United States Patent 6,933,395: Drospirenone Purity, Process and Patent-Landscape Analysis

U.S. Patent No. 6,933,395 protects high-purity drospirenone compositions, a process-defined drospirenone product, and an isolated drospirenone-related impurity. The patent is directed to drospirenone, the steroidal antimineralocorticoid and progestin used in products such as Yasmin, Yaz, Ocella, Gianvi and related oral contraceptives.

The patent’s core commercial significance was strongest before generic drospirenone products entered the U.S. market. Its principal U.S. patent term has expired, eliminating current enforcement risk from this patent alone. The claims remain relevant for historical litigation, validity analysis, freedom-to-operate reviews involving old products, and assessment of related international patents.

What compound does U.S. Patent 6,933,395 cover?

The compound identified in the claims is drospirenone.

Chemical designation	Identity
Claimed steroid	6β,7β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone
Common name	Drospirenone
Therapeutic class	Progestin and antimineralocorticoid
Principal use	Combined oral contraceptives and hormone-related products
Dosage forms	Tablets, coated tablets and other oral pharmaceutical compositions
Key commercial brands	Yasmin, Yaz, Beyaz, Ocella, Gianvi and equivalents

Drospirenone has a steroid nucleus with two methylene bridges and a spirolactone structure. The patent is not a basic composition-of-matter patent covering drospirenone in every form. Its claims focus on purity, process-related impurities and a defined isolated intermediate or impurity.

The patent issued to Schering AG, now associated with the Bayer group through corporate succession. The issued patent is available through the USPTO and Google Patents databases. (U.S. Patent No. 6,933,395, 2005).

What does claim 1 of U.S. Patent 6,933,395 protect?

Claim 1 covers a pharmaceutical composition containing:

Drospirenone;
A pharmaceutically acceptable carrier; and
Less than 0.2% by weight of contaminants, calculated relative to the amount of drospirenone.

The claim is a composition claim, not merely a process claim. A product can infringe claim 1 without being made by the patented manufacturing sequence if it contains the claimed drospirenone purity profile.

How should the 0.2% purity limitation be interpreted?

The wording means that contaminants must account for less than 0.2% by weight of the drospirenone component. In practical terms, the active ingredient must have more than 99.8% drospirenone relative to the specified contaminants.

The limitation does not necessarily require the entire finished tablet to contain less than 0.2% contaminants. It is tied to the weight of drospirenone. This distinction matters because excipients, coating materials and other carrier components are not necessarily contaminants for purposes of the claim.

A generic manufacturer could therefore face claim 1 exposure if:

Its drospirenone API contains less than 0.2% of the identified contaminants;
The API is incorporated into a pharmaceutical composition; and
The claim remains enforceable in the relevant jurisdiction and time period.

The claim is potentially broad because it does not require a particular tablet formulation, excipient, dosage strength or manufacturing route.

What does claim 2 protect?

Claim 2 appears to narrow claim 1 to specified contaminants generated by an acid-mediated reaction capable of opening the 6β,7β-methylene group.

The supplied text is incomplete. It refers to “X” and to contaminant structures that are not reproduced in the question. The issued claim must be read with the chemical structures and definitions appearing in the patent. The legally relevant limitation is not every impurity in a drospirenone batch. It is the specified class of process-related contaminants associated with acid opening of the 6β,7β-methylene group.

This distinction affects infringement:

A batch containing unrelated degradation products may not fall within claim 2.
A batch containing the named acid-opening impurities may fall within claim 2 even if those impurities are present at low levels.
The claim likely requires both the composition and the specified impurity relationship.
The contaminant identity, not only its concentration, is central to claim construction.

What does claim 3 protect?

Claim 3 is a product-by-process composition claim. It covers drospirenone made by a sequence that includes:

Catalytic hydrogenation of a Formula I compound;
Oxidation in the presence of a ruthenium salt to produce a Formula III compound;
Dehydration of the Formula III compound;
Incorporation of the resulting drospirenone into a pharmaceutical composition; and
Less than 0.2% by weight of specified by-products from the preparation process.

The supplied claim text omits the chemical structures for Formula I, Formula III and the by-products. Those structures are essential to a complete claim analysis.

What is the importance of the ruthenium oxidation step?

The ruthenium salt limitation identifies a particular route to the drospirenone intermediate. A process using a different oxidation catalyst may avoid literal infringement of the process limitations, although the resulting product could still be assessed under the composition claims.

The presence of a ruthenium salt can be established through:

Batch records;
Catalyst inventories;
Process validation documents;
Analytical residues;
Regulatory chemistry, manufacturing and controls files;
Supplier records; and
Discovery in patent litigation.

