United States Patent 4,935,437: Anastrozole Claim Scope, Expiry, Litigation, and Patent Landscape
U.S. Patent No. 4,935,437 is the principal composition-of-matter patent associated with anastrozole, marketed by AstraZeneca as Arimidex. Its claims cover a broad genus of substituted benzyl triazole compounds, narrower subgenera, anastrozole-specific compounds, pharmaceutical compositions, and treatment of steroid hormone-dependent tumors. The patent has expired, and the Orange Book-listed exclusivity associated with it ended in 2010 after patent-term extension and pediatric exclusivity.
What drug does U.S. Patent 4,935,437 protect?
The patent protects anastrozole and a large class of structurally related nonsteroidal aromatase inhibitors.
Anastrozole is:
2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-methylpropanenitrile)
Its structure is specifically recited in claim 7. The compound contains:
- A 1,3-disubstituted benzene ring.
- Two 2-methylpropanenitrile substituents.
- A 1H-1,2,4-triazol-1-ylmethyl group.
- No stereogenic center in the commercial active ingredient.
- Nonsteroidal aromatase-inhibitor pharmacology.
Anastrozole inhibits aromatase, the enzyme responsible for converting androgens to estrogens. FDA approved Arimidex tablets for postmenopausal women with hormone-receptor-positive or hormone-receptor-unknown advanced breast cancer and later expanded its indications to adjuvant treatment of early breast cancer and adjuvant treatment after tamoxifen therapy.[1]
Patent identification and regulatory milestones
| Item |
Detail |
| U.S. patent |
4,935,437 |
| Patent title |
Substituted aralkyl heterocyclic compounds |
| Original assignee |
Imperial Chemical Industries PLC, later associated with Zeneca and AstraZeneca |
| Grant date |
June 19, 1990 |
| Commercial active ingredient |
Anastrozole |
| Brand |
Arimidex |
| FDA NDA |
020541 |
| Initial U.S. approval |
December 27, 1996 |
| Dosage form |
1 mg oral tablet |
| Orange Book patent |
U.S. 4,935,437 |
| Listed patent expiry |
June 1, 2010 |
| Pediatric exclusivity |
Six-month period extending market protection into late 2010 |
| Current status |
Expired |
The patent was filed before the modern 20-year-from-filing patent-term regime applied to later applications. Its effective commercial life was extended through Hatch-Waxman patent-term extension and pediatric exclusivity reflected in FDA records.[2]
How broad are the claims in U.S. Patent 4,935,437?
Claim 1 is a broad Markush composition claim. It covers substituted aralkyl heterocyclic compounds containing a benzene-linked methylene or ethylene bridge and a triazole ring.
The principal structural elements are:
- A substituted benzene ring.
- Two ring substituent positions represented by R1/R2/R3 and R4/R5 variables.
- A methylene or ethylene bridge represented by A.
- A 1H-1,2,4-triazol-1-yl or 4H-1,2,4-triazol-4-yl group represented by R6.
- Pharmaceutically acceptable acid-addition salts.
The claim uses extensive substituent definitions covering alkyl, halogenated alkyl, cyano, nitro, hydroxy, alkoxy, thio, sulfoxide, sulfone, carbonyl, carbamoyl, ester, amide, and related substituents.
The claim is chemically broad because it covers many combinations of substituents rather than a single commercial molecule. Its practical scope depends on whether a competing compound falls within every required structural limitation, including:
- The substitution pattern on the phenyl ring.
- The identity of the triazole isomer.
- The carbon-chain length and substitution in A.
- The presence or absence of cyano, hydroxy, alkyl, halogen, or carbonyl groups.
- The specific acid-addition salt, where relevant.
What does "R1 R2 R3 C" mean?
The notation represents a carbon center attached to the aromatic ring and bearing three substituent positions. It is a condensed Markush expression, not multiplication. The claim permits that carbon environment to contain combinations such as:
- Two methyl groups and one cyano group.
- Two ethyl or halogenated alkyl groups and one cyano group.
- A dicyanoethyl arrangement.
- A trifluoromethylsulfonyl arrangement.
For anastrozole, each of the two nitrile-bearing side chains corresponds to a 2-methylpropanenitrile substituent.
Which claims most directly cover anastrozole?
Claims 5, 6, and 7 provide the strongest anastrozole-specific coverage.
| Claim |
Scope relevant to anastrozole |
| Claim 1 |
Broad genus of substituted aralkyl triazole compounds |
| Claim 2 |
Detailed enumerated substituent lists and A-group variants |
| Claim 3 |
Acid-addition salts, including hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and tosylate |
| Claim 4 |
Narrower preferred compound subgenus |
| Claim 5 |
Cyano-containing compound with a triazolyl group and defined nitrile-bearing R5 group |
| Claim 6 |
Methyl or trideuteriomethyl variants with methylene or dideuteriomethylene A group |
| Claim 7 |
Specifically identifies anastrozole and closely related deuterated or hydroxy analogues |
| Claim 8 |
Pharmaceutical and veterinary compositions |
| Claim 9 |
Treatment of steroid hormone-dependent tumors |
Claim 7 is the key commercial claim because it expressly recites anastrozole by chemical name. Claims 5 and 6 define narrower structural subsets that can also encompass the commercial molecule, depending on the claim construction applied to the substituent notation.
