Details for Patent: 4,386,085

Summary for Patent: 4,386,085

Title:	Novel steroids
Abstract:	Novel 19-nor steroids and 19-nor-D-homo-steroids of the formula ##STR1## wherein R1 is an organic radical of 1 to 18 carbon atoms containing at least one atom selected from the group consisting of nitrogen, phosphorous and silicon with the atom immediately adjacent to the 11-carbon atom being carbon, R2 is a hydrocarbon of 1 to 8 carbon atoms, X is selected from the group consisting of a pentagonal ring and a hexagonal ring optionally substituted and optionally containing a double bond, B and C together form a double bond or an epoxy group, the C═A group at position 3 is selected from the group consisting of C═O, ketal, ##STR2## --C═NOH, --C═NOAlK3 and ═CH2, AlK1, AlK2 and AlK3 are selected from the group consisting of alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts having anti-glucocorticoid activity and a process for their preparation.
Inventor(s):	Jean G. Teutsch, Germain Costerousse, Daniel Philibert, Roger Deraedt
Assignee:	Population Council Inc
Application Number:	US06/338,077
Patent Claim Types: see list of patent claims	Use; Composition; Process;

United States Patent 4,386,085 Landscape Analysis: scope, claim coverage, and competitive barriers for antiglucocorticoid 19-nor steroid compounds

United States Patent 4,386,085 claims a genus of “19-nor steroids and 19-nor-D-homo-steroids” defined by a shared steroid core and variable substituents at multiple positions, plus product-by-process and composition/method claims aimed at antiglucocorticoid activity. The claim set is broad at the structural-definition level (substituent ranges for R1, R2, X, C═A, and linked ring features B/C), and then narrows to specific exemplified molecules and to preparative processes using protected ketones/ketals/oximes and copper-mediated or organometallic transformations to install propargyl/propargyl-like functionality and related substituents.

What does US 4,386,085 claim: scope, genus boundaries, and where enforcement is most likely?

Direct answer: US 4,386,085 covers (1) a structural genus of specific 19-nor/19-nor-D-homo steroid compounds with defined functional-group and ring-closure constraints; (2) pharmaceutical compositions; (3) methods of inducing antiglucocorticoid activity in warm-blooded animals; and (4) manufacturing processes that use protected ketone intermediates and specific classes of reagents (deprotection/dehydration, ketalization/oximation, and cuprous-halide mediated organometallic additions).

How the core structural formula constrains the genus

Claim 1 is anchored to a steroid framework characterized as:

• Compound type: selected from “19-nor steroids and 19-nor-D-homo-steroids.”
• Core formula features:
  • R1: organic radical of 1–18 carbons containing at least one heteroatom selected from N, P, Si, with a specific adjacency rule: the atom immediately adjacent to the 11-carbon atom is carbon.
  • R2: hydrocarbon of 1–8 carbons.
  • X: pentagonal or hexagonal ring, optionally substituted and optionally containing a double bond.
  • B and C: together form either
    • a double bond, or
    • an epoxy group.
  • C═A group at position 3: limited to enumerated carbonyl/unsaturation/ketal/oxime/imino/“CH2” style possibilities (in the claim text: C═O, ketal, oxime/alkoxy-imino variants, CH2).
  • Saltability: includes “non-toxic, pharmaceutically acceptable acid addition salts.”
  • Alkyl/aralkyl definitions: AlK1/AlK2/AlK3 are alkyl (1–8) or aralkyl (7–15), which matters for the oxime/imino substitution permitted by claim 1’s “C═NOAlK3” type member.

Enforcement implication: the genus is broad but not arbitrary. Claim validity and infringement analysis tend to focus on whether an accused compound satisfies every constraint: (i) correct steroid family (19-nor or 19-nor-D-homo), (ii) correct C3 “C═A” identity from the enumerated set, (iii) correct ring system X, (iv) correct B/C relationship (double bond vs epoxy), and (v) the allowed heteroatom-containing R1 with the adjacency rule.

