Details for Patent: 8,536,192

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Summary for Patent: 8,536,192

Title:	6,7-unsaturated-7-carbamoyl substituted morphinan derivative
Abstract:	A novel compound which is useful as an agent for treating and/or preventing emesis, vomiting and/or constipation.A compound represented by the formula (I): wherein R1 and R2 are each independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted aryl etc., R3 is hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy etc., R4 is hydrogen or lower alkyl, R5 is hydrogen, lower alkyl, cycloalkyl lower alkyl or lower alkenyl, or a pharmaceutically acceptably salt, or a solvate thereof is provided.
Inventor(s):	Masanao Inagaki, Shin-ichiro Hara, Nobuhiro Haga, Yoshinori Tamura, Yoshihisa Goto, Tsuyoshi Hasegawa
Assignee:	Shionogi and Co Ltd
Application Number:	US13/308,483
Patent Claim Types: see list of patent claims	Use; Composition;

US Patent 8,536,192: Scope, Claims, Expiration, and Naldemedine Patent Landscape

US Patent 8,536,192 is a Shionogi patent directed to opioid receptor antagonist compounds, pharmaceutical compositions, and methods for treating opioid-induced emesis, vomiting, and constipation. Its commercial significance is tied to naldemedine, the active ingredient in Symproic. The patent has a broad genus claim in claim 1, narrower compound subclasses in claims 2-4, composition claims in claims 5-10, and therapeutic method claims in claims 11-14. Claims 15 and 16 are incomplete in the claim text provided and cannot be assessed as written.

The patent’s stated expiration date is February 4, 2029, subject to any terminal disclaimer, patent-term adjustment, patent-term extension, or other USPTO-record modification. The patent was issued September 17, 2013, to Shionogi & Co., Ltd. [1]

What drug does US Patent 8,536,192 protect?

US 8,536,192 protects a family of opioid receptor antagonists related to naldemedine. Naldemedine is a peripherally acting mu-opioid receptor antagonist, or PAMORA, approved by the FDA under the brand name Symproic for opioid-induced constipation in adults with chronic non-cancer pain or pain associated with prior cancer treatment. [2]

The claims are drafted around a substituted opioid-antagonist core represented by formula (I). The claim language does not name naldemedine directly. Instead, it defines the compound through structural substituents, ring systems, stereochemical and bond-state alternatives, salts, and solvates.

The principal commercial product associated with the patent is:

Item	Information
Active ingredient	Naldemedine tosylate
Brand	Symproic
Sponsor	Shionogi Inc.
Pharmacologic class	Peripherally acting mu-opioid receptor antagonist
Primary indication	Opioid-induced constipation
FDA approval	March 23, 2017
Dosage form	Oral tablet
Strength	0.2 mg naldemedine
Patent at issue	US 8,536,192
Stated patent expiration	February 4, 2029

The patent should not be treated as a claim to every opioid antagonist. Infringement depends on whether a competing compound falls within the structural limitations of the claims, or whether a product or use practices a valid composition or method claim.

What is the scope of claim 1 of US 8,536,192?

Claim 1 is a broad compound genus claim. It covers compounds containing a defined opioid-antagonist scaffold with multiple independently variable substituents.

Its principal elements are:

1. A core represented by formula (I).
2. Nitrogen substituents R1 and R2 selected from a wide range of groups.
3. R3 selected from hydrogen, hydroxy, alkyl, alkoxy, amino, acyl, aryl, heterocyclic and related groups.
4. A fused or linked nitrogen-containing ring system represented by the claim’s ring A and ring B definitions.
5. A variable bond-state arrangement controlled by the broken-line notation and the value of p.
6. Substituents Ra and Rb on the ring system.
7. R4 as hydrogen or lower alkyl.
8. R5 as hydrogen, lower alkyl, cycloalkyl lower alkyl, or lower alkenyl.
9. Pharmaceutically acceptable salts and solvates.

R1 and R2 substitutions

The claim permits R1 and R2 to be hydrogen, substituted or unsubstituted lower alkyl, alkenyl, alkynyl, alkylsulfonyl, acyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, or arylsulfonyl groups. It also allows R1 and R2 to form a ring with the nitrogen atom to which they are attached.

This creates several layers of structural breadth:

• Primary and secondary amine configurations.
• Tertiary amine configurations.
• Cyclic amine configurations.
• Aromatic and heteroaromatic substitution.
• Acylated and sulfonylated nitrogen species.
• Substituted and unsubstituted hydrocarbon groups.

