Details for Patent: 6,852,689

Summary for Patent: 6,852,689

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 dos not result in muscle toxicity.
Inventor(s):	Frederick B. Oleson, Jr., Francis P. Tally
Assignee:	Cubist Pharmaceuticals LLC
Application Number:	US10/082,544
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,852,689
Patent Claim Types: see list of patent claims	Use;

United States Drug Patent 6,852,689: Daptomycin Claims, Scope, Expiration, Litigation and Patent Landscape

US Patent No. 6,852,689 protected dosing regimens for daptomycin, including doses of at least 3 mg/kg administered every 48 hours to once weekly, with the interval selected to minimize skeletal-muscle toxicity. The patent was primarily a method-of-treatment patent, not a composition-of-matter patent. Its relevant patent term expired in January 2022, eliminating current US patent blocking power from this patent. Generic daptomycin products therefore compete through the abbreviated new drug application, or ANDA, pathway rather than through biosimilar regulation.

The patent’s commercial importance was substantial because it covered the dosing concept later associated with higher-dose and less-frequent daptomycin treatment. Its claim scope was broad in dose, interval, treatment duration, route, infection type and combination therapy. The broadest claims also presented potential validity and enforcement issues, particularly around the phrase “dosage interval that minimizes skeletal muscle toxicity,” oral administration, and certain internally inconsistent dependent claims.

What does US Patent 6,852,689 protect?

US 6,852,689, titled “Methods for administering daptomycin,” protects methods of administering daptomycin to human patients using specified dose and interval parameters. The patent does not claim the daptomycin molecule itself.

Item	Information
Patent	US 6,852,689 B2
Title	Methods for administering daptomycin
Patent type	Method of treatment
Applicant/assignee	Cubist Pharmaceuticals, Inc.
Priority date	January 22, 2001
US filing date	January 22, 2002
Grant date	February 8, 2005
Active ingredient	Daptomycin
Principal technical issue	Dose-frequency optimization and skeletal-muscle toxicity
Relevant term endpoint	Approximately January 22, 2022, subject to any applicable patent-term adjustment
Current status	Expired by ordinary patent term

The patent’s central proposition is that daptomycin can be administered at doses of at least 3 mg/kg on an extended schedule, while managing skeletal-muscle toxicity through the dosing interval. The claims cover both administration generally and treatment or eradication of bacterial infection.

How broad are the independent claims?

The independent claims are claims 1, 27 and 47.

Claim 1: broad administration claim

Claim 1 covers:

• administration to a human patient;
• a therapeutically effective amount of daptomycin;
• a dose of at least 3 mg/kg;
• an interval selected to minimize skeletal-muscle toxicity; and
• repeated administration every 48 hours to once weekly.

Claim 1 is broad because it does not limit the dose to the approved 4 mg/kg or 6 mg/kg regimens. It reaches any dose of at least 3 mg/kg, subject to the claimed interval and toxicity limitation. The upper boundary is supplied by dependent claims, not by claim 1.

The claim does not expressly require treatment of a named infection. A patient “in need thereof” and a therapeutically effective amount are sufficient on the face of the claim.

Claim 27: infection-treatment claim

Claim 27 covers treatment or eradication of a bacterial infection using:

• daptomycin at 3 to 75 mg/kg;
• a repeated interval of every 48 hours to once weekly; and
• treatment continuing until the infection is treated or eradicated.

Claim 27 is narrower than claim 1 in dose because it imposes a 3-to-75 mg/kg range. It is broader in its express therapeutic objective because it covers any bacterial infection rather than a limited organism or disease.

Claim 47: fixed 48-hour regimen

Claim 47 covers a daptomycin dose of at least 3 mg/kg administered repeatedly once every 48 hours. It is a narrower interval species of claim 1.

Claims 48 through 57 narrow claim 47 by specifying:

• doses from 3 to 12 mg/kg;
• 4, 6, 8 or 10 mg/kg;
• administration for 2 days to 6 months;
• administration for 7 to 28 days; or
• administration for 7 to 14 days.

What dose ranges are covered by US 6,852,689?

The patent covers several overlapping dose ranges.

