US Patent 10,028,946: Hydrocodone Hepatic-Impairment Claims, Scope, Expiry and Patent Landscape
US Patent 10,028,946 protects a method of treating pain in patients with mild or moderate hepatic impairment using a hydrocodone bitartrate oral dosage unit that combines immediate-release and extended-release hydrocodone. The central commercial limitation is that the initial dose is not reduced for hepatic impairment, provided the product satisfies specified hydrocodone exposure, dissolution, dose-strength and release-ratio parameters.
The patent is directed to a clinical-use method, not a broad composition-of-matter claim. Its practical relevance is greatest for products that use the same bead-based or multiparticulate hydrocodone extended-release architecture associated with Zohydro ER.
What drug does US Patent 10,028,946 protect?
US 10,028,946 is titled “Methods of treating pain using hydrocodone formulations in patients with hepatic impairment.” The patent concerns hydrocodone bitartrate administered as the only active ingredient in an oral dosage unit.
The claimed product must have:
| Claim limitation |
Required scope |
| Active ingredient |
Hydrocodone bitartrate as the only active ingredient |
| Patient |
A patient with mild or moderate hepatic impairment |
| Indication |
Treatment of pain |
| Initial dose |
Not adjusted relative to a patient without hepatic impairment |
| Release architecture |
Immediate-release and extended-release components |
| Immediate-release fraction |
Generally 15% to 25% of total hydrocodone; about 20% in narrower claims |
| Extended-release fraction |
Generally 75% to 85%; about 80% in narrower claims |
| Dose strengths |
10, 15, 20, 30, 40 or 50 mg, with narrower claims excluding 10 mg |
| Dosage form |
May comprise separate populations of immediate-release and extended-release beads |
| Pharmacokinetics |
Specified hydrocodone AUC and, in some claims, Cmax ranges |
| Dissolution |
Defined first-hour and 12-hour release percentages in pH 6.8 buffer |
The patent therefore does not cover every hydrocodone extended-release product. A competing product could avoid literal infringement by changing the active-ingredient combination, release ratio, dosage form, dissolution profile, dose-strength set or clinical dosing instruction.
How do claims 1 through 20 of US 10,028,946 differ?
Claims 1, 11 and 19 are the independent claims. The remaining claims add narrower technical or pharmacokinetic limitations.
Independent claim structure
| Claim |
Principal scope |
| Claim 1 |
Hepatic-impairment treatment method with 15%-25% immediate release, 75%-85% extended release and broad AUC ranges |
| Claim 11 |
Similar method, but with narrower AUC ranges corresponding to claims 2 and 11 |
| Claim 19 |
About 20% immediate release, about 80% extended release, listed dose strengths and broad AUC ranges |
Claims 1 and 19 are similar, but claim 19 requires the approximately 20:80 release composition and expressly recites the dose-strength set. Claim 11 uses the narrower AUC ranges from claim 2.
Dependent-claim clusters
Claims 2, 3 and 4 add pharmacokinetic limitations:
- Claim 2 narrows AUC for mild hepatic impairment to about 352-528 ng·h/mL per 20 mg and for moderate impairment to about 405-615 ng·h/mL per 20 mg.
- Claim 3 adds a mild-impairment Cmax range of about 19.2-28.8 ng/mL.
- Claim 4 adds a moderate-impairment Cmax range of about 20-30 ng/mL.
Claims 5 and 12 require an approximately 20:80 immediate-release-to-extended-release hydrocodone ratio.
Claims 6 and 13 require a first population of beads for the immediate-release component and a second bead population for the extended-release component.
Claims 7, 8 and 14-16 add dissolution limits. The principal ranges are:
| Dissolution period |
Broad range |
Narrower range |
| First hour |
About 10%-30% released |
About 15%-25% released |
| First 12 hours |
More than 60% and less than 98% |
About 65%-95% |
Claims 9, 10, 17, 18 and 20 limit the unit dose to specified hydrocodone bitartrate strengths.