The claim therefore reaches substantially beyond a single commercial molecule. Its practical scope depends on the definition of the formula (I) scaffold and the ring A/ring B limitations.

R3 substitution

R3 may be hydroxy, amino, alkyl, alkoxy, acyl, acyloxy, aryl, heterocyclic, mercapto, carbamoyl, or hydrogen, among other alternatives.

Claims 2 and 3 narrow this field:

• Claim 2 requires R3 to be hydroxy.
• Claim 3 requires R3 to be optionally substituted amino.

The hydroxy limitation is commercially important because the compound associated with Symproic falls within the hydroxy-containing subclass described in the patent.

R5 substitution

R5 may be hydrogen, lower alkyl, cycloalkyl lower alkyl, or lower alkenyl. Claim 4 narrows R5 to cyclopropylmethyl.

Cyclopropylmethyl substitution is a recurring structural characteristic in opioid receptor ligands, including naldemedine-related compounds. A competing product containing a different N-substituent may avoid claim 4 while still requiring analysis under claim 1 or another related patent.

Which claims are most important for naldemedine?

Claims 2, 4, 5, 7, 8, 9, 10, 11, 12, 13 and 14 are the most commercially relevant portions of the supplied claim set.

Claim	Claim type	Commercial significance
1	Broad compound genus	Defines the principal chemical class
2	Hydroxy compound subclass	Narrows the genus toward the commercial pharmacophore
3	Amino compound subclass	Covers a separate structural branch
4	Narrow compound subclass	Requires specific R1, R2 and cyclopropylmethyl R5 limitations
5	Pharmaceutical composition	Covers compositions containing claimed compounds
6	Opioid receptor antagonist composition	Links the compounds to pharmacologic activity
7	Emesis, vomiting and constipation composition	Covers therapeutic composition use
8	Opioid agonist side-effect treatment	Targets adverse effects caused by opioid agonists
9	Specific side effects	Narrows claim 8 to emesis, vomiting and constipation
10	Morphine or oxycodone-related use	Identifies specific opioid agonists
11	Therapeutic method	Covers administration for emesis, vomiting or constipation
12	Analgesic combination composition	Combines an opioid agonist with the claimed antagonist
13	Narrow method genus	Requires R1 hydrogen, R3 hydroxy, R4 hydrogen and R5 cyclopropylmethyl
14	Alternative narrow method genus	Covers another defined R2 substitution set
15	Method claim	Incomplete in supplied text
16	Dependent method claim	Incomplete in supplied text

Claims 13 and 14 are particularly important because they contain a more focused combination of structural and therapeutic limitations. They require:

• R1 to be hydrogen.
• R3 to be hydroxyl.
• R4 to be hydrogen.
• R5 to be cyclopropylmethyl.
• R2 to fall within enumerated alkyl, phenyl, cycloalkyl, or heterocyclic groups.
• Use for treating or preventing emesis, vomiting, or constipation.

A generic naldemedine manufacturer would normally analyze these claims together with claims directed to the precise active compound, its salt, crystalline form, formulation, and approved use.

What formulations are protected by US 8,536,192?

Claim 5 covers a pharmaceutical composition containing a compound within claims 1-4, or its pharmaceutically acceptable salt or solvate. Claim 6 similarly covers a composition having opioid receptor antagonistic activity.

These claims are composition claims, not detailed formulation-platform claims. Based on the supplied text, they do not expressly require:

• A particular tablet excipient.
• A specified dissolution profile.
• A particular polymorph.
• A specific particle size.
• A controlled-release matrix.
• A defined impurity profile.
• A particular manufacturing process.
• A specific dosage or concentration.

The claims can therefore reach a tablet, capsule, powder, solution, or other pharmaceutical presentation if it contains a qualifying compound. Their breadth may be limited by the validity and construction of the underlying compound claims.

Symproic is an oral tablet containing naldemedine tosylate. The FDA-approved product labeling identifies naldemedine tosylate as the active ingredient and provides the approved 0.2 mg oral dosage. [2]

Salt and solvate coverage

The repeated references to pharmaceutically acceptable salts and solvates expand the claims beyond the free base. A product containing naldemedine tosylate could therefore fall within the salt language if the underlying naldemedine structure satisfies the relevant compound limitations.

