Pharmaceutical composition and methods of vectoring adeno-associated virus

Description

"PHARMACEUTICAL COMPOSITION AND METHODS OF DELIVERING ADENO-ASSOCIATED VIRUSES" Divided from BR 112022006718-6 of 06 / 10 / 2020 CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of Application Provisional Order No. US 62 / 911,968, filed October 7, 2019, the contents of which are incorporated herein by reference in their entirety. REFERENCE TO THE LIST OF SEQUENCES SUBMITTED ELECTRONICALLY

[0002] This request incorporates as a reference a Sequence Listing submitted with this request as a text file titled “Sequence_Listing_12656-124-228.TXT” created on September 28, 2020 and with a size of 97,652 bytes. 1. BACKGROUND OF THE INVENTION

[0003] Adeno-associated virus (AAV), a member of the Parvoviridae family designated Dependovirus, is a small, non-enveloped icosahedral virus with linear single-stranded DNA genomes of approximately 4.7 kilobases (kb) to 6 kb. The properties of non-pathogenicity, wide range of host and cell type infectivity, including dividing and non-dividing cells, and the ability to establish long-term transgene expression make AAV an attractive tool for gene therapy (e.g., Gonçalves, 2005, Virology Journal, 2:43).

[0004] AAV products are frequently stored in buffers composed of various excipients to stabilize the product during manufacturing, transport, storage, and administration. However, AAV biotherapeutics are distributed at -80°C for safety against degradation and the negative effects of potential thawing of materials, even though shipping to certain territories may not provide adequate refrigerated storage at these temperatures. Maintaining the temperature is a challenge. Petition 870260012693, dated 09 / 02 / 2026, page 69 / 420 2 / 319 of the freezer at < -60 °C and providing a formulation robust to higher freezing temperatures, such as down to -20 °C and stable to multiple freeze-thaw excursions, is desirable from a logistical standpoint. Not all clinical sites have a -80 °C freezer, and this requirement would negatively impact the ability to distribute the product to a wide variety of clinical sites. Therefore, it is desirable to have a formulation that is stable for a short duration (up to 12 months) under refrigerated conditions to allow the clinical site to thaw and keep the product in a refrigerator until the patient is scheduled for dosing.

[0005] Maintaining various buffer properties within target specification ranges is crucial to ensure product stability, but storage at -80°C impacts the supply chain and distribution. Water crystallization during slow freezing can result in excipient concentration, which may affect the stability of biological products. Phase separation or pH changes can also occur, which can affect the stability of biological products. For the commercialization of any pharmaceutical product, it would be advantageous to identify formulations that offer stability over extended periods of time.It would be even more advantageous to identify formulations that are stable under frozen storage at -20 °C to account for freezer temperature variations, variability or temporary storage (up to 18 months) in a -20 °C freezer, refrigerated conditions to allow short-term storage (up to 12 months at 2-8 °C) in the clinic before dosing, at room temperature to allow for manufacturing and labeling, or under multiple free thaw cycles to allow for thawing of the medicinal substance and drug product for filling and labeling operations. 2. SUMMARY OF THE INVENTION

[0006] The disclosure provides a pharmaceutical composition comprising a recombinant adeno-associated virus (AAV), Petition 870260012693, dated 09 / 02 / 2026, p. 70 / 420 3 / 319 buffering agent, ionic salt, sucrose and surfactant, such as poloxamer 188. The sucrose is supplied in a concentration that prevents crystallization of the composition and maintains a pH between 6 and 9 during the frozen and liquid states.

[0007] In some embodiments, AAV comprises components of one or more adeno-associated virus serotypes selected from the group consisting of AAV1, AAV2, AAV2tYF, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, and AAVrh10, AAV.rh20, AAV.rh39, AAV.Rh74, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, rAAV.7m8, AAV.PHP.B, AAV.PHP.eB, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, or AAV.HSC16. In some embodiments, rAAV comprises a capsid protein of serotype AAV8 or AAV9.

[0008] In some forms, the pharmaceutical composition also includes an amino acid.

[0009] In some embodiments, the disclosure provides a pharmaceutical composition comprising a recombinant adeno-associated virus (AAV), an ionic salt excipient or buffering agent, sucrose, and poloxamer 188. In some embodiments, the ionic salt excipient or buffering agent may be one or more components of the group consisting of monobasic potassium phosphate, potassium phosphate, sodium chloride, anhydrous dibasic sodium phosphate, sodium phosphate hexahydrate, monobasic sodium phosphate monohydrate, tromethamine, tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl), amino acid, histidine, histidine hydrochloride (histidine-HCl), sodium succinate, sodium citrate, sodium acetate, and (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES), sodium sulfate, magnesium sulfate, magnesium chloride 6-hydrate, calcium sulfate, potassium chloride, calcium chloride, calcium citrate.

[0010] In some embodiments, the pharmaceutical composition has an ionic strength not exceeding about 150 mM, about Petition 870260012693, dated 09 / 02 / 2026, page 71 / 420 4 / 319 145 mM, approximately 140 mM, approximately 135 mM, approximately 130 mM, approximately 125 mM, approximately 120 mM, approximately 115 mM, or approximately 110 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of the buffering agent not exceeding approximately 150 mM, approximately 145 mM, approximately 140 mM, approximately 135 mM, approximately 130 mM, approximately 125 mM, approximately 120 mM, approximately 115 mM, or approximately 110 mM.

[0011] In some embodiments, the pharmaceutical composition has an ionic strength not exceeding 150 mM, 145 mM, 140 mM, 135 mM, 130 mM, 125 mM, 120 mM, 115 mM, or 110 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of the buffering agent not exceeding 150 mM, 145 mM, 140 mM, 135 mM, 130 mM, 125 mM, 120 mM, 115 mM, or 110 mM.

[0012] In certain embodiments, the pharmaceutical composition has an ionic strength of about 60 mM to 115 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 60 mM to 100 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 60 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 65 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 70 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 75 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 80 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 85 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 90 mM.

[0013] In certain embodiments, the pharmaceutical composition has an ionic strength of about 30 mM to 100 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 30 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 35 mM. In a specific embodiment, the Petition 870260012693, dated 09 / 02 / 2026, page 72 / 420 5 / 319 pharmaceutical composition has an ionic strength of about 40 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 45 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 50 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 55 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 60 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 65 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 70 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 75 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 80 mM. In a specific embodiment, the pharmaceutical composition has an ionic strength of about 85 mM.In one specific embodiment, the pharmaceutical composition has an ionic strength of approximately 90 mM. In another specific embodiment, the pharmaceutical composition has an ionic strength of approximately 95 mM. In another specific embodiment, the pharmaceutical composition has an ionic strength of approximately 100 mM.

[0014] In certain embodiments, the pharmaceutical composition has an ionic strength of about 60 mM to 115 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 65 mM to 95 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 70 mM to 90 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 75 mM to 85 mM.

[0015] In certain embodiments, the pharmaceutical composition has an ionic strength of about 30 mM to 100 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 35 mM to 95 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 40 mM to 90 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 45 mM to 85 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about Petition 870260012693, dated 09 / 02 / 2026, page 73 / 420 6 / 319 mM to 80 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 55 mM to 75 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 60 mM to 70 mM.

[0016] In certain embodiments, the pharmaceutical composition comprises potassium chloride at a concentration of 0.2 g / l.

[0017] In certain embodiments, the pharmaceutical composition comprises monobasic potassium phosphate at a concentration of 0.2 g / l.

[0018] In certain embodiments, the pharmaceutical composition comprises sodium chloride at a concentration of 5.84 g / L

[0019] In certain embodiments, the pharmaceutical composition comprises anhydrous dibasic sodium phosphate at a concentration of 1.15 g / l.

[0020] In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 3% (weight / volume, 30 g / l) to 18% (weight / volume, 180 g / l). In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 4% (weight / volume, 30 g / l) to 6% (weight / volume, 180 g / l). In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 3% (weight / volume, 30 g / l). In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 3% (weight / volume, 30 g / l). In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 4% (weight / volume, 40 g / l). In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 5% (weight / volume, 50 g / l). In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 6% (weight / volume, 60 g / l). In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 7% (weight / volume, 70 g / l).In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 8% (weight / volume, 80 g / l). In certain embodiments, the pharmaceutical composition... Petition 870260012693, dated 09 / 02 / 2026, page 74 / 420 7 / 319 comprises sucrose at a concentration of 9% (weight / volume, 90 g / l). In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 10% (weight / volume, 100 g / l). In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 11% (weight / volume, 110 g / l). In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 12% (weight / volume, 120 g / l). In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 13% (weight / volume, 130 g / l). In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 14% (weight / volume, 140 g / l). In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 15% (weight / volume, 150 g / l). In certain formulations, the pharmaceutical composition comprises sucrose at a concentration of 16% (weight / volume, 160 g / l).In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 17% (weight / volume, 170 g / l). In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 18% (weight / volume, 180 g / l).

[0021] In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.001% (weight / volume, 0.01 g / l).

[0022] In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.0005% (weight / volume, 0.005 g / l) to 0.05% (weight / volume, 0.5 g / l). In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.0001% (weight / volume, 0.001 g / l) to 0.01% (weight / volume, 0.1 g / l). In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.0005% (weight / volume, 0.005 g / l) to 0.001% (weight / volume, 0.01 g / l). In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.001% (weight / volume, 0.01 g / L) to 0.05% (weight / volume, 0.5 g / L). In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.0005%. Petition 870260012693, dated 09 / 02 / 2026, page 75 / 420 8 / 319 (weight / volume, 0.005 g / l). In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.0006% (weight / volume, 0.006 g / l). In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.0007% (weight / volume, 0.007 g / l). In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.0008% (weight / volume, 0.008 g / l). In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.0009% (weight / volume, 0.009 g / l). In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.001% (weight / volume, 0.01 g / l). In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.002% (weight / volume, 0.02 g / l). In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.003% (weight / volume, 0.03 g / l).In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.004% (weight / volume, 0.04 g / L). In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.005% (weight / volume, 0.05 g / L). In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.01% (weight / volume, 0.1 g / L). In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.05% (weight / volume, 0.5 g / L).

[0023] In some embodiments, the disclosure provides a pharmaceutical composition comprising a recombinant adeno-associated virus (AAV), an ionic salt excipient or buffering agent, sucrose, and a surfactant. In some embodiments, the ionic salt excipient or buffering agent may be one or more components of the group consisting of monobasic potassium phosphate, potassium phosphate, sodium chloride, anhydrous dibasic sodium phosphate, sodium phosphate hexahydrate, monobasic sodium phosphate monohydrate, tromethamine, tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl), amino acid, histidine, hydrochloride of Petition 870260012693, dated 09 / 02 / 2026, page 76 / 420 9 / 319 histidine (histidine-HCl), sodium succinate, sodium citrate, sodium acetate and (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES), sodium sulfate, magnesium sulfate, magnesium chloride 6-hydrate, calcium sulfate, potassium chloride, calcium chloride, calcium citrate. In some embodiments, the surfactant may be one or more components of the group consisting of poloxamer 188, polysorbate 20 and polysorbate 80.

[0024] In certain embodiments, the pharmaceutical composition comprises polysorbate 20 at a concentration of 0.0005% (weight / volume, 0.005 g / l) to 0.05% (weight / volume, 0.5 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 20 at a concentration of 0.0001% (weight / volume, 0.001 g / l) to 0.01% (weight / volume, 0.1 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 20 at a concentration of 0.0005% (weight / volume, 0.005 g / l) to 0.001% (weight / volume, 0.01 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 20 at a concentration of 0.001% (weight / volume, 0.01 g / l) to 0.05% (weight / volume, 0.5 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 20 at a concentration of 0.0005% (weight / volume, 0.005 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 20 at a concentration of 0.0006% (weight / volume, 0.006 g / l).In certain embodiments, the pharmaceutical composition comprises polysorbate 20 at a concentration of 0.0007% (weight / volume, 0.007 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 20 at a concentration of 0.0008% (weight / volume, 0.008 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 20 at a concentration of 0.0009% (weight / volume, 0.009 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 20 at a concentration of 0.001% (weight / volume, 0.01 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 20 at a concentration of 0.002% (weight / volume, 0.02 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 20 at a concentration of 0.003% (weight / volume, 0.03). Petition 870260012693, dated 09 / 02 / 2026, page 77 / 420 10 / 319 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 20 at a concentration of 0.004% (weight / volume, 0.04 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 20 at a concentration of 0.005% (weight / volume, 0.05 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 20 at a concentration of 0.01% (weight / volume, 0.1 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 20 at a concentration of 0.05% (weight / volume, 0.5 g / l).

[0025] In certain embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration of 0.0005% (weight / volume, 0.005 g / l) to 0.05% (weight / volume, 0.5 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration of 0.0001% (weight / volume, 0.001 g / l) to 0.01% (weight / volume, 0.1 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration of 0.0005% (weight / volume, 0.005 g / l) to 0.001% (weight / volume, 0.01 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration of 0.001% (weight / volume, 0.01 g / l) to 0.05% (weight / volume, 0.5 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration of 0.0005% (weight / volume, 0.005 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration of 0.0006% (weight / volume, 0.006 g / l).In certain embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration of 0.0007% (weight / volume, 0.007 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration of 0.0008% (weight / volume, 0.008 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration of 0.0009% (weight / volume, 0.009 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration of 0.001% (weight / volume, 0.01 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration of 0.002% (weight / volume, 0.02 g / l). Petition 870260012693, dated 09 / 02 / 2026, page 78 / 420 11 / 319 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration of 0.003% (weight / volume, 0.03 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration of 0.004% (weight / volume, 0.04 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration of 0.005% (weight / volume, 0.05 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration of 0.01% (weight / volume, 0.1 g / l). In certain embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration of 0.05% (weight / volume, 0.5 g / l).

[0026] In certain embodiments, the pH of the pharmaceutical composition is approximately 7.4.

[0027] In certain embodiments, the pH of the pharmaceutical composition is about 6.0 to 8.8. In certain embodiments, the pH of the pharmaceutical composition is about 6.0 to 9.0. In certain embodiments, the pH of the pharmaceutical composition is about 6.0. In certain embodiments, the pH of the pharmaceutical composition is about 6.1. In certain embodiments, the pH of the pharmaceutical composition is about 6.2. In certain embodiments, the pH of the pharmaceutical composition is 6.3. In certain embodiments, the pH of the pharmaceutical composition is 6.4. In certain embodiments, the pH of the pharmaceutical composition is 6.5. In certain embodiments, the pH of the pharmaceutical composition is 6.6. In certain embodiments, the pH of the pharmaceutical composition is 6.7.In certain modalities, the pHda is 6.8. In certain modalities, the pHda is 6.9. In certain modalities, the pHda is 7.0. In certain modalities, the pHda is 7.1. In certain modalities, the pHda is 7.2. In certain modalities, the pHda is 7.3. In certain modalities, the pHda is 7.4. In certain modalities, pHda. Petition 870260012693, dated 09 / 02 / 2026, p. 79 / 420 12 / 319 pharmaceutical composition is approximately 7.5. In certain embodiments, the pH is approximately 7.6. In certain embodiments, the pH is approximately 7.7. In certain embodiments, the pH is approximately 7.8. In certain embodiments, the pH is approximately 7.9. In certain embodiments, the pH is approximately 8.0. In certain embodiments, the pH is approximately 8.1. In certain embodiments, the pH is approximately 8.2. In certain embodiments, the pH is approximately 8.3. In certain embodiments, the pH is approximately 8.4. In certain embodiments, the pH is approximately 8.5. In certain embodiments, the pH is approximately 8.6. In certain modalities, the pH is 8.7.In certain formulations, the pH of the pharmaceutical composition is 8.8. In certain formulations, the pH of the pharmaceutical composition is 8.9. In certain formulations, the pH of the pharmaceutical composition is approximately 9.0.

[0028] In certain embodiments, the pH of the pharmaceutical composition is 7.4.

[0029] In certain embodiments, the pH of the pharmaceutical composition is from 6.0 to 8.8. In certain embodiments, the pH of the pharmaceutical composition is from 6.0 to 9.0. In certain embodiments, the pH of the pharmaceutical composition is 6.0. In certain embodiments, the pH of the pharmaceutical composition is 6.1. In certain embodiments, the pH of the pharmaceutical composition is 6.2. In certain embodiments, the pH of the pharmaceutical composition is 6.3. In certain embodiments, the pH of the pharmaceutical composition is 6.4. In certain embodiments, the pH of the pharmaceutical composition is 6.5. In certain embodiments, the pH of the pharmaceutical composition is 6.6. In certain embodiments, the pH of the pharmaceutical composition is 6.7. In certain embodiments, the pH of the pharmaceutical composition is 6.8. In certain embodiments, the pH of the pharmaceutical composition is 6.9. In certain embodiments, the pH of the pharmaceutical composition is 7.0. In certain Petition 870260012693, dated 09 / 02 / 2026, page 80 / 420 In certain embodiments, the pH of the pharmaceutical composition is 7.1. In certain embodiments, the pH of the pharmaceutical composition is 7.2. In certain embodiments, the pH of the pharmaceutical composition is 7.3. In certain embodiments, the pH of the pharmaceutical composition is 7.4. In certain embodiments, the pH of the pharmaceutical composition is 7.5. In certain embodiments, the pH of the pharmaceutical composition is 7.6. In certain embodiments, the pH of the pharmaceutical composition is 7.7. In certain embodiments, the pH of the pharmaceutical composition is 7.8. In certain embodiments, the pH of the pharmaceutical composition is 7.9. In certain embodiments, the pH of the pharmaceutical composition is 8.0. In certain embodiments, the pH of the pharmaceutical composition is 8.1. In certain embodiments, the pH of the pharmaceutical composition is 8.2. In certain embodiments, the pH of the pharmaceutical composition is 8.3. In certain embodiments, the pH of the pharmaceutical composition is 8.4. In certain embodiments, the pH of the pharmaceutical composition is 8.5. In certain formulations, the pH of the pharmaceutical composition is 8.6.In certain embodiments, the pH of the pharmaceutical composition is 8.7. In certain embodiments, the pH of the pharmaceutical composition is 8.8. In certain embodiments, the pH of the pharmaceutical composition is 8.9. In certain embodiments, the pH of the pharmaceutical composition is 9.0.

[0030] As used in this document and unless otherwise specified, the term “about” means approximately 10% of a given value or range.

[0031] In certain embodiments, the pharmaceutical composition is in a hydrophobically coated glass bottle.

[0032] In certain embodiments, the pharmaceutical composition is in a Cyclo Olefin Polymer (COP) bottle.

[0033] In certain embodiments, the pharmaceutical composition is in a Daikyo Crystal Zenith® (CZ) bottle.

[0034] In certain embodiments, the pharmaceutical composition is in a bottle coated with TopLyo.

[0035] In certain embodiments, a pharmaceutical composition consisting of: (a) the AAV is disclosed in this document. Petition 870260012693, dated 09 / 02 / 2026, p. 81 / 420 14 / 319 recombinant, (b) potassium chloride at a concentration of 0.2 g / l, (c) monobasic potassium phosphate at a concentration of 0.2 g / l, (d) sodium chloride at a concentration of 5.84 g / l, (e) anhydrous dibasic sodium phosphate at a concentration of 1.15 g / l, (f) sucrose at a concentration of 4% by weight / volume (40 g / l), (g) poloxamer 188 at a concentration of 0.001% by weight / volume (0.01 g / l) and (h) water and wherein the recombinant AAV is AAV8.

[0036] In certain embodiments, the vector genome concentration (VGC) of the pharmaceutical composition is 3 x 109GC / ml, 1 x 1010GC / ml, 1.2 x 1010GC / ml, 1.6 x 1010GC / ml, 4 x 1010GC / ml, 6 x 1010GC / ml, 2 x 1011GC / ml, 2.4 x 1011GC / ml, 2.5 x 1011GC / ml, 3 x 1011GC / ml, 3.2 x 1011GC / ml, 6.2 x 1011GC / ml, 6.5 x 1011GC / ml, 1 x 1012GC / ml, 3 x 1012GC / ml, 2 x 1013GC / ml or 3 x 1013GC / ml.

[0037] In certain modalities, the vector genome concentration (VGC) of the pharmaceutical composition is 3 x 109GC / ml, 4 x 109 GC / ml, 5 x 109GC / ml, 6 x 109GC / ml, 7 x 109GC / ml, 8 x 109GC / ml, 9 x 109 GC / ml, 1 x 1010GC / ml, 2 x 1010GC / ml, 3 x 1010GC / ml, 4 x 1010GC / ml, 5 x10 GC / ml, 6 x 1010GC / ml, 7 x 1010GC / ml, 8 x 1010GC / ml, 9 x 1010GC / ml, 1 x10 GC / ml, 2 x 1011GC / ml, 3 x 1011GC / ml, 4 x 1011GC / ml, 5 x 1011GC / ml, 6 x10 GC / ml, 7 x 1011GC / ml, 8 x 1011GC / ml, 9 x 1011GC / ml, 1 x 1012GC / ml, 2 x10 GC / ml, 3 χ 1012GC / ml, 4 χ 1012GC / ml, 5 χ 1012GC / ml, 6 χ 1012GC / ml, 7 χ 1012 GC / ml, 8 χ 1012GC / ml, 9 χ 1012GC / ml, 1 χ 1013GC / ml, 1 χ 1013GC / ml, 2 χ 1013 GC / ml or 3 χ 1013GC / ml.

[0038] In certain embodiments, the vector genome (VGC) concentration of the pharmaceutical composition is approximately 3 χ¹⁰⁹GC / ml, approximately 1 χ¹⁰GC / ml, approximately 1.2 χ¹⁰GC / ml, approximately 1.6 χ¹⁰GC / ml, approximately 4 χ¹⁰GC / ml, approximately 6 χ¹⁰GC / ml, approximately 2 χ¹⁰GC / ml, approximately 2.4 χ¹⁰GC / ml, approximately 2.5 χ¹⁰GC / ml, approximately 3 χ¹⁰GC / ml, approximately 3.2 χ¹⁰GC / ml, approximately 6.2 χ¹⁰GC / ml, approximately 6.5 χ¹⁰GC / ml, about 1 χ 1012GC / ml, about 3 χ 1012GC / ml, about 2 χ 1013GC / ml or about 3 χ 1013GC / ml. Petition 870260012693, dated 09 / 02 / 2026, page 82 / 420 15 / 319

[0039] In certain embodiments, the vector genome (VGC) concentration of the pharmaceutical composition is approximately 3 χ 109GC / ml, 4 χ 109GC / ml, 5 χ 109GC / ml, 6 χ 109GC / ml, 7 χ 109GC / ml, 8 χ 109GC / ml, 9 χ 109GC / ml, approximately 1 χ 1010GC / ml, approximately 2 χ 1010GC / ml, approximately 3 χ 1010GC / ml, approximately 4 χ 1010GC / ml, approximately 5 χ 1010GC / ml, approximately 6 χ 1010GC / ml, approximately 7 χ 1010GC / ml, approximately 8 χ 1010GC / ml, about 9 χ 1010GC / ml, about 1 χ 1011GC / ml, about 2 χ 1011GC / ml, about 3 χ 1011GC / ml, about 4 χ 1011GC / ml, about 5 χ 1011GC / ml, about 6 χ 1011GC / ml, about 7 χ 1011GC / ml, about 8 χ 1011GC / ml, about 9 χ 1011 GC / ml, about 1 χ 1012GC / ml, about 2 χ 1012GC / ml, about 3 χ10 GC / ml, about 4 χ 1012GC / ml, about 5 χ 1012GC / ml, about 6 χ10 GC / ml, about 7 χ 1012GC / ml, about 8 χ 1012GC / ml, about 9 χ10 GC / ml, about 1 χ 1013GC / ml, about 1 χ 1013GC / ml, about 2 χ10 GC / ml, about 3 χ 1013GC / ml.

[0040] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1000 times more stable to freeze / thaw cycles than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the stability of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0041] In certain embodiments, the recombinant AAV in the pharmaceutical composition has at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times greater infectivity than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the infectivity of the recombinant AAV virus is determined by an assay or assays disclosed in Section 4.5 and Section 5. In certain embodiments, infectivity is measured before or after cycles of Petition 870260012693, dated 09 / 02 / 2026, p. 83 / 420 16 / 319 freezing / thawing.

[0042] In certain embodiments, the recombinant AAV in the pharmaceutical composition has at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times less aggregation than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the aggregation of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5. In certain embodiments, aggregation is measured before or after freeze / thaw cycles.

[0043] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, 12 months, about 15 months, about 18 months, approximately 24 months, approximately 2 years, approximately 3 years, approximately 4 years longer than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the stability over a period of time of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0044] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months. Petition 870260012693, dated 09 / 02 / 2026, p. 84 / 420 17 / 319 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, approximately 4 years than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the stability over a period of time of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0045] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times greater in vitro relative potency (IVRP) than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the in vitro relative potency (IVRP) of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5. In certain embodiments, the in vitro relative potency (IVRP) is measured before or after freeze / thaw cycles.

[0046] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times less free DNA than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the free DNA of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5. In certain embodiments, aggregation is measured before or after freeze / thaw cycles.

[0047] In certain embodiments, the recombinant AAV in the pharmaceutical composition has a maximum size change of 20%, 15%, 10%, 8%, 5%, 4%, 3%, 2% or 1% over a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about Petition 870260012693, dated 09 / 02 / 2026, p. 85 / 420 18 / 319 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years. In certain embodiments, the size of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5. In certain embodiments, the size is measured before or after freeze / thaw cycles.

[0048] In certain embodiments, the recombinant AAV in the pharmaceutical composition has a maximum of 20%, 15%, 10%, 8%, 5%, 4%, 3%, 2% or 1% change in size over a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 24 months, about 2 years, about 3 years and about 4 years. In certain embodiments, the size of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5. In certain embodiments, the size is measured before or after freeze / thaw cycles.

