Details for Patent: 6,426,335

Summary for Patent: 6,426,335

Title:	Vascular endothelial growth factor (VEGF) nucleic acid ligand complexes
Abstract:	This invention discloses a method for preparing a complex comprised of a VEGF Nucleic Acid Ligand and a Non-Immunogenic, High Molecular Weight Compound or Lipophilic Compound by identifying a VEGF Nucleic Acid Ligand by SELEX methodology and associating the VEGF Nucleic Acid Ligand with a Non-Immunogenic, High Molecular Weight Compound or Lipophilic Compound. The invention further discloses Complexes comprising one or more VEGF Nucleic Acid Ligands in association with a Non-Immunogenic, High Molecular Weight Compound or Lipophilic Compound. The invention further includes a Lipid construct comprising a VEGF Nucleic Acid Ligand or Complex and methods for making the same.
Inventor(s):	Nebojsa Janjic, Larry Gold, Paul Schmidt, Chandra Vargeese, Michael Willis
Assignee:	Gilead Sciences Inc
Application Number:	US09/254,968
Patent Claim Types: see list of patent claims	Use;

United States Patent 6,426,335: Scope, Claims, Expiration, and VEGF Aptamer Patent Landscape

US 6,426,335 covers therapeutic and ocular use of a VEGF-binding nucleic acid ligand, particularly a 2'-fluoropyrimidine-modified aptamer conjugated to polyethylene glycol, a lipid, or another pharmacokinetic-enhancing compound. The patent is associated with the pegaptanib, or Macugen, technology platform. Its statutory patent term has expired, so the patent no longer creates a current U.S. exclusionary barrier. Its principal commercial importance is historical: it protected PEGylated VEGF aptamer products and supported development of an anti-VEGF ocular therapy before the market shifted toward antibody and fusion-protein products.

What does US Patent 6,426,335 protect?

The patent protects methods of administering a conjugated VEGF nucleic acid ligand. It does not principally claim a standalone aptamer composition. The asserted inventive combination is:

1. A VEGF-binding nucleic acid ligand;
2. 2'-fluoro-modified nucleotides;
3. Covalent attachment to PEG, another high-molecular-weight non-immunogenic compound, or a lipophilic compound; and
4. Administration for treatment, targeting, pharmacokinetic improvement, angiogenesis inhibition, tumor inhibition, macular-degeneration treatment, or ocular residence-time extension.

The central product concept is a PEGylated anti-VEGF aptamer. The disclosed ligand sequence corresponds to the VEGF aptamer used in the pegaptanib program.

Claim group	Claims	Principal subject matter
VEGF disease treatment	1-9	Administration of a VEGF aptamer conjugated to PEG or a lipid
PEG molecular-weight limitations	2-6	PEG, including approximately 10-80 kDa and 20-45 kDa ranges
Pharmacokinetics	10	Improving nucleic-acid-ligand pharmacokinetic properties
Targeting	11	Targeting an agent to VEGF-expressing biological sites
Angiogenesis and tumors	12-16	Inhibition of VEGF-mediated angiogenesis and tumor growth
Macular degeneration	17-22	Treatment with a PEGylated VEGF ligand
Ocular residence time	23	Prolonging ocular residence of a nucleic acid ligand

The claims are method claims. A party would generally need to practice the claimed administration method to create direct infringement exposure. Making or selling an unclaimed VEGF aptamer conjugate would not, by itself, necessarily infringe these claims, although other patents could cover the composition, sequence, manufacturing process, formulation, or use.

How should the independent claims be construed?

Claim 1: VEGF-mediated disease treatment

Claim 1 requires administration of a complex containing:

• A VEGF nucleic acid ligand;
• 2'-fluorinated nucleotides; and
• A non-immunogenic high-molecular-weight compound or a lipophilic compound.

The disease list is closed by the phrase "selected from the group consisting of." The listed conditions are cancer, psoriasis, ocular disorders involving excessive angiogenesis, collagen vascular diseases, and rheumatoid arthritis.

The claim does not require a specific PEG molecular weight or the exact sequence recited in dependent claim 6. It is therefore broader than the sequence-specific and PEG-range limitations that follow. Its breadth is limited by several structural requirements, particularly the 2'-F modification and covalent complex formation.