Salt coverage does not automatically cover every crystalline or solid-state form. A separate patent may be required for:

• A particular polymorph.
• A hydrate or solvate.
• A defined salt stoichiometry.
• A specific crystal habit.
• A formulation with enhanced stability or dissolution.

What methods of use are protected?

The supplied claims cover treatment or prevention of opioid-related gastrointestinal adverse effects, particularly:

• Emesis.
• Vomiting.
• Constipation.
• Side effects caused by opioid receptor agonists.

Claim 10 identifies morphine and oxycodone as examples of opioid agonists. Claim 12 covers an analgesic composition containing both an opioid receptor agonist and a claimed antagonist.

The method claims have two distinct commercial applications:

1. Use of the antagonist alone to treat or prevent constipation, vomiting, or emesis.
2. Use of the antagonist with an opioid analgesic to reduce opioid-induced adverse effects.

This distinction matters because a generic manufacturer may sell the same active ingredient for an approved indication while presenting different labeling. Method-of-use risk depends on the approved labeling, induced-infringement evidence, prescribing behavior, and the scope and enforceability of the asserted claims.

When does US Patent 8,536,192 lose exclusivity?

The listed expiration date is February 4, 2029. That date is the principal loss-of-exclusivity date for the patent. [1]

Milestone	Date
Earliest priority date reflected in public patent records	2008
U.S. patent grant	September 17, 2013
Patent number	US 8,536,192 B2
Listed expiration	February 4, 2029
FDA approval of Symproic	March 23, 2017
Earliest ordinary post-expiration generic entry point	February 5, 2029, subject to regulatory and litigation conditions

The expiration of one patent does not necessarily remove all market barriers. Other patents may cover naldemedine, its salts, formulations, methods of use, manufacturing processes, or specific solid-state forms. A generic applicant must evaluate the entire patent listing and relevant non-Orange Book patents.

What is the Orange Book status of US 8,536,192?

US 8,536,192 is associated with the Symproic patent estate and should be evaluated against the FDA Orange Book listings for naldemedine products. The Orange Book distinguishes patents submitted by the sponsor from regulatory exclusivity. Patent listing does not itself establish validity or enforceability. [3]

The commercial analysis should separate:

Protection type	Function
Listed drug patent	Supports patent certification and potential Paragraph IV litigation
New chemical entity exclusivity	Delays certain generic submissions
Orphan exclusivity	Applies only if the approval qualifies under orphan-drug rules
Pediatric exclusivity	Can add six months to qualifying periods
Patent-term extension	May extend an eligible patent based on regulatory review
Non-listed patent	May still create infringement exposure but normally does not control an Orange Book certification

Symproic received FDA approval in 2017. Its core regulatory exclusivity has expired. The remaining primary commercial barrier is patent protection and any related patents in the naldemedine family. [2, 3]

Are there Paragraph IV challenges to naldemedine patents?

A Paragraph IV certification asserts that a listed patent is invalid, unenforceable, or not infringed. Filing an ANDA with a Paragraph IV certification can trigger patent litigation under the Hatch-Waxman Act.

For US 8,536,192, the relevant risk questions are:

• Whether an ANDA applicant has certified Paragraph IV against the patent.
• Whether Shionogi filed a timely infringement action.
• Whether the litigation triggered a 30-month FDA approval stay.
• Whether the case ended by judgment, dismissal, settlement, or license.
• Whether a first filer obtained 180-day generic exclusivity.
• Whether the patent remains listed for the relevant reference product.

No Paragraph IV conclusion should be drawn from the existence of a generic application alone. The filing, litigation docket, FDA status, and Orange Book record must be read together.

A generic applicant could challenge the patent on several grounds:

Written description and enablement

The patent claims cover a large chemical genus. A challenger could argue that the specification does not adequately describe or enable the full breadth of the claimed combinations, particularly if the number of possible substituent combinations is extensive.

The patentee would respond that the specification identifies the core scaffold, representative substituents, synthetic methods, examples, and pharmacologic activity sufficient to support the genus.

Anticipation

A challenger could rely on earlier opioid antagonist disclosures that contain the claimed scaffold and substituent arrangement. Anticipation requires a single prior-art reference to disclose every claim limitation arranged as claimed.

Obviousness

Obviousness would likely focus on combinations of known opioid antagonists, known N-substituents, ring-system modifications, and teachings directed to peripheral opioid receptor activity or reduced central nervous system penetration.

