US Patent 4,642,346: Acyclovir Anhydrous Crystal Claims, Expiration, and Patent Landscape

US Patent 4,642,346 covers anhydrous crystalline acyclovir, specified crystal characteristics, and processes for producing that solid form. The patent is expired. Its claims no longer create a US exclusionary right, and they do not present a current Orange Book or Paragraph IV barrier to generic acyclovir. The patent remains relevant for historical polymorph, solid-state, manufacturing, and freedom-to-operate analysis.

What compound does US Patent 4,642,346 protect?

The claimed compound is acyclovir, identified in the patent by its chemical name, 9-(1,3-dihydroxy-2-propoxymethyl)guanine.

The patent does not claim acyclovir as a broad chemical entity in every physical form. It claims a specific solid-state form: anhydrous crystalline acyclovir.

Item	Description
Active ingredient	Acyclovir
Chemical name in patent	9-(1,3-dihydroxy-2-propoxymethyl)guanine
Patent	US 4,642,346
Patent assignee	Burroughs Wellcome Co.
Filing date	April 6, 1984
Priority date	April 8, 1983
Issue date	February 10, 1987
Patent status	Expired
Pre-URAA term	17 years from issue
Approximate expiration	February 10, 2004
Covered product	Anhydrous crystalline acyclovir
Covered processes	Solvent crystallization and thermal conversion

The underlying acyclovir compound was covered separately by earlier patent rights, including US Patent 4,199,574. Those compound claims expired before US 4,642,346. Patent 4,642,346 therefore operated as a later solid-form and manufacturing patent rather than as the foundational acyclovir composition-of-matter patent.

What does claim 1 of US 4,642,346 cover?

Claim 1 covers:

Anhydrous crystalline 9-(1,3-dihydroxy-2-propoxymethyl)guanine.

This is the broadest product claim in the patent. Its scope has two required elements:

The material must be acyclovir.
The material must be both crystalline and anhydrous.

The claim does not expressly require a particular particle size, dosage form, pharmaceutical excipient, route of administration, or therapeutic indication. It is a material claim directed to the solid active pharmaceutical ingredient.

The claim does not cover every acyclovir preparation. It excludes, at minimum, forms that are:

Amorphous rather than crystalline;
Hydrated rather than anhydrous;
Solvated with a non-water solvent;
Not acyclovir;
A solution or suspension lacking the claimed crystalline material.

The term "anhydrous" generally means that the crystal does not contain stoichiometric water of crystallization. Claims 2 and 3 impose more specific measurable limitations.

How do claims 2 through 4 narrow the anhydrous crystal?

Claims 2 through 4 create a dependency chain that progressively narrows the product definition.

Claim	Additional limitation	Practical significance
1	Anhydrous crystalline acyclovir	Broadest product claim
2	Water of hydration below 1% w/w	Quantitative low-water requirement
3	Melting point of 243°C to 245°C	Thermal identity and purity marker
4	Powder X-ray diffraction pattern shown in Figures IA, IB, or IC	Solid-form fingerprint

Claim 2: less than 1% water

Claim 2 requires water of hydration below 1% by weight. This limitation is directed to the physical state of the crystal and would normally be tested with a validated moisture or water-content method, such as Karl Fischer analysis or thermogravimetric analysis.

The claim language is narrower than claim 1 because a sample could be described as anhydrous in ordinary technical usage while still containing surface moisture or residual water above the claim’s quantitative threshold. The relevant issue is whether the accused material satisfies the claimed measurement and whether the water is present as hydration water or as absorbed or residual process moisture.

Claim 3: melting point of 243°C to 245°C

Claim 3 requires the crystal to have a melting point within the stated range. Melting point can be affected by:

Heating rate;
Instrument calibration;
Sample purity;
Particle characteristics;
Residual solvent or water;
Decomposition before or during melting.

The claim’s range is a product-identification limitation, not a formulation limitation. A finished tablet or cream may contain acyclovir crystals that meet the limitation, but the claim is directed to the crystal material itself.

Claim 4: powder X-ray diffraction pattern

Claim 4 adds the powder X-ray diffraction pattern shown in the patent figures. This is the most technically specific product claim. The figures function as a fingerprint for the claimed crystalline form.

An infringement analysis would ordinarily compare the accused material’s powder X-ray diffraction pattern with the claimed figures. Relevant variables include:

Radiation source and wavelength;
Instrument configuration;
Peak positions;
Relative peak intensities;
Sample preparation;
Preferred orientation;
Detection and reporting thresholds.

A product that meets the water and melting-point limitations but does not exhibit the claimed X-ray pattern may fall outside claim 4 while remaining potentially relevant to claims 1 through 3.

