United States Patent 4,517,199: Scope, Claims, Expiration, and Glaucoma Patent Landscape

US Patent 4,517,199 covers topical ophthalmic treatment of elevated intraocular pressure with substituted phenylimino-imidazolines, including apraclonidine-related compounds. The patent is expired. Its original 17-year term from the May 14, 1985 grant date ended on May 14, 2002, absent an earlier terminal disclaimer or an unusual term adjustment. It no longer creates a barrier to generic apraclonidine or to development of products using the claimed compounds.

The patent’s commercial importance came primarily from claim 4, which covers 2,6-dichloro-N1-(2-imidazolidinylidene)-1,4-benzenediamine, the active moiety associated with apraclonidine. The enforceable scope during the patent term was narrower than a broad composition-of-matter patent because the claims required a specific topical method of lowering intraocular pressure.

What does US Patent 4,517,199 cover?

US 4,517,199 claims methods for reducing intraocular pressure by topically applying a substituted phenylimino-imidazoline, or a pharmaceutically acceptable salt, to the eye. The patent does not claim every alpha-adrenergic glaucoma therapy. It covers a defined chemical genus and specified ophthalmic-use conditions.

The independent claim requires:

A method for lowering intraocular pressure.
Topical application to the eye.
An effective amount of the compound or salt.
A 2-(trisubstituted phenylimino)-imidazoline within the claimed Markush definitions.
Exclusion of a specifically identified chemical structure.

Claim 2 adds a pharmaceutically acceptable vehicle. Claim 3 narrows the method to a concentration that reduces intraocular pressure without significantly affecting the central nervous system.

Claims 4 through 14 identify individual chemical embodiments. These dependent claims are narrower than claim 1 and would have been useful for targeting particular clinical candidates or commercial formulations.

What chemical class is claimed?

The claimed compounds contain an imidazoline or imidazolidine-derived imino group attached to a multiply substituted phenyl ring. The substituent definitions include:

Methyl and ethyl groups.
Trifluoromethyl groups.
Fluoro, chloro, and bromo substituents.
Amino-derived substituents.
Acetamide, carboxamide, ester, phenol, and related functional groups.
Hydroxyalkyl-substituted nitrogen groups.
Pharmaceutically acceptable salts.

The claim architecture uses Markush language. A molecule can fall within the genus if its substituents satisfy one of the alternatives identified as I, II, or III, subject to the express exclusion.

The excluded structure in part III limits the breadth of the genus. It prevents the claim from covering at least one otherwise related phenylimino-imidazoline, likely reflecting prior-art, potency, toxicity, or patentability considerations.

Which compounds are specifically covered by claims 4 through 14?

The dependent claims identify a series of individual compounds. Their coverage can be summarized as follows:

Claim	Named compound or compound class	Claim type
4	2,6-Dichloro-N1-(2-imidazolidinylidene)-1,4-benzenediamine	Specific compound
5	2,6-Dichloro-N1-(2-imidazolidinylidene)-1,3-benzenediamine	Specific compound
6	2,6-Diethyl-N1-(2-imidazolidinylidene)-1,4-benzenediamine	Specific compound
7	N-[3,5-Diethyl-4-(2-imidazolidinyleneamino)-phenyl]-acetamide	Specific compound
8	3,5-Dichloro-4-(2-imidazolidinylideneamino)-phenol and esters	Compound class
9	3-Chloro-5-methyl-4-(2-imidazolidinylideneamino)-benzoic acid ethyl ester	Specific compound
10	3-Chloro-5-ethyl-4-(2-imidazolidinylideneamino)-benzoic acid ethyl ester	Specific compound
11	N-[3-chloro-5-methyl-4-(2-imidazolidinylideneamino)-phenyl]-acetamide	Specific compound
12	2-Chloro-6-methyl-N1-(2-imidazolidinylidene)-1,4-benzenediamine	Specific compound
13	2-Chloro-6-ethyl-N1-(2-imidazolidinylidene)-1,4-benzenediamine	Specific compound
14	3-Chloro-5-methyl-4-(2-imidazolidinylideneamino)-benzenecarboxamide	Specific compound

The names in the issued claims contain typographical and nomenclature irregularities, including “2imidazolidinylidene” and “acetamidne.” Claim interpretation would ordinarily rely on the patent specification, chemical drawings, prosecution history, and the understood identity of the compounds rather than on typographical errors alone.

Does claim 4 cover apraclonidine?

