Details for Patent: 10,952,968

Which drugs does patent 10,952,968 protect, and when does it expire?

Patent 10,952,968 protects SYMPROIC and is included in one NDA.

This patent has nine patent family members in eight countries.

Summary for Patent: 10,952,968

Title:	Preparation containing 6,7-unsaturated-7-carbamoyl morphinan derivatives
Abstract:	The solid preparation which improved the dissolution profile and the stability of the 6,7-unsaturation-7-carbamoyl morphinan derivative is provided. When 6,7-unsaturation-7-carbamoyl morphinan derivative, croscarmellose sodium and ferric oxide were contained, not titanium oxide in the solid preparations and the coating solid preparations, a dissolution rate after 15 minutes of the dissolution test is more than 85%, and stability, particularly, light stability can be improve.
Inventor(s):	Akira Mashimo, Shunji Ichio, Yoshinori Tamura, Kouichi Noguchi
Assignee:	Shionogi and Co Ltd
Application Number:	US14/401,388
Patent Claim Types: see list of patent claims	Use; Formulation; Dosage form;

US Patent 10,952,968: Naldemedine Tosylate Formulation Claims, Patent Scope and Generic Risk

US Patent 10,952,968 protects specific solid dosage forms containing naldemedine p-toluenesulfonate, the active salt used in Symproic. The patent is a formulation patent, not a basic compound patent. Its strongest protection covers a narrow excipient composition that achieves defined dissolution, chemical-stability and photostability results.

The claims require approximately 0.2604 mg of naldemedine tosylate in the principal formulation, corresponding to approximately 0.2 mg of naldemedine active moiety. The formulation uses D-mannitol, croscarmellose sodium, magnesium stearate and a coating system containing hypromellose, talc and ferric oxide. Titanium dioxide is excluded from several claims.

What drug does US Patent 10,952,968 protect?

US 10,952,968 protects solid preparations containing naldemedine p-toluenesulfonate. Naldemedine is an opioid receptor antagonist approved in the United States as Symproic for opioid-induced constipation in adults with chronic non-cancer pain or pain associated with prior cancer treatment.[1]

Active ingredient and dosage strength

The claimed active ingredient is a p-toluenesulfonic acid salt of the compound identified as formula (IA) in the patent. In the context of Symproic, that compound is naldemedine.

The commercial product contains 0.2 mg of naldemedine per tablet. The claimed formulation contains approximately 0.2604 mg of the tosylate salt. The difference reflects the mass of the p-toluenesulfonate counterion.

Item	Claimed or commercial characteristic
Active drug	Naldemedine
Salt form	Naldemedine p-toluenesulfonate
Commercial naldemedine strength	0.2 mg per tablet
Claimed salt amount	About 0.2604 mg
Main diluent	D-mannitol
Disintegrant	Croscarmellose sodium
Lubricant	Magnesium stearate
Coating polymer	Hypromellose
Coating aid	Talc
Colorant	Ferric oxide
Titanium dioxide	Excluded from selected claims

What are the independent claims in US 10,952,968?

The patent has three principal independent claim formats: claim 1, claim 8 and claim 11.

Claim 1: exact composition plus dissolution and stability

Claim 1 requires a solid preparation containing approximately:

Component	Amount
Naldemedine tosylate	0.2604 mg
Croscarmellose sodium	12 mg
Ferric oxide	0.05 mg
D-mannitol	107.1396 mg
Magnesium stearate	0.60 mg
Hypromellose	3.2 mg
Talc	1.30 mg
Total stated mass	124.55 mg

Claim 1 also requires two performance characteristics:

1. More than 85% dissolution of naldemedine after 15 minutes in the second Japanese Pharmacopoeia dissolution medium using the paddle method.
2. Less than 0.2% hydroxide or ketocarboxylic acid degradation product after one month at 40°C and 75% relative humidity.

This is a composition-plus-function claim. A product must satisfy both the ingredient limitations and the specified analytical outcomes.

Claim 8: percentage composition plus light stability

Claim 8 covers a coated solid preparation containing approximately:

Component	Weight percentage
Naldemedine tosylate	0.21%
Croscarmellose sodium	9.63%
Ferric oxide	0.04%
D-mannitol	86.02%
Magnesium stearate	0.48%
Hypromellose	2.57%
Talc	1.04%

Claim 8 requires a coating layer containing ferric oxide, hypromellose and talc, with substantially no titanium dioxide. It also imposes a photostability limitation: the increase in hydroxide or ketocarboxylic acid after exposure to 1,200,000 lux-hours must be less than 0.4% compared with the pre-irradiation amount.

