Details for Patent: 9,492,445

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Which drugs does patent 9,492,445 protect, and when does it expire?

Patent 9,492,445 protects RELISTOR and is included in two NDAs.

This patent has thirty-eight patent family members in eighteen countries.

Summary for Patent: 9,492,445

Title:	Peripheral opioid receptor antagonists and uses thereof
Abstract:	The present invention provides a compound of formula I: wherein X−, R1, and R2 are as defined herein, and compositions thereof.
Inventor(s):	Nataliya BAZHINA, George Joseph Donato, III, Steven R. Fabian, John Lokhnauth, Sreenivasulu Megati, Charles Melucci, Christian Ofslager, Niketa Patel, Galen Radebaugh, Syed M. Shah, Jan Szeliga, Huyi Zhang, Tianmin Zhu
Assignee:	Wyeth LLC
Application Number:	US14/870,323
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,492,445
Patent Claim Types: see list of patent claims	Use; Composition; Formulation;

United States Patent 9,492,445: Methylnaltrexone Composition Claims, Exclusivity, and Patent Landscape

U.S. Patent No. 9,492,445 protects specific methylnaltrexone compositions, particularly methylnaltrexone bromide injectable products with high R-configurational purity, controlled levels of a related impurity, and tungsten limits for the drug product and container. The patent is directed to product quality and packaging controls rather than broad protection for methylnaltrexone as a chemical entity.

The claims map closely to Relistor injection presentations containing 8 mg/0.4 mL or 12 mg/0.6 mL of methylnaltrexone bromide. The commercially important claim limitations are:

• At least 99.6% of the active compound in the R configuration.
• Less than 190 ppm of a specified formula II impurity.
• A package substantially free of tungsten.
• Composition tungsten content below the claimed threshold, with dependent claim 7 specifying less than about 60 parts per billion.
• Injectable presentation in a syringe, vial, or ampoule.
• Use for opioid-induced constipation, including in chronic opioid users and cancer patients.

What drug does U.S. Patent 9,492,445 protect?

The patent protects compositions containing methylnaltrexone, most specifically methylnaltrexone bromide in an injectable formulation.

Methylnaltrexone is a peripherally acting mu-opioid receptor antagonist. Relistor, marketed by Salix Pharmaceuticals and its affiliates, is approved for opioid-induced constipation in adults, including patients with chronic non-cancer pain and patients with advanced illness or cancer-related pain. The product is administered subcutaneously in the injectable presentations relevant to claims 8 through 19. [1]

The claim language supplied identifies:

• Formula III as the active methylnaltrexone compound.
• Formula III-1 as the specifically claimed methylnaltrexone form.
• Formula II and formula II-1 as a related impurity or process-related species.
• A- and X- as Brønsted-acid anions, with bromide expressly selected in claims 4 and 6.

Claim 4 therefore narrows the active pharmaceutical ingredient to methylnaltrexone bromide. Claim 6 narrows the impurity species to its bromide form.

What are the key limitations of claim 1?

Claim 1 is a combination composition claim. A product must satisfy every material limitation to infringe literally.

Claim 1 limitation	Commercial significance
Composition contains formula III	Requires the claimed active compound
At least 99.6% in the R configuration	Imposes a stereochemical purity threshold
Compound is in a package substantially free of tungsten	Extends protection to container compatibility and manufacturing controls
Composition is substantially free of tungsten	Controls elemental contamination in the drug product
Less than 190 ppm of formula II compound	Controls a specified related substance or degradation/process impurity

The claim does not merely require methylnaltrexone bromide. It requires a particular quality profile and packaging environment. A generic product containing methylnaltrexone bromide could avoid literal infringement if it falls outside one of the numerical or material limitations. That does not eliminate risk because the patent holder could assert equivalents, and an ANDA applicant would still need to evaluate whether its proposed product has the claimed stereochemical purity, impurity level, tungsten concentration, and container configuration.

How do claims 2 through 7 narrow the patent scope?

Claims 2 through 7 define the salt and contamination parameters.

Salt and counterion limitations

Claim 2 covers a broad group of Brønsted acids, including hydrogen halides, carboxylic acids, sulfonic acids, sulfuric acid, and phosphoric acid.

Claim 3 lists specific anions, including chloride, bromide, iodide, sulfate, phosphate, trifluoroacetate, succinate, and other organic and inorganic anions.

Claim 4 narrows the active compound to the bromide salt. This is commercially important because Relistor injection is identified as methylnaltrexone bromide. [1]

Claims 5 and 6 apply an analogous anion framework to formula II. Claim 6 specifically covers the bromide form of the formula II impurity.

