US Patent 6,469,030: Claim Scope, Alvimopan Coverage, Expiration, and Patent Landscape

US Patent 6,469,030 is a method-of-treatment patent assigned to Adolor Corporation that covers the use of broad classes of peripheral mu-opioid receptor antagonists to treat or prevent ileus. The claims reach postsurgical and postpartum ileus, including postsurgical paralytic ileus, and expressly cover coadministration with opioid analgesics. The patent is closely associated with the alvimopan development program and Entereg, although the broadest claims are not limited to alvimopan.

The patent’s nominal term expired on February 19, 2019, based on the 20-year term from the earliest claimed U.S. priority date. The patent therefore presents historical rather than current blocking risk, subject to any specific patent-term adjustment, extension, terminal disclaimer, or jurisdictional issue reflected in the official USPTO and FDA records.[1,2]

What does US Patent 6,469,030 protect?

The patent protects a therapeutic method with four principal elements:

Treating or preventing ileus.
Administering an effective amount of a compound within a large formula-I genus.
Permitting stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, and N-oxides.
Allowing specified coadministration with opioids, opioid analgesics, mu-opioid agonists, or compounds that slow gut motility.

Claim 1 is the controlling independent claim. It is written as a Markush claim covering substituted piperidine-related compounds with extensive variation in:

Alkyl, alkenyl, aryl, cycloalkyl, and substituted alkyl groups.
Alcohol, amine, amide, ester, carbamate, and related terminal groups.
Piperidine and pyrrole-containing substituents.
Stereochemical forms.
Pharmaceutical salts, hydrates, N-oxides, and prodrugs.

The claim is a use claim, not a composition claim. It does not claim the compound in the abstract or a formulation independent of ileus treatment.

How broad is claim 1?

Claim 1 has substantial chemical breadth but a defined therapeutic limitation. A product would need to satisfy both the structural formula and the ileus-treatment limitation.

Claim element	Scope
Disease	Ileus broadly
Purpose	Treatment or prevention
Patient	Patient receiving an effective amount
Compound	Formula-I Markush genus
Chemical forms	Stereoisomers, prodrugs, salts, hydrates, N-oxides
Route	Not expressly limited in claim 1
Dose	Not expressly limited
Opioid use	Not required by claim 1
Combination therapy	Added in claims 23-26

The breadth is narrowed by the requirement that the administered compound fall within the specific formula and substituent definitions. A compound that is merely a peripheral opioid antagonist but does not satisfy the formula would not infringe claim 1.

Conversely, claim 1 does not require:

Use after bowel resection.
A particular dose.
Oral administration.
A particular surgical procedure.
Concurrent opioid administration.
A particular duration of treatment.
A specific degree of gastrointestinal recovery.

Those limitations appear in the FDA-approved clinical context but not in the broadest patent claim.

What do claims 2 through 11 add?

Claims 2 through 11 progressively narrow the chemical genus.

Stereochemistry

Claim 2 requires a trans 3,4-isomer. Claim 11 requires the 3 and 4 positions of the piperidine ring to each have the R configuration. These limitations are important because the patent treats stereochemistry as a source of differentiated activity.

Claim 18 separately covers a substantially pure stereoisomer. This creates potential overlap between:

A racemic or mixed stereoisomer covered by claim 1.
A trans isomer under claim 2.
A defined 3R,4R stereoisomer under claim 11.
A substantially pure stereoisomer under claim 18.

Preferred substituent pattern

Claim 3 narrows the core to compounds where:

R1 is hydrogen.
R2 is alkyl.
n is 1 or 2.
R3 is benzyl, phenyl, cyclohexyl, or cyclohexylmethyl.
R4 is alkyl.

Claims 4 through 10 then regulate the A substituent and terminal functional groups. The resulting subgenera cover carboxylic acids, esters, amides, amino acids, substituted amides, and related derivatives.

Functional-group limitations

Claim 4 requires A to be OR5, with R5 being hydrogen or alkyl. This reaches alcohols and ethers.