What is the strongest patent scope in US 10,028,946?
The strongest practical scope is concentrated in the combination of:
- Hydrocodone bitartrate as the sole active ingredient.
- Treatment of mild or moderate hepatic impairment.
- No reduction in the initial dose.
- Approximately 20% immediate-release hydrocodone and 80% extended-release hydrocodone.
- Defined AUC ranges in impaired subjects.
- A multiparticulate bead formulation or equivalent release architecture.
- Dose strengths overlapping commercial hydrocodone ER products.
The claims are narrower than a conventional formulation patent because they require the treatment method and the hepatic-impairment dosing instruction. A product manufacturer that sells the same dosage form without labeling or instructing use in patients with hepatic impairment may present a different infringement analysis. The risk increases where the approved label expressly states that no starting-dose adjustment is needed for mild or moderate hepatic impairment.
The AUC limitations create a technical infringement issue. The patent measures exposure normalized to 20 mg of hydrocodone bitartrate. A generic sponsor could challenge whether its product achieves the claimed average population values, whether the ranges are inherent in the dosage form, and whether differences in study design, food conditions or patient selection affect the comparison.
When does US Patent 10,028,946 expire?
The patent record identifies a 2013 priority date and a July 24, 2018 issue date. On a standard 20-year patent term measured from the earliest effective nonprovisional filing, the expected term extends into 2033, subject to patent-term adjustment, terminal disclaimers, prosecution history and any applicable patent-term extension.
| Event |
Date |
| Earliest reported priority |
March 15, 2013 |
| US patent application publication |
2017 |
| Patent grant |
July 24, 2018 |
| Expected unadjusted term endpoint |
March 15, 2033 |
| Patent number |
US 10,028,946 B2 |
The controlling expiration date should be taken from the USPTO Patent Center record and the Orange Book entry for the relevant NDA. Patent expiration is distinct from FDA marketing exclusivity. A patent can remain enforceable after regulatory exclusivity ends, and an Orange Book-listed patent can affect ANDA timing even when the associated product has limited sales.
What is the Orange Book status of US 10,028,946?
The patent is associated with the hydrocodone bitartrate extended-release product Zohydro ER and its US NDA history. Zohydro ER was approved by FDA in 2013 as an extended-release hydrocodone product without an acetaminophen combination. FDA approval was based on hydrocodone bitartrate extended-release capsules for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment.[2]
The commercial and regulatory analysis must distinguish Zohydro ER from Hysingla ER. Hysingla ER is also hydrocodone bitartrate extended release, but it is a separate product with a different dosage form and sponsor history. Overlap in active ingredient does not establish infringement because US 10,028,946 requires a particular hepatic-impairment treatment method and release profile.
The relevant Orange Book questions are:
- Whether US 10,028,946 remains listed against the applicable NDA.
- Whether the NDA holder has submitted a timely patent-listing update.
- Whether the product has been formally discontinued or remains eligible for ANDA reference.
- Whether an ANDA applicant has certified Paragraph IV against the patent.
FDA’s Orange Book identifies listed patents and exclusivity information, but it does not resolve infringement or validity. The patent holder must enforce the patent in federal court under the Hatch-Waxman framework if an ANDA Paragraph IV notice creates a statutory cause of action.[3,4]
Are there Paragraph IV challenges to US 10,028,946?
A Paragraph IV certification alleges that a listed patent is invalid, unenforceable or will not be infringed by the proposed generic. The certification itself does not invalidate the patent or authorize immediate launch.
For US 10,028,946, the likely challenge points are:
Lack of written description or enablement
The claims cover defined pharmacokinetic ranges across mild and moderate hepatic impairment. An ANDA applicant could argue that the specification does not enable the full breadth of the claimed AUC and Cmax ranges across all dose strengths, formulations and patient populations.
Indefiniteness
Terms such as “about,” “starting dose,” “mild hepatic impairment,” “moderate hepatic impairment,” “average,” and “not adjusted” may attract claim-construction challenges. The patent specification and incorporated clinical definitions would control the analysis.
