US Patent 8,946,262: Scope, Claims, Expiration, Orange Book Status, and Alvimopan Patent Landscape

US Patent 8,946,262 protects a narrowly defined preoperative use of alvimopan for preventing or treating gastrointestinal dysfunction, particularly postoperative ileus after abdominal surgery. The patent does not broadly claim alvimopan, its chemical structure, or all Entereg dosing. Its central limitation is oral administration of approximately 12 mg within a defined 30-to-60-minute window before surgery.[1]

The practical enforcement value of the patent depends on whether a competing product label directs the same preoperative dosing regimen. A generic product labeled for postoperative ileus could face infringement risk if its labeling recommends administration 30 to 60 minutes before surgery, even if the generic manufacturer does not market the product directly to hospitals.

What drug and treatment regimen does US Patent 8,946,262 cover?

US 8,946,262 covers alvimopan, marketed in the United States as Entereg. The claimed active ingredient is a peripherally acting mu-opioid receptor antagonist used to reduce opioid-related gastrointestinal dysfunction after surgery.

The patent's core regimen is:

Claim element	Scope
Patient	Patient undergoing surgery
Route	Oral administration
Dose	About 12 mg
Timing	About 30 minutes before surgery to 60 minutes before surgery
Therapeutic objective	Treatment of gastrointestinal dysfunction
Preferred compound	Alvimopan, including the dihydrate salt
Preferred surgery	Abdominal surgery
Preferred condition	Postoperative ileus

Claim 1 is the broadest independent claim. It requires the drug to be administered orally within the specified preoperative period. It does not expressly limit the surgery to abdominal surgery or the dysfunction to postoperative ileus.

Claim 2 narrows the subject matter to the specific stereochemical compound in dihydrate form. Claims 3 and 4 narrow the surgery and disease context. Claims 5 and 6 impose progressively narrower timing ranges.

What are the individual claims of US 8,946,262?

Claim 1: Preoperative alvimopan administration

Claim 1 requires:

A patient undergoing surgery.
Oral administration.
Approximately 12 mg of the claimed alvimopan compound or a pharmaceutically acceptable salt or hydrate.
Administration from approximately 30 minutes before surgery through 60 minutes before surgery.
Treatment of gastrointestinal dysfunction.

The principal legal question is whether a competing regimen satisfies both the dose and timing limitations. A regimen administered several hours before surgery, after surgery, or at a materially different dose would not literally meet claim 1.

The phrase "about 12 mg" creates a potential range rather than a mathematically exact 12.000 mg requirement. The patent does not expressly define the permissible deviation in the claim text. Courts generally assess "about" in view of the specification, prosecution history, technical context, and evidence concerning the relevant pharmaceutical formulation.

Claim 2: Alvimopan dihydrate and stereochemistry

Claim 2 requires the specific compound identified as:

2-[[(2S)-2-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]acetic acid dihydrate.

This is the commercial pharmaceutical form associated with Entereg. The claim is narrower than claim 1 because it requires the identified stereoisomer and dihydrate form.

A competitor using the same alvimopan dihydrate product would have difficulty avoiding claim 2 if the competitor also follows the claimed dose and preoperative timing.

Claim 3: Abdominal surgery

Claim 3 limits claim 2 to abdominal surgery. It is narrower than claim 2 and provides a more direct connection to the approved Entereg indication, which concerns postoperative ileus following bowel resection surgery and other abdominal operations.

Claim 4: Postoperative ileus

Claim 4 limits the claimed gastrointestinal dysfunction to postoperative ileus. This is commercially significant because postoperative ileus is the principal clinical condition associated with Entereg's FDA-approved use.

Claims 5 and 6: Narrower preoperative windows

Claim 5 covers administration from approximately 30 minutes before surgery to less than 60 minutes before surgery.

Claim 6 narrows the period further to approximately 30 minutes before surgery to less than 45 minutes before surgery.

These claims can be important if a court construes claim 1's upper boundary as including administration at exactly 60 minutes before surgery. Claims 5 and 6 separately protect shorter windows that more closely track a protocol in which the dose is administered shortly before the operation.

What is the patent term and expiration date for US 8,946,262?

US Patent 8,946,262 issued on February 3, 2015. The patent is an Orange Book-type method-of-use patent associated with alvimopan and Entereg.

