United States Patent 6,133,251: Claim Scope, Natazia Coverage, Expiration and Generic Risk
U.S. Patent No. 6,133,251 protected a four-stage oral contraceptive regimen using natural estrogen, a two-level gestogen dose, a lower estrogen-only stage, and placebo tablets. Its strongest commercial relevance was Bayer’s Natazia product, which contains estradiol valerate and dienogest in a 26-tablet sequence. The patent issued on October 17, 2000, and its 20-year term from the earliest effective filing date expired in 2017. The patent is no longer an enforceable barrier to generic entry. [1][2]
The patent’s commercial claim center is the specific sequence of 2 to 4 estrogen-only tablets, 3 to 5 low-gestogen combination tablets, 13 to 17 higher-gestogen combination tablets, 2 to 4 lower-estrogen tablets, and 2 to 4 placebo tablets.
What does U.S. Patent 6,133,251 protect?
The patent protects both:
- A physical combination preparation, such as a blister pack containing tablets arranged in the claimed sequence; and
- A method of contraception involving administration of the tablets in that sequence.
Claims 1 and 4 are composition or combination-preparation claims. Claims 5 and 7 are method-of-use claims. Claims 2, 3 and 6 narrow the broader claims.
| Claim |
Claim type |
Principal limitations |
| 1 |
Combination preparation |
Four stages; natural estrogen; two gestogen groups; lower gestogen in first group; lower estrogen in third stage; placebo stage |
| 2 |
Dependent preparation |
Gestogen amount in second group is 1.5 to 3 times the amount in first group |
| 3 |
Dependent preparation |
Estradiol and dienogest |
| 4 |
Combination preparation |
Specific estrogen and gestogen Markush groups |
| 5 |
Method of contraception |
Administration sequence corresponding to claim 1 |
| 6 |
Dependent method |
Estradiol and dienogest |
| 7 |
Method of contraception |
Administration sequence corresponding to claim 4 |
The claims do not merely require an estrogen-progestin contraceptive. They require a defined temporal architecture and relative-dose relationship.
How is the claimed contraceptive regimen structured?
The regimen has five operational segments, although the patent describes four stages because the second stage has two dose groups.
| Segment |
Number of daily portions |
Required active content |
| First stage |
2-4 |
Natural estrogen only |
| Second stage, first group |
3-5 |
Natural estrogen plus lower amount of gestogen |
| Second stage, second group |
13-17 |
Natural estrogen plus higher amount of gestogen |
| Third stage |
2-4 |
Natural estrogen only, at a lower amount than in first stage |
| Additional stage |
2-4 |
Pharmaceutically acceptable placebo |
The total regimen can range from 22 to 36 daily portions. A 26-day active/placebo pack is squarely within the claim ranges:
- 2 first-stage tablets
- 5 first-group tablets
- 17 second-group tablets
- 2 third-stage tablets
- 2 placebo tablets
This 2/5/17/2 pattern is the commercially important embodiment.
What products most closely correspond to Patent 6,133,251?
Bayer’s Natazia contraceptive is the principal product associated with the patent. Natazia contains estradiol valerate and dienogest and uses a 28-tablet pack with 26 active tablets and 2 inactive tablets. Its labeled sequence is:
| Natazia tablet segment |
Number |
Composition |
| First segment |
2 |
Estradiol valerate 3 mg |
| Second segment, lower dienogest |
5 |
Estradiol valerate 2 mg plus dienogest 2 mg |
| Second segment, higher dienogest |
17 |
Estradiol valerate 3 mg plus dienogest 3 mg |
| Third segment |
2 |
Estradiol valerate 1 mg |
| Placebo segment |
2 |
Inactive ingredients |
The product therefore matches the numerical structure of claims 4 and 7. The ratio of dienogest between the two combination groups is 3 mg to 2 mg, or 1.5 to 1, which falls within claim 2’s stated range. [3]
A technical point matters in claim mapping. Claims 1, 3, 5 and 6 refer broadly to estradiol or estradiol compounds metabolized to estradiol, with claims 3 and 6 specifically naming estradiol and dienogest. Claims 4 and 7 expressly include estradiol valerate and dienogest. Natazia therefore fits most directly within claims 4 and 7 and, depending on claim construction, within the broader estradiol-compound language of claims 1 and 5.
How broad are the estrogen limitations?
The estrogen language creates two different claim layers.
Broad estrogen category
Claims 1, 3, 5 and 6 cover:
- Estradiol;
- Conjugated equine estrogen; and
- Estradiol compounds metabolized to form estradiol in the body.
This language potentially encompasses prodrugs and esterified forms of estradiol, subject to the requirement that the compound is metabolized to estradiol. Estradiol valerate is the commercially relevant example.
Defined Markush category
Claims 4 and 7 list:
- Estradiol;
- Conjugated equine estrogen; and
- Estradiol valerate.
The express inclusion of estradiol valerate strengthens direct application to Natazia but makes the claim set less open-ended than the “estradiol compounds” wording in claims 1 and 5.
How broad are the gestogen limitations?
The claims use both broad and closed lists.