Claim 8 extends protection from the molecule to pharmaceutical or veterinary compositions containing an effective amount of a claimed compound. Claim 9 covers administration of a claimed compound to treat steroid hormone-dependent tumors.
What formulation patents are protected by the patent?
U.S. Patent 4,935,437 does not claim a particular tablet excipient system, coating, dissolution profile, dosage strength, or manufacturing process. Claim 8 is a general composition claim requiring:
- A claimed active compound.
- A pharmaceutically or veterinarily acceptable diluent or carrier.
- An effective amount.
The claim therefore covers compositions containing anastrozole, but it does not provide detailed protection for the Arimidex tablet formulation. A generic tablet containing anastrozole could have avoided a narrow formulation claim because the patent does not recite specific excipients or processing parameters.
The relevant product protection was principally chemical composition protection, not a formulation platform.
Does the patent protect a specific dosage regimen?
Claim 9 does not state a dose, dosing interval, route, patient population, or treatment duration. It covers administration for steroid hormone-dependent tumors in general terms.
The FDA-approved Arimidex regimen is 1 mg orally once daily. That dosing information comes from the FDA-approved labeling, not from a narrow dosage claim in U.S. Patent 4,935,437.[1]
What is the Orange Book status of U.S. Patent 4,935,437?
FDA Orange Book records associated U.S. Patent 4,935,437 with Arimidex and anastrozole tablets. The listed patent expiry was June 1, 2010.[2]
The patent’s commercial protection ended before the current market. The relevant chronology was:
| Date |
Event |
| 1980s |
Priority and U.S. filing activity for the substituted aralkyl heterocycle invention |
| June 19, 1990 |
U.S. Patent 4,935,437 granted |
| December 27, 1996 |
FDA approved Arimidex |
| 2000s |
ANDA applicants filed Paragraph IV challenges |
| June 1, 2010 |
Orange Book-listed patent expiry |
| Late 2010 |
Pediatric exclusivity period ended |
| 2010 onward |
Generic anastrozole entered the U.S. market |
The patent is no longer an enforceable barrier to generic approval or launch. No current Paragraph IV risk remains against this expired patent.
Which companies challenged the anastrozole patent?
Generic manufacturers challenged AstraZeneca’s patent through ANDA litigation under Hatch-Waxman procedures. Reported defendants and applicants included Apotex and Mylan-related entities, among other generic manufacturers.
The principal litigation issue was whether the asserted anastrozole claims were valid and enforceable against generic entry. AstraZeneca litigated the patent against Apotex in federal court, with the dispute reaching the U.S. Court of Appeals for the Federal Circuit.[3]
The historical litigation record matters for two reasons:
- It established that generic entry was actively pursued before patent expiry.
- It reduced the practical value of the patent before the expiration date because a successful invalidity or noninfringement decision could have permitted earlier launch.
The patent is now expired regardless of the outcome of any historical litigation. Current generic manufacturers no longer need to overcome this patent through a Paragraph IV certification.
How strong was the patent estate for anastrozole?
The estate was strong in its original commercial configuration because it combined:
- A broad composition-of-matter genus.
- Narrower preferred subgenus claims.
- An express claim to anastrozole.
- Pharmaceutical composition coverage.
- A therapeutic-use claim.
- FDA Orange Book listing.
- Patent-term extension and pediatric exclusivity.
Its strongest feature was claim 7, which directly named the commercial molecule. A direct chemical claim generally creates a more substantial barrier than a formulation or method-of-use claim because infringement does not depend on the generic manufacturer’s labeling or selected formulation.
The estate also had weaknesses typical of broad Markush patents:
- Large structural breadth.
- Potential written-description and enablement disputes.
- Prior-art risk across a broad compound genus.
- Possible noninfringement arguments based on triazole orientation, bridge substitution, and ring-substitution pattern.
- Limited post-expiry value for licensing or enforcement.
Claim-strength ranking
| Claim category |
Relative strength |
Commercial relevance |
| Claim 7, named anastrozole |
Very high |
Direct product protection |
| Claims 5-6, narrow anastrozole subgenus |
High |
Backup structural coverage |
| Claim 1, broad Markush genus |
Medium to high |
Broad blocking position, validity exposure |
| Claims 2-4, preferred subgenera and salts |
Medium |
Species and salt coverage |
| Claim 8, composition |
Medium |
Supports product-form coverage |
| Claim 9, tumor treatment |
Medium to low |
Label and use dependent |
What generic entry risks existed before expiration?
Before expiration, a generic manufacturer faced four principal risks.
Paragraph IV litigation
An ANDA applicant could certify that the patent was invalid, unenforceable, or would not be infringed. AstraZeneca could then file a patent-infringement action, triggering a statutory 30-month stay of FDA approval in the relevant circumstances.[4]
Direct composition infringement
A generic product containing anastrozole would present the clearest infringement exposure because claim 7 specifically recited the molecule.
