Details for Patent: 8,394,406

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Summary for Patent: 8,394,406

Title:	Once daily formulations of tetracyclines
Abstract:	Disclosed are once-daily formulations containing tetracyclines, especially doxycycline. Such formulations are useful, for instance, for the treatment of collagenase destructive enzyme-dependent diseases, such as periodontal disease and acne, and acute and chronic inflammatory disease states, such as rosacea and arthritis.
Inventor(s):	Rong-Kun Chang, Arash Raoufinia, Niraj Shah
Assignee:	Tcd Royalty Sub Lp
Application Number:	US12/926,934
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,394,406
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Dosage form;

US Patent 8,394,406: Scope and claims map for once-daily oral doxycycline with IR/enteric DR ratio, exposure windows, and rosacea method-of-use

US Patent 8,394,406 claims a specific pharmacokinetic target for doxycycline exposure after once-daily dosing, tied to a two-part oral composition that mixes an immediate release (IR) doxycycline fraction with an enteric-delayed release (DR) doxycycline fraction in a defined 75:25 ratio, plus optional formulation embodiments and excipient/polymer selections. The estate is structured to create both composition-level protection and downstream use and manufacturing coverage.

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What is US Patent 8,394,406 protecting? (high-level claim scope)

Core protected subject matter. The patent protects an oral pharmaceutical composition of doxycycline administered once daily where:

• Total doxycycline dose is < 50 mg
• Exposure at steady state is constrained:
  • Steady state blood levels: 0.1 to 1.0 μg/mL
  • Cmax: 0.4 to 0.8 μg/mL
• The composition consists of:
  • (i) an immediate release (IR) doxycycline formulation
  • (ii) a delayed release (DR) doxycycline formulation with at least one enteric polymer
  • (iii) pharmaceutically acceptable excipients
• The doxycycline in IR and DR is at a 75:25 ratio (IR:DR by doxycycline amount)

Independent protection layers.

1. Composition product (Claim 1)
2. Composition PK refinement (Claim 2)
3. Dosage form embodiments (Claim 3–4, 7)
4. Enteric polymer definition (Claim 5–6)
5. Method-of-use for rosacea (Claim 17–20)
6. Manufacturing/process that assembles the 75% IR + 25% DR parts (Claim 21)

This creates an “overlapping injunction surface”: a competitor hitting the same exposure window with the same IR/enteric DR split and dose range risks composition infringement; a challenger marketing for rosacea risks method-of-use infringement; and if they build the product by mixing the specified IR and DR fractions, process infringement exposure increases.

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How do the claim limitations work together? (claim construction logic)

Claim 1 is the main gate. Everything else is narrower, dependent, or both. The patent’s infringement risk is highest where all of these are simultaneously met:

• Oral composition (not injectable)
• Once-daily regimen
• Total doxycycline < 50 mg
• Specific exposure targets at steady state:
  • trough/overall steady-state blood levels: 0.1–1.0 μg/mL
  • Cmax: 0.4–0.8 μg/mL
• Two-component release architecture:
  • IR component
  • DR component with enteric polymer
• 75:25 doxycycline amount split between IR and DR components

Exposure targets are not incidental. The patent uses PK bands as substantive limitations, which can be a strong differentiator versus prior art that uses different release profiles or dosing. In practical claim charts, these numbers become the decisive infringement factors.

The polymer list matters but is not the only path. Claim 6 enumerates exemplary enteric polymers. Claim 5 is broader (“at least one enteric polymer”), while Claim 6 provides a closed list for a dependent path. For freedom-to-operate (FTO), the critical question is whether a design avoids the exact polymers is less important than whether it still satisfies:

• “enteric polymer” requirement, and
• the same IR/DR functional performance driving the PK windows.

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What formulations are covered by Claim 1 beyond the IR/DR split?

Dosage forms and presentation (Claims 3–4, 7)

Claim 3 covers that IR and/or DR formulation can be in many physical forms:

• granule, tablet, pellet, powder, sachet, capsule
• gel, dispersion, suspension

Claim 4 adds an explicit sub-embodiment: “dosage form … of a combination of pellets.”

Claim 7 specifies DR can be granules/pellets/tablet. This supports generic-like engineering while still tying to the PK/exposure constraints and enteric polymer requirement.

Practical implication. A competitor cannot avoid infringement simply by choosing a different dosage unit operation (tablet vs pellet vs capsule) if the IR/enteric DR composition and PK limitations remain met.

