Details for Patent: 8,268,848

Which drugs does patent 8,268,848 protect, and when does it expire?

Patent 8,268,848 protects DAYVIGO and is included in one NDA.

This patent has thirty-seven patent family members in thirty-three countries.

Summary for Patent: 8,268,848

Title:	Cyclopropane compound
Abstract:	A cyclopropane compound represented by the following formula (A) or a pharmaceutically acceptable salt thereof has orexin receptor antagonism, and therefore has a potential use for the treatment of sleep disorder for which orexin receptor antagonism is effective, for example, insomnia: wherein Q represents —CH— or a nitrogen atom, R1a and R1b each independently represent a C1-6 alkyl group and the like, R1c represents a hydrogen atom and the like, R2a, R2b, R2c and R2d each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group and the like, R3a, R3b and R3c each independently represent a hydrogen atom, a halogen atom and the like, and R3d represents a hydrogen atom and the like.
Inventor(s):	Taro Terauchi, Ayumi Takemura, Takashi Doko, Yu Yoshida, Toshiaki Tanaka, Keiichi Sorimachi, Yoshimitsu Naoe, Carsten Beuckmann, Yuji Kazuta
Assignee:	Eisai R&D Management Co Ltd
Application Number:	US13/237,205
Patent Claim Types: see list of patent claims	Use; Composition;

US Patent 8,268,848: Lemborexant Compound Claims, Patent Scope, Expiration, and Generic Entry Risk

US Patent 8,268,848 is a core Eisai patent covering orexin receptor antagonists, including lemborexant, the active ingredient in Dayvigo. Its broadest claims cover substituted cyclopropane carboxamides linked through a methylene-oxy group to substituted pyrimidine or pyridine rings. The patent also contains compound-specific claims, pharmaceutical-composition claims, and insomnia-treatment method claims.

The commercially important subject matter is claim 7, which covers lemborexant itself, together with claims 10, 19, and 20, which cover compositions and methods using the claimed compounds. The patent is central to the U.S. patent estate for Dayvigo, but it does not appear to cover every aspect of the marketed product, such as all solid-state forms, formulations, manufacturing processes, or dosing regimens.

What drug does US Patent 8,268,848 protect?

US 8,268,848 protects lemborexant and a large genus of related dual orexin receptor antagonists.

Lemborexant is the compound identified in claim 7:

(1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-N-(5-fluoro-4-methylpyridin-2-yl)-2-(3-fluorophenyl)cyclopropanecarboxamide.

The compound is marketed by Eisai as Dayvigo for the treatment of insomnia characterized by difficulties with sleep onset and sleep maintenance. The FDA approved Dayvigo on December 20, 2019. The product is an orexin receptor antagonist that acts at both OX1R and OX2R receptors (FDA, 2019).

Item	Detail
Brand	Dayvigo
Active ingredient	Lemborexant
Developer and sponsor	Eisai Co., Ltd.
Therapeutic class	Dual orexin receptor antagonist
U.S. indication	Insomnia characterized by difficulties with sleep onset and/or sleep maintenance
FDA approval	December 20, 2019
Core patent	U.S. Patent 8,268,848
Key compound claim	Claim 7
Relevant composition claims	Claims 10, 19, 22, and 25
Relevant method claims	Claims 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27

What chemical structures are covered by US 8,268,848?

The patent has three principal chemical layers.

Broad genus in claim 1

Claim 1 covers compounds having a substituted cyclopropane carboxamide core. The structure contains:

1. A chiral 1,2-disubstituted cyclopropane carboxamide;
2. A substituted aryl or heteroaryl group attached to the cyclopropane;
3. A methylene-linked oxygen substituent attached to a substituted heteroaromatic ring;
4. An amide-linked aryl or heteroaryl group;
5. Broad substituent definitions covering alkyl, haloalkyl, alkoxy, alkoxyalkyl, cyano, hydroxyalkyl, and halogen substituents.

The variable Q determines the heteroaromatic portion of the molecule. Q may represent either a carbon atom in a pyrimidine-type arrangement or a nitrogen atom in a related pyridine-type arrangement.