Which dependent claims narrow the claim 1 “switches” most

Claim 2 and claim 6 narrow the B/C and C═A “modes”:

• Claim 2: “B and C form a double bond.”
• Claim 6: “C═A group is C═O.” (i.e., the C3 carbonyl-only subset)

Claims 3/7/8/9/10/11/12 are R1-focused:

• Claim 3: R2 is methyl.
• Claim 7: R1 is a hydrocarbon (1–18 carbons) containing at least one nitrogen atom.
• Claim 8: R1 is an alkyl (1–8) containing at least one heteroatom (including N).
• Claim 9: R1 is a nitrogen heterocycle optionally substituted with alkyl.
• Claim 10/11: R1 is aryl/aralkyl with specific linkage and allowed heteroatoms; claim 11 lists pyridyl positional isomers.

Enforcement implication: R1 tends to be the easiest axis to check in an infringement analysis because it typically corresponds to a discrete pendant substituent on the aromatic ring at the 11β position described in the exemplars.

What claim 4 does: adds a second-layer ring/functional substitution template

Claim 4 is the most complex “genus refinement” clause because it simultaneously recites:

• a constraint on X and the attached carbons forming a ring of a specific formula (STR101/STR124-like),
• R5/R6 definitions for substituents,
• Y substitution and n ∈ {1,2},
• R3/R4 options including hydroxyl, alkoxy/acyloxy, alkenyl/alkynyl, and —CN type substituents with AlK subdefinitions,
• and Z1/Z2 substituent limitations.

It is effectively a second-generation Markush structure that narrows X and the resulting steroid ring substitution pattern while expanding allowable functionalization.

Why claim 13 and claim 14 matter: specific exemplified molecules define the “center of gravity”

• Claim 13 lists multiple specific compounds (explicit names) including:

  • 11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-Δ4,9-estradiene-17β-ol-3-one,
  • the corresponding N,N-dimethylamino variant (methoxy vs amine),
  • N-oxide analogs,
  • N-oxide with epoxy-linked intermediates,
  • prop-1-ynyl vs prop-2-ynyl substitutions,
  • and a related “21-chloro-19-nor…” N-oxide compound.

• Claim 14 is a process claim for preparing “a compound of claim 1” using protected ketone intermediates (ketal, thioketal, oxime, methyloxime), dehydration to free ketone, then ketalization or reaction with NH2OH/NH2OAlK3 to form oxime-type intermediates, or selective reduction to enable etherification/esterification, and optional transformations to convert C═A to CH2 and adjust B/C epoxide/double bond features. It also includes a selective reduction step for oxidized nitrogen atoms (N-oxide to reduced N) in some routes.

• Claim 18/19 further nail down additional protected or di-protected examples (including “3,3-[1,2-ethanediyl-bisoxy]-…” compounds and epoxy variants).

Enforcement implication: in litigation, the presence of detailed compound lists often helps with claim construction and enables “literal match” arguments for compounds that are close to the exemplified products.

What patents protect antiglucocorticoid 19-nor steroid scaffolds like these?

Direct answer: US 4,386,085 is a primary “structural + process + use” filing covering a specific antiglucocorticoid steroid series, but the rest of the enforceable estate would typically be built from (i) continuation filings, (ii) related improvements on the same pendant group chemistry (R1 variations and N-oxide formation/reduction), (iii) improvements on the installation of propargyl/propargyl-like functionality (17α-substitution), and (iv) formulation and method-of-use variants.

This request requires the actual patent landscape (family members, co-pending continuations, assignment, and expiration dates by jurisdiction). No cited bibliographic data, patent family identifiers, or Orange Book/FDA reference drug linkage were provided, so a complete and accurate landscape cannot be produced.

When does US 4,386,085 lose exclusivity?

Direct answer: US patent exclusivity ends at patent expiration (and any terminal disclaimer dates), plus potential regulatory exclusivity layering if linked to an approved reference listed drug.

Because the filing date, patent term adjustment, and terminal disclaimer information for US 4,386,085 are not included, an accurate exclusivity timeline and expiration date cannot be calculated from the claim text alone.

How strong is the patent estate for US 4,386,085?

Direct answer: Claim strength is structurally broad but legally dependent on (1) adequate written description/support for the genus, (2) enablement across the full Markush range (R1 heteroatoms and lengths, C═A options, B/C modes), and (3) defensibility of the process claims if they are treated as product-by-process.

Claim coverage density: what looks defendable vs vulnerable

• Defendable anchors:

  • The genus is tied to a defined steroid system (19-nor / 19-nor-D-homo).
  • Multiple specific exemplars are recited in claim 13, and specific intermediates/products are recited in claim 18 and claim 19.
  • Process claims include detailed reagent classes and transformation sequences (deprotection/dehydration, oxime formation, and cuprous halide organometallic additions).

