United States Patent 5,264,423: Claim Scope, Expiration, and Antisense Patent Landscape

U.S. Patent No. 5,264,423 covers antisense oligonucleotides directed to foreign nucleic acids, with primary emphasis on HIV genes and the c-myc oncogene. Its claims encompass individual oligonucleotide compounds, pharmaceutical compositions, and administration methods. The patent issued on November 23, 1993, and its enforceable term has expired under the applicable 20-year patent-term framework. It therefore creates no current U.S. exclusionary barrier, although its claim architecture remains relevant to prior-art, freedom-to-operate, and validity analyses.[1][2]

What does U.S. Patent 5,264,423 cover?

The patent covers complementary oligonucleotides designed to bind a target nucleic-acid sequence and inhibit replication or cytopathic effects. The principal claimed variables are:

Claim variable	Scope
Oligonucleotide length, n	2 to 30 nucleoside units in independent formula claims
Preferred length	14 to 30 nucleoside units
Backbone/linkage options	Methyl, ethoxy, sulfur, and oxygen-containing linkages
Minimum sulfur content	At least one sulfur linkage in claims 1-42
High-sulfur embodiment	Greater than 95% sulfur linkages
Base B	Adenine, cytosine, guanine, or thymine
Target	A complementary segment of foreign nucleic acid
Viral targets	HIV gag, tat-III, art/trs, and reverse-transcriptase sequences
Oncogene target	c-myc
Claim categories	Compound, composition, and treatment method
Alternative backbone category	Mixed-linkage phosphorothioate oligonucleotides

The patent does not claim a single named drug. It claims a platform class of antisense molecules defined by sequence complementarity, oligonucleotide length, backbone chemistry, and intended biological effect.

What technical platform is claimed?

The claims are directed principally to short antisense oligonucleotides containing phosphorothioate linkages. Sulfur substitution in the phosphate backbone was intended to improve resistance to nuclease degradation relative to unmodified phosphodiester oligonucleotides.

Claims 1-42 use a structural formula that varies the linkage atoms or groups through the variable X. The disclosed alternatives include methyl, ethoxy, sulfur, and oxygen. At least one X must be sulfur. Claims 11, 22, 29, 32, 35, 38, and 42 narrow the scope to molecules in which more than 95% of the X groups are sulfur.

Claims 43-48 separately address mixed-linkage oligonucleotides. These claims allow alternating nucleoside and linkage units in which the linkages may include phosphorothioate, methylphosphonate, phosphorotriester, or phosphodiester groups.

How are the 48 claims organized?

The claims divide into four functional groups.

Claims 1-11: antisense compounds

Claims 1-11 cover the compound itself. Claim 1 is the broad independent compound claim. It requires:

An oligonucleotide-type structure;
A length of 2-30 units;
At least one sulfur-containing X group;
Standard nucleobases;
Complementarity to a portion of foreign nucleic acid; and
Capability to inhibit replication or cytopathic effects.

Claim 2 narrows length to 14-30 units. Claims 3-10 specify HIV or c-myc targets. Claim 11 requires more than 95% sulfur linkages.

The HIV target limitations are important because they identify specific genomic regions rather than merely claiming antiviral antisense activity. The listed targets are gag, tat-III, art/trs, and reverse transcriptase.

Claims 12-22: pharmaceutical compositions

Claims 12-22 cover a pharmaceutically acceptable carrier containing an effective amount of a claimed oligonucleotide.

The composition claims add a formulation element but do not require a particular dosage form, excipient, route, concentration, particle size, salt, or delivery vehicle. The claims therefore reach conventional pharmaceutical formulations containing a qualifying oligonucleotide, subject to the underlying structural and functional limitations.

Claim 21 contains an apparent dependency problem. It depends on claim 19 but identifies c-myc, while claim 19 is directed to the HIV art/trs branch. A claim-dependency defect of this type can affect interpretation and may have been treated as a drafting or prosecution issue. It does not expand the scope beyond the properly dependent claim structure.

Claims 23-42: treatment methods

Claims 23-42 cover administering the oligonucleotide to a host in an effective amount.

The independent method claim requires:

A host;
Administration of the claimed oligonucleotide;
A complementary foreign-nucleic-acid target; and
Inhibition of replication or cytopathic effect.

