Details for Patent: 8,455,536

Summary for Patent: 8,455,536

Title:	Methods of using (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline 1,3-dione
Abstract:	Stereomerically pure (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, substantially free of its (-) isomer, and prodrugs, metabolites, polymorphs, salts, solvates, hydrates, and clathrates thereof are discussed. Also discussed are methods of using and pharmaceutical compositions comprising the (+) enantiomer of 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione are disclosed. The methods include methods of treating and/or preventing disorders ameliorated by the reduction of levels of TNF-alpha or the inhibition of PDE4.
Inventor(s):	George W. Muller, Peter H. Schafer, Hon-Wah Man, Chuansheng Ge
Assignee:	Amgen Inc
Application Number:	US12/630,788
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,455,536
Patent Claim Types: see list of patent claims	Use; Delivery; Dosage form;

US Drug Patent 8,455,536: Apremilast Method-of-Treatment Claims, Scope and Patent Landscape

US Patent No. 8,455,536 protects specified methods of administering the (+) enantiomer of apremilast for psoriasis, rheumatoid arthritis and Behcet's disease. The patent does not claim apremilast as a chemical compound, a general pharmaceutical composition, or every use of the drug. Its enforceable scope depends on proving the claimed disease, stereochemical purity, dosage, route, dosage form and, for certain claims, twice-daily administration.

The patent issued June 4, 2013, to Celgene Corporation and is associated with the Otezla apremilast franchise, now commercialized by Amgen. The reported patent expiration date is March 26, 2028, subject to the controlling patent record, terminal-disclaimer provisions and any applicable regulatory patent-term adjustment.[1,2]

What drug does US Patent 8,455,536 protect?

The claimed active ingredient is the stereomerically pure (+) isomer of apremilast:

(+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione

Apremilast is an oral phosphodiesterase-4 inhibitor. Otezla is approved in the United States for:

• plaque psoriasis in adults who are candidates for phototherapy or systemic therapy;
• active psoriatic arthritis in adults; and
• oral ulcers associated with Behcet's disease in adults.[3]

The supplied claims focus on three inflammatory diseases:

Claimed disease	Independent claims	Principal claim structure
Psoriasis	1	Oral administration, 10-200 mg/day, tablet or capsule
Rheumatoid arthritis	17 and 36	Therapeutically effective amount, oral dosing, with claim 36 requiring a narrow regimen
Behcet's disease	37 and 56	Therapeutically effective amount, oral dosing, with claim 56 requiring a narrow regimen

Psoriatic arthritis is not expressly named in the supplied claims. That distinction matters. A product label directed only to psoriatic arthritis would not automatically practice the psoriasis, rheumatoid arthritis or Behcet's disease claims.

What are the independent claims of US 8,455,536?

The patent has six substantive independent method claims.

Claim	Disease	Required treatment conditions
1	Psoriasis	Oral administration of about 10-200 mg/day; tablet or capsule; single or divided dose
17	Rheumatoid arthritis	Administration of a therapeutically effective amount
36	Rheumatoid arthritis	Oral administration of 10-100 mg/day; greater than 97% (+) isomer; tablet or capsule; twice daily in equal doses
37	Behcet's disease	Administration of a therapeutically effective amount
56	Behcet's disease	Oral administration of 10-100 mg/day; greater than 97% (+) isomer; tablet or capsule; twice daily in equal doses

Claims 2-16 depend from the psoriasis method. Claims 18-35 depend from the broad rheumatoid arthritis method. Claims 38-55 depend from the broad Behcet's disease method.

The claims create two protection tiers:

1. Broad disease-method claims, particularly claims 1, 17 and 37.
2. Narrow regimen claims requiring specific oral dosing, high enantiomeric purity, solid dosage forms and twice-daily administration, particularly claims 36 and 56.

How broad is the psoriasis protection?

Claim 1 is the broadest psoriasis claim. It requires all of the following:

• a patient having psoriasis;
• oral administration;
• the specific (+) apremilast stereoisomer;
• a daily amount of about 10 mg to about 200 mg;
• administration as a tablet or capsule; and
• either a single daily dose or divided doses.

The claim does not require:

• a particular psoriasis subtype;
• a specific tablet or capsule excipient;
• a particular duration of treatment;
• combination therapy or monotherapy;
• a specific clinical endpoint;
• a named brand;
• a specific strength within the claimed range; or
• a particular manufacturing process.

The dependent claims narrow the scope by adding lower dosage ranges, twice-daily dosing, stereochemical purity thresholds and dosage strengths. Claims 8-11 cover 10 mg, 20 mg, 25 mg and 50 mg capsules. Claims 13-16 identify the same strengths for tablets.