[0049] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C. In certain embodiments, the stability of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0050] In certain embodiments, the recombinant AAV in the pharmaceutical composition has at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more infectivity than the same AAV. Petition 870260012693, dated 09 / 02 / 2026, p. 86 / 420 The infectivity of recombinant 19 / 319 in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 24 months, about 2 years, about 3 years and about 4 years, is greater than that of the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the infectivity of the recombinant AAV virus is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0051] In certain embodiments, the recombinant AAV in the pharmaceutical composition has at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more infectivity than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition.In certain embodiments, the infectivity of the recombinant AAV virus is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0052] In certain embodiments, the recombinant AAV in the pharmaceutical composition has at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times less aggregation than the same AAV. Petition 870260012693, dated 09 / 02 / 2026, page 87 / 420 20 / 319 recombinant in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 24 months, about 2 years, about 3 years and about 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the aggregation of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0053] In certain embodiments, the recombinant AAV in the pharmaceutical composition has at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times less aggregation than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time of at least, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition.In certain embodiments, the aggregation of recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0054] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable when stored at -20 °C for a Petition 870260012693, dated 09 / 02 / 2026, page 88 / 420 21 / 319 time period, for example, approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the stability over a time period of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0055] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable when stored at -20 °C for a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, compared to the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the stability over a period of time of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable than the same recombinant AAV in a reference pharmaceutical composition when (i) stored at -80 °C for an initial period of time; (ii) subsequently thawed; and (iii) after thawing, stored at 4 °C for a period of time. Petition 870260012693, dated 09 / 02 / 2026, p. 89 / 420 22 / 319 second time period. In certain embodiments, the stability over a time period of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5. In certain embodiments, the first time period is approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, or approximately 24 months. 28. In some embodiments, the second time period is approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, approximately 2 months.

[0056] In certain embodiments, the recombinant AAV is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable than the same recombinant AAV in a reference pharmaceutical composition when (i) stored at -80 °C for a first period of time; (ii) subsequently thawed; and (iii) after thawing, stored at 4 °C for a second period of time. In some modalities, the first time period is approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, or approximately 24 months. In some modalities, the second time period is approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, or approximately 2 months.

[0057] In some embodiments, the concentration of recombinant AAV vector genome after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of the concentration of recombinant AAV vector genome before being stored at -80 °C for said period of time. In some embodiments, the concentration of recombinant AAV vector genome after being stored at -20 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of the concentration of recombinant AAV vector genome. Petition 870260012693, dated 09 / 02 / 2026, page 90 / 420 23 / 319 recombinant before being stored at -20 °C for said period of time. In some embodiments, the concentration of recombinant AAV vector genome after being stored at 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the concentration of recombinant AAV vector genome before being stored at 4 °C for said period of time.

[0058] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times greater in vitro relative potency (IVRP) than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition.In certain embodiments, the in vitro relative potency (IVRP) of recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0059] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times greater in vitro relative potency (IVRP) than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 Petition 870260012693, dated 09 / 02 / 2026, p. 91 / 420 24 / 319 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the in vitro relative potency (IVRP) of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0060] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times greater in vitro relative potency (IVRP) than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition.In certain embodiments, the in vitro relative potency (IVRP) of recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0061] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times greater in vitro relative potency (IVRP) than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 Petition 870260012693, dated 09 / 02 / 2026, p. 92 / 420 25 / 319 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the in vitro relative potency (IVRP) of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0062] In certain embodiments, the recombinant AAV in the pharmaceutical composition has at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times less free DNA than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the DNA-free nature of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0063] In certain embodiments, the recombinant AAV in the pharmaceutical composition has at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times less free DNA than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about Petition 870260012693, dated 09 / 02 / 2026, p. 93 / 420 26 / 319 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the DNA-free recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0064] In certain embodiments, recombinant AAV in the pharmaceutical composition has a maximum of 20%, 15%, 10%, 8%, 5%, 4%, 3%, 2% or 1% change in size when stored at -20 °C over a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 24 months, about 2 years, about 3 years and about 4 years. In certain embodiments, the size of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0065] In certain embodiments, the recombinant AAV in the pharmaceutical composition has a maximum of 20%, 15%, 10%, 8%, 5%, 4%, 3%, 2% or 1% change in size when stored at -20 °C over a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 24 months, about 2 years, about 3 years and about 4 years. In certain embodiments, the size of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0066] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, Petition 870260012693, dated 09 / 02 / 2026, p. 94 / 420 27 / 319 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable than the same recombinant AAV in a reference pharmaceutical composition when stored at 37 °C. In certain embodiments, the stability of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0067] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more infectivity than the same recombinant AAV in a reference pharmaceutical composition when stored at 37°C for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, compared to the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the infectivity of the recombinant AAV virus is determined by an assay or assays disclosed in Section 4.5 and in Section 5.

[0068] In certain embodiments, the recombinant AAV in the pharmaceutical composition has at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more infectivity than the same recombinant AAV in a reference pharmaceutical composition when stored at 37°C for a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about Petition 870260012693, dated 09 / 02 / 2026, p. 95 / 420 28 / 319 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the infectivity of the recombinant AAV virus is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0069] In certain embodiments, the recombinant AAV in the pharmaceutical composition has at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times less aggregation than the same recombinant AAV in a reference pharmaceutical composition when stored at 37°C for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the aggregation of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0070] In certain embodiments, the recombinant AAV in the pharmaceutical composition has at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times less aggregation than the same recombinant AAV in a reference pharmaceutical composition when stored at 37 °C for a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 Petition 870260012693, dated 09 / 02 / 2026, p. 96 / 420 29 / 319 years and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the aggregation of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0071] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable when stored at 37°C for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, compared to the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the stability over a period of time of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0072] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable when stored at 37°C for a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, compared to the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, stability over a period of Petition 870260012693, dated 09 / 02 / 2026, p. 97 / 420 The time frame for the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5. In some embodiments, the concentration of recombinant AAV vector genome after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the concentration of recombinant AAV vector genome before being stored at -80 °C for said period of time. In some embodiments, the concentration of recombinant AAV vector genome after being stored at -20 °C for said period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the concentration of recombinant AAV vector genome before being stored at -20 °C for said period of time.In some embodiments, the concentration of recombinant AAV vector genome after being stored at 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of the concentration of recombinant AAV vector genome before being stored at 4 °C during said period of time. In some embodiments, the in vitro potency of recombinant AAV after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of the in vitro potency of recombinant AAV before being stored at -80 °C during said period of time. In some embodiments, the in vitro potency of the recombinant AAV after being stored at -20 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the in vitro potency of the recombinant AAV before being stored at -20 °C for said period of time.In some embodiments, the in vitro potency of the recombinant AAV after being stored at -20 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of the in vitro potency of the recombinant AAV before being stored at -20 °C for said period of time. In some embodiments, the size distribution of the recombinant AAV after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the size distribution of the recombinant AAV before being stored at -80 °C during said period of time. In some... Petition 870260012693, dated 09 / 02 / 2026, p. 98 / 420 In some embodiments, the size distribution of the recombinant AAV after being stored at -20 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the size distribution of the recombinant AAV before being stored at -20 °C during said period of time. In some embodiments, the size distribution of the recombinant AAV after being stored at 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the size distribution of the recombinant AAV before being stored at 4 °C during said period of time. In some modalities, the time period is approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, or approximately 24 months.

[0073] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times greater in vitro relative potency (IVRP) than the same recombinant AAV in a reference pharmaceutical composition when stored at 37 °C for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition.In certain embodiments, the in vitro relative potency (IVRP) of recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0074] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, Petition 870260012693, dated 09 / 02 / 2026, p. 99 / 420 32 / 319 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times greater in vitro relative potency (IVRP) than the same recombinant AAV in a reference pharmaceutical composition when stored at 37 °C for a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 24 months, about 2 years, about 3 years and approximately 4 years, respectively, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the in vitro relative potency (IVRP) of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0075] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times less free DNA than the same recombinant AAV in a reference pharmaceutical composition when stored at 37 °C for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the DNA-free nature of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0076] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, Petition 870260012693, dated 09 / 02 / 2026, p. 100 / 420 33 / 319 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times less free DNA than the same recombinant AAV in a reference pharmaceutical composition when stored at 37 °C for a period of time of at least, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 24 months, about 2 years, about 3 years and about 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the DNA-free recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0077] In certain embodiments, recombinant AAV in the pharmaceutical composition has a maximum of 20%, 15%, 10%, 8%, 5%, 4%, 3%, 2% or 1% change in size when stored at 37 °C for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 24 months, about 2 years, about 3 years and about 4 years. In certain embodiments, the size of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0078] In certain embodiments, the recombinant AAV in the pharmaceutical composition has a maximum of 20%, 15%, 10%, 8%, 5%, 4%, 3%, 2% or 1% change in size when stored at 37 °C for a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 Petition 870260012693, dated 09 / 02 / 2026, p. 101 / 420 34 / 319 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years. In certain embodiments, the size of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0079] In another aspect, a method of treating a subject diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME) or diabetic retinopathy (DR) is provided in this document, wherein the method comprises preparing a pharmaceutical composition provided in this document, storing the pharmaceutical composition at -80 °C for a first period of time; (ii) thawing the pharmaceutical composition; and (iii) after thawing, storing the pharmaceutical composition at 4 °C for a second period of time. In some embodiments, the first period of time is about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months or about 24 months. 61. In some modalities, the second time period is approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, or approximately 2 months.

[0080] In certain embodiments, the disclosure provides a pharmaceutical composition or formulation comprising a recombinant adeno-associated virus (AAV), monobasic potassium phosphate, sodium chloride, anhydrous dibasic sodium phosphate, sucrose, and poloxamer 188. In some embodiments, the AAV comprises AAV components. In some embodiments, the AAV is the AAV viral vectors provided herein comprising the following elements in the following order: a) a constitutive or hypoxia-inducible promoter sequence and b) a sequence encoding the transgene (e.g., a chemical portion of an anti-VEGF antigen-binding fragment). In some embodiments, the transgene is a post-translationally modified fully human antibody (HuPTM). Petition 870260012693, dated 09 / 02 / 2026, page 102 / 420 35 / 319 against VEGF. Antibodies include, but are not limited to, monoclonal antibodies, polyclonal antibodies, recombinant antibodies, human antibodies, humanized antibodies, chimeric antibodies, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-heavy chain pairs, intracorporeal antibodies, heteroconjugated antibodies, monovalent antibodies, full-length antibody antigen-binding fragments, and fusion proteins of the foregoing.Such antigen-binding fragments include, but are not limited to, single-domain antibodies (variable domain heavy chain antibodies (VHHs) or nanobodies), Fabs, F(ab')2s, and scFvs (variable single-chain fragments) of full-length anti-VEGF antibodies (preferably full-length anti-VEGF monoclonal antibodies (mAbs)) (collectively referred to herein as “antigen-binding fragments”). In a preferred embodiment, the fully human post-translationally modified antibody against VEGF is a fully human post-translationally modified antigen-binding fragment of a monoclonal antibody (mAb) against VEGF (“HuPTMFabVEGFi”). In another preferred embodiment, HuPTMFabVEGFi is a fully human glycosylated antigen-binding fragment of an anti-VEGF mAb (“HuGlyFabVEGFi”). In an alternative embodiment, full-length mAbs may be used.In a preferred embodiment, the AAV used to deliver the transgene must have a tropism for human retinal cells or photoreceptor cells. Such an AAV may include recombinant non-replicating adeno-associated virus vectors (“rAAVs”), particularly those carrying an AAV8 capsid are preferred. In a specific embodiment, the viral vector or other DNA expression construct described herein is Construct I, wherein Construct I comprises the following components: (1) inverted terminal repeats of. Petition 870260012693, dated 09 / 02 / 2026, page 103 / 420 36 / 319 AAV8s flanking the expression cassette; (2) control elements, which include a) the CB7 promoter, comprising the CMV enhancer / chicken β-actin promoter, b) a chicken β-actin intron, and c) a rabbit β-globin poly A signal; and (3) nucleic acid sequences encoding the heavy and light chains of the anti-VEGF antigen-binding fragment, separated by a furin (F) / F2A autocleavage linker, ensuring expression of equal amounts of the heavy and light chain polypeptides.In another specific embodiment, the viral vector or other DNA expression construct described herein is Construct II, wherein Construct II comprises the following components: (1) inverted terminal repeats of AAV2 flanking the expression cassette; (2) control elements, which include a) the CB7 promoter, comprising the CMV enhancer / chicken D-actin promoter, b) a chicken D-actin intron, and c) a rabbit β-globin poly A signal; and (3) nucleic acid sequences encoding the heavy and light chains of the anti-VEGF antigen-binding fragment, separated by a furin (F) / F2A autocleavage linker, ensuring the expression of equal amounts of the heavy and light chain polypeptides. In one specific embodiment, the construct described herein is illustrated in Figure 4.In some embodiments, the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 4 and a light chain comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3.

[0081] In some embodiments, the pharmaceutical composition consists of: (a) Construct II encoding an anti-human vascular endothelial growth factor (hVEGF) antibody, (b) potassium chloride at a concentration of 0.2 g / l, (c) monobasic potassium phosphate at a concentration of 0.2 g / l, (d) sodium chloride at a concentration of 5.84 g / l, (e) anhydrous dibasic sodium phosphate at a concentration of 1.15 g / l, (f) sucrose at a concentration of 4% by weight / volume (40 g / l), (g) poloxamer 188 at a concentration of 0.001% by weight / volume (0.01 g / l) and (h) water, wherein the anti-hVEGF antibody comprises a heavy chain comprising a. Petition 870260012693, dated 09 / 02 / 2026, page 104 / 420 37 / 319 amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 4 and a light chain comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3.

[0082] In some embodiments, the pharmaceutical composition is a liquid composition. In some embodiments, the pharmaceutical composition is a frozen composition. In some embodiments, the pharmaceutical composition is a lyophilized composition of a liquid composition disclosed herein. In some embodiments, the pharmaceutical composition is a reconstituted lyophilized formulation.

[0083] In some embodiments, the pharmaceutical composition is a lyophilized composition comprising a residual moisture content between about 1% and about 7%.

[0084] In certain aspects, a method of treating or preventing a disease in a subject is disclosed in this document, comprising administering the pharmaceutical composition to the subject.

[0085] In certain aspects, a method of treating or preventing a disease in a subject is disclosed in this document, comprising administering the pharmaceutical composition to the subject by intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection (e.g., through a suprachoroidal drug delivery device, such as a microinjector with a microneedle), subretinal injection via a transvitreal approach (a surgical procedure), subretinal administration through the suprachoroidal space (e.g., a surgical procedure through a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where a small needle injects into the subretinal space) and / or a posterior juxtascleral deposition procedure (e.g.,through a juxtascleral drug delivery device comprising a cannula whose tip, Petition 870260012693, dated 09 / 02 / 2026, page 105 / 420 38 / 319 can be inserted and held in direct apposition to the scleral surface).

[0086] In certain respects, the pharmaceutical composition is suitable for administration into the eye. In certain respects, the pharmaceutical composition is suitable for suprachoroidal injection, subretinal injection via a transvitreous approach, subretinal administration via the suprachoroidal space, or a posterior juxtascleral deposition procedure.

[0087] In certain embodiments, the pharmaceutical composition is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection (e.g., via a suprachoroidal drug delivery device, such as a microinjector with a microneedle), subretinal injection via a transvitreal approach (a surgical procedure), subretinal administration via the suprachoroidal space (e.g., a surgical procedure using a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where a small needle injects into the subretinal space) and / or a posterior juxtascleral deposition procedure (e.g., via a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface)).

[0088] In certain embodiments, the pharmaceutical composition has a desired density that is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection (e.g., via a suprachoroidal drug delivery device, such as a microinjector with a microneedle), subretinal injection via a transvitreal approach (a surgical procedure), subretinal administration via the suprachoroidal space (e.g., a surgical procedure via a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where Petition 870260012693, dated 09 / 02 / 2026, page 106 / 420 39 / 319 a small needle is injected into the subretinal space) and / or a posterior juxtascleral deposition procedure (e.g., via a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface)).

[0089] In certain embodiments, the pharmaceutical composition has a desired osmolality that is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection (e.g., via a suprachoroidal drug delivery device, such as a microinjector with a microneedle), subretinal injection via a transvitreal approach (a surgical procedure), subretinal administration via the suprachoroidal space (e.g., a surgical procedure via a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where a small needle is injected into the subretinal space) and / or a posterior juxtascleral deposition procedure (e.g.,through a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface. In specific embodiments, the desired osmolality for subretinal administration is 160 to 430 mOsm / kg H2O. In other specific embodiments, the desired osmolality for suprachoroidal administration is less than 600 mOsm / kg H2O.

[0090] In certain embodiments, the pharmaceutical composition has a desired viscosity that is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection (e.g., via a suprachoroidal drug delivery device, such as a microinjector with a microneedle), subretinal injection via a transvitreal approach (a surgical procedure), subretinal administration via the suprachoroidal space (e.g., a surgical procedure via a drug delivery device). Petition 870260012693, dated 09 / 02 / 2026, page 107 / 420 40 / 319 subretinal drug delivery comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where a small needle is injected into the subretinal space) and / or a posterior juxtascleral drug delivery procedure (e.g., using a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface)).

[0091] In certain embodiments, the pharmaceutical composition has an osmolality range of 200 mOsm / l to 660 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality range of 200 mOsm / l to 660 mOsm / l. In some embodiments, the osmolality is less than 600 mOsm / kg H2O. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 200 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 250 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 300 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 350 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 400 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 450 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 500 mOsm / l.In certain embodiments, the pharmaceutical composition has an osmolality of approximately 550 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 600 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 650 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 660 mOsm / l. In certain aspects, methods of treating a subject diagnosed with mucopolysaccharidosis type IVA (MPS IVA), mucopolysaccharidosis type I (MPS I), or mucopolysaccharidosis type II (MPS II) are disclosed in this document, comprising administering the pharmaceutical composition to the subject. Petition 870260012693, dated 09 / 02 / 2026, page 108 / 420 41 / 319

[0092] In some embodiments, the vector genome concentration of Construct II after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of the vector genome concentration of Construct II before being stored at -80 °C for said period of time. In some embodiments, the vector genome concentration of Construct II after being stored at -20 °C for said period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of the vector genome concentration of Construct II before being stored at -20 °C for said period of time. In some embodiments, the vector genome concentration of Construct II after being stored at 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of the vector genome concentration of the Construct.In some modalities, the time period is approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, or approximately 24 months.

[0093] In some embodiments, the in vitro potency of Construct II after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the in vitro potency of Construct II before being stored at -80 °C for said period of time. II before being stored at 4 °C for said period of time. In some embodiments, the in vitro potency of Construct II after being stored at -20 °C for said period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the in vitro potency of Construct II before being stored at -20 °C for said period of time. In some embodiments, the in vitro potency of Construct II after being stored at 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of the in vitro potency of Construct II before being stored at 4 °C for said period of time.In some modalities, the time period is approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months. Petition 870260012693, dated 09 / 02 / 2026, page 109 / 420 42 / 319 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, or approximately 24 months.

[0094] In some embodiments, the size distribution of Construct II after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the size distribution of Construct II before being stored at -80 °C for that period of time. In some embodiments, the size distribution of Construct II after being stored at -20 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the size distribution of Construct II before being stored at -20 °C for that period of time. In some embodiments, the size distribution of Construct II after being stored at 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the size distribution of Construct II before being stored at 4 °C for that period of time.In some embodiments, the time period is approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months. In certain embodiments, the pharmaceutical composition is capable of being stored at 4°C for 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, approximately 2 months after having been previously stored at -80°C for approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months.

[0095] In certain aspects, methods of treatment for a subject diagnosed with mucopolysaccharidosis type IVA (MPS IVA), mucopolysaccharidosis type I (MPS I) or mucopolysaccharidosis type II (MPS II) are disclosed in this document, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition by intravenous administration, subcutaneous administration or intramuscular injection. Petition 870260012693, dated 09 / 02 / 2026, page 110 / 420 43 / 319

[0096] In certain aspects, methods of treatment or prevention of a disease in a subject are disclosed in this document, comprising the treatment of a subject diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME) or diabetic retinopathy (DR) comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition.

[0097] In certain aspects, methods of treating a subject diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR) are disclosed in this document, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition by suprachoroidal injection (e.g., through a suprachoroidal drug delivery device, such as a microinjector with a microneedle), subretinal injection via a transvitreal approach (a surgical procedure), subretinal administration through the suprachoroidal space (e.g., a surgical procedure via a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where a small needle injects into the subretinal space), or a posterior juxtascleral deposition procedure (e.g.,by means of a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface).

[0098] In certain aspects, described in this document are methods of treating a human subject diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME) or diabetic retinopathy (DR) comprising the delivery into the retina of said human subject of a therapeutically effective amount of anti-hVEGF antigen-binding fragment. Petition 870260012693, dated 09 / 02 / 2026, page 111 / 420 44 / 319 produced by human retinal cells, by administration to the suprachoroidal space, subretinal space or outer surface of the sclera in the eye of said human subject (for example, by suprachoroidal injection (e.g., by means of a suprachoroidal drug delivery device, such as a microinjector with a microneedle), subretinal injection by means of a transvitreal approach (a surgical procedure), subretinal administration through the suprachoroidal space (e.g., a surgical procedure by means of a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where a small needle is injected into the subretinal space), or a posterior juxtascleral deposition procedure (e.g.,through a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface) the pharmaceutical composition.

[0099] In certain aspects, a method of treating a subject diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR) is provided in this document, wherein the method comprises preparing a pharmaceutical composition provided in this document, storing the pharmaceutical composition at -80 °C for a first period of time; (ii) thawing the pharmaceutical composition; and (iii) after thawing, storing the pharmaceutical composition at 4 °C for a second period of time. In some embodiments, the first period of time is about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, or about 24 months. In some modalities, the second time period is approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, or approximately 2 months.

[0100] Anti-human vascular endothelial growth factor (hVEGF) antibodies are described here, for example, fragments of Petition 870260012693, dated 09 / 02 / 2026, page 112 / 420 45 / 319 binding to anti-hVEGF antigen, produced by human retinal cells. Human VEGF (hVEGF) is a human protein encoded by the VEGF gene (VEGFA, VEGFB, VEGFC, or VEGFD). An example amino acid sequence of hVEGF can be found in GenBank Accession Number AAA35789.1. An example nucleic acid sequence of hVEGF can be found in GenBank Accession Number M32977.1.

[0101] In certain aspects of the methods described in this document, the antigen-binding fragment comprises a heavy chain comprising the amino acid sequence of SEQ ID NO. 2 or SEQ ID NO. 4 and a light chain comprising the amino acid sequence of SEQ ID NO. 1 or SEQ ID NO. 3.

[0102] In certain aspects of the methods described in this document, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 17-19 or SEQ ID NOs: 20, 18 and 21.

[0103] In a specific embodiment of the methods described in this document, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21, wherein the second amino acid residue of the CDR3 light chain (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation and pyroglutamation (pyro Glu). In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21, wherein the eighth and eleventh amino acid residues of the CDR1 light chain (i.e., the two Ns in SASQDISNYLN (SEQ ID NO. 14)) each carry one or more of the following chemical modifications: oxidation, acetylation, deamidation and pyroglutamation (pyro Glu) and the second amino acid residue of the CDR3 light chain (i.e., the second Q in QQYSTVPWTF (SEQ ID NO.16)) does not carry one or more of the following. Petition 870260012693, dated 09 / 02 / 2026, p. 113 / 420 46 / 319 chemical modifications: oxidation, acetylation, deamidation and pyroglutamation (pyro Glu). In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21, wherein the second amino acid residue of the CDR3 light chain (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) is not acetylated. In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21, wherein the eighth and eleventh amino acid residues of the CDR1 light chain (i.e., the two Ns in SASQDISNYLN (SEQ ID NO. 14)) each carry one or more of the following chemical modifications: oxidation, acetylation, deamidation and pyroglutamation (pyro Glu) and the second amino acid residue of the CDR3 light chain (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) is not acetylated.In a preferred embodiment, the chemical modification (or modifications) or lack thereof (as the case may be) described herein is determined by mass spectrometry.

[0104] In a specific embodiment of the methods described in this document, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21, wherein the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation and pyroglutamation (pyro Glu). In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the ninth amino acid residue of the heavy chain CDR1 (i.e., the M in GYDFTHYGMN (SEQ ID NO. 20)) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro-Glu), the third amino acid residue of the heavy chain CDR2 (i.e., the N in WINTYTGEPTYAADFKR (SEQ ID NO. 18)) carries one or more of the following: Petition 870260012693, dated 09 / 02 / 2026, p. 114 / 420 47 / 319 the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), and the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu). In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) is not acetylated. In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21, wherein the ninth amino acid residue of the heavy chain CDR1 (i.e., the M in GYDFTHYGMN (SEQ ID NO.20)) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), the third amino acid residue of the heavy chain CDR2 (i.e., the N in WINTYTGEPTYAADFKR (SEQ ID NO. 18)) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), and the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) is not acetylated.