Claim 10: Pharmacokinetic improvement

Claim 10 covers covalent linking followed by administration where pharmacokinetic properties are improved. The claim is functionally drafted. The relevant improvement could include longer circulation, reduced clearance, greater stability, improved exposure, or longer residence time.

The claim does not specify a disease. It could reach administration for therapeutic or potentially non-therapeutic development purposes if the accused conduct satisfies the method elements. Its enforceability would depend on proving that the conjugate improves pharmacokinetic properties and that the accused product has the claimed structural features.

Claim 11: VEGF-based targeting

Claim 11 covers covalently linking a therapeutic or diagnostic agent with a VEGF-ligand complex and administering it to target a VEGF-expressing biological site.

This claim is potentially broad because it is not limited to cancer, ophthalmology, or a particular payload. It is also structurally complex. The claim requires a therapeutic or diagnostic agent to be linked with a complex that already contains a VEGF ligand and PEG or lipid. The specification and prosecution history would be important in determining whether "with" requires direct covalent attachment, an intermediate linker, or attachment to the aptamer component.

Claims 12-16: Angiogenesis and tumor inhibition

These claims focus on inhibiting angiogenesis and tumor growth. Claims 14 and 15 add VEGF or VEGF-receptor expression by tumors or surrounding tissues. Claim 16 narrows the tumor to Kaposi's sarcoma.

The claims do not require a particular route of administration, dose, treatment schedule, or tumor type unless expressly recited. They are method-of-use claims, not claims to all VEGF aptamers or all anti-VEGF therapies.

Claims 17-22: Macular degeneration

Claims 17-22 are the most commercially relevant claims for pegaptanib. They require:

• A 2'-F-modified VEGF nucleic acid ligand;
• Covalent attachment to PEG or a lipophilic compound;
• Administration to inhibit macular degeneration.

Claims 18-22 narrow the conjugate to PEG and then to defined molecular-weight ranges. Claims 20 and 21 recite approximately 10-80 kDa and 20-45 kDa PEG, respectively. Claim 22 adds the identified VEGF ligand sequence.

These claims would have been directed toward a product such as pegaptanib sodium, which is a PEGylated aptamer administered by intravitreal injection for neovascular age-related macular degeneration.

Claim 23: Ocular residence time

Claim 23 is broader in two respects. It refers to a "Nucleic Acid Ligand" without expressly requiring a VEGF ligand or 2'-F modification, and it focuses on prolonging residence time in an ocular application.

The claim still requires attaching a non-immunogenic high-molecular-weight compound and administering the complex to the eye. A product using a different aptamer target could potentially fall within the literal language if the other limitations are met. The scope would be constrained by the patent's written description, enablement, prosecution history, and any applicable claim-construction principles.

What exact molecule is recited in claims 6, 9, and 22?

Claims 6, 9, and 22 recite the ligand component:

fCmGmGrArAfUfCmAmGfUmGmAmAfUmGfCfUfUmAfUmAfCmAfUfCfCmG-3'3'-dT

The notation identifies chemically modified nucleotides. The lower-case or prefix notation distinguishes modified residues, including 2'-fluoro substitutions. The terminal 3'-3'-dT identifies the inverted thymidine-type end modification used in the aptamer design.

The sequence limitation is materially narrower than the broader VEGF-ligand language in claim 1. A competing product using a different VEGF-binding sequence may avoid claims 6, 9, and 22 while still requiring analysis under the broader claims.

What PEG and lipid formulations are protected?

The patent covers PEGylation and lipid association as pharmacokinetic or residence-time strategies.

PEGylated complexes

Claims 2-6 and 18-22 cover polyalkylene glycol, particularly polyethylene glycol. The specified ranges are:

Claim limitation	PEG range
Claims 4 and 20	Approximately 10-80 kDa
Claims 5, 6, 21 and 22	Approximately 20-45 kDa

The term "about" creates some numerical flexibility, but the scope would depend on intrinsic evidence, prosecution statements, and the ordinary meaning of the range in the relevant technical field. A PEG conjugate outside these ranges could still fall within broader claims 1, 2, 3, 10, 17, or 18 if the remaining limitations are satisfied.

Lipophilic compounds and lipid constructs

Claims 7-9 cover glycerol lipids and complexes further associated with lipid constructs. These claims create a separate path to coverage that does not depend on PEG. The patent therefore addresses two broad pharmacokinetic approaches:

• Hydrodynamic-size and clearance modification through PEG;
• Membrane or lipid association through a lipophilic compound or lipid construct.

