Details for Patent: 8,802,628

Which drugs does patent 8,802,628 protect, and when does it expire?

Patent 8,802,628 protects LINZESS and is included in one NDA.

Protection for LINZESS has been extended six months for pediatric studies, as indicated by the *PED designation in the table below.

This patent has eighty patent family members in thirty-seven countries.

Summary for Patent: 8,802,628

Title:	Stable solid formulation of a GC-C receptor agonist polypeptide suitable for oral administration
Abstract:	Solid, stable formulations of linaclotide suitable for oral administration are described herein as are methods for preparing such formulations. The formulations described herein contain a polypeptide consisting of the amino acid sequence Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (“linaclotide”; SEQ ID NO:1) or a pharmaceutically acceptable salt thereof. The linaclotide formulations described herein are stable and have a sufficient shelf life for manufacturing, storing and distributing the drug.
Inventor(s):	Angelika Fretzen, Steven Witowski, Alfredo Grossi, Hong Zhao, Mahendra Dedhiya, Yun Mo
Assignee:	Allergan Pharmaceuticals International Ltd , Ironwood Pharmaceuticals Inc
Application Number:	US12/541,410
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,802,628
Patent Claim Types: see list of patent claims	Composition; Compound; Dosage form;

US Patent 8,802,628: Linaclotide Formulation Scope, Validity, Orange Book Status, and Generic Entry Risk

US Patent 8,802,628 is a formulation patent directed to solid oral linaclotide compositions containing a calcium cation and leucine. Its strongest commercial coverage is concentrated on a stabilized, bead-containing linaclotide capsule, particularly a formulation using calcium chloride and a calcium cation:leucine:linaclotide ratio of 60:30:1. The patent does not primarily protect the linaclotide molecule or the GC-C mechanism. It protects specified pharmaceutical compositions and associated purity, impurity, assay, and storage-performance characteristics.

The patent was granted on Aug. 12, 2014, to Ironwood Pharmaceuticals, Inc. The listed patent term is generally understood to extend to May 28, 2029, subject to any applicable patent-term adjustment or regulatory calculations. The patent is associated with LINZESS, whose active ingredient is linaclotide. [1][2][3]

What does US Patent 8,802,628 protect?

The patent protects a solid pharmaceutical composition for oral administration that contains four core elements:

1. A pharmaceutically acceptable carrier.
2. Linaclotide having the claimed 14-amino-acid sequence.
3. A calcium cation.
4. Leucine.

Claim 1 is the principal composition claim. It is drafted in open-ended "comprising" form, so additional excipients, coating materials, capsule shells, processing aids, and other ingredients may be present. A competing product can infringe even if it contains ingredients not identified in the claims, provided all required elements are present.

The claim does not require calcium chloride specifically. Any calcium source that provides the required Ca2+ cation may potentially satisfy claim 1. Claim 2 identifies calcium chloride, calcium phosphate, and calcium sulfate as specific sources. Claim 20 narrows the calcium source to calcium chloride.

Claim architecture

Claim group	Subject matter	Commercial relevance
1	Solid oral composition containing linaclotide, Ca2+, leucine, and carrier	Broadest composition protection
2, 20	Calcium source, including calcium chloride	Important for common formulation design
3-7	Binders and fillers	Covers routine solid-dose excipients
8-11	Hydrolysis and oxidation impurities below specified thresholds	Product-quality and impurity profile limitations
12-15	Chromatographic purity after storage	Stability-performance limitations
16-19	Linaclotide assay after storage	Potency-retention limitations
21-24	Molar ratios of calcium, leucine, and linaclotide	Core quantitative formulation limitation
25-26	Bead-containing capsule	Commercial dosage-form limitation

How broad is claim 1 of US 8,802,628?

Claim 1 is broad in ingredient identity but narrow in formulation category. It requires a solid pharmaceutical composition for oral administration. A liquid solution, injectable product, or oral composition lacking either calcium or leucine falls outside the literal scope of claim 1.

The linaclotide limitation is also specific. The claim identifies the peptide sequence as SEQ ID NO:1 and requires that the peptide activate the GC-C receptor. A structurally different GC-C agonist is not literally covered by this claim.

The main infringement questions for a generic capsule would be:

• Whether the product is a solid oral pharmaceutical composition.
• Whether it contains calcium in ionic or salt-derived form.
• Whether it contains leucine.
• Whether the product includes the claimed linaclotide sequence.
• Whether the calcium and leucine are present as formulation ingredients rather than incidental contaminants.
• Whether the product's manufacturing and analytical records establish the required composition.

Because the claim uses "comprising," a generic cannot avoid claim 1 merely by adding another excipient or changing the capsule shell.

What formulations are protected by US 8,802,628?

The patent covers a range of solid oral dosage forms, including formulations containing binders, fillers, and calcium salts. The dependent claims identify common pharmaceutical excipients:

• Polyvinyl alcohol.
• Povidone.
• Starch.
• Maltodextrin.
• Cellulose ethers.
• Microfine cellulose.
• Microcrystalline cellulose.
• Isomalt.
• Mannitol.
• Dibasic calcium phosphate.