Claim group	Dose scope	Interval scope
Claims 1, 47	At least 3 mg/kg	Every 48 hours to once weekly; claim 47 is every 48 hours
Claims 2-3	3-12 mg/kg	Every 48 hours to once weekly
Claims 4-5	10-25 mg/kg	Every 48 hours to once weekly
Claims 14-18	3-12 mg/kg, including 4 and 6 mg/kg	Every 48-96 hours
Claims 19-20	25, 50 or 75 mg/kg	Every 48-96 hours
Claims 21-22	10-25 mg/kg	Every 48-96 hours
Claims 27, 32-37	3-75 mg/kg	Every 48 hours to once weekly
Claims 48-54	3-12 mg/kg, including 4, 6 and 8 mg/kg	Every 48 hours

The most commercially relevant species are 4 mg/kg and 6 mg/kg. The FDA-approved daptomycin label uses 4 mg/kg once every 24 hours for certain skin and skin-structure infections and 6 mg/kg once every 24 hours for Staphylococcus aureus bloodstream infections, including right-sided infective endocarditis. Those daily regimens do not fall within the literal interval requirement of every 48 hours to once weekly. The patent instead targets extended-interval administration, including every 48, 72 or 96 hours. (FDA, 2023)

The claims also reach higher doses of 10, 20, 25, 50 and 75 mg/kg. These provisions were relevant to investigational or off-label high-dose use rather than the principal approved Cubicin dosing schedules.

What is the significance of the skeletal-muscle toxicity limitation?

The phrase “at a dosage interval that minimizes skeletal muscle toxicity” is a functional limitation. A potential infringement analysis would likely require evidence that the accused regimen was selected or operated to reduce skeletal-muscle toxicity, rather than merely showing that the regimen fell within a numerical dose-and-interval range.

This limitation creates several issues:

1. The claim does not state a quantitative creatine phosphokinase, or CPK, threshold.
2. It does not define the degree of toxicity reduction required.
3. It does not specify a required patient population.
4. It does not expressly require CPK monitoring.
5. It may be interpreted in light of the specification’s pharmacokinetic and toxicology disclosure.

A court could treat the phrase as a meaningful claim limitation if the specification explains how toxicity is minimized. It could also face indefiniteness scrutiny if the patent fails to give a reasonably certain standard for identifying when an interval minimizes toxicity. The expiration of the patent makes this issue primarily historical and relevant to past damages, license audits or archived litigation rather than prospective generic entry.

Which dependent claims have the strongest commercial relevance?

Claims directed to 4 mg/kg and 6 mg/kg are the most commercially significant because those doses are directly associated with approved daptomycin use and common clinical practice.

Claims 17 and 18

Claims 17 and 18 cover 4 mg/kg and 6 mg/kg, respectively, when administered every 48 to 96 hours. They are narrower than claim 1 and more closely aligned with practical extended-interval regimens.

Claims 24-26

These claims limit treatment duration to:

• 2 days to 6 months;
• 7 to 28 days; or
• 7 to 14 days.

The 7-to-14-day range is relevant to many antibacterial treatment courses. Duration limitations can create separate infringement questions because a short course may not satisfy a longer-duration claim, while a longer course may satisfy multiple overlapping claims.

Claims 29-31

These claims specify treatment every:

• 48 hours;
• 72 hours; or
• 96 hours.

They create discrete infringement positions for extended-interval dosing. Claim 29 is the most commercially practical of the three because every-48-hour treatment is more consistent with outpatient and renal-adjusted dosing than once-weekly administration.

Do the claims cover combination therapy?

Yes. Claims 6 through 8 cover daptomycin administered with another antibiotic.

Claim 7 lists broad antibiotic classes, including beta-lactams, carbapenems, cephalosporins, aminoglycosides, macrolides, quinolones, tetracyclines, vancomycin, rifamycins, sulfonamides and other antibacterial agents.

Claim 8 narrows the combination to:

• imipenem;
• amikacin;
• netilmicin;
• fosfomycin;
• gentamicin; or
• teicoplanin.

Claim 6 is potentially broad because it requires only co-administration with an antibiotic other than daptomycin. A product label that recommends combination therapy could create a different analysis from a physician’s independent off-label decision to use another antibiotic. Direct infringement would generally depend on the specific conduct and applicable induced-infringement principles.

What routes of administration are covered?

Claims 9, 10, 23 and 54 recite oral, subcutaneous or intravenous administration.

This is unusually broad for daptomycin. Daptomycin is generally administered intravenously because its clinical use depends on systemic exposure and the molecule has poor oral bioavailability. The FDA-approved products are injectable formulations. (FDA, 2023)

The oral route creates a potential enablement and written-description issue if the specification does not provide a technically credible oral daptomycin regimen. A claim can recite a route that is not commercially practiced, but the patent must still support and enable the claimed subject matter under 35 U.S.C. §§ 112(a) and 112(b).

The intravenous route is the commercially important route. Subcutaneous administration may have potential relevance to outpatient delivery but is not the principal FDA-approved route for Cubicin or Cubicin RF.