[0105] In a specific embodiment of the methods described in this document, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21, wherein the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation and pyroglutamation (pyro Glu) and the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) does not carry one or more of the following chemical modifications: Petition 870260012693, dated 09 / 02 / 2026, p. 115 / 420 48 / 319 oxidation, acetylation, deamidation and pyroglutamation (pyro Glu). In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21, wherein: (1) the ninth amino acid residue of the heavy chain CDR1 (i.e., the M in GYDFTHYGMN (SEQ ID NO. 20)) carries one or more of the following chemical modifications: acetylation, deamidation and pyroglutamation (pyro Glu), the third amino acid residue of the heavy chain CDR2 (i.e., the N in WINTYTGEPTYAADFKR (SEQ ID NO. 18)) carries one or more of the following chemical modifications: acetylation, deamidation and pyroglutamation (pyro Glu) and the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO.20)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation and pyroglutamation (pyro Glu); and (2) the eighth and eleventh amino acid residues of the CDR1 light chain (i.e., the two Ns in SASQDISNYLN (SEQ ID NO. 14)) each carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu) and the second amino acid residue of the CDR3 light chain (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu). In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the last amino acid residue of the CDR1 heavy chain (i.e., the N in GYDFTHYGMN) (SEQ ID NO.20)) is not acetylated and the second amino acid residue of the CDR3 light chain (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) is not acetylated. In a specific embodiment, the antigen-binding fragment comprises CDRs of light chains 1-3 from SEQ ID NOs: 14-16 and CDRs of heavy chains 1-3 from SEQ ID NOs: 20, 18 and 21, wherein: (1) the ninth amino acid residue of the CDR1 heavy chain (i.e., the M in GYDFTHYGMN (SEQ ID NO. 20)) carries one or more of the following chemical modifications: acetylation, deamidation and. Petition 870260012693, dated 09 / 02 / 2026, p. 116 / 420 49 / 319 pyroglutamation (pyro Glu), the third amino acid residue of the heavy chain CDR2 (i.e., the N in WINTYTGEPTYAADFKR (SEQ ID NO. 18)) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), and the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) is not acetylated; and (2) the eighth and eleventh amino acid residues of the light chain CDR1 (i.e., the two Ns in SASQDISNYLN (SEQ ID NO. 14) each carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu), and the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) is not acetylated.

[0106] In certain aspects, described in this document are methods of treating a human subject diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME) or diabetic retinopathy (DR), comprising: delivering to the eye of said human subject a therapeutically effective amount of an antigen-binding fragment of an mAb against hVEGF, said antigen-binding fragment containing an α2,6-sialylated glycan.In one specific aspect, described in this document are methods of treating a human subject diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME) or diabetic retinopathy (DR), comprising: delivering to the eye of said human subject a therapeutically effective amount of an antigen-binding fragment of an mAb against hVEGF, said antigen-binding fragment containing an α2,6-sialylated glycan, by administration to the suprachoroidal space, subretinal space or outer surface of the sclera in the eye of said human subject (e.g., by suprachoroidal injection (e.g., through a suprachoroidal drug delivery device, such as a microinjector with...). Petition 870260012693, dated 09 / 02 / 2026, page 117 / 420 50 / 319 a microneedle), subretinal injection via the transvitreous approach (a surgical procedure), subretinal administration via the suprachoroidal space (e.g., a surgical procedure using a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole where a small needle is injected into the subretinal space), or a posterior juxtascleral deposition procedure (e.g., using a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface)) the pharmaceutical composition comprising an expression vector encoding the antigen-binding fragment of an mAb against hVEGF.

[0107] In certain respects, described in this document are methods of treating a human subject diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME) or diabetic retinopathy (DR), comprising: delivery to the eye of said human subject of a therapeutically effective amount of a glycosylated antigen-binding fragment of an mAb against hVEGF, wherein said antigen-binding fragment does not contain detectable NeuGc and / or α-Gal antigen (i.e., as used in this document, “detectable” means levels detectable by standard assays described below).In one specific embodiment, this document describes methods for treating a human subject diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR), comprising: delivering to the eye of said human subject a therapeutically effective amount of a glycosylated antigen-binding fragment of an mAb against hVEGF, by administration to the suprachoroidal space, subretinal space, or outer scleral surface of the eye of said human subject (e.g., by suprachoroidal injection (e.g., by means of a suprachoroidal drug delivery device, such as a). Petition 870260012693, dated 09 / 02 / 2026, page 118 / 420 51 / 319 microinjector with microneedle), subretinal injection via transvitreous approach (a surgical procedure), subretinal administration via the suprachoroidal space (e.g., a surgical procedure via a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole where a small needle is injected into the subretinal space), or a posterior juxtascleral deposition procedure (e.g., via a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface)) the pharmaceutical composition comprising an expression vector encoding the glycosylated antigen-binding fragment of an mAb against hVEGF, wherein said antigen-binding fragment does not contain detectable NeuGc and / or α-Gal antigen.

[0108] Further details on the anti-hVEGF antibody or antigen-binding fragment of an mAb against hVEGF are provided in International Publication No: WO2019 / 067540 (incorporated by reference in its entirety herein).

[0109] In one specific aspect, the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO. 2 or SEQ ID NO. 4 and a light chain comprising the amino acid sequence of SEQ ID NO. 1 or SEQ ID NO. 3. In one specific aspect, the expression vector is an AAV8 vector.

[0110] In certain aspects of the methods described in this document, the antigen-binding fragment transgene encodes a leader peptide. A leader peptide may also be referred to as a signal peptide or leader sequence in this document.

[0111] In certain aspects of the methods described in this document, distribution to the eye includes distribution to the retina, choroid and / or vitreous humor of the eye. In certain aspects of the methods described in this document, the antigen-binding fragment includes a Petition 870260012693, dated 09 / 02 / 2026, page 119 / 420 52 / 319 heavy chain comprising one, two, three or four additional amino acids at the C-terminus.

[0112] In particular modalities, the methods encompass the treatment of patients who have been diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR) and identified as responsive to treatment with an anti-VEGF antibody. In more specific modalities, patients respond to treatment with an anti-VEGF antigen-binding fragment. In certain modalities, patients have demonstrated responsiveness to treatment with an intravitreal injected anti-VEGF antigen-binding fragment prior to gene therapy treatment. In specific modalities, patients were previously treated with LUCENTIS® (ranibizumab), EYLEA® (aflibercept), and / or AVASTIN® (bevacizumab) and were considered responsive to one or more of said LUCENTIS® (ranibizumab), EYLEA® (aflibercept), and / or AVASTIN® (bevacizumab).

[0113] Individuals to whom this viral vector or other DNA expression construct is delivered must respond to the anti-hVEGF antigen-binding fragment encoded by the transgene in the viral vector or expression construct. To determine responsiveness, the transgene product of the anti-VEGF antigen-binding fragment (e.g., produced in cell culture, bioreactors, etc.) can be administered directly to the subject, such as by intravitreal injection.

[0114] In certain aspects of the methods described in this document, the antigen-binding fragment comprises a heavy chain that does not include an additional amino acid at the C-terminus.

[0115] In certain aspects of the methods described in this document, a population of antigen-binding fragment molecules is produced, wherein the antigen-binding fragment molecules comprise a heavy chain and wherein 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, Petition 870260012693, dated 09 / 02 / 2026, page 120 / 420 53 / 319 or 20%, or less, of the population of antigen-binding fragment molecules comprise one, two, three, or four additional amino acids at the C-terminus of the heavy chain. In certain aspects of the methods described herein, a population of antigen-binding fragment molecules is produced wherein the antigen-binding fragment molecules comprise a heavy chain and wherein 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, or 20%, or less, but more than 0% of the population of antigen-binding fragment molecules comprises one, two, three, or four additional amino acids at the C-terminus of the heavy chain.

[0116] In certain aspects of the methods described in this document, a population of antigen-binding fragment molecules is produced, wherein the antigen-binding fragment molecules comprise a heavy chain and wherein 0.5 to 1%, 0.5% to 2%, 0.5% to 3%, 0.5% to 4%, 0.5% to 5%, 0.5% to 10%, 0.5% to 20%, 1% to 2%, 1% to 3%, 1% to 4%, 1% to 5%, 1% to 10%, 1% to 20%, 2% to 3%, 2% to 4%, 2% to 5%, 2% to 10%, 2% to 20%, 3% to 4%, 3% to 5%, 3% to 10%, 3% to 20%, 4% to 5%, 4% to 10%, 4% to 20%, 5% to 10%, 5% to 20%, or 10% to 20% of the antigen-binding fragment molecule population comprise one, two, three, or four additional amino acids at the C-terminus of the heavy chain.

[0117] HuPTMFabVEGFi, for example, The HuGlyFabVEGFi transgene may include, but is not limited to, an antigen-binding fragment of an antibody that binds to hVEGF, such as bevacizumab; an anti-hVEGF Fab chemical portion such as ranibizumab; or such Fab chemical portions of bevacizumab or ranibizumab genetically modified to contain additional glycosylation sites in the Fab domain (e.g., see Courtois et al, 2016, mAbs 8: 99-112, which is incorporated by reference herein in its entirety for its description of bevacizumab derivatives that are hyperglycosylated in the full-length antibody Fab domain).

[0118] The recombinant vector used to deliver the Petition 870260012693, dated 09 / 02 / 2026, page 121 / 420 The 54 / 319 transgene must have a tropism for human retinal cells or photoreceptor cells. Such vectors may include recombinant non-replicating adeno-associated virus (“rAAV”) vectors, particularly those carrying an AAV8 capsid, which are preferred. However, other viral vectors may be used, including, but not limited to, lentiviral vectors, vaccinia viral vectors, or non-viral expression vectors referred to as “naked DNA” constructs. Preferably, the HuPTMFabVEGFi transgene, for example, HuGlyFabVEGFi, should be controlled by appropriate expression control elements, for example, the CB7 promoter (a chicken β-actin promoter and CMV enhancer), the RPE65 promoter or opsin promoter, to name a few, and may include other expression control elements that increase the expression of the vector-driven transgene (e.g., introns such as the chicken β-actin intron, mouse minute virus (MVM) intron),Human factor IX intron (e.g., truncated FIX intron 1), β-globin splice donor intron / immunoglobulin heavy chain splice acceptor intron, adenovirus splice donor intron / immunoglobulin splice acceptor intron, SV40 late splice donor intron / splicing acceptor (19S / 16S), and hybrid adenovirus splice intron / IgG splice acceptor signals, and polyA such as rabbit β-globin polyA signal, human growth hormone (hGH) polyA signal, SV40 late polyA signal, synthetic polyA signal (SPA), and bovine growth hormone (bGH) polyA signal). See, for example, Powell and Rivera-Soto, 2015, Discov. Med., 19(102): 49-57.

[0119] Gene therapy constructs are genetically modified so that both heavy and light chains are expressed. More specifically, the heavy and light chains must be expressed in approximately equal amounts; in other words, the heavy and light chains are expressed in a ratio of approximately 1:1 between heavy and light chains. The coding sequences for the heavy and light chains can be manipulated into a single construct in which the heavy and light chains are separated by a cleavable linker or IRES. Petition 870260012693, dated 09 / 02 / 2026, page 122 / 420 55 / 319 so that the separated heavy and light chain polypeptides are expressed. See, for example, Section 5.2.4 for specific leader sequences and Section 5.2.5 for IRES, 2A and other specific linker sequences that can be used with the methods and compositions provided in this document.

[0120] In certain embodiments, gene therapy constructs are provided as a sterile, single-use frozen solution of the AAV vector active ingredient in a formulation buffer. In one specific embodiment, pharmaceutical compositions suitable for subretinal administration comprise a suspension of the recombinant vector (e.g., rHuGlyFabVEGFi) in a formulation buffer comprising a physiologically compatible aqueous buffer, a surfactant, and optional excipients.

[0121] In certain embodiments, gene therapy constructs are provided as a single-use, sterile frozen solution of the AAV vector active ingredient in a formulation buffer. In one specific embodiment, pharmaceutical compositions suitable for suprachoroidal, subretinal, juxtascleral and / or intraretinal administration comprise a suspension of the recombinant vector (e.g., rHuGlyFabVEGFi) in a formulation buffer comprising a physiologically compatible aqueous buffer, a surfactant and optional excipients.

[0122] Therapeutically effective doses of the recombinant vector should be administered subretinally and / or intraretinally (e.g., by subretinal injection via the transvitreal approach (a surgical procedure) or subretinal administration via the suprachoroidal space) in a volume ranging from >0.1 ml to <0.5 ml, preferably in 0.1 to 0.30 ml (100 to 300 pl) and more preferably in a volume of 0.25 ml (250 pl). Therapeutically effective doses of the recombinant vector may be administered in one or more injections during the same visit.

[0123] Therapeutically effective doses of the vector Petition 870260012693, dated 09 / 02 / 2026, page 123 / 420 Recombinant 56 / 319 should be administered suprachoroidally (e.g., by suprachoroidal injection) in a volume of 100 μI or less, for example, in a volume of 50 to 100 μI. Therapeutically effective doses of the recombinant vector should be administered to the outer surface of the sclera (e.g., by a posterior juxtascleral deposition procedure) in a volume of 500 μI or less, for example, in a volume of 10 to 20 μI, 20 to 50 μI, 50 to 100 μI, 100 to 200 μI, 200 to 300 μI, 300 to 400 μI, or 400 to 500 μI. Subretinal injection is a surgical procedure performed by trained retinal surgeons that involves a vitrectomy with the subject under local anesthesia and subretinal injection of gene therapy into the retina (see, for example, Campochiaro et al, 2017, Hum Gen Ther 28(1)): 99-111, which is incorporated herein by reference in its entirety).In one specific embodiment, subretinal administration is performed via the suprachoroidal space using a suprachoroidal catheter that injects drug into the subretinal space, such as a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space to the posterior pole, where a small needle injects into the subretinal space (see, for example, Baldassarre et al, 2017, Subretinal Delivery of Cells via the Suprachoroidal Space: Janssen Trial. In: Schwartz et al (eds) Cellular Therapies for Retinal Disease, Springer, Cham; International Patent Application Publication No. WO 2016 / 040635 A1;Suprachoroidal drug delivery procedures involve administering a drug into the suprachoroidal space of the eye and are typically performed using a suprachoroidal drug delivery device, such as a microinjector with a microneedle (see, for example, Hariprasad, 2016, Retinal Physician 13: 20-23; Goldstein, 2014, Retina Today 9(5): 82-87; each of which is incorporated by reference herein in its entirety). Suprachoroidal drug delivery devices that can be used to deposit the vector of... Petition 870260012693, dated 09 / 02 / 2026, page 124 / 420 57 / 319 Expression in the suprachoroidal space according to the invention described herein includes, but is not limited to, suprachoroidal drug delivery devices manufactured by Clearside® Biomedical, Inc. (see, for example, Hariprasad, 2016, Retinal Physician 13: 20-23) and MedOne suprachoroidal catheters. Subretinal drug delivery devices that can be used to deposit the expression vector into the subretinal space via the suprachoroidal space according to the invention described herein include, but are not limited to, subretinal drug delivery devices manufactured by Janssen Pharmaceuticals, Inc. (see, for example, International Patent Application Publication No. WO 2016 / 040635 A1).In one specific embodiment, administration to the outer surface of the sclera is performed using a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface. See Section 5.3.2 for more details on the different modes of administration. Suprachoroidal, subretinal, juxtascleral and / or intraretinal administration should result in the distribution of the soluble transgenic product into the retina, vitreous humor and / or aqueous humor. Expression of the transgenic product (e.g., the encoded anti-VEGF antibody) by retinal cells, e.g., rod, cone, retinal pigment epithelial cells, horizontal, bipolar, amacrine, ganglion cells and / or Müller cells, results in the distribution and maintenance of the transgene product in the retina, vitreous humor and / or aqueous humor.In one specific embodiment, doses that maintain a concentration of the transgenic product at a Cmin of at least 0.330 pg / ml in the vitreous humor or 0.110 pg / ml in the aqueous humor (the anterior chamber of the eye) for three months are desired; thereafter, vitreous Cmin concentrations of the transgenic product ranging from 1.70 to 6.60 pg / ml, and / or aqueous Cmin concentrations ranging from 0.567 to 2.20 pg / ml should be maintained. However, since the transgene product is produced continuously, maintaining lower concentrations may be effective. The concentration of the transgenic product can be measured. Petition 870260012693, dated 09 / 02 / 2026, page 125 / 420 58 / 319 in patient samples of vitreous and / or aqueous humor from the anterior chamber of the treated eye. Alternatively, vitreous humor concentrations can be estimated and / or monitored by measuring the patient's serum concentrations of the transgene product – the ratio between systemic and vitreous exposure to the transgene product is approximately 1:90000. (For example, see vitreous humor and serum ranibizumab concentrations reported in Xu L, et al, 2013, Invest. Ophthal. Vis. Sci. 54: 1616-1624, on page 1621 and Table 5 on page 1623, which is incorporated by reference herein in its entirety).

[0124] In certain modalities, dosages are measured by genome copies per ml or the number of genome copies administered to the patient's eye (e.g., by suprachoroidal injection (e.g., via a suprachoroidal drug delivery device, such as a microinjector with a microneedle), subretinal injection via the transvitreal approach (a surgical procedure), or subretinal administration via the suprachoroidal space). In certain modalities, 2.4 x 10¹¹ genome copies per ml to 1 x 10¹³ genome copies per ml are administered. In one specific modality, 2.4 x 10¹¹ genome copies per ml to 5 x 10¹¹ genome copies per ml are administered. In another specific modality, 5 x 10¹¹ genome copies per ml to 1 x 10¹² genome copies per ml are administered. In another specific modality, 1 x 1012 copies of the genome per ml to 5 x 1012 copies of the genome per ml are administered.In another specific modality, 5 x 10¹² copies of the genome are administered per ml to 1 x 10¹³ copies of the genome per ml. In another specific modality, approximately 2.4 x 10¹¹ copies of the genome are administered per ml. In another specific modality, approximately 5 x 10¹¹ copies of the genome are administered per ml. In another specific modality, approximately 1 x 10¹² copies of the genome are administered per ml. In another specific modality, approximately 5 x 10¹² copies of the genome are administered per ml. In another specific modality, approximately 1 x 10¹³ copies of the genome are administered per ml. In certain modalities, 1 x 10⁹ to 1 x 10¹² copies of the genome are administered. In. Petition 870260012693, dated 09 / 02 / 2026, page 126 / 420 In specific modalities, 3 x 10⁹ to 2.5 x 10¹¹ copies of the genome are administered. In specific modalities, 1 x 10⁹ to 2.5 x 10¹¹ copies of the genome are administered. In specific modalities, 1 x 10⁹ to 1 x 10¹¹ copies of the genome are administered. In specific modalities, 1 x 10⁹ to 5 x 10⁹ copies of the genome are administered. In specific modalities, 6 x 10⁹ to 3 x 10¹⁰ copies of the genome are administered. In specific modalities, 4 x 10¹⁰ to 1 x 10¹¹ copies of the genome are administered. In specific modalities, 2 x 10¹¹ to 1 x 10¹² copies of the genome are administered. In one specific modality, approximately 3 x 10⁹ copies of the genome are administered (which corresponds to approximately 1.2 x 10¹⁰ copies of the genome per ml in a volume of 250 μl). In another specific modality, approximately 1 x 10¹⁰ copies of the genome are administered (which corresponds to approximately 4 x 10¹⁰ copies of the genome per ml in a volume of 250 μl).In another specific modality, approximately 6 x 10¹⁰ copies of the genome are administered (which corresponds to approximately 2.4 x 10¹¹ copies of the genome per ml in a volume of 250 μl). In another specific modality, approximately 1.6 x 10¹¹ copies of the genome are administered (which corresponds to approximately 6.2 x 10¹¹ copies of the genome per ml in a volume of 250 μl). In another specific modality, approximately 1.6 x 10¹¹ copies of the genome are administered (which corresponds to approximately 6.4 x 10¹¹ copies of the genome per ml in a volume of 250 μl). In another specific modality, approximately 1.55 x 10¹¹ copies of the genome are administered (which corresponds to approximately 6.2 x 10¹¹ copies of the genome per ml in a volume of 250 μl). In another specific modality, approximately 2.5 x 1011 copies of the genome (which corresponds to approximately 1.0 x 1012 in a volume of 250 dl) are administered.

[0125] As used in this document and unless otherwise specified, the term “about” means approximately 10% of a given value or range.

[0126] The invention has several advantages over standard care treatments involving repeated ocular injections of high-dose VEGF inhibitor bolus doses that dissipate over time, Petition 870260012693, dated 09 / 02 / 2026, page 127 / 420 60 / 319 resulting in peak and trough levels. Sustained expression of the transgene product antibody, as opposed to repeatedly injecting an antibody, allows for more consistent antibody levels to be present at the site of action and is less risky and more convenient for patients, as fewer injections are needed, resulting in fewer medical visits. Consistent protein production can lead to better clinical outcomes, as rebound retinal edema is less likely to occur. Furthermore, antibodies expressed from transgenes are post-translationally modified differently than those injected directly due to the different microenvironment present during and after translation.Without being tied to any specific theory, this results in antibodies that have different characteristics of diffusion, bioactivity, distribution, affinity, pharmacokinetics, and immunogenicity, so that antibodies delivered to the site of action are "biologically superior" compared to antibodies injected directly.

[0127] Furthermore, antibodies expressed from transgenes in vivo likely do not contain degradation products associated with antibodies produced by recombinant technologies, such as protein aggregation and protein oxidation. Aggregation is a problem associated with protein production and storage due to high protein concentration, surface interaction with manufacturing equipment and containers, and purification with certain buffer systems. These conditions, which promote aggregation, do not exist in transgene expression in gene therapy. Oxidation, such as the oxidation of methionine, tryptophan, and histidine, is also associated with protein production and storage and is caused by stressed cell culture conditions, contact with metal and air, and impurities in buffers and excipients. Proteins expressed from transgenes in vivo may also oxidize under stress conditions.However, humans and many other organisms are equipped with an antioxidant defense system, which not only reduces oxidative stress, but also... Petition 870260012693, dated 09 / 02 / 2026, page 128 / 420 61 / 319 times it also repairs and / or reverses oxidation. Thus, proteins produced in vivo are probably not in an oxidized form. Both aggregation and oxidation can affect potency, pharmacokinetics (clearance), and immunogenicity.

[0128] Without being bound by theory, the methods and compositions provided in this document are based, in part, on the following principles:

[0129] (i) Human retinal cells are secretory cells that possess the cellular machinery for post-translational processing of secreted proteins - including glycosylation and tyrosine-O sulfation, a robust process in retinal cells. (See, for example, Wang et al, 2013, Analytical Biochem. 427: 20-28 and Adamis et al, 1993, BBRC 193: 631-638 reporting the production of glycoproteins by retinal cells; and Kanan et al, 2009, Exp. Eye Res. 89: 559-567 and Kanan & Al-Ubaidi, 2015, Exp. Eye Res. 133: 126-131 reporting the production of tyrosine-sulfated glycoproteins secreted by retinal cells, each of which is incorporated by way of reference in its entirety for post-translational modifications made by human retinal cells).

[0130] (ii) Contrary to the understanding of the state of the art, anti-VEGF antigen-binding fragments, such as ranibizumab (and the Fab domain of full-length anti-VEGF mAbs, such as bevacizumab) actually possess N-linked glycosylation sites. For example, see Figure 1 which identifies non-consensual asparaginal glycosylation sites (“N”) in the Ch domain (TVSWN165SGAL) and Cl domain (QSGN158SQE), as well as glutamine residues (“Q”) that are glycosylation sites in the Vh domain (Q115GT) and Vl domain (TFQ100GT) of ranibizumab (and corresponding sites in the Fab of bevacizumab). (See, for example, Valliere-Douglass et al., 2009, J. Biol. Chem. 284: 32493-32506 and Valliere-Douglass et al., 2010, J. Biol. Chem. 285: 16012-16022, each of which is incorporated by reference in its entirety for the identification of N-linked glycosylation sites in Petition 870260012693, dated 09 / 02 / 2026, p. 129 / 420 62 / 319 antibodies).

[0131] (iii) Although these non-canonical sites generally result in low-level glycosylation (e.g., about 1 to 5%) of the antibody population, the functional benefits can be significant in immunoprivileged organs such as the eye (see, for example, van de Bovenkamp et al., 2016, J. Immunol. 196: 1435-1441). For example, Fab glycosylation can affect the stability, half-life, and binding characteristics of an antibody. To determine the effects of Fab glycosylation on antibody affinity for its target, any technique known to an individual skilled in the art can be used, for example, enzyme-linked immunosorbent assay (ELISA) or surface plasmon resonance (SPR).To determine the effects of Fab glycosylation on antibody half-life, any technique known to a person skilled in the art may be used, for example, by measuring radioactivity levels in the blood or organs (e.g., the eye) of a subject to whom a radiolabeled antibody has been administered. To determine the effects of Fab glycosylation on stability, for example, protein aggregation or unfolding levels, of the antibody, any technique known to a person skilled in the art may be used, for example, differential scanning calorimetry (DSC), high-performance liquid chromatography (HPLC), for example, size exclusion high-performance liquid chromatography (SEC-HPLC), capillary electrophoresis, mass spectrometry, or turbidity measurement.Provided in this document, the HuPTMFabVEGFi transgene, for example, HuGlyFabVEGFi, results in the production of a Fab that is 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% or more glycosylated at non-canonical sites. In certain embodiments, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% or more of a population of Fabs are glycosylated at non-canonical sites. In certain embodiments, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% or more of non-canonical sites are glycosylated. In certain modalities, the glycosylation of Fab in these non-canonical sites is 25%, 50%, 100%, 200%, etc. Petition 870260012693, dated 09 / 02 / 2026, page 130 / 420 63 / 319 300%, 400%, 500% or more than the amount of glycosylation of these non-canonical sites in a Fab produced in HEK293 cells.

[0132] (iv) In addition to glycosylation sites, anti-VEGF Fabs, such as ranibizumab (and bevacizumab Fab), contain tyrosine sulfation (“Y”) sites within or near CDRs; see Figure 1 which identifies tyrosine-O-sulfation sites in the Vh (EDTAVY94Y95) and Vl (EDFATY86) domains of ranibizumab (and corresponding sites in the bevacizumab Fab). (See, for example, Yang et al, 2015, Molecules 20: 2138-2164, especially on page 2154, which is incorporated in its entirety as a reference for the analysis of amino acids involving tyrosine residues subjected to protein tyrosine sulfation. The "rules" can be summarized as follows: Y residues with E or D within the +5 to -5 position of Y, and where the -1 position of Y is a neutral or acidic amino acid – but not a basic amino acid, for example, R, K, or H, which eliminates sulfation).Human IgG antibodies can exhibit a range of other post-translational modifications, such as N-terminal modifications, C-terminal modifications, degradation or oxidation of amino acid residues, cysteine-related variants, and glycation (see, for example, Liu et al, 2014, mAbs 6(5):). 1145-1154).