A lipid nanoparticle, liposome, or other delivery system would require a separate element-by-element analysis. The claims do not automatically cover every formulation containing a lipid. The accused structure would need to satisfy the covalent-linking and complex requirements.

When did US 6,426,335 expire?

US 6,426,335 was issued on July 30, 2002. Its term was governed by the Uruguay Round Agreements Act, generally providing 20 years from the earliest effective nonprovisional filing date for the relevant application, subject to patent-term adjustment, terminal disclaimers, and any applicable regulatory extension.

Public patent records identify an effective priority framework reaching back to the late 1990s. The patent's ordinary term therefore ended in approximately 2018, rather than in 2022 based solely on the issue date. Current public patent-status records classify the patent as expired. The patent cannot presently support a new U.S. infringement action based on future conduct. See USPTO Patent Center; Google Patents, US6426335B1.

Event	Date or period
Earliest relevant priority period	1997-1998
U.S. grant	July 30, 2002
Expected ordinary term endpoint	Approximately 2017-2018
Current status	Expired
Current blocking value	None as an enforceable U.S. patent right

Patent expiration does not erase historical damages exposure for conduct occurring before expiration. It also does not eliminate live rights in related continuation, divisional, foreign, or later-filed patents.

What is the Orange Book status of US 6,426,335?

US 6,426,335 is associated with the pegaptanib technology, but an Orange Book listing is not the same as current patent enforceability. The FDA Orange Book identifies patents submitted by an NDA holder for an approved drug. A listed patent can remain visible in historical or current records after its enforceable term has ended.

For Macugen, the relevant regulatory product is pegaptanib sodium, an intravitreal anti-VEGF aptamer approved by the FDA in 2004 for neovascular age-related macular degeneration (FDA, 2004). The product's commercial protection also involved separate aptamer-composition, use, and formulation patents. The patent estate cannot be evaluated by looking at US 6,426,335 alone.

No current U.S. market-exclusion right should be attributed to US 6,426,335 because the patent has expired. A generic applicant would still need to address any other unexpired listed patent, regulatory exclusivity, product-specific requirements, and FDA requirements applicable to a complex oligonucleotide injection.

Did US 6,426,335 have Paragraph IV significance?

A Paragraph IV certification would have been relevant only while an unexpired patent was listed in the Orange Book for the reference product and while an abbreviated application was seeking approval for the relevant drug.

For US 6,426,335:

• A historical Paragraph IV challenge could have concerned pegaptanib or a related product.
• A new Paragraph IV challenge cannot create a current patent dispute against an expired patent.
• The patent's expiration removes the principal legal basis for an automatic 30-month stay under Hatch-Waxman.
• Any current ANDA strategy would focus on other listed patents, if any, and on FDA's standards for the product.

The patent claims methods of treatment rather than a simple composition claim. That distinction matters. An ANDA applicant may certify that it will not market for a patented indication, or may rely on a section viii statement for a use claim, depending on the Orange Book listing and the proposed labeling. The practical effect would depend on how the relevant claims were listed and how the proposed label was drafted.

Are biosimilar risks relevant to this patent?

Biosimilar analysis is generally not the correct framework for pegaptanib. Pegaptanib is a chemically synthesized oligonucleotide aptamer, not a protein biologic manufactured through a biological expression system.

The more relevant pathways are:

• An ANDA under section 505(j), if FDA determines that the proposed product can meet generic-drug requirements;
• A 505(b)(2) application, if the applicant relies on some existing data but differs in formulation, route, dosing, or other material respects;
• A full NDA if the product cannot rely on an abbreviated pathway.

The Purple Book and the section 351(k) biosimilar pathway are primarily relevant to biologic products such as ranibizumab, aflibercept, faricimab, and other protein-based anti-VEGF therapies. They do not determine the status of a PEGylated aptamer under US 6,426,335.

How does this patent compare with other anti-VEGF patent estates?

US 6,426,335 covers a nucleic-acid ligand platform. Competing anti-VEGF products use different molecular classes and therefore face different patent risks.

