Details for Patent: 6,468,967

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Summary for Patent: 6,468,967

Title:	Methods for administration of antibiotics
Abstract:	The invention provides methods for administering a therapeutically effective amount of daptomycin while minimizing skeletal muscle toxicity. The methods provide daptomycin administration at a dosing interval of 24 hours or greater. This long dosing interval minimizes skeletal muscle toxicity and allows for higher peak concentrations of daptomycin, which is related to daptomycin's efficacy. The invention also provides methods of administering lipopeptide antibiotics other than daptomycin while minimizing skeletal muscle toxicity by administering a therapeutically effective amount of the lipopeptide antibiotic at a dosage interval that does not result in muscle toxicity. The invention also provides methods of administering quinupristin/dalfopristin while minimizing skeletal muscle toxicity by administering a therapeutically effective amount of quinupristin/dalfopristin at a dosage interval that does not result in muscle toxicity.
Inventor(s):	Frederick B. Oleson, Jr., Francis P. Tally
Assignee:	Cubist Pharmaceuticals LLC
Application Number:	US09/406,568
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,468,967
Patent Claim Types: see list of patent claims	Use;

United States Patent 6,468,967: Daptomycin Dosage Claims, Expiration, Litigation and Patent Landscape

US Patent 6,468,967 protected once-daily or every-48-hour daptomycin dosing at 3 to 75 mg/kg, including the commercially important 4 mg/kg and 6 mg/kg intravenous regimens. The patent was assigned to Cubist Pharmaceuticals and listed in the FDA Orange Book for Cubicin. Its listed patent term ended on September 24, 2020. The patent is therefore expired and no longer creates an active US enforcement barrier to generic daptomycin.

The patent was commercially important because its claims covered the dosing regimens later used in the principal FDA-approved indications for Cubicin: 4 mg/kg every 24 hours for complicated skin and skin-structure infections and 6 mg/kg every 24 hours for Staphylococcus aureus bacteremia and right-sided endocarditis.[1]

What does US Patent 6,468,967 protect?

US 6,468,967 is a method-of-treatment patent. It does not claim the daptomycin molecule, a particular salt, a vial, a formulation, or a manufacturing process. Its central subject matter is the repeated administration of daptomycin at a dosing interval selected to minimize skeletal-muscle toxicity.

The independent claim concepts are:

Claim group	Protected subject matter
Claims 1-11	Administration of 3-75 mg/kg at intervals from every 24 to every 48 hours, with optional co-administration of another antibiotic
Claims 12-25	Administration of 3-75 mg/kg once every 24 hours
Claims 26-41	Treatment or eradication of bacterial infection using the claimed dose and interval
Claims 42-45	Intravenous administration of the 4 mg/kg and 6 mg/kg once-daily regimens

The most commercially significant claims are claims 16, 17, 34, 35, 42, 43, 44 and 45. Together, they expressly cover:

• 4 mg/kg every 24 hours;
• 6 mg/kg every 24 hours;
• intravenous administration of those regimens; and
• use for treatment of bacterial infection.

These claims correspond closely to the dosing instructions in the Cubicin label.[1]

How broad are the daptomycin dosage claims?

The independent claims are broad in dose and treatment duration.

Claim 1 covers:

• a human patient;
• a therapeutically effective amount of daptomycin;
• 3 to 75 mg/kg;
• repeated administration every 24 to every 48 hours; and
• a dosage interval that minimizes skeletal-muscle toxicity.

Claim 12 narrows the interval to once every 24 hours. Claim 26 adds the therapeutic objective of treating or eradicating a bacterial infection.

The dependent claims create several nested ranges:

Dose range or dose	Claims
3-75 mg/kg	1, 12, 26
3-12 mg/kg	3, 13, 27
4, 6, 8 or 10 mg/kg	5, 15
10-25 mg/kg	6, 20
25, 50 or 75 mg/kg	19
4 mg/kg every 24 hours	16, 34
6 mg/kg every 24 hours	17, 35

The patent also claims treatment courses of 3 days to 6 months, 7 to 28 days, and 7 to 14 days. Those periods were relevant to ordinary anti-infective treatment but did not materially expand the commercial scope beyond the core dose-and-interval claims.