The product-by-process structure also creates a legal issue. In U.S. patent law, a product-by-process claim generally requires the claimed product to have the recited structural or product characteristics, and process limitations may be treated differently depending on whether the issue is patentability or infringement. The Federal Circuit’s decisions in Abbott Laboratories v. Sandoz and Amgen v. F. Hoffman-La Roche are relevant to the treatment of product-by-process language. (Abbott Laboratories v. Sandoz, Inc., 566 F.3d 1282, 2009; Amgen Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340, 2009).

What does claim 4 add?

Claim 4 depends on claim 3 and requires that the dehydration step occur after isolation of the Formula III compound from the reaction medium.

This limitation is commercially important because it distinguishes:

A one-pot or in situ dehydration process; from
A process in which the intermediate is isolated and then dehydrated in a separate operation.

A manufacturer that performs dehydration before isolating Formula III may have a noninfringement position against claim 4, although it could still face claims 1 or 3 depending on the impurity profile and actual process.

The isolation requirement may be evaluated through:

Filtration or crystallization records;
Intermediate specifications;
Solvent exchange operations;
Drying records;
In-process testing; and
Batch manufacturing instructions.

What do claims 5 and 6 protect?

Claims 5 and 6, as supplied, are identical:

“6β,7β;15β,16β-dimethylene-5β-hydroxy-3-oxo-17α-androstane-21,17-carbolactone in isolated form.”

This compound is a drospirenone-related 5β-hydroxy compound and appears to be a process impurity or intermediate associated with the preparation of drospirenone.

The duplicate text creates a transcription or claim-publication issue. Two identical claims ordinarily do not provide two independent layers of protection. The issued patent should be checked to determine whether:

One claim contains a different stereochemical designation;
One claim includes a purity or salt limitation omitted from the supplied text;
The duplication resulted from OCR;
One claim was canceled or amended during prosecution; or
The claims were formally identical in the issued patent.

Why is the isolated-form limitation important?

Claims 5 and 6 do not appear to cover the compound merely because it exists transiently in a reaction mixture. “In isolated form” generally requires recovery as a discrete material, such as a solid, purified fraction or characterized intermediate.

Potentially relevant evidence includes:

Isolation by crystallization or precipitation;
Chromatographic recovery;
NMR, mass spectrometry or optical rotation data;
A defined analytical standard;
Storage as a separate intermediate; and
Sale or transfer of the compound as a discrete substance.

A manufacturer that produces the compound only as an in-process impurity may have a stronger defense to an isolated-form claim than a manufacturer that recovers and stores it separately.

How strong is the patent estate for drospirenone?

The patent estate was strongest when multiple patent categories operated together:

Patent category	Typical subject matter	Relevance to 6,933,395
Composition-of-matter patents	Drospirenone itself	Usually separate from 6,933,395
Process patents	Hydrogenation, oxidation, dehydration and purification	Directly related
Purity patents	Drospirenone with specified impurity levels	Central to 6,933,395
Formulation patents	Drospirenone with ethinyl estradiol and excipients	Separate product protection
Method-of-use patents	Contraception, premenstrual dysphoric disorder, acne or hormone therapy	Separate use protection
Regulatory listings	Patents submitted for approved products	May include related, not identical, patents

Patent 6,933,395 was technically narrower than a basic drospirenone composition-of-matter patent because it required a defined purity profile, process history or isolated impurity. Its commercial strength came from the difficulty of distinguishing the claimed impurities through ordinary product testing and from the ability to assert a composition claim against a finished pharmaceutical product.

Its principal weaknesses included:

Expiration of the patent term;
Possible indefiniteness or written-description issues concerning omitted chemical structures;
Questions over whether the 0.2% limitation is measured against total composition weight or drospirenone weight;
Product-by-process limitations in claim 3;
Whether an accused product contains the specified contaminants; and
Whether the impurity exists in isolated form under claims 5 and 6.

When did U.S. Patent 6,933,395 expire?

The patent issued on August 23, 2005. Its expected ordinary U.S. patent-term expiration was February 11, 2020, based on the national-stage filing date associated with the patent family. Any patent-term adjustment, terminal disclaimer or regulatory patent-term extension would need to be confirmed in the USPTO Patent Center record and the Orange Book entry for the relevant product.

The patent is therefore no longer a live U.S. blocking patent based on ordinary patent term. A patent’s expiration does not erase its historical relevance. It can remain relevant to:

Earlier generic launch disputes;
Damages periods before expiration;
Settlement agreements;
Invalidity records;
Foreign counterpart analysis; and
Patent-estate diligence for products launched during the protected period.

What is the FDA and Orange Book status?

