Details for Patent: 8,394,405

Summary for Patent: 8,394,405

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:	US12/926,932
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,394,405
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Dosage form;

US Patent 8,394,405 Scope, Claims, and Doxycycline Patent Landscape (Rosacea once-daily IR/DR blend)

US Patent 8,394,405 is directed to a once-daily oral doxycycline product for rosacea that blends two doxycycline populations in a fixed ratio: 70–80% immediate-release (IR) and 20–30% delayed-release (DR) such that steady-state systemic exposure at once daily dosing stays within defined plasma concentration windows. The claims cover (i) the drug product composition, (ii) a rosacea method-of-use, and (iii) a manufacturing process for producing the IR/DR blend. The estate is tightly scoped to product-defining pharmacokinetic bands and to specific delayed-release polymer classes that include common enteric polymers (e.g., cellulose acetate phthalate and related phthalates, succinates, and acrylate copolymers).

Claim-defining levers

• Dose level: about 40 mg total doxycycline.
• Dosing schedule: once daily.
• PK window (broad): steady-state Cmax/Ctr analog framed as minimum ≥0.1 μg/mL and maximum ≤1.0 μg/mL (Claim 1).
• PK window (narrow): 0.3–0.8 μg/mL (Claim 2 and indirectly Claim 19).
• IR/DR ratio: 70–80% IR and 20–30% DR (Claim 1), with a dependent “specific ratio” 75:25 (Claim 3).
• Dosage form flexibility: granules, tablets, pellets, powders, sachets, capsules, gels, dispersions, suspensions (Claim 4); also “combination of pellets” (Claim 5).
• DR mechanism: at least one enteric polymer (Claim 6) with a long non-exclusive list of specific polymer options (Claim 7).
• Process: combining IR and DR fractions in the same weight ranges (Claim 20).

Commercial read-through This claim set is engineered to protect a branded or authorized controlled-release doxycycline approach for rosacea against generic designs that either (a) use a different total dose, (b) shift IR/DR proportions outside 70–80/20–30 (or 75:25), (c) fail to land within the stated steady-state plasma range, (d) use non-enteric DR technologies, or (e) change manufacturing to avoid the IR/DR blend architecture.

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What patents protect once-daily doxycycline for rosacea using IR/DR blends in the US?

Answer: US 8,394,405 protects composition + rosacea method + IR/DR manufacturing

US 8,394,405 contains three claim families:

1. Composition claims (Claims 1–16, with dependent formulation and excipient selections).
2. Method-of-use claims for rosacea (Claims 17–19).
3. Preparation/process claim for making the once-daily IR/DR product (Claim 20).

What is the product definition in US 8,394,405?

The product is defined by a combination of:

• Quantitative dose (“about 40 mg total doxycycline”),
• IR/DR fraction split (70–80% IR, 20–30% DR),
• Once-daily dosing,
• Steady-state systemic concentration range(s),
• and optionally DR enteric polymer identity plus excipient lists.

This is a “tight but flexible” structure: formulation options exist (granules/tablets/pellets; multiple polymer types; many excipients), but the IR/DR split and PK windows are hard constraints.

Composition scope in Claim 1

• About 40 mg doxycycline total.
• Once daily produces steady-state doxycycline blood levels:
  • minimum ≥0.1 μg/mL and
  • maximum ≤1.0 μg/mL.
• Composition contains:
  • 70–80% IR doxycycline
  • 20–30% DR doxycycline

Narrower PK claim in Claim 2

• Same base composition and dosing schedule
• steady-state blood levels 0.3–0.8 μg/mL

Fixed split in Claim 3

• IR:DR = 75:25 (a likely “anchor” target in enforcement).

Dosage form variability in Claim 4–5

• Multiple oral dosage forms
• Including “combination of pellets” (important for infringement analysis because generic design can be pellet-based or tablet-based while still using IR + enteric DR pellet populations).

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How strong is the patent estate for US 8,394,405: what in the claims is most enforceable?

Answer: enforceability hinges on PK windows + IR/DR fraction split + enteric DR polymer requirement

In US infringement disputes, product-claims like these are often contested on:

• whether accused products fall within the IR/DR percentage,
• whether steady-state exposure falls within the stated plasma concentration boundaries, and
• whether the DR portion uses an enteric polymer as claimed.

Because the claims explicitly tie performance to steady-state blood levels and define the IR/DR mix in percentages, these elements are likely the most litigable.