What is the legal significance of “minimizes skeletal muscle toxicity”?

The phrase “at a dosage interval that minimizes skeletal muscle toxicity” is a functional limitation. It links the claimed dosing interval to a safety result rather than merely reciting a calendar interval.

The claims separately specify every-24-hour to every-48-hour dosing, which limits the practical importance of the functional language. A party asserting the patent would still need to establish that the accused regimen falls within the claimed dose and interval and satisfies the claim’s therapeutic and patient-related limitations.

The limitation creates several potential claim-construction issues:

1. Whether “minimizes” requires a measurable comparison against a different dosing schedule.
2. Whether the result must be demonstrated in the treated patient or can be established from clinical or pharmacological evidence.
3. Whether the functional language narrows the claims to regimens that produce a clinically meaningful reduction in muscle toxicity.
4. Whether a generic label that recommends the claimed regimen creates induced-infringement exposure.

Because the patent has expired, these issues no longer present a prospective US infringement risk for ordinary commercial launch. They remain relevant to historical litigation, damages analysis, and the interpretation of earlier settlement agreements.

What FDA-approved daptomycin regimens were covered?

The FDA-approved Cubicin dosing regimens fell directly within the patent claims.

FDA-approved use	Labeled adult dose	Relation to US 6,468,967
Complicated skin and skin-structure infections	4 mg/kg IV every 24 hours for 7-14 days	Expressly covered by claims 16 and 42
S. aureus bacteremia, including right-sided endocarditis	6 mg/kg IV every 24 hours for 2-6 weeks	Expressly covered by claims 17 and 43
Pediatric cSSSI and bacteremia indications	Weight-based dosing by age	Generally within the patent’s broad dose range, subject to claim-specific facts

The patent claims oral, subcutaneous and intravenous administration. Daptomycin’s approved commercial use, however, is intravenous. Daptomycin is not orally useful for systemic infection because of its peptide structure and poor gastrointestinal absorption. The oral and subcutaneous language broadened the literal claim set but had limited practical market relevance.

When did US Patent 6,468,967 expire?

The effective US patent-term endpoint was September 24, 2020. The patent issued on October 22, 2002. Its term reflected the post-1995 US patent regime, which generally measures patent term from the earliest effective nonprovisional filing date, subject to patent-term adjustment and other statutory adjustments.[2]

Milestone	Date or status
Patent	US 6,468,967
Issue date	October 22, 2002
Patent holder at commercial peak	Cubist Pharmaceuticals
FDA product associated with listing	Cubicin, NDA 021572
Orange Book status	Listed use patent during the product’s protected period
Expiration	September 24, 2020
Current enforceability	Expired

The patent did not receive a meaningful post-expiration extension that would preserve an active claim against generic daptomycin. FDA regulatory exclusivity and patent exclusivity were separate. FDA approval exclusivity ended before the patent expired.

What was the Orange Book status of US 6,468,967?

US 6,468,967 was listed in the Orange Book for Cubicin. It was a method-of-use patent rather than a compound patent. Its commercial function was to support the branded product’s approved dosage regimens and indications.

An Orange Book listing does not itself establish patent validity or infringement. It provides notice to an ANDA applicant and permits the reference-product sponsor to invoke the Hatch-Waxman certification and litigation framework.

The listed patent was relevant to ANDA applicants because a proposed generic label using the same 4 mg/kg or 6 mg/kg once-daily regimen could implicate the patented methods. Generic applicants could respond through:

• a Paragraph IV certification that the patent was invalid, unenforceable or not infringed;
• a section viii statement carving out a patented method of use, where the proposed label could omit the protected indication; or
• a settlement permitting launch before patent expiration.

Which companies challenged the daptomycin patent?

Cubist and, later, Merck faced ANDA challenges from multiple generic manufacturers. Publicly reported challengers and generic daptomycin participants included Teva, Hospira, Sandoz and other manufacturers seeking approval of injectable daptomycin products.

The principal Hatch-Waxman dispute centered on whether the generic product’s proposed label and dosing instructions would infringe the asserted daptomycin method claims and whether the claims were valid in view of earlier daptomycin clinical and pharmacokinetic disclosures.