Claim 4 is directed to the dichloro benzenediamine compound associated with apraclonidine. Apraclonidine is an alpha-2 adrenergic agonist used as a topical ophthalmic agent for lowering intraocular pressure. The FDA-approved product Iopidine contains apraclonidine hydrochloride ophthalmic solution, historically marketed in 0.5% and 1% strengths (U.S. Food and Drug Administration, 2015).

The patent claim is directed to the compound or its pharmaceutically acceptable salt, so the hydrochloride salt would generally be within the express salt language if the underlying free-base structure corresponds to the claimed compound.

The commercial relationship is important:

US 4,517,199 supplied early patent protection for the claimed chemical and ophthalmic use.
Iopidine was later approved as an ophthalmic product.
The patent’s term expired before the modern generic-apraclonidine market developed.
Current generic entry is therefore governed by FDA approval requirements, formulation quality, labeling, manufacturing, and any later unexpired patents, not by US 4,517,199.

The compound name should be checked against the patent drawing and the FDA active-ingredient record because positional nomenclature in the issued claim is difficult to parse from text-only reproductions.

What are the strongest claim limitations?

The principal limitations are the following.

Topical ophthalmic administration

The claim requires applying the active agent topically to the eye. Oral, injectable, intranasal, transdermal, or systemic administration would not satisfy this limitation.

A formulation used around the eye but not applied topically to the eye could also present a claim-construction issue. The ordinary commercial ophthalmic solution is the clearest case within the claim.

Intraocular-pressure reduction

The claimed method requires an intended therapeutic result: lowering intraocular pressure. A compound merely administered to the eye for another purpose would not necessarily infringe.

The limitation is functional, but it is connected to a defined therapeutic use. In a method case, evidence would likely focus on the product labeling, prescribing information, clinical data, and the defendant’s instructions.

Effective amount

The amount must be effective for lowering intraocular pressure. This limitation excludes amounts that do not produce the claimed pharmacologic effect, although infringement would not necessarily require the infringing party to conduct a new clinical trial.

Central-nervous-system limitation in claim 3

Claim 3 requires a concentration that lowers intraocular pressure without significantly affecting the central nervous system. This limitation narrows claims 4 through 14 because those claims depend on claim 3.

The phrase “without significantly affecting the central nervous system” is not a fixed numerical threshold in the claim. Its interpretation would depend on the specification, prosecution history, clinical context, and evidence concerning sedation, cardiovascular effects, systemic absorption, and other central or systemic pharmacology.

Pharmaceutically acceptable vehicle

Claim 2 requires a pharmaceutically acceptable vehicle. This is a conventional ophthalmic formulation limitation. A sterile aqueous solution would be the most direct example, but the language could encompass other ophthalmically acceptable vehicles, including suspensions or certain buffered formulations, depending on the specification.

How broad is the independent claim compared with the dependent claims?

Claim 1 is materially broader than claims 4 through 14 because it covers a genus of compounds defined by substituent alternatives. It also covers salts and does not require the specific “without significantly affecting the central nervous system” limitation found in claim 3.

The claim hierarchy is:

Claim level	Added limitation	Practical effect
Claim 1	Chemical genus plus topical IOP-lowering method	Broadest method scope
Claim 2	Pharmaceutically acceptable vehicle	Narrows administration to a formulated ophthalmic product
Claim 3	Concentration avoids significant CNS effect	Adds a pharmacologic and dosing limitation
Claims 4-14	Specific compounds or compound classes	Narrows chemical identity while retaining claims 2 and 3

A product using a compound outside the Markush definitions would not infringe claim 1 even if it had the same alpha-adrenergic mechanism and the same glaucoma indication. Conversely, a product using a listed compound could implicate the claim even if it used a different brand name or salt, subject to claim construction and the patent’s expired status.

When did US 4,517,199 lose exclusivity?

US 4,517,199 was granted on May 14, 1985. Under the pre-Uruguay Round patent-term rule applicable to a patent granted at that time, the term generally ran for 17 years from grant. On that basis, the patent expired on May 14, 2002 (U.S. Patent and Trademark Office, n.d.).

Event	Date
Patent grant	May 14, 1985
Standard pre-1995 term	17 years from grant
Projected expiration	May 14, 2002
Current status	Expired
Current enforceability	No enforceable exclusionary rights

The patent cannot currently support an injunction, damages claim, or Paragraph IV litigation against a generic applicant. Patent expiration also eliminates the need for a generic applicant to rely on a Paragraph IV certification against this patent.

What is the Orange Book status of US 4,517,199?

The Orange Book records approved drug products, patent information submitted by sponsors, and applicable exclusivity information. It does not convert an expired patent into an enforceable right.

