United States Patent 10,016,393: Atrasentan-L-Cysteine Formulation Claims, Exclusivity, and Patent Landscape

US Patent No. 10,016,393 protects a stable solid oral dosage form containing a low dose of atrasentan and L-cysteine in a defined molar ratio. The strongest commercial claim is claim 10, which narrows the formulation to atrasentan, L-cysteine, hydroxypropyl methylcellulose, crospovidone, lactose, silicon dioxide, and glyceryl behenate within specified concentration ranges. Claim 11 further covers a film-coated tablet core.

The patent is a formulation patent, not a basic atrasentan composition-of-matter patent. It does not claim atrasentan generally, a method of treating kidney disease, or a manufacturing process in the claims provided. Its practical value depends on whether a marketed or proposed generic product uses the claimed low-dose composition and excipient architecture.

What does US Patent 10,016,393 protect?

The patent protects a stable solid pharmaceutical dosage form containing:

Approximately 0.4 mg to 0.85 mg of atrasentan free base, or an equivalent amount of a pharmaceutically acceptable salt.
L-cysteine, or a pharmaceutically acceptable salt.
An L-cysteine-to-atrasentan molar ratio from approximately 2:1 to 1:2.

The independent scope is established by claim 1. The claim requires the combination of the active ingredient, cysteine, the dose range, the molar ratio, and stability of the solid dosage form.

The patent does not require the presence of lactose, crospovidone, hydroxypropyl methylcellulose, silicon dioxide, or glyceryl behenate unless a dependent claim is being asserted.

Core claim architecture

Claim	Principal limitation	Commercial significance
1	0.4-0.85 mg atrasentan and L-cysteine at a 2:1 to 1:2 molar ratio in a stable solid dosage form	Broadest formulation claim
2	Approximately 0.75 mg atrasentan	Targets a specific low-dose strength
3	Approximately 1:1 cysteine-to-atrasentan molar ratio	Narrows the stabilizer ratio
4	1-5 wt.% binder selected from specified cellulose polymers	Adds binder limitation
5	Hydroxypropyl methylcellulose as binder	Narrows claim 4
6	1-6 wt.% disintegrant and 85-99 wt.% diluent	Defines tablet excipient system
7	Crospovidone as disintegrant and lactose as diluent	Covers a likely preferred formulation
8	0.1-0.8 wt.% glidant and 0.5-2 wt.% lubricant	Adds processing excipients
9	Silicon dioxide and glyceryl behenate	Narrows claim 8
10	HPMC, crospovidone, lactose, silicon dioxide, and glyceryl behenate in specified ranges	Detailed commercial formulation claim
11	Claim 10 composition in a film-coated tablet core	Most specific dosage-form claim

How broad is claim 1 for atrasentan formulations?

Claim 1 is materially broader than claims 10 and 11 because it does not require a particular binder, disintegrant, diluent, glidant, lubricant, or coating.

A formulation may fall within claim 1 if it contains a different excipient system, provided it has the claimed atrasentan amount, cysteine relationship, and stability characteristics. The claim also covers pharmaceutically acceptable salts through the equivalent-amount language.

The principal limitations are:

The dosage form must be solid.
The formulation must be stable.
Atrasentan must be present at approximately 0.4-0.85 mg.
L-cysteine must be present.
The cysteine-to-atrasentan molar ratio must be approximately 2:1 to 1:2.

A liquid formulation, injectable product, implant, transdermal system, or solid formulation outside the stated dose range would not satisfy the literal limitations of claim 1.

What does “stable” mean in the patent claims?

“Stable” is a potentially important claim-construction issue. The claims supplied do not state a numerical impurity threshold, storage period, temperature, humidity condition, or degradation limit. The meaning will therefore depend heavily on the specification, analytical methods, stability examples, and prosecution history.

For infringement analysis, the relevant question is whether the accused dosage form satisfies the patent’s stability definition or the ordinary pharmaceutical meaning established by the intrinsic record. A generic manufacturer could challenge the stability limitation if the patent does not provide an adequately objective boundary. The patent owner could respond that the specification identifies the relevant degradation problem and demonstrates stability under defined conditions.

What is the scope of the 0.75 mg atrasentan claim?

Claim 2 targets a dosage form containing approximately 0.75 mg of atrasentan free base or its salt equivalent. This claim is narrower than claim 1 but commercially important because low-dose atrasentan products for renal indications may use a 0.75 mg strength.

The claim does not independently require the 1:1 cysteine ratio, HPMC, lactose, crospovidone, or film coating. Those limitations enter only through further dependent claims.

