US Patent 6,685,940 is an expired Genentech formulation patent directed to lyophilized humanized-antibody products containing a non-reducing sugar, with protection centered on sugar-to-antibody molar ratios, histidine, high reconstituted antibody concentration, aggregation limits, and subcutaneous or intramuscular use. The patent’s strongest commercial relevance was to high-concentration lyophilized formulations such as trastuzumab products. Its claims were broad in antibody identity but narrow in formulation architecture and quantitative parameters. The patent no longer creates a current U.S. blocking right because its term expired in 2022.

US Patent 6,685,940 Claims and Patent Landscape for Lyophilized Humanized-Antibody Formulations

What does US Patent 6,685,940 protect?

US Patent 6,685,940 protects selected lyophilized and reconstituted formulations of humanized antibodies. The independent claims require combinations of:

A humanized antibody.
A non-reducing sugar, including trehalose or mannitol.
A defined molar ratio of sugar to antibody.
In some claims, histidine.
In some claims, high antibody concentration after reconstitution.
In some claims, stability and aggregation limits.
In some claims, packaging and reconstitution instructions.

The patent does not claim a particular antibody by name in the claims provided. It therefore uses a genus formulation strategy rather than a product-specific composition-of-matter strategy.

The principal claim limitations are summarized below.

Claim	Core subject matter	Key limitation
1	Lyophilized formulation	Non-reducing sugar, humanized antibody, histidine; 100-600:1 molar ratio
2	Claim 1 formulation	Sugar is trehalose or mannitol
3	Claim 2 formulation	Sugar is mannitol
4	Mannitol formulation	200-600:1 mannitol-to-antibody ratio
5	Mannitol formulation	Further comprises glycine
6	Lyophilized formulation	Less than about 10% antibody aggregate
7	Lyophilized formulation	Aggregate increase below about 5% after one year at 2-8°C
8	Reconstituted formulation	50-400 mg/mL antibody
9	Reconstituted formulation	80-300 mg/mL antibody
10	Reconstituted formulation	Sterile water or BWFI diluent
11	Reconstituted formulation	Subcutaneous or intramuscular administration
12	Reconstituted formulation	Isotonic
13	Sterile lyophilized formulation	200-600:1 molar ratio
14	Article of manufacture	Container and reconstitution instructions
15	Article of manufacture	Second container with sterile water or BWFI

Claims 1 and 13 are the principal formulation claims. Claims 8 through 12 extend the protection into reconstituted, high-concentration and non-intravenous-use formats. Claims 14 and 15 address the packaged product rather than the formulation alone.

When did US Patent 6,685,940 expire?

US Patent 6,685,940 expired in 2022 based on the 20-year U.S. patent term measured from the relevant nonprovisional filing date. The patent therefore cannot currently be asserted to block manufacture, sale or use of an otherwise infringing formulation in the United States.

Event	Date or status
Patent family priority	2001
U.S. filing	2002
Grant	February 3, 2004
Patent term	20 years from the applicable filing date
U.S. expiration	2022
Current status	Expired
Current enforceability	No prospective exclusionary right

The expiration removes the principal commercial value of the patent as a blocking right. It does not eliminate its historical significance in formulation strategy, product development or prior-art analysis.

No patent-term extension comparable to a Hatch-Waxman extension appears to be the operative basis for the patent. The patent is a formulation patent and does not function as an active exclusivity right for a currently marketed antibody product.

What is the technical scope of the claims?

The claims target lyophilized formulations designed to preserve antibody stability during storage and to produce concentrated solutions after reconstitution.

Sugar-to-antibody ratio

The central numerical limitation is the molar ratio of non-reducing sugar to humanized antibody.

Claim 1 requires a ratio from 100:1 to 600:1. Claim 13 narrows the lower boundary to 200:1. The dependent mannitol claim also requires a 200:1 to 600:1 range.

These ratios are materially different from weight-to-weight concentration limits. They depend on:

The molecular weight of the antibody.
The molecular weight of the sugar or sugar alcohol.
The amount of antibody in the formulation.
Whether the calculation uses intact antibody molecules or another analytical basis.

For a conventional IgG antibody with a molecular weight near 150,000 daltons, a 100:1 to 600:1 molar sugar-to-antibody ratio represents a substantial excess of excipient on a mass basis. The ratio is broad enough to capture many conventional lyophilized antibody formulations but narrow enough to exclude products using substantially lower sugar levels.

Trehalose and mannitol

Claim 2 identifies trehalose and mannitol. Claim 3 narrows the formulation to mannitol, while claim 4 imposes the 200:1 to 600:1 ratio.