The precise litigation posture varied by defendant. The important commercial point is that generic entry did not wait for the September 2020 expiration date. Settlements and other commercial arrangements allowed generic daptomycin products to enter before the nominal patent endpoint.

What Paragraph IV risks did the patent create?

The patent created a substantial Paragraph IV risk because the approved generic regimen necessarily tracked the claimed 4 mg/kg or 6 mg/kg once-daily intravenous administration.

A generic applicant could challenge the patent on several grounds:

Anticipation and obviousness

The principal validity question was whether earlier daptomycin disclosures made the claimed dose range and dosing interval anticipated or obvious. Earlier documents disclosed daptomycin activity, dose-ranging, intravenous administration and various dosing schedules. The patent’s asserted distinction was the selection of a dosing interval that reduced skeletal-muscle toxicity while maintaining efficacy.

Claim construction

A challenger could argue that “minimizes skeletal muscle toxicity” was indefinite, unsupported or insufficiently limiting. The patent owner could respond that the specification and clinical data established a measurable relationship between dosing frequency, exposure and muscle toxicity.

Written description and enablement

The broad 3-75 mg/kg range raised written-description and enablement issues, particularly for high doses and less conventional administration routes. The commercial claims at 4 mg/kg and 6 mg/kg were easier to defend because they were supported by clinical use and later appeared in the FDA-approved labeling.

Induced infringement

Even if a generic manufacturer did not directly administer daptomycin, a label recommending the patented regimen could support an induced-infringement theory. This issue was central to the commercial significance of the Orange Book listing.

Did the patent protect a formulation or manufacturing process?

No. US 6,468,967 is not a formulation or manufacturing patent.

It does not claim:

• a specific excipient system;
• a lyophilized daptomycin cake;
• a particular vial configuration;
• reconstitution instructions;
• daptomycin purity or impurity limits;
• fermentation conditions;
• purification steps; or
• a crystalline or salt form.

Those technologies were addressed, if at all, in separate patent families. A generic manufacturer that avoided the expired method claims could still have faced other formulation, process or regulatory issues during the patent term. After September 24, 2020, the method claims in US 6,468,967 no longer supplied an active US barrier.

How strong was the patent estate for Cubicin?

The Cubicin estate was commercially strong during the period when the patent was active because US 6,468,967 aligned with the product’s labeled dosing instructions. Its strength came from practical overlap with the approved regimen, not from broad protection of the daptomycin molecule.

Estate component	Commercial function	Relevance after 2020
Original daptomycin compound patents	Protected the active ingredient	Expired before or around commercial launch
US 6,468,967	Protected once-daily and every-48-hour dosing methods	Expired September 24, 2020
Formulation patents	Could protect injectable presentation and stability	Must be analyzed separately by patent and expiration
Method-of-use patents	Could protect indications or patient populations	Potentially relevant only if unexpired and listed
Manufacturing patents	Could restrict production routes	Relevant only if valid, unexpired and practiced by the generic

The patent was strongest against a generic label that expressly adopted 4 mg/kg or 6 mg/kg once daily for the same indications. It was weaker against a product sold for non-infringing uses, a properly carved-out label, or a product launched after expiration.

What generic launch scenarios existed?

Three launch scenarios were commercially relevant.

Launch after a successful Paragraph IV challenge

A generic manufacturer could launch immediately after prevailing in litigation or securing a judgment that the patent was invalid, unenforceable or not infringed.

Settlement-based launch

A settlement could permit launch before September 24, 2020, subject to a negotiated date and other commercial terms. This was the most important pathway for early generic daptomycin availability.

Launch after patent expiration

All applicants could market the covered regimen after September 24, 2020, subject to FDA approval, manufacturing readiness and any separate unexpired patent rights.

Generic daptomycin products subsequently entered the US market. Daptomycin is an ANDA product, not a biosimilar, so competition proceeded through the small-molecule generic pathway under section 505(j) of the Federal Food, Drug, and Cosmetic Act.

Was there biosimilar risk for Cubicin?

No. Daptomycin is a chemically defined small-molecule antibiotic. It is not a biologic subject to the abbreviated biosimilar pathway under section 351(k) of the Public Health Service Act.

