Details for Patent: 4,866,048

Summary for Patent: 4,866,048

Title:	Novel vitamin D analogues
Abstract:	This invention relates to vitamin D analogues represented by the general formula I ##STR1## in which formula X stands for hydrogen, lower alkyl, halogen or hydroxy; Y stands for hydrogen or hydroxy; R1 and R2, which may be the same or different, stand for lower alkyl, optionally substituted with halogen or hydroxy with the proviso that R1 and R2 cannot both be methyl when X is other than lower alkyl, or, taken together with the carbon atom numbered 25, R1 and R2 can form a saturated or unsaturated C3 -C9 carbocyclic ring which may optionally be substituted at any possible position(s) with lower alkyl, halogen or hydroxy; R3 stands for hydrogen or lower alkyl; R4 and R5 represent either each hydrogen, or when taken together constitute a bond, with the result that a double bond connects carbon atoms numbered 22 and 23; and bioreversible derivatives thereof.The compounds of the invention have a favorable therapeutic index and are particularly useful in the treatment of human and veterinary disorders which are characterized by abnormal cell proliferation and/or cell differentiation.
Inventor(s):	Martin J. Calverley, Ernst T. Binderup
Assignee:	Leo Pharma AS
Application Number:	US07/034,391
Patent Claim Types: see list of patent claims	Use; Composition;

Executive summary: U.S. Patent No. 4,866,048 covers a broad class of vitamin D analogues, including calcipotriene, selected stereoisomers, crystalline forms, synthesis intermediates, manufacturing processes, pharmaceutical compositions, topical formulations and psoriasis treatment methods. The patent was granted on September 12, 1989, and its ordinary U.S. patent term expired in 2006. It therefore creates no current U.S. patent barrier to generic calcipotriene manufacture, formulation or sale. Later formulation and combination-product patents, rather than U.S. Patent No. 4,866,048, controlled portions of the commercial exclusivity history for products such as Dovonex, Taclonex and Enstilar.

U.S. Patent 4,866,048: Scope, Claims, Expiration and Calcipotriene Patent Landscape

What drug does U.S. Patent 4,866,048 protect?

U.S. Patent No. 4,866,048, titled “Vitamin D Analogues,” protects synthetic analogues of vitamin D with a modified side chain at carbon 25 and, in selected claims, a 22,23-double bond and 1α-hydroxy substitution. The patent is associated with Leo Pharmaceutical Products Ltd. [1]

The principal commercial compound within the claim set is calcipotriene, also called calcipotriol. Calcipotriene is a topical vitamin D analogue used primarily for plaque psoriasis and other disorders involving abnormal keratinocyte proliferation and differentiation.

The patent is broader than a single calcipotriene product. Claim 1 covers a genus defined by:

• A 9,10-seco-vitamin D steroid framework.
• Substituents X and Y that may include hydrogen, alkyl, halogen or hydroxy groups.
• A carbon-25 substituent forming a saturated or unsaturated C3-C9 carbocyclic ring.
• Optional aromatic substitution.
• Hydrogen or C1-C6 alkyl at R3.
• Either a saturated 22,23 side chain or a 22,23-double bond.
• Bioreversible derivatives, which may include prodrug-type derivatives converted to the active analogue in vivo.

Calcipotriene falls within the narrower cyclopropyl and hydroxy-substituted embodiments recited by claims 5, 10 and 11.

What is the prosecution and expiration history of U.S. Patent 4,866,048?

Event	Date or status
Earliest priority claimed	1985, based on the related European/Danish filing history
U.S. application	1986
U.S. patent grant	September 12, 1989
Patent term applicable to the patent	Generally 17 years from grant under pre-1995 U.S. law
Ordinary expiration	September 12, 2006
Current enforceability	Expired
Current Orange Book significance	Historical only

The patent is a pre-Uruguay Round patent. Its term was generally calculated from the grant date rather than the application filing date. Public patent records identify the patent as expired. [1, 2]

The expiration date is important because a patent can remain listed in historical regulatory records after it loses enforceability. An Orange Book listing does not extend an expired patent and does not independently create market exclusivity.