The term “about” creates a numerical boundary issue. The applicable range depends on the specification, prosecution history, measurement accuracy, and the ordinary meaning of “about” in the pharmaceutical formulation context. A product containing a nominally different strength could still create literal or doctrine-of-equivalents exposure if the difference is within the claim’s supported tolerance.

How does the L-cysteine molar ratio affect infringement risk?

The ratio is calculated on a molar, not weight, basis. For a 0.75 mg atrasentan free-base dose, using an approximate atrasentan molecular weight of 605.7 g/mol, the active ingredient amount is approximately 1.24 micromoles. A 1:1 formulation would therefore contain approximately 0.15 mg of L-cysteine, based on an L-cysteine molecular weight of about 121.16 g/mol.

Atrasentan dose	Approximate 1:1 L-cysteine amount
0.40 mg	0.080 mg
0.75 mg	0.150 mg
0.85 mg	0.170 mg

The permitted range is approximately 2:1 to 1:2. A formulation with materially less cysteine than the lower boundary, or materially more than the upper boundary, may avoid literal infringement of claim 1. The salt form and assay basis must be normalized correctly before comparing ratios.

What formulation is protected by claims 10 and 11?

Claims 10 and 11 cover the most detailed formulation disclosed in the claim set.

Claim 10 composition

The formulation must contain:

0.4-0.85 mg atrasentan under claim 1.
L-cysteine within the claim 1 molar ratio.
1-5 wt.% hydroxypropyl methylcellulose.
1-6 wt.% crospovidone.
85-99 wt.% lactose.
0.1-0.8 wt.% silicon dioxide.
0.5-2 wt.% glyceryl behenate.

Because claim 10 depends on claim 1, every limitation of claim 1 remains applicable. The excipient ranges are cumulative. A formulation outside any one of the listed ranges may avoid literal infringement of claim 10, although it could still fall within claim 1 or another dependent claim.

Claim 11 requires the claim 10 formulation to be a tablet core with a film coating. The coating itself is not specified by composition or thickness. The claim therefore focuses on the coated-tablet configuration rather than a particular coating polymer, pigment, plasticizer, or process.

Does US Patent 10,016,393 claim methods of treatment or manufacturing?

No. The claims provided are directed to dosage forms.

They do not expressly claim:

Treatment of IgA nephropathy.
Treatment of diabetic kidney disease.
Reduction of proteinuria.
Endothelin A receptor antagonism.
A method of administering atrasentan.
A granulation process.
A compression process.
A coating process.
A packaging system.
A specific impurity-control method.

The patent may still be relevant to a product-development program because a formulation claim can block commercial manufacture or sale even when a separate method-of-use or process patent is not infringed.

When does US Patent 10,016,393 lose exclusivity?

The patent’s enforceable term is generally governed by the 20-year term measured from the earliest effective nonprovisional filing date in the priority chain, subject to patent-term adjustment, terminal disclaimer, patent-term extension, and other USPTO-record events under 35 U.S.C. §§ 154 and 156.

The issue date was June 19, 2018. The issue date does not determine the ordinary patent expiration date. A precise expiration date must be taken from the patent’s current USPTO bibliographic and term-adjustment records, including the earliest nonprovisional filing and any PTA or terminal disclaimer.

Because atrasentan has no FDA-approved reference product listed in the Orange Book, a Hatch-Waxman patent-term extension tied to an approved atrasentan NDA is not presently apparent from the FDA regulatory record. FDA approval of an atrasentan product could change the commercial relevance of this patent but would not automatically create a patent-term extension.

Exclusivity timeline

Event	Relevance
Patent grant on June 19, 2018	Creates enforceable patent rights, subject to validity and maintenance
Patent term	Generally 20 years from the earliest effective nonprovisional filing
FDA approval of atrasentan	No approved atrasentan product is listed in the Orange Book
Orange Book listing	No current reference-product listing for atrasentan is identified
Generic approval pathway	ANDA timing depends on an FDA-listed reference product
Biosimilar pathway	Not applicable because atrasentan is a small molecule

What is the Orange Book status of atrasentan?

Atrasentan is not an FDA-approved reference drug listed in the Orange Book. As a result, US Patent 10,016,393 does not currently operate as a standard Orange Book-listed patent against an ANDA for an approved atrasentan reference product.

That distinction affects enforcement strategy. Without an approved reference product, there is no conventional Orange Book certification process for a generic applicant under the Hatch-Waxman framework. A future sponsor could pursue a new drug application, while a future generic applicant would need an approved reference product and an applicable abbreviated pathway before submitting a Paragraph IV certification.