[0133] (v) Glycosylation of anti-VEGF Fabs, such as ranibizumab or the Fab fragment of bevacizumab, by human retinal cells will result in the addition of glycans that can improve the stability, half-life, and reduce unwanted aggregation and / or immunogenicity of the transgenic product. (See, for example, Bovenkamp et al., 2016, J. Immunol. 196: 1435-1441 for a review of the emerging importance of Fab glycosylation). Significantly, the glycans that can be added to HuPTMFabVEGFi, for example, HuGlyFabVEGFi, provided in this document, are highly processed complex-type biantenna N-glycans containing 2,6-sialic acid (for example, see Figure 2 representing the glycans that can be incorporated into HuPTMFabVEGFi, for example, Petition 870260012693, dated 09 / 02 / 2026, page 131 / 420 64 / 319 HuGlyFabVEGFi) and bisecting GlcNAc, but not NGNA (N-glycolylneuraminic acid, Neu5Gc). These glycans are not present in ranibizumab (which is produced in E. coli and is not glycosylated) or bevacizumab (which is produced in CHO cells that lack the 2,6-sialyltransferase necessary to make this post-translational modification, nor do CHO cells produce bisecting GlcNAc, although they add Neu5Gc (NGNA) as a non-typical (and potentially immunogenic) sialic acid for humans instead of Neu5Ac (NANA)). See, for example, Dumont et al, 2015, Crit. Rev. Biotechnol. (Early Online, published online September 18, 2015, pages 1-13 on p. 5). Furthermore, CHO cells can also produce an immunogenic glycan, the α-Gal antigen, which reacts with anti-α-Gal antibodies present in most individuals and, at high concentrations, can trigger anaphylaxis. See, for example, Bosques, 2010, Nat Biotech 28: 1153-1156.The human glycosylation pattern of HuPTMFabVEGFi, for example, HuGlyFabVEGFi, provided in this document, should reduce the immunogenicity of the transgene product and improve efficacy.

[0134] (vi) Tyrosine sulfation of anti-VEGF Fabs, such as ranibizumab or the Fab fragment of bevacizumab – a robust post-translational process in human retinal cells – can result in transgenic products with increased VEGF avidity. In fact, tyrosine sulfation of the Fab of therapeutic antibodies against other targets has been shown to dramatically increase antigen avidity and activity. (See, for example, Loos et al, 2015, PNAS 112: 12675-12680 and Choe et al, 2003, Cell 114: 161-170). Such post-translational modifications are not present in ranibizumab (which is made in E. coli, a host that lacks the enzymes necessary for tyrosine sulfation) and, at best, are underrepresented in bevacizumab – a CHO cell product. Unlike human retinal cells, CHO cells are not secretory cells and have a limited capacity for post-translational tyrosine sulfation.(See, for example, Mikkelsen & Ezban, 1991, Biochemistry 30: 1533-1537.) Petition 870260012693, dated 09 / 02 / 2026, p. 132 / 420 65 / 319 especially the discussion on p. 1537).

[0135] For the reasons above, the production of HuPTMFabVEGFi, for example, HuGlyFabVEGFi, should result in a “biologically superior” molecule for the treatment of nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR) achieved through gene therapy – for example, by administering a viral vector or other DNA expression construct encoding HuPTMFabVEGFi, for example, HuGlyFabVEGFi, into the suprachoroidal space, subretinal space, or the outer surface of the sclera in the eye (or eyes) of patients (human subjects) diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR) (for example, by suprachoroidal injection (e.g., via a suprachoroidal drug delivery device such as a microneedle microinjector), subretinal injection through from the transvitreal approach (a surgical procedure),Subretinal administration via the suprachoroidal space, or a posterior juxtascleral deposition procedure), to create a permanent deposit in the eye that continuously delivers the sulfated transgene product, the fully human post-translationally modified transgene product, for example, human-glycosylated, produced by transduced retinal cells. The cDNA construct for FabVEGFi must include a signal peptide that ensures proper co- and post-translational processing (glycosylation and sulfation of proteins) by transduced retinal cells. Such signal sequences used by retinal cells may include, but are not limited to:

[0136] · MNFLLSWVHW SLALLLYLHH AKWSQA (VEGF-A signal peptide) (SEQ ID NO: 5)

[0137] MERAAPSRRV PLPLLLLGGL ALLAAGVDA (Fibulin-1 signal peptide) (SEQ ID NO: 6)

[0138] · MAPLRPLLIL ALLAWVALA (vitronectin signal peptide) (SEQ ID NO: 7) Petition 870260012693, dated 09 / 02 / 2026, page 133 / 420 66 / 319

[0139] · MRLLAKIICLMLWAICVA (signal peptide of Complement H Factor) (SEQ ID NO: 8)

[0140] · MRLLAFLSLL ALVLQETGT (Opticin signal peptide) (SEQ ID NO: 9)

[0141] · MKWVTFISLLFLFSSAYS (albumin signal peptide) (SEQ ID NO: 22)

[0142] · MAFLWLLSCWALLGTTFG (chymotrypsinogen signal peptide) (SEQ ID NO: 23)

[0143] · MYRMQLLSCIALILALVTNS (interleukin-2 signal peptide) (SEQ ID NO: 24)

[0144] · MNLLLILTFVAAAVA (trypsinogen-2 signal peptide) (SEQ ID NO: 25)

[0145] · MYRMQLLLLIALSLALVTNS (mutant Interleukin-2 signal peptide) (SEQ ID NO: 52).

[0146] · See, for example, Stern et al, 2007, Trends Cell. Mol. Biol., 2: 1-17 and Dalton & Barton, 2014, Protein Sci, 23: 517-525, each of which is incorporated by reference herein in its entirety for the signal peptides that may be used.

[0147] As an alternative or additional treatment to gene therapy, the product HuPTMFabVEGFi, for example, HuGlyFabVEGFi glycoprotein, can be produced in human cell lines by recombinant DNA technology and administered to patients diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME) or diabetic retinopathy (DR) by intravitreal or subretinal injection. The product HuPTMFabVEGFi, for example, glycoprotein, can also be administered to patients with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME) or diabetic retinopathy (DR). Human cell lines that can be used for such recombinant glycoprotein production include, but are not limited to, human kidney embryonic cells 293 (HEK293), fibrosarcoma HT-1080, HKB-11, CAP, HuH-7 and Petition 870260012693, dated 09 / 02 / 2026, page 134 / 420 67 / 319 retinal cell lines, PER.C6, or RPE to name a few (e.g., see Dumont et al., 2015, Crit. Rev. Biotechnol. (Early Online, published online September 18, 2015, pp. 1-13) “Human cell lines for biopharmaceutical manufacturing: history, status, and future perspectives”, which is incorporated by reference in its entirety for a review of human cell lines that could be used for the recombinant production of the product HuPTMFabVEGFi, e.g., HuGlyFabVEGFi glycoprotein). To ensure complete glycosylation, especially sialylation and sulfation of tyrosine, the cell line used for production can be enhanced by genetically modifying the host cells to co-express α-2,6-sialyltransferase (or both α-2,3- and α-2,6-sialyltransferases) and / or TPST-1 and TPST-2 enzymes responsible for tyrosine-O sulfation in retinal cells.

[0148] Distribution combinations of For example, HuPTMFabVEGFi, HuGlyFabVEGFi, delivered to the eye / retina along with other available treatments are encompassed by the methods provided in this document. Additional treatments may be administered before, concurrently with, or subsequently to gene therapy. Available treatments for nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR) that can be combined with the gene therapy provided in this document include, but are not limited to, laser photocoagulation, photodynamic therapy with verteporfin, and intravitreal injections (IVT) with anti-VEGF agents, including, but not limited to, pegaptanib, ranibizumab, aflibercept, or bevacizumab. Additional treatments with anti-VEGF agents, such as biologics, may be referred to as “salvage” therapy.

[0149] Unlike small molecule drugs, biological products generally comprise a mixture of many variants with different modifications or forms that have different potency, pharmacokinetics, and safety profiles. It is not essential that all of them Petition 870260012693, dated 09 / 02 / 2026, page 135 / 420 68 / 319 molecules produced in gene therapy or protein therapy are fully glycosylated and sulfated. Instead, the population of glycoproteins produced must have sufficient glycosylation (from about 1% to about 10% of the population), including 2,6-sialylation and sulfation to demonstrate efficacy. The goal of the gene therapy treatment provided in this document is to slow or halt the progression of retinal degeneration and delay or prevent vision loss with minimally invasive intervention / procedures. Efficacy can be monitored by measuring BCVA (best corrected visual acuity), intraocular pressure, slit-lamp biomicroscopy, indirect ophthalmoscopy, SD-OCT (SD optical coherence tomography), electroretinography (ERG). Signs of vision loss, infection, inflammation, and other safety events, including retinal detachment, can also be monitored.Retinal thickness can be monitored to determine the effectiveness of the treatments provided in this document. Without being tied to any particular theory, retinal thickness can be used as a clinical readout, where the greater the reduction in retinal thickness or the longer the time period before retinal thickening, the more effective the treatment. Retinal thickness can be determined, for example, by SD-OCT. SD-OCT is a three-dimensional imaging technology that uses low-coherence interferometry to determine the echo time delay and magnitude of backscattered light reflected from an object of interest. OCT can be used to scan the layers of a tissue sample (e.g., the retina) with axial resolution of 3 to 15 μm, and SD-OCT improves axial resolution and scan speed compared to previous forms of the technology (Schuman, 2008, Trans. Am. Opthamol. Soc. 106: 426-458).Retinal function can be determined, for example, by ERG. ERG is a non-invasive electrophysiological test of retinal function, approved by the FDA for use in humans, that examines the light-sensitive cells of the eye (rods and cones) and their connecting ganglion cells, in particular, their response to instantaneous stimulation. Petition 870260012693, dated 09 / 02 / 2026, page 136 / 420 69 / 319

[0150] In preferred embodiments, the antigen-binding fragments do not contain detectable NeuGc and / or α-Gal. The phrase “detectable NeuGc and / or α-Gal” used in this document means chemical moieties of NeuGc and / or α-Gal detectable by standard test methods known in the art. For example, NeuGc can be detected by HPLC according to Hara et al, 1989, “Highly sensitive determination of N-Acetyl and N-glycolneuramine acids in human serum and rat urine by reverse-phase liquid chromatography with fluorescence detection”. J. Chromatogr., B: Biomed. 377: 111-119, which is incorporated herein by reference to the method of detecting NeuGc. Alternatively, NeuGc can be detected by mass spectrometry. α-Gal can be detected using an ELISA; see, for example, Galili et al., 1998, "A sensitive assay for measuring the expression of alpha-Gal epitopes in cells by a monoclonal anti-Gal antibody". Transplantation.65(8): 1129-32, ou por espectrometria de massa, consultar, por exemplo, Ayoub et al, 2013, “Correct primary structure assessment and extensive glyco-profiling of cetuximab by a combination of intact, middle-up, middle-down and bottom-up ESI and MALDI mass spectrometry techniques.” Landes Bioscience. 5(5): 699-710. Consultar também as referências citadas em Platts-Mills et al, 2015, “Anaphylaxis to the Carbohydrate Side-Chain Alpha-gal” Immunol Allergy Clin North Am. 35(2): 247-260.

[0151] In certain respects, anti-VEGF antigen-binding fragments (i.e., antigen-binding fragments that bind immunospecifically to VEGF) comprising light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21 are also provided in this document, wherein the second amino acid residue of the CDR3 light chain (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation and pyroglutamation (pyro Glu). In a specific embodiment, the antigen-binding fragment Petition 870260012693, dated 09 / 02 / 2026, p. 137 / 420 70 / 319 comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21, wherein the eighth and eleventh amino acid residues of light chain CDR1 (i.e., the two Ns in SASQDISNYLN (SEQ ID NO. 14)) each carries one or more of the following chemical modifications: oxidation, acetylation, deamidation and pyroglutamation (pyro Glu) and the second amino acid residue of light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation and pyroglutamation (pyro Glu). NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21, where the second amino acid residue of the CDR3 light chain (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) is not acetylated.In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21, wherein the eighth and eleventh amino acid residues of the CDR1 light chain (i.e., the two Ns in SASQDISNYLN (SEQ ID NO. 14)) each carry one or more of the following chemical modifications: oxidation, acetylation, deamidation and pyroglutamation (pyro Glu) and the second amino acid residue of the CDR3 light chain (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) is not acetylated. The anti-VEGF antigen-binding fragments provided herein may be used in any method according to the invention described herein. The chemical modifications (as the case may be) described herein are determined by mass spectrometry.

[0152] In certain respects, anti-VEGF antigen-binding fragments comprising light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21 are also provided in this document, wherein the last residue of Petition 870260012693, dated 09 / 02 / 2026, p. 138 / 420 71 / 319 heavy chain amino acid CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu). In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21, wherein the ninth amino acid residue of the heavy chain CDR1 (i.e., the M in GYDFTHYGMN (SEQ ID NO. 20)) carries one or more of the following chemical modifications: acetylation, deamidation and pyroglutamation (pyro Glu), the third amino acid residue of the heavy chain CDR2 (i.e., the N in WINTYTGEPTYAADFKR (SEQ ID NO. 18)) carries one or more of the following chemical modifications: acetylation, deamidation and pyroglutamation (pyro Glu) and the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO.20)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu). In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) is not acetylated. In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21, wherein the ninth amino acid residue of the heavy chain CDR1 (i.e., the M in GYDFTHYGMN (SEQ ID NO. 20)) carries one or more of the following chemical modifications: acetylation, deamidation and pyroglutamation (pyro Glu), the third amino acid residue of the heavy chain CDR2 (i.e., the N in WINTYTGEPTYAADFKR (SEQ ID NO.18) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), and the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) is not acetylated. Anti-VEGF antigen-binding fragments provided in this document may be used. Petition 870260012693, dated 09 / 02 / 2026, p. 139 / 420 72 / 319 in any method according to the invention described herein. In a preferred embodiment, the chemical modification (or modifications) or lack of chemical modification (or modifications), as the case may be, described herein is determined by mass spectrometry.

[0153] In certain respects, anti-VEGF antigen-binding fragments comprising light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21 are also provided in this document, wherein the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation and pyroglutamation (pyro Glu) and the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation and pyroglutamation (pyro Glu). In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21, wherein: (1) the ninth amino acid residue of the heavy chain CDR1 (i.e., the M in GYDFTHYGMN (SEQ ID NO.(20)) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro-Glu); the third amino acid residue of the heavy chain CDR2 (i.e., the N in WINTYTGEPTYAADFKR (SEQ ID NO. 18)) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro-Glu); and the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro-Glu); and (2) the eighth and eleventh amino acid residues of the light chain CDR1 (i.e., the two Ns in SASQDISNYLN (SEQ ID NO. 14)) each carries one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu) and the second amino acid residue of the CDR3 light chain (i.e., the. Petition 870260012693, dated 09 / 02 / 2026, p. 140 / 420 73 / 319 second Q in QQYSTVPWTF (SEQ ID NO. 16)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu). In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) is not acetylated and the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) is not acetylated. In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18 and 21, wherein: (1) the ninth amino acid residue of the heavy chain CDR1 (i.e., the M in GYDFTHYGMN (SEQ ID NO.(20)) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), the third amino acid residue of the heavy chain CDR2 (i.e., the N in WINTYTGEPTYAADFKR (SEQ ID NO. 18)) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), and the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) is not acetylated; and (2) the eighth and eleventh amino acid residues of the light chain CDR1 (i.e., the two Ns in SASQDISNYLN (SEQ ID NO. 14)) each carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu), and the second amino acid residue of the light chain CDR3 (i.e., the second The Q in QQYSTVPWTF (SEQ ID NO. 16)) is not acetylated.In a preferred embodiment, the chemical modification (or modifications) or lack thereof (as the case may be) described herein is determined by mass spectrometry.

[0154] Another administration route being considered is Petition 870260012693, dated 09 / 02 / 2026, page 141 / 420 74 / 319 Subretinal administration via the suprachoroidal space, using a subretinal drug delivery device that has a catheter inserted and tunneled through the suprachoroidal space to inject into the subretinal space towards the posterior pole, where a small needle injects into the subretinal space. This route of administration allows the vitreous to remain intact and therefore there are fewer risks of complications (lower risk of gene therapy breakoff and complications such as retinal detachments and macular holes), and without a vitrectomy, the resulting bleb can spread more diffusely, allowing more of the retinal surface area to be transduced with a smaller volume. The risk of cataract-induced development after this procedure is minimized, which is desirable for younger patients.Furthermore, this procedure can deliver a bleb under the fovea more safely than the standard transvitreal approach, which is desirable for patients with hereditary retinal diseases affecting central vision where the target cells for transduction are in the macula. This procedure is also favorable for patients who have neutralizing antibodies (Nabs) to AAVs present in the systemic circulation that may impact other delivery pathways. Additionally, this method has been shown to create blebs with less protrusion from the retinotomy site than the standard transvitreal approach.

[0155] Juxtascleral administration provides an additional route of administration that avoids the risk of intraocular infection and retinal detachment, side effects commonly associated with injecting therapeutic agents directly into the eye.

[0156] In certain embodiments, a kit comprising one or more containers and instructions for use is described herein, wherein the one or more containers comprise the pharmaceutical composition. In certain embodiments, at least one of the one or more containers is produced from a hydrophobically coated glass bottle. In certain embodiments, at least one of the one or more containers is produced from a Daikyo Crystal Zenith® (CZ) bottle. In certain embodiments, at least one of the one or more containers Petition 870260012693, dated 09 / 02 / 2026, p. 142 / 420 75 / 319 is produced from a bottle coated with TopLyo. In certain embodiments, at least one of the containers is produced from Cyclo Olefin Polymer (COP).

[0157] In another aspect provided in this document are single unit dosage forms comprising 3.2 x 1011GC / ml, 6.5 x 1011GC / ml, 2.5 x 1012GC / ml, 3 x 1013GC / ml of Construct II, 0.2 g / l potassium chloride, 0.2 g / l monobasic potassium phosphate, 8.01 g / l sodium chloride, 1.15 g / l anhydrous dibasic sodium phosphate, pH 7.4 and P188 at 0.001% in a volume of at least about 0.5 ml, at least about 0.8 ml, about 0.6 ml, about 0.95 ml in a cycloolefin polymer (COP) bottle. In some embodiments, the single unit dose form can be stored at 4°C for approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, approximately 2 months. In some embodiments, the single unit dose form can be stored at -80°C for approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months.In some embodiments, the single unit dose form is capable of being stored at 4°C for 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, approximately 2 months after having been previously stored at -80°C for approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months. In some embodiments, the vector genome concentration of Construct II after being stored at -80 °C, -20 °C, or 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of the vector genome concentration of Construct II before being stored at -80 °C, -20 °C, or 4 °C for said period of time. In some embodiments, the in vitro potency of Construct II after being stored at -80 °C, -20 °C, or 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of the in vitro potency of the Construct. Petition 870260012693, dated 09 / 02 / 2026, p. 143 / 420 76 / 319 II before being stored at -80 °C, -20 °C, or 4 °C for said period of time. In some embodiments, the size distribution of Construct II after being stored at -80 °C, -20 °C, or 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the size distribution of Construct II before being stored at -80 °C, -20 °C, or 4 °C for said period of time. In some modalities, the time period is approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, or approximately 24 months.

[0158] In another aspect provided in this document are single unit dosage forms comprising 3.2 x 1011GC / ml, 6.5 x 1011GC / ml, 2.5 x 1012GC / ml, 3 x 1013GC / ml of Construto II, 0.2 g / l potassium chloride, 0.2 g / l monobasic potassium phosphate, 8.01 g / l sodium chloride, 1.15 g / l anhydrous dibasic sodium phosphate, pH 7.4, 4% sucrose and 0.001% P188 in a volume of at least about 0.5 ml, at least about 0.8 ml, about 0.6 ml, about 0.95 ml in a COP bottle. In some embodiments, the single unit dose form can be stored at 4°C for approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, approximately 2 months. In some embodiments, the single unit dose form can be stored at -80°C for approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months.In some embodiments, the single unit dose form is capable of being stored at 4°C for approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, approximately 2 months after having been previously stored at -80°C for approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months. In some embodiments, a. Petition 870260012693, dated 09 / 02 / 2026, p. 144 / 420 77 / 319 Vector genome concentration of Construct II after being stored at -80 °C, -20 °C, or 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of the vector genome concentration of Construct II before being stored at -80 °C, -20 °C, or 4 °C for said period of time. In some embodiments, the in vitro potency of Construct II after being stored at -80 °C, -20 °C, or 4 °C for said period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of the in vitro potency of Construct II before being stored at -80 °C, -20 °C, or 4 °C for said period of time. In some embodiments, the size distribution of Construct II after being stored at -80 °C, -20 °C, or 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the size distribution of Construct II before being stored at -80 °C, -20 °C, or 4 °C for said period of time.In some modalities, the time period is approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, or approximately 24 months.

[0159] In another aspect, a pre-filled syringe containing a single unit dosage form provided in this document is supplied herein. In another aspect, a kit comprising the pre-filled syringe containing the single unit dosage form supplied in this document is supplied herein. 2.1 Illustrative Modalities

[0160] 1. A pharmaceutical composition comprising:

[0161] (a) a recombinant adeno-associated virus (AAV),

[0162] (b) potassium chloride,

[0163] (c) monobasic potassium phosphate, Petition 870260012693, dated 09 / 02 / 2026, page 145 / 420 78 / 319

[0164] (d) sodium chloride,

[0165] (e) anhydrous dibasic sodium phosphate,

[0166] (f) sucrose and

[0167] (e) poloxamer 188, polysorbate 20 or polysorbate 80.

[0168] 2. The pharmaceutical composition of paragraph 1, wherein the recombinant AAV comprises components of one or more adeno-associated virus serotypes selected from the group consisting of AAV1, AAV2, AAV2tYF, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAVrh10, AAV.rh20, AAV.rh39, AAV.Rh74, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, rAAV.7m8, AAV.PHP.B, AAV.PHP.eB, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15 and AAV.HSC16.

[0169] 3. The pharmaceutical composition of any of the paragraphs 1-2, wherein the recombinant AAV is AAV8.

[0170] 4. The pharmaceutical composition of any of paragraphs 1-2, wherein the recombinant AAV is AAV9.

[0171] 5. The pharmaceutical composition of any of the paragraphs 1-4, wherein the pharmaceutical composition further comprises one or more amino acids.

[0172] 6. The pharmaceutical composition of any of the paragraphs 1-5, wherein the ionic strength of the pharmaceutical composition is in the range of about 60 mM to about 115 mM.

[0173] 7. The pharmaceutical composition of paragraph 4, wherein the ionic strength of the pharmaceutical composition is in the range of about 30 mM to about 100 mM.

[0174] 8. The pharmaceutical composition in accordance with any of paragraphs 1-3, wherein the pharmaceutical composition Petition 870260012693, dated 09 / 02 / 2026, page 146 / 420 79 / 319 includes

[0175] (a) potassium chloride at a concentration of 0.2 g / l

[0176] (b) monobasic potassium phosphate at a concentration of 0.2 g / l,

[0177] (c) sodium chloride at a concentration of 5.84 g / l

[0178] (d) anhydrous dibasic sodium phosphate at a concentration of 1.15 g / l.

[0179] 9. The pharmaceutical composition of any of paragraphs 1-8, wherein the pharmaceutical composition comprises sucrose in a concentration in the range of 3% (weight / volume, 30 g / l) to 18% (weight / volume, 180 g / l).

[0180] 10. The pharmaceutical composition of any of paragraphs 1-8, wherein the pharmaceutical composition comprises sucrose at a concentration of 4% (weight / volume, 40 g / l).

[0181] 11. The pharmaceutical composition of any of paragraphs 1-10, wherein the pharmaceutical composition comprises poloxamer 188, polysorbate 20 or polysorbate 80; and wherein the poloxamer 188, polysorbate 20 or polysorbate 80 is in a concentration in the range of 0.0005% (weight / volume, 0.005 g / l) to 0.05% (weight / volume, 0.5 g / l).

[0182] 12. The pharmaceutical composition of any of the paragraphs 1-10, wherein the pharmaceutical composition comprises poloxamer 188, polysorbate 20 or polysorbate 80; and wherein the poloxamer 188, polysorbate 20 or polysorbate 80 is at a concentration of 0.001% (weight / volume, 0.01 g / l)).

[0183] 13. The pharmaceutical composition of any of paragraphs 48-54, wherein the pH of the pharmaceutical composition is in the range of about 6.0 to about 9.0.

[0184] 14. The pharmaceutical composition of any Petition 870260012693, dated 09 / 02 / 2026, page 147 / 420 80 / 319 one of paragraphs 1-12, in which the pH of the pharmaceutical composition is approximately 7.4.

[0185] 15. The pharmaceutical composition of any of the paragraphs 1-14, wherein the osmolality of the pharmaceutical composition is in the range of about 200 mOsm / l to about 660 mOsm / l.

[0186] 16. The pharmaceutical composition of any of the paragraphs 1-15, wherein the pharmaceutical composition is in a hydrophobically coated glass bottle.

[0187] 17. The pharmaceutical composition of any of paragraphs 1-15, wherein the pharmaceutical composition is in a cycloolefin polymer (COP) bottle.

[0188] 18. The pharmaceutical composition of any of the paragraphs 1-15, where the pharmaceutical composition is in a Daikyo Crystal Zenith® (CZ) bottle.

[0189] 19. The pharmaceutical composition of any of paragraphs 1-15, wherein the pharmaceutical composition is in a bottle coated with TopLyo.