No current U.S. patent term extension appears to have preserved enforceability of U.S. Patent No. 4,866,048 for calcipotriene products. Patent term extension under 35 U.S.C. § 156 applies only when statutory requirements are met and would be reflected in the relevant patent and regulatory records. [2, 3]

How broad is claim 1 of U.S. Patent 4,866,048?

Claim 1 is a Markush genus claim. It does not require one particular commercial product. Instead, it defines a structural family through variable substituents and ring options.

Core structural limitations

The claim requires a compound of formula I with the following key elements:

1. A vitamin D-type 9,10-seco steroid core.
2. A defined side chain attached at the carbon-20 region.
3. A carbon-25 substituent in which R1 and R2, together with carbon 25, form a C3-C9 carbocyclic ring.
4. Optional hydroxy, halogen and alkyl substitutions.
5. Optional saturation or unsaturation at the 22,23 position.
6. Bioreversible derivatives of the claimed compounds.

The carbon-25 ring limitation is commercially important. It captures cyclopropyl-substituted vitamin D analogues, including calcipotriene, while also extending to cyclobutyl, cyclopentyl, cyclohexyl and other carbocyclic variants within the claimed size range.

Scope by variable

Claim variable	Scope
X	Hydrogen, C1-C6 alkyl, halogen or hydroxy
Y	Hydrogen or hydroxy
R1 and R2	Together form a saturated or unsaturated C3-C9 carbocyclic ring, including an aromatic ring
R3	Hydrogen or C1-C6 alkyl
R4 and R5	Either both hydrogen or together form a 22,23-double bond
Derivatives	Bioreversible derivatives of the claimed compounds

The inclusion of “bioreversible derivatives” potentially extends the claim beyond the unmodified active molecule. A derivative would need to convert biologically or metabolically to a claimed compound. The language would not automatically cover every salt, ester, ether or formulation derivative. Coverage would depend on the structural relationship and whether the derivative is properly characterized as bioreversible.

Which claims specifically cover calcipotriene?

Claims 5, 10 and 11 provide the clearest route to calcipotriene coverage.

Claim 5: named stereochemical species

Claim 5 identifies seven groups of compounds, including analogues with:

• Cyclopropyl, cyclopentyl, cyclohexyl or phenyl substitution.
• 1α,3-dihydroxy substitution in several embodiments.
• A 22,23-double bond in the trans configuration for the relevant species.
• 3'R and 3'S stereoisomers.
• A cyclopropyl-substituted hydroxybutenyl side chain in one embodiment.

The claim is significant because it moves from a broad genus to specifically enumerated molecular species. A product matching one of these listed structures would face less claim-construction debate than a compound relying only on the general Markush language of claim 1.

Claims 10 and 11: saturated ring and cyclopropyl ring

Claim 10 narrows the carbon-25 substituent to a saturated carbocyclic ring.

Claim 11 narrows that further to a saturated cyclopropyl ring. This is the most direct structural limitation for calcipotriene-type compounds.

Calcipotriene is commonly described as a 1α,24-dihydroxy vitamin D analogue containing a cyclopropyl group in the side chain. Its chemical identity is also expressed as a 24-cyclopropyl vitamin D analogue. The exact nomenclature used in product labeling and patent literature varies, but the cyclopropyl limitation in claim 11 is the central claim feature.

What formulations are protected by U.S. Patent 4,866,048?

Claims 12 through 14 protect pharmaceutical preparations containing an effective amount of a claim 1 compound with pharmaceutically acceptable carriers or auxiliary agents.

Claim	Subject matter
12	Pharmaceutical preparation containing a compound of claim 1
13	Topical pharmaceutical preparation
14	Oral pharmaceutical preparation

These are composition claims, not claims to a particular excipient system, concentration, vehicle or dosage form. Claim 13 is broad enough to cover topical administration but does not, on its face, require a particular cream, ointment, gel, lotion, foam or solution.

A later product-specific formulation patent could therefore have provided narrower, separate protection for:

• A specified calcipotriene concentration.
• A particular cream or ointment vehicle.
• A stable formulation.
• A foam or aerosol delivery system.
• A combination with betamethasone dipropionate.
• A particular preservative, solvent, surfactant or stabilizer.
• A defined particle size or crystalline form.

The expiration of the base compound patent did not necessarily eliminate later formulation patents.

What method-of-use claims does the patent contain?