• Potential vulnerability points:

  • R1 breadth (1–18 carbon heteroatom-containing radicals including N/P/Si, with adjacency rule) can be attacked on enablement and written description if the disclosure doesn’t teach the full range.
  • C═A group breadth (C═O vs ketal vs oxime/imino variants vs CH2) can raise “covering too much” arguments.
  • Process claims may be limited by product-by-process interpretation: infringement may require that the product is the same as the claimed product and/or that the process steps yield the same product characteristics.

How do the process claims limit manufacturing workarounds?

Direct answer: The process claims are not generic “make the compound.” They define specific intermediate classes and reagent-driven steps, including protection/deprotection patterns, selective functional-group manipulations, and cuprous-halide mediated additions. That can create enforcement hooks against process-specific manufacturing routes, but they also provide clear design-around targets: use alternative intermediate protections, different metalation/addition chemistry, or alternative routes to the same 17α substituent.

Claim 14: key operational steps in manufacturing scope

Claim 14 requires, at a minimum, a route that includes:

• reacting a compound of a defined formula IA where K is a ketone blocked as ketal, thioketal, oxime, or methyloxime,
• using a dehydration agent to “free” the ketone group,
• then either:
  • ketalization (to obtain a ketal intermediate), or
  • reaction with NH2OH or NH2OAlK3 to obtain an oxime-type intermediate,
• then optional pathways:
  • selective reduction of the 3-keto group,
  • etherification to introduce AlK1,
  • esterification to introduce COAlK2,
  • conversion of the C═A group to CH2 via known methods,
• and branching for:
  • formation of acid salts,
  • oxidation to obtain N-oxide when R1 contains oxidizable nitrogen,
  • formation of an epoxide bridge when B/C are in that mode,
  • selective reduction of N-oxide back to reduced nitrogen when needed.

Design-around implication: any manufacturing route that avoids the enumerated protection/deprotection architecture or uses different functional-group interconversions (especially for the N-oxide and C3/C═A manipulations) can reduce exposure under claim 14-type process theories.

Claim 16: cuprous-halide and lithium/copper reagents

Claim 16 specifies reacting a ketal/thioketal/oxime/methyloxime ketal intermediate with compounds such as:

• LiCu(R1)2
• LiR1
• R1MgHal in the presence of cuprous halide.

Claims 17: propargyl/propargyl-like and functional group installation

Claim 17 adds layered operational restrictions:

• starting from a formula I with defined R3’ and R4’ substituent types (OH/ORc etc.),
• again employing LiCu(R1)2 / R1Li / R1MgHal + cuprous halide to obtain a substituted intermediate,
• then reducing/protecting hydroxy groups,
• then converting to 17α-substituted-17β-ol steroids, or converting to 17β-cyano via cyanuration agent,
• then etherification/esterification,
• and in triple-bond-containing cases, reducing to an ethylenic derivative.

Enforcement implication: claim 17 is likely aimed at the specific synthetic logic that creates the 17α propargylated and related products in the examples.

What formulations and salt forms are protected by US 4,386,085?

Direct answer: The patent protects pharmaceutical compositions containing the claimed steroid compounds with an inert carrier (composition claims 20–32, including dependent composition narrowing to specific genus subsets and specific compound lists). It also protects acid addition salts of the exemplified compounds.

Composition claims 20–32: what is claimed beyond the API

• Claim 20: antiglucocorticoidally effective amount of at least one claim 1 compound + inert carrier.
• Claims 21/22/25/26–31: narrow B/C mode, R2=methyl, C═A=C═O, R1 classes, and R1 containing oxidized nitrogen.
• Claim 32: recites the active compound set explicitly (the same type of list as in claim 13), tying the composition to named individual steroid molecules.

Enforcement implication: formulation infringement can be easier to establish for generic/supplement products that use the same API and claim the same therapeutic intent.

What method-of-use claims expand enforceability?

Direct answer: The patent includes method claims for inducing antiglucocorticoid activity in warm-blooded animals (claims 33–46), with dependent claims mirroring the structural refinement options (B/C, R2, C═A, R1 heteroatom classes) and specific compound selections.

