United States Patent 6,635,278: Scope, Claims, Expiration, and Tenofovir Disoproxil Formulation Landscape

US Patent 6,635,278 covers pharmaceutical compositions containing tenofovir disoproxil, historically described as bis-pivaloyloxymethyl phosphonomethoxyethyl adenine, together with an alkaline excipient. Its principal technical limitations are alkaline-excipient chemistry, low moisture content, excipient concentration, unit-dose presentation, and specified tablet formulations. The patent was assigned to Gilead Sciences and its ordinary 20-year term appears to have ended in March 2020. It therefore presents no current US patent barrier to generic manufacture, although other tenofovir disoproxil patents, regulatory exclusivities, contractual restrictions, or formulation patents must be evaluated separately.

What drug and formulation does US Patent 6,635,278 protect?

The claimed active ingredient is tenofovir disoproxil, also known as bis-POC-PMPA. Commercial Viread contains tenofovir disoproxil fumarate, or TDF, the fumarate salt of tenofovir disoproxil. The claims supplied for US 6,635,278 do not expressly require the fumarate salt. They recite the neutral bis-pivaloyloxymethyl prodrug together with an alkaline excipient.

The patent is directed to an oral solid dosage formulation designed to improve stability and manufacturing performance. The central formulation concept combines:

Tenofovir disoproxil;
An alkaline excipient;
An excipient having a conjugate-acid pKa of at least approximately 4.0;
A specified solubility product, or Ksp, range;
In several claims, low loss on drying at 75°C;
Conventional tablet or capsule excipients.

The alkaline excipient is not an incidental formulation component. It is a required limitation in independent claim 1.

What is the scope of independent claim 1?

Claim 1 is the principal composition claim. It requires a composition "consisting essentially of":

Tenofovir disoproxil; and
An alkaline excipient satisfying the stated chemical parameters.

The phrase "consisting essentially of" generally permits components that do not materially alter the basic and novel characteristics of the claimed composition. Conventional binders, fillers, lubricants, disintegrants, and glidants may therefore be compatible with the claim if they do not materially change the claimed alkaline formulation behavior. Claims 13 through 26 expressly add many such excipients and dosage-form limitations.

The claim requires an alkaline excipient with:

Limitation	Claimed requirement
Conjugate-acid pKa	At least about 4.0
Ksp	About 1 × 10^-3 to about 1 × 10^-15
Active ingredient	Tenofovir disoproxil
Formulation type	Composition, not necessarily limited to a tablet in claim 1
Excipient function	Alkaline excipient

The Ksp limitation is potentially important in an infringement analysis. A generic formulation containing calcium carbonate or magnesium carbonate would not automatically fall within claim 1. The patentee would need to establish that the selected excipient satisfies the claimed pKa and Ksp parameters under the relevant measurement conditions.

Which alkaline excipients are expressly covered?

Claims 3 through 5 and 9 through 11 identify specific alkaline carbonates and hydroxides.

Expressly listed alkaline carbonates

The claims identify:

Calcium carbonate;
Magnesium carbonate;
Zinc carbonate;
Manganese carbonate;
Aluminum carbonate;
Ferrous carbonate;
Cobalt carbonate.

Expressly listed alkaline hydroxides

The claims identify:

Magnesium hydroxide;
Calcium hydroxide;
Aluminum hydroxide;
Iron hydroxide.

The dependent claims do not necessarily limit the invention to only these materials. Claims 1 and 2 are broader in structure and could potentially reach another alkaline excipient if it satisfies the pKa, Ksp, and other applicable limitations.

The patent's strongest practical relevance is likely to formulations using magnesium carbonate or calcium carbonate. Those materials recur in the detailed tablet examples and are the most commercially significant excipients among the listed alternatives.

What moisture and loss-on-drying limitations apply?