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Which enteric polymers are within scope? (Claim 6 polymer estate)

Claim 6 lists enteric polymers including:

• cellulose acetate phthalate (CAP)
• hydroxypropyl methylcellulose phthalate (HPMCP)
• polyvinyl acetate phthalate (PVAP)
• hydroxypropyl methylcellulose acetate succinate (HPMCAS)
• cellulose acetate trimellitate
• hydroxypropyl methylcellulose succinate (HPMCS)
• cellulose acetate succinate
• cellulose acetate hexahydrophthalate
• cellulose propionate phthalate
• methylmethacrylic acid / methyl methacrylate copolymer
• methyl acrylate / methylmethacrylate / methacrylic acid copolymer
• methylvinyl ether / maleic anhydride copolymer
• ethyl methyacrylate–methylmethacrylate–chlorotrimethylammonium ethyl acrylate copolymer
• zein
• shellac
• poly(methacylic acid-co-ethyl acrylate) 1:1
• combinations

How this shapes design-around.

• If the DR component uses any of these polymers, the design lands squarely in Claim 6 dependent coverage.
• If a developer uses different “enteric” materials, they may avoid Claim 6 but still fall within Claim 5 if the polymer qualifies as an enteric polymer and the formulation still achieves the claim’s exposure bands with the 75:25 IR/DR split.

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What excipients are disclosed/covered as limitations? (Claims 8–15)

Claim 8 says excipients can be incorporated in IR, DR, or both. Claim 9 lists binder/disintegration agent/filling agent/surfactant/solubilizer/stabilizer categories. Claims 10–15 give selection lists.

Binders (Claim 10)

• methylcellulose
• hydroxyethyl cellulose
• hydroxypropyl cellulose
• hydroxypropyl methylcellulose
• polyvinylpyrrolidone
• polyvinylpyrrolidone/vinyl acetate copolymer

Disintegration agents (Claim 11)

• cornstarch
• pregelatinized starch
• cross-linked carboxymethylcellulose
• sodium starch glycolate
• cross-linked polyvinylpyrrolidone

Filling agents (Claim 12)

• lactose
• calcium carbonate/phosphate/sulfate
• microcrystalline cellulose
• dextran
• starches
• sucrose
• xylitol, lactitol, mannitol, sorbitol
• sodium chloride
• polyethylene glycol

Surfactants (Claim 13)

• sodium lauryl sulfate
• sorbitan monooleate
• polyoxyethylene sorbitan monooleate
• bile salts
• glyceryl monostearate

Solubilizers (Claim 14)

• citric, succinic, fumaric, malic, tartaric, maleic, glutaric acids
• sodium bicarbonate, sodium carbonate

Stabilizers (Claim 15)

• antioxidation agents
• buffers
• acids

Key scope point: these excipient lists appear as dependent limitations (Claim 9 onward). A generic could attempt to avoid these dependent claims by using different excipients. But Claim 1 still requires “pharmaceutically acceptable excipients” generally. If the excipients are “acceptable” and the core IR/DR ratio and PK targets are met, Claim 1 is still the main infringement vector.

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What is the second exposure refinement in Claim 2?

Claim 2 depends on Claim 1 but tightens steady-state blood levels:

• Steady-state blood levels: 0.3 to 0.8 μg/mL

This narrower band reduces design-around options. A product that meets Claim 1 but produces higher/low steady-state average blood levels may fall outside Claim 2 but still inside Claim 1 if Claim 1’s broader “0.1–1.0” range is met.

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How broad is the rosacea method-of-use protection?

Rosacea method-of-use claim coverage (Claims 17–20)

Claim 17 is a rosacea treatment method that administers the same claimed oral pharmaceutical composition with the same once-daily PK limitations and IR/DR ratio:

• total doxycycline < 50 mg
• once daily steady-state blood levels: 0.1–1.0 μg/mL
• once daily Cmax: 0.4–0.8 μg/mL
• IR/DR doxycycline ratio: 75:25
• IR and DR formulations with DR requiring enteric polymer and both with excipients

Claim 18 specifies the mammal is human.

Claim 19 restates a steady-state blood band (but the text provided appears inconsistent): it references “between 0.3 pg/mL to 0.8 μg/mL.” The intended unit is likely μg/mL, but the claim text as provided includes “pg/mL.” Claim construction disputes can occur on unit precision, but the independent basis remains Claim 17.

Claim 20 states a specific Cmax: 0.6 μg/mL.

Practical implication for challenges and licensing.

• If a product hits the Claim 1 composition boundaries and is marketed/used for rosacea, Claim 17 is a direct infringement hook.
• If a product does not match the rosacea indication but still meets the composition PK limitations, composition infringement risk remains; method-of-use infringement risk depends on labeling/use.

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When does a once-daily doxycycline product avoid infringement risk? (design-around map)

Based on the claim structure, the highest-leverage design changes are:

1) Break the 75:25 doxycycline split

A formulation with different IR:DR doxycycline amounts can avoid the “ratio of 75:25” limitation. This is the cleanest physical design lever in the claim set.

2) Move Cmax outside 0.4–0.8 μg/mL at once-daily steady state

Even with a similar IR/enteric DR split, shifting the exposure band can exit Claim 1’s PK limitations. Any IR/DR blend that creates a higher or lower Cmax may avoid infringement.