Claim 15 covers treatment of patients with disorders characterized by abnormal cell proliferation or differentiation using a preparation of claim 12.

Claim 16 narrows the use to topical treatment of psoriasis.

These method claims have three principal limitations:

1. The patient must have the specified disorder.
2. The administered preparation must contain a compound within claim 1.
3. The treatment must follow the recited administration route and therapeutic purpose.

Claim 16 is particularly relevant to the original commercial use of calcipotriene. It is not a general claim to every use of calcipotriene. It is directed to topical psoriasis treatment.

Because the patent has expired, these method-of-use claims no longer create a current U.S. exclusivity barrier. During the patent term, they could have been relevant to direct treatment conduct and, depending on the facts, inducement or contributory-infringement theories involving commercial promotion.

What manufacturing processes are covered by claims 6 through 9?

Claims 6 through 9 cover processes for preparing the claimed compounds and intermediates.

Claim 6: triplet-sensitized photoisomerization

Claim 6 requires:

• A compound of formula IV.
• Triplet-sensitized photoisomerization.
• Optional deprotection of hydroxy groups.
• Flexible ordering of photoisomerization and deprotection steps.

This reflects the photochemical conversion of a provitamin or pre-vitamin D intermediate into the desired vitamin D analogue. The claim is process-specific. It does not cover every method of making calcipotriene.

A manufacturer using a substantially different synthetic route would not necessarily practice claim 6. Conversely, the use of the same photochemical transformation, even with different protecting-group details, could have raised infringement issues during the patent term.

Claim 7: side-chain construction and reduction

Claim 7 covers preparation of formula IV by reacting compound N with compound D, followed where necessary by:

• Reduction of the 22,23-double bond.
• Conversion of a 24-oxo intermediate to a 24-hydroxy compound.
• Use of a reducing agent when R3 is hydrogen.
• Use of an organometallic reagent when R3 is alkyl.

This claim addresses side-chain assembly and conversion of a 24-ketone or 24-oxo intermediate into the corresponding alcohol or alkyl-substituted product.

Claim 8: protected formyl intermediates

Claim 8 claims two specific compounds of formula N:

• A 3-tert-butyldimethylsilyloxy protected intermediate.
• A 1,3-bis-tert-butyldimethylsilyloxy protected intermediate.

These intermediates are commercially relevant only if a manufacturing process actually uses them or a sufficiently close equivalent. They are not product claims to calcipotriene itself.

Claims 9: thermal isomerization

Claim 9 covers thermal isomerization of the corresponding pre-vitamin, followed where necessary by deprotection.

This claim is narrower than claim 1 because it protects a preparation step rather than the end product. It can be avoided through a route that does not use the claimed thermal conversion or through a materially different process, subject to the doctrine of equivalents and other legal issues applicable during the patent term.

How does U.S. Patent 4,866,048 compare with later calcipotriene patents?

U.S. Patent No. 4,866,048 is the foundational compound and first-generation process patent. Later patents generally shifted toward formulation, delivery and combination-product protection.

Patent category	Typical protected subject matter	Strategic function
4,866,048	Calcipotriene-type compounds, intermediates, processes and broad uses	Original molecule and platform
Later formulation patents	Creams, ointments, solutions, foams and stability systems	Product lifecycle management
Combination patents	Calcipotriene plus betamethasone dipropionate	Combination-product exclusivity
Delivery patents	Aerosol foam and other topical systems	Differentiated dosage form
Use patents	Defined psoriasis regimens or patient populations	Narrower regulatory and commercial positioning

A later patent cannot revive an expired claim to the old compound. It can, however, protect a specific formulation or combination that requires more than the expired patent’s generic composition claim.

The relevant commercial products include:

Product	Active ingredient(s)	FDA status
Dovonex	Calcipotriene	Approved topical product
Sorilux	Calcipotriene foam	Approved topical product
Taclonex	Calcipotriene and betamethasone dipropionate	Approved combination topical product
Enstilar	Calcipotriene and betamethasone dipropionate foam	Approved combination topical product

FDA product records and labeling identify calcipotriene as a topical vitamin D analogue and identify the approved dosage forms and strengths for these products. [3-6]

What is the Orange Book status of U.S. Patent 4,866,048?

U.S. Patent No. 4,866,048 has historical Orange Book relevance but no current exclusionary force after expiration.