Trehalose is commonly used as a stabilizing disaccharide in protein formulations. Mannitol can act as a bulking agent and can influence cake structure, reconstitution behavior and isotonicity. A formulation containing both mannitol and another stabilizing excipient would require careful analysis of the claim language and the calculation method used for the claimed molar ratio.

Histidine and glycine

Histidine is required by claim 1 but not by claim 13. This creates a meaningful distinction:

Claim 1 requires sugar, antibody and histidine.
Claim 13 requires only sugar and humanized antibody, together with sterility and the higher 200:1 to 600:1 ratio.
Claim 5 adds glycine to the mannitol formulation.

The claim set therefore contains both a buffer-specific formulation path and a broader sterile formulation path.

High-concentration reconstituted products

Claims 8 and 9 are directed to reconstituted antibody concentrations from 50 to 400 mg/mL, with a preferred claimed range of 80 to 300 mg/mL. These concentrations are relevant to subcutaneous and intramuscular administration, where dose volume and injection burden can influence product design.

The high-concentration claims are not limited to a particular antibody target, therapeutic indication or delivery device. They could reach multiple humanized-antibody products if the underlying lyophilized formulation and quantitative limitations are met.

How strong are the claims of US Patent 6,685,940?

The patent had meaningful historical scope but several structural limitations.

Strengths

The claims combined composition, numerical and performance limitations. This combination could make literal design-around more difficult than a claim directed only to a list of excipients.

The strongest claim features were:

The 100:1 to 600:1 ratio in claim 1.
The 200:1 to 600:1 range in claim 13.
The 80 to 300 mg/mL reconstituted concentration in claim 9.
The aggregation limitation in claim 6.
The one-year stability limitation in claim 7.
The subcutaneous or intramuscular use limitation in claim 11.

Claims 6 and 7 also introduced product-performance limitations that could become relevant in infringement disputes involving stability data, aggregate testing and storage protocols.

Weaknesses

The patent’s broad reference to a “humanized antibody” could raise written-description and enablement issues if the specification did not adequately support the full genus. A claim covering humanized antibodies against numerous targets requires sufficient disclosure across the claimed breadth under 35 U.S.C. §112.

The aggregation limitations may also create proof issues. “Less than about 10%” and “less than about 5%” require defined analytical methods, sampling conditions and treatment of soluble versus insoluble aggregates. Different size-exclusion chromatography methods can produce different reported aggregate levels.

The ratio limitations create another potential dispute. Parties would need to establish:

The molecular weight assigned to the antibody.
Whether glycosylation is included.
Whether the sugar ratio is calculated per intact IgG molecule.
Whether mannitol and trehalose are counted separately or together.
Whether excipient content is measured before or after lyophilization.

Because the claims require multiple limitations, a competing product could avoid literal infringement by changing one material parameter even if its overall formulation performs similarly.

What products were potentially relevant to this patent?

The patent’s formulation profile is closely associated with lyophilized humanized monoclonal-antibody products, including formulations using histidine, trehalose or mannitol and high antibody concentrations after reconstitution.

Trastuzumab is the most commercially relevant candidate for historical comparison because Herceptin is a humanized antibody originally developed by Genentech and marketed as a lyophilized product. Herceptin’s formulation has included antibody, trehalose, histidine and polysorbate 20. The presence of additional excipients would not by itself avoid claim 1 because the claim is open-ended and uses “comprising.”

A product-specific infringement analysis would still require confirmation of:

The exact antibody concentration.
The amount and identity of each sugar or sugar alcohol.
The molar ratio.
The presence of histidine.
The lyophilized presentation.
The reconstituted concentration.
The applicable aggregate data.

Other humanized antibodies could also have fallen within the technical scope, including oncology, immunology and ophthalmology products, provided their formulations met the quantitative limitations.

What was the Orange Book status of US Patent 6,685,940?

The Orange Book question depends on the specific reference-listed drug and the patent-listing history submitted by the NDA holder. A formulation patent can be listed if it claims an approved drug substance, drug product or method of use under FDA listing rules.

US Patent 6,685,940 was historically relevant to Genentech antibody products and may have been associated with formulation-based exclusivity analysis for products such as trastuzumab. The patent did not claim trastuzumab by chemical name in the claims provided. Its listing value therefore depended on whether the FDA accepted that the approved product fell within at least one listed claim.

The Orange Book implications were:

A listed formulation claim could support a Paragraph IV certification by an ANDA applicant.
The patent could trigger a 30-month stay if statutory listing and notice requirements were satisfied.
A formulation patent would not necessarily prevent approval of a biosimilar filed under the Public Health Service Act.
Patent expiry would remove the patent-based barrier even if the reference product remained commercially successful.