Method claims 33–46: intended therapeutic positioning

• Claim 33: administration to warm-blooded animals of an antiglucocorticoidally effective amount.
• Claims 38/44: specify C═A=C═O and R1 containing an oxidized nitrogen atom.
• Claims 45/46: narrow to specific exemplified compounds.

Regulatory/IP implication: method-of-use claims can create enforcement leverage against label-adjacent or indication-adjacent products, though actual enforceability depends on claim scope, jurisdiction, and whether the accused product’s labeling/practice meets the “antiglucocorticoid” standard.

What are the key infringement “claim elements” to map for US 4,386,085?

Direct answer: For any accused compound or process, the highest-yield claim-element mapping is:

1. Steroid family: 19-nor steroid or 19-nor-D-homo-steroid.
2. C3 “C═A group” identity: must be one of the enumerated states (C═O carbonyl is covered by claim 6 subset).
3. B/C relationship: double bond vs epoxy bridge.
4. R1 pendant substitution: heteroatom-containing radical (N/P/Si), with adjacency rule.
5. R2 identity: hydrocarbon, often methyl in narrower dependent claims.
6. X ring type: pentagonal/hexagonal optionally substituted, and claim 4’s specific ring constraint if asserted.
7. Salt form: whether an acid addition salt is used.

For process infringement, map:

• whether the route starts from the protected ketone/ketal/oxime/methyloxime intermediates,
• whether dehydration liberates ketone,
• whether cuprous halide is used in LiCu/LiR1/R1MgHal additions,
• and whether selective reductions and etherification/esterification steps match the claim’s required transformations.

Key Takeaways

• US 4,386,085 is a multi-axis patent: structural genus (claim 1) plus narrowed genus refinements (claims 2–12 and 4), specific exemplified APIs (claim 13 and related claims), and broad enforceability wrappers through composition (20–32) and method-of-use (33–46).
• The most actionable claim-construction bottlenecks are the enumerated constraints on C═A at position 3, B/C double bond vs epoxy, the R1 heteroatom radical with the 11-carbon adjacency rule, and the steroid core classification (19-nor and 19-nor-D-homo).
• Process coverage (claims 14, 16, 17) is chemistry-detailed enough to support process-specific enforcement theories, but it also invites design-arounds using alternative intermediates or replacement chemistry that avoids the cuprous-halide LiCu/R1Li/R1MgHal pattern and the claim’s protection/deprotection sequence.
• Without bibliographic metadata (filing date, family/continuations) and without regulatory linkage (reference product, Orange Book/NDC), exclusivity timing and a complete competitive patent landscape cannot be computed from the claim text alone.

FAQs

1. Does US 4,386,085 cover N-oxide metabolites as separate compounds?
   Yes. The exemplified lists in claims 13 and 32 include N-oxide variants, and claim 14 includes oxidation steps for nitrogen-containing R1 followed by optional selective reduction.

2. What is the practical difference between claim 1 and claim 4 scope?
   Claim 4 tightens the structural ring constraints (X and attached carbons) and expands specified substituent options (R5/R6/Y/n/R3/R4/Z1/Z2), creating a narrower structural window than claim 1 while still permitting substantial variation.

3. Are acid addition salts independently covered for the exemplified APIs?
   Yes. The claims expressly include “non-toxic, pharmaceutically acceptable acid addition salts” for the compound genus and for the listed specific exemplars.

4. Do the method-of-use claims require proof of antiglucocorticoid mechanism, or just the labeled/observed effect?
   The claims require “antiglucocorticoidally effective” administration to warm-blooded animals. In infringement practice, the central question becomes whether the administered compound produces that antiglucocorticoid activity.

5. Can manufacturing avoid infringement by using different protection chemistry than ketal/oxime?
   If the asserted process claim requires the claimed protection/deprotection architecture and the cuprous-halide metalation/addition sequence, a route that avoids those defined intermediates and steps can reduce risk under the process claims.

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References

1. United States Patent 4,386,085. (Claim text provided by user).

Drugs Protected by US Patent 4,386,085

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: 4,386,085

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
France	81 00272	Jan 09, 1981

International Family Members for US Patent 4,386,085

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0057115		SPC/GB93/030	United Kingdom
Austria	12239
Austria	23167
Austria	23344
Austria	396787
Austria	46702