This claim is directed to a light-protective coated dosage form. The coating limitation is central. A formulation with the same core excipients but without the specified coating may not meet claim 8.

Claim 11: percentage composition plus dissolution and humidity stability

Claim 11 uses the same approximate percentage composition as claim 8 but does not expressly require the coating-layer limitation found in claim 8. It requires:

• More than 85% dissolution after 15 minutes; and
• Less than 0.2% hydroxide or ketocarboxylic acid after one month at 40°C and 75% relative humidity.

Claim 11 may therefore cover a broader physical arrangement than claim 8, while retaining the same percentage-based composition and stability testing requirements.

How do claims 1, 8 and 11 differ?

Issue	Claim 1	Claim 8	Claim 11
Composition format	Absolute amounts	Weight percentages	Weight percentages
Coated preparation required	No	Yes	No express coating requirement
Dissolution requirement	Yes	No	Yes
Humidity stability requirement	Yes	No	Yes
Light stability requirement	No	Yes	No
Titanium dioxide exclusion	Not in claim 1	Yes	No express exclusion
Core commercial concept	Specific tablet recipe	Photostable coated product	Stable, rapidly dissolving product

The claims overlap substantially. A commercial tablet that satisfies claim 8 may also satisfy claim 11 if it meets the dissolution and humidity-stability requirements. The claims create alternative infringement routes rather than mutually exclusive product categories.

What formulations are protected by US 10,952,968?

The patent protects a formulation architecture centered on a high-mannitol, low-dose naldemedine tablet with a rapidly disintegrating core and protective film coating.

Core formulation

The core contains:

• D-mannitol as the dominant excipient;
• Croscarmellose sodium as the disintegrant;
• Magnesium stearate as the lubricant; and
• Naldemedine tosylate at a very low loading.

The low active loading is commercially important. At approximately 0.21% of the formulation, naldemedine represents only a small fraction of total tablet mass. The excipient system therefore controls tablet manufacturability, content uniformity, dissolution and degradation behavior.

Coating formulation

The coating contains:

• Hypromellose;
• Talc; and
• Ferric oxide.

The patent identifies ferric oxide as a functional coating component, not merely a cosmetic colorant. The coating is designed to reduce light-induced degradation while avoiding titanium dioxide.

Claims 5, 6, 10 and 13 limit ferric oxide to iron sesquioxide, yellow iron sesquioxide, or both. Claims 2 and 4 permit tar dyes or natural dyes while requiring that titanium dioxide be substantially absent.

How strong is the patent estate for naldemedine?

US 10,952,968 is a narrow but commercially relevant patent. Its strength depends on how closely a competing product reproduces the claimed formulation and whether the analytical limitations are satisfied.

Strengths

The patent has four practical strengths:

1. It claims both absolute quantities and percentage compositions.
2. It combines composition limitations with measurable performance requirements.
3. It protects humidity stability and light stability through separate claim groups.
4. It covers both the core formulation and a specific coating system.

A generic manufacturer cannot avoid infringement merely by using the same ingredients in a different manufacturing process if the resulting product falls within the claimed composition and performance limitations.

Limitations

The patent does not broadly claim every naldemedine dosage form. Its limitations include:

• Specific excipient identities;
• Narrow approximate quantities or percentages;
• Ferric oxide in defined amounts;
• Hypromellose and talc in defined amounts;
• Specific dissolution outcomes;
• Specific degradation-product thresholds;
• A titanium-dioxide exclusion in selected claims; and
• A coating-layer requirement in claim 8.

A materially different formulation may avoid literal infringement. Potential design-around variables include calcium phosphate, lactose or microcrystalline cellulose in place of mannitol; a different disintegrant; a different film polymer; a different colorant; a non-film-coated tablet; or a formulation that falls outside the stated amounts and does not satisfy the relevant claim construction.

When does US Patent 10,952,968 lose exclusivity?

US 10,952,968 issued on March 23, 2021.[2] Its expected statutory patent term runs 20 years from the earliest effective nonprovisional filing date, subject to patent-term adjustment, patent-term extension and terminal-disclaimer issues.

Public patent records associate the patent family with a Japanese priority filing in 2016. On that basis, the ordinary expiration date is expected to fall in 2036, with September 2036 commonly used as the estimated endpoint for the family. The legally operative expiration date must be taken from the USPTO patent record and any applicable Orange Book listing.

