AAAACCTTGCTTGGATACCAAGAGTGTTCAGTTGATTGTTAGCTGTAGATTGCAT TGCACTCCTTCACAGAAGACATGAAGGCACAAAAGTATATGCTATGGTTGGTGA TAGGAAATAGAATTTTTCAGTATGGGATAAAAATCAGAACAAGACAAGAATAAA TTTTTTTAAAGAGTTATATACATTGGGAGAGAAAACAATAACTTCCTAATACAAA TCAACAATAAATGTAAACATAAAATAATGAAATCCCTGTGGATTGATTTGAGCAC AAACCTAGAAAATTCTAACCAGATCATAATGTCTAAGAATTACAAAGTTTCCACT CTTACTATAATAGTAGCACACATGTACCATATGAATTATTGGGGGTAGGGGTGGG GTCCAAGTCTCCACATTTCAGGAGTGAAGAGGGAGAAAATCTGAGCACCAAAAT ACAACAAAAATGGCAAAAAATAAAAATTTCAGTTTGAGTAATGTTGGAAAAGAA AGTTTAAAATAATTCAGGCATGAAATTTTCATATTCAATCGACTATTTAATTGTTA GAGAGGTATATATCTTTATCTAACTATCTATAGGTAGATAGATAGGTTTAATGTT AAAAATCTCAATTCTAGTCATAGACCCAAGCTGCAAAATAAAAACTACAAATAG AGAATGGATTTCACCTTATAATACAATGGCATCTGGTAGTGGTAATTATTATAAA CAGCCAATGATATTACATGCTTTAAAAATCTTTCTGTAAGCTCAGAATCTGAAAC AGTGTACCAAGAGTGGAAGATATAAAAGTTATTTGTCACTAGCCTTTAAAGTACT AGCTTTAGAACATATAAACAAATCCACAACCTAACATAAGCTATAAACTACAGC AGCCCATTCAATTTCCCCCTTTGTCCTAGTTTCTTTTTTTGCTGGGAAGAGGCGTA GTGGGATAATAATAGCAGGAAGTAAGGTGGAGCAGCTGCACACCAAGATGAGG TGCTGTGTGTGCTTCACCTCCATGCTGGCCTACTGCTGCCTCGATCTTACAAAAAT GAAATTAGCTATTTGGGAAGCTACAAGTTATAAATATTACTGGAATCAAGATGTA ATCTCCTACTTTCTCACGTTTGTCAGAATCTGTTTTAGGTCTCTAGTTTGATTCGGT TGAAGCAATAAAAGCTACATTTCTAGTATTTTTTGCAAGGGAACCCTAATGCTAG CAATAGATATTTGATAGAGACACTGGAGCTAGAAAAACCAGCTTCCTTTTAGTTC CCACAAATTTATGGGAATAATCCATGTTAACAGACTATAAAAAGAAGAAAAGAC 95MF-363253604Attorney Docket No.: 15979-20192.40 CATCTAAATTTCTATTGTAATGTATAATGAGGTATCACTAGAGTTCACATTAAAA TTGTTGCTATTTTGCTGATGAGAAATGTTTCCCAGCAGTGATAATAACACAAATG TACTTTCTTGTTTGGGCATGTGTGAACAAGGGTATGCATGTTCAGGCCAGAGGAC AACCTCATTTCATTTTTCAGGAATTCTTTCCCCACAACTCAGACAGGGTCTCTTAC TAGCCTAAACTGGACAAGTAGGCCAGGCTGACCAGTGAGTAAGCCCTAGAGACC TGGCATCTCTGTCTGCCCAGGGCTGGGATTACAAGCAGCACACACAATTTTACGT GAGTTTGAGAAACTGAACTCAAGTACTCTTTTTACAAATACCTGACCAACTGAGC CTTCGACCAGTCTTTTAATTTTTTTTCAGATCAAAATATTTTGTGTACTGTAACTG CCAAGACTGCCATACTTAAAATAAAATGTTACATGGGTAACATGCTGTACTTCTT TTTACAAAAGAGAGAAATGATGCAAAACAAAACAACAAAAACTCGATCAATGTA CATTACATGCAGCATTCTGGTTATGTTCGTCTACAACAATGTCTTCTTTGCTACAC AAAGTAATCATCATTCCGATTCTCTATCTCACTCAAGCAACAGATGTGCTCTTGG AAAAACAGTTCAAGGATTTCTAAAAATTAATTCTCTTAAAGCAAAACATTCGTTC GTGGAAATGTGCTGTCATATACTACTCTATAAGGAAGAACTTTTGTAATCTAAAT AACTACTGTCTAATTTGTGAGTGTAATTTTTAAAATGAACTAGCATACATGTAAC ATTTGACATTTCCTTTAAAGTACCTGAAATGATTCAGGATAGAGTCTTTAACATTT TAATAACACCTTCAACAGGAACCTAATTTTGGCAGTATCTCTCATGGCTTTGCCT ATAAGAGATACAACTTACACACCTCTAACACCATAATTTTCATTAAGTAATAAGC TAGATGCAATCACCTTTTGCTGAGAGTCAAGCACAAACTAATAGAATTAAGCCTA AACTAAAAGATGGGGACAGGTAGTAATCTCCAGAGCATATCAGATTCTGCAGGA AGTAGGAGGAAGACTGAAACAATAAGGTAAGCTCTCCTTATGTGTTTGGGGGTG GGGAGGAAGGGGGTTCCTGTATGTTTGTTTGTTGATACAAGAGTCTTATTCTTTTT TTTTGTTTTTTTTTGTTTTTGTTTTTGTTTTTTGTTTTTTGAGACAGGGTTTCTCTGT GTAGCCCTGGCTGTCCTGGAACTCACTCTGTAGACCAGGCTGGCCTCGAACTCAG AAATTCACCTGTCTCTACCTCCCAAGTGCTGGGATTAAAGGCGTGCGCCACCACA CCCGGCAGAGTCTTATTTTATAGTTTGGCTGGCATCAGTCTTTGGCTCAGTCTCTT GAGTCAGTTTCCTGAGTACAGAACATACAGATGTAAGCTAAAAGGCCCTTATAA AAATCCTTTTTCAGTTCACATTTTACATAATGATCAAACATATAAATATTGCACA AAGGAAAACAGTACACCTTGTCAAATCTAAACCCAACTAAACATACTGCATATA CTGAAATACAAATTTACTTTACACAGAATAGGTCATTCCAATCATTACTAAAACC TAGATGCTCTAGACCTGGTCCACTAAGGAGGCAACTTACATTTATAAGGACAGG GAACATGGAACTCACTTTAATCCATACAAAGCTTTGGGGCCTCCCCACTCCTCAG AAGATAGGATAGGTTCTTTCTGATTTCTAGACCGTATGAAATTTGGGTTTTAAAA GTATGTGCTTGACATAAATTAAAGGCGTAAGTGAAAACTAAAAACAGTTTCTTTA 96MF-363253604Attorney Docket No.: 15979-20192.40 ATTGTAAACCAAAGTGAATACTCTCCTAGGGGGAAAAAAAAATCTCTTTCCTTCC CTACCTCCGGCCCCTCCCCCACCAACACTGCCTCCCTGCTGTGCAAAGAGCCCTT TGTCCTGCCCCGCACTTATCTAGCTGTTTGGCCATATTGACAGGCCTACTGGAGG CATAATAAGGGAGTCAGTCTGACATAAGCAGCTGGCGATTTCAAACAAAAATCT TCCTTTTCTACTCACACAAAATCCTGCTGCAGAGGTCTGTGGCTCCTCCCATACTT CCACCTAGTTCTCAAATAGAGCAGCAAGGAACTGGCATTTCCCCTCGATTCCGTA GTATAAATCAAAAACTTGATTCTCTAGCCAGAATTCTTATAGCCACTGATTTGTT GCTGTTTTGTGTTGTAATCCCTAAATTAGGTTTCTTCATCTCTGGTATATACATGT ATGATTATCACTTCAATGTGCCATGAAAACTCTGGGAAGCCTCATACTACAAGAC AGAAGAGACATGGAAGTGGCAAACACACACACCACAAACAAAACTGAGCAATA CTCTTAGGGTTTTGAGAATACCAATGATTTTTAAAAGATTAAAAAAAAAAATCAC TTTCCTGACACCAAAGATACTTTATGGAAATTTACATTCAGGCATTTCCCTAGAT ACTCTGAAAAAAAGAAAGAAAGAAAGAAAGAAAGGAAGGAAGGAAGGAAGGA AGGAAGGAAGGAAGGAAGGAAGGAAACAGTAATGGAAGGAAGGGGTTGGGGTT TGAGAACCCTTACTCATAAGAAAAACATAGACTGTACTTTTGTGTACCTCACAGC TCCTTTCTTCAAGTACTGAGTAAGAACTCGTCCAAGGGATGCTTTCTAACAGAAC CAACTCTCAGGGTTACTGGCATGTCTACCCAGTTTATAACTTAATACACAACAAG ACAATTTCACTATACGTATCGTTAAGTGAAAGAAAGGCTACTCCTTTTACCTTTTG CAATTTCCCTGAATTCCAGCCACTAGAGAAACGAATCACAATACCAAATGAAGG TCATGCCATTTACTAGATGTGTTAGAATATCTGGGCTCCAAGACTTATCTACCTC ATAGGTGCATTGCTCTTCTTTTCTAAGTCTATCTGAAAGGACACTTTAAACCAAAT TATAAATGACTACCAGTTTAAAAAAAATGACTACCAGTTGAACTATTATACGCAT ATTATACGCATATTTCAGTCTAAGTTCACCACTAGTCAGGCCTCCTAATTTCAAAT TAAACTGAAAAAAAAAAAAAAAAACTAGTTTAGCCAAAAGTTGTAATAAAATTT TATTTTACTTATGATCTAATTTATTGTAGATATGTACTCAATAATTACTGACTACT ATTGCCTTATGTTTCAAAGTTCCACCTTCATCAAAAGGGTCAGAATAATTTCTAA AGTATACAGGCTTCTAGATACTAAGCAGTATCAAGATGTAGGCATTTTTAAGTGT GTCAGTTCAAGTAATCCTTCTAAGAAAAAAGCCTCTTGATCTTCCAGAGATTACT GTAAGACCACAATCAGATCCAAAAAAACAGGAAATAAAAGTGGTAGTCATTATT TTCTAAGGGAACTTGTATATTATAATTAAGCTCAAAACACTTGCACCTTAACTGT AAATACCTTGAACTGTAATATCAGTATGAGTGATATCATACTTATGGGATACAGC ACCTAATCTACGTAACAAAAATATTATTACAACCATCTAAAACAATCATTAACAG AGTTTTGTTTTATGGACTTGCTTTTAGCACTGGAAAAACAATATGAACTACATTTG TGAATTCAAAATACTCTACAATGTTTCTTCATTTTTTGCTACAAATTCTAGAACCA 97MF-363253604Attorney Docket No.: 15979-20192.40 TTACATTTATGGGATCTAAATAAATTTGTACAAAATTAAACAGACTCCCGAAGGA AAAGGCATTGGTTGCAGTAATAATCCTAGGGAGGAAAAACCCTACGATTTTATGT GCTGCACATGCCTGGGTGATGGTTCAGTTTCAAATATTCCTTGCCAGACAAACTA CTTAAAAAGGCTTAATCAAAGATCACCCTGGTTCTATTTGGTTAGGGGTAGGGTG GGCTTAGAATGGACTCTTGCTGCCTTCTTAGTATCTTGAACTAAACTTACTCAATT TCTGAATATTCCTTCTGTGTCTCTGATGGATTACTGCCAAAACACATCTTTGTTCG GTGGAAAGTCTATAATCCAACACATACACGATTAATCCAATTTATAGGTCAGATA TCAGTAAGTATATCTAATCTGGAGAGGTCTACAGATTAATTTAGAATTAACAACA AACCAAGCATTAATCCAAAAGCAGCTCTTTTTAGTTTAGGCATCCAAATATATAG TAAGATGTTTCAAAGAACATCAATCTATTCACAAAGGTAAATACGGCCTAATAC GGAGAGACAAATACAAATCTGAAATGACTCAAGCAATTAAAAGATGGAGGAATT CATGTCACTTGCACTGGGAAAACAAAACAAAGATCCTCCTCACCCTATTACCCAC ATTACTATTTTTAGGTTTTTTAGGGGTTAAAAAAGATCAAAACACTAATGAACTT TAAGTCCTGTGAAGGGTAAAACCTCAGATAGTAACAAAAAGCTTCCAACCCCTC CTCAAACAAAAAACCCCAAGTCTTTAACTTTGATCCAGTTTTCAGATGCTGATAT CCATAAATGGATACAGTTATGAATTGCTAATTCTGGTCTCTTCACTAGCAAAAAG CAAAGCAGCTCAGCAGTACAATTTCCCAGGAAAGCAAGCAAGGTTTCTTTCCAG CCTGAGCAGCCATCACTAAGTGCAGTTCCCTGCAGCCAACAGCATTAATGGACG CTGCACTGCTGTCCTTCCCTGGAGACAGCAGCCAGCACTACTCAAGCTTCTCACG TAGCAACCAGAGCTCCAGAGCCAGCAGCTGCTGCCGCCTTGTATACTCACTCCTG TGATCCAACACAGGAGCAACCTTTTCTTTACCCCACCCCCACTTCTTAACACACTT TTTTTTGGGGGGGGGGGGGAACAAGTGCTCCATGCTGGAAGGATTGGAACTATG CTTTTAGAAAGGAACAATCCTAAGGTCACTTTTAAATTGAGGTCTTTGATTTGAA AATCAACAAATACCAAATTCCAAATATTCGTTTTAATTAAACCAGCAATGTGGAT ATAAGCATTAAGTTTTAGTTTTAAAAAGGTCAATTTTCCAAACATTCAGCAATCA TATTTAAATTTACAGCTAGGAACAAGAGCCTTGGGTCATGTCCTACCAAAGAACA TAACTCAATATTCTACACATGACAATCTGAATAACCTTAAAGCCTCTAATCCCAT AACAGGCCACAAATTTTGGACAGAGAACTAATGATCCTCCTGAGAAAACTGGAA GAAATCCAGGGAAAAGAAATTCCTGTGTCCTCCAAACTCAGAAATCTCTAATTAT GTCAGTATTCTCTGCTTTAGTCCTAGGTCAGATTGCACACATCTAAAATAACCTCT TAAAGTTTTCCTCCTAGCGACCTAAACCATTATTAATATCAAATTAACCATCAAA ACACTTTCCTCTCAATATGCTGCACACAAACCTCCTCCTGGAACCTCCTCCATCTG GATCCTCCCCAATCAAAAGTATAGGTATTTAACATATAAGCAAGGAAGTAATGT AAACATGACCTTGGTCACAAATATGTCATCTAAAAACAATTTAGTCAAGGTATGG 98MF-363253604Attorney Docket No.: 15979-20192.40 AGGAAATTCGAGAACCTGAATCTTTTTAAGTATTTTGAGCACAGGAACAATTGGC AAAAGGAATCCAGGTATAGACAAAACCCAGAGCCCAGAGCTCTGGGCGAAAAA TGAGTTGCTGGTGAAGACGTTACACAAGTAACATGAGAAAGCAGAAAATGCAGG TCATCCACGCACCCCTGACCCAGGCCAGCAGGGCGGGCTGCAGCATCAGTACAC AGGAGAAAGATCCTTATTCCTAAGAATGAGAAAGGCAAAGGCGCCCGATAGAAT AAATTAGCATAGAAGGGGCTTTCCCAGGAGTTAAAACTTTCCTTCTGAGCGATTA CCTACTAAAACCAGGGCTTTTGCCCACTACCATTTACCTAGGATCTTGGCTTGCA CGGATTCATAGGGGCATATCCCTCCCCCTCTTCTTTAGAGTCGTTCTTAAAAGATC GCTCTCCACGCCCTAGGCAGGGAAAACGACAAAATCTGGCTCAATTCCAGGCTA GAACCCTACAAATTCAACAGGGATATCGCAAGGATACTGGGGCATACGCCACAG GGAGTCCAAGAATGTGAGGTGGGGGTGGCGAAGGTAATGTCTTTGGTGTGGGAA AAGCAGCAGCCATCTGAGATAGGAACTGGAAAACCAGAGGAGAGGCGTTCAGG AAGATTATGGAGGGGAGGACTGGGCCCCCACGAGCGACCAGAGTTGTCACAAGG CCGCAAGAACAGGGGAGGTGGGGGGCTCAGGGACAGAAAAAAAAGTATGTGTA TTTTGAGAGCAGGGTTGGGAGGCCTCTCCTGAAAAGGGTATAAACGTGGAGTAG GCAATACCCAGGCAAAAAGGGGAGACCAGAGTAGGGGGAGGGGAAGAGTCCTG ACCCAGGGAAGACATTAAAAAGGTAGTGGGGTCGACTAGATGAAGGAGAGCCTT TCTCTCTGGGCAAGAGCGGTGCAATGGTGTGTAAAGGTAGCTGAGAAGACGAAA AGGGCAAGCATCTTCCTGCTACCAGGCTGGGGAGGCCCAGGCCCACGACCCCGA GGAGAGGGAACGCAGGGAGACTGAGGTGACCCTTCTTTCCCCCGGGGCCCGGTC GTGTGGTTCGGTGTCTCTTTTCTGTTGGACCCTTACCTTGACCCAGGCGCTGCCGG GGCCTGGGCCCGGGCTGCGGCGCACGGCACTCCCGGGAGGCAGCGAGACTCGAG TTAGGCCCAACGCGGCGCCACGGCGTTTCCTGGCCGGGAATGGCCCGTACCCGT