Product	Active modality	Representative sponsor	Primary patent-risk category
Macugen	PEGylated VEGF aptamer, pegaptanib	Eyetech/Pfizer	Aptamer sequence, PEG conjugation, ocular use, formulation
Lucentis	Anti-VEGF antibody fragment, ranibizumab	Genentech/Novartis	Antibody sequence, formulation, dosing, ophthalmic use
Eylea	VEGF receptor fusion protein, aflibercept	Regeneron/Bayer	Protein sequence, formulation, manufacturing, dosing
Beovu	Anti-VEGF antibody fragment, brolucizumab	Novartis	Antibody sequence, formulation, dosing, use
Vabysmo	Bispecific antibody, faricimab	Genentech/Roche	Bispecific structure, formulation, dosing, use

A biosimilar or interchangeable product targeting Eylea, Lucentis, or another biologic does not ordinarily practice the aptamer-specific claims of US 6,426,335. Conversely, a generic or follow-on pegaptanib product would need to evaluate the aptamer sequence and conjugation estate rather than relying only on the absence of biologic patent claims.

How strong was the patent estate?

The expired patent had meaningful historical strength against products using the same technical architecture, but its strength varied by claim.

Stronger claim characteristics

• Claims 6, 9, and 22 identify a specific ligand sequence.
• Claims 5, 6, 21, and 22 identify a narrower PEG range.
• Claims 17-22 focus on the commercially relevant ocular use.
• The claims connect a known VEGF aptamer to a defined pharmacokinetic modification.

These limitations improve infringement clarity when a product uses the same ligand and PEG architecture.

Weaker or more contestable characteristics

• "Non-immunogenic, high molecular weight compound" is broad.
• "Lipophilic compound" and "lipid construct" may require factual analysis of the accused structure.
• Claim 10 relies on the functional concept of improved pharmacokinetics.
• Claim 11 uses broad targeting language.
• Claim 23 omits express VEGF and 2'-F limitations but may face written-description and enablement arguments depending on its prosecution record.
• The patent does not claim every VEGF inhibitor or every anti-angiogenic ocular therapy.

The estate's practical value was highest when combined with related patents covering the aptamer itself, PEGylated composition, manufacturing, and pegaptanib's ocular indication.

What manufacturing and formulation barriers remain after expiration?

Patent expiration does not eliminate technical barriers. A follow-on manufacturer would still need to control:

• Aptamer sequence fidelity;
• 2'-F nucleotide substitution patterns;
• Stereochemistry and impurity profile;
• PEG molecular-weight distribution;
• Site-specific conjugation;
• Free aptamer and free PEG levels;
• Aggregation and particulate matter;
• Sterility and endotoxin control;
• Ocular tolerability;
• Stability during storage;
• Intravitreal syringe or vial presentation;
• Comparability of pharmacokinetic and pharmacodynamic behavior.

For an ophthalmic oligonucleotide, FDA review may focus on more than chemical identity. The applicant would need to establish consistent product quality and a clinically acceptable ocular safety profile. These factors can delay entry even when patent barriers have expired.

What litigation and settlement risks exist?

US 6,426,335 no longer supports prospective infringement litigation. Historical disputes could still matter for:

• Pre-expiration sales;
• Royalty accounting;
• License compliance;
• Settlement releases;
• Ownership or inventorship issues;
• Related patents with later expiration dates.

The commercial pegaptanib program involved collaboration and licensing relationships among the aptamer developers, Eyetech, and Pfizer. Pfizer and Eyetech entered a development and commercialization alliance for Macugen, while later corporate transactions affected control of the technology and commercial rights (Pfizer, 2002; OSI Pharmaceuticals, 2005).

No settlement involving US 6,426,335 should be inferred solely from the patent's association with Macugen. Any freedom-to-operate opinion requires review of the complete family, continuation history, Orange Book records, assignment records, and litigation docket.

What is the commercial exposure associated with this patent?

The principal historical product exposure was Macugen. The FDA approved pegaptanib in December 2004 for neovascular age-related macular degeneration, with intravitreal administration at six-week intervals (FDA, 2004).

Macugen's commercial position weakened as ranibizumab and aflibercept gained adoption. Those products offered broader VEGF inhibition and became dominant therapies for retinal vascular disease. The result was a sharp reduction in the practical value of the pegaptanib patent estate even before every patent in the family expired.