Claim 5 requires A to be NR6R7, with R6 hydrogen and R7 an alkylene-linked carbonyl group. Claims 6 through 10 further narrow that group to:

Carboxylic acids and esters.
Primary and secondary amides.
Amino acid-type structures.
Glycine and alanine-derived substituents.
Alkyl-substituted oxycarbonyl groups.

These claims are more vulnerable to design-around strategies because a competitor can change the terminal substituent while preserving peripheral mu-opioid antagonist activity.

What do claims 12 through 18 protect?

Claims 12 through 18 identify specific chemical examples, stereoisomers, and preferred compounds. They are narrower than claim 1 and provide fallback positions if the broad Markush genus is challenged.

Claim 12 lists compounds using the shorthand designations Q, G, and Z. The definitions of those groups are not included in the claim text supplied in the question. Their complete chemical interpretation therefore depends on the patent specification and drawings. The claim cannot be mapped reliably to a commercial compound from the text alone.

Claim 13 selects the Q-CH2CH(CH2(C6H5))C(O)OH structure.

Claim 14 narrows that compound to a defined stereochemical form identified as (3R,4R,S).

Claims 15 through 17 select Z-series compounds, including the positive and negative enantiomers of Z-NHCH2C(O)OH. Claim 17 narrows the subject matter to the positive enantiomer.

Claim 18 protects a substantially pure stereoisomer. This is important in pharmaceutical patent practice because a substantially pure enantiomer can remain separately enforceable even where a racemate or broader genus faces prior-art challenges.

Which ileus indications are covered?

Claims 19 through 21 expressly cover:

Ileus generally.
Postsurgical ileus.
Postpartum ileus.
Postsurgical paralytic ileus.

The approved Entereg indication is narrower than the patent language. FDA approved alvimopan for accelerating the time to upper and lower gastrointestinal recovery following partial large or small bowel resection with primary anastomosis.[3] The FDA indication does not establish approval for every form of ileus recited by the patent.

Indication	Expressly covered by patent claims	FDA-approved Entereg indication
Ileus generally	Yes	No
Postsurgical ileus	Yes	Within approved surgical context
Postsurgical paralytic ileus	Yes	Functionally related, but label wording controls
Postpartum ileus	Yes	No
Opioid-associated gut dysfunction	Potentially relevant under broad claim language	Not the primary approved indication

Does the patent cover opioid coadministration?

Yes. Claims 23 through 25 require coadministration with an opiate or opioid, including an opioid analgesic and a mu-opioid agonist.

These claims are commercially important because postoperative ileus commonly occurs in patients receiving opioid analgesics. The patent therefore covers a treatment regimen in which the peripheral antagonist is administered while the patient receives a centrally acting opioid for pain.

Claim 26 adds administration of a compound that slows gut motility. This is broad functional language and could encompass certain drugs with constipating or motility-reducing effects, depending on claim construction and the facts of use.

The combination claims do not require that the opioid and peripheral antagonist be coformulated. Separate administration can satisfy a coadministration limitation if the timing and clinical facts meet the applicable claim construction.

What is the relationship to alvimopan and Entereg?

The patent is associated with the alvimopan/Entereg program, but the supplied claims do not identify the commercial product by name. Alvimopan must be mapped against the formula-I structure and the Q, G, or Z definitions in the specification before a definitive claim chart can be prepared.

Entereg is alvimopan, a peripherally acting mu-opioid receptor antagonist developed to reduce opioid-related gastrointestinal dysfunction without materially reversing central analgesia. FDA approved Entereg in 2008 under NDA 021775 for acceleration of gastrointestinal recovery after partial bowel resection with primary anastomosis.[3]

The commercial product is a 12-mg oral capsule administered under a restricted hospital-use program. The label limits use to hospitals enrolled in the Entereg Access Support and Education program because of safety concerns identified in the broader chronic-use development program.[3]

When did US Patent 6,469,030 expire?