GAGGTGGGGGTGGGGGGCAGAAAAGGCGGAGCGAGCCCGAGGCGGGGAGGGG GAGGGCCAGGGGCGGAGGGGGCCGGCACTACTGTGTTGGCGGACTGGCGGGACT AGGGCTGCGTGAGTCTCTGAGCGCAGGCGGGCGGCGGCCGCCCCTCCCCCGGCG GCGGCAGCGGCGGCAGCGGCGGCAGCTCACTCAGCCCGCTGCCCGAGCGGAAAC GCCACTGACCGCACGGGGATTCCCAGTGCCGGCGCCAGGGGCACGCGGGACACG CCCCCTCCCGCCGCGCCATTGGCCTCTCCGCCCACCGCCCCACACTTATTGGCCG GTGCGCCGCCAATCAGCGGAGGCTGCCGGGGCCGCCTAAAGAAGAGGCTGTGCT TTGGGGCTCCGGCTCCTCAGAGAGCCTCGGCTAGGTAGGGGATCGGGACTCTGG CGGGAGGGCGGCTTGGTGCGTTTGCGGGGATGGGCGGCCGCGGCAGGCCCTCCG AGCGTGGTGGAGCCGTTCTGTGAGACAGCCGGGTACGAGTCGTGACGCTGGAAG GGGCAAGCGGGTGGTGGGCAGGAATGCGGTCCGCCCTGCAGCAACCGGAGGGG 99MF-363253604Attorney Docket No.: 15979-20192.40 GAGGGAGAAGGGAGCGGAAAAGTCTCCACCGGACGCGGCCATGGCTCGGGGGG GGGGGGGCAGCGGAGGAGCGCTTCCGGCCGACGTCTCGTCGCTGATTGGCTTCTT TTCCTCCCGCCGTGTGTGAAAACACAAATGGCGTGTTTTGGTTGGCGTAAGGCGC CTGTCAGTTAACGGCAGCCGGAGTGCGCAGCCGCCGGCAGCCTCGCTCTGCCCA CTGGGTGGGGCGGGAGGTAGGTGGGGTGAGGCGAGCTGGACGTGCGGGCGCGG TCGGCCTCTGGCGGGGCGGGGGAGGGGAGGGAGGGTCAGCGAAAGTAGCTCGC GCGCGAGCGGCCGCCCACCCTCCCCTTCCTCTGGGGGAGTCGTTTTACCCGCCGC CGGCCGGGCCTCGTCGTCTGATTGGCTCTCGGGGCCCAGAAAACTGGCCCTTGCC ATTGGCTCGTGTTCGTGCAAGTTGAGTCCATCCGCCGGCCAGCGGGGGCGGCGA GGAGGCGCTCCCAGGTTCCGGCCCTCCCCTCGGCCCCGCGCCGCAGAGTCTGGCC GCGCGCCCCTGCGCAACGTGGCAGGAAGCGCGCGCTGGGGGCGGGGACGGGCA GTAGGGCTGAGCGGCTGCGGGGCGGGTGCAAGCACGTTTCCGACTTGAGTTGCC TCAAGAGGGGCGTGCTGAGCCAGACCTCCATCGCGCACTCCGGGGAGTGGAGGG AAGGAGCGAGGGCTCAGTTGGGCTGTTTTGGAGGCAGGAAGCACTTGCTCTCCC AAAGTCGCTCTGAGTTGTTATCAGTAAGGGAGCTGCAGTGGAGTAGGCGGGGAG AAGGCCGCACCCTTCTCTTAATtaagtgacctgcacgtctagggcgcagtagtccagggtttccttgatgatgtcat acttatcctgtcccttttttttccacagctcgcggttgaggacaaactcttcgcggtctttccagtatttGCTGGCGCGCCTCGC GATGAATAAATGAAAGCTTGCAGATCTGCGACTCTAGAGGATCTGCGACTCTAG AGGATCATAATCAGCCATACCACATTTGTAGAGGTTTTACTTGCTTTAAAAAACC TCCCACACCTCCCCCTGAACCTGAAACATAAAATGAATGCAATTGTTGTTGTTAA CTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAATTTC ACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTGGTTTGTCCAAACTCATCAA TGTATCTTATCATGTCTGGATCTGCGACTCTAGAGGATCATAATCAGCCATACCA CATTTGTAGAGGTTTTACTTGCTTTAAAAAACCTCCCACACCTCCCCCTGAACCTG AAACATAAAATGAATGCAATTGTTGTTGTTAACTTGTTTATTGCAGCTTATAATG GTTACAAATAAAGCAATAGCATCACAAATTTCACAAATAAAGCATTTTTTTCACT GCATTCTAGTTGTGGTTTGTCCAAACTCATCAATGTATCTTATCATGTCTGGATCT GCGACTCTAGAGGATCATAATCAGCCATACCACATTTGTAGAGGTTTTACTTGCT TTAAAAAACCTCCCACACCTCCCCCTGAACCTGAAACATAAAATGAATGCAATTG TTGTTGTTAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATC ACAAATTTCACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTGGTTTGTCCAA ACTCATCAATGTATCTTATCATGTCTGGATCCCCATCAAGCTGATCCGGAACCCT TAATGCGATCGCATCGATGGCCCCAGGTTAATTTTTAAAAAGCAGTCAAAAGTCC AAGTGGCCCTTGGCAGCATTTACTCTCTCTGTTTGCTCTGGTTAATAATCTCAGGA 100MF-363253604Attorney Docket No.: 15979-20192.40 GCACAAACATTCCTGGAGGCAGGAGAAGAAATCAACATCCTGGACTTATCCTCT GGGCCTCTCCCCACCTTCGATGGCCCCAGGTTAATTTTTAAAAAGCAGTCAAAAG TCCAAGTGGCCCTTGGCAGCATTTACTCTCTCTGTTTGCTCTGGTTAATAATCTCA GGAGCACAAACATTCCTGGAGGCAGGAGAAGAAATCAACATCCTGGACTTATCC TCTGGGCCTCTCCCCACCTTCGAACTAGCCACTAGCCTGAGGCTGGTCAAAATTG AACCTCCTCCTGCTCTGAGCAGCCTGGGGGGCAGACTAAGCAGAGGGCTGTGCA GACCCACATAAAGAGCCTACTGTGTGCCAGGCACTTCACCCGAGGCACTTCACA AGCATGCTTGGGAATGAAACTTCCAACTCTTTGGGATGCAGGTGAAACAGTTCCT GGTTCAGAGAGGTGAAGCGGCCTGCCTGAGGCAGCACAGCTCTTCTTTACAGAT GTGCTTCCCCACCTCTACCCTGTCTCACGGCCCCCCATGCCAGCCTGACGGTTGT GTCTGCCTCAGTCATGCTCCATTTTTCCATCGGGACCATCAAGAGGGTGTTTGTGT CTAAGGCTGACTGGGTAACTTTGGATGAGCGGTCTCTCCGCTCTGAGCCTGTTTC CTCATCTGTCAAATGGGCTCTAACCCACTCTGATCTCCCAGGGCGGCAGTAAGTC TTCAGCATCAGGCATTTTGGGGTGACTCAGTAAATGGTAGATCTTGCTACCAGTG GAACAGCCACTAAGGATTCTGCAGTGAGAGCAGAGGGCCAGCTAAGTGGTACTC TCCCAGAGACTGTCTGACTCACGCCACCCCCTCCACCTTGGACACAGGACGCTGT GGTTTCTGAGCCAGGTACAATGACTCCTTTCGGTAAGTGCAGTGGAAGCTGTACA CTGCCCAGGCAAAGCGTCCGGGCAGCGTAGGCGGGCGACTCAGATCCCAGCCAG TGGACTTAGCCCCTGTTTGCTCCTCCGATAACTGGGGTGACCTTGGTTAATATTCA CCAGCAGCCTCCCCCGTTGCCCCTCTGGATCCACTGCTTAAATACGGACGAGGAC AGGGCCCTGTCTCCTCAGCTTCAGGCACCACCACTGACCTGGGACAGGCCACCatg ccgtcttctgtctcgtggggcatcctcctgctggcaggcctgtgctgcctggtccctgtctccctggctgaggatccccagggagatgct gcccagaagacagatacatcccaccatgatcaggatcacccaaccttcaacaagatcacccccaacctggctgagttcgccttcagcc tataccgccagctggcacaccagtccaacagcaccaatatcttcttctccccagtgagcatcgctacagcctttgcaatgctctccctgg ggaccaaggctgacactcacgatgaaatcctggagggcctgaatttcaacctcacggagattccggaggctcagatccatgaaggctt ccaggaactcctccgtaccctcaaccagccagacagccagctccagctgaccaccggcaatggcctgttcctcagcgagggcctga agctagtggataagtttttggaggatgttaaaaagttgtaccactcagaagccttcactgtcaacttcggggacaccgaagaggccaag aaacagatcaacgattacgtggagaagggtactcaagggaaaattgtggatttggtcaaggagcttgacagagacacagtttttgctct ggtgaattacatcttctttaaaggcaaatgggagagaccctttgaagtcaaggacaccgaggaagaggacttccacgtggaccaggtg accaccgtgaaggtgcctatgatgaagcgtttaggcatgtttaacatccagcactgtaagaagctgtccagctgggtgctgctgatgaa atacctgggcaatgccaccgccatcttcttcctgcctgatgaggggaaactacagcacctggaaaatgaactcacccacgatatcatca ccaagttcctggaaaatgaagacagaaggtctgccagcttacatttacccaaactgtccattactggaacctatgatctgaagagcgtcc tgggtcaactgggcatcactaaggtcttcagcaatggggctgacctctccggggtcacagaggaggcacccctgaagctctccaagg tgagatcaccctgacgaccttgttgcaccctggtatctgtagggaagaatgtgtgggggctgcagctctgtcctgaggctgaggaagg 101MF-363253604Attorney Docket No.: 15979-20192.40 ggccgagggaaacaaatgaagacccaggctgagctcctgaagatgcccgtgattcactgacacgggacgtggtcaaacagcaaag ccaggcaggggactgctgtgcagctggcactttcggggcctcccttgaggttgtgtcactgaccctgaatttcaactttgcccaagacct tctagacattgggccttgatttatccatactgacacagaaaggtttgggctaagttgtttcaaaggaatttctgactccttcgatctgtgagat ttggtgtctgaattaatgaatgatttcagctaaagatgacacttattttggaaaactaaaggcgaccaatgaacaactgcagttccatgaat ggctgcattatcttggggtctgggcactgtgaaggtcactgccagggtccgtgtcctcaaggagcttcaagccgtgtactagaaagga gagagccctggaggcagacgtggagtgacgatgctcttccctgttctgagttgtgggtgcacctgagcagggggagaggcgcttgtc aggaagatggacagaggggagccagccccatcagccaaagccttgaggaggagcaaggcctatgtgacagggagggagaggat gtgcagggccagggccgtccagggggagtgagcgcttcctgggaggtgtccacgtgagccttgctcgaggcctgggatcagcctta caacgtgtctctgcttctctcccctccaggccgtgcataaggctgtgctgaccatcgacAagaaagggactgaagctgctggggccat gtttttagaggccatacccatgtctatcccccccgaggtcaagttcaacaaaccctttgtcttcttaatgattgaacaaaataccaagtctcc cctcttcatgggaaaagtggtgaatcccacccaaaaataactgcctctcgctcctcaacccctcccctccatccctggccccctccctgg atgacattaaagaagggttgagctggtccctgcctgcatgtgactgtaaatccctcccatgttttctctgagtctccctttgcctgctgagg ctgtatgtgggctccaggtaacagtgctgtcttcgggccccctgaactgtgttcatggagcatctggctgggtaggcacatgctgggctt gaatccaggggggactgaatcctcagcttacggacctgggcccatctgtttctggagggctccagtcttccttgtcctgtcttggagtcc ccaagaaggaatcacaggggaggaaccagataccagccatgaccccaggctccaccaagcatcttcatgtccccctgctcatccccc actcccccccacccagagttgctcatcctgccagggctggctgtgcccaccccaaggctgccctcctgggggccccagaactgcctg atcgtgccgtggcccagttttgtggcatctgcagcaacacaagagagaggacaatgtcctcctcttgacccgctgtcacctaaccagac tcgggccctgcacctctcaggcacttctggaaaatgactgaggcagattcttcctgaagcccattctccatggggcaacaaggacacct attctgtccttgtccttccatcgctgccccagaaagcctcacatatctccgtttagaatcaggtcccttctccccagatgaagaggagggt ctctgctttgttttctctatctcctcctcagacttgaccaggcccagcaggccccagaagaccattaccctatatcccttctcctccctagtc acatggccataggcctgctgatggctcaggaaggccattgcaaggactcctcagctatgggagaggaagcacatcacccattgaccc ccgcaacccctccctttcctcctctgagtcccgactggggccacatgcagcctgacttctttgtgcctgttgctgtccctgcagtcttcaga gggccaccgcagctccagtgccacggcaggaggctgttcctgaatagcccctgtggtaagggccaggagagtccttccatcctccaa ggccctgctaaaggacacagcagccaggaagtcccctgggcccctagctgaaggacagcctgctccctccgtctctaccaggaatg gccttgtcctatggaaggcactgccccatcccaaactaatctaggaatcactgtctaaccactcactgtcatgaatgtgtacttaaaggat gaggttgagtcataccaaatagtgatttcgatagttcaaaatggtgaaattagcaattctacatgattcagtctaatcaatggataccgact gtttcccacacaagtctcctgttctcttaagcttactcactgacagcctttcactctccacaaatacattaaagatatggccatcaccaagcc ccctaggatgacaccagacctgagagtctgaagacctggatccaagttctgacttttccccctgacagctgtgtgaccttcgtgaagtcg ccaaacctctctgagccccagtcattgctagtaagacctgcctttgagttggtatgatgttcaagttagataacaaaatgtttatacccatta gaacagagaataaatagaactacatttcttgcacttatgagctttctgtgaatcagacatccctatgaagtacctcccctggctgtttctcatt tactcactgtagcagcactgcgatgtgtgagtatatctgctgtgctcttaaactccaaatctgaggaaactgaggctcagagaggctact ggtctcccacaatgtcacacagctcataagtggcaaagctggcttgatgggctacttgttcctctgaaccataccacctcaccacactct ccccttcgagggtcacgctaaacttctgcagaggtaattcctccttaaaccagaagggtACGCGTCGGAGGGGGGAG GGGAGTGTTGCAATACCTTTCTGGGAGTTCTCTGCTGCCTCCTGGCTTCTGAGGA 102MF-363253604Attorney Docket No.: 15979-20192.40 CCGCCCTGGGCCTGGGAGAATCCCTTCCCCCTCTTCCCTCGTGATCTGCAACTCC AGTCTTTCTAGAAGATGGGCGGGAGTCTTCTGGGCAGGCTTAAAGGCTAACCTG GTGTGTGGGCGTTGTCCTGCAGGGGAATTGAACAGGTGTAAAATTGGAGGGACA AGACTTCCCACAGATTTTCGGTTTTGTCGGGAAGTTTTTTAATAGGGGCAAATAA GGAAAATGGGAGGATAGGTAGTCATCTGGGGTTTTATGCAGCAAAACTACAGGT TATTATTGCTTGTGATCCGCCTCGGAGTATTTTCCATCGAGGTAGATTAAAGACA TGCTCACCCGAGTTTTATACTCTCCTGCTTGAGATCCTTACTACAGTATGAAATTA