For apraclonidine, the relevant FDA product is Iopidine, an ophthalmic solution containing apraclonidine hydrochloride. The NDA and product records provide the regulatory framework for generic applications, including the applicable abbreviated new drug application pathway (FDA, n.d.-a).

Any historical Orange Book listing for US 4,517,199 would have ceased to block approval once the patent expired. A current generic sponsor would evaluate the Orange Book’s active patent and exclusivity records, but US 4,517,199 itself is not a current patent barrier.

FDA regulatory exclusivity and patent exclusivity are separate:

Patent exclusivity arises from enforceable patent claims.
New-drug exclusivity arises under the Federal Food, Drug, and Cosmetic Act.
An expired patent does not extend FDA exclusivity.
FDA approval of a generic does not revive an expired patent.

What Paragraph IV challenges affect apraclonidine?

US 4,517,199 cannot presently support a Paragraph IV challenge because it expired in 2002. A Paragraph IV certification is relevant when an applicant states that a listed patent is invalid, unenforceable, or will not be infringed. For an expired patent, the applicant generally does not need to attack the patent to obtain approval.

The commercial issues for generic apraclonidine are more likely to involve:

Bioequivalence to the reference listed drug.
Sterility assurance.
Preservative concentration and antimicrobial effectiveness.
Container-closure compatibility.
Ophthalmic pH, osmolality, viscosity, and particulate control.
Manufacturing process validation.
Labeling and substitution requirements.

The relevant FDA pathway is an ANDA for a generic equivalent, subject to FDA’s requirements for ophthalmic products and the reference listed drug record (FDA, n.d.-b).

Are there biosimilar risks associated with this patent?

No. Apraclonidine is a chemically synthesized small molecule, not a biologic. The biosimilar pathway under section 351(k) of the Public Health Service Act is not applicable.

The relevant competitive products are generic small-molecule ophthalmic solutions. A generic applicant does not need to demonstrate biosimilarity. It must establish pharmaceutical equivalence, bioequivalence where applicable, quality, sterility, and compliance with the approved labeling framework.

What later patents could matter more than US 4,517,199?

The expired patent does not exhaust the potential patent landscape. A commercial product could still encounter later patent rights involving:

Ophthalmic formulations.
Preservative systems.
Container and delivery devices.
Stabilization methods.
Combination therapy.
New dosing regimens.
Treatment of specific glaucoma populations.
Manufacturing processes.
Crystalline forms or salt forms, if separately claimed.
Improved tolerability or reduced systemic absorption.

For apraclonidine, the largest practical risk is likely regulatory and manufacturing execution rather than a remaining composition patent based on US 4,517,199. Any current freedom-to-operate review would need to examine later US patents and applications assigned to the original sponsor, product manufacturers, formulation developers, and generic applicants.

How does apraclonidine compare with brimonidine and other glaucoma drugs?

Apraclonidine and brimonidine are alpha-adrenergic agonists used in ophthalmology, but they have different commercial and patent histories.

Product	Active ingredient	Drug type	Principal patent issue
Iopidine	Apraclonidine hydrochloride	Alpha-2 adrenergic agonist	Original compound/use patent expired
Alphagan	Brimonidine tartrate	Alpha-2 adrenergic agonist	Later composition, formulation, and method patents
Timoptic	Timolol maleate	Beta blocker	Separate compound and formulation estate
Trusopt	Dorzolamide hydrochloride	Carbonic anhydrase inhibitor	Separate composition and formulation estate
Xalatan	Latanoprost	Prostaglandin analog	Separate composition, formulation, and use estate

Brimonidine became commercially important in part because apraclonidine’s adverse-effect profile and tachyphylaxis limited chronic use. Apraclonidine was often used for short-term intraocular-pressure reduction, including perioperative or acute pressure-control settings, while brimonidine became more established for chronic therapy.

This therapeutic distinction does not change the legal scope of US 4,517,199. A brimonidine product would not ordinarily fall within the patent’s chemical claims because brimonidine is a different active compound.

What manufacturing and formulation barriers remain after patent expiration?

Patent expiration removes the principal legal exclusivity but does not eliminate technical barriers. Ophthalmic products face a higher manufacturing burden than many oral solid dosage forms.

Relevant barriers include:

Sterile manufacturing and aseptic processing.
Control of particulate contamination.
Container-closure integrity.
Preservative performance in multidose bottles.
Stability of the active ingredient in the final vehicle.
Control of pH and tonicity.
Extractables and leachables from the bottle and dropper.
Consistent delivered drop volume.
Microbial limits and sterility testing.
Equivalence of concentration, dosage form, route, and labeling.

These barriers can delay generic launches even when no enforceable patent remains. They are regulatory and technical barriers, not extensions of the patent term.