What processes are protected by claims 5 through 13?

The process claims cover two principal routes:

Crystallization from a heated oxygen-containing solvent;
Heating another form of acyclovir, particularly acyclovir hydrate, to produce the anhydrous crystals.

Claims 5 through 10: solvent crystallization

Claim 5 requires the following sequence:

Add acyclovir to a heated oxygen-containing solvent.
Cool the resulting mixture to room temperature.
Recover the crystals formed during cooling.

The claim is result-limited because the process must prepare the anhydrous crystals of claim 1. A process using similar steps but producing a different solid form would not satisfy the claim merely because the process conditions resemble those described in the patent.

The dependent claims narrow the solvent and temperature conditions:

Claim	Limitation
5	Heated oxygen-containing solvent, cooling, and crystal recovery
6	Dimethylacetamide or water
7	Solvent warmed to 60°C to 100°C
8	Methanol or acetone added to the warm solution
9	C1-C4 alcohol
10	Alcohol warmed to 40°C to 80°C

Claim 5 is the broadest solvent-process claim. Claims 6 through 8 focus on dimethylacetamide or water systems, while claims 9 and 10 cover lower molecular weight alcohols, including methanol, ethanol, propanol, and butanol within the one-to-four-carbon range.

The phrase "oxygen-containing solvent" may include water, alcohols, ethers, esters, amides, and other oxygenated solvents, subject to the claim’s technical and legal interpretation. The dependent claims confirm that water, dimethylacetamide, and C1-C4 alcohols were important embodiments.

Claims 11 through 13: thermal conversion

Claim 11 covers heating a suitable form of acyclovir to prepare the anhydrous crystals.

Claim 12 narrows the starting material to acyclovir hydrate.

Claim 13 further limits the heating range to 200°C to 220°C.

This group is potentially significant for manufacturers that remove water from acyclovir hydrate by thermal treatment rather than by solvent crystallization. The process must result in the claimed anhydrous crystalline form. Mere heating of acyclovir for drying would not necessarily infringe if it does not produce the claimed crystal or if the temperature and starting-material limitations of the relevant claim are not met.

When did US Patent 4,642,346 lose exclusivity?

US 4,642,346 expired approximately on February 10, 2004, based on the pre-URAA 17-year term measured from its February 10, 1987 issue date.

Event	Date
Priority	April 8, 1983
US filing	April 6, 1984
Patent grant	February 10, 1987
Approximate expiration	February 10, 2004
Current enforceability	None; expired

The patent was issued before the Uruguay Round Agreements Act changed US patent-term rules. Its term was therefore generally calculated from issue rather than from the earliest effective nonprovisional filing date.

No current patent term extension or patent term adjustment creates an active right under this patent. Any historical exclusivity period ended before the current generic acyclovir market structure developed.

What was the relationship between US 4,642,346 and the original acyclovir patent?

The key distinction is between the original acyclovir compound patent and the later crystalline-form patent.

Patent category	Representative patent	Subject matter	Current status
Compound patent	US 4,199,574	Acyclovir chemical entity and therapeutic use	Expired
Solid-form patent	US 4,642,346	Anhydrous crystalline acyclovir	Expired
Product-specific patents	Various later patents	Formulations, delivery systems, or combinations	Must be assessed individually
Regulatory exclusivity	FDA NDA exclusivity	Market exclusivity tied to approval	Expired for original acyclovir products

Expiration of the compound patent did not automatically eliminate later patents directed to a crystal form, formulation, manufacturing method, or specific indication. Conversely, expiration of US 4,642,346 means that the claimed anhydrous form and claimed production methods cannot independently block current US manufacture or sale.

What is the Orange Book status of US 4,642,346?

US 4,642,346 is not a current Orange Book barrier for acyclovir products.

The Orange Book lists patents submitted by NDA holders for approved drug products. Patent listing depends on the relationship between the patent claims and the approved drug product, not simply on whether a patent concerns the active ingredient.

A crystalline API patent may face listing limitations where its claims do not expressly cover:

The approved drug product;
The drug substance used in the product;
An approved method of use;
A formulation or dosage form.

For current acyclovir tablets, capsules, oral suspensions, creams, and ointments, the relevant Orange Book status must be evaluated by NDA and dosage form. The original Zovirax-related regulatory exclusivity and the principal acyclovir patent rights have expired. US 4,642,346 does not create a current listed-patent obstacle to ANDA approval.

Were Paragraph IV challenges relevant to this patent?

Paragraph IV litigation is no longer commercially relevant to US 4,642,346 because the patent expired in 2004.