CAGTGTCGCGAGTTAGACTATGTAAGCAGAATTTTAATCATTTTTAAAGAGCCCA GTACTTCATATCCATTTCTCCCGCTCCTTCTGCAGCCTTATCAAAAGGTATTTTAG AACACTCATTTTAGCCCCATTTTCATTTATTATACTGGCTTATCCAACCCCTAGAC AGAGCATTGGCATTTTCCCTTTCCTGATCTTAGAAGTCTGATGACTCATGAAACC AGACAGATTAGTTACATACACCACAAATCGAGGCTGTAGCTGGGGCCTCAACAC TGCAGTTCTTTTATAACTCCTTAGTACACTTTTTGTTGATCCTTTGCCTTGATCCTT AATTTTCAGTGTCTATCACCTCTCCCGTCAGGTGGTGTTCCACATTTGGGCCTATT CTCAGTCCAGGGAGTTTTACAACAATAGATGTATTGAGAATCCAACCTAAAGCTT AACTTTCCACTCCCATGAATGCCTCTCTCCTTTTTCTCCATTTATAAACTGAGCTA TTAACCATTAATGGTTTCCAGGTGGATGTCTCCTCCCCCAATATTACCTGATGTAT CTTACATATTGCCAGGCTGATATTTTAAGACATTAAAAGGTATATTTCATTATTGA GCCACATGGTATTGATTACTGCTTACTAAAATTTTGTCATTGTACACATCTGTAAA AGGTGGTTCCTTTTGGAATGCAAAGTTCAGGTGTTTGTTGTCTTTCCTGACCTAAG GTCTTGTGAGCTTGTATTTTTTCTATTTAAGCAGTGCTTTCTCTTGGACTGGCTTG ACTCATGGCATTCTACACGTTATTGCTGGTCTAAATGTGATTTTGCCAAGCTTCTT CAGGACCTATAATTTTGCTTGACTTGTAGCCAAACACAAGTAAAATGATTAAGCA ACAAATGTATTTGTGAAGCTTGGTTTTTAGGTTGTTGTGTTGTGTGTGCTTGTGCT CTATAATAATACTATCCAGGGGCTGGAGAGGTGGCTCGGAGTTCAAGAGCACAG ACTGCTCTTCCAGAAGTCCTGAGTTCAATTCCCAGCAACCACATGGTGGCTCACA ACCATCTGTAATGGGATCTGATGCCCTCTTCTGGTGTGTCTGAAGACCACAAGTG TATTCACATTAAATAAATAAATCCTCCTTCTTCTTCTTTTTTTTTTTTTTAAAGAGA ATACTGTCTCCAGTAGAATTTACTGAAGTAATGAAATACTTTGTGTTTGTTCCAAT ATGGTAGCCAATAATCAAATTACTCTTTAAGCACTGGAAATGTTACCAAGGAACT AATTTTTATTTGAAGTGTAACTGTGGACAGAGGAGCCATAACTGCAGACTTGTGG GATACAGAAGACCAATGCAGACTTTAATGTCTTTTCTCTTACACTAAGCAATAAA GAAATAAAAATTGAACTTCTAGTATCCTATTTGTTTAAACTGCTAGCTTTACTTAA CTTTTGTGCTTCATCTATACAAAGCTGAAAGCTAAGTCTGCAGCCATTACTAAAC 103MF-363253604Attorney Docket No.: 15979-20192.40 ATGAAAGCAAGTAATGATAATTTTGGATTTCAAAAATGTAGGGCCAGAGTTTAG CCAGCCAGTGGTGGTGCTTGCCTTTATGCCTTTAATCCCAGCACTCTGGAGGCAG AGACAGGCAGATCTCTGAGTTTGAGCCCAGCCTGGTCTACACATCAAGTTCTATC TAGGATAGCCAGGAATACACACAGAAACCCTGTTGGGGAGGGGGGCTCTGAGAT TTCATAAAATTATAATTGAAGCATTCCCTAATGAGCCACTATGGATGTGGCTAAA TCCGTCTACCTTTCTGATGAGATTTGGGTATTATTTTTTCTGTCTCTGCTGTTGGTT GGGTCTTTTGACACTGTGGGCTTTCTTTAAAGCCTCCTTCCTGCCATGTGGTCTCT TGTTTGCTACTAACTTCCCATGGCTTAAATGGCATGGCTTTTTGCCTTCTAAGGGC AGCTGCTGAGATTTGCAGCCTGATTTCCAGGGTGGGGTTGGGAAATCTTTCAAAC ACTAAAATTGTCCTTTAATTTTTTTTTTAAAAAATGGGTTATATAATAAACCTCAT AAAATAGTTATGAGGAGTGAGGTGGACTAATATTAAATGAGTCCCTCCCCTATAA AAGAGCTATTAAGGCTTTTTGTCTTATACTTAACTTTTTTTTTAAATGTGGTATCTT TAGAACCAAGGGTCTTAGAGTTTTAGTATACAGAAACTGTTGCATCGCTTAATCA GATTTTCTAGTTTCAAATCCAGAGAATCCAAATTCTTCACAGCCAAAGTCAAATT AAGAATTTCTGACTTTTAATGTTAATTTGCTTACTGTGAATATAAAAATGATAGCT TTTCCTGAGGCAGGGTCTCACTATGTATCTCTGCCTGATCTGCAACAAGATATGT AGACTAAAGTTCTGCCTGCTTTTGTCTCCTGAATACTAAGGTTAAAATGTAGTAA TACTTTTGGAACTTGCAGGTCAGATTCTTTTATAGGGGACACACTAAGGGAGCTT GGGTGATAGTTGGTAAAATGTGTTTCAAGTGATGAAAACTTGAATTATTATCACC GCAACCTACTTTTTAAAAAAAAAAGCCAGGCCTGTTAGAGCATGCTTAAGGGAT CCCTAGGACTTGCTGAGCACACAAGAGTAGTTACTTGGCAGGCTCCTGGTGAGA GCATATTTCAAAAAACAAGGCAGACAACCAAGAAACTACAGTTAAGGTTACCTG TCTTTAAACCATCTGCATATACACAGGGATATTAAAATATTCCAAATAATATTTC ATTCAAGTTTTCCCCCATCAAATTGGGACATGGATTTCTCCGGTGAATAGGCAGA GTTGGAAACTAAACAAATGTTGGTTTTGTGATTTGTGAAATTGTTTTCAAGTGAT AGTTAAAGCCCATGAGATACAGAACAAAGCTGCTATTTCGAGGTCTCTTGGTTTA TACTCAGAAGCACTTCTTTGGGTTTCCCTGCACTATCCTGATCATGTGCTAGGCCT ACCTTAGGCTGATTGTTGTTCAAATAAACTTAAGTTTCCTGTCAGGTGATGTCATA TGATTTCATATATCAAGGCAAAACATGTTATATATGTTAAACATTTGTACTTAAT GTGAAAGTTAGGTCTTTGTGGGTTTGATTTTTAATTTTCAAAACCTGAGCTAAATA AGTCATTTTTACATGTCTTACATTTGGTGGAATTGTATAATTGTGGTTTGCAGGCA AGACTCTCTGACCTAGTAACCCTACCTATAGAGCACTTTGCTGGGTCACAAGTCT AGGAGTCAAGCATTTCACCTTGAAGTTGAGACGTTTTGTTAGTGTATACTAGTTT ATATGTTGGAGGACATGTTTATCCAGAAGATATTCAGGACTATTTTTGACTGGGC 104MF-363253604Attorney Docket No.: 15979-20192.40 TAAGGAATTGATTCTGATTAGCACTGTTAGTGAGCATTGAGTGGCCTTTAGGCTT GAATTGGAGTCACTTGTATATCTCAAATAATGCTGGCCTTTTTTAAAAAGCCCTT GTTCTTTATCACCCTGTTTTCTACATAATTTTTGTTCAAAGAAATACTTGTTTGGA TCTCCTTTTGACAACAATAGCATGTTTTCAAGCCATATTTTTTTTCCTTTTTTTTTT TTTTTTTGGTTTTTCGAGACAGGGTTTCTCTGTATAGCCCTGGCTGTCCTGGAACT CACTTTGTAGACCAGGCTGGCCTCGAACTCAGAAATCCGCCTGCCTCTGCCTCCT GAGTGCCGGGATTAAAGGCGTGCACCACCACGCCTGGCTAAGTTGGATATTTTGT TATATAACTATAACCAATACTAACTCCACTGGGTGGATTTTTAATTCAGTCAGTA GTCTTAAGTGGTCTTTATTGGCCCTTCATTAAAATCTACTGTTCACTCTAACAGAG GCTGTTGGTACTAGTGGCACTTAAGCAACTTCCTACGGATATACTAGCAGATTAA GGGTCAGGGATAGAAACTAGTCTAGCGTTTTGTATACCTACCAGCTTTATACTAC CTTGTTCTGATAGAAATATTTCAGGACATCTAGAGTGTACTATAAGGTTGATGGT AAGCTTATAAGGAACTTGAAAGTGGAGTAACTACTCCATTTCTCTGAGGGGAGA ATTAAAATTTTTGACCAAGTGTTGTTGAGCCACTGAGAATGGTCTCAGAACATAA CTTCTTAAGGAACCTTCCCAGATTGCCCTCAACACTGCACCACATTTGGTCCTGCT TGAACATTGCCATGGCTCTTAAAGTCTTAATTAAGAATATTAATTGTGTAATTATT GTTTTTCCTCCTTTAGATCATTCCTTGAGGACAGGACAGTGCTTGTTTAAGGCTAT ATTTCTGCTGTCTGAGCAGCAACAGGTCTTCGAGATCAACATGATGTTCATAATC CCAAGATGTTGCCATTTATGTTCTCAGAAGCAAGCAGAGGCATGATGGTCAGTG ACAGTAATGTCACTGTGTTAAATGTTGCTATGCAGTTTGGATTTTTCTAATGTAGT GTAGGTAGAACATATGTGTTCTGTATGAATTAAACTCTTAAGTTACACCTTGTAT AATCCATGCAATGTGTTATGCAATTACCATTTTAAGTATTGTAGCTTTCTTTGTAT GTGAGGATAAAGGTGTTTGTCATAAAATGTTTTGAACATTTCCCCAAAGTTCCAA ATTATAAAACCACAACGTTAGAACTTATTTATGAACAATGGTTGTAGTTTCATGC TTTTAAAATGCTTAATTATTCAATTAACACCGTTTGTGTTATAATATATATAAAAC TGACATGTAGAAGTGTTTGTCCAGAACATTTCTTAAATGTATACTGTCTTTAGAG AGTTTAATATAGCATGTCTTTTGCAACATACTAACTTTTGTGTTGGTGCGAGCAAT ATTGTGTAGTCATTTTGAAAGGAGTCATTTCAATGAGTGTCAGATTGTTTTGAAT GTTATTGAACATTTTAAATGCAGACTTGTTCGTGTTTTAGAAAGCAAAACTGTCA GAAGCTTTGAACTAGAAATTAAAAAGCTGAAGTATTTCAGAAGGGAAATAAGCT ACTTGCTGTATTAGTTGAAGGAAAGTGTAATAGCTTAGAAAATTTAAAACCATAT AGTTGTCATTGCTGAATATCTGGCAGATGAAAAGAAATACTCAGTGGTTCTTTTG AGCAATATAACAGCTTGTTATATTAAAAATTTTCCCCACAGATATAAACTCTAAT CTATAACTCATAAATGTTACAAATGGATGAAGCTTACAAATGTGGCTTGACTTGT 105MF-363253604Attorney Docket No.: 15979-20192.40 CACTGTGCTTGTTTTAGTTATGTGAAAGTTTGGCAATAAACCTATGTCCTAAATA GTCAAACTGTGGAATGACTTTTTAATCTATTGGTTTGTCTAGAACAGTTATGTTGC CATTTGCCCTAATGGTGAAAGAAAAAGTGGGGAGTGCCTTGGCACTGTTCATTTG TGGTGTGAACCAAAGAGGGGGGCATGCACTTACACTTCAAACATCCTTTTGAAA GACTGACAAGTTTGGGTCTTCACAGTTGGAATTGGGCATCCCTTTTGTCAGGGAG GGAGGGAGGGAGGGAGGCTGGCTTGTTATGCTGACAAGTGTGATTAAATTCAAA CTTTGAGGTAAGTTGGAGGAACTTGTACATTGTTAGGAGTGTGACAATTTGGACT CTTAATGATTTGGTCATACAAAATGAACCTAGACCAACTTCTGGAAGATGTATAT AATAACTCCATGTTACATTGATTTCACCTGACTAATACTTATCCCTTATCAATTAA ATACAGAAGATGCCAGCCATCTGGGCCTTTTAACCCAGAAATTTAGTTTCAAACT CCTAGGTTAGTGTTCTCACTGAGCTACATCCTGATCTAGTCCTGAAAATAGGACC ACCATCACCCCCAAAAAAATCTCAAATAAGATTTATGCTAGTGTTTCAAAATTTT AGGAATAGGTAAGATTAGAAAGTTTTAAATTTTGAGAAATGGCTTCTCTAGAAA GATGTACATAGTGAACACTGAATGGCTCCTAAAGAGCCTAGAAAACTGGTACTG AGCACACAGGACTGAGAGGTCTTTCTTGAAAAGCATGTATTGCTTTACGTGGGTC ACAGAAGGCAGGCAGGAAGAACTTGGGCTGAAACTGGTGTCTTAAGTGGCTAAC ATCTTCACAACTGATGAGCAAGAACTTTATCCTGATGCAAAAACCATCCAAACA AACTAAGTGAAAGGTGGCAATGGATCCCAGGCTGCTCTAGAGGAGGACTTGACT TCTCATCCCATCACCCACACCAGATAGCTCATAGACTGCCAATTAACACCAGCTT CTAGCCTCCACAGGCACCTGCACTGGTACACATAATTTCACACAAACACAGTAA GAAGCCTTCCACCTGGCATGGTATTGCTTATCTTTAGTTCCCAACACTTGGGAGG CAGAGGCCAGCCAGGGCTATGTGACAAAAACCTTGTCTAGAGGAGAAACTTCAT AGCTTATTTCCTATTCACGTAACCAGGTTAGCAAAATTTACCAGCCAGAGATGAA GCTAACAGTGTCCACTATATTTGTAGTGTTTTAAGTCAATTTTTTAAATATACTTA ATAGAATTAAAGCTATGGTGAACCAAGTACAAACCTGGTGTATTAACTTGAGAA CTTAGCATAAAAAGTAGTTCATTTGTTCAGTAAATATTAAATGCTTACTGGCAAA GATTATGTCAGGAACTTGGTAAATGGTGATGAAACAATCATAGTTGTACATCTTG GTTCTGTGATCACCTTGGTTTGAGGTAAAAGTGGTTCCTTTGATCAAGGATGGAA TTTTAAGTTTATATTCAATCAATAATGTATTATTTTGTGATTGCAAAATTGCCTAT CTAGGGTATAAAACCTTTAAAAATTTCATAATACCAGTTCATTCTCCAGTTACTA ATTCCAAAAAGCCACTGACTATGGTGCCAATGTGGATTCTGTTCTCAAAGGAAGG ATTGTCTGTGCCCTTTATTCTAATAGAAACATCACACTGAAAATCTAAGCTGAAA GAAGCCAGACTTTCCTAAATAAATAACTTTCCATAAAGCTCAAACAAGGATTACT TTTAGGAGGCACTGTTAAGGAACTGATAAGTAATGAGGTTACTTATATAATGATA 106MF-363253604Attorney Docket No.: 15979-20192.40 GTCCCACAAGACTATCTGAGGAAAAATCAGTACAACTCGAAAACAGAACAACCA GCTAGGCAGGAATAACAGGGCTCCCAAGTCAGGAGGTCTATCCAACACCCTTTT CTGTTGAGGGCCCCAGACCTACATATTGTATACAAACAGGGAGGTGGGTGATTTT AACTCTCCTGAGGTACCTTGGTAAATCTTTGTCCTGAGTAAGCAGTACAGTGTAC AGTTTACATTTTCATTTAAAGATACATTAGCTCCCTCTACCCCCTAAGACTGACA GGCACTTTGGGGGTGGGGAGGGCTTTGGAAAATAACGCTTCCATACACTAAAAG AGAAATTTCTTTAATTAGGCTTGTTGGTTCCATACATCTACTGGTGTTTCTACTAC TTAGTAATATTATAATAGTCACACAAGCATCTTTGCTCTGTTTAGGTTGTATATTT ATTTTAAGGCAGATGATAAAACTGTAGATCTTAAGGGATGCTTCTGCTTCTGAGA TGATACAAAGAATTTAGACCATAAAACAGTAGGTTGCACAAGCAATAGAATATG GCCTAAAGTGTTCTGACACTTAGAAGCCAAGCAGTGTAGGCTTCTTAAGAAATAC CATTACAATCACCTTGCTAGAAATCAAGCATTCTGGAGTGGTCAAGCAGTGTAAC CTGTACTGTAAGTTACTTTTCTGCTATTTTTCTCCCAAAGCAAGTTCTTTATGCTG ATATTTCCAGTGTTAGGAACTACAAATATTAATAAGTTGTCTTCACTCTTTTCTTT ACCAAGGAGGGTCTCTTCCTTCATCTTGATCTGAAGGATGAACAAAGGCTTGAGC AGTGCGCTTTAGAAGATAAACTGCAGCATGAAGGCCCCCGATGTTCACCCAGAC TACATGGACCTTTCGCCACACATGTCCCATTCCAGATAAGGCCTGGCACACACAA AAAACATAAGTCATTAGGCTACCAGTCTGATTCTAAAACAACCTAAAATCTTCCC ACTTAAATGCTATGGGTGGTGGGTTGGAAAGTTGACTCAGAAAATCACTTGCTGT