The practical scope is strongest against an approved or marketed oral apremilast product whose labeling directs treatment of psoriasis within the claimed dose range. The claim is less useful against a product labeled exclusively for an unclaimed disease or a nonoral route.

What rheumatoid arthritis claims are covered?

Claim 17 is materially broader than claim 36. It covers administering a therapeutically effective amount of the (+) apremilast enantiomer to a patient with rheumatoid arthritis, without reciting a fixed dose, dosage form or route.

Claim 18 narrows claim 17 to oral administration. Claims 19-21 specify daily dose ranges:

• 5-500 mg/day;
• 10-200 mg/day; and
• 10-100 mg/day.

Claim 22 requires twice-daily administration in equal doses. Claims 23-25 require greater than 90%, 95% or 97% by weight of the (+) isomer. Claims 26-35 identify capsules and tablets at 10 mg, 20 mg, 25 mg and 50 mg strengths.

Claim 36 combines the principal limitations into a single narrow regimen:

• rheumatoid arthritis;
• oral administration;
• 10-100 mg/day;
• greater than 97% (+) isomer;
• tablet or capsule; and
• twice-daily dosing in equal portions.

The rheumatoid arthritis claims have commercial value as method claims, but they do not necessarily align with Otezla's current US indications, which are psoriasis, psoriatic arthritis and Behcet's disease rather than rheumatoid arthritis.[3]

What Behcet's disease claims are covered?

Claim 37 broadly covers administering a therapeutically effective amount of the (+) apremilast enantiomer to a patient with Behcet's disease.

The dependent claims narrow the method by adding:

• oral administration;
• 5-500 mg/day, 10-200 mg/day or 10-100 mg/day;
• twice-daily equal dosing;
• greater than 90%, 95% or 97% (+) isomer;
• capsule or tablet administration; and
• 10 mg, 20 mg, 25 mg or 50 mg strengths.

Claim 56 is the narrow Behcet's disease counterpart to claim 36. It requires oral administration of 10-100 mg/day of material containing greater than 97% of the (+) isomer in a tablet or capsule administered twice daily in equal doses.

These claims have direct relevance to Otezla's FDA-approved Behcet's disease indication. The FDA label identifies a standard maintenance regimen of 30 mg twice daily, after titration.[3] A labeled 30 mg twice-daily regimen falls within the 10-100 mg/day range in claims 41 and 56, although the claims' listed dependent dosage strengths do not include a 30 mg tablet or capsule.

What formulations are protected by US 8,455,536?

The patent claims dosage-form categories rather than detailed formulation compositions.

Formulation limitation	Claims
Tablet or capsule	1, 36, 56 and related claims
Capsule	7-11, 26-30, 46-50
Tablet	12-16, 31-35, 51-55
10 mg strength	8, 13, 27, 32, 47, 52
20 mg strength	9, 14, 28, 33, 48, 53
25 mg strength	10, 15, 29, 34, 49, 54
50 mg strength	11, 16, 30, 35, 50, 55

The patent does not, based on the supplied claims, require particular excipients, dissolution characteristics, particle size, coating technology, polymorph, salt, amorphous form or release profile. A separate formulation patent could therefore provide additional protection around a commercial tablet even if US 8,455,536 were unavailable.

Claims 12-16 present a drafting anomaly. Claim 12 depends from claim 11, which requires a 50 mg capsule, and then states that the compound is administered in tablet form. A literal reading creates an apparent capsule-tablet inconsistency. The same issue does not appear in the tablet series beginning with claim 31. This inconsistency could affect claim construction and validity analysis for claims 12-16.

When does US 8,455,536 lose exclusivity?

The patent's reported expiration date is March 26, 2028.[1,2]

Milestone	Date or status
Patent issued	June 4, 2013
Patent term basis	20 years from the relevant nonprovisional filing, subject to adjustment and disclaimer rules
Reported expiration	March 26, 2028
Primary commercial product	Otezla, apremilast
FDA approval of Otezla	March 21, 2014
Current holder of Otezla franchise	Amgen

The patent is a method-of-treatment patent. Its expiration does not necessarily eliminate every patent barrier affecting apremilast. Core compound, formulation, polymorph, manufacturing and other method-of-use patents may have different expiration dates.

What other patents protect Otezla and apremilast?