Historically, an ANDA applicant could have challenged the patent by certifying that it was invalid, unenforceable, or would not be infringed. The most likely commercial setting would have been an ANDA for an acyclovir product using anhydrous crystalline acyclovir or a process capable of producing it.

The practical status is:

Issue	Assessment
Current Paragraph IV exposure	None
Current 30-month stay risk	None
Current injunction risk	None from this patent
Historical ANDA relevance	Possible, depending on listing and product
Current generic approval barrier	None

A Paragraph IV certification against an expired patent does not provide a viable basis for delaying approval. Generic applicants may instead rely on a Paragraph II certification for a patent that has expired or a Paragraph III certification where approval is deferred until expiration.

Which companies challenged or relied on the acyclovir patent estate?

The principal commercial originator was Burroughs Wellcome, whose acyclovir product was marketed as Zovirax. Glaxo Wellcome later became the relevant corporate successor, followed by GlaxoSmithKline in the broader corporate chain.

Acyclovir is now supplied by multiple generic manufacturers. Generic products have been approved in several dosage forms, including oral tablets, capsules, oral suspension, creams, and ointments. The generic market includes manufacturers such as Apotex, Teva, Mylan, Sandoz, and other approved suppliers, depending on product and time period.

Public regulatory records support a broad generic acyclovir market, but the existence of an approved generic does not establish that a specific company challenged US 4,642,346 through Paragraph IV litigation. The public record for this patent should not be treated as evidence of a particular settlement or challenger unless supported by a docket, FDA patent certification record, or settlement document.

What patent litigation affects US 4,642,346?

No current US litigation can enforce US 4,642,346 because the patent is expired.

The relevant litigation distinction is:

Historical infringement claims may have existed while the patent was in force.
New infringement claims cannot accrue for post-expiration conduct.
A patent owner may retain historical damages claims for conduct occurring before expiration, subject to statutory limitations and procedural defenses.
An expired patent cannot support a current injunction against manufacture, importation, or sale.

No current generic launch restriction, ANDA stay, or market injunction arises from this patent.

The original acyclovir patent estate may have generated disputes involving compound rights, formulations, dosage forms, or methods of use. Those disputes should not be conflated with the legal status of US 4,642,346.

How strong was the patent estate for anhydrous acyclovir?

The patent had moderate historical strength for a narrow solid-state and process portfolio but weak breadth against alternative acyclovir forms and manufacturing routes.

Strength factor	Assessment
Chemical identity	Strongly defined
Solid-form scope	Narrow
X-ray fingerprint	Stronger evidentiary definition
Process coverage	Meaningful but dependent on product result
Alternative forms	Not covered if amorphous or materially different
Expiration position	Weak after 2004
Orange Book leverage	Limited
Manufacturing relevance	Potentially significant during patent term
Current commercial leverage	None

The strongest practical feature was the combination of anhydrous status, water content, melting point, and powder X-ray diffraction. Those parameters could distinguish the claimed form from acyclovir hydrate or other solid states.

The main weakness was that a competitor could potentially design around the process claims by using:

A different solvent;
A different crystallization sequence;
A different temperature profile;
A different starting solid;
A different drying or isolation technique;
A non-infringing crystal form.

Design-around analysis would still require laboratory characterization because a process outside the literal conditions could independently produce the same anhydrous crystal and implicate claim 1.

What formulations are protected by this patent?

US 4,642,346 does not claim a specific acyclovir formulation.

It does not expressly claim:

Tablets;
Capsules;
Oral suspensions;
Creams;
Ointments;
Ophthalmic products;
Intravenous solutions;
Transdermal systems;
Specific excipient combinations;
Controlled-release dosage forms.

A formulation could contain acyclovir crystals that satisfy claim 1, but the patent claim is directed to the incorporated API rather than the finished dosage form. A formulation manufacturer’s risk during the patent term would depend on whether the product contained the claimed anhydrous crystal and whether the relevant jurisdiction recognized direct or indirect infringement on the facts.

Later formulation patents, if any, must be evaluated separately. The expiration of US 4,642,346 does not eliminate active rights covering a distinct delivery system or dosage form.

Does this patent create biosimilar risk?

No. Acyclovir is a small-molecule antiviral, not a biologic.

The relevant US pathway is the abbreviated new drug application, or ANDA, rather than the biosimilar pathway under the Public Health Service Act. Biosimilar concepts such as reference-product exclusivity, interchangeability, and patent dance procedures do not apply to acyclovir.

The relevant competitive risks are:

Generic API sourcing;
ANDA approval;
Formulation differentiation;
Manufacturing cost;
Regulatory compliance;
Supply continuity;
Potential later patents on delivery systems or combinations.

