United States Patent 6,645,961: Indinavir Sulfate Formulation Claims, Expiration, and Patent Landscape

US Patent 6,645,961 protected a high-load, low-moisture indinavir sulfate capsule and the associated dry-granulation manufacturing process. The patent was assigned to Merck & Co. and issued on November 11, 2003. Its enforceable term ended on December 21, 2021, based on the patent-family priority and term information reported in public patent records.[1] It no longer creates a live US patent barrier to generic indinavir sulfate products.

The strongest historical protection covered a capsule containing approximately 76% indinavir sulfate, 23% anhydrous lactose and 1% magnesium stearate, made through roller compaction, milling, post-blending with lubricant and encapsulation. The claims did not cover indinavir as a molecule, all indinavir formulations, or all methods of manufacturing indinavir products.

What does US Patent 6,645,961 protect?

The patent has three principal claim groups:

Claim group	Claims	Protected subject matter
Composition	1-7	Indinavir sulfate composition with low-moisture or anhydrous excipient and lubricant
Manufacturing process	8-18	Mixing, roller compaction, milling, lubrication and capsule formation
Product-by-process	19	Pharmaceutical composition made by the process of claim 8

The independent composition claim requires:

Indinavir sulfate at about 50% to 90% by weight;
A low-moisture or anhydrous excipient at about 10% to 50% by weight; and
A lubricant at about 0.5% to 2% by weight.

Claim 1 is open-ended because it uses “comprises.” A product may contain additional ingredients, but the accused product must still contain the required indinavir sulfate, excipient and lubricant elements within the claimed ranges.

The patent’s commercial target was Crixivan capsules, the branded indinavir sulfate product approved by the FDA in 1996.[2]

What formulations are protected by US 6,645,961?

The most specific formulation path is claims 4 through 7:

Anhydrous lactose is the excipient.
Magnesium stearate is the lubricant.
Indinavir sulfate is approximately 75% to 78% by weight.
Anhydrous lactose is approximately 22% to 25% by weight.
Magnesium stearate is approximately 0.9% to 1.1% by weight.
The product is a capsule.

Claim 6 narrows the formula to approximately:

Component	Weight percentage
Indinavir sulfate	76%
Anhydrous lactose	23%
Magnesium stearate	1%

The principal excipient alternatives are:

Anhydrous lactose;
Low-moisture microcrystalline cellulose; and
Anhydrous dibasic calcium phosphate.

The listed lubricant alternatives are:

Magnesium stearate;
Sodium lauryl sulfate;
Sodium stearyl fumarate; and
Hydrogenated vegetable oil.

The claims do not require a particular capsule shell, capsule size, dissolution profile, particle-size distribution, polymorphic form, coating, preservative or release mechanism. They also do not require that an accused formulation be identical to the Crixivan commercial formula if the claim elements are otherwise met.

How broad is claim 1?

Claim 1 is materially broader than claims 4 through 7. It covers a range-based formulation using any low-moisture or anhydrous excipient and any lubricant, provided the composition falls within the stated weight ranges.

The claim has several practical limitations:

It is limited to indinavir sulfate, not indinavir free base or another salt.
It requires a low-moisture or anhydrous excipient.
It requires a lubricant.
It is limited by weight ranges.
It does not expressly require a capsule.

A generic manufacturer could historically have attempted to design around claim 1 by using:

A non-anhydrous or higher-moisture excipient;
A different dosage form;
Indinavir free base or a different salt, subject to pharmaceutical and regulatory feasibility;
A formulation outside the claimed ranges;
A process that produced a product with no claim-required composition elements.

A design-around would have required analysis of the doctrine of equivalents, formulation equivalence, and the actual water content and composition of the commercial product.

What manufacturing process does US 6,645,961 claim?

Claims 8 through 18 protect a dry-granulation process. The required sequence is:

Mix indinavir sulfate, excipient and a first lubricant.
Compact the mixture.
Mill the compacts into granules.
Add a second lubricant to the granules.
Form the lubricated granules into a pharmaceutical composition.

Claim 8 divides lubrication into two stages. The first lubricant is added before compaction, and the second lubricant is added after milling. Each lubricant is present at approximately 0.25% to 1% by weight.