The Orange Book distinguishes between:

• Patent listings submitted for an approved drug.
• Regulatory exclusivity periods.
• Patent term and expiration.
• Certification consequences for an ANDA applicant.

A listed patent can trigger a Paragraph IV notice and a potential 30-month stay when it is unexpired and properly listed. An expired patent does not provide a basis for a current 30-month stay or an enforceable blocking right.

For calcipotriene products, the commercially important Orange Book landscape moved from the original compound patent to later product and formulation patents. The FDA’s Orange Book is the controlling public source for patent listings associated with approved drug products. [2]

Which companies challenged calcipotriene exclusivity?

Generic competition has developed around calcipotriene topical products after expiration of the original compound patent and subsequent product-specific protections. Companies active in the broader topical dermatology generic market have included Taro, Perrigo, Fougera, Glenmark, Teva and related generic manufacturers, depending on the dosage form and product approval.

The relevant regulatory pathway is generally an abbreviated new drug application, or ANDA, for a therapeutically equivalent topical product. A generic applicant may:

• Certify that no relevant patent is listed.
• File a Paragraph III certification agreeing to wait until patent expiration.
• File a Paragraph IV certification alleging that a listed patent is invalid, unenforceable or not infringed.
• Use a 505(b)(2) application where the product relies partly on an existing product but differs in formulation, delivery system or clinical use.

Because U.S. Patent No. 4,866,048 expired in 2006, it is no longer a viable Paragraph IV target that can delay current generic approval. Paragraph IV disputes involving calcipotriene products would instead center on later, unexpired formulation or combination patents. [2, 7]

What patent litigation affects calcipotriene products?

The original patent’s expired status materially limits present litigation exposure. Any current dispute would more likely involve:

• A formulation patent.
• A foam or aerosol delivery patent.
• A combination of calcipotriene and betamethasone dipropionate.
• A method-of-use patent.
• A trademark or trade-dress issue.
• Manufacturing know-how or confidential process information.

The patent itself could still appear in historical litigation records, licensing documents or invalidity analyses. Its expiration, however, eliminates the ordinary remedy of an injunction against practicing its expired claims.

A complete current litigation determination would require a live review of PACER, PTAB records, FDA patent listings and the relevant assignee and product names. The patent’s expired status is independently established by the patent record and is sufficient to assess its present exclusionary effect. [1, 2]

Are biosimilar risks relevant to this patent?

No. Calcipotriene is a chemically synthesized small molecule, not a biologic. Biosimilar provisions under the Public Health Service Act do not apply.

Competitive entry occurs through small-molecule pathways, primarily:

• ANDA approval under section 505(j) of the Federal Food, Drug, and Cosmetic Act.
• 505(b)(2) approval for certain reformulated or modified products.

The commercial risk is therefore generic and formulation competition, not biosimilar substitution.

How strong is the patent estate for calcipotriene today?

Strength of U.S. Patent 4,866,048

Factor	Assessment
Original compound coverage	Broad
Coverage of cyclopropyl analogues	Direct through claims 10 and 11
Stereochemical coverage	Specific species in claim 5
Formulation coverage	Broad but generic
Manufacturing coverage	Route-dependent
Current enforceability	None after expiration
Current blocking value	None
Historical licensing value	High during the patent term
Current freedom-to-operate significance	Primarily historical

The patent was technically strong during its term because claim 1 covered a broad chemical genus and narrower claims identified commercially relevant species. The strongest commercial claim combination was the combination of:

• Claim 1’s vitamin D analogue genus.
• Claim 5’s named species.
• Claim 11’s cyclopropyl ring limitation.
• Claim 13’s topical pharmaceutical preparation.
• Claim 16’s topical psoriasis use.

Today, the estate’s value lies in historical patent analysis, prior-art mapping and interpretation of later patents. It does not support a current U.S. exclusivity premium.

What generic launch scenarios exist for calcipotriene?

Scenario 1: Plain generic calcipotriene

A manufacturer can pursue a conventional ANDA for an approved calcipotriene dosage form, subject to FDA requirements for pharmaceutical equivalence, bioequivalence or other applicable topical-product standards.

The expired compound patent does not block this route.