Claims 2, 6, 7, and 25 add moisture-related limitations:

Claim	Loss on drying limitation
Claim 2	No more than 5% at 75°C
Claim 6	No more than about 2% at 75°C
Claim 7	No more than about 1.5% at 75°C
Claim 25	Dried granules with LOD no more than about 2.0%

These limitations narrow the claims but may also create evidentiary issues. In a product case, the relevant questions would include:

Whether LOD is measured on the final dosage form or an intermediate;
The test method and drying conditions;
Whether "about" permits analytical variation;
Whether the accused product remains within the claimed range across commercial lots;
Whether the limitation applies to the complete composition or a granulated intermediate.

A formulation with the correct alkaline excipient but LOD above the applicable threshold would not meet claims requiring the lower LOD range.

How do the dependent claims narrow the formulation?

The claims create several nested protection layers.

Claims	Main limitation
1	Tenofovir disoproxil plus qualifying alkaline excipient
2, 6, 7	Progressive low-LOD requirements
3-5	Carbonate or hydroxide excipient categories
8, 12	Alkaline excipient at about 1-20% or 2-6%
13-16	Unit dose, tablet or capsule, active dose and weight percentages
17-18	Carbonate excipient plus lactose or microcrystalline cellulose
19	L-carnitine salt or microencapsulated L-carnitine formulation
20-24	Specific tablet compositions
25	Dried granules with low LOD
26	Additional conventional excipients

The formulation claims are cumulative. For example, claim 17 requires the limitations of claims 16 and 17, including the tablet format, active-ingredient percentage, alkaline-excipient percentage, and specified carbonate group.

What dosage strengths and tablet compositions are claimed?

Claims 14 and 20 through 24 cover several dose ranges and compositions.

Claim	Active ingredient limitation	Other principal limitations
14	About 1-300 mg	Unit-dose tablet
15	About 5-30% w/w	Tablet or capsule
16	About 2-6% w/w alkaline excipient	Tablet or capsule
20	About 10 mg	Carbonate, lactose, cellulose, starch, croscarmellose, optional talc
21	About 30 mg	About 410 mg magnesium carbonate plus lactose and processing excipients
22	About 60 mg	About 12 mg magnesium carbonate and defined excipient quantities
23	About 120 mg	About 12-24 mg magnesium carbonate and defined excipient quantities
24	About 4-8% w/w	L-carnitine-L-tartrate, cellulose, starch and lubricant system

Claims 20 through 23 are close to formulation-example claims. They may be difficult to enforce against a substantially different generic formulation unless the accused product meets the specified component and quantity ranges.

Claim 21 deserves separate review. It recites about 30 mg of active ingredient and about 410 mg of magnesium carbonate, an unusually large amount relative to the other examples. That language should be checked against the issued patent and prosecution history because the supplied text may contain a transcription or OCR error. Claim 24 also contains apparent typographical defects, including "16-% w/w" and misspelled excipient names. The issued patent controls.

What is the strongest claim category?

The broadest and commercially most important claim is claim 1. It does not require a tablet, a particular active dose, a specified carbonate, or a particular moisture level. A product may fall within claim 1 even if it avoids the narrow examples in claims 20 through 24.

The most technically vulnerable limitation in claim 1 is likely the combined pKa and Ksp requirement. A generic manufacturer could seek to design around the claim by:

Using a nonalkaline stabilizer;
Using an alkaline material outside the stated Ksp range;
Selecting an excipient whose conjugate acid has a pKa below the claimed threshold;
Altering the active ingredient salt or chemical form;
Using a formulation that does not contain the claimed tenofovir disoproxil species;
Avoiding the claimed excipient concentration ranges in the narrower claims.

Whether those strategies succeed depends on formulation performance and the construction of "alkaline excipient," "about," and "consisting essentially of."

When did US Patent 6,635,278 expire?