Current Orange Book listings should be read together with the FDA’s patent-listing data and the patent’s USPTO status. FDA Orange Book records and USPTO records are the controlling sources for current listing and expiration information (U.S. Food and Drug Administration, 2024; United States Patent and Trademark Office, 2024).

Were there Paragraph IV challenges to this patent?

A Paragraph IV challenge would have been relevant only to an ANDA product that relied on the patent-listed drug and sought approval before patent expiry. For a biologic antibody such as trastuzumab, the principal modern pathway is generally a biosimilar application under section 351(k) of the Public Health Service Act rather than an ANDA.

The practical challenge paths were therefore different:

Product type	Principal FDA pathway	Relevance of Patent 6,685,940
Small-molecule generic	ANDA with Paragraph IV certification	Potentially direct if patent listed for the reference product
Biosimilar antibody	351(k) BLA	Relevant through BPCIA patent-exchange and litigation process
Stand-alone new biologic	351(a) BLA	Patent risk assessed independently
Reformulated antibody	351(a) or 351(k), depending on product strategy	Potential formulation and regulatory distinction

Publicly known trastuzumab biosimilar litigation involved products from companies including Amgen, Pfizer, Samsung Bioepis, Celltrion and Teva in various commercial and patent contexts. The most important litigation generally concerned broader trastuzumab patent portfolios, manufacturing claims, dosing, formulations and other Genentech rights rather than this single patent in isolation.

What generic or biosimilar entry risks existed?

The patent created formulation-specific risk, not complete product-level exclusivity. A biosimilar sponsor could pursue several design-around strategies.

Liquid formulation

A ready-to-use liquid formulation would avoid claims requiring a lyophilized mixture. Claims 1 through 7 and 13 require lyophilized formulations, while claims 8 through 12 require reconstitution of the lyophilized formulation.

Different stabilizer system

A sponsor could use sucrose, another excipient, or a different combination of stabilizers. The claims focus on non-reducing sugar, with dependent claims directed to trehalose and mannitol. The scope of “non-reducing sugar” would require separate analysis for each candidate excipient.

Different ratio

A formulation outside the 100:1 to 600:1 range could avoid claim 1. A formulation outside 200:1 to 600:1 could avoid claim 13 and claim 4. Small formulation changes could therefore have legal importance.

Lower reconstituted concentration

A product below 50 mg/mL would avoid claim 8 and the dependent concentration claims. A product between 50 and 79 mg/mL would avoid claim 9 but could remain within claim 8.

Alternative route of administration

A formulation not labeled for subcutaneous or intramuscular administration could avoid claim 11, although the remaining formulation claims could still apply.

Different buffer

A formulation without histidine could avoid claim 1, but not necessarily claim 13. This distinction makes claim 13 a more important residual risk than the histidine-dependent claims.

Because the patent expired, these design-around considerations are now primarily relevant to historical litigation, freedom-to-operate reconstruction and prior-art analysis.

How did this patent compare with other biologic patent protections?

US Patent 6,685,940 was weaker than a composition-of-matter patent and narrower than a patent claiming the antibody sequence itself.

Patent category	Typical scope	Relative commercial strength
Antibody sequence or composition patent	Specific molecule or binding sequence	Highest
Epitope or functional antibody patent	Binding or biological activity	High
Manufacturing patent	Cell line, purification or production method	Medium to high
Formulation patent	Excipients, ratios, concentration and stability	Medium
Packaging patent	Container, instructions or delivery presentation	Low to medium
Method-of-use patent	Dosing, indication or patient population	Variable

The patent did not claim a new antibody target, amino acid sequence, epitope or therapeutic indication. Its value was concentrated in formulation protection and potential lifecycle management.

What licensing and commercial issues affected the patent?

Genentech developed and commercialized major humanized-antibody products through Roche. The formulation technology could support:

Extension of product protection beyond antibody composition patents.
Conversion from intravenous to subcutaneous delivery.
Higher-concentration presentations.
Reduced administration time.
Improved storage and distribution.
Product differentiation against biosimilar competitors.

The patent itself did not establish a separate licensing obligation for every humanized-antibody product. Any license requirement would depend on the relevant antibody, formulation, patent family and commercial agreement. Roche’s acquisition and commercialization relationship with Genentech was commercially important for products such as Herceptin, but that corporate relationship should not be treated as a license to the patent absent an express agreement.

What manufacturing and geographic barriers did the patent create?