The process claims therefore focus on manufacturing architecture rather than only the final composition. A process using direct compression, wet granulation, spray drying or a single lubrication step could have presented a stronger noninfringement position, depending on the final product and the scope of any applicable equivalents.

What does claim 10 add?

Claim 10 adds a recycle loop:

The discharged compacts are sieved or “bieved” before milling.
Uncompacted material is collected.
The material is recycled to the roller compactor.

This limitation narrows the process to a manufacturing operation that recycles material failing to form compacts. A process without that recycle step would not literally meet claim 10.

What does claim 16 add?

Claim 16 introduces operating parameters:

Process variable	Claimed range or condition
Initial mixer	Ribbon mixer
Mixing time and speed	Approximately 10 minutes at 20 rpm
Compaction force	4 to 10 tons
Milling screen	0.062 inch
Milling speed	2,000 to 2,500 rpm
Final dosage form	Capsule

Claim 18 is narrower and more production-specific. It requires anhydrous lactose, magnesium stearate for both lubrication stages, a 10-cubic-foot ribbon mixer, approximately 200 revolutions in the initial blend, specified roller-compactor speeds, a CoMil machine, approximately 100 revolutions during final lubrication and a Bosch GKF encapsulation machine.

The equipment references in claim 18 create substantial literal-scope limitations. A competing manufacturer using materially different equipment or operating conditions would have a stronger argument against literal infringement of claim 18, although the broader process claims could remain relevant.

How should claim 19 be interpreted?

Claim 19 covers a pharmaceutical composition made by the process of claim 8. It is a product-by-process claim.

For infringement purposes, the analysis generally turns on whether the accused product was made by the claimed process, rather than merely whether it has the same composition. US product-by-process doctrine distinguishes the patentability analysis from infringement analysis. The Federal Circuit has held that process limitations in a product-by-process claim can limit infringement even when the resulting product appears structurally identical.[3]

Claim 19 therefore has less value against a manufacturer that produces a similar indinavir sulfate composition using a materially different process. The claim would have been more useful where process evidence, manufacturing records or discovery established use of the claimed compaction and milling sequence.

When did US Patent 6,645,961 lose exclusivity?

The patent expired on December 21, 2021.[1]

Event	Date
Patent issued	November 11, 2003
FDA approval of Crixivan	March 13, 1996
Patent-term endpoint	December 21, 2021
Current status	Expired

The patent’s expiration is separate from FDA regulatory exclusivity. Crixivan’s five-year new chemical entity exclusivity expired long before the patent term ended. Any pediatric or other regulatory exclusivity would also have been distinct from the formulation patent.

After December 21, 2021, the patent cannot support a new US patent-infringement action against a generic formulation or manufacturing process. Earlier activities may still be relevant to historical litigation, damages or settlement questions, but the patent no longer creates prospective US exclusivity.

What was the Orange Book status of Crixivan?

Crixivan was approved under NDA 020685 for indinavir sulfate capsules.[2] The FDA Orange Book is the relevant source for listed patents and certifications associated with approved small-molecule products.[4]

US 6,645,961 was a formulation and process patent associated with the Crixivan product rather than the basic indinavir compound patent. A formulation patent can be listed in the Orange Book if it claims the approved drug product or an approved method of use under applicable FDA listing rules. Its listing would have been relevant to an ANDA applicant making a Paragraph IV certification.

The listing did not extend the patent term. Once the patent expired, the Orange Book entry ceased to function as a prospective barrier to approval based on that patent.

Were Paragraph IV challenges possible?

Yes. An ANDA applicant seeking approval before expiration could have addressed US 6,645,961 through:

A Paragraph IV certification asserting that the patent was invalid or not infringed;
A Paragraph III certification accepting delayed approval until patent expiration;
A formulation or process design that avoided the listed claims;
A challenge directed to the scope, validity or enforceability of the patent.

For a formulation and process patent, the central Paragraph IV issues would likely have included:

Whether the proposed generic composition met the claimed weight ranges;
Whether its excipient qualified as low-moisture or anhydrous;
Whether its lubricant was one of the claimed materials;
Whether the manufacturing process used compaction, milling and two-stage lubrication;
Whether the patent claims were enabled across their full scope;
Whether the claimed formulation and process were obvious over prior indinavir formulations and dry-granulation technology.