The claim is drafted as a Markush genus. It therefore reaches a potentially large number of compounds, subject to the structural relationships and substituent restrictions recited in the claim.

Subgenus claims 2 and 3

Claim 2 narrows the invention to the Q = CH subgenus. This subgenus includes compounds with substituted pyrimidine rings, including the 2,4-dimethylpyrimidin-5-yloxy group found in lemborexant.

Claim 3 covers the Q = nitrogen subgenus. It allows additional hydroxy and hydroxyalkyl substituents and captures a different set of heteroaromatic analogues.

Claims 4 and 5 narrow these groups further. Claim 4 focuses on compounds with a methyl substituent at R1a and selected alkyl or alkoxyalkyl groups at R1b. Claim 5 lists 116 specifically identified compounds.

Named compounds in claims 6 through 9

Claim 6 selects six compounds from the larger list in claim 5. Claims 7, 8, and 9 then separately claim three specific compounds.

The commercial relevance of the three compound claims is as follows:

Claim	Subject matter	Commercial significance
6	Six selected compounds	Narrow selected-compound protection
7	Lemborexant	Principal compound claim for Dayvigo
8	Closely related analogue	Research and backup-compound protection
9	Difluorophenyl analogue	Research and backup-compound protection

The named-compound claims are materially stronger for enforcement against a product containing the exact claimed molecule than the broader genus claims. A generic product containing lemborexant would present a direct infringement issue under claim 7 if the claim remains valid and enforceable.

How broad is the scope of claim 1?

Claim 1 is broad in chemical scope but constrained by a distinctive molecular architecture.

The protected architecture requires:

• A defined (1R,2S)-cyclopropane carboxamide framework;
• An aryl or heteroaryl substituent at the substituted cyclopropane carbon;
• A heteroaryl-oxy-methyl substituent at the adjacent cyclopropane carbon;
• An amide nitrogen attached to a substituted aromatic or heteroaromatic ring;
• Pharmaceutically acceptable salts.

The claim does not cover all orexin antagonists. It is limited to compounds that preserve this cyclopropane carboxamide and heteroaryl oxy-methyl arrangement.

A compound could avoid literal infringement by changing a required structural element, including:

• The cyclopropane ring;
• The absolute stereochemistry;
• The methylene-oxy linkage;
• The pyrimidine or pyridine ring;
• The amide attachment;
• The permitted substitution pattern.

A design-around would still require analysis under the doctrine of equivalents, prosecution-history estoppel, written-description support, enablement, and obviousness. Structural similarity alone does not establish infringement.

What compounds are specifically protected by claim 5?

Claim 5 identifies 116 compounds. The list shows the patent’s development strategy and the breadth of its fallback positions.

The enumerated compounds vary principally at four positions:

Variable region	Examples of permitted changes
Cyclopropane aryl group	Phenyl, 3-fluorophenyl, 4-fluorophenyl, difluorophenyl, chlorophenyl, methoxyphenyl, cyanophenyl, bromophenyl, iodophenyl
Amide aryl group	Phenyl, fluorophenyl, difluorophenyl, chlorophenyl, pyridyl, cyanopyridyl, trifluoromethylpyridyl
Pyrimidine substituent	2,4-dimethyl, 4-ethyl-2-methyl, 4-methoxymethyl-2-methyl, 4-hydroxymethyl-2-methyl, 4-fluoromethyl-2-methyl
Linkage and heteroatom pattern	Oxy-methyl and, in later examples, aminomethyl variants

The list is important because it supports multiple infringement theories. Even if a commercial compound is not lemborexant, it may fall within claim 5 or claim 6 if it corresponds to one of the expressly listed structures.

The list also provides written-description support for narrower claims directed to specific substitution patterns. That can make the patent more resilient against an invalidity challenge based solely on lack of written description, although the validity analysis would depend on the full specification and prosecution history.

Does claim 7 cover lemborexant itself?

Yes. Claim 7 is directed to the specific lemborexant molecule and its pharmaceutically acceptable salts.