The patent issued on October 22, 2002.[1] Its nominal expiration date was February 19, 2019, calculated from the earliest claimed U.S. priority date.[2]

Event	Date
Earliest claimed U.S. priority	February 19, 1999
U.S. patent grant	October 22, 2002
Nominal 20-year expiration	February 19, 2019
Current status	Expired by term

The legal term must be distinguished from regulatory exclusivity. FDA approval of Entereg did not preserve the patent after its statutory expiration. Any patent-term adjustment or patent-term extension would need to appear in the USPTO patent record or FDA Orange Book entry. The central commercial conclusion is that the 6,469,030 claims are no longer a live U.S. patent barrier based solely on the ordinary patent term.

What is the Orange Book status of the Entereg patents?

The relevant regulatory records are the FDA Orange Book and the Entereg labeling history. Orange Book-listed patents can delay approval of an ANDA through the Hatch-Waxman framework while they remain in force. After expiration, the listing no longer creates a patent-based statutory barrier, although a generic applicant may still face formulation, bioequivalence, manufacturing, market-size, or commercial-launch issues.[4]

The 6,469,030 patent should be analyzed with related alvimopan patents rather than in isolation. Patent families and later filings may have addressed:

The active compound.
Specific stereoisomers.
Therapeutic use in ileus.
Opioid-induced bowel dysfunction.
Salt forms.
Formulations.
Dosing regimens.
Manufacturing and intermediates.

A complete Orange Book determination requires matching the exact NDA, patent number, listed claims, expiration date, and delisting history. Patent 6,469,030 alone does not establish the full remaining Entereg estate.

How many patents cover alvimopan and ileus treatment?

The landscape historically included multiple patent categories rather than a single blocking patent.

Patent category	Typical protection	Relevance to alvimopan
Compound patents	Chemical entity and core scaffold	Highest value during early development
Stereochemistry patents	Enantiomers and substantially pure isomers	Can separate commercial product from racemate
Method-of-use patents	Ileus and opioid-induced bowel dysfunction	Directly relevant to treatment use
Combination patents	Peripheral antagonist plus opioid	Relevant to postoperative analgesia
Formulation patents	Dosage form, excipients, release profile	Relevant to generic substitution
Process patents	Synthesis, intermediates, purification	Manufacturing barrier
Regulatory exclusivity	NDA and pediatric exclusivity	Separate from patent term

Patent 6,469,030 is strongest as a historical use patent. It is less effective as a current commercial barrier because its term has ended and because its broad chemical genus creates potential validity and claim-construction issues.

What patent litigation and Paragraph IV risks existed?

The patent creates several possible historical Paragraph IV theories:

The proposed generic compound does not fall within formula I.
The generic label does not instruct treatment or prevention of ileus.
The use is outside the patented indication.
The patent claims are anticipated or obvious.
The Markush genus lacks adequate written description or enablement.
The asserted claims are indefinite.
The patent expired before commercial launch.

A Paragraph IV notice against an unexpired use patent could have triggered Hatch-Waxman litigation and a 30-month stay. A generic applicant might also use a section viii skinny-label strategy by omitting patented ileus indications, although that strategy would depend on the scope of the approved labeling and the remaining Orange Book-listed claims.[4]

No active litigation conclusion should be drawn from the existence of the patent number alone. Patent expiration materially changes the analysis. A historical suit or settlement would not revive an expired patent or create post-expiration exclusivity.

How strong is the patent estate?

Strengths

Claim 1 covers a large chemical genus.
The treatment limitation directly corresponds to the intended clinical use.
Claims expressly cover stereoisomers, salts, prodrugs, hydrates, and N-oxides.
Claims 19 through 21 address commercially relevant postsurgical indications.
Claims 23 through 26 capture common opioid-related postoperative treatment settings.
Narrow claims provide fallback protection for selected stereoisomers and examples.

Weaknesses

The broad genus may face written-description and enablement scrutiny.
“Effective amount” is functional language rather than a fixed dose.
“Ileus” is broad and includes clinically distinct conditions.
The claims do not require the approved surgical procedure or a specific dosage regimen.
A competitor may design around terminal amide, ester, or amino-acid substituents.
The patent is expired, eliminating current U.S. exclusivity based on this patent.

The patent was commercially meaningful during the Entereg development period, but its present value is primarily historical, freedom-to-operate, and patent-landscape information.