[0190] 20. The pharmaceutical composition of any of paragraphs 1-19, wherein the pharmaceutical composition consists of:

[0191] (a) recombinant AAV,

[0192] 0.2 g / l, (b) potassium chloride at a concentration of

[0193] 0.2 g / l, (c) monobasic potassium phosphate at a

[0194] 5.84 g / l, (d) sodium chloride at a concentration of

[0195] 1.15 g / l, (e) anhydrous dibasic sodium phosphate at a

[0196] weight / volume (40 g / l), (f) sucrose at a concentration of 4% in Petition 870260012693, dated 09 / 02 / 2026, page 148 / 420 81 / 319

[0197] (g) poloxamer 188, polysorbate 20 or polysorbate 80 at a concentration of 0.001% by weight / volume (0.01 g / l) and

[0198] (h) water and

[0199] where the recombinant AAV is AAV8.

[0200] 21. The pharmaceutical composition of any of the paragraphs 1-20, wherein the vector genome (VGC) concentration of the pharmaceutical composition is about 3 χ¹⁰⁹GC / ml, about 1 χ¹⁰GC / ml, about 1.2 χ¹⁰GC / ml, about 1.6 χ¹⁰GC / ml, about 4 χ¹⁰GC / ml, about 6 χ¹⁰GC / ml, about 2 χ¹⁰GC / ml, about 2.4 χ¹⁰GC / ml, about 2.5 χ¹⁰GC / ml, about 3 χ¹⁰GC / ml, about 3.2 χ¹⁰GC / ml, about 6.2 χ¹⁰GC / ml, about 6.5 χ 1011GC / ml, about 1 χ 1012GC / ml, about 3 χ 1012GC / ml, about 2 χ 1013GC / ml or about 3 χ 1013GC / ml.

[0201] 22. The pharmaceutical composition of any of the paragraphs 1-21, in which the recombinant AAV is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable to freeze / thaw cycles than the same recombinant AAV in a reference pharmaceutical composition.

[0202] 23. The pharmaceutical composition of any of the paragraphs 1-22, wherein the recombinant AAV is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1000 times more stable than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time, wherein the period of time is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, or approximately 24 months.

[0203] 24. The pharmaceutical composition of any Petition 870260012693, dated 09 / 02 / 2026, p. 149 / 420 82 / 319 one of paragraphs 1-23, wherein the recombinant AAV is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable than the same recombinant AAV in a reference pharmaceutical composition when stored at -80 °C for a period of time, wherein the period of time is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, or approximately 24 months.

[0204] 25. The pharmaceutical composition of any of the paragraphs 1-24, wherein the recombinant AAV is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable than the same recombinant AAV in a reference pharmaceutical composition when stored at room temperature for a period of time, wherein the period of time is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, or approximately 24 months.

[0205] 26. The pharmaceutical composition of any of the paragraphs 1-25, wherein the recombinant AAV is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable than the same recombinant AAV in a reference pharmaceutical composition when (i) stored at -80 °C for a first period of time; (ii) subsequently thawed; and (iii) after thawing, stored at 4 °C for a second period of time. Petition 870260012693, dated 09 / 02 / 2026, p. 150 / 420 83 / 319

[0206] 27. The pharmaceutical composition of the paragraph 26, where the first time period is approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, or approximately 24 months.

[0207] 28. The pharmaceutical composition of the paragraph 26, where the second time period is approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, approximately 2 months.

[0208] 29. The pharmaceutical composition of any of paragraphs 1-22, in which the concentration of recombinant AAV vector genome after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the concentration of recombinant AAV vector genome before being stored at -80 °C for said period of time.

[0209] 30. The pharmaceutical composition of any of paragraphs 1-22, in which the concentration of recombinant AAV vector genome after being stored at -20 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the concentration of recombinant AAV vector genome before being stored at -20 °C for said period of time.

[0210] 31. The pharmaceutical composition of any of paragraphs 1-22, in which the concentration of recombinant AAV vector genome after being stored at 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the concentration of recombinant AAV vector genome before being stored at 4 °C for said period of time.

[0211] 32. The pharmaceutical composition of any of the paragraphs 1-22, in which the in vitro potency of the recombinant AAV after being stored at -80 °C for a period of time is at least 70%, 75%, Petition 870260012693, dated 09 / 02 / 2026, page 151 / 420 84 / 319 80%, 85%, 90%, 95%, 98% or 99% of the in vitro potency of the recombinant AAV before being stored at -80 °C for said period of time.

[0212] 33. The pharmaceutical composition of any of paragraphs 1-22, in which the in vitro potency of the recombinant AAV after being stored at -20 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the in vitro potency of the recombinant AAV before being stored at -20 °C for said period of time.

[0213] 34. The pharmaceutical composition of any of paragraphs 1-22, in which the in vitro potency of the recombinant AAV after being stored at 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the in vitro potency of the recombinant AAV before being stored at 4 °C for said period of time.

[0214] 35. The pharmaceutical composition of any of paragraphs 1-22, in which the size distribution of the recombinant AAV after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to the size distribution of the recombinant AAV before being stored at -80 °C for said period of time.

[0215] 36. The pharmaceutical composition of any of paragraphs 1-22, in which the size distribution of the recombinant AAV after being stored at -20 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to the size distribution of the recombinant AAV before being stored at -20 °C for said period of time.

[0216] 37. The pharmaceutical composition of any of paragraphs 1-22, in which the size distribution of the recombinant AAV after being stored at 4°C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to the size distribution of the recombinant AAV before being stored at 4°C during said period of time.

[0217] 38. The pharmaceutical composition of any Petition 870260012693, dated 09 / 02 / 2026, p. 152 / 420 85 / 319 one of the paragraphs 29 to 37, where the time period is approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months or approximately 24 months.

[0218] 39. The pharmaceutical composition of any of paragraphs 1-21, wherein the stability of the recombinant AAV is determined by the infectivity of the recombinant AAV.

[0219] 40. The pharmaceutical composition of any of paragraphs 1-21, wherein the stability of recombinant AAV is determined by the recombinant AAV aggregation levels.

[0220] 41. The pharmaceutical composition of any of paragraphs 1-21, wherein the stability of recombinant AAV is determined by the levels of free DNA released by recombinant AAV particles.

[0221] 42. The pharmaceutical composition according to any of paragraphs 1-41, wherein the pharmaceutical composition is a liquid composition.

[0222] 43. The pharmaceutical composition in accordance with any of paragraphs 1-41, wherein the pharmaceutical composition is a frozen composition.

[0223] 44. The pharmaceutical composition of any of the paragraphs 1-41, wherein the pharmaceutical composition is a lyophilized composition or a reconstituted lyophilized composition.

[0224] 45. The pharmaceutical composition of any of the paragraphs 1-44, the pharmaceutical composition has a property that is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection, subretinal injection via transvitreal approach, subretinal administration via the suprachoroidal space or a posterior juxtascleral deposition procedure. Petition 870260012693, dated 09 / 02 / 2026, page 153 / 420 86 / 319

[0225] 46. The pharmaceutical composition of any of the paragraphs 1-44, the pharmaceutical composition has a desired density that is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection, subretinal injection via a transvitreal approach, subretinal administration via the suprachoroidal space or a posterior juxtascleral deposition procedure.

[0226] 47. The pharmaceutical composition of any of the paragraphs 1-44, the pharmaceutical composition has a desired osmolality that is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection, subretinal injection via a transvitreal approach, subretinal administration via the suprachoroidal space or a posterior juxtascleral deposition procedure.

[0227] 48. The pharmaceutical composition of the paragraph 47, where the osmolality is 160-230 mOsm / kg H2O.

[0228] 49. The pharmaceutical composition of the paragraph 47, in which the osmolality is less than 600 mOsm / kg H2O.

[0229] 50. The pharmaceutical composition of any of the paragraphs 1-44, the pharmaceutical composition has a desired viscosity that is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection, subretinal injection via a transvitreal approach, subretinal administration via the suprachoroidal space or a posterior juxtascleral deposition procedure.

[0230] 51. The pharmaceutical composition of any of the paragraphs 1-44, the pharmaceutical composition is suitable for administration to the eye.

[0231] 52. The pharmaceutical composition of the paragraph 45, the pharmaceutical composition is suitable for suprachoroidal injection, subretinal injection via a transvitreous approach, subretinal administration through the suprachoroidal space, or a posterior juxtascleral deposition procedure. Petition 870260012693, dated 09 / 02 / 2026, p. 154 / 420 87 / 319

[0232] 53. The pharmaceutical composition of any of the paragraphs 1-52, wherein the pharmaceutical composition is capable of being stored at 4 °C for 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, approximately 2 months after having previously been stored at -80 °C for approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months.

[0233] 54. A method of treating or preventing a disease in a subject, comprising administering to the subject the pharmaceutical composition of any of paragraphs 1-53.

[0234] 55. A method of treating a subject diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME) or diabetic retinopathy (DR) comprising administering to the subject the pharmaceutical composition of any one of any of paragraphs 1-53.

[0235] 56. A method of treating an individual diagnosed with mucopolysaccharidosis type IVA (MPS IVA), mucopolysaccharidosis type I (MPS I), mucopolysaccharidosis type II (MPS II), familial hypercholesterolemia (FH), homozygous familial hypercholesterolemia (HoFH), coronary artery disease, cerebrovascular disease, Duchenne muscular dystrophy, Limb Girdle muscular dystrophy, Becker muscular dystrophy and sporadic inclusion body myositis or kallikrein-related disease comprising administering to the subject the pharmaceutical composition of any of paragraphs 1-53.

[0236] 57. The method of any of the paragraphs 54-56, wherein the pharmaceutical composition is administered by intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection, subretinal injection via a transvitreal approach, subretinal administration via the suprachoroidal space or a posterior juxtascleral deposition procedure. Petition 870260012693, dated 09 / 02 / 2026, page 155 / 420 88 / 319

[0237] 58. The method of any of the paragraphs 54-57, in which the subject is a human subject.

[0238] 59. A method of treating a subject diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME) or diabetic retinopathy (DR), wherein the method comprises preparing the pharmaceutical composition of any of paragraphs 1 to 53, storing the pharmaceutical composition at -80 °C for a first period of time; (ii) thawing the pharmaceutical composition; and (iii) after thawing, storing the pharmaceutical composition at 4 °C for a second period of time.

[0239] 60. The method of paragraph 59, where the first time period is approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months or approximately 24 months.

[0240] 61. The method of paragraph 59, where the second time period is approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, approximately 2 months.

[0241] 62. A kit comprising one or more containers and instructions for use, wherein the one or more containers comprise the pharmaceutical composition of any of paragraphs 1-53.

[0242] 63. The kit of paragraph 62, in which at least one of the one or more containers is produced from hydrophobically coated glass bottle.

[0243] 64. The kit in paragraph 62, in which at least one of the one or more containers is produced from Daikyo Crystal Zenith® (CZ) bottles.

[0244] 65. The kit in paragraph 62, in which at least one of the one or more containers is produced from a bottle coated with TopLyo.

[0245] 66. The kit in paragraph 62, in which at least Petition 870260012693, dated 09 / 02 / 2026, page 156 / 420 89 / 319 one or more containers are produced from Cyclo Olefin Polymer (COP).

[0246] 67. A pharmaceutical composition comprising:

[0247] (a) a Construct II encoding an anti-human vascular endothelial growth factor (hVEGF) antibody,

[0248] (b) potassium chloride,

[0249] (c) monobasic potassium phosphate,

[0250] (d) sodium chloride,

[0251] (e) anhydrous dibasic sodium phosphate,

[0252] (f) sucrose and

[0253] (e) poloxamer 188, polysorbate 20 or polysorbate 80 and

[0254] wherein the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 4 and a light chain comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3.

[0255] 68. The pharmaceutical composition of the paragraph 67, in which the ionic strength of the pharmaceutical composition is in the range of about 60 mM to about 100 mM.

[0256] 69. The pharmaceutical composition according to any of paragraphs 67-68, wherein the pharmaceutical composition comprises:

[0257] (a) potassium chloride at a concentration of 0.2 g / l

[0258] (b) monobasic potassium phosphate at a concentration of 0.2 g / l,

[0259] (c) sodium chloride at a concentration of 5.84 g / l

[0260] (d) anhydrous dibasic sodium phosphate in Petition 870260012693, dated 09 / 02 / 2026, page 157 / 420 90 / 319 concentration of 1.15 g / l.

[0261] 70. The pharmaceutical composition of any of paragraphs 67-69, wherein the pharmaceutical composition comprises sucrose in a concentration in the range of 3% (weight / volume, 30 g / l) to 18% (weight / volume, 180 g / l).

[0262] 71. The pharmaceutical composition of any of paragraphs 67-69, wherein the pharmaceutical composition comprises sucrose at a concentration of 4% (weight / volume, 40 g / l).

[0263] 72. The pharmaceutical composition of any of paragraphs 67-71, wherein the pharmaceutical composition comprises poloxamer 188, polysorbate 20 or polysorbate 80; and wherein the poloxamer 188, polysorbate 20 or polysorbate 80 is in a concentration in the range of 0.0005% (weight / volume, 0.005 g / l) to 0.05% (weight / volume, 0.5 g / l).

[0264] 73. The pharmaceutical composition of any of paragraphs 67-71, wherein the pharmaceutical composition comprises poloxamer 188, polysorbate 20 or polysorbate 80 at a concentration of 0.001% (weight / volume, 0.01 g / l).

[0265] 74. The pharmaceutical composition of any of paragraphs 67-73, wherein the pH of the pharmaceutical composition is in the range of about 6.0 to about 9.0.

[0266] 75. The pharmaceutical composition of any of paragraphs 67-73, wherein the pH of the pharmaceutical composition is approximately 7.4.

[0267] 76. The pharmaceutical composition of any of paragraphs 67-75, wherein the osmolality of the pharmaceutical composition is in the range of about 200 mOsm / l to about 660 mOsm / l.

[0268] 77. The pharmaceutical composition of any of paragraphs 67-76, wherein Construct II comprises the capsid of AAV8.

[0269] 78. The pharmaceutical composition of any Petition 870260012693, dated 09 / 02 / 2026, page 158 / 420 91 / 319 one of paragraphs 67-77, wherein Construct II is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable to freeze / thaw cycles than the same Construct II in a reference pharmaceutical composition.

[0270] 78. The pharmaceutical composition of any of the paragraphs 67-77, wherein Construct II is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable than the same Construct II in a reference pharmaceutical composition when stored at -20 °C for a period of time, wherein the period of time is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, or approximately 24 months.

[0271] 79. The pharmaceutical composition of any of the paragraphs 67-77, wherein Construct II is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable than the same Construct II in a reference pharmaceutical composition when stored at -80 °C for a period of time, wherein the period of time is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, or approximately 24 months.

[0272] 80. The pharmaceutical composition of any of the paragraphs 67-77, where Construct II is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 Petition 870260012693, dated 09 / 02 / 2026, p. 159 / 420 92 / 319 times, 5 times, 10 times, 100 times or 1,000 times more stable than the same Construct II in a reference pharmaceutical composition when stored at room temperature for a period of time, wherein the period of time is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months or about 24 months.

[0273] 81. The pharmaceutical composition of any of the paragraphs 67-77, wherein the recombinant AAV is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable than the same Construct II in a reference pharmaceutical composition when (i) stored at -80 °C for a first period of time; (ii) subsequently thawed; and (iii) after thawing, stored at 4 °C for a second period of time.

[0274] 82. The pharmaceutical composition of the paragraph 81, where the first time period is approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, or approximately 24 months.

[0275] 83. The pharmaceutical composition of the paragraph 81, where the second time period is approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, approximately 2 months.

[0276] 84. The pharmaceutical composition of any of paragraphs 67-79, in which the vector genome concentration of Construct II after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the concentration of Petition 870260012693, dated 09 / 02 / 2026, page 160 / 420 93 / 319 vector genome of Construct II before being stored at -80 °C for said period of time.

[0277] 85. The pharmaceutical composition of any of paragraphs 67-79, in which the vector genome concentration of Construct II after being stored at -20 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the vector genome concentration of Construct II before being stored at -20 °C for said period of time.

[0278] 86. The pharmaceutical composition of any of paragraphs 67-79, in which the vector genome concentration of Construct II after being stored at 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the vector genome concentration of Construct II before being stored at 4 °C for said period of time.

[0279] 87. The pharmaceutical composition of any of paragraphs 67-79, in which the in vitro potency of Construct II after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the in vitro potency of Construct II before being stored at -80 °C for said period of time.

[0280] 88. The pharmaceutical composition of any of paragraphs 67-79, in which the in vitro potency of Construct II after being stored at -20 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the in vitro potency of Construct II before being stored at -20 °C for said period of time.

[0281] 89. The pharmaceutical composition of any of paragraphs 67-79, in which the in vitro potency of Construct II after being stored at 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the in vitro potency of Construct II before being stored at 4 °C for said period of time.

[0282] 90. The pharmaceutical composition of any Petition 870260012693, dated 09 / 02 / 2026, page 161 / 420 94 / 319 one of paragraphs 67-79, where the size distribution of Construct II after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to the size distribution of Construct II before being stored at -80 °C for that period of time.

[0283] 91. The pharmaceutical composition of any of paragraphs 67-79, in which the size distribution of Construct II after being stored at -20 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to the size distribution of Construct II before being stored at -20 °C for that period of time.

[0284] 92. The pharmaceutical composition of any of paragraphs 67-79, in which the size distribution of Construct II after being stored at 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to the size distribution of Construct II before being stored at 4 °C for that period of time.

[0285] 93. The pharmaceutical composition of any of the paragraphs 84 to 92, where the time period is approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months or approximately 24 months.

[0286] 94. The pharmaceutical composition of any of paragraphs 77-83, where the stability of Construct II is determined by the infectivity of the recombinant AAV.

[0287] 95. The pharmaceutical composition of any of paragraphs 77-83, wherein the stability of Construct II is determined by the levels of aggregation of recombinant AAV.

[0288] 96. The pharmaceutical composition of any of paragraphs 77-83, wherein the stability of Construct II is determined by the levels of free DNA released by recombinant AAV particles.

[0289] 97. The pharmaceutical composition of any Petition 870260012693, dated 09 / 02 / 2026, page 162 / 420 95 / 319 one of paragraphs 67-96, in which the pharmaceutical composition is in a hydrophobically coated glass bottle.

[0290] 98. The pharmaceutical composition of any of paragraphs 67-96, wherein the pharmaceutical composition is in a cycloolefin polymer (COP) bottle.

[0291] 99. The pharmaceutical composition of any of paragraphs 67-96, where the pharmaceutical composition is in a Daikyo Crystal Zenith® (CZ) bottle.

[0292] 100. The pharmaceutical composition of any of paragraphs 67-96, wherein the pharmaceutical composition is in a bottle coated with TopLyo.

[0293] 101. The pharmaceutical composition of any of paragraphs 67-100, wherein the pharmaceutical composition consists of:

[0294] (a) Construct II encoding an anti-human vascular endothelial growth factor (hVEGF) antibody,

[0295] (b) potassium chloride at a concentration of 0.2 g / l

[0296] (c) monobasic potassium phosphate at a concentration of 0.2 g / l,

[0297] (d) sodium chloride at a concentration of 5.84 g / l

[0298] (e) anhydrous dibasic sodium phosphate at a concentration of 1.15 g / l,

[0299] (f) sucrose at a concentration of 4% by weight / volume (40 g / l),

[0300] (g) poloxamer 188, polysorbate 20 or polysorbate 80 at a concentration of 0.001% by weight / volume (0.01 g / l) and

[0301] (h) water and

[0302] wherein the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID Petition 870260012693, dated 09 / 02 / 2026, page 163 / 420 96 / 319 NO: 2 or SEQ ID NO: 4 and a light chain comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3.

[0303] 102. The pharmaceutical composition of the paragraph 101, wherein the vector genome (VGC) concentration of the pharmaceutical composition is approximately 3 χ¹⁰⁹GC / ml, approximately 1 χ¹⁰GC / ml, approximately 1.2 χ¹⁰GC / ml, approximately 1.6 χ¹⁰GC / ml, approximately 4 χ¹⁰GC / ml, approximately 6 χ¹⁰GC / ml, approximately 2 χ¹⁰GC / ml, approximately 2.4 χ¹⁰GC / ml, approximately 2.5 χ¹⁰GC / ml, approximately 3 χ¹⁰GC / ml, approximately 3.2 χ¹⁰GC / ml, approximately 6.2 χ¹⁰GC / ml, approximately 6.5 χ¹⁰GC / ml, approximately 1 χ 1012GC / ml, about 3 χ 1012GC / ml, about 2 χ 1013GC / ml or about 3 χ 1013GC / ml.

[0304] 103. The pharmaceutical composition of any of the paragraphs 67-102, the pharmaceutical composition has a property that is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection, subretinal injection via a transvitreal approach, subretinal administration via the suprachoroidal space or a posterior juxtascleral deposition procedure.

[0305] 104. The pharmaceutical composition of any of paragraphs 67-102, wherein the pharmaceutical composition has a desired density that is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection, subretinal injection via a transvitreal approach, subretinal administration via the suprachoroidal space or a posterior juxtascleral deposition procedure.

[0306] 105. The pharmaceutical composition of any of paragraphs 67-102, wherein the pharmaceutical composition has a desired osmolality that is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection, subretinal injection via a transvitreal approach, subretinal administration via the suprachoroidal space or a posterior juxtascleral deposition procedure. Petition 870260012693, dated 09 / 02 / 2026, page 164 / 420 97 / 319

[0307] 106. The pharmaceutical composition of the paragraph 105, where the osmolality is 160-230 mOsm / kg H2O.

[0308] 107. The pharmaceutical composition of the paragraph 105, where the osmolality is less than 600 mOsm / kg H2O.

[0309] 108. The pharmaceutical composition of any of paragraphs 67-102, wherein the pharmaceutical composition has a desired viscosity that is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection, subretinal injection via a transvitreal approach, subretinal administration via the suprachoroidal space or a posterior juxtascleral deposition procedure.

[0310] 109. The pharmaceutical composition in accordance with any of paragraphs 67-108, wherein the pharmaceutical composition is a liquid composition.

[0311] 110. The pharmaceutical composition in accordance with any of paragraphs 67-108, wherein the pharmaceutical composition is a frozen composition.

[0312] 111. The pharmaceutical composition of any of paragraphs 67-108, wherein the pharmaceutical composition is a lyophilized composition or a reconstituted lyophilized composition.

[0313] 112. The pharmaceutical composition of any of the paragraphs 67-111, where the pharmaceutical composition is capable of being stored at 4 °C for 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, approximately 2 months after having previously been stored at -80 °C for approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months.

[0314] 113. A method of treating a subject diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME) or diabetic retinopathy (DR) Petition 870260012693, dated 09 / 02 / 2026, p. 165 / 420 98 / 319 comprising administering to the subject the pharmaceutical composition of any of the paragraphs 67-111.

[0315] 114. The method of paragraph 113, in which the pharmaceutical composition is administered by suprachoroidal injection, subretinal injection via a transvitreal approach, subretinal administration via the suprachoroidal space or a posterior juxtascleral deposition procedure.

[0316] 115. The method of any of the paragraphs 113 or 114, where the subject is a human subject.

[0317] 116. A method of treating a subject diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME) or diabetic retinopathy (DR), wherein the method comprises preparing the pharmaceutical composition of any of paragraphs 67-108, storing the pharmaceutical composition at -80 °C for a first period of time; (ii) thawing the pharmaceutical composition; and (iii) after thawing, storing the pharmaceutical composition at 4 °C for a second period of time.

[0318] 117. The method of paragraph 119, where the first time period is about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months or about 24 months.

[0319] 118. The method of paragraph 119, where the second time period is approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, approximately 2 months.

[0320] 119. A kit comprising one or more containers and instructions for use, wherein one or more containers comprise the pharmaceutical composition of any of paragraphs 67-102.

[0321] 120. The kit of paragraph 119, in which at least one of the one or more containers is produced from Cyclo Olefin Polymer (COP). Petition 870260012693, dated 09 / 02 / 2026, p. 166 / 420 99 / 319

[0322] 121. A stable liquid pharmaceutical composition comprising:

[0323] (a) a recombinant adeno-associated virus (rAAV),

[0324] (b) a buffering agent comprising an ionic salt and having an ionic strength between 60 mM and 150 mM,

[0325] (d) sucrose and

[0326] (e) surfactant.

[0327] 122. The composition of paragraph 121, wherein rAAV comprises AAV1, AAV2, AAV2tYF, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAVrh10, AAV.rh20, AAV.rh39, AAV.Rh74, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, rAAV.7m8, AAV.PHP.B, AAV.PHP.eB, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15 or AAV.HSC16.

[0328] 123. The composition of paragraph 121 or 122, wherein the composition comprises 3-16% sucrose.

[0329] 124. The composition of any of paragraphs 121-123, wherein the buffering agent maintains the pH between about pH 6 and about pH 9 over the temperature range of -20 °C to room temperature.

[0330] 125. The composition of any one of paragraphs 121-124, wherein the composition comprises 4-6% sucrose.

[0331] 126. The composition of any one of paragraphs 121-125, wherein the buffering agent has an ionic strength not exceeding about 150 mM, about 145 mM, about 140 mM, about 135 mM, about 130 mM, about 125 mM, about 120 mM, about 115 mM or about 110 mM.

[0332] 127. The composition of any of the Petition 870260012693, dated 09 / 02 / 2026, page 167 / 420 100 / 319 paragraphs 121-126, in which the buffering agent has an ionic strength between about 60 mM and about 115 mM.

[0333] 128. The composition of any of paragraphs 121-127, in which the buffering agent has an ionic strength between about 60 mM and about 110 mM.

[0334] 129. The composition of any of paragraphs 121-128, wherein the composition comprises between 60 mM and 100 mM of NaCl.

[0335] 130. The composition of any of paragraphs 121-129, wherein the composition comprises 4-6% sucrose.

[0336] 131. The composition of any of paragraphs 121-130, wherein the composition is frozen at a temperature of about -20 °C.

[0337] 132. The composition of any of paragraphs 121-131, wherein the frozen composition maintains the pH between about pH 6 to about pH 9.