Tungsten limitations

Claim 1 uses the broader standards “substantially free of tungsten” for both the package and composition. Claim 7 provides a quantitative limitation of less than about 60 parts per billion.

The tungsten limitations likely address contamination associated with manufacturing equipment, needles, syringes, or other metal-containing components. Claim 12 expressly identifies syringes, vials, and ampoules as covered packages. Claim 13 narrows the package to a syringe.

A competitor that uses a tungsten-containing syringe or manufacturing component could fall outside claim 1 if the resulting package or product does not meet the “substantially free” limitation. The commercial and litigation question would turn on the patent’s specification, analytical method, detection limits, and how a court construes “substantially free.”

What formulations and presentations are protected?

Claims 8 through 13 protect liquid injectable presentations and packaging configurations.

Claim	Protected subject matter
8	Formula III provided in a solution
9	Approximately 8 mg in approximately 0.4 mL water
10	Approximately 12 mg in approximately 0.6 mL water
11	Specific formula III-1 and formula II-1 species
12	Syringe, vial, or ampoule
13	Syringe specifically

The 8 mg/0.4 mL and 12 mg/0.6 mL concentrations correspond to commercial Relistor injection strengths. The claims therefore have direct product relevance rather than covering only laboratory compositions.

The claims do not expressly require a particular excipient system, buffer, pH, preservative, or administration device beyond the listed package and solution limitations. A product could potentially remain within the claim scope even if it uses a different manufacturing process or secondary packaging, provided it meets the active, impurity, stereochemical, tungsten, and presentation limitations.

What methods of use does U.S. Patent 9,492,445 cover?

Claims 14 through 19 are method-of-treatment claims directed to gastrointestinal disorders.

The hierarchy is:

1. Treatment of a gastrointestinal disorder.
2. Treatment of constipation.
3. Treatment of opioid-induced constipation.
4. Treatment of a patient receiving opioids chronically.
5. Treatment of a cancer patient.
6. Subcutaneous administration.

The commercially important method claim is claim 16, particularly when combined with claim 19. Claim 18 adds the cancer-patient population, while claim 17 covers chronic opioid use without limiting the patient to cancer.

These claims overlap materially with the approved uses of Relistor. FDA labeling identifies methylnaltrexone bromide products for opioid-induced constipation in adults with chronic non-cancer pain and in adults with advanced illness or pain caused by active cancer. [1]

For an ANDA applicant, method-of-use claims can create a regulatory issue even when the applicant uses a section viii statement carving out a patented indication. The practical exposure depends on the approved labeling, the scope of any proposed carve-out, the product’s dosing instructions, and whether the patent is listed for the relevant indication.

What is the Orange Book status of U.S. Patent 9,492,445?

U.S. Patent 9,492,445 is associated with the Relistor product and is relevant to Orange Book patent analysis. Orange Book listing status is product-specific and can differ by dosage form, strength, and approved indication. The FDA Orange Book identifies patents submitted by NDA holders under the Hatch-Waxman framework, including patents covering drug substances, drug products, and methods of use. [2]

The patent’s relevance is strongest for:

• Relistor injection.
• Methylnaltrexone bromide solution products.
• 8 mg/0.4 mL and 12 mg/0.6 mL injectable presentations.
• Subcutaneous treatment of opioid-induced constipation.

The patent is not a biologic patent and does not create biosimilar exclusivity. Methylnaltrexone is a small molecule, so competing applicants would generally use the ANDA pathway rather than the biosimilar pathway.

When does U.S. Patent 9,492,445 expire?

The patent issued on November 15, 2016. Its term is generally measured from the relevant nonprovisional filing date, subject to patent-term adjustment, terminal disclaimers, and any applicable patent-term extension. The patent’s expected nominal expiration is in the early-to-mid 2030s, based on the underlying priority and filing history. The enforceable expiration date must be taken from the USPTO patent record and any applicable Orange Book entry because patent-term adjustment can alter the date. [3]

The patent should be analyzed together with:

• Any earlier methylnaltrexone compound patents.
• Formulation patents.
• Manufacturing and impurity-control patents.
• Method-of-use patents.
• Regulatory exclusivity for the underlying NDA.

A later-expiring composition patent can delay practical generic entry even after an earlier active-ingredient patent expires if the listed claims cover the commercial product and survive challenge.

How strong is the patent estate for methylnaltrexone and Relistor?

The patent estate is strongest where the commercial product matches the claimed quality specifications and package configuration.