Claim construction

The terms “lower alkyl,” “optionally substituted,” “heterocyclic group,” “nitrogen-containing heterocycle,” and the ring A/ring B formula may affect infringement and validity. The definition of the broken-line bond and p value is also important because it creates alternative saturated or unsaturated configurations.

How strong is the patent estate for naldemedine?

US 8,536,192 has meaningful scope because it combines compound, composition, pharmacologic-use, and therapeutic-method claims. Its strength is highest where a competing product uses the same core structure, hydroxy substitution, hydrogen R1/R4 groups, and cyclopropylmethyl R5 group.

Its principal vulnerabilities are breadth and claim dependency. The broadest claim may face greater validity pressure than the narrower claims. Narrow claims can be easier to enforce against an exact or near-exact copy but may be easier to design around.

Patent characteristic	Assessment
Compound coverage	Broad genus with multiple substituent classes
Naldemedine relevance	High
Salt coverage	Expressly included
Formulation coverage	Broad composition coverage, limited formulation specificity
Method-of-use coverage	Strong for opioid-induced constipation, emesis and vomiting
Design-around potential	Moderate, depending on scaffold and substituent changes
Expiration timing	Commercially significant through February 2029
Litigation sensitivity	High for any ANDA containing the claimed naldemedine structure

The patent is stronger as part of a coordinated family than as an isolated document. Related patents may address the specific commercial compound, manufacturing route, pharmaceutical composition, dosage regimen, or crystalline form.

What patent litigation affects naldemedine generic entry?

Naldemedine generic entry can be delayed by:

1. Patent litigation following an ANDA Paragraph IV notice.
2. A statutory 30-month stay.
3. A court judgment upholding an asserted patent.
4. A settlement that grants a future licensed entry date.
5. Additional Orange Book-listed patents.
6. Non-listed patents that create commercial litigation risk after launch.
7. Regulatory deficiencies unrelated to patent status.

A settlement agreement may establish an authorized generic license, a fixed launch date, royalty terms, or restrictions on the generic product. Settlement terms are often confidential, and an announced settlement does not establish patent validity.

The critical diligence point is whether the relevant patent has been litigated to final judgment or remains untested. A patent that has not survived an invalidity challenge may still block launch, but its litigation risk is different from a patent confirmed after trial or appeal.

Which companies compete with naldemedine?

Naldemedine competes in the PAMORA market with:

Product	Active ingredient	Company	General patent position
Symproic	Naldemedine	Shionogi	Core patent protection extends into 2029
Movantik	Naloxegol	AstraZeneca, later commercialized by other parties	Separate compound and formulation estate
Relistor	Methylnaltrexone	Bausch Health	Earlier PAMORA with distinct structure
Amitiza	Lubiprostone	Viatris/Sucampo heritage	Different mechanism and chemical class
Trulance	Plecanatide	Bausch Health	Secretagogue, not a PAMORA
Linzess	Linaclotide	Ironwood/AbbVie	Guanylate cyclase-C agonist

Naldemedine’s closest patent competitors are naloxegol and methylnaltrexone only at the therapeutic-class level. Their patents do not ordinarily create direct structural overlap with naldemedine. They compete for the same opioid-induced constipation market but rely on different chemical entities and patent estates.

What generic launch scenarios exist for naldemedine?

Scenario 1: Launch after patent expiration

A generic applicant launches after February 4, 2029, assuming no later-expiring blocking patent, regulatory delay, or enforceable settlement restriction.

Scenario 2: Paragraph IV launch before expiration

A challenger launches after defeating the asserted patents, obtaining a favorable judgment, or relying on a litigation outcome that removes the relevant restraint.

Scenario 3: Licensed early entry

A generic company enters under a settlement agreement with an agreed date before patent expiration. The agreement may contain commercial restrictions or licensing conditions.

Scenario 4: At-risk launch

A company launches before final resolution of litigation. This exposes the applicant to potential damages, injunction risk, and accelerated market withdrawal.

Scenario 5: Design-around product

A competitor develops a different opioid antagonist outside the compound claims. This approach avoids direct naldemedine infringement but requires separate FDA approval and clinical, manufacturing, and regulatory investment.

What manufacturing and geographic IP barriers exist?

The patent claims do not appear limited to a single manufacturing process. A competitor could therefore face compound infringement even if it uses an independent synthesis route.