[0338] 133. The composition of any of paragraphs 121-132, wherein the buffering agent comprises one or more components selected from the group consisting of monobasic potassium phosphate, potassium phosphate, sodium chloride, anhydrous dibasic sodium phosphate, sodium phosphate hexahydrate, monobasic sodium phosphate monohydrate, sodium phosphate hexahydrate, monobasic sodium phosphate monohydrate, tromethamine, tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl), amino acid, histidine, histidine hydrochloride (histidine-HCl), sodium succinate, sodium citrate, sodium acetate and (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES), sodium sulfate, magnesium sulfate, magnesium chloride 6-hydrate, calcium sulfate, potassium chloride, calcium chloride and citrate calcium.

[0339] 134. The composition of any of paragraphs 121-132, in which the buffering agent comprises potassium chloride, Petition 870260012693, dated 09 / 02 / 2026, page 168 / 420 101 / 319 monobasic potassium phosphate, sodium chloride, anhydrous dibasic sodium phosphate.

[0340] 135. The composition of any of paragraphs 121-132, wherein the buffering agent comprises sodium chloride and Tris hydrochloride.

[0341] 136. The composition of any of the paragraphs 121-133, in which the surfactant is poloxamer 188, polysorbate 20 or polysorbate 80.

[0342] 137. The composition of any of the paragraphs 121-133, wherein the surfactant is poloxamer 188, polysorbate 20 or polysorbate 80; and wherein the poloxamer 188, polysorbate 20 or polysorbate 80 is in a concentration in the range of 0.005% (weight / volume, 0.005 g / l) to 0.05% (weight / volume, 0.5 g / l).

[0343] 138. The composition of any of the paragraphs 121-133, wherein the surfactant is poloxamer 188, polysorbate 20 or polysorbate 80; and wherein the poloxamer 188, polysorbate 20 or polysorbate 80 is at a concentration of 0.001% (weight / volume, 0.01 g / l).

[0344] 139. The composition of any of paragraphs 121-138, wherein the liquid pharmaceutical composition is still lyophilized.

[0345] 140. The composition of any of paragraphs 121-138, wherein the liquid pharmaceutical composition is a reconstituted lyophilized powder.

[0346] 141. The pharmaceutical composition of any of paragraphs 121-140, in which the concentration of recombinant AAV vector genome after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the concentration of recombinant AAV vector genome before being stored at -80 °C for said period of time.

[0347] 142. The pharmaceutical composition of any Petition 870260012693, dated 09 / 02 / 2026, page 169 / 420 102 / 319 one of paragraphs 121-140, whereby the concentration of recombinant AAV vector genome after being stored at -20 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the concentration of recombinant AAV vector genome before being stored at -20 °C during said period of time.

[0348] 143. The pharmaceutical composition of any of paragraphs 121-140, in which the concentration of recombinant AAV vector genome after being stored at 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the concentration of recombinant AAV vector genome before being stored at 4 °C for said period of time.

[0349] 144. The pharmaceutical composition of any of paragraphs 121-140, in which the in vitro potency of the recombinant AAV after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the in vitro potency of the recombinant AAV before being stored at -80 °C for said period of time.

[0350] 145. The pharmaceutical composition of any of paragraphs 121-140, in which the in vitro potency of the recombinant AAV after being stored at -20 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the in vitro potency of the recombinant AAV before being stored at -20 °C for said period of time.

[0351] 146. The pharmaceutical composition of any of paragraphs 121-140, in which the in vitro potency of the recombinant AAV after being stored at 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the in vitro potency of the recombinant AAV before being stored at 4 °C for said period of time.

[0352] 147. The pharmaceutical composition of any of the paragraphs 121-140, in which the size distribution of the recombinant AAV after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to the distribution of Petition 870260012693, dated 09 / 02 / 2026, p. 170 / 420 103 / 319 size of recombinant AAV before being stored at -80 °C for said period of time.

[0353] 148. The pharmaceutical composition of any of paragraphs 121-140, in which the size distribution of the recombinant AAV after being stored at -20 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to the size distribution of the recombinant AAV before being stored at -20 °C during said period of time.

[0354] 149. The pharmaceutical composition of any of paragraphs 121-140, in which the size distribution of the recombinant AAV after being stored at 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to the size distribution of the recombinant AAV before being stored at 4 °C during said period of time.

[0355] 150. The pharmaceutical composition of any of the paragraphs 141-149, where the time period is approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months or approximately 24 months.

[0356] 151. The pharmaceutical composition of any of the paragraphs 121-140, wherein the pharmaceutical composition is capable of being stored at 4 °C for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months after having been previously stored at -80 °C for about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 24 months.

[0357] 152. A method of treating a disease of interest comprising administering to the subject the pharmaceutical composition Petition 870260012693, dated 09 / 02 / 2026, page 171 / 420 104 / 319 of any of paragraphs 121-140, wherein the rAAV encodes a transgene that treats or improves, prevents or delays the progression of the disease of interest.

[0358] 153. A method of treating a subject diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME) or diabetic retinopathy (DR), wherein the method comprises preparing the pharmaceutical composition of any of paragraphs 121-140, storing the pharmaceutical composition at -80 °C for a first period of time; (ii) thawing the pharmaceutical composition; and (iii) after thawing, storing the pharmaceutical composition at 4 °C for a second period of time.

[0359] 154. The composition of the paragraph method 153, where the first time period is approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, or approximately 24 months.

[0360] 155. The method of paragraph 153, where the second time period is approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, approximately 2 months.

[0361] 156. A kit comprising one or more containers and instructions for use, wherein one or more containers comprise the pharmaceutical composition of any of paragraphs 121-140.

[0362] 157. A stable liquid formulation comprising the pharmaceutical composition of any of paragraphs 1-53, 67-111 and 121-140.

[0363] 158. A single unit dosage form comprising 3.2 x 1011GC / ml of Construto II, 0.2 g / l potassium chloride, 0.2 g / l monobasic potassium phosphate, 8.01 g / l sodium chloride, 1.15 g / l anhydrous dibasic sodium phosphate, pH 7.4 and P188 at 0.001% in a volume of about 0.95 ml in a cycloolefin polymer (COP) bottle.

[0364] 159. A single unit dosage form Petition 870260012693, dated 09 / 02 / 2026, page 172 / 420 105 / 319 comprising 3.2 x 1011GC / ml of Construto II, 0.2 g / l potassium chloride, 0.2 g / l monobasic potassium phosphate, 8.01 g / l sodium chloride, 1.15 g / l anhydrous dibasic sodium phosphate, pH 7.4 and P188 at 0.001% in a volume of at least 0.8 ml in a COP bottle.

[0365] 160. A single unit dosage form comprising 3.2 x 1011GC / ml of Construto II, 0.2 g / l potassium chloride, 0.2 g / l monobasic potassium phosphate, 8.01 g / l sodium chloride, 1.15 g / l anhydrous dibasic sodium phosphate, pH 7.4, 4% sucrose and 0.001% P188 in a volume of about 0.95 ml in a COP bottle.

[0366] 161. A single unit dosage form comprising 3.2 x 1011GC / ml of Construto II, 0.2 g / l potassium chloride, 0.2 g / l monobasic potassium phosphate, 8.01 g / l sodium chloride, 1.15 g / l anhydrous dibasic sodium phosphate, pH 7.4, 4% sucrose and 0.001% P188 in a volume of at least 0.8 ml in a COP bottle.

[0367] 162. A single unit dosage form comprising 6.5 x 1011GC / ml of Construto II, 0.2 g / l potassium chloride, 0.2 g / l monobasic potassium phosphate, 8.01 g / l sodium chloride, 1.15 g / l anhydrous dibasic sodium phosphate, pH 7.4 and P188 at 0.001% in a volume of about 0.95 ml in a COP bottle.

[0368] 163. A single unit dosage form comprising 6.5 x 1011GC / ml of Construto II, 0.2 g / l potassium chloride, 0.2 g / l monobasic potassium phosphate, 8.01 g / l sodium chloride, 1.15 g / l anhydrous dibasic sodium phosphate, pH 7.4 and P188 at 0.001% in a volume of at least 0.8 ml in a COP bottle.

[0369] 164. A single unit dosage form comprising 6.5 x 1011GC / ml of Construto II, 0.2 g / l potassium chloride, 0.2 g / l monobasic potassium phosphate, 8.01 g / l sodium chloride, 1.15 g / l anhydrous dibasic sodium phosphate, pH 7.4, 4% sucrose and 0.001% P188 in a volume of about 0.95 ml in a COP bottle.

[0370] 165. A single unit dosage form Petition 870260012693, dated 09 / 02 / 2026, page 173 / 420 106 / 319 comprising 6.5 x 1011GC / ml of Construto II, 0.2 g / l potassium chloride, 0.2 g / l monobasic potassium phosphate, 8.01 g / l sodium chloride, 1.15 g / l anhydrous dibasic sodium phosphate, pH 7.4, 4% sucrose and 0.001% P188 in a volume of at least 0.8 ml in a COP bottle.

[0371] 166. A single unit dosage form comprising 2.5 x 1012GC / ml of Construto II, 0.2 g / l potassium chloride, 0.2 g / l monobasic potassium phosphate, 8.01 g / l sodium chloride, 1.15 g / l anhydrous dibasic sodium phosphate, pH 7.4 and P188 at 0.001% in a volume of about 0.6 ml in a COP bottle.

[0372] 167. A single unit dosage form comprising 2.5 x 1012GC / ml of Construto II, 0.2 g / l potassium chloride, 0.2 g / l monobasic potassium phosphate, 8.01 g / l sodium chloride, 1.15 g / l anhydrous dibasic sodium phosphate, pH 7.4 and P188 at 0.001% in a volume of at least 0.5 ml in a COP bottle.

[0373] 168. A single unit dosage form comprising 3 x 1013GC / ml of Construto II, 0.2 g / l potassium chloride, 0.2 g / l monobasic potassium phosphate, 8.01 g / l sodium chloride, 1.15 g / l anhydrous dibasic sodium phosphate, pH 7.4, 4% sucrose and 0.001% P188 in a volume of about 0.6 ml in a COP bottle.

[0374] 169. A single unit dosage form comprising 3 x 1013GC / ml of Construto II, 0.2 g / l potassium chloride, 0.2 g / l monobasic potassium phosphate, 8.01 g / l sodium chloride, 1.15 g / l anhydrous dibasic sodium phosphate, pH 7.4, 4% sucrose and 0.001% P188 in a volume of at least 0.5 ml in a COP bottle.

[0375] 170. The single unit dosage form of any of paragraphs 158-169, which is capable of being stored at 4 °C for 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 1 month, approximately 2 months.

[0376] 171. The single unit dosage form of any of paragraphs 158-169, which is capable of being stored at -80 °C Petition 870260012693, dated 09 / 02 / 2026, p. 174 / 420 107 / 319 for about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 24 months.

[0377] 172. The single unit dosage form of any of paragraphs 158-169, which is capable of being stored at 4 °C for 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months after having been previously stored at -80 °C for about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 24 months.

[0378] 173. The single unit dosage form of any of paragraphs 158-169, wherein the vector genome concentration of Construct II after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the vector genome concentration of Construct II before being stored at -80 °C for said period of time.

[0379] 174. The single unit dosage form of any of paragraphs 158-169, wherein the vector genome concentration of Construct II after being stored at -20 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the vector genome concentration of Construct II before being stored at -20 °C for said period of time.

[0380] 175. The single unit dosage form of any of paragraphs 158-169, wherein the vector genome concentration of Construct II after being stored at 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the vector genome concentration of Construct II before being stored at 4 °C for said period of time.

[0381] 176. The single unit dosage form of any of paragraphs 158-169, in which the in vitro potency of Construct II Petition 870260012693, dated 09 / 02 / 2026, page 175 / 420 108 / 319 after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the in vitro potency of Construct II before being stored at -80 °C for said period of time.

[0382] 177. The single unit dosage form of any of paragraphs 158-169, wherein the in vitro potency of Construct II after being stored at -20 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the in vitro potency of Construct II before being stored at -20 °C for said period.

[0383] 178. The single unit dosage form of any of paragraphs 158-169, wherein the in vitro potency of Construct II after being stored at 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the in vitro potency of Construct II before being stored at 4 °C for said period of time.

[0384] 179. The single unit dosage form of any of paragraphs 158-169, wherein the size distribution of Construct II after being stored at -80 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to the size distribution of Construct II before being stored at -80 °C for said period.

[0385] 180. The single unit dosage form of any of paragraphs 158-169, wherein the size distribution of Construct II after being stored at -20 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to the size distribution of Construct II before being stored at -20 °C for said period.

[0386] 181. The single unit dosage form of any of paragraphs 158-169, wherein the size distribution of Construct II after being stored at 4 °C for a period of time is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to the size distribution of Construct II before being stored at 4 °C for said period.

[0387] 182. The single unit dosage form of any of paragraphs 173-181, where the time period is approximately Petition 870260012693, dated 09 / 02 / 2026, p. 176 / 420 109 / 319 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, or approximately 24 months.

[0388] 183. A pre-filled syringe containing the single unit dosage form of any of paragraphs 158-183.

[0389] 184. A kit comprising the pre-filled syringe of paragraph 183. 2.2 Conventions and Abbreviations Abbreviation Convention AAV Adeno-associated virus DLS Dynamic light scattering SEC Size exclusion chromatography FDP End-drug substance BDS Bulk drug substance VEGF Vascular endothelial growth factor ddPCR Digital droplet PCR AUC Analytical Ultracentrifugation USP United States Pharmacopeia IVRP in vitro relative potency VGC Vector genome concentration HRP Horseradish peroxidase DSC Differential Scanning Calorimetry dPBS Dulbecco's phosphate-buffered saline ELISA Enzyme-linked immunosorbent assay SF Slow freeze ST Slow thaw FT Rapid thaw FF Rapid freeze Petition 870260012693, dated 09 / 02 / 2026, page 177 / 420 110 / 319 Tg' Glass transition temperature 3. BRIEF DESCRIPTION OF THE DRAWINGS

[0390] Figure 1. The amino acid sequence of ranibizumab (top) showing 5 different residues in the Fab of bevacizumab (below). The beginnings of the variable and constant heavy chains (Vh and Ch) and light chains (Vl and Cl) are indicated by arrows (^) and the CDRs are underlined. Glycosylation sites without consensus (“G site”) are indicated by tyrosine-O sulfation sites (“Y site”).

[0391] Figure 2. Glycans that can be attached to HuGlyFabVEGFi. (Adapted from Bondt et al, 2014, Mol & Cell Proteomics 13.1: 3029-3039).

[0392] Figure 3. The amino acid sequence of hyperglycosylated Fab variants of ranibizumab (above) and bevacizumab (below). The beginnings of the variable and constant heavy chains (Vh and Ch) and light chains (Vl and Cl) are indicated by arrows (^) and the CDRs are underlined. Non-consensual glycosylation sites (“G site”) and tyrosine-O sulfation sites (“Y site”) are indicated. Four hyperglycosylated variants are indicated with an asterisk (*).

[0393] Figure 4. Schematic of the genome AAV8-antiVEGFfab.

[0394] Figure 5. A suprachoroidal drug delivery device manufactured by Clearside® Biomedical, Inc.

[0395] Figure 6. A subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where a small needle is injected into the subretinal space, manufactured by Janssen Pharmaceuticals, Inc.

[0396] Figures 7A to 7D. Illustration of the posterior juxtascleral deposition procedure. Petition 870260012693, dated 09 / 02 / 2026, page 178 / 420 111 / 319

[0397] Figure 8. Sequence Alignment Multiple Clustals of AAV 1-9 capsids (SEQ ID NOs: 41-51). Amino acid substitutions (shown in bold in the lower lines) can be made in AAV9 and AAV8 capsids by “recruiting” amino acid residues from the corresponding position of other aligned AAV capsids. Sequence regions designated as “HVR” = hypervariable regions.

[0398] Figure 9. Fast freeze / slow thaw (FF / ST) temperature profile.

[0399] Figure 10. Enlarged view of SEC outcome profiles for Construction II in Formulation A of DPBS. Pre-peaks are free DNA and aggregates. Post-peaks contain buffer species and excipients.

[0400] Figure 11. Enlarged view of SEC outcome profiles for Construction II in Formulation B. Post-peaks contain buffer and excipient species. The post-peak due to sucrose was higher in Formulation B.

[0401] Figure 12. Cumulative dynamic light scattering results for Construct II in the Formulation A (dark gray) and Formulation B (light gray) control and after exposure to permutations of five fast and slow freeze / thaw cycles.

[0402] Figure 13. Low temperature DSC thermogram for formulation buffer A of Constructor II DPBS.

[0403] Figure 14. Low temperature DSC thermogram for Construto II in buffer B of DPBS formulation modified with 4% sucrose and 0.001% Poloxamer 188, pH 7.4'.

[0404] Figure 15. Stability trend for the potency of Construct II in formulation A (dark gray circles) and formulation B (light gray squares) at 1.0 χ 1012GC / ml at 37 °C.

[0405] Figure 16. Stability trend for Construct II-free DNA was detected by dye fluorescence in formulation A (dark gray circles) and formulation B (light gray squares) at 1.0 χ¹⁰¹²GC / ml at 37 °C. Petition 870260012693, dated 09 / 02 / 2026, page 179 / 420 112 / 319

[0406] Figure 17. Stability trend for the potency of Construct II in formulation B at 1.0 χ 1012GC / ml at -80 °C and -20 °C.

[0407] Figure 18. Stability trend for the potency of Construct II in formulation B at 2.1 χ 1011GC / ml at -80 °C and -20 °C.

[0408] Figure 19A. Temperature profile measured for 2 different filling volumes in Nalgene HDPE BDS bottles.

[0409] Figure 19B. Temperature profiles recorded for 0.6 ml fills in 2 ml cryogenic vials with cycles between -80 °C and ambient temperature or -20 °C.

[0410] Figure 20A. Fast freeze / fast thaw (FF / FT) temperature profile.

[0411] Figure 20B. Fast freeze / fast thaw (FF / FT) temperature profile (left geometric axis) and rates for shelf and probes (right geometric axis).

[0412] Figure 21. Fast freeze / slow thaw (FF / ST) temperature profile.

[0413] Figure 22. Slow freeze / rapid thaw (SF / FT) temperature profile.

[0414] Figure 23. Slow freeze / slow thaw (SF / ST) temperature profile.

[0415] Figure 24. Slow freeze / slow thaw (SF / ST) temperature profile (left geometric axis) and rates for the shelf and probes (right geometric axis).

[0416] Figure 25. Enlarged view of SEC result profiles for control formulation buffer.

[0417] Figure 26. Enlarged view of SEC outcome profiles for Construct II in dPBS formulation buffer.

[0418] Figure 27. Enlarged view of SEC outcome profiles for Construct II in sucrose-buffered modified dPBS.

[0419] Figure 28. DLS diameter results for Petition 870260012693, dated 09 / 02 / 2026, pp. 180 / 420 113 / 319 Construct II in freeze-thaw samples of dPBS.

[0420] Figure 29. DLS diameter results for Construct II in modified dPBS with freeze-thaw sucrose samples

[0421] Figure 30. Comparison of the DLS cumulant diameter result for Construct II in dPBS compared to dPBS modified with freeze-thaw sucrose samples.

[0422] Figure 31. Comparison of the DLS regularization diameter result for Construct II in dPBS compared to dPBS modified with freeze-thaw sucrose samples.

[0423] Figure 32. Low temperature DSC thermogram for Constructo II dPBS formulation buffer.

[0424] Figure 33. Low-temperature DSC thermogram for Construto II “dPBS modified with sucrose” formulation buffer.

[0425] Figure 34. Formulation B contains an amorphous excipient that inhibits crystallization / eutectic transition, improving robustness to freeze / thaw stress.

[0426] Figure 35. Free DNA increases with each freeze / thaw cycle for Formulation A.

[0427] Figure 36. The potency of formulation a decreases with >5x freeze / thaw cycles, and the potency is maintained in formulation b for 30x freeze / thaw cycles. Formulation B of “4% sucrose-modified dPBS” (dark gray bars) maintained potency after 30 freeze-thaw cycles. In contrast, the potency of the reference formulation (dPBS, light gray bars) decreased to between 66% and 72% after 15 to 30 freeze-thaw cycles. An example is for AAV8 with a gene for green fluorescent protein. Freeze-thaw cycles are used to simulate temperature changes in transport logistics and Petition 870260012693, dated 09 / 02 / 2026, page 181 / 420 114 / 319 storage and also as an “accelerated” stress to force the degradation of AAV for formulation optimization work.

[0428] Figure 37. Adsorption losses occur in glass vials, but are not detected in copper vials.

[0429] Figure 38. Formulations A and B had similar long-term frozen stability at -80 °C; Formulation B was also stable at -20 °C. The “4% sucrose-modified dPBS” formulation maintained potency for 12 months at -20 °C (circles) and -80 °C (squares). The reference formulation (dPBS) is shown for storage at -80 °C as a comparator.

[0430] Figure 39. Real-time monitoring of pH and temperature of Formulation No. 2, dPBS modified with 4% sucrose, in the -20 AD freezer showing an approximate acidification of 3 pH units after freezing the formulation (upper trace, left geometric axis). The temperature trace (lower trace, right geometric axis) shows the temperature fluctuation as the freezer's automatic defrost cycle occurs. The pH of the frozen solution, measured directly with the frozen pH electrode, shows fluctuations between approximately 4.3 and 5.5 when frozen, which correlate with the temperature of the frozen formulation.

[0431] Figure 40. Comparison of the pH of different buffers after being stressed by several thaw cycles. The DPBS formulation changed from 7.4 to about 4.3 when frozen. The sucrose formulations had a lower pH change from 7.4 to about 6.2 after freezing. The TRIS formulation initially changes relative to room temperature and then is stable when frozen.

[0432] Figure 41. Comparison of the pH of the buffers as the temperature decreases from 0 to -20 °C. Formulation no. 1, based on phosphate, had a large pH change upon freezing. Formulations 2-7 showed a much smaller acidification shift upon freezing, which is preferable for product stability. Formulation 8 changed Petition 870260012693, dated 09 / 02 / 2026, page 182 / 420 115 / 319 slightly more basic and within acceptable limits for formulation stability.

[0433] Figure 42. Magnitude of pH change of the different buffer after stabilization.

[0434] Figure 43. Low temperature DSC thermogram for Formulation no. 1: dPBS formulation buffer.

[0435] Figure 44. Low-temperature DSC thermogram for Formulation No. 2: dPBS modified with 4% sucrose formulation buffer.

[0436] Figure 45. Thermogram comparison Low-temperature DSC of the phase transition behavior of different formulations. Formulation 1 (dPBS) does not show a glass transition (trace indicated with text). Formulation 2 (Formulation B) and variations (formulations nos. 3-7) and with TRIS buffer (formulation 8) showed phase transition behavior similar to Formulation no. 2, with a glass transition between -40 and -45 °C.

[0437] Figure 46. The aggregation of viral particles is affected by ionic strength.

[0438] Figure 47. Minimum ionic strength to prevent aggregation. Effective diameter of an AAV8 particle in 1.8 x 1013GC / ml prepared at different NaCl concentrations. Ionic strength > 90 mM appears to be necessary to prevent particle aggregation as indicated by the particle diameters.

[0439] Figure 48. Minimum ionic strength depends on serotype. Effective diameter of an AAV8 (open square) and an AAV9 (open triangle) prepared at different NaCl concentrations. Vector concentration was 6 x 1011GC / ml.

[0440] Figure 49. Formulation C is a variant of the “sucrose-modified dPBS” with 60 mM NaCl and 6% sucrose (light gray triangles) and was stable for 2 years at -20 °C. The formulation of Petition 870260012693, dated 09 / 02 / 2026, page 183 / 420 The 116 / 319 reference (dPBS) is shown for storage at -20 °C as a comparator (dark gray squares) and was not stable at -20 °C. Formulations B and C showed comparable and superior long-term stability at -20 °C.

[0441] Figure 50. Power Trend for Construct II in Formulation B at 2 to 8 °C.

[0442] Figure 51. Power trend for the Lot 200320-314-DL7 of FDP from Construction II at 3.0 χ 1013GC / ml at controlled ambient temperature.

[0443] Figure 52. Stability trend for the potency of Construct II in formulation B at 1.0 χ 1012GC / ml at -80 °C and -20 °C.

[0444] Figure 53. Stability trend for the potency of Construct II in formulation B at 2.1 χ 1011GC / ml at -80 °C and -20 °C.

[0445] Figure 54. Formulations A and B had similar long-term frozen stability at -80 °C; Formulation B was also stable at -20 °C. The “4% sucrose-modified dPBS” formulation maintained potency for 12 months at -20 °C (circles) and -80 °C (squares). The reference formulation (dPBS) is shown for storage at -80 °C as a comparator. 4. DETAILED DESCRIPTION OF THE INVENTION

[0446] Pharmaceutical compositions, a treatment method related to the pharmaceutical compositions, and kits related to the pharmaceutical compositions are provided in this document. In some embodiments, compositions provided in Section 4.1 are formulated so that they have one or more functional properties described in Section 4.2. In certain embodiments, the pharmaceutical compositions provided in this document have several advantages, for example, improved stability after free / thaw cycles and improved long-term stability under various conditions. Assays that can be used in related studies are also provided in this document (Section 4.5). Petition 870260012693, dated 09 / 02 / 2026, page 184 / 420 117 / 319 4.1 PHARMACEUTICAL COMPOSITION FORMULATION

[0447] The disclosure provides a pharmaceutical composition comprising a recombinant adeno-associated virus (AAV), monobasic potassium phosphate, sodium chloride, anhydrous dibasic sodium phosphate, sucrose and surfactant.

[0448] In some forms, the pharmaceutical composition also includes amino acids.