What is the current litigation and settlement position?

US 4,517,199 is expired and therefore cannot support current infringement litigation. It also cannot form the basis of a new generic settlement that delays market entry under the Hatch-Waxman framework.

Historical litigation may have involved the patent, its family members, the Iopidine product, or related alpha-adrenergic compounds. Those historical disputes would not restore enforceability after expiration. The relevant current questions are whether later patents remain active and whether any settlement contains contractual provisions independent of US 4,517,199.

No biosimilar litigation is relevant because apraclonidine is a small molecule.

What is the commercial exposure tied to this patent?

The patent’s historical commercial exposure was the apraclonidine ophthalmic market, particularly Iopidine. Its present direct revenue-protection value is zero because the patent is expired.

The commercial value of the patent should be separated into three periods:

Period	Commercial effect
1985-1988	Patent protection before or around commercial regulatory launch
1988-2002	Potential exclusivity for the claimed compounds and method
2002-present	No enforceable patent exclusivity from US 4,517,199

Current revenue exposure depends on the competitive position of branded and generic apraclonidine, not on this patent. The main competitive pressures are generic substitution, limited chronic use because of tolerability concerns, and competition from brimonidine, beta blockers, carbonic anhydrase inhibitors, and prostaglandin analogs.

Key Takeaways

US 4,517,199 claims topical treatment of elevated intraocular pressure with substituted phenylimino-imidazolines.
Claim 4 covers the dichloro benzenediamine compound associated with apraclonidine.
Claims 2 and 3 add ophthalmic vehicle and reduced-central-nervous-system-effect limitations.
Claims 4 through 14 are narrower compound-specific embodiments.
The patent was granted May 14, 1985 and expired approximately May 14, 2002 under the 17-year pre-1995 patent-term rule.
The patent cannot support current infringement litigation, a Paragraph IV challenge, or a market-entry delay.
Apraclonidine is a small molecule, so biosimilar law does not apply.
Current barriers are likely to involve FDA approval, sterile ophthalmic manufacturing, formulation equivalence, and later patent rights, not US 4,517,199.
Any present freedom-to-operate analysis must review later formulation, delivery, method-of-use, manufacturing, and combination patents.

FAQs About US Patent 4,517,199

Does US Patent 4,517,199 cover apraclonidine hydrochloride?

Yes, claim 4 is directed to the apraclonidine-related free-base structure and expressly includes pharmaceutically acceptable salts. Apraclonidine hydrochloride would be the relevant commercial salt if the structural identity matches the issued claim and specification.

Can a company launch generic apraclonidine without challenging US 4,517,199?

Yes. Because the patent expired in 2002, a generic applicant does not need to invalidate or avoid the patent to launch. Current approval depends on FDA requirements and any later unexpired patents.

Is claim 3 limited to a particular concentration?

No specific numerical concentration appears in the supplied claim language. Claim 3 requires a concentration that lowers intraocular pressure without significantly affecting the central nervous system. The specification and prosecution history would control how that functional limitation is interpreted.

Does the patent cover brimonidine?

No. Brimonidine is a different chemical entity. Similar pharmacology or use in glaucoma does not place brimonidine within the chemical genus unless its structure independently satisfies every limitation of claim 1, which it does not ordinarily do.

Does patent expiration eliminate all barriers to apraclonidine competition?

No. It eliminates the enforceable rights arising from US 4,517,199. FDA approval, sterile manufacturing, product-quality testing, formulation development, commercial scale-up, and later patents can still affect generic entry.

References

Food and Drug Administration. (n.d.-a). Approved drug products with therapeutic equivalence evaluations: Orange Book. U.S. Department of Health and Human Services. https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book

Food and Drug Administration. (n.d.-b). Abbreviated new drug application ANDA process. U.S. Department of Health and Human Services. https://www.fda.gov/drugs/types-applications/abbreviated-new-drug-application-anda

Food and Drug Administration. (2015). Iopidine (apraclonidine hydrochloride ophthalmic solution) prescribing information. U.S. Department of Health and Human Services.

U.S. Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation. U.S. Department of Commerce. https://www.uspto.gov/patents/laws/adjustment

United States Patent No. 4,517,199. (1985). Treatment of elevated intraocular pressure with substituted phenylimino-imidazolines. U.S. Patent and Trademark Office.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0081924	⤷ Start Trial	SPC/GB93/103	United Kingdom	⤷ Start Trial
Austria	18006	⤷ Start Trial
Canada	1194418	⤷ Start Trial
Canada	1201066	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,517,199

Summary for Patent: 4,517,199