Obviousness
A challenger could combine known hydrocodone extended-release formulations with known hepatic-impairment pharmacokinetic studies and dosing guidance. The patent holder would rely on the claimed combination of no starting-dose adjustment, a defined release ratio and specific exposure ranges.
Infringement by a different formulation
A generic product using a tablet matrix, an altered immediate-release fraction or a different dissolution profile could argue that it does not meet the express formulation limitations. The doctrine of equivalents could remain relevant, but the numerical ranges make equivalence fact-intensive.
No biosimilar pathway applies. Hydrocodone bitartrate is a chemically synthesized small molecule, so the relevant competitive pathway is an ANDA under section 505(j), not a biosimilar application under section 351(k).
What formulation patents compete with US 10,028,946?
The surrounding patent landscape includes several distinct categories:
| Patent category |
Typical protected subject matter |
Relevance to US 10,028,946 |
| Hydrocodone composition patents |
Hydrocodone salts, dosage forms and release systems |
May overlap with the same commercial product |
| Multiparticulate patents |
Immediate-release and coated extended-release beads |
Directly relevant to claims 6 and 13 |
| Dissolution patents |
Release percentages at defined pH and time points |
Relevant to claims 7, 8 and 14-16 |
| Hepatic-impairment method patents |
Dose selection based on liver function |
Directly covered by the independent claims |
| Abuse-deterrence patents |
Physical or chemical resistance to manipulation |
Separate issue unless incorporated into the claimed product |
| Method-of-use patents |
Treatment of chronic pain with hydrocodone ER |
May overlap in indication but not necessarily in hepatic dosing |
A product can face multiple patent barriers. Avoiding US 10,028,946 does not establish freedom to operate if another listed formulation or method-of-use patent covers the same dosage form.
How does US 10,028,946 compare with Hysingla ER patent risk?
Zohydro ER and Hysingla ER both contain hydrocodone bitartrate, but the commercial products differ materially.
| Issue |
Zohydro ER |
Hysingla ER |
| Active ingredient |
Hydrocodone bitartrate |
Hydrocodone bitartrate |
| Release design |
Extended-release capsule with multiparticulate technology associated with Zohydro ER |
Extended-release tablet |
| US approval |
2013 |
2014 |
| Patent 10,028,946 relevance |
Directly aligned with its claimed bead and release architecture |
Less direct where the product does not satisfy the claimed formulation limitations |
| Hepatic method |
No starting-dose adjustment for mild or moderate impairment is central to the patent |
Label and product-specific data require separate analysis |
| Competitive pathway |
ANDA |
ANDA |
The patent should not be treated as a patent on hydrocodone ER generally. Its value depends on whether the accused product reproduces the claimed clinical and formulation combination.
What litigation and settlement issues affect the patent?
A Paragraph IV notice could trigger a 30-month stay of FDA approval if the NDA holder or patent owner files a timely infringement action under 21 U.S.C. § 355(j)(5)(B)(iii). A settlement could provide a licensed launch date, a supply arrangement or other terms, subject to antitrust and FTC scrutiny.
The patent’s claim format creates two litigation tracks:
- Product-focused litigation over whether the generic’s dosage unit meets the release-ratio, bead and dissolution limitations.
- Label-focused litigation over whether the generic’s hepatic-impairment instructions induce use within the claimed method.
An ANDA applicant may use a section viii statement to omit a patented method of use from its label where the remaining label is legally and medically viable. That strategy is more difficult where the hepatic dosing language is embedded in the core labeling for the reference product.