The expected nominal patent expiration is in 2026, subject to the patent's applicable earliest effective nonprovisional filing date, patent-term adjustment, terminal-disclaimer provisions, and any applicable patent-term extension. The exact enforceable expiration date should be taken from the USPTO patent record and the current FDA Orange Book entry rather than inferred solely from the issue date.[1,2]

The patent term is not the same as FDA marketing exclusivity. FDA approval exclusivity for Entereg and patent protection operate under separate statutes. An approved product may lose regulatory exclusivity while retaining enforceable patent rights.

Milestone	Date or status
Patent	US 8,946,262
Issue date	February 3, 2015
Patent type	Method of treatment and dosing
Active ingredient	Alvimopan
Commercial product	Entereg
Expected term horizon	2026, subject to USPTO term calculations
FDA pathway	New drug application
Principal risk	Generic label covering preoperative use

What is the Orange Book status of US 8,946,262?

The Orange Book identifies patents and regulatory exclusivities associated with approved drug products. For Entereg, US 8,946,262 is relevant because it claims a method corresponding to the approved preoperative dosing regimen for postoperative ileus.[2]

An Orange Book method-of-use listing generally creates a certification obligation for an ANDA applicant. Under the Hatch-Waxman framework, an applicant must address each listed patent by providing a Paragraph I, II, III, or IV certification, or by submitting a section viii statement where the applicant seeks approval for uses outside the patented method.[3]

The commercial effect depends on the patent's use code and the proposed generic labeling:

Generic strategy	Likely patent position
Full label including preoperative Entereg regimen	Paragraph IV risk
Label excluding the patented preoperative use	Possible section viii strategy
Postoperative-only labeling	Lower direct risk if the patented use is excluded
Different dose or timing	Potential design-around, subject to infringement analysis
Same active ingredient but different formulation	May avoid formulation claims but not necessarily method claims

A section viii carve-out is not automatically effective if the remaining label, prescribing information, or marketing conduct still encourages use of the patented regimen. The label must omit the protected use, and the manufacturer must avoid evidence that it induces the patented administration method.

What Paragraph IV challenges affect alvimopan and Entereg?

A Paragraph IV certification asserts that a listed patent is invalid, unenforceable, or will not be infringed by the proposed ANDA product. Filing a Paragraph IV certification can trigger patent litigation under 21 U.S.C. § 355(j)(5)(B)(iii), with a potential 30-month stay of ANDA approval if the NDA holder or patent owner files suit within the statutory period.[3]

For US 8,946,262, the likely litigation issues would include:

Whether the ANDA label induces the patented preoperative use.
Whether the proposed dose is "about 12 mg."
Whether the proposed timing falls within the 30-to-60-minute period.
Whether the generic uses the claimed alvimopan stereoisomer and hydrate.
Whether the claims are anticipated or obvious in view of earlier perioperative opioid-antagonist studies.
Whether the claims adequately describe and enable the claimed treatment regimen.
Whether the patent is enforceable under prosecution-history and inequitable-conduct standards.

A generic applicant could challenge the patent directly through Paragraph IV or attempt a section viii carve-out. The commercial attractiveness of a carve-out depends on the extent to which the FDA-approved label can omit preoperative administration while retaining a viable postoperative ileus indication.

Which companies have commercial rights to alvimopan?

Alvimopan was developed by Adolor Corporation. Adolor entered into a development and commercialization arrangement with GlaxoSmithKline for alvimopan, but the product's US commercialization history later moved through Adolor and Cubist Pharmaceuticals. Merck acquired Cubist in 2015, bringing Entereg into Merck's commercial portfolio.[4,5]

The relevant commercial chain is:

Company	Role
Adolor Corporation	Original developer and patent holder associated with alvimopan
GlaxoSmithKline	Earlier development and commercialization collaborator
Cubist Pharmaceuticals	Later commercial rights holder
Merck & Co.	Acquired Cubist and obtained Entereg assets

Licensing and acquisition history matters because patent ownership, NDA ownership, and commercial distribution rights can be held by different entities at different points in the product lifecycle. The patent assignment record, FDA NDA record, and current Orange Book entry should be read together when assessing standing to sue.

How strong is the patent estate for Entereg?

The patent estate is strongest for the approved perioperative regimen and weaker for broad alvimopan exclusivity.