TTTTAGAGAGGATCTGGGTTCAGTTTCTGATACATTGTGGCTTACAACTATAACTC CAGTTCTAGGGGGTCCATCCAACATCCTCTTCTGTTGAGGGCACCAAATAAATGT ATTGTGTACAAACAGGGAGGTGAGTGATTTAACTCTCGTGTATAGTACCTTGGTA AAACATTTCTTGTCCTGAGTAAGCAGTACAGCTCTGCCTGTCCCTGGTCTACAGA CACGGCTCATTTCCCGAAGGCAAGCTGGATAGAGATTCCAATTTCTCTTCTTGGA TCCCATCCTATAAAAGAAGGTCAAGTTTAATCTATTGCAAAAGGTAAATAGGTAG TTTCTTACATGAGACAAGAACAAATCTTAGGTGTGAAGCAGTCATCTTTTACAGG CCAGAGCCTCTATTCTATGCCAATGAAGGAAACTGTTAGTCCAGTGTTATAGAGT TAGTCCAGTGTATAGTTTTCTATCAGAACACTTTTTTTTTAAACAACTGCAACTTA GCTTATTGAAGACAAACCACGAGTAGAAATCTGTCCAAGAAGCAAGTGCTTCTC AGCCTACAATGTGGAATAGGACCATGTAATGGTACAGTGAGTGAAATGAATTAT GGCATGTTTTTCTGACTGAGAAGACAGTACAATAAAAGGTAAACTCATGGTATTT ATTTAAAAAGAATCCAATTTCTACCTTTTTCCAAATGGCATATCTGTTACAATAAT ATCCACAGAAGCAGTTCTCAGTGGGAGGTTGCAGATATCCCACTGAACAGCATC AATGGGCAAACCCCAGGTTGTTTTTCTGTGGAGACAAAGGTAAGATATTTCAATA 107MF-363253604Attorney Docket No.: 15979-20192.40 TATTTTCCCAAGCTAATGAGATGGCTCAGCAAATAATGGTACTGGCCATTAAGTC TCATGACCTGAGCTTGATCCTCAGGGACCATGTGGTACAAGGAGAGACCTAAAT CCTTCAGTTGGACTTCAATCTTCTACCCTCATGTCCACACACAAATAAATACAAT AAAAAACATTCTGCAGTCTGAATTTCTAAAGGTTGTTTTTCTAAAAAGAAATGTT AAAGTAACATAGGAAGAAATATGTCCATAACTGAAATACAAGTTTTTTAAATGG TTAAGACTGGTTTTCAAAGGATGTATGGTTAAGAAAATACCAGGGAAAATGAGC TTACATGTAAAAAAGTGTCTAAAAGGCCAGAGAAATGACCCAGCTGGCAAAGGT GTCTGCCCTAAGCCAGACAAAAGGAATTTGATTCACAGGAAGAAGAGACCCAAC TCTCACTAGTTATCCTCTGACTTCCACACCATGACACAGCTCCATGGCACTCTCA GGCCCCCACACATATACAGATATAAACAGAAACCTAATCCACCAGCCTTCAGAA GCAAAGCAATTGGAGGATTTAAACAGGCCATGGCTACTAATAGAGATAACTGGT AGTTTAAAAGTTATGGTAATGACTTTCATGCTTCTTTCAACTCATATTGTTCTAAA TAATTAATTTGGTTTTTCAAGGCAGGGTTTCTCTGTGTAGTTCTGGCTGTCCTGGA ACTCACTCTGTAGACCAGGCTGGCCTTGAACTCAGATCCATCTGCCTCTGGAATA AGGGCACGTGCGTGCCTTTTCTACATAACAAAACCTATACTATAACAAAACCTAT ACCATACTGTACCGTTTTGGGAAAAGACAAAAAATAATGAACAAAAAAGGAGA AATAACATTCCAATAAAGTATGGAAATGGTAGTTAAATTAATTACAAATGTTTTT CAGTAAATTAGATGTGACTTCTCATACTGTTCATTTGGCTATAATGATACCACAA AGCACTGGGGGTGAATAATAATTCCAAGTCAGTAGGGAGAGAGACTTGAAAAGA TGCAATGCAATCATTGAAGTTAAACTTACCCATCTTTAATCTGGCTCTTAGTCAAT AGAGATGAGATGTTATTTGCTGCTCTGTTCACTGCCAGTGGGTTATTGTCCCCAG CAATATGGTAACAGTGAGACCACTCAGTAGCCCCCTATGAGACAGGAGTGTTGG TTAAACATGCCACAAGAGAAAAGGGAAAAGTCACTATGGCCAACTCTCAGTAAC ATGGCAATCCGTGCCATTCATTTCCTTGCCAGAAATGTCTTCCCTGTTCTTCTGCC TACTGAACTTTCACCCACTAGAAATGTGGCTCCAATGTCATCCACTATGACATCA ATGTCAGCGCTAGAAGCACTTTGCACACCTCTGTTGCTGACTTAGCCCATTTGAA ACTATGTCTATCACCTCTGCCTAAGTAATCCAGCAATTCCTTCCAGATAGGTCTA GTATTTTCTTTCTACCCGGCAATGGCTGGCACATATAAGGGACTGCATTCTCTTA ATTAACATGATTTTTAAAAATTTACCTAACTAACCAGACCTATGCTGTCTTGGATT GTGAGTTTAGCTTTTAAAAGATAACCACATTTCTGAAAAGATTTTGTAGTTAAGT AAAAAATGTCAGCAGCATATAAATGCCAAGCAGTGACATATTTGTGAAACAAAG TGACATACTATGGTACTGTTTCTGCCACAAAGACATGCATGCATGAATACAGCAC TTCATAACTATTTTGCCCAGACCCTTTAGGATGATGACATTCTGGTCTATTATTCT ATAATGACAGCAAACAAGAGGAATGTTCAAGTATGCCATAAACTGGGTGTGCAG 108MF-363253604Attorney Docket No.: 15979-20192.40 GGATACAGGAAGAACTCACAGGTGTGATCTGTGCTTGCCAACCTTTTTATTTTTTT TAATTATTATTTTAATGTTTAATCCAGGATGGATTTCCTACCTTGGGCTACATTTA CAGTACTTCTAAATCTCAGTGTCTTCTAGGACAGGTATTAGATAATTTAATGGGC ACATCTGTACACAGACCCTTCAGTTTCCATCATGACTCAGCTGAAGTTTCCACGT AGGTACTCTCTCTCATGCCTACTTTTACGTGGAAATGGCTTAATCTGGTTTTCCCA CCCCACCCCTTTTATTCTGATGTCTACTTTGATTGTGTGTTTCTTCATCATGGTCAG TTTACCTGCCATTTCGCAGATAAGTCATGGTTTAATGATGGAGAACTACAGTTTG GTTTCCAGAATTCTTGACTATAATAATTCAGCTCCTGTTCAGATCTCAAGAAGTA GTCACTCACTAGCCACCACCAGTGGAACATTCAAACTAGGTGCATTTTCCTCTTG GATTTTAACTCCCAATCAAAGTCAGACCAGAGATTTCCTAATTATACTAGATTAT TTTTCCCTTTGTGGGTTGCTTTGGGCTTGCTCATCTGTCCAATTTCTGCCCGCTCA ACACAACCTGTGGTACCATGAATTCAAGGTGAGCCTGTGCTACATACCAAGACCT TGCCTCAAAAGGATTAAAAAAAAGAAAGAAAGAAAACATCTTCCCATTTCTTAC TTTGCCTTCTGTAATGTTTTGTTTTGTTTTTGTTTTTGTGACTGGCTTTCTCTGTGC AGCTCTGACTGTCCTGGAACTCACAAGAGATCTGCCTGCCTCTGCCTCTTGAGTA CTGGGATAAATGTATATGCCACCACCACCACCTAGTACCTTCTGTAGTTTTTTGA GTGTTGTAGCAATTCTGAAAATTATTGATGGTCACTGGGTATGTAGCCTTGTCAG ATTTCCTAAAATACGTTTTTTTTTTAAAAAAAAGGTCAAACGGCCAGGTAGTTTG TGCCCTAGAGGAGATGGGTGAATCCCTGTGAGTTTGAGGACAGCCAGGGCTACA TAATAAGACCCCCATCTCAAAACAAACATAAAGAATACTTATAGGTATTCTTTTT TTTTTTCCGAGACAGGGTTTCCTCTGTATAGCCCTGGCTGTCCTGGAACTCACTTT GTAGACCAGGCTGGCCTCGAACTCAGAAATCCGCCTGCCTCTGCCTCCTGAGTGC TGAGATTAAGGGTGTGCGCCACCACGCCCGGCAATTTAGGTATTCTTATGGGTTT GTTTTGCAGTGCTGGAGATCAAGCCCAGAACACCTGTTTTGCATGCAGATGCCCT GGCACTGAGCTGCAATGCTGTGGTTTCTCCTTCCCACTTATTCACTCCAGGAAGC TCTAATTATGTGGACGTTTATGACCCCCTCAGTTATCCTCTGCTGTTCAACCTAGT GCCTCGTCCATTCATTACAGGGAAAAAGGCTTATCAGTTTGCCGTTCTCAGCTCG CTTCTCTACCACTTCAGCTTTCACCATCTAACCACACGGTACTTGGCTGTGTGAAA TCAATGCTTACAATGCTTTAACAGAACTTTTACCCTGACTATGAGAAGTTTTTTCA AACTTTTGGGGTTTTTCTCATTGGATCCAATTTGCCCACCATTTTGAATAGATCAC TTGCTTATGTAAAAATAAAAAGCTGTTATTACCTCTATTGGTATTGCCCCTGTTCC ACACATTGGGTCCACTATTACATCAGTAGGCTTAGGTTCACAGAGCCTGGAGGG AGAAAACAATCCAGCACATGTGAAAACCAACCAAAAACTAAGACTGGGATCTAC TACTGGCATAGGATCTGCACACCAGCGTGAAGGATCAGCAATTTATGGTTTGAA 109MF-363253604Attorney Docket No.: 15979-20192.40 AGTCAGCCTGGGGTTGACACTCAGTAGCAGCCCTCGCCTATGCGTACAATGCTTC TGGTGGTAGGGGAGAGAGCGAGAGATACTGATTTGTTATCCTAGCACTCAGGAA GCTGAGGCAGGGAGATTTTTAGTGGGCATTTGCTGACAACCAGACATTCAGTCTC CTTTCATTTTGGATTTAACTATGGAGATACAGTCCTTAACATAAAATAACTGCTTT AACTTTATACACTTGAAATTCTTTAAACAACCCTATTACCATTTAACAGACAAAA TGATCCAAAGAAACATTTTTCCTAGGACACAAAATAAGGAGTCAAGACTACATG TGACTAGCTTTAAATGTTACTTACCAGTCCTCAGGTTACTAAGTTTTATCTGATTT TTCTATTCTGTTTGAGACCTTGCATCATGCATGTTAATGATCTCCCTCATAAGACG GATTCTTGGGCAAGCCTGTAATGCCAGTCATTGTTAATGGGCCAGAATTGGGCAC TTGATCAAATTATGTCACTCAAATCCTCTTAGGAATGTGGAATAAAGAGCAAGTA ACCCTGGGTCGTTTGAGCCAGTCATGTGCAACTGGAGGACAGGCAGTCAAGTGC ACAGGCGAGCTAAGCCAGAACACACAAGCTTTTAGAAGACAGGAAAGCAGTCCT TTGCATTTTCTACTATCTAGTTTCTGCACCTCTTAATTTTTAGCCTTTATGTCTATG GATATATTGCTGTCATGTATATCTGTATCACATGTGAGCACTGCCTGTCAAATCA AAAAGAGGGCATCTGACCCCTTGAGGCAAGTTATTAACCATTATGAGCCACCAT GTCAGTGCTAGGAATTGAACCCAGGTTCTCTGGAACAGCCATCTGTCTAGCCCTG TAGTTTCTGCCTTTCTTGAGAATCGCCCAAGGGTTTTTTGTGGATCTGGTATAATC TTTGCTCATCTCTCCAACCACCGCAATCCTCAGCATAATTATCACTTCATGTGTCT GTACACTTGTGTTTGCCACATGCACATGAAAGCCAAAAATAGAAATCAAGATCT GGCATCCCAATCCACCACCCTGCTTGCCTCTTGTTTTGGTTTTTTTGAGAGAGGGT CTCTACAGAGCCCTGGCTGTCCTGGAACTATGTAGGCCAAGCCCAAGCTGGCCTT GAGTTCACAGAAATCTATCTGCCTCAGCCTCCTAAGTGCTGAGATTAAAGGTATG TGCCACTGCACTCAGCTGGGCACCTTTCTCAATTGCTCTTTACCTCACAACCTAGA GCTCACAAATTCAGTTAGAGTGGCTGGCCAGAAAGCCTGGGGTATCCTCCTGTCT CAGCCTCCTCAATGCTAGGATTATTGACAATAGCGATGCTGTGAGGCTGGGGTTA GGCTTGTGCGGAGAGTGCACCAGGCTGTCTCCTCAGCCCAATCATTACTTTTTTA TTCTATTTAGTTTTTAATACCAGCACTCAACTCTGTATGCTGGTTTCTATAATCAT GGTTGGAGGCAGATAGTAAATATCTGTTTAGTGAAAGAAGCTTAGGAGTGTTTCT CTTAAGTTTTCTGTTACTAACTTAATGTGTTCCAGTTGTGAGGAACTGTGACCATG ACAAAAGAGGAAGCAAAAATTGAAAAGGAAGAAAATGTAATTATGTAACTCACT AGATCATGCCAGGAACTGTACAGAATAAGATAATCTGACTATGTTTCTGCATTTA ATCCTTATGAACAAAATTTTTTAATAAATATTTTCACATTTTATTTATACATGTGT GTTAGTACCTCTGTGTGTGTACCCAAAGACCAGAAGAGGATATTGGAAGAGAGT ATGGAGCTGGAATTAAAGACTGTTGTAAGCTGCCAGGCATGGAAGTCTAGAACT 110MF-363253604Attorney Docket No.: 15979-20192.40 GAGCTCTGGTCATATGGAAAACCAGCATCAACATTAACTGTTGAGCCATCTCTCT AGCCCTAAAGTCAGTCACCACGTTTTTTTTTTTAAGTATGCATATGTGTGGGTGGG ATTTTTAAAGTATGTATGTGCTGGTGCCTACAGAAGACAGGTGTTGAATCCCCTG GAGCTGAAGTTGCAGGTTGTTGTTATCTACCAACCTGAATGTTAGGAACCAAACT TAGGTCCTCTGCAAGAGCAGCAGACATTCTTAAAGCTCTGAGCCATCTCTCCAGC ATGAGTAAACCTTTTCTTCTTTTTCTTTTTCTTTTCATATAGAACACTTCACAAATC TGTCTGTCATCTTTATGCAGGGGCCATACTAATCTTCTCTATATTGCTTTAGTTGA GTGTATGTGCTGCCAAGTTGAGCACATGAATAATCTTTGGCATCCCATGTCAAGC CCATTTTGCAGTACTGAAATCTCAAGTGTAGGGGGGAAAAAGACTTATTTGAGA AAGAAAACACCAAGAACGTAAGACTGACAACAGAGGCAGGCTGCTTGTCTTGCA CTTGTCAAAGTCCCAACACGATCCCTAGGTTACAGCCAGTGTAACATTTAAAACT ATGAGTAAATGGGGTGTGGTGATATGTACCATGATCCCAGCACTCAGGCTACCA AGCTGCATGCCAGCACTGTCACTCAACAGACAAGGTCTGTACTCACTCACACATC ACAAGGATCTCCTCTGCTTCACTCTATTGCCTAAAGCAGCACAGCCTCTCTCGAC AGAAGCAGCTCCTCGCTGAAGACACACAACACCACTCTCACATGTATAACCAAG AATACTAATAAACCATCCACGTGGTGTTTTCTGCATCAAAAACTGACAACAGTAA ATACTGAAGAGAAAATAGGTACTTTGTAATTCTAACTAAGAAAATGGTTTTGGGA GTTTTTGTTTTGTTTTTTTTTAGAAAATGAGTGATTTAATTCAGAGCAAAGTGTTC ATTACAATATGGACAGCAAAATCCCCTTCTGTTACCTGAGCATCCCATAGGCAAG AGTTGACCTAAGAGTTGTAGGTCCAAAATGTGTAATATTTCTGCGATGGAGACTC TCTTCTGTCAGTGCAATAGCAACAATGACTTCATTATCATGGATGTTCAGGAGAA CCTACATCAAATTAGAGACAAACGAGAAAGTCAACAGTCTTCGAACTGTACCTA CTAACAAGACCCTTAAAAACAATCCAGGGCCTTATCTGGCTGTGGTACTACCTCC CAAGTGCTCTAACTAATCCCAGCACTTAGAAGGCAGAGGCAGGCGGATCTCTGT AAGTTCAAGGCCAACCAGGTCTACACAGTGAGTTCCAGGGCAGCCAGGACTAGA TAGAAAGACTGTCTCAAACAAACAACAACAAAATAAATAAATAAATAAATTTAA AAGAGTAAAATAAACAGAGCCTTGAAGCCAAAATTGGCTTGAATTCTTAGATAG GCTAGCTGGACTGAAACTCAAAATCCTCTTGCCTCTGCCTCATAAATGCTGTGAT CACAAGAAAGAGATACATGTCTTCCTTATTAAGACTTTTTGAATTAAGATAAAAA CAACAAAACCAGGGCTAGGTCTGAGGTGAGCCAATGGGAAGAGTACTTGCTTGG CAAGTATGAAGATCTGAGTTTATCCCTGGAACCCAAGTAAAAGCCAAGCATGGC