The dependent claims specify HIV genes and c-myc. Claims 28, 31, 34, 37, and 41 add a blood concentration of 0.1 to 100 micromoles per liter. The supplied text uses “micromoles/cl,” which appears to be a transcription or formatting error for micromoles per liter.

Claims 29, 32, 35, 38, and 42 impose the more-than-95%-sulfur limitation.

Claims 43-48: mixed-linkage phosphorothioates

Claims 43, 45, and 47 are independent claims covering compounds, compositions, and methods involving a mixed-linkage oligonucleotide phosphorothioate.

Claim 43 is materially broader in some respects than claim 1 because it does not state a numerical chain length, a specific nucleobase set, a named HIV target, or the X-variable formula. It requires a mixed-linkage phosphorothioate with a complementary base sequence and the claimed inhibitory capability.

Claims 44, 46, and 48 narrow the mixed-linkage category by listing phosphorothioate, methylphosphonate, phosphorotriester, and phosphodiester linkages.

What is the likely claim construction?

The central claim-construction issues are complementarity, functional capability, linkage identity, and target disclosure.

Complementary base sequence

The molecule must have a sequence complementary to a portion of the foreign nucleic acid. This limitation distinguishes the patent from generic oligonucleotide formulations and from non-sequence-specific antiviral compounds.

A product would need to be assessed against the relevant target sequence, including:

The exact antisense sequence;
The orientation of the oligonucleotide;
Permitted mismatches;
Whether the claim requires complete Watson-Crick complementarity; and
Whether a target sequence is actually present in the accused viral or oncogenic nucleic acid.

“Capable of inhibiting” language

The claims use functional language requiring capability to inhibit replication or cytopathic effect. This language may permit a patentee to rely on biological activity rather than a narrow sequence-only definition. It also creates potential validity and infringement disputes concerning:

The threshold for inhibition;
The required assay;
Whether activity must be demonstrated in vitro, in cells, or in an animal;
Whether any complementary sequence with theoretical activity satisfies the limitation; and
Whether the claimed result is inherent in the structure.

The broader the sequence and chemistry interpretation, the greater the potential enablement and written-description pressure under 35 U.S.C. §112.

Sulfur-linkage limitations

Claims 1-42 require at least one sulfur-containing linkage. The claims do not require every linkage to be phosphorothioate unless the relevant dependent claim imposes the greater-than-95% sulfur limitation.

A fully phosphorothioate oligonucleotide would fall within the high-sulfur embodiments if the remaining structural limitations are satisfied. A mixed phosphorothioate/phosphodiester molecule may fall within the broader claims but not necessarily the greater-than-95%-sulfur claims.

When did U.S. Patent 5,264,423 expire?

Event	Date
Earliest priority date reported for the patent family	November 1989
U.S. application filing	1991
Patent issue date	November 23, 1993
Pre-1995 U.S. patent-term rule	17 years from issue
Post-1995 term framework	20 years from earliest effective nonprovisional filing
Expected U.S. expiration under the 20-year framework	2011
Current enforceability	Expired

The patent issued before the Uruguay Round Agreements Act changed U.S. patent term rules. For patents filed on or after June 8, 1995, the standard term is generally 20 years from the earliest effective nonprovisional filing date. Earlier patents commonly received the longer of the 17-year-from-issue term or the 20-year-from-filing term, subject to terminal disclaimers, disclaimers, patent-term adjustment, and patent-term extension.[2][3]

U.S. Patent 5,264,423 is therefore a historical patent, not a live blocking patent. No current Paragraph IV challenge is required to clear this patent because an expired patent cannot support a present U.S. infringement injunction or an Orange Book-based generic certification obligation.

What is the Orange Book status of U.S. Patent 5,264,423?

U.S. Patent 5,264,423 is not a current Orange Book barrier for an approved HIV or oncology product.

The patent claims an antisense platform and specific target classes. The record does not establish that an FDA-approved product was approved with this patent listed as a drug-substance, drug-product, or method-of-use patent. The patent also predates the modern commercial development of most approved antisense medicines.

Orange Book relevance would require all of the following:

An FDA-approved drug associated with the claimed active ingredient;
A patent submitted by the NDA holder or authorized agent;
A patent that meets FDA listing rules; and
An unexpired listed patent or regulatory exclusivity period.