3) Move steady-state blood levels outside 0.1–1.0 μg/mL

Similarly, shifting absorption kinetics so steady-state levels fall below 0.1 or above 1.0 μg/mL avoids Claim 1 regardless of the intended dose concept.

4) Remove “enteric polymer” delayed release

A DR component that is not enteric-delayed or lacks at least one enteric polymer should not satisfy Claim 1’s DR limitation, assuming the release mechanism changes materially.

5) Keep the composition but avoid rosacea use

This can reduce method-of-use infringement exposure, but composition claims are still at issue.

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How does Claim 21 expand protection into manufacturing?

Claim 21 covers a process:

• “preparing a once-daily oral pharmaceutical composition according to claim 1”
• by combining:
  • (i) IR formulation comprising 75 percent of the total doxycycline
  • (ii) DR formulation comprising 25 percent of the total doxycycline

This is a process claim that captures mixing/assembling steps consistent with the 75:25 split. If a contract manufacturer assembles the same IR/DR fractionation, process infringement is a potential add-on to composition infringement.

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What other patent estate items are typically paired with claims like this? (landscape structure)

The claim set itself suggests a formulation-centric estate likely distributed across:

• IR/enteric DR architecture patents,
• PK-targeted dosage patents,
• rosacea method-of-use patents,
• and excipient/solid form/dosage unit manufacturing patents.

However, the provided prompt does not include bibliographic metadata (assignee, filing dates, priority, jurisdictions, continuation family) or any related U.S. patents. Without those elements, a definitive family-wide landscape cannot be produced from the claim text alone.

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Claim-by-claim infringement checklist (useful for FTO and litigation positions)

Composition infringement (Claim 1). A product infringes if it is:

• oral, once-daily
• doxycycline total dose < 50 mg
• has steady-state exposure:
  • steady-state blood levels 0.1–1.0 μg/mL
  • Cmax 0.4–0.8 μg/mL
• uses a formulation architecture:
  • IR doxycycline formulation
  • DR doxycycline formulation with at least one enteric polymer
  • excipients
• where doxycycline amount is in 75:25 IR:DR ratio

Additional composition limitations (dependent claims).

• Claim 2: tighter steady-state band (0.3–0.8 μg/mL)
• Claim 3: physical form of IR/DR can be varied
• Claim 4: combination of pellets
• Claim 5–6: enteric polymer definition, with a detailed polymer list in Claim 6
• Claims 8–15: excipient categories and selection lists

Method-of-use infringement (Claim 17).

• administer the infringing composition to treat rosacea in mammals (human specified in Claim 18)
• includes the same PK boundaries and 75:25 IR:DR ratio
• Claim 20 pins Cmax to 0.6 μg/mL (dependent)

Process infringement (Claim 21).

• preparing by combining IR 75% doxycycline with DR 25% doxycycline consistent with Claim 1 composition.

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Key takeaways

• US 8,394,406 is a formulation-and-PK patent for once-daily oral doxycycline with a 75:25 IR:enteric DR split and defined steady-state exposure and Cmax bands.
• Rosacea use is directly claimed using the same composition and PK limitations, increasing litigation leverage for any product used for rosacea with matching exposure.
• Enteric polymer scope is broad at the concept level (“at least one enteric polymer”) and supported by an enumerated polymer list in a dependent claim.
• Excipients are compartmentalized into dependent lists; avoiding those alone likely does not defeat Claim 1 if the core PK/exposure and IR/DR split remain.
• Process claim coverage exists through mixing/combining IR 75% + DR 25% fractions, supporting manufacturing-related enforcement.

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FAQs

1) What is the single most important limitation in US 8,394,406?
The combination of (a) once-daily dosing and (b) the 75:25 IR:enteric DR doxycycline ratio plus (c) the stepped PK bands (steady-state 0.1–1.0 μg/mL and Cmax 0.4–0.8 μg/mL).

2) Does changing the physical dosage form (tablet vs pellet) avoid infringement?
No. Claim 3 and Claim 7 permit multiple forms (granules, pellets, tablets, capsules, dispersions, gels). Avoidance would require changing release architecture, PK outcomes, or the 75:25 split.

3) If a competitor uses a different enteric polymer, can they avoid the patent?
They may avoid the dependent polymer list in Claim 6, but not necessarily Claim 1’s “at least one enteric polymer” requirement, especially if the formulation still meets the exposure targets and IR/DR split.

4) Can a product infringe Claim 17 without being labeled for rosacea?
Claim 17 is tied to treating rosacea, so infringement risk depends on intended use and actual administration for rosacea. Composition infringement is separate.

5) What manufacturing step is most relevant to Claim 21?
Assembling the composition by combining an IR fraction at 75% of total doxycycline with a DR fraction at 25% of total doxycycline.

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References

1. United States Patent 8,394,406, “Oral pharmaceutical composition comprising doxycycline with immediate release and delayed release fractions,” claims provided in prompt.

Drugs Protected by US Patent 8,394,406

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 8,394,406

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	2521885
Canada	2803922
Canada	2894736