The principal US patent landscape includes the following categories:

Patent category	Representative patent	Strategic role
Core compound	US 6,962,940	Protects apremilast chemical matter and related compounds
Use and treatment methods	US 7,427,638 and US 8,455,536	Protect disease-specific administration methods
Later use or formulation coverage	Later Celgene/Amgen patents listed for Otezla	May extend barriers for specific indications, formulations or regimens
Regulatory exclusivity	FDA approval-based exclusivity	Applies separately from patent term

US 6,962,940 is commonly identified as the principal apremilast compound patent, with an expiration date reported in 2023. US 7,427,638 is associated with later method-of-use protection and has been reported with an expiration in 2025. US 8,455,536 is reported to expire in 2028.[1,2]

The commercial effect is cumulative. A generic applicant may avoid one method claim yet remain exposed to a compound, formulation or other listed use patent. Conversely, a Paragraph IV certification can challenge particular Orange Book patents without resolving every patent in the estate.

What is the Orange Book status of US 8,455,536?

Method-of-use patents may be listed in the FDA Orange Book when they cover an approved use reflected in the product labeling and satisfy FDA listing requirements.[2] Otezla's Orange Book profile should be evaluated by:

• patent number;
• expiration date;
• use code;
• whether the patent remains listed;
• whether the listed use appears in the current labeling; and
• whether the patent has been disclaimed, delisted or removed.

For US 8,455,536, the critical regulatory question is whether the listed use code maps to an FDA-approved Otezla indication. The Behcet's disease claims have a stronger product-label connection than the rheumatoid arthritis claims because Behcet's disease is an approved Otezla indication. Psoriasis also has a direct label connection. Rheumatoid arthritis is not identified as an approved Otezla indication in the current FDA labeling.[3]

FDA approval does not itself establish infringement. The patent inquiry remains claim-specific. A product label that directs use for psoriasis or Behcet's disease, within the claimed oral dose and dosage form, creates a materially greater induced-infringement risk than a label limited to psoriatic arthritis.

Which companies are challenging Otezla exclusivity?

Apremilast is a small molecule, so the relevant competitive pathway is an abbreviated new drug application, not a biosimilar application. Generic manufacturers can file ANDAs with:

• Paragraph I certification, if no relevant patent is listed;
• Paragraph II certification, if the patent has expired;
• Paragraph III certification, accepting delayed approval until expiration; or
• Paragraph IV certification, asserting that a listed patent is invalid, unenforceable or not infringed.[4]

Publicly available litigation and regulatory records should be reviewed for each ANDA filer, including Teva, Sandoz, Zydus, Hetero, Dr. Reddy's and other potential applicants. The existence of an ANDA filing does not establish a commercial launch date. The timing depends on patent litigation, a 30-month stay, first-filer status, settlement terms, pediatric exclusivity and FDA approval.

No biosimilar risk applies because apremilast is a chemically synthesized small molecule. The relevant threat is generic substitution after ANDA approval.

What Paragraph IV risks does the patent create?

A Paragraph IV challenge to US 8,455,536 would likely focus on claim scope and proof of induced infringement.

Possible noninfringement positions

A generic applicant could argue that:

• its label omits psoriasis or Behcet's disease;
• its label directs treatment only for psoriatic arthritis;
• the labeled dose falls outside the claimed range;
• the product is not labeled as a tablet or capsule;
• the label does not direct twice-daily administration where that limitation applies; or
• the claim requires a stereochemical purity limitation not established by the proposed product.

These arguments are strongest against narrow claims 36 and 56. They are less effective against claim 1 if the label directly instructs oral treatment of psoriasis at 10-200 mg/day.

Possible validity positions

A challenger could target:

• anticipation by earlier apremilast treatment disclosures;
• obviousness based on prior art involving apremilast, PDE4 inhibition and the claimed diseases;
• written-description support for the specific dosage and stereochemical purity combinations;
• enablement across the full dose ranges;
• indefiniteness involving terms such as "about," "therapeutically effective amount" and "stereomerically pure"; and
• claim dependency or internal inconsistency in claims 12-16.

The broad claims 17 and 37 may face stronger written-description and obviousness attacks because they recite a disease and therapeutically effective amount without many operational constraints. The narrower claims have greater technical specificity but may be easier to design around.

How strong is the patent estate for apremilast?

The patent estate is strongest where three conditions overlap:

1. The proposed generic label includes an FDA-approved indication covered by a listed method patent.
2. The dosage and route match the claim.
3. A separate compound or formulation patent remains enforceable.

US 8,455,536 has meaningful protection for psoriasis and Behcet's disease because those uses correspond to approved Otezla labeling. Its rheumatoid arthritis claims are commercially less aligned with the current label. The patent's principal weakness is that it is use-specific. It does not prevent all manufacture, sale or use of apremilast outside the claimed disease and regimen.