Are there Paragraph IV challenges to US Patent 10,016,393?

No publicly established Paragraph IV challenge is identified for this patent in connection with an FDA-approved atrasentan reference product. The absence of an Orange Book-listed atrasentan product means there is no ordinary Hatch-Waxman Paragraph IV timetable comparable to those for marketed small-molecule drugs.

A Paragraph IV challenge could become relevant after FDA approval of an atrasentan product if the patent is listed for the approved product and an ANDA applicant certifies that the patent is invalid, unenforceable, or not infringed.

Potential future challenge theories would likely focus on:

Lack of written description for the full dose and ratio ranges.
Enablement of all stable solid dosage forms within the broad claim.
Obviousness over atrasentan formulations combined with known cysteine stabilizers.
Indefiniteness of “stable” and “about.”
Noninfringement based on dose, molar ratio, or excipient composition.
Failure to meet the statutory requirements for listing or maintaining the patent in the Orange Book.

What companies control or have commercial rights to atrasentan?

Atrasentan originated in the AbbVie research portfolio. Chinook Therapeutics obtained rights to atrasentan and developed it for kidney disease. Novartis acquired Chinook in 2023, making Novartis the principal current commercial developer associated with the atrasentan renal-development program (Novartis, 2023).

Patent ownership and development rights should be separated. The commercial sponsor may hold development rights without owning every patent in the family. Assignment records, security interests, and licenses should be reviewed in the USPTO patent file and applicable transaction documents before relying on a final ownership conclusion.

How strong is the patent estate for atrasentan?

US Patent 10,016,393 has moderate formulation blocking power and limited standalone breadth.

Strengths

Claim 1 covers multiple excipient systems.
The active dose range is narrow enough to target a likely clinical strength.
The cysteine ratio is defined numerically.
Salt-equivalent language reduces simple salt-form design-around opportunities.
Claims 10 and 11 identify a commercially realistic tablet formulation.

Weaknesses

The patent does not claim atrasentan itself.
It does not claim a therapeutic indication.
The “stable” limitation may require detailed intrinsic evidence.
The “about” ranges create boundary disputes.
A competitor may design around the specific excipient combinations.
The absence of Orange Book listing limits immediate Hatch-Waxman leverage.
A challenge could argue that cysteine stabilization of a pharmaceutical compound was predictable.

The strongest assertion position would involve a low-dose coated tablet using the claimed cysteine ratio and the claim 10 excipient system. The weakest position would involve a different solid dosage form outside the dose range or with a cysteine ratio outside the claimed range.

What generic entry risks exist?

Generic-entry risk is currently regulatory rather than immediate commercial litigation risk because atrasentan lacks an approved reference product in the Orange Book.

If atrasentan receives FDA approval, entry scenarios could include:

A generic product uses the same 0.75 mg strength, cysteine ratio, and excipient platform. This creates the highest infringement risk.
A generic uses the same active dose but a different stabilizer or cysteine ratio. Claim 1 remains the principal risk.
A generic uses a different dose outside 0.4-0.85 mg. This may avoid the asserted claims but could conflict with clinical labeling or dose requirements.
A generic uses a capsule or another solid dosage form. Claim 1 could still apply because it is not limited to tablets.
A generic uses a different formulation that avoids cysteine entirely. This creates the clearest design-around route, subject to stability and regulatory performance.

A product that avoids claims 10 and 11 may still infringe claim 1. A noninfringing formulation must be assessed against every limitation of the independent and asserted dependent claims.

Does biosimilar risk apply to atrasentan?

No. Atrasentan is a synthetic small-molecule drug, not a biologic. The Public Health Service Act biosimilar pathway and FDA Purple Book framework do not apply. Competitive entry would proceed through small-molecule pathways, a full NDA, or another applicable regulatory route rather than a biosimilar application.

What are the manufacturing and IP barriers?

The patent does not expressly claim a manufacturing method, but the formulation may create process-development barriers. A manufacturer may need to control:

Uniform distribution of a very low atrasentan dose.
Accurate cysteine incorporation at submilligram quantities.
Compatibility between cysteine and the active ingredient.
Blend uniformity across lactose-heavy tablets.
Compression and friability characteristics.
Lubrication with glyceryl behenate.
Film-coating conditions.
Stability-indicating impurity methods.
Moisture and oxygen exposure during manufacturing and packaging.

These technical barriers do not independently establish patent infringement. They can, however, make a noninfringing formulation more difficult to develop and validate.

What patent litigation and settlements affect this patent?