Claims 1, 3, 5 and 6 refer to “at least one natural or synthetic gestogen,” with claims 3 and 6 narrowing the combination to dienogest.
Claims 4 and 7 identify the following compounds:
- Progesterone
- Desogestrel
- Gestodene
- Levonorgestrel
- Medroxyprogesterone acetate
- Chlormadinone acetate
- Dienogest
The listed alternatives cover several generations of progestins. The most commercially significant limitation is dienogest because the estradiol valerate/dienogest combination corresponds to Natazia.
A competing product using a different progestin could avoid claims 3 and 6 but could still fall within claims 1, 2, 4, 5 or 7 if the other structural and dosing limitations are satisfied.
What are the key claim-construction issues?
The patent’s scope depends heavily on how several functional and quantitative terms are interpreted.
“Daily dosage portions”
The claims require dosage portions administered on successive days. A manufacturer using a pack with the same ingredients but a different administration schedule would present a stronger non-infringement position than a manufacturer using the same order and daily dosing.
“More gestogen”
Claims 1, 4, 5 and 7 require the second group to contain more gestogen than the first group. The comparison is directed to gestogen amount, not necessarily total tablet mass or total hormonal content.
Claim 2 is narrower because it requires the second group to contain 1.5 to 3 times more gestogen than the first group.
Constant estrogen amounts
The estrogen amount must be constant within the first stage and constant within the third stage. The third-stage amount must be lower than the first-stage amount. A product with changing estrogen doses within either stage could fall outside the literal language.
“Consisting of”
The use of “consisting of” narrows the composition language. In a literal infringement analysis, additional active ingredients in a dosage portion may create a non-infringement argument, although courts assess the claim language, prosecution history and the role of the added ingredient.
Placebo stage
The final stage must consist of pharmaceutically acceptable placebo portions. A continuous-use pack with no placebo stage would not literally satisfy this limitation, although it could raise issues under the doctrine of equivalents depending on the facts.
When did Patent 6,133,251 expire?
The patent’s enforceable term expired in 2017 based on the earliest effective filing date and the 20-year patent-term rule applicable to the application. The patent is therefore not a current blocking patent for U.S. generic development or launch.
| Event |
Date |
| Earliest priority filing |
April 11, 1996 |
| U.S. patent grant |
October 17, 2000 |
| Nominal 20-year term endpoint |
April 11, 2017 |
| Current enforceability |
Expired |
The expiration analysis should be distinguished from FDA exclusivity. FDA regulatory exclusivity is separate from patent term and does not revive an expired patent.
What was the FDA and Orange Book status?
Natazia was approved by the FDA on May 6, 2010, under NDA 022252. The product is an oral contraceptive containing estradiol valerate and dienogest. [3]
Patent 6,133,251 was the principal Orange Book-listed patent associated with the product. Its listing protected the product’s staged formulation and dosing regimen rather than a broad composition-of-matter claim directed solely to estradiol valerate or dienogest. [2][4]
The relevant regulatory milestones were:
| FDA milestone |
Date |
| Natazia approval |
May 6, 2010 |
| Initial three-year new-drug exclusivity period |
Through approximately May 2013 |
| Patent expiration |
2017 |
| Post-expiration regulatory position |
ANDA-based generic entry permitted, subject to FDA approval |
The three-year exclusivity period could have limited certain abbreviated applications before 2013, but it did not extend the patent.
Were there Paragraph IV challenges and patent litigation?
A Paragraph IV filing would have been the principal route for an ANDA applicant seeking approval before patent expiration. The relevant theories would have included:
- Non-infringement based on a different tablet sequence;
- Non-infringement based on different estrogen or gestogen amounts;
- Invalidity for anticipation or obviousness;
- Invalidity for indefiniteness, particularly concerning “effective amount,” “daily dosage portions” or the stage structure;
- Failure of the accused product to include the claimed placebo stage.
The patent’s narrow numerical structure would have made design-around strategies practical. An ANDA applicant could attempt to alter the number of tablets in one segment, remove the placebo stage, use a continuous regimen, change the gestogen ratio, or use a different estrogen-progestin combination.
The patent is now expired, so historical Paragraph IV disputes no longer create a forward-looking U.S. injunction risk under this patent. No current exclusionary litigation risk remains from Patent 6,133,251 itself. Any present litigation involving estradiol valerate/dienogest products would need to rely on later patents, regulatory exclusivity, trademarks, manufacturing rights or other intellectual-property assets.
What other patents and IP rights matter in the landscape?
Patent 6,133,251 should be analyzed as one layer of a broader contraceptive-product estate.
Formulation patents
Formulation patents may claim:
- Specific estradiol valerate and dienogest strengths;
- Tablet excipient systems;
- Coated tablet structures;
- Dissolution profiles;
- Stability characteristics;
- Blister-pack arrangements; or
- A particular sequence of active and placebo tablets.
These rights can be narrower than the 6,133,251 regimen claims but may create separate launch risk if unexpired.