TTATACATACATAACAGCCACAACACAGAGAACTTTCTTTTCAGAACATTTTAAA TTTTTATTCTATGTGCACAAATGTTTTGCCTGAATGTATATCTGTGCACCACATGC ACACTTGGTGCCCATGGAAGCTAGAAAGAGGTGTGTGATCCCTTGGAACTAGAG 111MF-363253604Attorney Docket No.: 15979-20192.40 TTACAGCTACCTACCGTATGGGTGCTGGGAATTAAACTTGTATCCTCTGAAAGAG CAGACAATTCTTTTAACTGCTAAGCTATCTTGCCAGCCTATACAAACTTTCTGATT GAATTATACTTTACAGGTTTACTATACAGTACATAAAATTCAGTTATTTGCGTATT TATTTGTGTTTGTGTATGGATTGGGTTTGGGGATCAGAGGACAACTTCTACCATG CATCCTAGGAACTGAACTCAGGTCAGCAACCTTAGTGGTAAATCTGCCTACCTAG TGAGCCCAGAGGTGTAAGCCTTCTGCATATACATTTCAGTGAGCTCTGACCTATA CTCAGTACCCTTTACAAAGTTCTCTTTTGTCTCTTTCCTGGGTGATCATTAATCTA ACCACTATTATTATAAGTTAGTTGTATCAGTTTTTGGAGTTAACAAAAATGAAAT AGTATATGTACTATTTTCATTTAATTTTAAAACATTTTATTCTTTTTACTCCCCCCA CACACAGGCTATTAATAAGTTATCTCCCAGTTTTTATTATATGAACATATTTTGAT GGTATAGATTTAAAATATGTATGTATGTTTTGGGTTTTTTTTTTTTCTACCACCTTT TATTTTCTCAATACAGGCTTCTCTGTGTAACTTTGGCTGTCTTGGAACTCACTCTA TAGACCAGGCTGGCCTCAACTCAGAGATTCATCTGCCTCTGTCTCCCAAATGCTG GGATTAAAGGTGTGTACAACCACTGCCTGGGTGTGTGTGTGTGTTTCACTGTGCC CTTTGGCTGGCATGGAAGTCACTATGGAGACCAGGCTGGCCTTAAAATTAGAGA TCTGACAGTCTCTGTCTCCTGAGTCTGGGATCCAAGGCATGTGCCACCACATTTG GTCTACATATATTTTTTAAATTACTACGTGTTTTTGAAGAACACTTCAAACACTTT AACGGTGGCCTCTCAAAACATACCCTTTATCCAAAGCTGACACCACGTCATGTTT GCTTTTATTTTGTTTTCCTAGTAGTTTGTCTTTCTTTCTTTCTTTTTTTTTTTTTTTTT TTTTTTTTTTTTTTTTTTGAGACAGGGTTTTTCTGTGTAGCCTTGGCTGTCCTGGAA CTCACTCTGTAGACCAGGTTGACCTCAAACTCAGAAATCTGCCTGCCTCTGCCTC CCAAGTGCTGGGATCACAGGCGTGCACCACCACGCCCAGCTCCTGGTAGTTTTAT AACAATGTCTGATTATGACTACCTTTGTCCTAGTTTTCCTAACTCACAAACATTCT AAGAAGATAAAATGTTCCCCAGTATTCCCCCTAAAATGTCCTCATCATGGCCTTA CCAAAGGCAGAGGTCTAGAGCTAACACTCTAACATGCAAGGCCCTGTCCTACAT ATCTTATTCACATGGCCTCATTTCCTAGGAAGCCCTCTGAGCCTGGGACACAGAG ACACCAGTTCATACAGGATTTGTCTTCTGTGCTACCTTGGAGACTTCTGGACATG GCCTTTGTTAGCCTCTTTGTTCTTACAGCTGTGTAAGAAAATATAGAATGGAGAA TTGTTCTTGTCTGACATTAAAAAAAAAAAAAAAGTTACAAAGAGAGTGATATGC CCCAGGCTTGAGTATCCCAAATGAAACAAAAATTGACTTCTTGGTAAAAATGTCA ACTGCTAAGGACCTACATAAACCATCAGAAATTTAAAGAACTCCAATTACCATTA TCAACAAAAGTCACCCAGTAGTCACAAGGATACTCAAGCTAACAGGAGGCATTT GGTTTTAAGAACCTAGCTGACTTTAAAAAGAACAAAGCTGGCTCTAGATGAAGA TTAGCTCTAAAACCCTGATAGAAGGTTCTGAAAACTATATTCTATTATTGTTTAGT 112MF-363253604Attorney Docket No.: 15979-20192.40 AGCAGAATTTCCAACTAAGGTAGAAGTAAGTTTATTTTAGGTTAAGTTACAATCT AGAAATCCATATAATGTAGAAAAATACTAGATTAGAAATAAGAAGACTGGGGCT GGTGA SEQ ID NO:11 (5′ homology arm genomic sequence, nucleic acid) CCTCCTAGCGACCTAAACCATTATTAATATCAAATTAACCATCAAAACACTTTCC TCTCAATATGCTGCACACAAACCTCCTCCTGGAACCTCCTCCATCTGGATCCTCCC CAATCAAAAGTATAGGTATTTAACATATAAGCAAGGAAGTAATGTAAACATGAC CTTGGTCACAAATATGTCATCTAAAAACAATTTAGTCAAGGTATGGAGGAAATTC GAGAACCTGAATCTTTTTAAGTATTTTGAGCACAGGAACAATTGGCAAAAGGAA TCCAGGTATAGACAAAACCCAGAGCCCAGAGCTCTGGGCGAAAAATGAGTTGCT GGTGAAGACGTTACACAAGTAACATGAGAAAGCAGAAAATGCAGGTCATCCACG CACCCCTGACCCAGGCCAGCAGGGCGGGCTGCAGCATCAGTACACAGGAGAAAG ATCCTTATTCCTAAGAATGAGAAAGGCAAAGGCGCCCGATAGAATAAATTAGCA TAGAAGGGGCTTTCCCAGGAGTTAAAACTTTCCTTCTGAGCGATTACCTACTAAA ACCAGG SEQ ID NO:12 (3′ homology arm genomic sequence, nucleic acid) GACACGGCTCATTTCCCGAAGGCAAGCTGGATAGAGATTCCAATTTCTCTTCTTG GATCCCATCCTATAAAAGAAGGTCAAGTTTAATCTATTGCAAAAGGTAAATAGGT AGTTTCTTACATGAGACAAGAACAAATCTTAGGTGTGAAGCAGTCATCTTTTACA GGCCAGAGCCTCTATTCTATGCCAATGAAGGAAACTGTTAGTCCAGTGTTATAGA GTTAGTCCAGTGTATAGTTTTCTATCAGAACACTTTTTTTTTAAACAACTGCAACT TAGCTTATTGAAGACAAACCACGAGTAGAAATCTGTCCAAGAAGCAAGTGCTTC TCAGCCTACAATGTGGAATAGGACCATGTAATGGTACAGTG SEQ ID NO:13 (region of human SERPINA1 gene sequence upstream of exon 1, nucleic acid) tctcccatagtccccacgcaagggtgagtcttgcacgctcagccctgcctgtggttcccagaaggcctctgtcactgcgtgcttgctttct ctcccagggaagataccccagtgccatgtcttggggcaagagaaaatgaagacagacctggaacatgaacatggtggccttgccag aaagcaagtgtgtgttgctgaaacatcagcagagattgtcaaagggataaagagataacttaaaagggttcctattgaccaaaatgcga caagttgaccatctaaaatcaaatcataattatagttcaataggacacattgagtctcttaaaagcttccaatccgtaatgaccatcaaggc ccataacctcaaaagagtaaagttaaaataaagttcagaaaaggttagctgcaataaaacatgagttttagtaattttaacaagaagggg atgaagctatagatgcatttttattccttcttttaactatgttgccccttataatgtatagctttgccttatttttctctgtctgagtaaggataaag 113MF-363253604Attorney Docket No.: 15979-20192.40 agtaaaggccaggcacagtggctcacacctgtaattccagcactttgggaggccgaggcgggcagataacttgaggccaggagtttg agaccagcctggccaacatggtgaaaccctgtcactactaaaaatacaaaaattaactggaattggtagcacatgcctgtaatgccagc tactctggaggctgaggcacgagaatcgctcgtaattccagaattcgagaggtggagtttgcagtaagccaagattgcgccactgtact ccagcctgggtgactgagtgagactctgtctcaaaaaaaaaaaaaaaaagaagaagctgtgagtaggccacatagttccagaaaatg cagaaatcccccctcccctccccaacacacaggaagtggctcaggagattacacacagaaggaaagtgtgtctgctggggttttgcaa gttggctaatttgaaaggtgactggaggaggtgaaaaaatggtgcaaacttcattcattcattaaatgagttataagaagacagacacaa gtgtccattatgctaacagagctctgtgttaaacaccccaccagcatcgcctcatctaagcctcagaagagctatgtgggaaagaaactt ttatccctattttatagatgaggaaaccaaggctcagagaactgagggcctcccccggatccaagtccacctagctgcagtcaccccac atcctctgcatgtcacaggtgctcagaaagatgctgaaggcacctggcccttcaccttcggaaagccaaaatgagcacggcccctaaa gaggggattgacagccttttctggaaaaaatggaagtttgaatctgaggaggtgtccctcaacaacaggtgctgctccccaaatctggg gccaaacgcagcagttgttcccccacttagacccctgagacccatctatatggtttttcagagccaggacacatccccaaaggtcatgg cctttggtggttagcattgacttggggcccatcacatgccagaggctgcccgaagtgcttaaatgttattatctcattcgatcttcacagtc ctgatggaagtgactcttcttagagtcttcctatctcacagatgaggaaaccgaggcacagagaggttaagtggcttgtctaagagctca caaaaagagcgatggagctaaggcttggccccagatattagatcccgaacccacgccttaaccagtgacctgcactgactctcaaag aaggaagctggtgcctgggaaggagggtgcatagtgagggtgtgcatggggtgtgtgtgtttgtggggtggccagcactctccggg ggcactttgccaatgagttcagctcccatgaagtccactgttgttctcctgaccagccactcagtcttgatttacttggcccagggccact ggcacacctcacccccttacccgattccttgctgcagaccccaaatctcgactctcacatccctatccagcccataccacgaggctccc atctccaggcagggccctgtggtggggcagggcctcccccagatgccccttactcatgaccagctcacaggatcttcccatgatgcat ttcctctggggggatcagcccagatgctgcaatagacaattgtggaagtaaccaggtggacaagactttccccctcatgtcctggggtt cctgggggcacagtatccttgtgaatggccactgagtactcccacccctcccaccacaacccccgggattttgtcctggtgcgtttttcc agattatcctagcccttcctcccaggatggatgtccagagcagggcgggggctgagcctagagccctgccaaaagagcaggacccc aaattctgagccccttacttgcctcacctgctcccacccatgctttcttcattcctcctccaaaagccccagctccccactgcaatcccttct gcacccagccaggtcctatgacacacacctccccagtgcacacagacctgcccaactgtggggctgcccactgggcatttcataggt ggctcagtcctcttccctctgcagctggccccagaaacctgccagttattggtgccaggtctgtgccaggagggcgaggcctgtcattt ctagtaatcctctgggcagtgtgactgtacctcttgcggcaactcaaagggagagggtgacttgtcccgggtcacagagctgaaaggg caggtacaacaggtgacatgccgggctgtctgagtttatgagggcccagtcttgtgtctgccgggcaatgagcaaggctccttcctgtc caagctccccgcccctccccagcctactgcctccacccgaagtctacttcctgggtgggcaggaactgggcactgtgcccagggcat gcactgcctccacgcagcaaccctcagagtcctgagctgaaccaagaaggaggagggggtcgggcctccgaggaaggcctagcc gctgctgctgccaggaattccaggttggaggggcggcaacctcctgccagccttcaggccactctcctgtgcctgccagaagagaca gagcttgaggagagcttgaggagagcaggaaaggtgggacattgctgctgctgctcactcagttccacaggtgggagggacagcag ggcttagagtgggggtcattgtgcagatgggaaaacaaaggcccagagaggggaagaaatgcccaggagctaccgagggcaggc gacctcaaccacagcccagtgctggagctgtgagtggatgtagagcagcggaatatccattcagccagctcaggggaaggacagg ggccctgaagccaggggatggagctgcagggaagggagctcagagagaaggggaggggagtctgagctcagtttcccgctgcct gaaaggagggtggtacctactcccttcacagggtaactgaatgagagactgcctggaggaaagctcttcaagtgtggcccaccccac 114MF-363253604Attorney Docket No.: 15979-20192.40 cccagtgacaccagcccctgacacgggggagggagggcagcatcaggaggggctttctgggcacacccagtacccgtctctgagc tttccttgaactgttgcattttaatcctcacagcagctcaacaaggtacataccgtcaccatccccattttacagatagggaaattgaggct cggagcggttaaacaactcacctgaggcctcacagccagtaagtgggttccctggtctgaatgtgtgtgctggaggatcctgtgggtc actcgcctggtagagccccaaggtggaggcataaatgggactggtgaatgacagaaggggcaaaaatgcactcatccattcactctg caagtatctacggcacgtacgccagctcccaagcaggtttgcgggttgcacagcgggcgatgcaatctgatttaggcttttaaagggat tgcaatcaagtggggccccactagcctcaaccctgtacctcccctcccctccacccccagcagtctccaaaggcctccaacaacccca gagtgggggccatgtatccaaagaaactccaagctgtatacggatcacactggttttccaggagcaaaaacagaaacaggcctgagg ctggtcaaaattgaacctcctcctgctctgagcagcctggggggcagactaagcagagggctgtgcagacccacataaagagcctac tgtgtgccaggcacttcacccgaggcacttcacaagcatgcttgggaatgaaacttccaactctttgggatgcaggtgaaacagttcctg gttcagagaggtgaagcggcctgcctgaggcagcacagctcttctttacagatgtgcttccccacctctaccctgtctcacggcccccc atgccagcctgacggttgtgtctgcctcagtcatgctccatttttccatcgggaccatcaagagggtgtttgtgtctaaggctgactgggt aactttggatgagcggtctctccgctctgagcctgtttcctcatctgtcaaatgggctctaacccactctgatctcccagggcggcagtaa gtcttcagcatcaggcattttggggtgactcagtaaatggtagatcttgctaccagtggaacagccactaaggattctgcagtgagagca gagggccagctaagtggtactctcccagagactgtctgactcacgccaccccctccaccttggacacaggacgctgtggtttctgagc caggtacaatgactcctttcggtaagtgcagtggaagctgtacactgcccaggcaaagcgtccgggcagcgtaggcgggcgactca gatcccagccagtggacttagcccctgtttgctcctccgataactggggtgaccttggttaatattcaccagcagcctcccccgttgccc