What manufacturing and geographic barriers remain?

There is no current US patent barrier under US 4,642,346. Manufacturing risk may still arise from other sources:

Active patent claims in jurisdictions where related rights had different expiration dates;
Process patents covering impurity control or improved crystallization;
Regulatory requirements for API quality;
DMF ownership and supplier qualification;
Residual solvent and water-content specifications;
Good Manufacturing Practice compliance;
Trade secrets involving crystallization, drying, or particle engineering;
Import controls and supply-chain qualification.

Patent rights are territorial. Expiration in the United States does not establish the status of corresponding foreign patents. A global launch requires separate review of Europe, Japan, Canada, China, India, Australia, and other relevant markets.

How does US 4,642,346 compare with competing acyclovir patent rights?

Issue	US 4,642,346	Original acyclovir compound patent	Later formulation or use patent
Claim type	Crystal form and process	Chemical entity and use	Dosage form or indication
Breadth	Narrow	Broad within chemical scope	Variable
Main infringement question	Is the API the claimed crystal?	Is acyclovir made, used, or sold?	Does the product meet formulation or use limitations?
Generic impact	Historical API-form risk	Primary historical entry barrier	Product-specific risk
Current status	Expired	Expired	Must be checked individually
Biosimilar relevance	None	None	None
Orange Book relevance	Limited or historical	Historically greater	Often more direct if product or method claims

What generic launch scenarios existed?

During the patent term, a generic manufacturer could have pursued several strategies:

Wait for patent expiration.
File a Paragraph IV certification if the patent was listed and the applicant believed it was invalid or not infringed.
Use a different acyclovir solid form.
Use a process that did not practice the claimed solvent or heating limitations.
Obtain acyclovir from a supplier without practicing a claimed manufacturing process in the United States, subject to importation and contributory-infringement analysis.
Launch after expiration under an ANDA approved for the relevant dosage form.

After February 2004, the first strategy became commercially available without waiting for this patent. Current generic manufacturers face ordinary regulatory, quality, supply, and competition risks rather than exclusivity risk from US 4,642,346.

Key Takeaways

US 4,642,346 claims anhydrous crystalline acyclovir, not acyclovir in every chemical or physical form.
Claims 2 through 4 narrow the product by water content, melting point, and powder X-ray diffraction.
Claims 5 through 10 cover solvent-based crystallization processes.
Claims 11 through 13 cover thermal conversion, including heating acyclovir hydrate at 200°C to 220°C.
The patent issued on February 10, 1987, and expired approximately on February 10, 2004.
It is not a current US patent obstacle to generic acyclovir.
It does not create biosimilar risk because acyclovir is a small molecule.
Current freedom-to-operate analysis should focus on later formulation, delivery, use, process, and foreign patents.
A patent landscape should distinguish the expired acyclovir compound patent from this narrower crystal-form patent.

FAQs

Is US Patent 4,642,346 still enforceable?

No. The patent expired approximately on February 10, 2004.

Does US 4,642,346 cover acyclovir hydrate?

No. The patent claims anhydrous crystalline acyclovir. Claim 12 identifies acyclovir hydrate as a starting material for producing the anhydrous form, but does not claim the hydrate itself as the product.

Can a generic manufacturer sell anhydrous acyclovir in the United States?

Yes, US 4,642,346 no longer prevents manufacture or sale of anhydrous acyclovir in the United States. Other active patents, regulatory requirements, or contractual restrictions must be evaluated separately.

Is a powder X-ray diffraction test required to assess claim 1 infringement?

Not necessarily. Claim 1 does not expressly require the X-ray pattern limitation in claim 4. Powder X-ray diffraction may be useful to characterize the crystal, but claim 1 must be analyzed according to all of its own limitations.

Does the patent cover acyclovir cream or oral tablets?

It does not claim a cream or tablet formulation. A finished product may contain acyclovir crystals, but the patent is directed to the API crystal and its production processes rather than to a specific dosage form.

References

United States Patent and Trademark Office. (1987). U.S. Patent No. 4,642,346: Anhydrous 9-(1,3-dihydroxy-2-propoxymethyl)guanine. U.S. Department of Commerce.
United States Patent and Trademark Office. (1982). U.S. Patent No. 4,199,574: 9-(2-hydroxyethoxymethyl)guanine. U.S. Department of Commerce.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration. (2024). Drugs@FDA: FDA-approved drugs. U.S. Department of Health and Human Services.
World Intellectual Property Organization. (2024). Patent law and patent term resources. World Intellectual Property Organization.
U.S. Congress. (1984). Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585.

Details for Patent: 4,642,346

Summary for Patent: 4,642,346