The relevant competitive threats were:

• ANDA-based generic daptomycin;
• hospital purchasing substitution;
• injectable antibiotic contracting;
• product shortages and supply reliability; and
• alternative anti-MRSA agents such as vancomycin, linezolid, ceftaroline and dalbavancin.

What was the revenue exposure associated with the patent?

Cubicin was one of Cubist Pharmaceuticals’ main commercial assets. Cubist reported approximately $1 billion in annual Cubicin net sales in the years immediately before Merck acquired Cubist in 2015.[3] The product’s commercial value depended heavily on maintaining the branded 4 mg/kg and 6 mg/kg regimens and delaying generic substitution.

Because US 6,468,967 covered those regimens directly, its expiration created material US revenue exposure. The exposure was moderated by early generic settlements, hospital purchasing dynamics and the availability of competing anti-MRSA therapies.

What is the current competitive and legal position?

US 6,468,967 is expired. It should not be treated as an active US blocking patent for daptomycin dosing.

A current freedom-to-operate review should therefore focus on:

1. remaining US formulation patents;
2. manufacturing and purification patents;
3. unexpired method-of-use patents;
4. FDA labeling and section viii carve-out requirements;
5. product-specific regulatory exclusivity;
6. ANDA litigation records and settlement terms; and
7. patent rights outside the United States.

Geographic protection was jurisdiction-specific. Expiration in the United States did not automatically terminate corresponding rights in Europe, Japan, Canada or other markets. Each national family member required separate status review.

Key Takeaways

• US 6,468,967 claimed daptomycin administration at 3-75 mg/kg every 24-48 hours.
• The most important claims covered 4 mg/kg and 6 mg/kg intravenously once every 24 hours.
• The patent was a method-of-treatment patent, not a compound, formulation or manufacturing patent.
• It was listed in the FDA Orange Book for Cubicin.
• Its effective US expiration date was September 24, 2020.
• Generic daptomycin entry occurred through ANDA litigation, Paragraph IV challenges and settlement-based launch arrangements.
• Daptomycin has generic, not biosimilar, competition.
• Any current US blocking analysis must examine separate formulation, manufacturing and method-of-use patents.

FAQs

Does US 6,468,967 cover the daptomycin molecule itself?

No. It covers methods of administering daptomycin. The compound itself was protected by separate earlier patent rights.

Does the patent cover 4 mg/kg daptomycin every 48 hours?

Potentially, under the broader claims covering 3-75 mg/kg at intervals from every 24 to every 48 hours, subject to the remaining claim limitations. The expressly narrowed 4 mg/kg claim is directed to once-daily administration.

Can a generic daptomycin company use a non-infringing label?

During the patent term, a company could seek a section viii carve-out for a patented method of use if the proposed labeling omitted the protected indication. The feasibility depended on the Orange Book use code and the remaining unpatented uses.

Is intravenous administration required by the patent?

No. Certain claims recite oral, subcutaneous or intravenous administration. Commercially, however, FDA-approved systemic daptomycin treatment is intravenous.

Did expiration of US 6,468,967 eliminate all Cubicin patent risk?

No. It eliminated the active US claims of that patent. Separate unexpired formulation, manufacturing or method-of-use patents, if any, required independent analysis.

References

1. U.S. Food and Drug Administration. (2020). Cubicin (daptomycin for injection) prescribing information. FDA.
2. United States Patent and Trademark Office. (2002). U.S. Patent No. 6,468,967: Methods of administering daptomycin. U.S. Department of Commerce.
3. Cubist Pharmaceuticals, Inc. (2014). Annual report pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934. U.S. Securities and Exchange Commission.
4. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA Orange Book.
5. U.S. Food and Drug Administration. (2024). Daptomycin ANDA approvals and labeling information. FDA.

Drugs Protected by US Patent 6,468,967

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 6,468,967

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1115417		91254	Luxembourg
European Patent Office	1115417		CA 2006 00018	Denmark
European Patent Office	1115417		300232	Netherlands
European Patent Office	1115417		06C0022	France
European Patent Office	1115417		SPC 018/2006	Ireland
European Patent Office	1115417		SPC/GB06/024	United Kingdom
European Patent Office	1115417		SZ 22/2006	Austria