ctctggatccactgcttaaatacggacgaggacagggccctgt SEQ ID NO:14 (human SERPINA1 gene sequence of exon 1 through exon 5, nucleic acid) ctcctcagcttcaggcaccaccactgacctgggacagtgaatcgtaagtatgcctttcactgcgagaggttctggagaggcttctgagc tccccatggcccaggcaggcagcaggtctggggcaggaggggggttgtggagtgggtatccgcctgctgaggtgcagggcagatg gagaggctgcagctgagctcctattttcataataacagcagccatgagggttgtgtcctgtttcccagtcctgcccggtcccccctcggt acctcctggtggatacactggttcctgtaagcagaagtggatgagggtgtctaggtctgcagtcctggcaccccaggatgggggacac cagccaagatacagcaacagcaacaaagcgcagccatttctttctgtttgcacagctcctctgtctgtcgggggctcctgtctgttgtctc ctataagcctcaccacctctcctactgcttgggcatgcatctttctccccttctatagatgaggaggttaaggtccagagaggggtgggg aggaacgccggctcacattctccatcccctccagatatgaccaggaacagacctgtgccaggcctcagccttacatcaaaatgggcct ccccatgcaccgtggacctctgggccctcctgtcccagtggaggacaggaagctgtgaggggcactgtcacccagggctcaagctg gcattcctgaataatcgctctgcaccaggccacggctaagctcagtgcgtgattaagcctcataaccctccaaggcagttactagtgtga ttcccattttacagatgaggaagatggggacagagaggtgaataactggccccaaatcacacaccatccataattcgggctcaggcac ctggctccagtccccaaactcttgaacctggccctagtgtcactgtttctcttgggtctcaggcgctggatggggaacaggaaacctgg gctggacttgaggcctctctgatgctcggtgacttcagacagttgctcaacctctctgttctcttgggcaaaacatgataacctttgacttct gtcccctcccctcaccccacccgaccttgatctctgaagtgttggaaggatttaatttttcctgcactgagttttggagacaggtcaaaaag atgaccaaggccaaggtggccagtttcctatagaacgcctctaaaagacctgcagcaatagcagcaagaactggtattctcgagaact tgctgcgcagcaggcacttcttggcattttatgtgtatttaatttcacaatagctctatgacaaagtccacctttctcatctccaggaaactga 115MF-363253604Attorney Docket No.: 15979-20192.40 ggttcagagaggttaagtaacttgtccaaggtcacacagctaatagcaagttgacgtggagcaatctggcctcagagcctttaattttag ccacagactgatgctcccctcttcatttagccaggctgcctctgaagttttctgattcaagacttctggcttcagctttgtacacagagatga ttcaatgtcaggttttggagtgaaatctgtttaatcccagacaaaacatttaggattacatctcagttttgtaagcaagtagctctgtgattttt agtgagttatttaatgctctttggggctcaatttttctatctataaaatagggctaataatttgcaccttatagggtaagctttgaggacagatt agatgatacggtgcctgtaaaacaccaggtgttagtaagtgtggcaatgatggtgacgctgaggctgatgtttgcttagcatagggttag gcagctggcaggcagtaaacagttggataatttaatggaaaatttgccaaactcagatgctgttcactgctgagcaggagccccttcctg ctgaaatggtcctggggagtgcagcaggctctccgggaagaaatctaccatctctcgggcaggagctcaacctgtgtgcaggtacag ggagggcttcctcacctggtgcccactcatgcattacgtcagttattcctcatccctgtccaaaggattcttttctccattgtacagctatga agctagtgctcaaagaagtgaagtcatttaccccaggccccctgccagtaagtgacagggcctggtcacacttgggtttatttattgccc agttcaacaggttgtttgaccataggcgagattctcttccctgcaccctgccgggttgctcttggtcccttattttatgctcccgggtagaaa tggtgtgagattaggcagggagtggctcgcttccctgtccctggccccgcaaagagtgctcccacctgccccgatcccagaaatgtca ccatgaagccttcattcttttggtttaaagcttggcctcagtgtccgtacaccatggggtacttggccagatggcgactttctcctctccagt cgccctcccaggcactagcttttaggagtgcagggtgctgcctctgatagaagggccaggagagagcaggttttggagtcctgatgtt ataaggaacagcttgggaggcataatgaacccaacatgatgcttgagaccaatgtcacagcccaattctgacattcatcatctgagatct gaggacacagctgtctcagttcatgatctgagtgctgggaaagccaagacttgttccagctttgtcactgacttgctgtatagcctcaaca aggccctgaccctctctgggcttcaaactcttcactgtgaaaggaggaaaccagagtaggtgatgtgacaccaggaaagatggatgg gtgtgggggaatgtgctcctcccagctgtcaccccctcgccaccctccctgcaccagcctctccacctcctttgagcccagaattcccct gtctaggagggcacctgtctcatgcctagccatgggaattctccatctgttttgctacattgaacccagatgccattctaaccaagaatcct ggctgggtgcaggggctctcgcctgtaaccccagcactttgggaggccaaggcaggcggatcaagaggtcaggagttcaagacct gcctggccaacacggtgaaacctcagctctactaaaaatacaaaaattagccaggcgtggtggcacacgcctgtaatcccagctatttg ggaagctgagacagaagaatttcttgaacccgggaggtggaggtttcagtgagccgagatcacgccactgcactccaccctggcag ataaagcgagactctgtctcaaaaaaaacccaaaaacctatgttagtgtacagagggccccagtgaagtcttctcccagccccactttg cacaactggggagagtgaggccccaggaccagaggattcttgctaaaggccaagtggatagtgatggccctgccagggctagaag ccacaacctctggccctgaggccactcagcatatttagtgtccccaccctgcagaggcccaactccctcctgaccactgagccctgtaa tgatgggggaatttccataagccatgaaggactgcacaaagttcagttgggaagtgaaagagaaattaaagggagatggaaatataca gcactaattttagcaccgtctttagttctaacaacactagctagctgaagaaaaatacaaacatgtattatgtaatgtgtggtctgttccattt ggattacttagaggcacgagggccaggagaaaggtggtggagagaaaccagctttgcacttcatttgttgctttattggaaggaaacttt taaaagtccaagggggttgaagaatctcaatatttgttatttccagctttttttctccagtttttcatttcccaaattcaaggacacctttttctttg tattttgttaagatgatggttttggttttgtgactagtagttaacaatgtggctgccgggcatattctcctcagctaggacctcagttttcccat ctgtgaagacggcaggttctacctagggggctgcaggctggtggtccgaagcctgggcatatctggagtagaaggatcactgtgggg cagggcaggttctgtgttgctgtggatgacgttgactttgaccattgctcggcagagcctgctctcgctggttcagccacaggccccac cactccctattgtctcagccccgggtatgaaacatgtattcctcactggcctatcacctgaagcctttgaatttgcaacacctgccaaccc ctccctcaaaagagttgccctctcagatccttttgatgtaaggtttggtgttgagacttatttcactaaattctcatacataaacatcactttatg tatgaggcaaaatgaggaccagggagatgaatgacttgtcctggctcatacacctggaaagtgacagagtcagattagatcccaggtc 116MF-363253604Attorney Docket No.: 15979-20192.40 tatctgaagttaaaagaggtgtcttttcacttcccacctcctccatctactttaaagcagcacaaacccctgctttcaaggagagatgagcg tctctaaagcccctgacagcaagagcccagaactgggacaccattagtgacccagacggcaggtaagctgactgcaggagcatcag cctattcttgtgtctgggaccacagagcattgtggggacagccccgtctcttgggaaaaaaaccctaagggctgaggatccttgtgagt gttgggtgggaacagctcccaggaggtttaatcacagcccctccatgctctctagctgttgccattgtgcaagatgcatttcccttctgtg cagcagtttccctggccactaaatagtgggattagatagaagccctccaagggcttccagcttgacatgattcttgattctgatctggccc gattcctggataatcgtgggcaggcccattcctcttcttgtgcctcattttcttcttttgtaaaacaatggctgtaccatttgcatcttagggtc attgcagatgtaagtgttgctgtccagagcctgggtgcaggacctagatgtaggattctggttctgctacttcctcagtgacattgaatag ctgacctaatctctctggctttggtttcttcatctgtaaaagaaggatattagcattagcacctcacgggattgttacaagaaagcaatgaat taacacatgtgagcacggagaacagtgcttggcatatggtaagcactacgtacattttgctattcttctgattctttcagtgttactgatgtcg gcaagtacttggcacaggctggtttaataatccctaggcacttccacgtggtgtcaatccctgatcactgggagtcatcatgtgccttgac tcggggcctggcccccccatctctgtcttgcaggacaatgccgtcttctgtctcgtggggcatcctcctgctggcaggcctgtgctgcct ggtccctgtctccctggctgaggatccccagggagatgctgcccagaagacagatacatcccaccatgatcaggatcacccaaccttc aacaagatcacccccaacctggctgagttcgccttcagcctataccgccagctggcacaccagtccaacagcaccaatatcttcttctc cccagtgagcatcgctacagcctttgcaatgctctccctggggaccaaggctgacactcacgatgaaatcctggagggcctgaatttca acctcacggagattccggaggctcagatccatgaaggcttccaggaactcctccgtaccctcaaccagccagacagccagctccagc tgaccaccggcaatggcctgttcctcagcgagggcctgaagctagtggataagtttttggaggatgttaaaaagttgtaccactcagaa gccttcactgtcaacttcggggacaccgaagaggccaagaaacagatcaacgattacgtggagaagggtactcaagggaaaattgtg gatttggtcaaggagcttgacagagacacagtttttgctctggtgaattacatcttctttaaaggtaaggttgctcaaccagcctgagctgtt cccatagaaacaagcaaaaatattctcaaaccatcagttcttgaactctccttggcaatgcattatgggccatagcaatgcttttcagcgtg gattcttcagttttctacacacaaacactaaaatgttttccatcattgagtaatttgaggaaataatagattaaactgtcaaaactactgacag ctctgcagaacttttcagagcctttaatgtccttgtgtatactgtatatgtagaatatataatgcttagaactatagaacaaattgtaatacact gcataaagggatagtttcatggaacatactttacacgactctagtgtcccagaatcagtatcagttttgcaatctgaaagacctgggttcaa atcctgcctctaacacaattagcttttgacaaaaacaatgcattctacctctttgaggtgctaatttctcatcttagcatggacaaaataccat tcttgctgtcaggtttttttaggattaaacaaatgacaaagactgtggggatggtgtgtggcatacagcaggtgatggactcttctgtatctc aggctgccttcctgcccctgaggggttaaaatgccagggtcctgggggccccagggcattctaagccagctcccactgtcccaggaa aacagcataggggaggggaggtgggaggcaaggccaggggctgcttcctccactctgaggctcccttgctcttgaggcaaaggag ggcagtggagagcagccaggctgcagtcagcacagctaaagtcctggctctgctgtggccttagtgggggcccaggtccctctcca gccccagtctcctccttctgtccaatgagaaagctgggatcaggggtccctgaggcccctgtccactctgcatgcctcgatggtgaagc tctgttggtatggcagaggggaggctgctcaggcatctgcatttcccctgccaatctagaggatgaggaaagctctcaggaatagtaag cagaatgtttgccctggatgaataactgagctgccaattaacaaggggcagggagccttagacagaaggtaccaaatatgcctgatgc tccaacattttatttgtaatatccaagacaccctcaaataaacatatgattccaataaaaatgcacagccacgatggcatctcttagcctga catcgccacgatgtagaaattctgcatcttcctctagttttgaattatccccacacaatctttttcggcagcttggatggtcagtttcagcacc ttttacagatgatgaagctgagcctcgagggatgtgtgtcgtcaagggggctcagggcttctcagggaggggactcatggtttctttatt ctgctacactcttccaaaccttcactcacccctggtgatgcccaccttcccctctctccaggcaaatgggagagaccctttgaagtcaag 117MF-363253604Attorney Docket No.: 15979-20192.40 gacaccgaggaagaggacttccacgtggaccaggtgaccaccgtgaaggtgcctatgatgaagcgtttaggcatgtttaacatccag cactgtaagaagctgtccagctgggtgctgctgatgaaatacctgggcaatgccaccgccatcttcttcctgcctgatgaggggaaact acagcacctggaaaatgaactcacccacgatatcatcaccaagttcctggaaaatgaagacagaaggtgattccccaacctgagggt gaccaagaagctgcccacacctcttagccatgttgggactgaggcccatcaggactggccagagggctgaggagggtgaacccca catccctgggtcactgctactctgtataaacttggcttccagaatgaggccaccactgagttcaggcagcgccatccatgctccatgag gaggacagtacccaggggtgaggaggtaaaggtctcgtccctggggacttcccactccagtgtggacactgtcccttcccaatatcca gtgcccagggcagggacagcagcaccaccacacgttctggcagaaccaaaaaggaacagatgggcttcctggcaaaggcagcag