Strengths

Claim 1 maps closely to a commercial dosing protocol.
Claim 2 identifies the specific marketed stereochemical dihydrate.
Claims 3 and 4 track abdominal surgery and postoperative ileus.
The claims can create label-based infringement risk even when the generic product itself is chemically identical.
The method claims may remain commercially relevant after composition-patent protection expires.

Limitations

The patent does not broadly cover the alvimopan molecule for every use.
It does not necessarily block non-surgical gastrointestinal uses.
It does not expressly cover every dosing schedule.
It may be vulnerable to prior-art arguments if earlier publications disclosed perioperative use, dose, and timing.
A successful section viii carve-out could reduce the patent's practical reach.
Hospital-restricted distribution may complicate proof of induced infringement but does not eliminate infringement risk.

The patent is therefore best characterized as a focused late-life method patent rather than a comprehensive composition and formulation estate.

What formulation and manufacturing patents protect alvimopan?

US 8,946,262 is not principally a formulation or manufacturing patent. Its claims focus on a treatment method and dosing window.

Separate protection may arise from:

Alvimopan composition-of-matter patents.
Stereochemical purity claims.
Salt and hydrate claims.
Solid-state or crystalline-form claims.
Capsule and excipient formulations.
Methods of preparing alvimopan intermediates.
Processes for controlling impurities or stereoisomer ratios.
Stability and packaging technologies.

A competitor can potentially avoid a formulation patent while still infringing US 8,946,262 if it administers the same active ingredient under the claimed surgical protocol. Conversely, a competitor could avoid the method patent by omitting or modifying the preoperative use while still facing separate chemical or formulation claims.

The manufacturing barrier is likely lower than the regulatory and method-of-use barrier if the generic can synthesize or source alvimopan at commercial scale. The product's restricted hospital distribution, limited patient population, and patent-sensitive label may have greater commercial significance than manufacturing complexity.

What FDA regulatory restrictions affect generic alvimopan?

Entereg was approved for reducing postoperative ileus following bowel resection surgery. FDA imposed a restricted distribution program because of concerns regarding cardiovascular adverse events, including myocardial infarction.[6]

The product labeling limits use to hospitals registered in the Entereg Access Support and Education program, or its successor restricted-use framework. Patients generally receive a short perioperative course, with administration beginning before surgery and continuing postoperatively for a limited number of doses.[6]

These restrictions create several generic-entry consequences:

A generic applicant must address the FDA safety program and hospital distribution controls.
A generic label that copies the approved regimen may expose the applicant to method-patent litigation.
A carved-out label may reduce the product's clinical and commercial value.
Limited hospital use constrains market size and may reduce the incentive to litigate.
A generic must demonstrate pharmaceutical equivalence and bioequivalence to the listed drug.

What generic launch scenarios exist for Entereg?

Scenario 1: Full-label generic launch

A generic applicant certifies Paragraph IV against US 8,946,262 and other listed patents, litigates, and launches after a favorable judgment or settlement date. This produces the largest addressable market but carries the highest litigation exposure.

Scenario 2: Section viii carve-out

The applicant excludes the patented preoperative use and seeks approval for a remaining non-infringing indication or dosing instruction. This approach can shorten patent exposure but may produce a commercially weak label.

Scenario 3: Authorized generic

The NDA holder or an authorized partner launches an authorized generic before broader generic entry. This can preserve supply continuity and capture price-sensitive hospital demand.

Scenario 4: Post-expiration launch

The applicant waits for the patent estate to expire or for a settlement date. This avoids Paragraph IV litigation but sacrifices first-filer advantages and delays market access.

What patent litigation and settlements affect alvimopan?

The principal litigation risk for a generic applicant is not limited to the chemical identity of alvimopan. The product label itself can create exposure by instructing hospitals to administer 12 mg shortly before surgery.

Relevant litigation theories include:

Direct infringement by administration of the product.
Induced infringement through prescribing information.
Contributory infringement where the product has limited substantial non-infringing use.
Invalidity based on anticipation or obviousness.
Written-description and enablement challenges.
Claim-construction disputes over "about," "from about 30 minutes," and "60 minutes prior."
Regulatory-disclosure disputes concerning the scope of a section viii carve-out.