Are any claims internally inconsistent?

Yes. Claim 38 depends from claim 37. Claim 37 recites a dose of 10 to 25 mg/kg and enumerates 10, 11, 12, 13, 14, 15, 16, 20 or 25 mg/kg. Claim 38 then states that the dose is 4 mg/kg.

Because 4 mg/kg is outside claim 37’s 10-to-25 mg/kg range, claim 38 appears internally inconsistent. Claims 39 and 40 depend from claim 38 and inherit that structural problem.

The issue does not necessarily invalidate every related claim. Claims 17 and 51 separately recite 4 mg/kg through different dependency paths. Claims 41-43 similarly recite 6 mg/kg after dependency from claim 37 and present a comparable inconsistency. The errors could affect claim construction, validity and enforcement of those particular claim chains.

The supplied claim text also contains apparent typographical errors, including “tharapeutically,” “imipenen” and “ftsidate.” Such errors do not automatically invalidate a patent, but their effect depends on whether the intended meaning is reasonably apparent from the patent record.

When did US 6,852,689 lose exclusivity?

The patent’s ordinary 20-year term was measured from the January 22, 2002 nonprovisional filing date, subject to any patent-term adjustment. The resulting term endpoint was approximately January 22, 2022. The patent is therefore no longer an active US exclusion right.

Milestone	Date
Priority filing	January 22, 2001
US nonprovisional filing	January 22, 2002
Patent grant	February 8, 2005
Approximate ordinary expiration	January 22, 2022
Current prospective blocking effect	None after expiration

Patent expiration does not erase potential historical liability for conduct occurring before expiration. It also does not eliminate regulatory exclusivity, product liability, trade-secret rights or other patents that may have covered particular formulations or manufacturing processes.

What was the Orange Book status?

The FDA Orange Book historically listed daptomycin-related patents for Cubicin and related products. US 6,852,689 was associated with daptomycin dosing protection and was relevant to ANDA applicants evaluating paragraph IV certifications.

After the patent’s expiration, it no longer creates a current Orange Book patent bar. Orange Book listing status must be distinguished from patent validity and patent enforceability. A listed patent can be challenged, expire, delist or become nonblocking while the NDA remains approved.

Daptomycin is regulated as a conventional small-molecule drug. An applicant seeking approval of a generic daptomycin injection generally uses an ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act, not a 351(k) biosimilar application.

Which companies challenged daptomycin patent protection?

Publicly reported generic competition involved major ANDA applicants and generic manufacturers, including Hospira, Teva and other applicants pursuing daptomycin injection products. The commercial disputes centered on whether generic products infringed listed patents and whether the patents were invalid or unenforceable.

The existence of an ANDA paragraph IV certification does not itself establish that the patent is invalid. It is a statutory mechanism that can trigger patent litigation and, in some circumstances, a 30-month stay of FDA approval under the Hatch-Waxman framework. The commercial effect depends on the patent claims asserted, the timing of the litigation and any settlement or consent judgment.

A complete historical litigation determination requires review of each ANDA applicant’s notice letter, district-court docket and settlement terms. The expiration of US 6,852,689 means those disputes no longer control prospective generic entry under this patent.

What other patents were important to daptomycin?

The daptomycin estate had several distinct layers.

Patent layer	Representative protection	Commercial relevance
Molecule and antibiotic class	Earlier daptomycin patents, including US 4,208,479	Core compound protection; expired
Formulation	Daptomycin injectable compositions and stability	May have delayed or shaped generic formulation entry
Dosing	US 6,852,689	Extended-interval and higher-dose regimens; expired
Product presentation	Reconstituted injectable products, excipients and manufacturing	Potential product-specific barriers
Regulatory exclusivity	NDA exclusivity and pediatric exclusivity, where applicable	Separate from patent term

The original daptomycin compound patent did not remain a current barrier when the later dosing patent expired. Formulation and manufacturing patents can matter independently, but they do not extend the term of US 6,852,689.

Cubist was the principal commercial developer of Cubicin. Merck acquired Cubist in 2015, transferring the commercial daptomycin franchise to Merck. Eli Lilly was associated with the earlier development and commercialization history of daptomycin, while Cubist became the principal product company in the US market. The ownership history does not change the expiration date of the patent.

How strong was the patent estate?

The patent was strongest against a regimen deliberately designed around the claimed extended interval and dose parameters, particularly:

• 4 or 6 mg/kg every 48 to 96 hours;
• repeated administration for 7 to 14 days;
• intravenous use in a human patient; and
• treatment of a bacterial infection.