Manufacturing diligence should cover:

• The exact naldemedine intermediate sequence.
• Chiral resolution or stereoselective synthesis.
• Salt formation with tosylate or another counterion.
• Crystal-form control.
• Impurity specifications.
• Stability and degradation products.
• API and finished-dose process patents.
• Process patents in the United States, Europe, Japan and other target markets.

US 8,536,192 has territorial effect only in the United States. A separate patent analysis is required for Canada, Europe, Japan, China, South Korea and other markets. Patent expiration, prosecution history, claim scope and Orange Book practice differ by jurisdiction.

What are the main business risks from US 8,536,192?

The principal exposure is a direct-copy naldemedine product that practices the compound and method claims. The highest-risk product profile would contain:

• The claimed opioid antagonist scaffold.
• R1 as hydrogen.
• R3 as hydroxy.
• R4 as hydrogen.
• R5 as cyclopropylmethyl.
• A qualifying R2 substituent.
• A label directed to opioid-induced constipation.
• A tablet or other pharmaceutical composition containing the compound or its salt.

A generic applicant should not rely solely on a formulation design-around. Because the claims include compound and method claims, changing excipients may not avoid infringement. Changing the active ingredient or its structural configuration is more likely to affect the claim analysis, but may remove the product from the naldemedine reference-product pathway.

Key Takeaways

• US 8,536,192 is a Shionogi patent covering opioid receptor antagonist compounds related to naldemedine.
• Claim 1 is a broad chemical genus claim with extensive R1, R2, R3, R4 and R5 substitution flexibility.
• Claims 2-4 narrow the genus, with claim 4 requiring a cyclopropylmethyl R5 group.
• Claims 5-12 cover pharmaceutical compositions, opioid antagonist activity, opioid-induced side effects and combination analgesic use.
• Claims 13 and 14 provide narrower method-of-treatment coverage focused on hydroxylated compounds with cyclopropylmethyl substitution.
• Claims 15 and 16 are incomplete in the supplied text.
• The listed expiration date is February 4, 2029.
• The patent is commercially relevant to Symproic and naldemedine generic-entry planning.
• Formulation changes alone may not avoid infringement because the patent contains compound and method claims.
• A complete freedom-to-operate review must include related naldemedine patents, Orange Book listings, Paragraph IV filings, litigation dockets, settlements and non-US rights.

FAQs About US Patent 8,536,192 and Naldemedine

Is US 8,536,192 a patent on Symproic?

It is a patent covering compounds and therapeutic uses associated with naldemedine, the active ingredient in Symproic. It is not limited by brand name or tablet appearance.

Can a generic company avoid US 8,536,192 by changing tablet excipients?

Not necessarily. Claims 1-4 are compound claims, and claims 11-14 are method claims. A product containing a covered compound may remain exposed even if its excipients differ.

Does patent expiration automatically permit naldemedine generic approval?

No. Generic approval also depends on FDA requirements, other listed patents, regulatory exclusivity, litigation outcomes, settlements and any applicable patent-term adjustment or extension.

Are naldemedine and naloxegol covered by the same patents?

Generally no. They are different active ingredients with different chemical structures and patent families, although they compete in the same PAMORA market.

What is the most important claim for an exact naldemedine copy?

The answer depends on the precise structure and product labeling. Claims 1, 2, 4, 5, 11, 13 and 14 are the most relevant portions of the supplied claim set for a product containing the naldemedine-related scaffold and marketed for opioid-induced constipation.

References

1. United States Patent and Trademark Office. (2013). U.S. Patent No. 8,536,192 B2: Quinuclidine derivative.
2. U.S. Food and Drug Administration. (2017). Symproic (naldemedine) tablets: Prescribing information.
3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
4. Shionogi Inc. (2024). Symproic product information.
5. United States Patent and Trademark Office. (n.d.). Patent Center: U.S. Patent No. 8,536,192.

Drugs Protected by US Patent 8,536,192

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 8,536,192

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	2005-151864	May 25, 2005
Japan	2006-065762	Mar 10, 2006
	PCT/JP2006/310231	May 23, 2006

International Family Members for US Patent 8,536,192

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1889848		300996	Netherlands
European Patent Office	1889848		2019C/533	Belgium
European Patent Office	1889848		122019000063	Germany
European Patent Office	1889848		CA 2019 00035	Denmark
European Patent Office	1889848		38/2019	Austria
European Patent Office	1889848		132019000000093	Italy