Most “attackable” elements

• Steady-state blood level windows: generics can attempt to demonstrate that clinical PK profiles at steady-state differ from the claim’s upper/lower bounds.
• IR/DR percent composition: a generic can try to adjust the IR/DR split and argue design-around.
• DR polymer type: although Claim 6 requires an enteric polymer, the dependent list (Claim 7) is detailed. A generic can attempt to use an enteric mechanism that arguably does not match claimed polymer classes or does not map to the enumerated options.

Most “defensive” elements

• Total dose ~40 mg: if the accused product uses a clearly different total doxycycline strength, it may fall outside “about 40 mg,” depending on claim construction.
• Once-daily schedule: many doxy regimens are once daily for rosacea, limiting generic differentiation if they must match indication-related exposure.

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What formulations are protected by US 8,394,405 (IR/DR ratio, dosage forms, polymers, excipients)?

Answer: any oral IR/enteric DR doxycycline composition meeting 40 mg, 70–80/20–30, and steady-state exposure windows

IR/DR architecture

• IR population: 70–80% of doxycycline.
• DR population: 20–30% doxycycline, enteric.

DR polymer coverage (Claim 6–7)

Claim 6 mandates at least one enteric polymer. Claim 7 lists specific candidates, including:

• Cellulose acetate phthalate (CAP)
• Hydroxypropyl methylcellulose phthalate (HPMCP)
• Polyvinyl acetate phthalate (PVAP)
• Hydroxypropyl methylcellulose acetate succinate
• Cellulose acetate trimellitate
• Hydroxypropyl methylcellulose succinate
• Cellulose acetate succinate
• Cellulose acetate hexahydrophthalate
• Cellulose propionate phthalate
• Copolymers such as:
  • methylmethacrylic acid and methyl methacrylate
  • methyl acrylate, methylmethacrylate, methacrylic acid
  • methylvinyl ether and maleic anhydride
  • ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer
• Zein, shellac
• Poly(methacylic acid-co-ethyl acrylate) 1:1
• and combinations of these

This breadth makes it harder to design around using a conventional enteric polymer strategy.

Dosage form and physical presentation (Claim 4–5)

• granules, tablet, pellets, powder, sachet, capsule, gel, dispersion, suspension
• and explicitly combination of pellets

That supports an infringement theory even if the product is marketed as tablets or capsules, as long as the internal IR and enteric DR doxycycline populations map to the claimed percentages and PK window.

Excipient coverage in the IR and/or DR fractions

Claim 9–16 include excipient selections in general terms. Examples:

• binders: methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, HPMC, PVP, PVP/VA
• disintegrants: cornstarch, pregelatinized starch, cross-linked CMC, sodium starch glycolate, cross-linked PVP
• fillers: lactose, calcium carbonate/phosphate/sulfate, MCC, dextran, starches, sucrose, xylitol/lactitol, mannitol, sorbitol, NaCl, PEG, etc.
• surfactants: sodium lauryl sulfate, sorbitan monooleate, polysorbates, bile salts, glyceryl monostearate
• solubilizers: citric/succinic/fumaric/malic/tartaric acids, maleic acid, glutaric acid, sodium bicarbonate/carbonate
• stabilizers: antioxidants, buffers, acids

Because the excipient lists are permissive “selected from,” they likely function as fallback dependent scope rather than a primary limitation in disputes, unless the accused product uses an excipient profile outside the enumerated group and the claim is enforced in the dependent form.

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When does US 8,394,405 lose exclusivity: what is the expiration timing logic for a US drug product patent?

Answer: expiration is determined by filing date and patent term rules; the claim set itself does not specify a calendar expiry

No expiration date is stated in the provided claim text. Patent term for a US utility patent is generally linked to the earliest effective non-provisional filing date (typically 20 years from earliest priority date, subject to adjustments). Without the patent’s filing/priority dates and any PTA/PTE values, a calendar expiration cannot be derived from the claim language alone.

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What generic entry risks exist for doxycycline rosacea IR/DR blends protected by US 8,394,405?

Answer: risk concentrates on “same-dose, same IR/DR split, same steady-state PK window” generic designs

For a generic to materially avoid infringement, it must typically do at least one of the following:

• use a different total doxycycline strength (not “about 40 mg”),
• alter the IR/DR fraction away from 70–80% IR / 20–30% DR (or avoid 75:25),
• shift steady-state systemic levels outside:
  • ≤1.0 μg/mL maximum or ≥0.1 μg/mL minimum (Claim 1), and/or
  • 0.3–0.8 μg/mL (Claim 2),
• use a delayed-release technology that does not rely on an enteric polymer as claimed (Claim 6),
• or change the architecture so the product cannot be described as the claimed IR/DR combination process (Claim 20).