The patent also has no biosimilar-style interchangeability barrier. Once relevant small-molecule patents and regulatory exclusivities expire, FDA-approved generics can generally substitute through pharmacy channels under state law.

What generic launch scenarios exist for Otezla?

Scenario	Commercial consequence
Full patent challenge succeeds	Earlier approval and potential launch, subject to other listed patents
Settlement permits a negotiated entry date	Delayed generic entry with defined litigation closure
Skinny-label approval	Generic omits patented indications, reducing induced-infringement exposure
Paragraph III certification	Approval delayed until the relevant patent expiration
Patent survives through March 2028	Otezla retains a method-of-use barrier for covered indications
Compound and formulation barriers expire earlier	Generic may enter for noncovered uses if labeling and remaining patents permit

A skinny-label strategy would be particularly relevant if a generic seeks approval for psoriatic arthritis while omitting psoriasis and Behcet's disease. The commercial value of that strategy depends on whether the omitted indications account for a significant share of prescriptions and whether physicians can readily substitute the generic for off-label or unlisted use.

How does US 8,455,536 compare with the core apremilast patent?

Issue	US 6,962,940	US 8,455,536
Patent type	Chemical compound	Method of treatment
Active ingredient	Apremilast and related chemical matter	Specific (+) apremilast stereoisomer
Disease limitation	Generally broader chemical protection	Psoriasis, rheumatoid arthritis or Behcet's disease
Dosage limitation	Not the central claim feature	Central to many dependent claims
Formulation limitation	Generally not central	Tablet and capsule claims
Design-around potential	Lower if compound claims cover the product	Higher through label and indication changes
Commercial relevance	Broadest product barrier	Targeted use and regimen barrier

Key Takeaways

• US 8,455,536 is a method-of-treatment patent for the (+) enantiomer of apremilast.
• The principal claimed diseases are psoriasis, rheumatoid arthritis and Behcet's disease.
• The reported expiration date is March 26, 2028.
• Claims 1, 17 and 37 are the broadest disease-method claims.
• Claims 36 and 56 require greater than 97% (+) isomer, 10-100 mg/day, oral administration, tablet or capsule dosing and twice-daily equal doses.
• The patent does not claim apremilast composition-of-matter protection.
• Otezla's Behcet's disease and psoriasis labels create the clearest method-of-use exposure.
• Rheumatoid arthritis claims are less aligned with the current FDA-approved Otezla label.
• Generic challengers face ANDA Paragraph IV, skinny-label and settlement strategies rather than biosimilar litigation.
• Claims 12-16 contain an apparent capsule-tablet dependency inconsistency.
• Remaining compound, formulation and method patents must be analyzed separately before determining a generic launch date.

FAQs

Is US 8,455,536 a composition-of-matter patent?

No. It claims methods of treating specified diseases using the (+) stereoisomer of apremilast.

Does US 8,455,536 cover psoriatic arthritis?

The supplied claims do not expressly recite psoriatic arthritis. They recite psoriasis, rheumatoid arthritis and Behcet's disease.

Can a generic apremilast product avoid US 8,455,536 with a skinny label?

Potentially. Omitting patented indications can reduce induced-infringement risk, but the strategy depends on the precise label, Orange Book use codes and other patents.

Does the patent cover a 30 mg twice-daily Otezla regimen?

The supplied claims do not list a 30 mg tablet or capsule strength in the dependent dosage-form claims. A 30 mg twice-daily regimen equals 60 mg/day and falls within the 10-100 mg/day range in certain broad and narrow claims, subject to the other limitations.

Is a biosimilar required to compete with Otezla?

No. Apremilast is a small-molecule drug. Competition proceeds through the ANDA generic-drug pathway.

References

1. United States Patent and Trademark Office. (2013). US Patent No. 8,455,536, Methods of treating psoriasis, rheumatoid arthritis and Behcet's disease.
2. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Otezla, apremilast. Orange Book.
3. U.S. Food and Drug Administration. (2023). Otezla (apremilast) prescribing information. Amgen Inc.
4. U.S. Food and Drug Administration. (2024). Abbreviated new drug application submissions: Patent certifications and the 30-month stay.

Drugs Protected by US Patent 8,455,536

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

International Family Members for US Patent 8,455,536

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2962690		300994	Netherlands
European Patent Office	2962690		LUC00125	Luxembourg
European Patent Office	2962690		122019000070	Germany
European Patent Office	2962690		CA 2019 00033	Denmark
European Patent Office	2962690		2019C/008	Belgium
European Patent Office	2962690		37/2019	Austria
European Patent Office	2962690		132019000000096	Italy