[0449] In some embodiments, the disclosure provides a pharmaceutical composition comprising a recombinant adeno-associated virus (AAV), an ionic salt excipient or buffering agent, sucrose, and poloxamer 188. In some embodiments, the ionic salt excipient or buffering agent may be one or more components of the group consisting of monobasic potassium phosphate, potassium phosphate, sodium chloride, anhydrous dibasic sodium phosphate, sodium phosphate hexahydrate, monobasic sodium phosphate monohydrate, tromethamine, tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl), amino acid, histidine, histidine hydrochloride (histidine-HCl), sodium succinate, sodium citrate, sodium acetate, and (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES), sodium sulfate, magnesium sulfate, magnesium chloride. 6-hydrate, calcium sulfate, potassium chloride, calcium chloride, calcium citrate.

[0450] In certain embodiments, the pharmaceutical composition has an ionic strength of about 60 mM to 115 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 60 mM to 100 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 65 mM to 95 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 70 mM to 90 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 75 mM to 85 mM.

[0451] In certain embodiments, the pharmaceutical composition has an ionic strength of about 30 mM to 100 mM. In certain Petition 870260012693, dated 09 / 02 / 2026, page 185 / 420 In certain embodiments, the pharmaceutical composition has an ionic strength of about 35 mM to 95 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 40 mM to 90 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 45 mM to 85 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 50 mM to 80 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 55 mM to 75 mM. In certain embodiments, the pharmaceutical composition has an ionic strength of about 60 mM to 70 mM.

[0452] In certain embodiments, the pharmaceutical composition has an ionic strength ranging from 60 mM to 115 mM. In certain embodiments, the pharmaceutical composition has an ionic strength ranging from 60 mM to 100 mM. In certain embodiments, the pharmaceutical composition has an ionic strength ranging from 65 mM to 95 mM. In certain embodiments, the pharmaceutical composition has an ionic strength ranging from 70 mM to 90 mM. In certain embodiments, the pharmaceutical composition has an ionic strength ranging from 75 mM to 85 mM.

[0453] In certain embodiments, the pharmaceutical composition has an ionic strength range of 30 mM to 100 mM. In certain embodiments, the pharmaceutical composition has an ionic strength range of 35 mM to 95 mM. In certain embodiments, the pharmaceutical composition has an ionic strength range of 40 mM to 90 mM. In certain embodiments, the pharmaceutical composition has an ionic strength range of 45 mM to 85 mM. In certain embodiments, the pharmaceutical composition has an ionic strength range of 50 mM to 80 mM. In certain embodiments, the pharmaceutical composition has an ionic strength range of 55 mM to 75 mM. In certain embodiments, the pharmaceutical composition has an ionic strength range of 60 mM to 70 mM.

[0454] In certain embodiments, the pharmaceutical composition comprises potassium chloride at a concentration of 0.2 g / l.

[0455] In certain embodiments, the pharmaceutical composition comprises monobasic potassium phosphate at a concentration Petition 870260012693, dated 09 / 02 / 2026, page 186 / 420 119 / 319 of 0.2 g / l.

[0456] In certain embodiments, the pharmaceutical composition comprises sodium chloride at a concentration of 5.84 g / L

[0457] In certain embodiments, the pharmaceutical composition comprises anhydrous dibasic sodium phosphate at a concentration of 1.15 g / l.

[0458] In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 3% (weight / volume, 30 g / l) to 18% (weight / volume, 180 g / l). In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 4% (weight / volume, 40 g / l).

[0459] In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.001% (weight / volume, 0.01 g / l).

[0460] In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.0005% (weight / volume, 0.005 g / l) to 0.05% (weight / volume, 0.5 g / l). In certain embodiments, the pharmaceutical composition comprises poloxamer 188 at a concentration of 0.001% (weight / volume, 0.01 g / l).

[0461] In some embodiments, the disclosure provides a pharmaceutical composition comprising a recombinant adeno-associated virus (AAV), an ionic salt excipient or buffering agent, sucrose, and a surfactant. In some embodiments, the ionic salt excipient or buffering agent may be one or more components of the group consisting of monobasic potassium phosphate, potassium phosphate, sodium chloride, anhydrous dibasic sodium phosphate, sodium phosphate hexahydrate, monobasic sodium phosphate monohydrate, tromethamine, tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl), amino acid, histidine, histidine hydrochloride (histidine-HCl), sodium succinate, sodium citrate, sodium acetate, and (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES), sodium sulfate, Petition 870260012693, dated 09 / 02 / 2026, page 187 / 420 120 / 319 magnesium sulfate, magnesium chloride 6-hydrate, calcium sulfate, potassium chloride, calcium chloride, calcium citrate. In some embodiments, the surfactant may be one or more components of the group consisting of poloxamer 188, polysorbate 20 and polysorbate 80.

[0462] In certain embodiments, the pharmaceutical composition comprises polysorbate 20 at a concentration of 0.0005% (weight / volume, 0.05 g / l) to 0.05% (weight / volume, 0.5 g / l).

[0463] In certain embodiments, the pharmaceutical composition comprises polysorbate 80 at a concentration of 0.0005% (weight / volume, 0.05 g / l) to 0.05% (weight / volume, 0.5 g / l).

[0464] In certain embodiments, the pH of the pharmaceutical composition is approximately 7.4.

[0465] In certain embodiments, the pH of the pharmaceutical composition is approximately 6.0 to 9.0.

[0466] In certain embodiments, the pH of the pharmaceutical composition is 7.4.

[0467] In certain embodiments, the pH of the pharmaceutical composition is 6.0 to 9.0.

[0468] As used in this document and unless otherwise specified, the term “about” means approximately 10% of a given value or range.

[0469] In certain embodiments, the pharmaceutical composition is in a hydrophobically coated glass bottle.

[0470] In certain embodiments, the pharmaceutical composition is in a Cyclo Olefin Polymer (COP) bottle.

[0471] In certain embodiments, the pharmaceutical composition is in a Daikyo Crystal Zenith® (CZ) bottle.

[0472] In certain embodiments, the pharmaceutical composition is in a bottle coated with TopLyo.

[0473] In certain modalities, it is disclosed in Petition 870260012693, dated 09 / 02 / 2026, page 188 / 420 121 / 319 present document a pharmaceutical composition consisting of: (a) recombinant AAV, (b) potassium chloride at a concentration of 0.2 g / l, (c) monobasic potassium phosphate at a concentration of 0.2 g / l, (d) sodium chloride at a concentration of 5.84 g / l, (e) anhydrous dibasic sodium phosphate at a concentration of 1.15 g / l, (f) sucrose at a concentration of 4% by weight / volume (40 g / l), (g) poloxamer 188 at a concentration of 0.001% by weight / volume (0.01 g / l) and (h) water and wherein the recombinant AAV is AAV8.

[0474] In certain embodiments, the vector genome (VGC) concentration of the pharmaceutical composition is approximately 3 χ109GC / ml, approximately 1 χ1010GC / ml, approximately 1.2 χ1010GC / ml, approximately 1.6 χ10 GC / ml, about 4 χ 1010GC / ml, about 6 χ 1010GC / ml, about 2 χ10 GC / ml, about 2.4 χ 1011GC / ml, about 2.5 χ 1011GC / ml, about 3 χ10 GC / ml, about 6.2 χ 1011GC / ml, about 1 χ 1012GC / ml, about 3 χ10 GC / ml, approximately 2χ 1013GC / ml or approximately 3χ 1013GC / ml.

[0475] In certain embodiments, the disclosure provides a pharmaceutical composition or formulation comprising a recombinant adeno-associated virus (AAV), monobasic potassium phosphate, sodium chloride, anhydrous dibasic sodium phosphate, sucrose, and poloxamer 188. In some embodiments, the AAV comprises AAV8 components. In some embodiments, the AAV is the AAV viral vectors provided herein comprising the following elements in the following order: a) a constitutive or hypoxia-inducible promoter sequence and b) a sequence encoding the transgene (e.g., a chemical portion of an anti-VEGF antigen-binding fragment). In some embodiments, the transgene is a post-translationally modified fully human antibody (HuPTM) against VEGF.Antibodies include, but are not limited to, monoclonal antibodies, polyclonal antibodies, recombinant antibodies, human antibodies, humanized antibodies, chimeric antibodies, synthetic antibodies, tetrameric antibodies comprising two heavy chain molecules and two light chain molecules, and light chain monomers. Petition 870260012693, dated 09 / 02 / 2026, page 189 / 420 122 / 319 antibody, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-heavy chain pairs, intrabodies, heteroconjugated antibodies, monovalent antibodies, antigen-binding fragments of full-length antibodies, and fusion proteins of the foregoing. Such antigen-binding fragments include, but are not limited to, single-domain antibodies (variable domain heavy chain antibodies (VHHs) or nanobodies), Fabs, F(ab')2s, and scFvs (variable single-chain fragments) of full-length anti-VEGF antibodies (preferably full-length anti-VEGF monoclonal antibodies (mAbs) (collectively referred to herein as “antigen-binding fragments”).In a preferred embodiment, the fully human post-translationally modified antibody against VEGF is a fully human post-translationally modified antigen-binding fragment of a monoclonal antibody (mAb) against VEGF (“HuPTMFabVEGFi”). In another preferred embodiment, the... HuPTMFabVEGFi is a fully human glycosylated antigen-binding fragment of an anti-VEGF mAb (“HuGlyFabVEGFi”). In an alternative embodiment, full-length mAbs may be used. In a preferred embodiment, the AAV used to deliver the transgene must have a tropism for human retinal cells or photoreceptor cells. Such an AAV may include recombinant non-replicating adeno-associated virus vectors (“rAAVs”), particularly those carrying an AAV8 capsid are preferred.In one particular embodiment, the viral vector or other DNA expression construct described herein is Construct I, wherein Construct I comprises the following components: (1) inverted terminal repeats of AAV8 flanking the expression cassette; (2) control elements, which include a) the CB7 promoter, comprising the CMV enhancer / chicken β-actin promoter, b) a chicken β-actin intron, and c) a rabbit β-globin poly A signal; and (3) nucleic acid sequences encoding the heavy and light chains of the anti-VEGF antigen-binding fragment, separated by . Petition 870260012693, dated 09 / 02 / 2026, pp. 190 / 420 123 / 319 a furin (F) / F2A autocleavage linker, ensuring the expression of equal amounts of heavy and light chain polypeptides. In another specific embodiment, the viral vector or other DNA expression construct described in this document is Construct II, wherein Construct II comprises the following components: (1) inverted terminal repeats of AAV2 flanking the expression cassette; (2) control elements, which include a) the CB7 promoter, comprising the CMV enhancer / chicken β-actin promoter, b) a chicken β-actin intron and c) a rabbit β-globin poly A signal; and (3) nucleic acid sequences encoding the heavy and light chains of the anti-VEGF antigen-binding fragment, separated by a furin (F) / F2A autocleavage linker, ensuring the expression of equal amounts of heavy and light chain polypeptides.In some embodiments, the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence SEQ ID NO: 2 or SEQ ID NO: 4 and a light chain comprising the amino acid sequence SEQ ID NO: 1 or SEQ ID NO: 3.

[0476] In another embodiment, the viral vector or other expression construct suitable for packaging into an AAV capsid comprises (1) AAV inverted terminal repeats (ITRs) flanking the expression cassette; (2) regulatory control elements, consisting essentially of one or more enhancers and / or promoters, d) a poly A signal and e) optionally an intron; and (3) a transgene providing (e.g., encoding) one or more RNA or protein products of interest.

[0477] In some embodiments, the pharmaceutical composition consists of: (a) Construct II encoding an anti-human vascular endothelial growth factor (hVEGF) antibody, (b) potassium chloride at a concentration of 0.2 g / l, (c) monobasic potassium phosphate at a concentration of 0.2 g / l, (d) sodium chloride at a concentration of 5.84 g / l, (e) anhydrous dibasic sodium phosphate at a concentration of 1.15 g / l, (f) sucrose at a concentration of 4% by weight / volume (40 g / l), (g) poloxamer 188 at a Petition 870260012693, dated 09 / 02 / 2026, page 191 / 420 124 / 319 concentration of 0.001% by weight / volume (0.01 g / l) and (h) water and wherein the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 4 and a light chain comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3.

[0478] In some embodiments, the pharmaceutical composition consists of: (a) an AAV capsid packaging vector encoding a transgene of interest, (b) potassium chloride at a concentration of 0.2 g / l, (c) monobasic potassium phosphate at a concentration of 0.2 g / l, (d) sodium chloride at a concentration of 5.84 g / l, (e) anhydrous dibasic sodium phosphate at a concentration of 1.15 g / l, (f) sucrose at a concentration of 4% w / v (40 g / l), (g) poloxamer 188 at a concentration of 0.001% w / v (0.01 g / l) and (h) water, wherein the transgene of interest encodes an RNA of interest or a protein of interest, for example, an antibody or enzyme.

[0479] In some embodiments, the pharmaceutical composition consists of: (a) Construct II encoding an anti-human vascular endothelial growth factor (hVEGF) antibody, (b) potassium chloride at a concentration of 0.2 g / l, (c) monobasic potassium phosphate at a concentration of 0.2 g / l, (d) sodium chloride at a concentration of 5.84 g / l, (e) anhydrous dibasic sodium phosphate at a concentration of 1.15 g / l, (f) sucrose at a concentration of 4% w / v (40 g / l), (g) poloxamer 188 at a concentration of 0.001% w / v (0.01 g / l) and (h) water, wherein the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 4 and a light chain comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3, wherein the pharmaceutical composition has viscosity, density and / or osmolality suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection (e.g.,through a suprachoroidal drug delivery device, such as a Petition 870260012693, dated 09 / 02 / 2026, page 192 / 420 125 / 319 microinjector with a microneedle), subretinal injection via a transvitreal approach (a surgical procedure), subretinal administration through the suprachoroidal space (e.g., a surgical procedure using a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where a small needle is injected into the subretinal space) and / or a posterior juxtascleral deposition procedure (e.g., using a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface)).

[0480] In some embodiments, the pharmaceutical composition consists of: (a) Construct II encoding an anti-human vascular endothelial growth factor (hVEGF) antibody, (b) potassium chloride at a concentration of 0.2 g / l, (c) monobasic potassium phosphate at a concentration of 0.2 g / l, (d) sodium chloride at a concentration of 5.84 g / l, (e) anhydrous dibasic sodium phosphate at a concentration of 1.15 g / l, (f) sucrose at a concentration of 4% by weight / volume (40 g / l), (g) poloxamer 188 at a concentration of 0.001% by weight / volume (0.01 g / l) and (h) water, wherein the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 4 and a light chain comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3, wherein the pharmaceutical composition has an ionic strength of approximately 60 mM to 100 mM.

[0481] In some embodiments, the pharmaceutical composition consists of: (a) Construct II encoding an anti-human vascular endothelial growth factor (hVEGF) antibody, (b) potassium chloride at a concentration of 0.2 g / l, (c) monobasic potassium phosphate at a concentration of 0.2 g / l, (d) sodium chloride at a concentration of 5.84 g / l, (e) anhydrous dibasic sodium phosphate at a concentration of 1.15 g / l, (f) sucrose at a concentration of 4% by weight / volume (40 g / l), (g) poloxamer 188 at a Petition 870260012693, dated 09 / 02 / 2026, page 193 / 420 126 / 319 concentration of 0.001% by weight / volume (0.01 g / l) and (h) water, and wherein the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 4 and a light chain comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3, wherein the pharmaceutical composition has viscosity, density and / or osmolality suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection (e.g., via a suprachoroidal drug delivery device, such as a microinjector with a microneedle), subretinal injection via a transvitreal approach (a surgical procedure), subretinal administration via the suprachoroidal space (e.g., a surgical procedure via a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole,where a small needle is injected into the subretinal space) and / or a posterior juxtascleral deposition procedure (e.g., via a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface)).

[0482] In some embodiments, the pharmaceutical composition is a liquid composition. In some embodiments, the pharmaceutical composition is a frozen composition. In some embodiments, the pharmaceutical composition is a lyophilized composition of a liquid composition disclosed herein. In some embodiments, the pharmaceutical composition is a reconstituted lyophilized formulation.

[0483] In some embodiments, the pharmaceutical composition is a lyophilized composition comprising a residual moisture content between about 1% and about 7%. In some embodiments, the pharmaceutical composition is a lyophilized composition comprising a residual moisture content between about 2% and about 6%. In some Petition 870260012693, dated 09 / 02 / 2026, page 194 / 420 In embodiments 127 / 319, the pharmaceutical composition is a lyophilized composition comprising a residual moisture content of between about 3% and about 4%. In some embodiments, the pharmaceutical composition is a lyophilized composition comprising a residual moisture content of about 5%.

[0484] In certain aspects, a method of treating or preventing a disease in a subject is disclosed herein comprising administering the pharmaceutical composition to the subject. In some embodiments, a pharmaceutical composition provided herein is suitable for administration by one, two or more routes of administration (for example, suitable for suprachoroidal and subretinal administration).

[0485] The methods provided are suitable for use in the production of pharmaceutical compositions comprising recombinant AAV encoding a transgene. In some embodiments, viral vectors encoding an anti-VEGF or anti-VEGF Fab antibody are provided herein. In some embodiments, viral vectors based on rAAV8 encoding an anti-VEGF Fab or anti-VEGF antibody are provided herein. In further embodiments, viral vectors based on rAAV8 encoding ranibizumab are provided herein. In some embodiments, viral vectors encoding Iduronidase (IDUA) are provided herein. In some embodiments, viral vectors based on rAAV9 encoding IDUA are provided herein. In some embodiments, viral vectors encoding Iduronate 2-Sulfatase (IDS) are provided herein.In some embodiments, viral vectors based on rAAV9 encoding IDS are provided in this document. In some embodiments, viral vectors of rAAV encoding a low-density lipoprotein receptor (LDLR) are provided in this document. In some embodiments, viral vectors based on rAAV8 encoding LDLR are provided in this document. In some embodiments, the following are provided in this document. Petition 870260012693, dated 09 / 02 / 2026, page 195 / 420 128 / 319 document viral vectors rAAV encoding the tripeptidyl peptidase 1 (TPP1) protein. In some embodiments, viral vectors based on rAAV9 encoding TPP1 are provided in this document. In some embodiments, viral vectors rAAV encoding the microdystrophin protein are provided in this document. In some embodiments, viral vectors based on rAAV8 encoding microdystrophin are provided in this document. In some embodiments, viral vectors based on rAAV9 encoding microdystrophin are provided in this document. In some embodiments, viral vectors rAAV encoding the anti-kallikrein (anti-pKal) protein are provided in this document. In some embodiments, viral vectors based on rAAV8 or based on rAAV9 encoding lanadelumab Fab or full-length antibody are provided in this document.In some embodiments, viral vectors encoding human alpha-sarcoglycan-gamma-sarcoglycan are provided in this document. In some embodiments, viral vectors encoding huFollistatin344 are provided in this document. In some embodiments, viral vectors encoding human alpha-sarcoglycan-gamma-sarcoglycan are provided in this document. In some embodiments, viral vectors encoding CLN2 are provided in this document. In some embodiments, viral vectors encoding CLN3 are provided in this document. In some embodiments, viral vectors encoding CLN6 are provided in this document. In some embodiments, viral vectors based on rAAV8 or based on rAAV9 that encode human alpha-sarcoglycan-gamma-sarcoglycan are provided in this document.In some embodiments, viral vectors based on rAAV8 or rAAV9 encoding huFollistatin344 are provided in this document. In some embodiments, viral vectors based on rAAV8 or rAAV9 encoding alpha-sarcoglycan-gamma-sarcoglycan are provided in this document. Petition 870260012693, dated 09 / 02 / 2026, page 196 / 420 129 / 319 human. In some embodiments, viral vectors based on rAAV8 or rAAV9 encoding CLN2 are provided in this document. In some embodiments, viral vectors based on rAAV8 or rAAV9 encoding CLN3 are provided in this document. In some embodiments, viral vectors based on rAAV8 or rAAV9 encoding CLN6 are provided in this document.

[0486] In certain aspects, a method of treating or preventing a disease in a subject is disclosed in this document, comprising administering the pharmaceutical composition to the subject by intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection (e.g., through a suprachoroidal drug delivery device, such as a microinjector with a microneedle), subretinal injection via a transvitreal approach (a surgical procedure), subretinal administration through the suprachoroidal space (e.g., a surgical procedure through a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where a small needle injects into the subretinal space) and / or a posterior juxtascleral deposition procedure (e.g.,through a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface).

[0487] In certain embodiments, the pharmaceutical composition provided herein is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection (e.g., via a suprachoroidal drug delivery device, such as a microinjector with a microneedle), subretinal injection via a transvitreal approach (a surgical procedure), subretinal administration via the suprachoroidal space (e.g., a surgical procedure via a subretinal drug delivery device comprising a catheter that can be inserted and tunneled). Petition 870260012693, dated 09 / 02 / 2026, page 197 / 420 130 / 319 through the suprachoroidal space towards the posterior pole, where a small needle injects into the subretinal space), and / or a posterior juxtascleral deposition procedure (e.g., through a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface)).

[0488] In certain embodiments, the pharmaceutical composition has a desired viscosity that is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection (e.g., via a suprachoroidal drug delivery device, such as a microinjector with a microneedle), subretinal injection via a transvitreal approach (a surgical procedure), subretinal administration via the suprachoroidal space (e.g., a surgical procedure via a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where a small needle is injected into the subretinal space) and / or a posterior juxtascleral deposition procedure (e.g.,through a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface).

[0489] In certain embodiments, the pharmaceutical composition has a desired density that is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection (e.g., via a suprachoroidal drug delivery device, such as a microinjector with a microneedle), subretinal injection via a transvitreal approach (a surgical procedure), subretinal administration via the suprachoroidal space (e.g., a surgical procedure via a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where a small needle is injected into the subretinal space) and / or a procedure Petition 870260012693, dated 09 / 02 / 2026, pp. 198 / 420 131 / 319 posterior juxtascleral deposition (e.g., via a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface)).

[0490] In certain embodiments, the pharmaceutical composition has a desired osmolality that is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection (e.g., via a suprachoroidal drug delivery device, such as a microinjector with a microneedle), subretinal injection via a transvitreal approach (a surgical procedure), subretinal administration via the suprachoroidal space (e.g., a surgical procedure via a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where a small needle is injected into the subretinal space) and / or a posterior juxtascleral deposition procedure (e.g.,through a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface. In specific embodiments, the desired osmolality for subretinal administration is 160-430 mOsm / kg H2O. In other specific embodiments, the desired osmolality for suprachoroidal administration is less than 600 mOsm / kg H2O.

[0491] In certain embodiments, the pharmaceutical composition has an osmolality of about 100 to 500 mOsm / kg H2O. In certain embodiments, the pharmaceutical composition has an osmolality of about 130 to 470 mOsm / kg H2O. In certain embodiments, the pharmaceutical composition has an osmolality of about 160 to 430 mOsm / kg H2O. In certain embodiments, the pharmaceutical composition has an osmolality of about 200 to 400 mOsm / kg H2O. In certain embodiments, the pharmaceutical composition has an osmolality of about 240 to 340 mOsm / kg H2O. In certain embodiments, the pharmaceutical composition has an osmolality of about Petition 870260012693, dated 09 / 02 / 2026, p. 199 / 420 132 / 319 from 280 to 300 mOsm / kg H2O. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 295 to 395 mOsm / kg H2O. In certain embodiments, the pharmaceutical composition has an osmolality of less than 600 mOsm / kg H2O. In certain embodiments, the pharmaceutical composition has an osmolality range of 200 mOsm / l to 660 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 200 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 250 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 300 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 350 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 400 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 450 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 500 mOsm / l.In certain embodiments, the pharmaceutical composition has an osmolality of approximately 550 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 600 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 650 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 660 mOsm / l. In certain aspects, this document discloses methods for treating a subject diagnosed with mucopolysaccharidosis type IVA (MPS IVA), mucopolysaccharidosis type I (MPS I), mucopolysaccharidosis type II (MPS II), familial hypercholesterolemia (FH), homozygous familial hypercholesterolemia (HoFH), coronary artery disease, cerebrovascular disease, Duchenne muscular dystrophy, Limb Girdle muscular dystrophy, Becker muscular dystrophy, and sporadic inclusion body myositis or kallikrein-related disease, comprising administering the pharmaceutical composition to the subject.

[0492] In certain aspects, methods of treatment for a subject diagnosed with are disclosed in this document. Petition 870260012693, dated 09 / 02 / 2026, pp. 200 / 420 133 / 319 mucopolysaccharidosis type IVA (MPS IVA), mucopolysaccharidosis type I (MPS I), mucopolysaccharidosis type II (MPS II), familial hypercholesterolemia (FH), homozygous familial hypercholesterolemia (HoFH), coronary artery disease, cerebrovascular disease, Duchenne muscular dystrophy, Limb Girdle muscular dystrophy, Becker muscular dystrophy and sporadic inclusion body myositis or kallikrein-related disease comprising the administration to the subject of the pharmaceutical composition.

[0493] In certain aspects, methods of treatment for a subject diagnosed with mucopolysaccharidosis type IVA (MPS IVA), mucopolysaccharidosis type I (MPS I), mucopolysaccharidosis type II (MPS II), familial hypercholesterolemia (FH), homozygous familial hypercholesterolemia (HoFH), coronary artery disease, cerebrovascular disease, Duchenne muscular dystrophy, Limb Girdle muscular dystrophy, Becker muscular dystrophy and sporadic inclusion body myositis or kallikrein-related disease are disclosed in this document, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition by intravenous administration, subcutaneous administration or intramuscular injection.

[0494] In certain aspects, methods of treatment or prevention of a disease in a subject are disclosed in this document, comprising the treatment of a subject diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy (DR), or Batten disease comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition.

[0495] In certain aspects, methods of treatment for a subject diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy (DR) or Batten are disclosed in this document, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition by suprachoroidal injection (e.g., via a device). Petition 870260012693, dated 09 / 02 / 2026, page 201 / 420 134 / 319 suprachoroidal drug delivery, such as a microinjector with a microneedle), subretinal injection via a transvitreous approach (a surgical procedure), subretinal administration via the suprachoroidal space (e.g., a surgical procedure using a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where a small needle injects into the subretinal space), or a posterior juxtascleral deposition procedure (e.g., using a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface)).