No current Paragraph IV risk remains from this patent because the patent expired. A generic applicant can no longer trigger a new 30-month stay based on this patent.

How strong was the patent estate?

The estate was moderate for the commercial formulation but narrow outside it.

Factor	Assessment
Molecular protection	Not provided by US 6,645,961
Broad formulation protection	Moderate, subject to composition ranges
Specific Crixivan-like formula	Stronger, because claims 5-7 narrow to anhydrous lactose and magnesium stearate
Manufacturing protection	Moderate to strong where the exact two-stage process was used
Equipment-specific claims	Narrow
Product-by-process claim	Dependent on proving the claimed manufacturing process
Current enforceability	None after December 21, 2021
Biosimilar relevance	None

The composition claims are vulnerable to ordinary formulation design-around strategies because they depend on measurable percentages and named excipient categories. The process claims are more difficult to avoid if a manufacturer uses roller compaction followed by milling and separate post-milling lubrication, but they become progressively narrower in claims 10, 16 and 18.

The patent had stronger commercial value during the period when Crixivan was sold and the approved product was difficult to formulate because of moisture sensitivity and high active-ingredient loading. Its practical value declined as indinavir use decreased and as generic developers could select alternative solid-dose manufacturing routes.

What other patents covered indinavir?

The broader indinavir patent landscape included several categories:

Patent category	Typical subject matter	Relevance to US 6,645,961
Core compound patents	Hydroxyethylamino sulfonamide protease inhibitors and indinavir-related compounds	Separate from the formulation patent
Salt and pharmaceutical-form patents	Indinavir sulfate and solid pharmaceutical forms	Potentially closer technical overlap
Formulation patents	Moisture control, excipients, capsule compositions and stability	Directly adjacent
Process patents	Granulation, compaction, milling and encapsulation	Directly adjacent
Method-of-use patents	HIV treatment using indinavir or protease-inhibitor regimens	Separate claim category
Manufacturing know-how	Blend uniformity, moisture control, scale-up and equipment settings	May remain confidential after patent expiration

The foundational indinavir compound protection was associated with earlier Merck patents, including US 5,413,999.[5] Those earlier patents addressed the active pharmaceutical ingredient and related compounds, not the specific 76:23:1 capsule formulation claimed in US 6,645,961. The compound-patent term ended years before the formulation patent.

The relevant landscape should therefore be separated into two periods:

Pre-2012: compound and primary active-ingredient protection was the main barrier.
2012-2021: formulation and process protection, including US 6,645,961, had greater potential relevance.
Post-2021: no live US patent barrier remains from this patent, although regulatory, manufacturing and commercial barriers may continue.

Did the patent create biosimilar risk?

No. Indinavir is a chemically synthesized small molecule. Generic applicants use the ANDA pathway, not the biosimilar pathway under the Public Health Service Act.

The relevant competitive risks were:

ANDA approval;
Paragraph IV patent litigation before expiration;
Formulation design-around;
Supply and manufacturing capability;
Bioequivalence and dissolution performance.

The FDA Purple Book is not the relevant exclusivity database for Crixivan or indinavir.[6]

What litigation and settlement issues matter?

The patent expired, so current litigation risk is limited to historical conduct or disputes unrelated to prospective enforcement. The principal litigation questions during the patent term would have been:

Whether an ANDA formulation contained the claimed excipient and lubricant;
Whether “about” permitted the accused percentages;
Whether moisture content met the low-moisture or anhydrous limitation;
Whether the generic process used the claimed compaction and milling sequence;
Whether a process performed outside the United States could support liability for imported products;
Whether the patent was obvious in view of known high-load solid-dose formulations.

A settlement agreement involving this patent could have included a delayed generic entry date, a license, a covenant not to sue or manufacturing restrictions. No publicly established licensing transaction or settlement specific to US 6,645,961 is identified in the core patent and FDA records cited here. The absence of a known public agreement does not alter the patent’s expiration date.

What generic launch scenarios existed?

Launch before patent expiration

A generic sponsor could have launched before expiration only through:

A successful Paragraph IV challenge;
A settlement license;
A formulation and process that avoided all asserted claims;
An authorized-generic arrangement with the patent holder;
A separate regulatory pathway where legally available.