Public patent records identify US 6,635,278 as a Gilead Sciences patent granted on October 21, 2003. Its ordinary term is tied to a 2000 nonprovisional filing and appears to have expired in March 2020, subject to any patent-term adjustment or terminal-disclaimer information recorded by the USPTO.[1]

Event	Date
Earliest relevant US filing	March 2000
Grant	October 21, 2003
Ordinary 20-year expiration	Approximately March 2020
Current status	Expired by ordinary term

The patent should not be analyzed as a current standalone US exclusivity barrier. A historical patent may still matter to prior generic launch dates, settlement rights, damages periods, or patent-family diligence, but an expired patent ordinarily cannot block a new US launch.

What is the Orange Book status of US 6,635,278?

The Orange Book status must be distinguished from the patent's technical scope. FDA Orange Book listing is a regulatory disclosure associated with an approved drug product; it is not a determination that every claim is valid or infringed.

Viread is an FDA-approved TDF product. Its US patent and exclusivity records have included patents directed to tenofovir chemistry, prodrug forms, salts, and pharmaceutical compositions. The precise listing status of US 6,635,278 should be confirmed in the FDA Orange Book patent listing for the relevant Viread strength and approval number.[2]

Because US 6,635,278 appears to have expired in 2020:

It is not a current patent barrier if the expiration date is confirmed in USPTO records;
A new ANDA applicant would not face a present Paragraph IV challenge to an expired patent;
Any former Paragraph IV dispute involving this patent would have historical rather than forward-looking significance;
Other unexpired Viread or TDF patents could still be relevant.

How does Paragraph IV risk apply?

A Paragraph IV certification is relevant only when an Orange Book-listed patent remains unexpired. For US 6,635,278, the practical risk is historical unless the patent record shows an unusual term extension, patent-term adjustment, or later enforceable right.

For a generic TDF tablet, the more relevant questions are:

Which patents were listed for the reference listed drug?
Which listed patents were unexpired on the proposed ANDA filing date?
Does the ANDA formulation use tenofovir disoproxil fumarate or another salt?
Does the formulation use magnesium carbonate, calcium carbonate, or another alkaline excipient?
Does the product meet the pKa, Ksp, LOD, and percentage limitations?
Are method-of-use patents implicated by the proposed labeling?

A Paragraph IV certification directed to an expired patent has limited commercial value. The generic applicant would normally certify that the patent has expired or is not applicable rather than litigate a live infringement dispute.

Are biosimilars relevant to this patent?

No. Tenofovir disoproxil fumarate is a chemically synthesized small molecule, not a biologic. The relevant US pathway is an ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act, not a biosimilar application under section 351(k) of the Public Health Service Act.

The competitive risk is therefore generic substitution, not biosimilar substitution. FDA approval depends on pharmaceutical equivalence, bioequivalence, quality, manufacturing controls, and labeling requirements.

What other patents matter in the tenofovir disoproxil landscape?

US 6,635,278 should be evaluated as one formulation patent within a larger TDF portfolio. The surrounding landscape has historically included:

Patent category	Typical subject matter	Commercial relevance
Tenofovir base patents	PMPA and related nucleotide analogs	Core chemistry
Prodrug patents	Tenofovir disoproxil and related bis-acyloxy prodrugs	Active pharmaceutical ingredient
Salt patents	Tenofovir disoproxil fumarate	Commercial TDF form
Formulation patents	Alkaline excipients, moisture control, tablets	Product stability and manufacture
Method-of-use patents	HIV treatment, pre-exposure prophylaxis, hepatitis B	Label-driven patent risk
Manufacturing patents	Prodrug synthesis, crystallization, purification	Process design and supply chain

Relevant family review should include US Patent Nos. 5,935,946, 6,043,230, 6,319,754, 6,642,245, and later patents relating to tenofovir formulations and uses. Each patent requires separate confirmation of claims, terminal disclaimers, PTA, continuations, and expiration dates. The existence of a related patent does not establish that it covers the formulation claimed in US 6,635,278.

What litigation and settlement issues affect this patent?

The principal commercial disputes surrounding Viread and TDF have involved generic entry, patent challenges, and settlement arrangements concerning Gilead's broader TDF estate. A litigation search should separate:

Cases naming US 6,635,278 specifically;
Cases involving related TDF patents;
Cases involving combination products such as Truvada or Atripla;
Cases involving tenofovir alafenamide rather than tenofovir disoproxil;
Patent settlements with generic manufacturers;
Antitrust or reverse-payment allegations.