Method-of-use patents
The patent already contains method claims, but later patents could address:
- Treatment of heavy menstrual bleeding;
- Cycle control;
- Reduction of estrogen exposure;
- Specific patient populations;
- Regimens for minimizing breakthrough bleeding; or
- Use in patients with contraindications to other oral contraceptives.
A generic applicant must assess the Orange Book patent listing and the proposed labeling, not only the active ingredients.
Manufacturing and process rights
Manufacturing barriers can include:
- Production of high-purity estradiol valerate;
- Dienogest synthesis and impurity control;
- Simultaneous control of multiple tablet strengths;
- Stability of low-dose hormone tablets;
- Packaging and serialization of sequential tablet packs.
These are commercial and operational barriers, not necessarily patent barriers. A process patent would need separate analysis for validity, enforceability and freedom to operate.
Geographic coverage
U.S. Patent 6,133,251 had no continuing U.S. exclusivity after its 2017 expiration. Foreign counterparts may have expired on different dates because of national filing dates, patent-term adjustments, supplementary protection certificates or national prosecution history. European, Canadian, Japanese and other country rights must be evaluated separately. U.S. expiration does not establish global freedom to operate.
How strong was the patent estate?
The patent was commercially strong during the protected period because it captured the exact multi-phase regimen used by Natazia. Its strength came from the combination of:
- A recognizable 26-day dosing pattern;
- A defined two-step increase in gestogen;
- A lower estrogen dose near the end of the active regimen;
- A placebo interval; and
- Specific coverage of estradiol valerate and dienogest.
Its weaknesses were structural. The claims required numerous numerical and sequencing limitations, creating several design-around routes. The patent also did not provide perpetual exclusivity for the active ingredients themselves. Once the patent expired, an entrant could pursue a product using the same active ingredients while relying on FDA approval and any remaining unexpired rights elsewhere in the estate.
What generic launch scenarios existed?
The principal U.S. launch scenarios were:
| Scenario |
Commercial effect |
| Exact Natazia-equivalent pack after patent expiry |
Direct substitution opportunity |
| Same ingredients with a modified sequence |
Potential design-around, subject to FDA requirements |
| Estradiol valerate with a different progestin |
Avoids dienogest-specific claims but changes clinical product |
| Continuous-use regimen without placebos |
Potentially avoids placebo-stage limitation |
| Authorized generic or licensed product |
Lower litigation exposure but dependent on commercial agreement |
| Generic using different strengths |
May avoid literal claim scope but require separate bioequivalence strategy |
Natazia’s differentiated regimen and lower estrogen positioning may preserve brand value after patent expiry, but the core regimen patent itself no longer supports a premium based on exclusivity.
Key Takeaways
- Patent 6,133,251 covers a staged oral contraceptive regimen, not merely an estradiol-progestin combination.
- Claims 4 and 7 are the closest claims to Natazia because they expressly include estradiol valerate and dienogest.
- The commercially relevant regimen is 2/5/17/2: 2 estrogen-only tablets, 5 lower-dienogest tablets, 17 higher-dienogest tablets and 2 placebo tablets.
- Claim 2 requires a 1.5-to-3-fold increase in gestogen between the two combination groups.
- Natazia was FDA-approved on May 6, 2010, under NDA 022252.
- The patent expired in 2017 and no longer creates a current U.S. injunction or Paragraph IV barrier.
- Current generic risk depends on later patents, regulatory exclusivity, manufacturing rights, labeling strategy and any separate Orange Book listings.
- Foreign patent expiration dates must be evaluated independently from the U.S. term.
FAQs
Does Patent 6,133,251 cover all estradiol valerate contraceptives?
No. It covers a particular staged regimen with specified numbers of tablets, estrogen-only stages, two gestogen levels, a lower estrogen dose in the third stage and a placebo stage.
Does a product with estradiol valerate and dienogest automatically infringe?
No. The active ingredients alone are insufficient. The product must also satisfy the claimed sequence, tablet counts, relative gestogen amounts, estrogen-dose relationships and placebo-stage limitations.
Can a generic omit the placebo tablets and avoid the patent?
Omitting the placebo stage would create a strong non-infringement position against the literal claims, but FDA labeling, substitution and other patents would require separate analysis.
Is dienogest itself protected by Patent 6,133,251?
No. The patent does not claim dienogest as a standalone compound. Dienogest is one component of the claimed staged contraceptive preparation and method.
Does expiration of Patent 6,133,251 eliminate all Natazia launch risk?
No. It eliminates the patent’s direct blocking effect. Later formulation, method-of-use, manufacturing or packaging patents, FDA requirements, trademarks and commercial agreements could still affect launch timing and economics.
References
-
U.S. Patent and Trademark Office. (2000). U.S. Patent No. 6,133,251, Pharmaceutical preparation for contraception. https://patents.google.com/patent/US6133251A/en
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U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/
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U.S. Food and Drug Administration. (2010). Natazia prescribing information, NDA 022252. https://www.accessdata.fda.gov/drugsatfda_docs/label/
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U.S. Food and Drug Administration. (n.d.). Drugs@FDA: FDA-approved drugs. https://www.accessdata.fda.gov/scripts/cder/daf/