Salt and formulation strategy
Changing excipients would not avoid claims 1 or 7 if the active ingredient remained anastrozole. A different salt might have been relevant to claim 3, but it would not necessarily avoid the underlying compound claims.
Labeling and method-of-use exposure
A generic label covering steroid hormone-dependent tumors could implicate claim 9. In practice, the composition claims were more important because they applied to the active ingredient itself.
How does anastrozole compare with competing aromatase inhibitors?
Anastrozole competed primarily with letrozole and exemestane.
| Drug |
Chemical class |
Primary sponsor |
Core patent profile |
Current patent risk |
| Anastrozole |
Nonsteroidal triazole aromatase inhibitor |
AstraZeneca |
U.S. 4,935,437 composition patent |
Expired |
| Letrozole |
Nonsteroidal triazole aromatase inhibitor |
Novartis |
Separate compound and regulatory estate |
Expired for core product protection |
| Exemestane |
Steroidal irreversible aromatase inhibitor |
Pfizer/Pharmacia |
Structurally distinct steroidal compound estate |
Core patents expired |
Anastrozole and letrozole share a nonsteroidal triazole aromatase-inhibitor profile but have different chemical structures and patent families. Exemestane has a steroidal structure and operates through irreversible aromatase inhibition. A generic manufacturer could not rely on anastrozole patent analysis to assess letrozole or exemestane freedom to operate.
What manufacturing and intellectual-property barriers remain?
U.S. Patent 4,935,437 no longer creates a manufacturing barrier. A manufacturer can produce anastrozole tablets without infringing an enforceable claim of this patent.
Residual barriers may arise from:
- Manufacturing know-how and process economics.
- API impurity control.
- Crystallization and solid-state form control.
- Supply-chain qualification.
- FDA abbreviated new drug application requirements.
- Other patents not listed in the original Orange Book record.
- Foreign patents with different expiry dates.
- Regulatory exclusivity unrelated to this patent.
The patent itself does not claim a specific synthetic route in the supplied claims. It is therefore not a process patent that would block API manufacture after compound-patent expiry.
What is the current commercial and licensing significance?
The historical commercial exposure was substantial. Arimidex generated approximately $1 billion in annual global sales near the end of its life-cycle, making the patent a major pharmaceutical asset for AstraZeneca.[5]
That revenue base supported:
- Early generic litigation.
- Regulatory patent-term extension efforts.
- Settlement and launch-timing negotiations.
- Commercial importance of a direct compound claim.
Today, the patent has no meaningful licensing value for ordinary U.S. anastrozole manufacture or sale. Its value is historical, evidentiary, and relevant to patent-landscape reconstruction rather than current exclusion.
Key Takeaways
- U.S. Patent 4,935,437 is the core anastrozole composition patent.
- Claim 7 expressly covers anastrozole by chemical name.
- Claims 1 and 2 establish a broad Markush genus of substituted benzyl triazole compounds.
- Claims 5 and 6 provide narrower structural coverage around the commercial molecule.
- Claim 8 covers pharmaceutical compositions, while claim 9 covers treatment of steroid hormone-dependent tumors.
- The patent did not depend on a specific tablet formulation or manufacturing process.
- FDA Orange Book protection ended June 1, 2010, followed by the end of pediatric exclusivity.
- Historical Paragraph IV litigation involved generic applicants including Apotex and Mylan-related entities.
- No current biosimilar issue exists because anastrozole is a small-molecule drug, not a biologic.
- The patent is expired and does not currently block generic U.S. anastrozole entry.
FAQs
Does U.S. Patent 4,935,437 cover generic anastrozole today?
No. The patent expired in 2010 and cannot currently block generic anastrozole manufacture, approval, or sale in the United States.
Was anastrozole protected by a formulation patent?
The cited patent contains a general pharmaceutical composition claim but does not recite a specific Arimidex excipient system, tablet coating, or manufacturing process.
Does the patent cover letrozole?
No. Letrozole is a separate chemical compound with a different patent family. Structural similarity as a triazole aromatase inhibitor does not place letrozole within the anastrozole claims.
Are there biosimilar challenges to anastrozole?
No. Anastrozole is a chemically synthesized small molecule regulated through the ANDA pathway, not a biologic regulated through the biosimilar pathway.
Can a manufacturer avoid the patent by using a different anastrozole salt?
That strategy was potentially relevant to salt-specific claim 3, but it would not necessarily avoid the underlying anastrozole compound claims. The patent is now expired in any event.
References
-
U.S. Food and Drug Administration. (2011). Arimidex (anastrozole) tablets prescribing information. FDA.
-
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.
-
AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042 (Fed. Cir. 2010).
-
Drug Price Competition and Patent Term Restoration Act of 1984, 21 U.S.C. § 355(j).
-
AstraZeneca PLC. (2010). Annual report and form 20-F 2009. AstraZeneca.