[0496] In certain embodiments, compositions and methods are described for the delivery of a pharmaceutical composition comprising a post-translationally modified fully human antibody (HuPTM) against VEGF for the retina / vitreous humor in the eye (or eyes) of patients (human individuals) diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME) or diabetic retinopathy (DR).Antibodies include, but are not limited to, monoclonal antibodies, polyclonal antibodies, recombinant antibodies, human antibodies, humanized antibodies, chimeric antibodies, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-heavy chain pairs, intracorporeal antibodies, heteroconjugated antibodies, monovalent antibodies, and antigen-binding fragments of full-length antibodies and fusion proteins of the foregoing. Such antigen-binding fragments include, but are not limited to, single-domain antibodies (variable domain heavy chain antibodies (VHHs) or nanobodies), Fabs, F(ab')2s, and scFvs (variable single-chain fragments) of antibodies. Petition 870260012693, dated 09 / 02 / 2026, page 202 / 420 135 / 319 full-length anti-VEGF antibodies (preferably full-length anti-VEGF monoclonal antibodies (mAbs)) (collectively referred to herein as “antigen-binding fragments”). In a preferred embodiment, the fully human post-translationally modified antibody against VEGF is a fully human post-translationally modified antigen-binding fragment of a monoclonal antibody (mAb) against VEGF (“HuPTMFabVEGFi”). In another preferred embodiment, the HuPTMFabVEGFi is a fully human glycosylated antigen-binding fragment of an anti-VEGF mAb (“HuGlyFabVEGFi”). See also International Patent Application Publication No. WO / 2017 / 180936 (International Patent Application No. PCT / US2017 / 027529, filed April 14, 2017), International Patent Application Publication No. WO / 2017 / 181021 (International Patent Application No. PCT / US2017 / 027650, filed April 14, 2017) and International Patent Application Publication No. WO2019 / 067540 (International Patent Application No. PCT / US2018 / 052855, filed September 26, 2018), each of which is incorporated by reference herein in its entirety, for compositions and methods that may be used in accordance with the invention described herein. Alternatively, full-length mAbs can be used.Delivery can be achieved through gene therapy – for example, by administering a viral vector or other DNA expression construct encoding an anti-VEGF or mAb antigen-binding fragment (or a hyperglycosylated derivative) to the suprachoroidal space, subretinal space (from a transvitreal approach or with a catheter through the suprachoroidal space), intraretinal space, and / or outer scleral surface (i.e., juxtascleral administration) in the eye (or eyes) of patients (human individuals) diagnosed with nAMD (wet AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR), to create a permanent deposit in the eye that continuously delivers the human PTM, e.g., glycosylated transgene product. Petition 870260012693, dated 09 / 02 / 2026, page 203 / 420 136 / 319 human. See, for example, administration methods described in Section 5.3.2.

[0497] In certain modalities, patients have demonstrated responsiveness to treatment with an anti-VEGF antigen-binding fragment injected intravitreally prior to gene therapy treatment. In specific modalities, patients were previously treated with LUCENTIS® (ranibizumab), EYLEA® (aflibercept), and / or AVASTIN® (bevacizumab) and were considered responsive to one or more of said LUCENTIS® (ranibizumab), EYLEA® (aflibercept), and / or AVASTIN® (bevacizumab).

[0498] Individuals to whom this viral vector or other DNA expression construct is delivered must respond to the anti-VEGF antigen-binding fragment encoded by the transgene in the viral vector or expression construct. To determine responsiveness, the transgene product of the anti-hVEGF antigen-binding fragment (e.g., produced in cell culture, bioreactors, etc.) can be administered directly to the subject, such as by intravitreal injection.

[0499] HuPTMFabVEGFi, for example, The HuGlyFabVEGFi transgene may include, but is not limited to, an antigen-binding fragment of an antibody that binds to hVEGF, such as bevacizumab; an anti-hVEGF Fab chemical portion such as ranibizumab; or such Fab chemical portions of bevacizumab or ranibizumab genetically modified to contain additional glycosylation sites in the Fab domain (e.g., see Courtois et al, 2016, mAbs 8: 99-112, which is incorporated by reference herein in its entirety for its description of bevacizumab derivatives that are hyperglycosylated in the full-length antibody Fab domain).

[0500] The recombinant vector used to deliver the transgene must have a tropism for human retinal cells or photoreceptor cells. Such vectors may include adeno-associated virus vectors. Petition 870260012693, dated 09 / 02 / 2026, page 204 / 420 137 / 319 recombinant non-replicating (“rAAV”) vectors, particularly those carrying an AAV8 capsid, are preferred. However, other viral vectors may be used, including, but not limited to, lentiviral vectors, vaccinia viral vectors, or non-viral expression vectors referred to as “naked DNA” constructs. Preferably, the HuPTMFabVEGFi transgene, for example, HuGlyFabVEGFi, should be controlled by appropriate expression control elements, for example, the CB7 promoter (a chicken β-actin promoter and CMV enhancer), the RPE65 promoter or opsin promoter, to name a few, and may include other expression control elements that enhance the expression of the vector-driven transgene (e.g., introns such as chicken β-actin intron, mouse minute virus (MVM) intron, human factor IX intron (e.g., truncated FIX 1 intron), β-globin splice donor / immunoglobulin heavy chain acceptor intron,adenovirus splice donor / immunoglobulin splice acceptor intron, SV40 late splice donor / splice acceptor intron (19S / 16S), and hybrid adenovirus splice donor / IgG splice acceptor intron, and polyA signals such as rabbit β-globin polyA signal, human growth hormone (hGH) polyA signal, SV40 late polyA signal, synthetic polyA signal (SPA), and bovine growth hormone (bGH) polyA signal. See, for example, Powell and Rivera-Soto, 2015, Discov. Med., 19(102): 49-57.

[0501] In preferred embodiments, gene therapy constructs are genetically modified so that both heavy and light chains are expressed. More specifically, the heavy and light chains should be expressed in approximately equal amounts; in other words, the heavy and light chains are expressed at a ratio of approximately 1:1 between heavy and light chains. The coding sequences for the heavy and light chains can be manipulated into a single construct in which the heavy and light chains are separated by a cleavable linker or IRES so that the separated heavy and light chain polypeptides are expressed. See, for example, Section 5.2.4 for leader sequences. Petition 870260012693, dated 09 / 02 / 2026, page 205 / 420 138 / 319 specific and Section 5.2.5 for IRES, 2A and other specific linker sequences that can be used with the methods and compositions provided in this document.

[0502] In certain embodiments, gene therapy constructs are provided as a sterile, single-use frozen solution of the AAV vector active ingredient in a formulation buffer. In one specific embodiment, pharmaceutical compositions suitable for subretinal administration comprise a suspension of the recombinant vector (e.g., rHuGlyFabVEGFi) in a formulation buffer comprising a physiologically compatible aqueous buffer, a surfactant, and optional excipients. In one specific embodiment, the construct is formulated in Dulbecco's phosphate-buffered saline solution with 0.001% poloxamer 188, pH = 7.4. 4.2. FUNCTIONAL PROPERTIES

[0503] In certain embodiments, the pharmaceutical composition described herein is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection (e.g., via a suprachoroidal drug delivery device, such as a microinjector with a microneedle), subretinal injection via a transvitreal approach (a surgical procedure), subretinal administration via the suprachoroidal space (e.g., a surgical procedure via a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where a small needle injects into the subretinal space), and / or a posterior juxtascleral deposition procedure (e.g.,through a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface).

[0504] In certain embodiments, the pharmaceutical composition has a desired density that is suitable for administration. Petition 870260012693, dated 09 / 02 / 2026, page 206 / 420 139 / 319 intravenous, subcutaneous administration, intramuscular injection, suprachoroidal injection (e.g., via a suprachoroidal drug delivery device, such as a microinjector with a microneedle), subretinal injection via a transvitreal approach (a surgical procedure), subretinal administration via the suprachoroidal space (e.g., a surgical procedure via a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where a small needle is injected into the subretinal space) and / or a posterior juxtascleral deposition procedure (e.g., via a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface)).

[0505] In certain embodiments, the pharmaceutical composition has a desired osmolality that is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection (e.g., via a suprachoroidal drug delivery device, such as a microinjector with a microneedle), subretinal injection via a transvitreal approach (a surgical procedure), subretinal administration via the suprachoroidal space (e.g., a surgical procedure via a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where a small needle is injected into the subretinal space) and / or a posterior juxtascleral deposition procedure (e.g.,through a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface).

[0506] In certain embodiments, the pharmaceutical composition has a desired viscosity that is suitable for intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection (e.g., via a delivery device). Petition 870260012693, dated 09 / 02 / 2026, page 207 / 420 140 / 319 suprachoroidal drug delivery, such as a microinjector with a microneedle), subretinal injection via a transvitreous approach (a surgical procedure), subretinal administration through the suprachoroidal space (e.g., a surgical procedure using a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space towards the posterior pole, where a small needle is injected into the subretinal space) and / or a posterior juxtascleral deposition procedure (e.g., using a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and held in direct apposition to the scleral surface)).

[0507] In certain embodiments, the pharmaceutical composition has an osmolality of about 100 to 500 mOsm / kg H2O. In certain embodiments, the pharmaceutical composition has an osmolality of about 130 to 470 mOsm / kg H2O. In certain embodiments, the pharmaceutical composition has an osmolality of about 160 to 430 mOsm / kg H2O. In certain embodiments, the pharmaceutical composition has an osmolality of about 200 to 400 mOsm / kg H2O. In certain embodiments, the pharmaceutical composition has an osmolality of about 280 to 300 mOsm / kg H2O. In certain embodiments, the pharmaceutical composition has an osmolality of about 240 to 340 mOsm / kg H2O. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 295 to 395 mOsm / kg H2O. In certain embodiments, the pharmaceutical composition has an osmolality of less than 600 mOsm / kg H2O. In certain embodiments, the pharmaceutical composition has an osmolality range of 200 mOsm / l to 660 mOsm / l.In certain embodiments, the pharmaceutical composition has an osmolality of approximately 200 mOsm / L. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 250 mOsm / L. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 300 mOsm / L. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 350 mOsm / L. In certain embodiments, the pharmaceutical composition has a... Petition 870260012693, dated 09 / 02 / 2026, pp. 208 / 420 141 / 319 osmolality of approximately 400 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 450 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 500 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 550 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 600 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 650 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality of approximately 660 mOsm / l.In certain aspects, this document discloses methods for treating a subject diagnosed with mucopolysaccharidosis type IVA (MPS IVA), mucopolysaccharidosis type I (MPS I), mucopolysaccharidosis type II (MPS II), familial hypercholesterolemia (FH), homozygous familial hypercholesterolemia (HoFH), coronary artery disease, cerebrovascular disease, Duchenne muscular dystrophy, Limb Girdle muscular dystrophy, Becker muscular dystrophy, and sporadic inclusion body myositis or kallikrein-related disease, comprising administering the pharmaceutical composition to the subject.

[0508] In certain embodiments, the pharmaceutical composition has an osmolality range of 200 mOsm / l to 660 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality range of 250 mOsm / l to 600 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality range of 300 mOsm / l to 550 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality range of 350 mOsm / l to 500 mOsm / l. In certain embodiments, the pharmaceutical composition has an osmolality range of 400 mOsm / l to 500 mOsm / l.

[0509] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable to freeze / thaw cycles than the same recombinant AAV in a Petition 870260012693, dated 09 / 02 / 2026, p. 209 / 420 142 / 319 reference pharmaceutical composition. In certain embodiments, the stability of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0510] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more infectivity than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the infectivity of the recombinant AAV virus is determined by an assay or assays disclosed in Section 4.5 and Section 5. In certain embodiments, infectivity is measured before or after freeze / thaw cycles.

[0511] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times less aggregated than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the aggregated AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5. In certain embodiments, the aggregated AAV is measured before or after freeze / thaw cycles.

[0512] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, 12 months, about 15 months, about 18 months, approximately 24 months, approximately 2 years, Petition 870260012693, dated 09 / 02 / 2026, pp. 210 / 420 143 / 319 approximately 3 years, approximately 4 years longer than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the stability over a period of time of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0513] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable for a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, 12 months, about 15 months, about 18 months, approximately 24 months, approximately 2 years, approximately 3 years, approximately 4 years than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the stability over a period of time of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0514] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times greater in vitro relative potency (IVRP) than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the in vitro relative potency (IVRP) of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5. In certain embodiments, the in vitro relative potency (IVRP) is measured before or after freeze / thaw cycles.

[0515] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 Petition 870260012693, dated 09 / 02 / 2026, p. 211 / 420 144 / 319 times, 100 times, or 1,000 times less free DNA than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the free DNA of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5. In certain embodiments, aggregation is measured before or after freeze / thaw cycles.

[0516] In certain embodiments, the recombinant AAV in the pharmaceutical composition has a maximum of 20%, 15%, 10%, 8%, 5%, 4%, 3%, 2% or 1% change in size over a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 24 months, about 2 years, about 3 years and about 4 years. In certain embodiments, the size of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5. In certain embodiments, the size is measured before or after freeze / thaw cycles.

[0517] In certain embodiments, the recombinant AAV in the pharmaceutical composition has a maximum of 20%, 15%, 10%, 8%, 5%, 4%, 3%, 2% or 1% change in size over a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 24 months, about 2 years, about 3 years and about 4 years. In certain embodiments, the size of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5. In certain embodiments, the size is measured before or after freeze / thaw cycles. Petition 870260012693, dated 09 / 02 / 2026, p. 212 / 420 145 / 319

[0518] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1000 times more stable than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C. In certain embodiments, the stability of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0519] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more infectivity than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, compared to the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the infectivity of the recombinant AAV virus is determined by an assay or assays disclosed in Section 4.5 and in Section 5.

[0520] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more infectivity than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about Petition 870260012693, dated 09 / 02 / 2026, p. 213 / 420 146 / 319 of 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the infectivity of the recombinant AAV virus is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0521] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times less aggregated than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, compared to the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the aggregation of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0522] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times less aggregated than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time of at least, for example, at least about 11 weeks, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about Petition 870260012693, dated 09 / 02 / 2026, pp. 214 / 420 147 / 319 of approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the aggregation of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0523] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable when stored at -20 °C for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, compared to the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the stability over a period of time of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0524] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more stable when stored at -20 °C for a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, approximately 18 Petition 870260012693, dated 09 / 02 / 2026, pp. 215 / 420 148 / 319 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the stability over a period of time of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0525] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times greater in vitro relative potency (IVRP) than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition.In certain embodiments, the in vitro relative potency (IVRP) of recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0526] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times greater in vitro relative potency (IVRP) than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 Petition 870260012693, dated 09 / 02 / 2026, pp. 216 / 420 149 / 319 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the in vitro relative potency (IVRP) of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0527] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times greater in vitro relative potency (IVRP) than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition.In certain embodiments, the in vitro relative potency (IVRP) of recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0528] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times greater in vitro relative potency (IVRP) than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 Petition 870260012693, dated 09 / 02 / 2026, pp. 217 / 420 150 / 319 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the in vitro relative potency (IVRP) of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0529] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times less free DNA than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the DNA-free nature of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0530] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times less free DNA than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C for a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about Petition 870260012693, dated 09 / 02 / 2026, pp. 218 / 420 151 / 319 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, than the same recombinant AAV in a reference pharmaceutical composition. In certain embodiments, the DNA-free recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0531] In certain embodiments, recombinant AAV in the pharmaceutical composition has a maximum of 20%, 15%, 10%, 8%, 5%, 4%, 3%, 2% or 1% change in size when stored at -20 °C over a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 24 months, about 2 years, about 3 years and about 4 years. In certain embodiments, the size of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0532] In certain embodiments, recombinant AAV in the pharmaceutical composition has a maximum of 20%, 15%, 10%, 8%, 5%, 4%, 3%, 2% or 1% change in size when stored at -20 °C over a period of time, for example, at least about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 24 months, about 2 years, about 3 years and about 4 years. In certain embodiments, the size of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0533] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, Petition 870260012693, dated 09 / 02 / 2026, pp. 219 / 420 152 / 319 times, 100 times or 1,000 times more stable than the same recombinant AAV in a reference pharmaceutical composition when stored at 37 °C. In certain embodiments, the stability of the recombinant AAV is determined by an assay or assays disclosed in Section 4.5 and Section 5.

[0534] In certain embodiments, the recombinant AAV in the pharmaceutical composition is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1,000 times more infectivity than the same recombinant AAV in a reference pharmaceutical composition when stored at 37°C for a period of time, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 24 months, approximately 2 years, approximately 3 years, and approximately 4 years, compared to the same recombinant AAV in a reference pharmaceutical composition. In certa...

Claims

1. Pharmaceutical composition for use in the treatment of Batten disease in a subject, characterized in that it comprises: (a) a recombinant adeno-associated virus (rAAV), (b) potassium chloride, (c) monobasic potassium phosphate, (d) sodium chloride, (e) anhydrous dibasic sodium phosphate, (f) sucrose, and (e) poloxamer 188.

2. Pharmaceutical composition, according to claim 1, characterized in that the rAAV virus comprises components of one or more adeno-associated virus serotypes selected from the group consisting of AAV1, AAV2, AAV2tYF, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV.rh20, AAV.rh39, AAV.Rh74, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, rAAV.7m8, AAV.PHP.B, AAV.PHP.eB, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15 and AAV.HSC16.

3. Pharmaceutical composition, according to claim 1, characterized in that rAAV is AAV9 or AAV10.

4. Pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition comprises an ionic strength of 60 mM to about 150 mM.

5. Pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is characterized in that it comprises (a) potassium chloride at a concentration of about 0.2 g / L; (b) monobasic potassium phosphate at a concentration of about 0.2 g / L; (c) sodium chloride at a concentration of about 5.84 g / L; and Petition 870260012693, dated 09 / 02 / 2026, page 413 / 420 2 / 7 (d) anhydrous dibasic sodium phosphate at a concentration of about 1.15 g / L.

6. Pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is characterized in that it comprises sucrose in a concentration in the range of 3% (weight / volume, 30 g / L) to 18% (weight / volume, 180 g / L).

7. Pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is characterized in that it comprises sucrose at a concentration of approximately 4% (weight / volume, 40 g / L).

8. Pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is characterized in that it comprises poloxamer 188, and wherein the poloxamer 188 is in a concentration in the range of 0.0005% (weight / volume, 0.005 g / L) to 0.05% (weight / volume, 0.5 g / L).

9. Pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is characterized in that it comprises poloxamer 188; wherein the poloxamer 188 is in a concentration of about 0.001% (weight / volume, 0.01 g / L).

10. Pharmaceutical composition according to claim 1, characterized in that rAAV comprises an AAV capsid and a vector genome packaged therein, and wherein the vector genome comprises: (a) a 5' inverted terminal repeat (ITR) of AAV; (b) a promoter; (c) a transgene; and (d) a 3' ITR of AAV.

11. Pharmaceutical composition, according to claim 1, characterized in that the pharmaceutical composition comprises a vector genome (VGC) concentration of about 3.0 χ 109 GC / mL to about 3.0 χ 1013 GC / mL.

12. Pharmaceutical composition, according to claim 1, characterized in that the pharmaceutical composition comprises a vector genome (VGC) concentration of approximately 1.0 χ 1011 GC / mL.

13. Pharmaceutical composition, according to claim 1, Petition 870260012693, dated 09 / 02 / 2026, pp. 414 / 420 3 / 7, characterized in that rAAV comprises a transgene associated with the treatment of Batten disease.

14. Pharmaceutical composition, according to claim 1, characterized in that rAAV comprises a transgene, wherein the transgene is CLN2.

15. Pharmaceutical composition, according to claim 1, characterized in that rAAV comprises a transgene, wherein the transgene encodes the tripeptidyl peptidase 1 (TPP1) protein.

16. Pharmaceutical composition, according to claim 1, characterized in that the pharmaceutical composition comprises a pH of about 6.0 to about 9.

0.

17. Pharmaceutical composition, according to claim 1, characterized in that the osmolality of the pharmaceutical composition is in a range of about 200 mOsm / L to about 660 mOsm / L.

18. Pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is characterized by the fact that it is suitable for administration to the eye.

19. Pharmaceutical composition, according to claim 1, characterized in that the treatment comprises intravenous administration, subcutaneous administration, intramuscular injection, suprachoroidal injection, subretinal injection via a transvitreous approach, subretinal administration through the suprachoroidal space and / or posterior juxtascleral administration.

20. Use of a pharmaceutical composition according to any one of claims 1 to 19, characterized in that it is used to prepare a medicament for treating Batten disease in a subject, wherein said use comprises administering the pharmaceutical composition to the subject.

21. A stable liquid formulation characterized by comprising the pharmaceutical composition of any one of claims 1 to 19.

22. A stable liquid formulation conforming to the pharmaceutical composition of any of claims 1 to 19, characterized in that the concentration of the recombinant AAV vector genome is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the recombinant AAV vector genome concentration before freeze / thaw cycles.

23. A stable liquid formulation conforming to the pharmaceutical composition of any one of claims 1 to 19; characterized in that the genome concentration of the recombinant AAV vector, after being stored at -20 °C, -80 °C, 4 °C or at room temperature for a period of time, is at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the genome concentration of the recombinant AAV vector before being stored at -20 °C, -80 °C, 4 °C or at room temperature for said period, the period of time being about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months or about 24 months.

24. A stable liquid formulation conforming to the pharmaceutical composition of any of claims 1 to 19, characterized in that the recombinant AAV is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1000 times more stable to freeze / thaw cycles than the same recombinant AAV in a reference pharmaceutical composition.

25. A stable liquid formulation conforming to the pharmaceutical composition of any of claims 1 to 19, characterized in that the recombinant AAV is at least 2%, 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 100%, 2 times, 3 times, 5 times, 10 times, 100 times or 1000 times more stable than the same recombinant AAV in a reference pharmaceutical composition when stored at -20 °C, -80 °C, 4 °C or at room temperature for a period of time, the period of time being about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, approximately 7 months, approximately 8 Petition 870260012693, dated 09 / 02 / 2026, page 416 / 420 5 / 7 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 12 months, approximately 15 months, approximately 18 months or approximately 24 months.

26. A single unit dosage form comprising a pharmaceutical composition for the treatment of Batten disease in a container, characterized in that the pharmaceutical composition comprises: i. (a) a vector genome (VGC) concentration at a concentration of about 1.0 χ 1010 GC / mL to about 1.0 χ 1013 GC / mL; (b) potassium chloride at a concentration of about 0.2 g / L; (c) monobasic potassium phosphate at a concentration of about 0.2 g / L; (d) sodium chloride at a concentration of about 5.84 g / L; (e) anhydrous dibasic disodium phosphate at a concentration of about 1.15 g / L; (f) sucrose at a concentration ranging from about 3% (weight / volume, 30 g / L) to about 18% (weight / volume, 180 g / L); and (g) poloxamer 188 at a concentration of about 0.001% (weight / volume, 0.01 g / L); or ii.(a) a vector genome concentration (VGC) at a concentration of about 1.0 χ 1011 GC / mL; (b) potassium chloride at a concentration of about 0.2 g / L; (c) monobasic potassium phosphate at a concentration of about 0.2 g / L; (d) sodium chloride at a concentration of about 5.84 g / L; (e) anhydrous dibasic disodium phosphate at a concentration of about 1.15 g / L; (f) sucrose at a concentration ranging from about 3% (weight / volume, 30 g / L) to about 18% (weight / volume, 180 g / L); and (g) poloxamer 188 at a concentration of about 0.001% (weight / volume, 0.01 g / L). Petition 870260012693, dated 09 / 02 / 2026, pp. 417 / 420 6 / 7.

27. A single unit dosage form comprising a pharmaceutical composition for the treatment of Batten disease in a container, characterized in that the pharmaceutical composition comprises: i. (a) a vector genome (VGC) concentration at a concentration of about 1.0 χ 1010 GC / mL to about 1.0 χ 1013 GC / mL; (b) potassium chloride at a concentration of about 0.2 g / L; (c) monobasic potassium phosphate at a concentration of about 0.2 g / L; (d) sodium chloride at a concentration of about 5.84 g / L; (e) anhydrous dibasic disodium phosphate at a concentration of about 1.15 g / L; (f) sucrose at a concentration of about 4% (weight / volume, 40 g / L); and (g) poloxamer 188 at a concentration of about 0.001% (weight / volume, 0.01 g / L); or ii.(a) a vector genome concentration (VGC) at a concentration of about 1.0 χ 1011 GC / mL; (b) potassium chloride at a concentration of about 0.2 g / L; (c) monobasic potassium phosphate at a concentration of about 0.2 g / L; (d) sodium chloride at a concentration of about 5.84 g / L; (e) anhydrous dibasic disodium phosphate at a concentration of about 1.15 g / L; (f) sucrose at a concentration of about 4% (weight / volume, 40 g / L); and (g) poloxamer 188 at a concentration of about 0.001% (weight / volume, 0.01 g / L). Petition 870260012693, dated 09 / 02 / 2026, p. 418 / 420 7 / 7.

28. A single unit dosage form characterized by comprising the pharmaceutical composition of any one of claims 1 to 19 in a container.

29. A pre-filled syringe characterized by containing the single unit dosage form of any one of claims 26 to 28.

30. Kit characterized in that it comprises: (i) one or more containers and instructions for use, wherein the container(s) comprise the pharmaceutical composition of any of claims 1-19; (ii) one or more containers and instructions for use, wherein the container(s) comprise the stable liquid form of any of claims 21-25; (iii) one or more containers and instructions for use, wherein the container(s) comprise the single unit dosage form of any of claims 26-28; or (iv) the pre-filled syringe of claim 29 and instructions for use; and optionally, wherein at least one of the container(s) is / are (a) a hydrophobically coated glass vial; (b) a Daikyo Crystal Zenith® (CZ) vial; (c) a TopLyo-coated vial; or (d) a vial produced from Cyclo Olefin Polymer (COP).

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