tggagtgtggagttcaagggtagaatgtccctggggggacgggggaagagcctgtgtggcaaggcccagaaaagcaaggttcgga attggaacagccaggccatgttcgcagaaggcttgcgtttctctgtcactttatcggtgctgttagattgggtgtcctgtagtaagtgatact taaacatgagccacacattagtgtatgtgtgtgcattcgtgattatgcccatgccctgctgatctagttcgttttgtacactgtaaaaccaag atgaaaatacaaaaggtgtcgggttcataataggaatcgaggctggaatttctctgttccatgccagcacctcctgaggtctctgctcca ggggttgagaaagaacaaagaggctgagagggtaacggatcagagagcccagagccaagctgcccgctcacaccagaccctgct cagggtggcattgtctccccatggaaaaccagagaggagcactcagcctggtgtggtcactcttctcttatccactaaacggttgtcact gggcactgccaccagccccgtgtttctctgggtgtagggccctggggatgttacaggctgggggccaggtgacccaacactacagg gcaagatgagacaggcttccaggacacctagaatatcagaggaggtggcatttcaagcttttgtgattcattcgatgttaacattctttgac tcaatgtagaagagctaaaagtagaacaaaccaaagccgagttcccatcttagtgtgggtggaggacacaggagtaagtggcagaaa taatcagaaaagaaaacacttgcactgtggtgggtcccagaagaacaagaggaatgctgtgccatgccttgaatttcttttctgcacgac aggtctgccagcttacatttacccaaactgtccattactggaacctatgatctgaagagcgtcctgggtcaactgggcatcactaaggtct tcagcaatggggctgacctctccggggtcacagaggaggcacccctgaagctctccaaggtgagatcaccctgacgaccttgttgca ccctggtatctgtagggaagaatgtgtgggggctgcagctctgtcctgaggctgaggaaggggccgagggaaacaaatgaagaccc aggctgagctcctgaagatgcccgtgattcactgacacgggacgtggtcaaacagcaaagccaggcaggggactgctgtgcagctg gcactttcggggcctcccttgaggttgtgtcactgaccctgaatttcaactttgcccaagaccttctagacattgggccttgatttatccata ctgacacagaaaggtttgggctaagttgtttcaaaggaatttctgactccttcgatctgtgagatttggtgtctgaattaatgaatgatttcag ctaaagatgacacttattttggaaaactaaaggcgaccaatgaacaactgcagttccatgaatggctgcattatcttggggtctgggcact gtgaaggtcactgccagggtccgtgtcctcaaggagcttcaagccgtgtactagaaaggagagagccctggaggcagacgtggagt gacgatgctcttccctgttctgagttgtgggtgcacctgagcagggggagaggcgcttgtcaggaagatggacagaggggagccag ccccatcagccaaagccttgaggaggagcaaggcctatgtgacagggagggagaggatgtgcagggccagggccgtccagggg gagtgagcgcttcctgggaggtgtccacgtgagccttgctcgaggcctgggatcagccttacaacgtgtctctgcttctctcccctccag gccgtgcataaggctgtgctgaccatcgacAagaaagggactgaagctgctggggccatgtttttagaggccatacccatgtctatcc cccccgaggtcaagttcaacaaaccctttgtcttcttaatgattgaacaaaataccaagtctcccctcttcatgggaaaagtggtgaatcc cacccaaaaataa SEQ ID NO:15 (human SERPINA1 gene sequence of exon 2+exon 3+exon 4+intron 6+exon 5, synthetic nucleic acid) 118MF-363253604Attorney Docket No.: 15979-20192.40 atgccgtcttctgtctcgtggggcatcctcctgctggcaggcctgtgctgcctggtccctgtctccctggctgaggatccccagggagat gctgcccagaagacagatacatcccaccatgatcaggatcacccaaccttcaacaagatcacccccaacctggctgagttcgccttca gcctataccgccagctggcacaccagtccaacagcaccaatatcttcttctccccagtgagcatcgctacagcctttgcaatgctctccc tggggaccaaggctgacactcacgatgaaatcctggagggcctgaatttcaacctcacggagattccggaggctcagatccatgaag gcttccaggaactcctccgtaccctcaaccagccagacagccagctccagctgaccaccggcaatggcctgttcctcagcgagggcc tgaagctagtggataagtttttggaggatgttaaaaagttgtaccactcagaagccttcactgtcaacttcggggacaccgaagaggcc aagaaacagatcaacgattacgtggagaagggtactcaagggaaaattgtggatttggtcaaggagcttgacagagacacagtttttg ctctggtgaattacatcttctttaaaggcaaatgggagagaccctttgaagtcaaggacaccgaggaagaggacttccacgtggacca ggtgaccaccgtgaaggtgcctatgatgaagcgtttaggcatgtttaacatccagcactgtaagaagctgtccagctgggtgctgctga tgaaatacctgggcaatgccaccgccatcttcttcctgcctgatgaggggaaactacagcacctggaaaatgaactcacccacgatatc atcaccaagttcctggaaaatgaagacagaaggtctgccagcttacatttacccaaactgtccattactggaacctatgatctgaagagc gtcctgggtcaactgggcatcactaaggtcttcagcaatggggctgacctctccggggtcacagaggaggcacccctgaagctctcc aaggtgagatcaccctgacgaccttgttgcaccctggtatctgtagggaagaatgtgtgggggctgcagctctgtcctgaggctgagg aaggggccgagggaaacaaatgaagacccaggctgagctcctgaagatgcccgtgattcactgacacgggacgtggtcaaacagc aaagccaggcaggggactgctgtgcagctggcactttcggggcctcccttgaggttgtgtcactgaccctgaatttcaactttgcccaa gaccttctagacattgggccttgatttatccatactgacacagaaaggtttgggctaagttgtttcaaaggaatttctgactccttcgatctgt gagatttggtgtctgaattaatgaatgatttcagctaaagatgacacttattttggaaaactaaaggcgaccaatgaacaactgcagttcca tgaatggctgcattatcttggggtctgggcactgtgaaggtcactgccagggtccgtgtcctcaaggagcttcaagccgtgtactagaa aggagagagccctggaggcagacgtggagtgacgatgctcttccctgttctgagttgtgggtgcacctgagcagggggagaggcgc ttgtcaggaagatggacagaggggagccagccccatcagccaaagccttgaggaggagcaaggcctatgtgacagggagggaga ggatgtgcagggccagggccgtccagggggagtgagcgcttcctgggaggtgtccacgtgagccttgctcgaggcctgggatcag ccttacaacgtgtctctgcttctctcccctccaggccgtgcataaggctgtgctgaccatcgacAagaaagggactgaagctgctggg gccatgtttttagaggccatacccatgtctatcccccccgaggtcaagttcaacaaaccctttgtcttcttaatgattgaacaaaataccaa gtctcccctcttcatgggaaaagtggtgaatcccacccaaaaataa SEQ ID NO:16 (human SERPINA13′ UTR, nucleic acid) CTGCCTCTCGCTCCTCAACCCCTCCCCTCCATCCCTGGCCCCCTCCCTGG ATGACATTAAAGAAGGGTTGAGCTGGTCCCTGCCTGCATGTGACTGTAAA TCCCTCCCATGTTTTCTCTGAGTCTCCCTTTGCCTGCTGAGGCTGTATGT GGGCTCCAGGTAACAGTGCTGTCTTCGGGCCCCCTGAACTGTGTTCATGG AGCATCTGGCTGGGTAGGCACATGCTGGGCTTGAATCCAGGGGGGACTGA 119MF-363253604Attorney Docket No.: 15979-20192.40 ATCCTCAGCTTACGGACCTGGGCCCATCTGTTTCTGGAGGGCTCCAGTCTTCCTTG TCCTGTCTTGGAGTCCCCAAGAAGGAATCACAGGGGAGGAACCAGATACCAGCC ATGACCCCAGGCTCCACCAAGCATCTTCATGTCCCCCTGCTCATCCCCCACTCCC CCCCACCCAGAGTTGCTCATCCTGCCAGGGCTGGCTGTGCCCACCCCAAGGCTGC CCTCCTGGGGGCCCCAGAACTGCCTGATCGTGCCGTGGCCCAGTTTTGTGGCATC TGCAGCAACACAAGAGAGAGGACAATGTCCTCCTCTTGACCCGCTGTCACCTAA CCAGACTCGGGCCCTGCACCTCTCAGGCACTTCTGGAAAATGACTGAGGCAGATT CTTCCTGAAGCCCATTCTCCATGGGGCAACAAGGACACCTATTCTGTCCTTGTCC TTCCATCGCTGCCCCAGAAAGCCTCACATATCTCCGTTTAGAATCAGGTCCCTTCT CCCCAGATGAAGAGGAGGGTCTCTGCTTTGTTTTCTCTATCTCCTCCTCAGACTTG ACCAGGCCCAGCAGGCCCCAGAAGACCATTACCCTATATCCCTTCTCCTCCCTAG TCACATGGCCATAGGCCTGCTGATGGCTCAGGAAGGCCATTGCAAGGACTCCTC AGCTATGGGAGAGGAAGCACATCACCCATTGACCCCCGCAACCCCTCCCTTTCCT CCTCTGAGTCCCGACTGGGGCCACATGCAGCCTGACTTCTTTGTGCCTGTTGCTGT CCCTGCAGTCTTCAGAGGGCCACCGCAGCTCCAGTGCCACGGCAGGAGGCTGTT CCTGAATAGCCCCTGTGGTAAGGGCCAGGAGAGTCCTTCCATCCTCCAAGGCCCT GCTAAAGGACACAGCAGCCAGGAAGTCCCCTGGGCCCCTAGCTGAAGGACAGCC TGCTCCCTCCGTCTCTACCAGGAATGGCCTTGTCCTATGGAAGGCACTGCCCCAT CCCAAACTAATCTAGGAATCACTGTCTAACCACTCACTGTCATGAATGTGTACTT AAAGGATGAGGTTGAGTCATACCAAATAGTGATTTCGATAGTTCAAAATGGTGA AATTAGCAATTCTACATGATTCAGTCTAATCAATGGATACCGACTGTTTCCCACA CAAGTCTCCTGTTCTCTTAAGCTTACTCACTGACAGCCTTTCACTCTCCACAAATA CATTAAAGATATGGCCATCACCAAGCCCCCTAGGATGACACCAGACCTGAGAGT CTGAAGACCTGGATCCAAGTTCTGACTTTTCCCCCTGACAGCTGTGTGACCTTCG TGAAGTCGCCAAACCTCTCTGAGCCCCAGTCATTGCTAGTAAGACCTGCCTTTGA GTTGGTATGATGTTCAAGTTAGATAACAAAATGTTTATACCCATTAGAACAGAGA ATAAATAGAACTACATTTCTTGCA SEQ ID NO:17 (bGH polyA, nucleic acid) CTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTG ACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCAT CGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAG CAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCT CTATGG 120MF-363253604Attorney Docket No.: 15979-20192.40 SEQ ID NO:18 (FRT-Neomycin-FRT cassette, nucleic acid) GAAGTTCCTATTCTCTAGAAAGTATAGGAACTTCAGGTCTGAAGAGGAGTTTACG TCCAGCCAAGCTAGCTTGGCTGCAGGTCGTCGAAATTCTACCGGGTAGGGGAGG CGCTTTTCCCAAGGCAGTCTGGAGCATGCGCTTTAGCAGCCCCGCTGGGCACTTG GCGCTACACAAGTGGCCTCTGGCCTCGCACACATTCCACATCCACCGGTAGGCGC CAACCGGCTCCGTTCTTTGGTGGCCCCTTCGCGCCACCTTCTACTCCTCCCCTAGT CAGGAAGTTCCCCCCCGCCCCGCAGCTCGCGTCGTGCAGGACGTGACAAATGGA AGTAGCACGTCTCACTAGTCTCGTGCAGATGGACAGCACCGCTGAGCAATGGAA GCGGGTAGGCCTTTGGGGCAGCGGCCAATAGCAGCTTTGCTCCTTCGCTTTCTGG GCTCAGAGGCTGGGAAGGGGTGGGTCCGGGGGCGGGCTCAGGGGCGGGCTCAG GGGCGGGGCGGGCGCCCGAAGGTCCTCCGGAGGCCCGGCATTCTGCACGCTTCA AAAGCGCACGTCTGCCGCGCTGTTCTCCTCTTCCTCATCTCCGGGCCTTTCGACCT GCAGCCTGTTGACAATTAATCATCGGCATAGTATATCGGCATAGTATAATACGAC AAGGTGAGGAACTAAACCATGGGATCGGCCATTGAACAAGATGGATTGCACGCA GGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAG ACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGG TTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAGGACGAGGC AGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGCTGTGCTCGAC GTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCAG GATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATG CAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGC GAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCA GGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAG GCTCAAGGCGCGCATGCCCGACGGCGATGATCTCGTCGTGACCCATGGCGATGC CTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGACTGT GGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGTGAT ATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTA TCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTC TGAGGGGATCAATTCTCTAGAGCTCGCTGATCAGCCTCGACTGTGCCTTCTAGTT GCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCC ACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTA GGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATT GGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTATGGCTTCTGAGG 121MF-363253604Attorney Docket No.: 15979-20192.40 CGGAAAGAACCAGCTGGGGCTCGACTAGAGCTTGCGGAACCCTTCGAAGTTCCT ATTCTCTAGAAAGTATAGGAACTTC 122MF-363253604