The patent does not itself confer FDA approval, clinical efficacy, or marketing exclusivity. FDA approval and patent rights are separate legal systems.[4]

Which companies challenged or licensed this patent?

No current U.S. litigation or Paragraph IV activity is associated with the expired patent. The principal commercial antisense companies that later developed products, including Ionis Pharmaceuticals and licensees, operated in a landscape containing many later patents covering sequence selection, backbone chemistry, conjugation, delivery, and manufacturing.

Publicly available patent records establish the patent’s inventorship, ownership history, prosecution, and expiration, but the patent record alone does not establish a continuing commercial license agreement. A historical assignment or exclusive license should not be treated as evidence that a license remains commercially active after expiration.

The commercially important distinction is between:

Rights under U.S. Patent 5,264,423, which have expired;
Later platform patents covering phosphorothioate chemistry;
Sequence-specific patents;
Conjugate and delivery patents;
Manufacturing-process patents; and
Foreign counterparts with separate legal terms.

How does this patent compare with later antisense patent estates?

Issue	U.S. Patent 5,264,423	Later antisense portfolios
Core technology	Short complementary oligonucleotides	Chemically optimized, sequence-specific oligonucleotides
Backbone	Phosphorothioate and mixed linkages	Phosphorothioate, phosphorodiamidate morpholino, 2'-MOE, LNA, constrained analogues
Targeting	HIV genes and c-myc examples	Disease-specific RNA targets
Delivery	No detailed modern conjugate platform in the claims	GalNAc, lipid, peptide, antibody, and nanoparticle delivery
Formulation	Pharmaceutically acceptable carrier	Sterile injectable products, buffers, stabilizers, depot systems
Manufacturing	No dominant process claim in the listed claims	Solid-phase synthesis, purification, impurity control, scale-up
Current legal value	Prior art and historical platform disclosure	Potentially active blocking and licensing rights

Approved antisense products illustrate the shift in patent value from broad early platform claims toward narrowly defined chemical and clinical products.

Product	Active technology	Primary commercial developer
Fomivirsen	Phosphorothioate antisense oligonucleotide	Ionis and partner development
Mipomersen	2'-MOE phosphorothioate antisense	Ionis/Sanofi
Nusinersen	2'-MOE phosphorothioate antisense	Ionis/Biogen
Inotersen	2'-MOE phosphorothioate antisense	Ionis/Akcea
Eteplirsen	Phosphorodiamidate morpholino oligomer	Sarepta
Golodirsen	Phosphorodiamidate morpholino oligomer	Sarepta
Viltolarsen	Phosphorodiamidate morpholino oligomer	NS Pharma
Tofersen	2'-MOE antisense oligonucleotide	Ionis/Biogen

These products do not automatically practice every limitation of Patent 5,264,423. Their relevant patent exposure depends on exact sequence, backbone, sugar chemistry, formulation, indication, manufacturing process, and jurisdiction.

What patent risks remain for an antisense product?

The expired patent does not remove later-stage patent risk. A product targeting HIV, c-myc, or another nucleic acid may still face rights in several categories.

Formulation patents

Potentially relevant claims include sterile injectable compositions, pH-controlled solutions, surfactants, stabilizers, lyophilized forms, and concentration ranges. These claims may be listed in the Orange Book for approved small-molecule or oligonucleotide products if they satisfy FDA requirements.

Method-of-use patents

Later patents may claim treatment of a named disease, patient subgroup, biomarker-defined population, dosing interval, loading regimen, or combination therapy. Such patents can remain enforceable after the foundational composition patent expires.

Sequence-specific patents

A later patent may claim a particular antisense sequence, a defined set of sequences, a target region, or a sequence modified with specified chemistry. Sequence-specific rights generally present more direct product risk than the broad functional target language in Patent 5,264,423.

Manufacturing and purification patents

Commercial oligonucleotide production may implicate patents on:

Solid-phase synthesis;
Sulfurization reagents;
Stereochemical control;
Deprotection;
Conjugation;
Chromatographic purification;
Reduction of truncated sequences; and
Analytical release testing.

These rights can create licensing or supply-chain constraints even when the composition patent is expired.

Biosimilar risk

Traditional biosimilar analysis does not apply directly to most antisense oligonucleotides because they are chemically synthesized products rather than biologics licensed under the Public Health Service Act. A follow-on product may proceed through an abbreviated or full NDA pathway depending on its regulatory classification. The principal competitor is generally a generic or follow-on oligonucleotide, not a biosimilar.