Drospirenone is an approved small-molecule active ingredient. Generic versions proceed through the abbreviated new drug application pathway, not the biosimilar pathway.

Regulatory issue	Status
FDA pathway	ANDA for generic products
Biosimilar pathway	Not applicable
Reference products	Drospirenone/ethinyl estradiol products, including Yasmin and Yaz-related products
Orange Book relevance	Product-specific listed patents and exclusivities
Patent 6,933,395	Historically relevant; ordinary U.S. term expired
Current generic risk from this patent	No current blocking risk from the expired patent alone

Orange Book listing and patent enforceability are separate questions. A patent can be listed for an approved drug and later expire. Conversely, a patent that is not listed may still create litigation exposure if it remains enforceable and covers a product or process.

FDA generic entry also depends on more than patent expiration. An ANDA applicant must address:

Bioequivalence;
Strength and dosage form;
Labeling;
Impurity controls;
Stability;
Manufacturing validation;
Patent certifications; and
Any remaining listed patents covering the reference product.

What Paragraph IV challenges affected drospirenone products?

Drospirenone/ethinyl estradiol generics entered after ANDA applicants challenged branded-product patents through Paragraph IV certifications. These disputes generally involved product patents and formulation patents covering Yasmin or Yaz-related products, rather than only the purity and process claims of Patent 6,933,395.

A Paragraph IV certification asserts that a listed patent is invalid, unenforceable or not infringed. The filing can trigger a Hatch-Waxman action within 45 days and a potential 30-month stay of approval. The relevant commercial dispute is therefore the entire Orange Book-listed patent set, not one patent viewed in isolation. (U.S. Food and Drug Administration, 2024a; 21 U.S.C. § 355(j)).

Publicly reported generic entrants included Barr Laboratories and later manufacturers marketing drospirenone/ethinyl estradiol products under generic labels. Launch timing was affected by patent litigation, settlements and the expiration of listed patents.

What formulation patents and method-of-use patents matter?

Patent 6,933,395 does not primarily claim:

A specific drospirenone/ethinyl estradiol ratio;
A particular tablet coating;
A specific micronization range;
A sustained-release system;
A particular pack regimen;
A method of contraception; or
Treatment of premenstrual dysphoric disorder.

Those subjects are typically addressed by separate formulation or method-of-use patents.

Formulation patent exposure

Formulation analysis should examine:

Drospirenone particle size;
Ethinyl estradiol content;
Excipients;
Coating composition;
Dissolution profile;
Packaging and regimen;
Low-dose or extended-cycle presentations; and
Stability protection.

A generic product can avoid one formulation claim while still infringing a purity or process claim. The reverse is also true.

Method-of-use exposure

Method claims can cover treatment or prevention of:

Pregnancy;
Premenstrual dysphoric disorder;
Acne;
Hormonal symptoms; or
Mineralocorticoid-related effects.

FDA labeling and the proposed generic label are central to method-of-use risk. A section viii statement may be available for a protected indication, but that strategy does not eliminate exposure to composition or process patents.

Which companies challenged the drospirenone patent estate?

The principal competitive pressure came from ANDA applicants seeking generic versions of drospirenone/ethinyl estradiol products. Public litigation and regulatory records associated with Yasmin and Yaz included disputes involving Barr Laboratories, Watson Laboratories, Teva-related entities and other generic manufacturers.

The relevant patent families included:

Bayer/Schering patents covering drospirenone pharmaceutical products;
Formulation and combination patents;
Method-of-use patents;
Process and purity patents, including U.S. Patent 6,933,395; and
Related international family members.

The precise defendant, patent, product and settlement terms must be matched to the individual case docket. Patent 6,933,395 should not be treated as interchangeable with all drospirenone litigation involving Yasmin or Yaz.

What was the revenue exposure?

Drospirenone products generated substantial branded revenue before generic entry. Yasmin and Yaz were major Bayer women’s-health products, with annual sales historically reaching the high hundreds of millions of dollars across global markets. U.S. generic entry materially reduced branded revenue and shifted value from product exclusivity to manufacturing scale, distribution and portfolio management.

For a damages analysis involving Patent 6,933,395, the relevant period would be limited to:

The patent’s enforceable term;
The accused product’s launch and sales dates;
Any applicable regulatory exclusivity period;
The specific claims asserted; and
Any settlement or license restrictions.

After February 2020, this patent alone could not support prospective U.S. patent damages for continued manufacture or sale.

What manufacturing and IP barriers remain?

The expired patent does not remove technical barriers to drospirenone manufacture. Commercial production still requires control of:

Stereochemical purity;
Ruthenium-mediated oxidation or an alternative oxidation route;
Acid-sensitive methylene groups;
Dehydration conditions;
Residual solvents and catalyst residues;
The 5β-hydroxy impurity;
Related steroidal impurities;
Crystallization and particle-size distribution; and
Batch-to-batch purity.