What generic launch risks remain after expiration?

After expiration of 6,469,030, the main risks shift from patent infringement to regulatory and commercial execution:

Whether other unexpired alvimopan patents remain listed.
Whether a generic can demonstrate bioequivalence to the 12-mg capsule.
Whether the restricted hospital distribution system complicates substitution.
Whether the small postoperative ileus market supports launch economics.
Whether manufacturing requires specialized intermediates or stereochemical purification.
Whether the generic label can obtain approval without including unprotected or still-patented uses.
Whether formulation or process patents remain enforceable.

Biosimilar risk is not material because alvimopan is a small-molecule drug, not a biologic. The appropriate competitive pathway is an ANDA, not a biosimilar application under the Public Health Service Act.

What licensing and ownership issues affect the landscape?

Adolor was the original developer associated with the alvimopan program. The commercial and development rights later moved through collaborations and corporate transactions involving larger pharmaceutical companies. Cubist Pharmaceuticals acquired Adolor in 2011, and Merck acquired Cubist in 2015.[5,6]

Ownership history matters for:

Chain-of-title review.
Royalty obligations.
Patent assignments.
Litigation standing.
Orange Book certification records.
Commercial rights in the United States and foreign jurisdictions.

Patent ownership and marketing rights should be analyzed separately. A company may own a patent without holding current commercialization rights, and a licensee may have enforcement rights subject to the agreement.

Key Takeaways

US Patent 6,469,030 is a broad method-of-treatment patent for treating or preventing ileus with specified peripheral mu-opioid antagonist compounds.
Claim 1 is a large Markush genus, not an alvimopan-only claim.
Claims 2 through 18 narrow the genus by stereochemistry, substituent structure, specific examples, and substantially pure isomers.
Claims 19 through 21 cover postsurgical, postpartum, and postsurgical paralytic ileus.
Claims 23 through 26 cover opioid coadministration and compounds that slow gut motility.
The patent is closely associated with the alvimopan/Entereg development program.
The nominal U.S. patent term expired on February 19, 2019.
Current generic risk depends on later compound, formulation, use, process, and regulatory protections, not on 6,469,030 alone.
No biosimilar pathway applies because alvimopan is a small molecule.
The Q, G, and Z structures in claims 12 through 17 must be read with the specification for definitive chemical mapping.

FAQs

Is US 6,469,030 a composition-of-matter patent?

No. Its claims are directed to methods of treating or preventing ileus using compounds within a defined chemical genus. The patent does not independently claim the drug substance outside the treatment method.

Does claim 1 require opioid administration?

No. Claim 1 does not require an opioid. Claims 23 through 25 add opioid or opioid-analgesic coadministration limitations.

Does the patent cover postpartum ileus?

Yes. Claim 19 expressly lists postpartum ileus, although that indication was not the primary FDA-approved Entereg indication.

Can a generic avoid the patent by using a different salt or hydrate?

Not necessarily. Claim 1 expressly includes pharmaceutically acceptable salts and hydrates. A different salt or hydrate could remain within the claim if the underlying compound satisfies formula I.

Is alvimopan protected by biosimilar exclusivity?

No. Alvimopan is a small-molecule drug regulated through the drug-approval framework, generally including an ANDA pathway for generics. Biosimilar exclusivity does not apply.

References

United States Patent and Trademark Office. (2002). U.S. Patent No. 6,469,030, Methods of treating ileus.
United States Patent and Trademark Office. (n.d.). Patent term and patent term adjustment records for U.S. Patent No. 6,469,030.
U.S. Food and Drug Administration. (2008). Entereg (alvimopan) prescribing information.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
Cubist Pharmaceuticals, Inc. (2011). Cubist Pharmaceuticals to acquire Adolor Corporation.
Merck & Co., Inc. (2015). Merck completes acquisition of Cubist Pharmaceuticals.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	432076	⤷ Start Trial
Australia	2005203041	⤷ Start Trial
Australia	3970501	⤷ Start Trial
Australia	780738	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,469,030

Summary for Patent: 6,469,030