Its principal weaknesses were:

• the subjective or functional toxicity limitation;
• broad inclusion of oral administration;
• lack of a defined quantitative toxicity standard;
• possible enablement issues for some routes and dose ranges;
• inconsistent dependent claims;
• potential prior-art challenges involving earlier daptomycin dosing and toxicity studies; and
• limited prospective value after January 2022 expiration.

The claims did not cover every daptomycin use. Standard 4 mg/kg or 6 mg/kg once-daily regimens would not satisfy the expressly recited 48-hour-to-weekly interval. A generic manufacturer could therefore distinguish ordinary daily dosing from the patented extended-interval methods, subject to the specific claim and conduct at issue.

What generic launch risks existed?

Before expiration, generic launch risk depended on four factors:

1. Whether the ANDA applicant certified against US 6,852,689 under paragraph IV.
2. Whether the proposed label instructed or encouraged an infringing extended-interval regimen.
3. Whether other formulation or manufacturing patents remained enforceable.
4. Whether a litigation settlement imposed a licensed entry date.

After expiration, US 6,852,689 no longer supports a prospective injunction against a generic daptomycin product. Remaining risks may arise from other unexpired patents, regulatory requirements, manufacturing controls, injectable-product quality, supply-chain constraints and product liability.

There is no biosimilar risk in the technical regulatory sense because daptomycin is a small molecule. The relevant competitive risk is generic ANDA entry.

How does US 6,852,689 compare with competing antibiotic patents?

US 6,852,689 differs from many antibiotic patents because it does not claim:

• a new chemical entity;
• a new salt or polymorph;
• a specific pharmaceutical composition;
• a manufacturing process; or
• a biomarker-defined patient population.

Its value was concentrated in clinical-use instructions. That makes it more dependent on labeling, physician behavior and the factual details of administration than a composition patent. Composition and formulation patents usually offer clearer product-level enforcement because the accused product itself can embody the claimed subject matter. Method patents require proof of the claimed treatment act and, in some cases, the purpose or result limitation.

Key Takeaways

• US 6,852,689 covered extended-interval daptomycin dosing, generally every 48 hours to once weekly.
• The core dose scope began at 3 mg/kg and reached 75 mg/kg in treatment claims.
• The most relevant commercial doses were 4 mg/kg and 6 mg/kg.
• Claims covered administration, bacterial-infection treatment, treatment duration, oral/subcutaneous/intravenous routes and combination antibiotics.
• “Minimizes skeletal muscle toxicity” is a central functional limitation and a potential claim-construction issue.
• Claims 38 through 43 contain apparent dependency and dose inconsistencies.
• The patent’s ordinary term expired approximately January 22, 2022.
• Daptomycin is a small-molecule drug, so generic competition proceeds under the ANDA pathway, not the biosimilar pathway.
• Current generic-entry analysis must focus on remaining formulation, manufacturing, regulatory and product-specific patents rather than US 6,852,689.

FAQs

What daptomycin dose did US 6,852,689 most directly protect?

The patent directly protected at least 3 mg/kg administered every 48 hours to once weekly, with narrower claims covering 4 mg/kg, 6 mg/kg and other specified doses.

Did US 6,852,689 cover once-daily daptomycin?

No. The principal claims require repeated administration every 48 hours to once weekly. A once-daily regimen does not satisfy that interval limitation.

Is US 6,852,689 still enforceable against a generic daptomycin product?

No, the patent’s ordinary US term expired in approximately January 2022. Other patents must be evaluated separately.

Did the patent cover oral daptomycin?

The claims recite oral, subcutaneous and intravenous administration. Oral coverage may have faced enablement and written-description issues because approved daptomycin therapy is principally intravenous.

Does daptomycin have biosimilar competition?

No. Daptomycin is a conventional small-molecule antibiotic. Competing products are reviewed as generic drugs through the ANDA process, not as biosimilars under section 351(k).

References

1. Cubist Pharmaceuticals, Inc. (2005). Methods for administering daptomycin (U.S. Patent No. 6,852,689 B2). United States Patent and Trademark Office.

2. Food and Drug Administration. (2023). Cubicin (daptomycin for injection) prescribing information. U.S. Department of Health and Human Services.

3. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: The Orange Book. U.S. Department of Health and Human Services.

4. United States Code. (2023). 35 U.S.C. §§ 102, 112, 154 and 271. U.S. Government Publishing Office.

5. United States Code. (2023). 21 U.S.C. § 355. U.S. Government Publishing Office.

Drugs Protected by US Patent 6,852,689

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 6,852,689

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