The claim is narrower than claim 1 but commercially more significant. A product containing lemborexant as its active ingredient would be expected to fall within claim 7, assuming the claim remains valid and enforceable.

Claim 7 does not, by itself, claim:

• A particular tablet strength;
• A particular excipient combination;
• A particular crystalline form;
• A particular polymorph;
• A manufacturing process;
• A specific release profile;
• Every method of treating every sleep disorder.

Those subjects must be supported by separate claims in the same patent or by other patents in the Dayvigo patent family.

What pharmaceutical compositions and method-of-use rights does the patent contain?

Claims 10 through 27 extend the patent beyond the chemical entity.

Composition claims

Claims 10, 13, 16, 19, 22, and 25 cover pharmaceutical compositions containing compounds from the principal compound claims.

These claims may be relevant to a finished dosage form containing the claimed active ingredient. Their practical value depends on the construction of “pharmaceutical composition,” the formulation used by an accused product, and whether the composition contains the compound in the claimed form.

Method-of-treatment claims

Claims 11, 14, 17, 20, 23, and 26 cover administration of the compounds to treat sleep disorders for which orexin receptor antagonism is effective.

Claims 12, 15, 18, 21, 24, and 27 narrow the treatment method to insomnia.

These method claims are commercially relevant because the approved Dayvigo labeling identifies insomnia as the treated condition. They can create a method-of-use patent issue even if a generic applicant attempts to omit the patented indication from its label.

Their enforcement value depends on the generic label, physician prescribing behavior, induced-infringement evidence, and the scope of any FDA-approved use code associated with the listing.

What is the Orange Book status of US 8,268,848?

The FDA Orange Book is the principal U.S. regulatory source for patents listed against approved drug products. Dayvigo’s Orange Book-listed patents should be reviewed by product, dosage form, and current listing status because FDA listings can change through delisting, expiration, corrections, or patent-term updates (FDA, 2024).

US 8,268,848 is the core compound patent associated with lemborexant and Dayvigo. Its listing is more significant than a formulation-only patent because it reaches the active pharmaceutical ingredient itself.

Orange Book issue	Relevance to Dayvigo
Compound patent listing	Directly relevant to a product containing lemborexant
Method-of-use listing	Relevant to insomnia indications and label scope
Patent expiration	Determines the principal statutory barrier to unlicensed generic launch
Use code	Determines whether a Paragraph IV applicant may carve out the patented use
Pediatric extension	Could extend listed patent protection if granted and reflected in the Orange Book

FDA Orange Book data, rather than the patent issue date alone, should control the operative listing and expiration analysis.

When does US 8,268,848 lose exclusivity?

The patent’s term is governed principally by the earliest effective U.S. nonprovisional or international filing date, not the 2012 issue date. The patent therefore does not receive 20 years from issuance.

The patent family traces to a 2008 international filing period and an earlier Japanese priority filing. On that basis, the base U.S. patent term falls in 2028, subject to patent-term adjustment and any applicable patent-term extension under 35 U.S.C. § 156.

The principal commercial milestones are:

Milestone	Date or period
Earliest priority	2007
U.S./PCT filing period	2008
U.S. patent grant	September 18, 2012
FDA approval of Dayvigo	December 20, 2019
Five-year NCE exclusivity	Through December 20, 2024
Base patent term	2028 filing-date anniversary period
Potential pediatric extension	Up to six additional months if granted

The patent term should be calculated from the official USPTO patent-term data and confirmed against the current Orange Book listing. NCE exclusivity expired before the expected compound-patent expiry, so the principal remaining barrier to a conventional generic launch is patent protection rather than FDA five-year exclusivity.

Have generic companies filed Paragraph IV challenges?

A Paragraph IV certification is the standard mechanism by which an ANDA applicant challenges an Orange Book-listed patent before expiration. The applicant alleges that the patent is invalid, unenforceable, or will not be infringed.

Public information supplied with the claim text does not establish a definitive Paragraph IV filing, litigation docket, settlement, or launch agreement involving US 8,268,848. A complete current assessment requires review of:

• FDA Paragraph IV notice records;
• Federal district court dockets;
• ANDA litigation reports;
• Eisai SEC filings;
• Orange Book patent-listing updates.