What generic launch scenarios exist?

Because Patent 5,264,423 has expired, a generic or follow-on developer does not need to wait for this patent. The commercial launch analysis would instead turn on:

Whether an FDA-approved reference product exists;
Whether the proposed product has the same sequence and chemical structure;
Whether later patents remain unexpired;
Whether the reference product has listed formulation or method patents;
Whether clinical bridging or comparative pharmacology is required;
Whether the product qualifies for an abbreviated NDA; and
Whether manufacturing capacity can meet pharmaceutical-grade purity requirements.

For a new HIV antisense product, the central barriers would likely be clinical development, target validation, delivery, safety, and manufacturing economics rather than Patent 5,264,423.

How strong is the patent estate for U.S. Patent 5,264,423?

As an expired patent, its present enforcement strength is zero. Its historical claim breadth was substantial but exposed to several weaknesses:

Broad functional language;
Multiple structural alternatives in X;
A wide chain-length range;
Generic “foreign nucleic acid” language;
Limited target-specific restrictions in independent claims;
Potential enablement concerns across all claimed sequences and chemistries;
Apparent claim-dependency irregularity in claim 21; and
A mixed-linkage genus extending across several backbone types.

Its residual business value lies in prior-art analysis, freedom-to-operate history, patent landscaping, and understanding the origin of antisense phosphorothioate claims. It does not provide current U.S. exclusivity over HIV antisense therapy, c-myc targeting, or phosphorothioate oligonucleotides generally.

Key Takeaways

U.S. Patent 5,264,423 claims antisense oligonucleotide compounds, compositions, and administration methods.
Claims 1-42 focus on oligonucleotides containing at least one sulfur linkage, with preferred 14-30-unit chains and high-sulfur embodiments.
Claims 3-10 and 14-21 identify HIV gag, tat-III, art/trs, reverse transcriptase, and c-myc targets.
Claims 43-48 cover mixed-linkage phosphorothioate oligonucleotides.
The patent expired under the applicable U.S. patent-term rules, with the effective term ending around 2011.
It is not a current Orange Book or Paragraph IV barrier.
Later sequence, chemistry, formulation, delivery, manufacturing, and method-of-use patents remain the relevant commercial risks.
Antisense products are generally analyzed as generic or follow-on products rather than biosimilars.
The patent’s current value is historical and analytical, not exclusionary.

FAQs

Does U.S. Patent 5,264,423 cover all phosphorothioate oligonucleotides?

No. The claims require additional limitations, including complementary sequence, specified structural features, chain length in the formula claims, and an inhibitory capability. Later phosphorothioate oligonucleotides may also be subject to separate patents.

Does the patent cover antisense treatment of HIV?

Historically, yes. The claims specifically identify HIV gag, tat-III, art/trs, and reverse-transcriptase nucleic acids. The patent no longer blocks such treatment in the United States because it has expired.

Is a license needed to practice the patent in the United States?

No license is required under an expired U.S. patent. Separate licenses may still be required for later patents covering the same product’s sequence, chemistry, delivery system, formulation, indication, or manufacturing process.

Are the HIV target claims limited to a particular oligonucleotide sequence?

The supplied claims do not recite a fixed nucleotide sequence. They require a complementary base sequence to a portion of the identified HIV gene or nucleic acid. The specification and prosecution history would control the interpretation of particular target regions.

Could a modern antisense drug infringe the patent’s former claims?

A product launched during the patent term could have raised infringement issues if it satisfied the structural, sequence, and functional limitations. A product launched today cannot infringe an expired U.S. patent, although its technical design may still overlap with the patent as prior art.

References

United States Patent and Trademark Office. (1993). U.S. Patent No. 5,264,423, Oligonucleotides for inhibiting gene expression.
United States Code, 35 U.S.C. §§ 154, 156.
United States Patent and Trademark Office. (2024). Patent term adjustment and patent term expiration guidance.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	116857	⤷ Start Trial
Australia	1571788	⤷ Start Trial
Australia	619180	⤷ Start Trial
Canada	1322723	⤷ Start Trial
Germany	3852714	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,264,423

Summary for Patent: 5,264,423