Scenario 2: Generic combination product

A calcipotriene/betamethasone product may face later combination, formulation and delivery patents. The applicant’s risk depends on the specific product, strength, dosage form and Orange Book listings.

Scenario 3: New topical delivery system

A foam, aerosol, gel or other differentiated delivery system may require an ANDA or 505(b)(2) pathway. The principal patent risk shifts to formulation and device-related claims.

Scenario 4: Alternative vitamin D analogue

A structurally distinct analogue may fall outside the expired patent, but later patents may protect the analogue, its formulation or its use. Chemical freedom to operate must therefore be assessed at the compound, process and dosage-form levels.

Does U.S. Patent 4,866,048 cover oral calcipotriene products?

Yes, claim 14 expressly covers oral pharmaceutical preparations containing a claim 1 compound. The patent’s commercial focus, however, was strongly associated with topical use and psoriasis, as reflected in claims 13 and 16.

An oral product would still need to satisfy the structural limitations of claim 1. The expired status means the claim no longer blocks oral development in the United States.

Key Takeaways

• U.S. Patent No. 4,866,048 is the foundational U.S. patent for a broad class of vitamin D analogues that includes calcipotriene.
• Claim 1 is a broad Markush compound claim covering cycloalkyl-substituted vitamin D analogues and bioreversible derivatives.
• Claims 5, 10 and 11 provide narrower protection for named stereoisomers, saturated carbocyclic rings and the cyclopropyl embodiment associated with calcipotriene.
• Claims 6 through 9 cover photochemical, thermal and side-chain manufacturing processes.
• Claims 12 through 14 cover pharmaceutical preparations, including topical and oral forms.
• Claims 15 and 16 cover treatment of abnormal cell proliferation and topical psoriasis treatment.
• The patent was granted September 12, 1989, and expired in 2006.
• It has no current U.S. blocking or Paragraph IV litigation value.
• Current calcipotriene competition is governed primarily by later formulation, delivery-system and combination-product patents.
• Biosimilar risk is irrelevant because calcipotriene is a small-molecule drug.
• Generic entry risk is high for the base molecule and depends on later patents for specific dosage forms and combinations.

FAQs About U.S. Patent 4,866,048 and Calcipotriene

Is calcipotriene still patented in the United States?

The original calcipotriene compound protection in U.S. Patent No. 4,866,048 expired. Separate later patents may have covered particular formulations, combinations or delivery systems.

Can a company manufacture calcipotriene without a license to the original patent holder?

The expired U.S. patent does not require a current license. A manufacturer must still evaluate later patents, regulatory requirements, trademarks and confidential manufacturing rights.

Did U.S. Patent 4,866,048 cover Dovonex?

It covered the calcipotriene active ingredient and broad pharmaceutical preparations containing covered compounds. Product-specific Dovonex formulations may also have been protected by later patents.

Does the patent cover betamethasone dipropionate?

No. The claims provided are directed to vitamin D analogues and preparations containing them. They do not claim betamethasone dipropionate as an active ingredient.

What is the principal patent risk for a new calcipotriene foam?

The principal risk is not U.S. Patent No. 4,866,048. It is later formulation, aerosol, vehicle, stability, combination and method-of-use patents associated with the specific foam product.

References

1. U.S. Patent No. 4,866,048. (1989). Vitamin D analogues. U.S. Patent and Trademark Office.
2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. U.S. Food and Drug Administration. (2024). Drugs@FDA: FDA-approved drugs.
4. U.S. Food and Drug Administration. (2010). Sorilux (calcipotriene) foam prescribing information.
5. U.S. Food and Drug Administration. (2006). Taclonex (calcipotriene and betamethasone dipropionate) prescribing information.
6. U.S. Food and Drug Administration. (2015). Enstilar (calcipotriene and betamethasone dipropionate) foam prescribing information.
7. U.S. Food and Drug Administration. (2024). Abbreviated new drug application process and patent certifications.

Drugs Protected by US Patent 4,866,048

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: 4,866,048

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	8519502	Aug 02, 1985

PCT Information
PCT Filed	July 14, 1986	PCT Application Number:	PCT/DK86/00081
PCT Publication Date:	February 12, 1987	PCT Publication Number:	WO87/00834

International Family Members for US Patent 4,866,048

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	603340
Australia	6196186
Canada	1307288
Germany	3666587
Denmark	142987