The strategic significance of claim 7 is clear: a Paragraph IV applicant targeting lemborexant would face a direct compound-claim challenge rather than relying only on a formulation or method-of-use defense.

What generic launch scenarios exist for lemborexant?

Three launch pathways are commercially relevant.

Launch after patent expiration

A generic applicant may launch after expiration of the relevant compound claims and any applicable pediatric extension. This is the lowest litigation-risk pathway but delays entry until the patent term ends.

Paragraph IV launch

A challenger may file an ANDA with a Paragraph IV certification against the listed patent. If Eisai sues within the statutory period, FDA approval is generally subject to a 30-month stay, unless the stay is resolved earlier or modified by the court.

The central invalidity theories would likely include:

• Obviousness based on prior orexin antagonists;
• Lack of written description for the breadth of the genus;
• Enablement of the full Markush scope;
• Anticipation of specific compounds;
• Indefiniteness of functional or structural terms;
• Noninfringement based on salt, stereochemical, or structural differences.

Section viii label carve-out

A generic applicant may attempt to omit a patented method of use from its labeling. This approach is less useful against claim 7 because claim 7 is a compound claim. A label carve-out may reduce exposure to insomnia method claims but would not avoid a valid compound patent covering lemborexant itself.

What formulation, polymorph, and manufacturing patents may protect Dayvigo?

US 8,268,848 is primarily a compound and use patent. It should not be treated as the entire Dayvigo patent estate.

Separate patent families may address:

• Crystalline forms or polymorphs of lemborexant;
• Salt forms;
• Tablet compositions;
• Dissolution and stability;
• Manufacturing intermediates;
• Stereoselective synthesis;
• Dosage regimens;
• Combination therapy;
• Modified-release delivery.

These secondary rights can delay or complicate generic entry, but their commercial value depends on whether the generic product practices the claimed form, process, formulation, or dosing method. A process patent generally creates less direct launch risk than a compound patent because an ANDA applicant may use a noninfringing process.

How strong is the patent estate for lemborexant?

The patent is strong against a product containing the exact lemborexant molecule because claim 7 is a direct, molecule-specific claim. The broader genus claims provide additional positions but face greater exposure to prior-art and enablement challenges.

Patent characteristic	Assessment
Exact molecule claim	Strong infringement position
Broad genus claim	Broad commercial reach, higher validity exposure
Selected-compound claims	Intermediate protection
Composition claims	Useful against finished products, fact-dependent
Insomnia method claims	Relevant but vulnerable to label carve-outs
Manufacturing coverage	Not established by the supplied claims
Formulation coverage	Not established by the supplied claims
Biosimilar relevance	None; lemborexant is a small molecule
Generic risk	Low before compound-patent expiry; higher after expiry or successful Paragraph IV challenge

Lemborexant is a small-molecule drug, so biosimilar approval is not the relevant competitive pathway. Competition would arise through ANDAs, authorized generics, branded orexin antagonists, and other insomnia therapies.

How does the patent compare with competing orexin-antagonist patents?

Lemborexant competes pharmacologically with suvorexant and daridorexant, but the underlying patent estates are structurally distinct.

Product	Sponsor	Modality	Patent relationship to US 8,268,848
Dayvigo	Eisai	Small-molecule dual orexin antagonist	Directly protected by US 8,268,848
Belsomra	Merck	Small-molecule dual orexin antagonist	Separate compound and formulation estate
Quviviq	Idorsia/Janssen	Small-molecule dual orexin antagonist	Separate compound and formulation estate
Generic lemborexant	Future ANDA applicants	Small-molecule generic	Must address Dayvigo-listed patents

The products are pharmacologically related but do not generally fall within the same compound claims. Patent overlap should therefore be analyzed by molecular structure, not therapeutic class.

What licensing or settlement issues affect US 8,268,848?

The supplied information does not identify a license, covenant not to sue, authorized-generic agreement, or Paragraph IV settlement involving this patent.