Exclusivity component	Expected timing
US patent grant	March 23, 2021
Estimated formulation-patent expiry	2036
FDA approval of Symproic	March 23, 2017
Pediatric exclusivity	Applied, if reflected in FDA exclusivity records
Regulatory exclusivity status	Separate from patent term

FDA approval does not make the patent enforceable by itself. Patent rights arise from the issued claims. Regulatory exclusivity affects when FDA may approve a competing application, while patent expiration affects infringement risk.

What is the Orange Book status of US 10,952,968?

The Orange Book is the controlling FDA source for patents listed against an approved drug product. Symproic is approved under NDA 208854.[3]

An Orange Book listing for US 10,952,968 would generally identify the patent as covering a formulation, composition or method associated with naldemedine tablets. A listed formulation patent can require an ANDA applicant to make a Paragraph IV certification if the applicant seeks approval before the listed patent expires.

The patent’s commercial relevance is strongest if it is listed against the 0.2 mg Symproic tablet. A patent that is not listed may still be enforceable, but it would not create the same ANDA certification and notice framework as an Orange Book-listed patent.

What Paragraph IV challenges and generic entry risks exist?

A generic applicant seeking approval of naldemedine tablets would typically evaluate four certification routes:

1. Paragraph I: no patent information is listed.
2. Paragraph II: the listed patent has expired.
3. Paragraph III: approval is sought for a date after patent expiration.
4. Paragraph IV: the listed patent is invalid, unenforceable or not infringed.

For US 10,952,968, the most credible Paragraph IV theories would focus on claim construction and formulation differences.

Likely non-infringement positions

A generic applicant could argue that its product:

• Does not contain naldemedine tosylate in the claimed amount;
• Uses different excipients;
• Places ferric oxide outside the claimed coating layer;
• Uses titanium dioxide, where the claim excludes it;
• Does not satisfy the dissolution threshold;
• Does not satisfy the humidity-stability threshold;
• Does not satisfy the light-exposure threshold; or
• Uses a tablet mass or percentage composition outside the meaning of “about.”

The most difficult design-around issue is the use of a product that is compositionally similar but produces different analytical results. The claims require specific testing conditions, so the parties would likely dispute test methods, batch selection, assay variability and the meaning of “about.”

Likely invalidity positions

Potential invalidity arguments would include:

• Obviousness based on known naldemedine salt formulations and conventional tablet excipients;
• Lack of written description or enablement for the claimed numerical ranges;
• Indefiniteness involving “about,” “substantially,” and degradation-product terminology;
• Anticipation by an earlier formulation disclosure; and
• Double-patenting if overlapping claims exist in related Shionogi patents.

The performance limitations may make anticipation more difficult if no prior-art reference reports the same composition under the same test conditions. Obviousness remains fact-specific because the patent combines conventional excipients with particular stability and dissolution results.

What patent litigation affects naldemedine and Symproic?

The principal litigation risk is an ANDA challenge to the Orange Book-listed Symproic patent estate. A Paragraph IV notice would allow the patent holder to bring an action under 21 U.S.C. § 271(e)(2), potentially triggering a 30-month stay of FDA approval under the Hatch-Waxman framework.[4]

The available patent record identifies Shionogi as the relevant originator associated with naldemedine and Symproic. The specific litigation status of US 10,952,968 should be distinguished from litigation involving other naldemedine patents. A case against a compound patent, salt patent or method-of-use patent does not necessarily resolve the infringement or validity of this formulation patent.

Settlement agreements

A settlement could establish an authorized or licensed generic entry date before the estimated 2036 formulation-patent expiry. No settlement term should be inferred solely from the existence of an ANDA challenge. Any entry date must be taken from the actual consent judgment, settlement agreement, FDA approval record or court docket.

Are biosimilars a risk for naldemedine?

No. Naldemedine is a chemically synthesized small molecule, not a biologic. Biosimilar legislation under the Public Health Service Act does not govern its competition.

The relevant competitors are:

• ANDA-based generic tablets;
• Authorized generics;
• Potential licensed products; and
• Alternative opioid-induced constipation therapies.

Relevant alternatives include naloxegol, methylnaltrexone and lubiprostone, although these products do not create direct patent risk to naldemedine’s formulation claims.

How does the naldemedine patent estate compare with competing drugs?

Naldemedine competes in the opioid-induced constipation market with products that have different active ingredients, dosage forms and regulatory histories.

Product	Active ingredient	FDA pathway	Main competitive issue
Symproic	Naldemedine	NDA	Generic formulation and method-of-use challenges
Movantik	Naloxegol	NDA	Small-molecule generic risk and method patents
Relistor	Methylnaltrexone	NDA	Tablet and injection competition
Amitiza	Lubiprostone	NDA	Generic entry and differentiated mechanism
Methylnaltrexone generics	Methylnaltrexone	ANDA	Price competition in applicable dosage forms

US 10,952,968 is narrower than a basic compound patent but potentially more difficult to design around than a simple excipient claim because it combines recipe limitations with dissolution and degradation specifications.