The patent’s impurity limits may have influenced industry analytical methods and specifications. A manufacturer designing a new process should avoid relying solely on freedom from Patent 6,933,395. It should assess later process patents, foreign counterparts, trade secrets, regulatory specifications and third-party manufacturing agreements.

How does Patent 6,933,395 compare with a basic drospirenone patent?

Issue	Patent 6,933,395	Basic compound patent
Principal subject	High-purity composition, process-defined product and isolated impurity	Drospirenone molecule
Breadth	Narrower and impurity-specific	Broadest if valid and unexpired
Infringement proof	Requires impurity and/or process evidence	Usually product identity is sufficient
Design-around potential	Higher through alternative process or impurity control	Low during term
Manufacturing relevance	High	Moderate
Finished-product relevance	Claim 1 can reach pharmaceutical compositions	Depends on claim language
Current U.S. blocking effect	None after expiration	Depends on separate patent status

What is the current generic launch risk?

For U.S. products, Patent 6,933,395 presents no current patent-term barrier. Generic launch risk now depends on:

Remaining valid patents listed for the reference product;
Any unexpired formulation or method-of-use claims;
Regulatory exclusivity;
ANDA approval timing;
Labeling carve-outs;
Manufacturing capacity;
Active-ingredient sourcing; and
Commercial settlement restrictions.

Because drospirenone is a small molecule, biosimilar risk is not the correct framework. The relevant competition is generic ANDA competition.

Key Takeaways

U.S. Patent 6,933,395 is directed to drospirenone.
Claim 1 covers a pharmaceutical composition containing drospirenone with less than 0.2% of specified contaminants.
Claim 2 narrows the impurity concept to acid-opening contaminants associated with the 6β,7β-methylene group.
Claim 3 is a product-by-process composition claim involving catalytic hydrogenation, ruthenium-salt oxidation and dehydration.
Claim 4 requires isolation of the Formula III intermediate before dehydration.
Claims 5 and 6, as supplied, are identical and should be checked against the issued patent for transcription or amendment errors.
The patent’s expected U.S. term expired on February 11, 2020.
It is not a current U.S. blocking patent for generic drospirenone products.
Drospirenone products use the ANDA pathway, not the biosimilar pathway.
Current launch and licensing analysis must focus on other Orange Book-listed patents, formulation patents, method-of-use claims and manufacturing rights.

FAQs

Is drospirenone the same compound claimed in Patent 6,933,395?

Yes. The chemical name in the principal claims identifies drospirenone.

Does Patent 6,933,395 cover every drospirenone tablet?

No. The composition claims require the specified purity and contaminant limitations. Other patents may cover particular combinations, formulations, dosage regimens or uses.

Can a manufacturer avoid claim 3 by using a non-ruthenium oxidation catalyst?

Potentially, if the alternative process does not meet the claim’s process limitations and the resulting product does not independently satisfy another asserted claim. Claim construction and product-by-process doctrine remain material.

Does an impurity formed in a reaction mixture infringe claims 5 or 6?

Not necessarily. The supplied claims require the compound in isolated form. Transient formation in an unisolated reaction mixture is materially different from recovery as a discrete compound.

Are there biosimilar applications for drospirenone?

No. Drospirenone is a synthetic small molecule. FDA competition proceeds through ANDAs for generic drugs rather than applications under the biosimilar pathway.

References

Bayer Schering Pharma AG. (2005). U.S. Patent No. 6,933,395, compositions and processes relating to drospirenone. United States Patent and Trademark Office. https://patents.google.com/patent/US6933395B2/en
U.S. Food and Drug Administration. (2024a). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/
U.S. Food and Drug Administration. (2024b). Abbreviated new drug application (ANDA) process. https://www.fda.gov/drugs/types-applications/abbreviated-new-drug-application-anda
Abbott Laboratories v. Sandoz, Inc., 566 F.3d 1282 (Fed. Cir. 2009).
Amgen Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340 (Fed. Cir. 2009).
United States Patent and Trademark Office. (2024). Patent Center. https://patentcenter.uspto.gov/
Bayer Schering Pharma AG. (2004). U.S. Patent No. 6,787,531. United States Patent and Trademark Office. https://patents.google.com/patent/US6787531B2/en

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	196 33 685	Aug 12, 1996

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0918791	⤷ Start Trial	PA2006009	Lithuania	⤷ Start Trial
Austria	215557	⤷ Start Trial
Austria	420098	⤷ Start Trial
Austria	446966	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,933,395

Summary for Patent: 6,933,395