No current US enforcement value should be assigned to US 6,635,278 without a live case docket or an unexpired term. Licensing or settlement rights may have affected historical entry dates, but they do not revive an expired patent.

How strong is the patent estate for this formulation?

The patent was technically meaningful when unexpired because it combined formulation chemistry with specific commercial tablet architectures. Its strongest features were:

Broad claim 1 coverage of tenofovir disoproxil plus a qualifying alkaline excipient;
Explicit coverage of magnesium and calcium carbonate;
Low-moisture granule and tablet claims;
Dose-specific claims corresponding to oral solid dosage forms;
Detailed excipient combinations that could support product-specific infringement allegations.

Its weaknesses include:

Dependence on measurable but potentially disputed pKa and Ksp parameters;
Narrow numerical ranges in many dependent claims;
Potential design-around options using alternative stabilizers or excipient systems;
Possible prosecution-history limitations;
Expiration in approximately 2020.

The estate is therefore historically strong as a formulation-positioning patent but weak as a current exclusionary right.

Key Takeaways

US 6,635,278 covers tenofovir disoproxil compositions containing a qualifying alkaline excipient.
Magnesium carbonate and calcium carbonate are the most commercially important expressly listed excipients.
Claim 1 is the broadest claim and requires the pKa and Ksp limitations.
Claims 2, 6, 7, and 25 add low-moisture requirements based on LOD at 75°C.
Claims 20 through 24 target specific tablet compositions and dose formats.
The patent appears to have expired in March 2020 under its ordinary 20-year term.
It is not a current biosimilar issue; generic applicants would use the ANDA pathway.
Current TDF launch risk depends on other unexpired patents, Orange Book listings, method-of-use claims, and any applicable settlements.
The supplied text contains apparent transcription errors in claims 21 and 24; the issued patent and prosecution history control.

FAQs About US Patent 6,635,278

Does US 6,635,278 cover Viread itself?

It covers certain compositions containing tenofovir disoproxil and alkaline excipients. It is a formulation patent, not a general claim to every Viread product or every use of TDF.

Can a generic TDF tablet use magnesium carbonate?

Yes, subject to independent review of the remaining patent landscape. Magnesium carbonate is expressly listed in the claims, but the relevant patent appears expired. The generic product may still need to address other formulation, compound, or method-of-use patents.

Is tenofovir disoproxil fumarate the same compound named in the claims?

Not exactly. The claims recite tenofovir disoproxil, while commercial TDF is the fumarate salt. Claim construction and the specification would determine whether a particular salt formulation falls within a claim.

Does the patent cover injectable or topical tenofovir products?

The claims are directed principally to compositions, unit doses, tablets, capsules, and dried granules. They do not expressly claim an injectable or topical dosage form.

What is the most important document for determining infringement?

The issued patent, its prosecution history, the specification's definitions and analytical methods, and the accused product's complete qualitative and quantitative formulation data are the controlling materials.

References

United States Patent and Trademark Office. (2003). United States Patent No. 6,635,278: Pharmaceutical compositions containing bis-POC-PMPA. U.S. Department of Commerce. https://patents.google.com/patent/US6635278
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/
U.S. Food and Drug Administration. (n.d.). Viread prescribing information. Gilead Sciences, Inc. https://www.accessdata.fda.gov/drugsatfda_docs/label/
U.S. Patent and Trademark Office. (n.d.). Patent Center. U.S. Department of Commerce. https://patentcenter.uspto.gov/

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	021670	⤷ Start Trial
Austria	298576	⤷ Start Trial
Australia	2361300	⤷ Start Trial
Australia	759869	⤷ Start Trial
Brazil	9916820	⤷ Start Trial
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Details for Patent: 6,635,278

Summary for Patent: 6,635,278