Commercial factor	Effect on US 6,426,335
FDA approval of Macugen	Created the main product opportunity
PEGylated aptamer architecture	Supported differentiated ocular exposure
Six-week dosing	Commercially relevant but less competitive than later regimens
Ranibizumab and aflibercept adoption	Reduced market share and royalty potential
Patent expiration	Removed U.S. exclusionary leverage
Manufacturing complexity	Continues to raise entry costs
Lack of biosimilar classification	Shifts analysis toward ANDA or 505(b)(2) pathways

Key Takeaways

• US 6,426,335 covers methods using a 2'-F-modified VEGF aptamer conjugated to PEG, lipids, or other pharmacokinetic-enhancing compounds.
• Claims 17-22 are the most directly connected to pegaptanib's ophthalmic use.
• Claims 6, 9, and 22 narrow protection to the disclosed VEGF ligand sequence.
• Claim 23 is broader because it addresses ocular residence time for a nucleic acid ligand without expressly requiring a VEGF target.
• The patent expired approximately 20 years after its late-1990s effective filing framework, and it is no longer a current U.S. blocking right.
• Paragraph IV analysis is historical for this patent. Current entry analysis must focus on any related unexpired patents and FDA requirements.
• Biosimilar law is generally not the relevant pathway because pegaptanib is a chemically synthesized aptamer.
• The remaining business barriers are product characterization, PEG conjugation control, ocular manufacturing, sterility, and clinical comparability.
• The patent's strongest historical position was against products using the same VEGF aptamer sequence and PEGylation architecture.
• Competitor anti-VEGF biologics generally do not practice these aptamer-specific claims.

FAQs About US Patent 6,426,335

Is US 6,426,335 still enforceable?

No. Public patent-status records classify the patent as expired, and its ordinary U.S. term ended approximately in 2017-2018.

Does US 6,426,335 cover aflibercept or ranibizumab?

No. Aflibercept is a VEGF receptor fusion protein and ranibizumab is an antibody fragment. The patent is directed to nucleic acid ligands, particularly VEGF aptamers with PEG or lipid conjugation.

Does the patent cover unmodified VEGF aptamers?

The principal claims require a VEGF nucleic acid ligand comprising 2'-F-modified nucleotides. The broader wording of claim 23 should be analyzed separately, but it still requires attachment of a non-immunogenic high-molecular-weight compound and ocular administration.

Can a company launch a pegaptanib generic without reviewing this patent?

Yes, the expired patent itself is no longer a blocking right. A launch review must still address related patents, Orange Book records, FDA product requirements, formulation differences, and potential regulatory exclusivity.

What is the most important claim for an ocular competitor?

Claims 17-22 are the principal ocular claims for a PEGylated VEGF aptamer. Claim 23 is also important because it covers prolonged ocular residence of a conjugated nucleic acid ligand and is not expressly limited to VEGF.

References

1. Food and Drug Administration. (2004). Macugen (pegaptanib sodium) injection: Prescribing information. U.S. Department of Health and Human Services.

2. Google Patents. (n.d.). US6426335B1: Methods for improving the pharmacokinetic properties of nucleic acid ligands. Retrieved 2025, from https://patents.google.com/

3. Pfizer Inc. (2002). Pfizer and Eyetech announce strategic alliance for Macugen. Pfizer investor and corporate communications materials.

4. U.S. Patent and Trademark Office. (n.d.). Patent Center: US6426335. U.S. Department of Commerce. https://patentcenter.uspto.gov/

5. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book. U.S. Department of Health and Human Services. https://www.accessdata.fda.gov/scripts/cder/ob/

6. OSI Pharmaceuticals, Inc. (2005). Annual report. U.S. Securities and Exchange Commission.

Drugs Protected by US Patent 6,426,335

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 6,426,335

PCT Information
PCT Filed	October 17, 1997	PCT Application Number:	PCT/US97/18944
PCT Publication Date:	May 07, 1998	PCT Publication Number:	WO98/18480

International Family Members for US Patent 6,426,335

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0957929		91252	Luxembourg
European Patent Office	0957929		300234	Netherlands
European Patent Office	0957929		PA2006004	Lithuania
European Patent Office	0957929		CA 2006 00021	Denmark
European Patent Office	0957929		SPC024/2006	Ireland
European Patent Office	0957929		PA2006004,C0957929	Lithuania