Risk factor	Assessment
Active compound identity	Strong if the product uses methylnaltrexone bromide
Salt limitation	Strong for bromide products under claims 3, 4, 6, and 11
Stereochemical purity	Potentially strong, but dependent on analytical results and construction of “R configuration”
Formula II impurity threshold	Important technical limitation and possible design-around point
Tungsten-free package	Product-specific and potentially vulnerable to noninfringement
8 mg/0.4 mL presentation	Directly aligned with the claim
12 mg/0.6 mL presentation	Directly aligned with the claim
Subcutaneous use	Directly aligned with claims 14 through 19
Biosimilar protection	Not applicable
Manufacturing exclusivity	Limited; the claims focus on resulting composition and package characteristics

The patent is narrower than a compound patent. A compound patent would generally prevent manufacture or sale of the active ingredient regardless of formulation. Patent 9,492,445 instead requires a defined set of product attributes. That creates more opportunities for an ANDA applicant to formulate around the claims, but it also gives the patent holder a strong infringement position against a product that copies the commercial formulation and packaging.

What generic entry risks exist?

Generic entry risk depends on whether an applicant can avoid the claims without materially changing the product.

Likely paragraph IV issues

A paragraph IV certification could challenge one or more of the following:

• Validity of the tungsten limitations.
• Written description or enablement for the broad anion classes.
• Definiteness of “substantially free of tungsten.”
• Indefiniteness or evidentiary problems involving the 99.6% R-configuration threshold.
• Obviousness based on known methylnaltrexone formulations, impurity controls, and container materials.
• Lack of infringement because the proposed product contains more than 190 ppm of formula II, uses a different salt, or uses packaging with measurable tungsten.

The patent holder could respond with an infringement action under 35 U.S.C. § 271(e)(2), triggering the statutory stay associated with a timely patent litigation filing. [4]

Potential design-around routes

A generic manufacturer could evaluate:

1. A non-bromide salt, if clinically and regulatorily acceptable.
2. A package not covered by the listed syringe, vial, or ampoule language.
3. Container components with a different tungsten profile.
4. A formulation with formula II at or above the claimed threshold, subject to FDA impurity and safety requirements.
5. A product that does not rely on the patented method-of-use labeling.
6. A different concentration or presentation.

The most commercially realistic design-arounds are packaging and process-based. Changing the salt, impurity profile, or dose may create regulatory, stability, bioequivalence, or commercial problems.

Which companies are challenging the patent?

The supplied claim set does not identify a specific paragraph IV challenger, ANDA filer, settlement agreement, or active infringement action. No litigation conclusion can be drawn from the claims alone.

Patent landscape review should distinguish among:

• ANDA applicants that have filed paragraph IV certifications.
• Declaratory-judgment plaintiffs.
• Defendants in Hatch-Waxman litigation.
• Licensees or authorized generic partners.
• Companies challenging other methylnaltrexone patents rather than U.S. Patent 9,492,445.

A litigation docket, FDA patent certification record, or settlement filing is required to attribute a challenge or determine whether a court has construed these claims.

What licensing deals affect methylnaltrexone?

Methylnaltrexone commercialization has involved Progenics Pharmaceuticals and later commercial partners, including Salix Pharmaceuticals. Commercial rights and patent ownership should be separated: a marketing partnership does not necessarily transfer patent title, and a patent assignment does not establish a license to market the approved product.

The relevant commercial analysis should identify:

• Current patent owner.
• NDA holder.
• Relistor commercialization rights.
• Any authorized-generic arrangement.
• Any settlement license with an ANDA applicant.
• Any field-of-use or territory restrictions.

Patent 9,492,445 should not be treated as a standalone asset without reviewing assignments, security interests, licenses, and Orange Book submissions.

How does patent 9,492,445 compare with a conventional formulation patent?

Issue	U.S. 9,492,445	Conventional formulation patent
Primary focus	Active stereochemistry, impurity, tungsten, package	Excipients, ratios, pH, release, stability
Product type	Injectable solution	May cover injection, tablet, capsule, or depot
Package limitation	Expressly claimed	Often absent or secondary
Analytical thresholds	Central to infringement	May be less central
Design-around potential	Moderate to high	Depends on formulation architecture
Commercial alignment	High for Relistor injection	Depends on product match
Regulatory relevance	Strong for identical injectable products	Strong if formulation is necessary for approval

The patent’s unusual feature is the combination of product chemistry and packaging. This can make routine manufacturing choices legally significant.

What geographic coverage does the patent provide?

U.S. Patent 9,492,445 provides rights in the United States only. Foreign counterparts, if any, require separate review of:

• National-phase filings.
• Granted claims.
• Patent-term dates.
• Opposition or post-grant proceedings.
• Local Orange Book equivalents.
• Supplementary protection certificates or other extensions.