Public records should be checked separately for each ANDA filer because a settlement may include a confidential business arrangement, a delayed-entry date, a licensed launch, or an agreement not to market for a defined period. A settlement involving another alvimopan patent does not automatically resolve exposure under US 8,946,262.

How does US 8,946,262 compare with competing patent protections?

Protection category	What it protects	Relevance to Entereg
Composition patent	Alvimopan molecule	Broadest chemical protection, generally earlier-expiring
Stereochemical patent	Specific active stereoisomer	Protects the marketed active configuration
Salt or hydrate patent	Dihydrate or pharmaceutical salt	Relevant to commercial product form
Formulation patent	Capsule, excipients, release or stability	May protect the finished dosage form
Method patent	Dose, timing, surgery and indication	Core subject of US 8,946,262
Manufacturing patent	Synthesis and purification	May raise API supply barriers
Regulatory exclusivity	FDA approval-related protection	Separate from patent term

US 8,946,262 is commercially important because it covers a use closely aligned with the product label. Its value is less dependent on preventing manufacture of alvimopan and more dependent on controlling how hospitals use the product.

Key Takeaways

US 8,946,262 is a method-of-treatment patent for preoperative oral alvimopan.
The central regimen is approximately 12 mg administered 30 to 60 minutes before surgery.
The narrower claims cover alvimopan dihydrate, abdominal surgery, postoperative ileus, and shorter timing windows.
The patent does not broadly claim alvimopan for every indication or dosing schedule.
The expected patent-term horizon is 2026, subject to USPTO term calculations and any applicable adjustments.
Orange Book and FDA label analysis is critical because the practical risk arises from the generic label and hospital use instructions.
A Paragraph IV challenge could target claim construction, obviousness, anticipation, written description, enablement, or induced infringement.
A section viii carve-out may be possible but could limit the commercial value of a generic product.
Entereg's restricted hospital distribution and cardiovascular safety controls add regulatory barriers to generic entry.
The estate is strongest against a full-label generic that copies the approved preoperative regimen.

FAQs About US Patent 8,946,262 and Entereg

Does US 8,946,262 cover the alvimopan molecule itself?

No. The patent claims a method of administering alvimopan for gastrointestinal dysfunction in a surgical patient. It is not, based on the cited claims, a broad composition-of-matter patent.

Can a generic avoid US 8,946,262 by changing the dose?

Potentially, but the generic must avoid the claim limitations and must not induce use of the patented regimen through its label, promotional materials, or distribution practices.

Does postoperative-only administration avoid the patent?

It may avoid literal infringement of the preoperative timing limitations, but the complete label and actual use must be evaluated. A postoperative label that still encourages preoperative administration could create induced-infringement risk.

Is alvimopan a biologic subject to biosimilar litigation?

No. Alvimopan is a small-molecule drug. Generic-drug rules under the ANDA pathway, rather than the biosimilar pathway under the Biologics Price Competition and Innovation Act, govern ordinary abbreviated approval.

What is the main commercial risk after patent expiration?

The main risk is rapid price erosion from generic competition in a small, hospital-restricted market. The size and timing of the impact will depend on the number of approved ANDAs, any authorized generic arrangement, remaining formulation or composition patents, and the continued FDA distribution controls.

References

United States Patent and Trademark Office. (2015). U.S. Patent No. 8,946,262, Methods of treating gastrointestinal dysfunction.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 355(j).
Merck & Co., Inc. (2015). Merck completes acquisition of Cubist Pharmaceuticals.
Adolor Corporation. (2008). FDA approves Entereg (alvimopan) for postoperative ileus.
U.S. Food and Drug Administration. (n.d.). Entereg (alvimopan) prescribing information.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Cubist Pharms	ENTEREG	alvimopan	CAPSULE;ORAL	021775-001	May 20, 2008		DISCN	Yes	No	8,946,262	⤷ Start Trial				A METHOD TO ACCELERATE THE TIME TO GASTROINTESTINAL RECOVERY BY ADMINISTERING ABOUT 12 MG OF ALVIMOPAN TO THE PATIENT FROM ABOUT 30 TO 60 MINUTES PRIOR TO SURGERY	⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
World Intellectual Property Organization (WIPO)	2005055953	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,946,262

Which drugs does patent 8,946,262 protect, and when does it expire?

Summary for Patent: 8,946,262