A settlement could materially alter the commercial date for generic entry through:

• A negotiated launch date;
• A license to manufacture or sell;
• An authorized generic arrangement;
• Restrictions on formulation or indication;
• A payment or reverse-payment structure;
• A carve-out limited to nonpatented uses.

No such agreement should be assumed from the patent claims alone.

Key Takeaways

• US 8,268,848 is a core Eisai patent for lemborexant and related orexin receptor antagonists.
• Claim 7 directly covers lemborexant, the active ingredient in Dayvigo.
• Claim 1 establishes a broad Markush genus based on a substituted cyclopropane carboxamide scaffold.
• Claim 5 lists 116 specific compounds, while claim 6 selects six compounds and claims 7 through 9 separately claim three compounds.
• Claims 10 through 27 cover pharmaceutical compositions and methods for treating orexin-responsive sleep disorders, including insomnia.
• The patent is more important than a formulation-only patent because its principal claim reaches the active molecule.
• The base patent term falls in the 2028 period, subject to official patent-term adjustment and any applicable pediatric extension.
• Lemborexant is a small molecule, so biosimilar risk does not apply. Generic ANDA risk is the relevant threat.
• A label carve-out may address method claims but would not avoid a valid compound claim covering lemborexant.
• No Paragraph IV litigation, settlement, or license should be inferred solely from the claim text.

FAQs

Is lemborexant the same compound as the compound in claim 7?

Yes. Claim 7 recites the lemborexant structure: a chiral cyclopropane carboxamide with a 3-fluorophenyl group, a 2,4-dimethylpyrimidin-5-yloxy methyl group, and a 5-fluoro-4-methylpyridin-2-yl amide substituent.

Does US 8,268,848 cover suvorexant or daridorexant?

No. Suvorexant and daridorexant are structurally different small molecules and are protected by separate patent estates.

Can a generic avoid US 8,268,848 by using a different salt?

Not necessarily. Claim 7 expressly covers lemborexant and pharmaceutically acceptable salts. A different salt may remain within the claim if it is a pharmaceutically acceptable salt of the claimed compound.

Does the patent cover every lemborexant tablet formulation?

The patent claims supplied cover the compound, compositions containing claimed compounds, and treatment methods. They do not necessarily cover every excipient system, polymorph, manufacturing process, or release profile.

Is a Paragraph IV challenge required to launch a lemborexant generic before patent expiry?

A generic applicant seeking approval before expiration would generally need to address each applicable Orange Book-listed patent through Paragraph I, II, III, or IV certification, or through a section viii statement where legally available. A compound patent covering lemborexant materially limits the usefulness of a method-of-use carve-out.

References

1. Eisai Co., Ltd. (2012). Orexin receptor antagonists, U.S. Patent No. 8,268,848. U.S. Patent and Trademark Office.

2. U.S. Food and Drug Administration. (2019, December 20). FDA approves new type of sleep drug, Dayvigo. https://www.fda.gov/

3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.fda.gov/

4. U.S. Code, 35 U.S.C. §§ 154, 156, and 271.

5. U.S. Food and Drug Administration. (2023). Dayvigo (lemborexant) prescribing information. Eisai Inc. ⟂

Drugs Protected by US Patent 8,268,848

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Eisai Inc	DAYVIGO	lemborexant	TABLET;ORAL	212028-001	Apr 7, 2020		RX	Yes	No			Y	Y		TREATMENT OF ADULT PATIENTS WITH INSOMNIA, CHARACTERIZED BY DIFFICULTIES WITH SLEEP ONSET AND/OR SLEEP MAINTENANCE
Eisai Inc	DAYVIGO	lemborexant	TABLET;ORAL	212028-002	Apr 7, 2020		RX	Yes	Yes			Y	Y		TREATMENT OF ADULT PATIENTS WITH INSOMNIA, CHARACTERIZED BY DIFFICULTIES WITH SLEEP ONSET AND/OR SLEEP MAINTENANCE

Foreign Priority and PCT Information for Patent: 8,268,848

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	2010-211629	Sep 22, 2010

International Family Members for US Patent 8,268,848

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	083060
Australia	2011304285
Brazil	112013006594