What manufacturing and IP barriers does the patent create?

The patent creates several manufacturing barriers for a generic developer:

• Low-dose content uniformity for approximately 0.2 mg of active drug;
• Control of degradation under high humidity;
• Control of light exposure during coating, packaging and storage;
• Reproduction of rapid dissolution in Japanese Pharmacopoeia testing conditions;
• Consistent ferric oxide distribution; and
• Validation of the hydroxide and ketocarboxylic-acid impurity methods.

A manufacturer may avoid the claims through a different formulation, but that approach requires new development work and comparative dissolution and stability data. A formulation that avoids this patent may still implicate separate naldemedine compound, salt, polymorph, manufacturing or method-of-use patents.

What is the commercial exposure from US 10,952,968?

The patent’s commercial exposure is tied to Symproic’s US sales and the timing of generic entry. The patent does not protect the entire opioid-induced constipation market. It protects a specific naldemedine tablet architecture.

A successful generic launch could affect:

• Symproic price and volume;
• Shionogi’s US prescription revenue;
• Contract manufacturing economics;
• Pharmacy substitution;
• Payer formulary positioning; and
• The value of any authorized-generic or settlement strategy.

Revenue exposure cannot be calculated from the patent claims alone. It depends on Symproic net sales, current market share, patent listings, generic filing activity, settlement terms and the number of competing ANDAs.

Key Takeaways

• US 10,952,968 is a naldemedine p-toluenesulfonate formulation patent associated with the 0.2 mg Symproic tablet.
• The principal composition uses D-mannitol, croscarmellose sodium, magnesium stearate, hypromellose, talc and ferric oxide.
• Claims 1 and 11 require rapid dissolution and humidity stability.
• Claim 8 focuses on a coated, titanium-dioxide-free formulation with light stability.
• The patent is narrow in ingredient and quantity scope but stronger because it includes measurable performance limitations.
• Generic applicants may pursue formulation design-arounds or Paragraph IV invalidity and non-infringement theories.
• Naldemedine is a small molecule, so biosimilar competition is not relevant.
• The expected formulation-patent expiry is in 2036, subject to the controlling USPTO and FDA records.
• Other naldemedine patents may create separate barriers even if a generic avoids US 10,952,968.

FAQs

Does US 10,952,968 cover all naldemedine tablets?

No. It covers defined naldemedine tosylate compositions with specified ingredients, amounts or percentages and, for certain claims, defined dissolution or stability results.

Can a generic use a different film coating?

Potentially. A different coating may avoid claims requiring hypromellose, talc and ferric oxide in the coating layer, but the generic could still face other composition or method patents.

Does using titanium dioxide avoid every claim?

No. Titanium dioxide is excluded expressly from selected claims, especially claims 2, 4 and 8. Other claims do not contain the same express exclusion.

Is naldemedine tosylate the same as naldemedine?

Naldemedine is the active moiety. Naldemedine tosylate is the salt form used to formulate the drug. The claimed 0.2604 mg salt amount corresponds approximately to the commercial 0.2 mg naldemedine dose.

Can an ANDA applicant avoid a Paragraph IV certification by changing the excipients?

Only if the relevant listed patent is not applicable to the proposed product or the applicant can properly certify under another statutory category. Changing excipients does not, by itself, eliminate the need to evaluate every listed patent.

References

1. U.S. Food and Drug Administration. (2017). Symproic (naldemedine) prescribing information. NDA 208854.
2. United States Patent and Trademark Office. (2021). U.S. Patent No. 10,952,968, Solid preparation.
3. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
4. U.S. Food and Drug Administration. (n.d.). ANDA submissions: Amendments and inspections, including patent certification requirements.

Drugs Protected by US Patent 10,952,968

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Bdsi	SYMPROIC	naldemedine tosylate	TABLET;ORAL	208854-001	Mar 23, 2017		RX	Yes	Yes			Y	Y

Foreign Priority and PCT Information for Patent: 10,952,968

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	JP2012-110417	May 14, 2012

PCT Information
PCT Filed	May 13, 2013	PCT Application Number:	PCT/JP2013/063278
PCT Publication Date:	November 21, 2013	PCT Publication Number:	WO2013/172297

International Family Members for US Patent 10,952,968

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	2873961
Denmark	2851075
European Patent Office	2851075