Why PK is central

Unlike pure structural claims, these claims tie the product to steady-state plasma levels at once daily dosing. This gives the patent owner an evidentiary path using bioequivalence or in-use pharmacokinetic testing.

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Is there biosimilar or biologics risk for US 8,394,405?

Answer: no biosimilar framework applies

US 8,394,405 is for an oral pharmaceutical composition of doxycycline (small molecule antibiotic), not a biologic. The risk category is generic/oral solid dosage form design-around rather than biosimilar.

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What method-of-use claims does US 8,394,405 cover for rosacea?

Answer: administering the claimed once-daily IR/enteric DR doxycycline composition to treat rosacea

• Claim 17: method of treating rosacea using the claimed composition (about 40 mg; once daily; steady-state blood levels and IR/DR split).
• Claim 18: mammal is human.
• Claim 19: specifies the 0.3–0.8 μg/mL steady-state blood range at once-daily administration.

This creates a separate infringement lane against acts of administration even if the product form details are contested, as long as the administered doxycycline product fits the claim’s defining parameters.

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How does the claimed process (Claim 20) affect infringement and manufacturing/IP barriers?

Answer: the process claim targets assembling IR and DR fractions in the claimed proportions

Claim 20 covers “process for preparing” the once-daily oral composition by combining:

• (i) IR formulation comprising 70–80% doxycycline, and
• (ii) DR formulation comprising 20–30% doxycycline.

This can matter for:

• disputes over toll-manufacturing supply chains,
• claims against entities making the intermediate pellet fractions,
• and leverage in discovery (batch composition, blend ratios, and process parameters).

If a generic redesign shifts IR/DR percentages or changes how dosing units incorporate the two populations, it may avoid both product and process claims.

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How does US 8,394,405 compare with other doxycycline patents for rosacea (claim focus differences)?

Answer: US 8,394,405 is PK-window + fixed IR/enteric DR split focused

Compared with:

• patents that cover only formulation (e.g., enteric coatings in general) without tying to steady-state concentration bands,
• patents that cover only method-of-use without product definitions,
• or patents that cover a single formulation with a broader dose range, US 8,394,405 has a narrower set of definitional anchors: dose ~40 mg, once daily, IR/DR 70–80/20–30, and steady-state blood level windows.

This tends to reduce the number of “accidentally covered” products, but it increases the importance of PK testing and compositional analysis for enforcement.

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What is the Orange Book status of US 8,394,405 and what does that imply for Paragraph IV challenges?

Answer: Orange Book status cannot be concluded from claim text alone

US Orange Book listing status depends on the NDA and patent registration records. The claim text provided does not include Orange Book patent codes, NDA numbers, or listing identifiers, and no linking references are included here.

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Key Takeaways

• US 8,394,405 protects a once-daily oral doxycycline rosacea product that uses a fixed IR/enteric DR composition split (70–80% IR, 20–30% DR) at ~40 mg total doxycycline.
• The scope is tightened by explicit steady-state blood level windows: ≥0.1 μg/mL and ≤1.0 μg/mL (Claim 1) and 0.3–0.8 μg/mL (Claim 2/19).
• Dependent claims expand into enteric polymer identity and excipient selections, but the enforceable core is the IR/DR ratio + PK band + enteric DR requirement.
• Generic design-around risk is highest where a candidate aims to match the same dose and PK target while using similar enteric polymer systems.
• The estate includes product, method-of-use, and a manufacturing/process claim that targets combining IR and DR fractions in the claimed proportions.

FAQs

1. Can a generic avoid US 8,394,405 by changing only excipients?
   Changing excipients alone is unlikely to avoid the core claim limits tied to dose, IR/DR split, and steady-state blood levels.

2. Does US 8,394,405 require a specific dosage form (tablet vs capsule)?
   No. Claim 4 includes multiple oral dosage forms, including granules/tablets/pellets/capsules and suspensions.

3. Is the 75:25 IR:DR ratio always required?
   No. Claim 3 adds a specific 75:25 dependent limitation. Independent Claim 1 covers any 70–80/20–30 split.

4. What is the role of steady-state plasma concentrations in infringement?
   The claims define composition by resulting steady-state blood level ranges, making PK evidence central to infringement and validity disputes.

5. Is there biosimilar-style regulatory or patent risk under US 8,394,405?
   No. The patent is for a small-molecule antibiotic formulation, so the competitive risk is generic oral product design-around rather than biologics.

Drugs Protected by US Patent 8,394,405

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 8,394,405

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	2521885
Canada	2803922
Canada	2894736
Denmark	1615622
Denmark	2204168