Launch after December 21, 2021

After expiration, a sponsor no longer needed to avoid US 6,645,961 for patent reasons. The relevant requirements became:

ANDA approval;
Pharmaceutical equivalence;
Bioequivalence;
Manufacturing-process validation;
Stability and dissolution performance;
Adequate supply of indinavir sulfate;
Commercial demand.

The expired patent still has technical value as a public description of a workable high-load capsule process. It cannot be used to block a competing manufacturer.

What manufacturing and IP barriers remain?

Patent expiration removed the legal exclusivity barrier, but it did not eliminate operational barriers. Indinavir sulfate is used at a high percentage of capsule fill weight, making powder flow, compaction, blend uniformity and capsule-fill control important.

The disclosed process identifies several scale-up variables:

Moisture control for excipients;
Initial and final magnesium stearate addition;
Roller-compaction force;
Feed and roll speeds;
Milling-screen size;
Milling speed;
Recycle of uncompacted material;
Capsule-machine settings.

These parameters may affect manufacturability and product quality, but they are not proprietary merely because they appeared in the expired patent. Any continuing protection would have to arise from separate, unexpired patents, trade secrets, regulatory data or manufacturing know-how.

How does US 6,645,961 compare with the Crixivan compound patents?

Issue	Compound patent protection	US 6,645,961
Protected subject	Indinavir-related active ingredient	Indinavir sulfate formulation and process
Main claim type	Chemical compounds and intermediates	Composition and manufacturing claims
FDA product relevance	Active ingredient	Capsule formulation
Expiration period	Generally earlier	December 21, 2021
Design-around	Difficult at molecule level	More feasible through excipient or process changes
Current status	Expired	Expired
Generic pathway	ANDA	ANDA

US 6,645,961 was an incremental formulation patent. It did not recreate exclusivity for indinavir after the foundational compound patents expired, but it extended potential control over a particular commercial formulation and manufacturing method.

Key Takeaways

US 6,645,961 protected indinavir sulfate capsules using low-moisture or anhydrous excipients and lubricants.
The narrowest commercial formulation was approximately 76% indinavir sulfate, 23% anhydrous lactose and 1% magnesium stearate.
Claims 8-18 covered a dry-granulation process with roller compaction, milling and two-stage lubrication.
Claim 19 was a product-by-process claim and required analysis of how the product was made.
The patent expired on December 21, 2021.
It no longer creates a live US patent barrier to generic indinavir sulfate.
The patent never covered indinavir as a molecule or all indinavir formulations.
Indinavir is a small molecule, so biosimilar analysis is inapplicable.
Current commercial barriers are regulatory approval, manufacturing capability, supply and demand rather than this patent.

FAQs About US Patent 6,645,961

What was the expiration date of indinavir patent 6,645,961?

US 6,645,961 expired on December 21, 2021.

Did US 6,645,961 cover Crixivan’s active ingredient?

No. It covered indinavir sulfate pharmaceutical compositions and manufacturing processes. Earlier patents covered the active compound and related chemical subject matter.

Could a generic indinavir manufacturer use anhydrous lactose?

Yes, after expiration of US 6,645,961. Before expiration, use of anhydrous lactose with the claimed indinavir sulfate and magnesium stearate ranges could have raised infringement issues.

Is indinavir subject to biosimilar competition?

No. Indinavir is a small-molecule drug and competes through the FDA ANDA generic pathway.

Does the expired patent still protect the roller-compaction process?

No enforceable US patent rights remain under US 6,645,961 after December 21, 2021. The process disclosure may still guide manufacturing, but it is no longer exclusive.

References

United States Patent and Trademark Office. (2003). US Patent No. 6,645,961, Pharmaceutical compositions containing indinavir sulfate.
U.S. Food and Drug Administration. (1996). Crixivan (indinavir sulfate) prescribing information, NDA 020685.
Abbott Laboratories v. Sandoz, Inc., 566 F.3d 1282 (Fed. Cir. 2009) (en banc).
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
United States Patent and Trademark Office. (1995). US Patent No. 5,413,999, Hydroxyethylamino sulfonamide compounds.
U.S. Food and Drug Administration. (2024). Purple Book: Database of licensed biological products.

Details for Patent: 6,645,961

Summary for Patent: 6,645,961