No established Paragraph IV litigation, patent settlement, or launch agreement involving US Patent 10,016,393 is identified in connection with an approved atrasentan product. The absence of a current Orange Book reference product also means that ordinary ANDA litigation and 30-month-stay mechanics are not presently central to this patent.

A future settlement would likely address:

The date of authorized generic or independent generic entry.
Patent challenge rights.
Royalty or license terms.
Formulation restrictions.
Regulatory exclusivity.
Confidential manufacturing or stability data.

How does US Patent 10,016,393 compare with other atrasentan patent categories?

Patent category	Status or relevance
Composition-of-matter patents	Historically important but generally earlier-expiring than later formulation patents
Formulation patents	US 10,016,393 protects low-dose atrasentan with L-cysteine
Method-of-use patents	Could cover kidney disease or proteinuria indications, but are not present in the claims supplied
Manufacturing patents	Not present in the supplied claim set
Salt or crystal-form patents	Could create separate barriers if disclosed and still enforceable
Regulatory exclusivity	No Orange Book exclusivity currently associated with an approved atrasentan product
Biosimilar exclusivity	Not applicable

Key Takeaways

US Patent 10,016,393 is a formulation patent covering stable solid atrasentan dosage forms with L-cysteine.
Claim 1 is the principal broad claim and covers 0.4-0.85 mg atrasentan with a 2:1 to 1:2 cysteine molar ratio.
Claim 2 targets approximately 0.75 mg atrasentan.
Claims 10 and 11 cover a specific lactose-based, HPMC-bound, crospovidone-containing, film-coated tablet formulation.
The patent does not claim atrasentan generally, a treatment method, or a manufacturing process.
Atrasentan has no FDA-approved Orange Book reference product identified, so no conventional Paragraph IV framework is currently active.
Atrasentan is a small molecule, making biosimilar analysis irrelevant.
The highest infringement risk concerns a 0.75 mg tablet using the claimed cysteine ratio and excipient platform.
The leading design-around options are a different stabilizer system, a cysteine ratio outside the claimed range, or a formulation outside the claimed atrasentan dose range.
Novartis is the principal current commercial developer associated with atrasentan after its acquisition of Chinook Therapeutics.

FAQs

Can a capsule infringe US Patent 10,016,393?

Yes. Claim 1 covers a stable solid pharmaceutical dosage form and does not limit the product to a tablet or capsule. Claims 10 and 11 are narrower and focus on the claimed excipient system and coated tablet configuration.

Does using N-acetylcysteine avoid the patent?

Not necessarily. The claims recite L-cysteine or a pharmaceutically acceptable salt thereof. N-acetylcysteine is chemically distinct from L-cysteine, so it may avoid literal compliance with that limitation, but the complete formulation and any doctrine-of-equivalents theory require separate analysis.

Can a formulation with 0.9 mg atrasentan infringe?

It may avoid the literal 0.4-0.85 mg range, subject to the construction of “about.” It could also face an equivalents argument if the difference from the claimed range is insubstantial and the other claim limitations are met.

Does a formulation without lactose avoid all claims?

No. It would likely avoid claim 7 and the lactose limitation in claims 10 and 11, but claim 1 does not require lactose. A lactose-free formulation could still fall within claim 1 or claims 2-6, depending on its composition.

Is a patent license currently needed to sell atrasentan in the United States?

Patent licensing depends on the proposed product, patent term, ownership, and commercial rights. FDA approval alone does not resolve patent infringement. A product-specific freedom-to-operate analysis must assess US Patent 10,016,393 together with the broader atrasentan patent family and any surviving method, salt, crystal, or manufacturing claims.

References

United States Patent and Trademark Office. (2018). U.S. Patent No. 10,016,393, pharmaceutical compositions comprising atrasentan.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Food and Drug Administration. (2024). Purple Book: Database of licensed biological products.
Hatch, W. E., & Waxman, H. A. (1984). Drug Price Competition and Patent Term Restoration Act, Pub. L. No. 98-417, 98 Stat. 1585.
Novartis. (2023). Novartis completes acquisition of Chinook Therapeutics.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Novartis	VANRAFIA	atrasentan hydrochloride	TABLET;ORAL	219208-001	Apr 2, 2025		RX	Yes	Yes	10,016,393	⤷ Start Trial	Y				⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2014287496	⤷ Start Trial
Canada	2916033	⤷ Start Trial
Chile	2016000027	⤷ Start Trial
Chile	2016000788	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 10,016,393

Which drugs does patent 10,016,393 protect, and when does it expire?

Summary for Patent: 10,016,393