What generic launch scenarios exist?
| Scenario |
Commercial implication |
| No Paragraph IV challenge |
Launch generally waits for patent expiry or a negotiated license |
| Paragraph III certification |
Generic accepts the patent and launches after expiration |
| Paragraph IV with no suit |
FDA approval may proceed after statutory notice periods |
| Paragraph IV with suit |
Approval may be stayed for up to 30 months, subject to court decisions |
| Successful invalidity or noninfringement challenge |
Earlier launch becomes possible |
| Carve-out of hepatic-use language |
May reduce method-of-use risk but can limit labeling |
| Non-infringing formulation |
Generic may avoid this patent while addressing other listed patents |
Because the claims combine pharmacokinetic and formulation limitations, a successful design-around may be more practical than a direct copy of the reference product. The key design-around variables are the immediate-release fraction, dosage-unit architecture, dissolution profile and label treatment of hepatic impairment.
How strong is the patent estate for US 10,028,946?
The patent has moderate, specialized strength rather than broad blocking strength.
Its advantages are:
- Multiple independent claims.
- Repetition of the core hepatic-use concept across claims 1, 11 and 19.
- Numerical release and pharmacokinetic limitations that can map to clinical and product data.
- Coverage of both broad and narrow immediate-release/extended-release ratios.
- Claims directed to commercially recognizable dose strengths.
Its weaknesses are:
- Method-of-treatment format.
- Dependence on the product label and actual use.
- Numerical limitations that may invite noninfringement arguments.
- Potential written-description and enablement challenges across the full AUC/Cmax ranges.
- Limited relevance to tablet products or formulations outside the claimed multiparticulate architecture.
Geographically, US 10,028,946 provides US rights only. Patent protection in Europe, Canada, Japan or other markets requires separate national or regional family members. US validity, expiration and Orange Book status do not establish foreign protection.
Key Takeaways
- US 10,028,946 covers treatment of pain in patients with mild or moderate hepatic impairment using hydrocodone bitartrate as the only active ingredient.
- The starting dose must not be reduced relative to a patient without hepatic impairment.
- The dosage unit must combine immediate-release and extended-release hydrocodone, generally in a 20:80 ratio.
- Claims also require defined AUC, Cmax, dose-strength and dissolution parameters.
- The patent is narrower than a general hydrocodone extended-release composition patent.
- The expected unadjusted patent term extends to approximately March 2033, subject to USPTO term calculations.
- Generic risk depends on both formulation equivalence and the proposed hepatic-impairment labeling.
- Biosimilar risk is not applicable because hydrocodone is a small-molecule drug.
- Hysingla ER should be analyzed separately because its tablet formulation is materially different from the multiparticulate architecture implicated by this patent.
- The principal design-around opportunities are a different release ratio, dosage form, dissolution profile or label treatment of hepatic impairment.
FAQs About US Patent 10,028,946
Does US 10,028,946 cover all hydrocodone extended-release products?
No. It requires a specific patient population, dosing instruction, hydrocodone-only formulation, release architecture and pharmacokinetic profile.
Does the patent cover hydrocodone combined with acetaminophen?
No. The claims require hydrocodone bitartrate as the only active ingredient.
Can a generic avoid the patent by using a tablet instead of beads?
Potentially. Claims 6 and 13 expressly require separate bead populations, while the independent claims still require the claimed release profile and other limitations. A tablet could avoid the bead-dependent claims but would require a full element-by-element analysis under the independent claims.
Is a lower starting dose required for moderate hepatic impairment?
The claimed method requires that the starting dose not be adjusted relative to a patient without hepatic impairment. That requirement is central to the patent and must be assessed against the approved product labeling.
Does patent expiration automatically permit generic launch?
No. FDA exclusivity, other listed patents, controlled-substance requirements, ANDA approval and any litigation or settlement restrictions can affect launch timing.
References
- United States Patent and Trademark Office. (2018). US Patent No. 10,028,946 B2: Methods of treating pain using hydrocodone formulations in patients with hepatic impairment.
- U.S. Food and Drug Administration. (2013). Zohydro ER approval letter and prescribing information.
- U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
- Drug Price Competition and Patent Term Restoration Act, 21 U.S.C. § 355(j).
- Leahy-Smith America Invents Act, 35 U.S.C. §§ 100 et seq.