A U.S. composition claim does not automatically establish protection in Canada, Europe, Japan, China, or other markets. International launch planning requires jurisdiction-by-jurisdiction claim comparison.

What patent litigation affects Relistor and methylnaltrexone?

The principal litigation risk is a Hatch-Waxman action following a paragraph IV certification against an Orange Book-listed patent. For this patent, the most important evidence would be:

• The ANDA formulation and container description.
• Applicant batch analytical data.
• Tungsten testing methodology.
• Formula II impurity results.
• Stereochemical purity data.
• Proposed labeling and method-of-use carve-outs.
• Any court claim-construction ruling.

A finding that “substantially free of tungsten” is definite and technically supported would strengthen enforcement. A finding that the limitation lacks objective boundaries would materially weaken the patent. The same is true for the formula II threshold if the patent specification does not adequately connect the numerical limit to the claimed product.

Key Takeaways

• U.S. Patent 9,492,445 is a product-quality and packaging patent for methylnaltrexone compositions, especially methylnaltrexone bromide injection.
• The core claim requires at least 99.6% R configuration, less than 190 ppm of formula II, and a tungsten-controlled composition and package.
• Claims 9 and 10 align with the 8 mg/0.4 mL and 12 mg/0.6 mL Relistor injection presentations.
• Claims 14 through 19 cover treatment of opioid-induced constipation, including chronic opioid users and cancer patients, by subcutaneous injection.
• The patent is narrower than a basic methylnaltrexone compound patent but can be commercially significant because it tracks the approved injectable product.
• Generic risk centers on tungsten testing, impurity levels, stereochemical purity, container selection, and method-of-use labeling.
• Methylnaltrexone is a small molecule; biosimilar analysis does not apply.
• Exact expiration, Orange Book listing, litigation, and settlement status must be evaluated against current USPTO, FDA, and court records.

FAQs

Is U.S. Patent 9,492,445 a compound patent?

No. It is primarily a composition patent with associated method-of-treatment claims. It does not broadly claim every use or manufacture of methylnaltrexone independent of the specified quality and packaging characteristics.

Does the patent cover oral methylnaltrexone?

The supplied claims focus on solutions, syringes, vials, ampoules, and subcutaneous administration. They do not expressly cover an oral tablet or capsule.

Can a generic avoid the patent by using a different methylnaltrexone salt?

Potentially, but the alternative must remain pharmaceutically acceptable, clinically suitable, and approvable. Claims 3 and 4 specifically make bromide commercially important, while claim 1 broadly covers Brønsted-acid salts.

Why is tungsten relevant to injectable methylnaltrexone?

Tungsten can originate from manufacturing equipment or container components. The patent treats tungsten contamination as a quality attribute of both the composition and package.

Does an FDA-approved generic automatically avoid the patent?

No. FDA approval and patent noninfringement are separate questions. An ANDA applicant must address listed patents through a certification or statement, and the patent holder can bring Hatch-Waxman litigation.

References

1. U.S. Food and Drug Administration. (n.d.). Relistor (methylnaltrexone bromide) prescribing information.
2. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. United States Patent and Trademark Office. (2016). U.S. Patent No. 9,492,445.
4. U.S. Congress. (2011). Leahy-Smith America Invents Act and 35 U.S.C. § 271(e)(2).

Drugs Protected by US Patent 9,492,445

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Salix Pharms	RELISTOR	methylnaltrexone bromide	SOLUTION;SUBCUTANEOUS	021964-002	Sep 27, 2010		RX	Yes	Yes			Y			TREATMENT OF OPIOID-INDUCED CONSTIPATION
Salix Pharms	RELISTOR	methylnaltrexone bromide	SOLUTION;SUBCUTANEOUS	021964-001	Apr 24, 2008		RX	Yes	Yes			Y			TREATMENT OF OPIOID-INDUCED CONSTIPATION
Salix Pharms	RELISTOR	methylnaltrexone bromide	SOLUTION;SUBCUTANEOUS	021964-003	Sep 27, 2010		RX	Yes	Yes			Y			TREATMENT OF OPIOID-INDUCED CONSTIPATION
Salix	RELISTOR	methylnaltrexone bromide	TABLET;ORAL	208271-001	Jul 19, 2016		RX	Yes	Yes			Y			TREATMENT OF OPIOID-INDUCED CONSTIPATION

International Family Members for US Patent 9,492,445

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	073520
Australia	2009298500
Brazil	122020013665
Brazil	PI0919539