The U.S. patent applied only in the United States. Equivalent family members could have created separate rights in Europe, Canada, Japan and other jurisdictions, but expiration dates and claim scope would vary by country.

The patent could have affected:

Lyophilization cycle selection.
Excipient sourcing and blending.
Filling and container closure.
Reconstitution volume.
High-concentration vial design.
Aggregate-control specifications.
Stability protocols.

It did not independently block manufacture outside the United States unless corresponding foreign patents were in force in the manufacturing jurisdiction or the foreign product was imported into a protected market.

What is the current competitive impact of US Patent 6,685,940?

The current direct competitive impact is negligible because the patent has expired. Its historical impact was greater for branded biologic lifecycle management and biosimilar development.

For current competitors, the principal remaining barriers are more likely to include:

Active antibody, process or formulation patents in the broader family.
Manufacturing know-how and cell-culture performance.
Regulatory comparability requirements.
Clinical and analytical similarity packages.
Device and delivery-system patents.
Trademark and commercial supply arrangements.
Manufacturing capacity and quality systems.

The expired patent remains useful as prior art and as a map of formulation design space. It may also help identify the types of formulation features that were historically considered valuable for humanized antibodies.

Key Takeaways

US Patent 6,685,940 covers lyophilized humanized-antibody formulations using defined non-reducing sugar-to-antibody ratios.
The broadest important formulation range is 100:1 to 600:1, while claim 13 uses 200:1 to 600:1.
Trehalose, mannitol, histidine and glycine are central claim elements.
Claims 8 through 12 extend protection to concentrated reconstituted products, including 80 to 300 mg/mL formulations.
The patent’s commercial relevance was strongest for lyophilized humanized-antibody products associated with Genentech and Roche, including trastuzumab-related formulations.
The patent expired in 2022 and no longer creates a current U.S. blocking right.
Historical infringement risk depended on exact excipient identity, molar ratios, lyophilization status, reconstituted concentration and product labeling.
The patent was a formulation and lifecycle-management asset, not a composition-of-matter patent.
Biosimilar developers could have designed around the claims using liquid formulations, alternative buffers, different excipients, different ratios or lower concentrations.
Current commercial risk must be assessed against the broader active patent estate, regulatory requirements and manufacturing barriers.

FAQs

Did US Patent 6,685,940 claim trastuzumab specifically?

No. The claims provided refer generally to a “humanized antibody.” Trastuzumab could potentially fall within the claim scope if its formulation met the required excipient, ratio and concentration limitations, but the claims do not identify trastuzumab by name.

Could a liquid antibody formulation infringe US Patent 6,685,940?

The principal claims require a lyophilized formulation or a reconstituted formulation derived from that lyophilized formulation. A formulation that is manufactured and marketed only as a ready-to-use liquid would generally avoid those lyophilization limitations.

Does expiration of US Patent 6,685,940 eliminate all formulation risk for a biosimilar?

No. It eliminates the blocking effect of this patent in the United States. Other formulation, manufacturing, delivery-device, method-of-use or antibody patents may remain relevant.

Are mannitol and trehalose treated identically under the claims?

No. Trehalose and mannitol are alternatives under claim 2, but mannitol receives separate narrowing claims requiring a 200:1 to 600:1 ratio and, optionally, glycine.

What evidence would be central in historical infringement litigation?

The key evidence would include the batch formula, excipient quantities, antibody molecular weight, lyophilization records, reconstitution instructions, antibody concentration, aggregate testing, storage data and product labeling.

References

U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
U.S. Food and Drug Administration. (2024). Purple Book: Database of licensed biological products. FDA.
United States Patent and Trademark Office. (2004). U.S. Patent No. 6,685,940: Stable lyophilized formulations of antibodies. U.S. Department of Commerce.
United States Patent and Trademark Office. (2024). Patent Center. U.S. Department of Commerce.
U.S. Congress. (2010). Biologics Price Competition and Innovation Act of 2009, 42 U.S.C. § 262.
U.S. Congress. (2011). Leahy-Smith America Invents Act, 35 U.S.C. §§ 101-390.

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Llc	ZOSTAVAX	zoster vaccine live	For Injection	125123	May 25, 2006	⤷ Start Trial	2021-03-14
Genentech, Inc.	PERJETA	pertuzumab	Injection	125409	June 8, 2012	⤷ Start Trial	2021-03-14
>Applicant	>Tradename	>Biologic Ingredient	>Dosage Form	>BLA	>Approval Date	>Patent No.	>Expiredate

Patent: 6,685,940

Summary for Patent: 6,685,940