Claims

Attorney Docket No.: 15979-20192.40 CLAIMS What is claimed is:

1. A rodent comprising a single copy of a human SERPINA1 transgene.

2. The rodent of claim 1, wherein the human SERPINA1 transgene comprises the coding sequence of exons 2, 3, 4, and 5 and the sequence of intron 6 of a human SERPINA1 gene.

3. The rodent of claim 1, wherein the human SERPINA1 transgene comprises the genomic sequence from exon 1 through exon 5 and intron 1 through intron 6 of a human SERPINA1 gene.

4. The rodent of any one of claims 1-3, wherein the human SERPINA1 transgene comprises a mutation in exon 5.

5. The rodent of claim 4, wherein the mutation is a point mutation.

6. The rodent of claim 5, wherein the point mutation occurs at nucleotide position 1096.

7. The rodent of claim 6, wherein the point mutation is G1096A.

8. The rodent of any of claims 1-7, wherein the human SERPINA1 transgene encodes an A1AT protein comprising a substitution at residue 366.

9. The rodent of claim 8, wherein the substitution is E366K.

10. The rodent of any one of claims 1, 2, and 4-9, wherein the human SERPINA1 transgene comprises the nucleic acid sequence of SEQ ID NO:

2.

11. The rodent of any one of claims 1 and 3-9, wherein the human SERPINA1 transgene comprises the nucleic acid sequence of SEQ ID NO:

3.

12. The rodent of any one of claims 1-11, wherein the rodent is further characterized by having decreased or no functional endogenous rodent Serpina1 expression.

13. The rodent of claim 12, wherein each endogenous rodent Serpina1 allele is disrupted.

14. The rodent of claim 13, wherein each endogenous rodent Serpina1 allele is deleted from the rodent genome. 123MF-363253604Attorney Docket No.: 15979-20192.40 15. The rodent of any one of claims 1-14, further characterized as having Alpha-1 antitrypsin deficiency (A1ATD).

16. The rodent of claim 15, wherein the A1ATD is characterized by misfolded alpha-1 antitrypsin protein (A1AT).

17. The rodent of claim 16, wherein the misfolded A1AT accumulates in hepatocytes.

18. The rodent of any one of claims 1-17, wherein the rodent has reduced circulating levels of A1AT compared to a rodent without A1ATD.

19. The rodent of claim 18, wherein the reduced circulating levels of A1AT are decreased by at least about 50% compared to the circulating levels of A1AT in a rodent without A1ATD.

20. The rodent of any one of claims 1-19, wherein the rodent has liver dysfunction selected from the group consisting of liver disease, liver damage, liver injury, and hepatocellular carcinoma.

21. The rodent of any one of claims 1-20, wherein the rodent has lung tissue damage or lung disease.

22. The rodent of claim 21, wherein the lung tissue damage or lung disease is selected from the group consisting of emphysema, asthma, and chronic obstructive pulmonary disease (COPD).

23. The rodent of any one of claims 1-22, wherein the rodent is a mouse.

24. A method for assessing the efficacy of a treatment for Alpha-1 antitrypsin deficiency (A1ATD), comprising administering to the rodent of any one of claims 1-23 an effective amount of the treatment.

25. The method of claim 24, wherein the treatment is selected from the group consisting of liver transplantation, respiratory agents, purified alpha-1 antitrypsin (A1AT) protein, and gene therapy. 124MF-363253604Attorney Docket No.: 15979-20192.40 26. The method of claim 25, wherein the treatment is gene therapy and wherein the gene therapy comprises editing the human SERPINA1 gene to correct a point mutation at nucleotide position 1096.

27. The method of claim 26, wherein the point mutation to be corrected is G1096A, and wherein the corrected nucleotide is A1096G.

28. The method of claim 26 or 27, wherein the edited human SERPINA1 gene encodes a wildtype human A1AT protein.

29. The method of claim 28, wherein the wildtype human A1AT protein is set forth in SEQ ID NO:

4.

30. A construct comprising a human SERPINA1 transgene comprises the coding sequence of exons 2, 3, 4, and 5 and the sequence of intron 6 of a human SERPINA1 gene.

31. A nucleic acid construct comprising a human SERPINA1 transgene comprises the genomic sequence from exon 1 through exon 5 and intron 1 through intron 6 of a human SERPINA1 gene.

32. The nucleic acid construct of claim 30 or 31, wherein the human SERPINA1 transgene comprises a mutation in exon 5.

33. The nucleic acid construct of claim 32, wherein the mutation is a point mutation.

34. The nucleic acid construct of claim 33, wherein the point mutation occurs at nucleotide position 1096.

35. The nucleic acid construct of claim 34, wherein the point mutation is G1096A.

36. The nucleic acid construct of any one of claims 30-35, wherein the human SERPINA1 transgene encodes an A1AT protein comprising a substitution at residue 366.

37. The nucleic acid construct of claim 36, wherein the substitution is E366K.

38. The nucleic acid construct of any one of claims 30 and 32-37, wherein the human SERPINA1 transgene comprises the nucleic acid sequence of SEQ ID NO:

2. 125MF-363253604Attorney Docket No.: 15979-20192.40 39. The nucleic acid construct of any one of claims 31-37, wherein the human SERPINA1 transgene comprises the nucleic acid sequence of SEQ ID NO:

3.

40. A vector comprising the nucleic acid construct of any one of claims 30-39.

41. The vector of claim 40, wherein the vector is a plasmid, a phagemid, a cosmid, a transposon, or a viral vector.

42. The vector of claim 41, wherein the viral vector is selected from the group consisting of adenovirus, Chimpanzee adenovirus, lentivirus, alphavirus, retrovirus, poxvirus, flavivirus, adeno-associated virus, rhabdoviridae, herpes simplex virus, chimeric virus, arenavirus, fowlpox virus, vesicular stomatitis virus, vaccinia virus, modified vaccinia virus Ankara, human cytomegalovirus, Sendai virus, measles virus, and Newcastle disease virus.

43. A method of making the rodent of any one of claims 1-23, comprising introducing into a rodent the construct of any one of claims 30-39 or the vector of any one of claims 40- 42.

44. The method of claim 43, further comprising disrupting each endogenous rodent Serpina1 allele in the rodent genome.

45. The method of claim 43, further comprising deleting each endogenous rodent Serpina1 allele from the rodent genome.

46. A rodent produced by the method of any one of claims 43-45. 126MF-363253604

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