Claims 3 through 7 create layered protection around conventional formulation approaches. A product using a different binder or filler may avoid those dependent claims, but it could still fall within claim 1 if the product contains the required linaclotide, calcium, leucine, carrier, and solid oral dosage form.

Bead-containing capsules

Claims 25 and 26 specifically cover bead-containing capsules. This is commercially important because LINZESS is supplied as oral capsules containing linaclotide-containing beads. A generic capsule that uses a materially different dosage form may avoid these claims while remaining exposed to the broader claims.

The bead claims require the relevant calcium, leucine, linaclotide, and ratio limitations through their dependency chain. They do not independently cover every bead formulation containing linaclotide.

What calcium and leucine ratios are claimed?

Claims 21 through 24 provide the main quantitative formulation limitations.

Claim 21 recites a molar ratio of:

Ca2+ cation:leucine:linaclotide = 40-100:20-50:1

Claim 22 identifies specific ratios, including:

• 100:30:1
• 80:40:1
• 80:30:1
• 80:20:1
• 60:30:1
• 60:20:1
• 50:30:1
• 50:20:1
• 40:20:1
• 20:20:1
• 10:10:1
• 10:5:1
• 5:10:1
• 5:5:1

Claim 23 narrows the formulation to a 60:30:1 ratio. Claim 24 further requires calcium chloride.

Ratio-related claim issue

Claim 22 depends on claim 21 but includes several listed ratios, such as 20:20:1 and 10:10:1, that do not appear to fall within claim 21's stated 40-100:20-50:1 range. That dependency creates a claim-construction issue. A court could interpret the specific ratio list as controlling, or could limit claim 22 by the range inherited from claim 21. The outcome would depend on the patent specification, prosecution history, and the asserted claim construction.

For product clearance, the 60:30:1 calcium chloride formulation is the highest-risk configuration because it falls squarely within claims 21, 23, and 24 and may also satisfy claims 25 and 26 if supplied as a bead-containing capsule.

Do the impurity claims protect the linaclotide drug substance?

Claims 8 through 11 cover compositions containing specified degradation products at low levels. They require:

• A hydrolysis product below 2% by weight relative to linaclotide.
• A narrower threshold below 0.1% or 0.05%.
• An oxidation product with a molecular weight of 1542.8.
• The same less-than-2%, less-than-0.1%, or less-than-0.05% thresholds.

The structure of the hydrolysis product is missing from the claim text supplied here. The actual patent drawing and sequence definition are therefore necessary for a complete structure-specific infringement analysis.

These claims are unusual because low impurity levels can be inherent in a stable commercial product. A product may satisfy the impurity limitations without deliberately manufacturing the impurity. The practical dispute would likely concern:

• The correct analytical method.
• Whether the impurity is actually the claimed hydrolysis or oxidation product.
• The appropriate denominator for the percentage calculation.
• Lot-to-lot variation.
• Whether the limitation is met at release, during storage, or both.
• Whether the impurity threshold is an inherent property of the accused product.

The impurity claims may be difficult to use as standalone product screens unless the patent holder can obtain reliable analytical evidence from commercial samples or ANDA-related discovery.

What stability and assay performance does the patent require?

Claims 12 through 19 impose functional or performance limitations based on storage conditions.

The principal conditions are:

• 18 months at 25°C and 60% relative humidity in a sealed container with desiccant; or
• 6 months at 40°C and 75% relative humidity in a sealed container with desiccant.

The claims address two different analytical attributes:

1. Chromatographic purity of linaclotide.
2. Linaclotide assay value on a weight/weight basis.

The patent recites decreases of less than 10%, with narrower dependent thresholds down to less than 1% for assay and less than 4% for chromatographic purity. Other claims require chromatographic purity or assay of at least 90% after storage.

Stability-claim implications

These claims can create litigation exposure even when the formulation composition is not identical in every respect. A generic product may be tested against the stability limitations if its formulation contains the claimed ingredients and the patent owner asserts that the performance limitation is met.

The practical strength of these claims depends on whether the limitations are interpreted as:

• Product characteristics that must be present in the marketed product.
• Results that must be demonstrated under the specified test protocol.
• Limitations that are inherent in any composition meeting the structural formulation requirements.

The sealed container and desiccant requirements are material. A stability result generated under different packaging, humidity, temperature, or desiccant conditions may not establish literal infringement.

When does US Patent 8,802,628 lose exclusivity?

The expected expiration date is May 28, 2029, based on the patent's priority and term information. [1][2]

Milestone	Date or status
Earliest stated priority	May 28, 2009
US patent grant	Aug. 12, 2014
Patent number	US 8,802,628 B2
Expected ordinary expiration	May 28, 2029
Earlier composition or molecule patents	Potentially expired or separately timed
Orange Book impact	Depends on current listing and the scope of approved-product claims

Patent expiration does not guarantee immediate generic launch. Launch timing may also depend on:

• ANDA approval.
• Paragraph IV litigation.
• Settlement restrictions.
• Other unexpired Orange Book patents.
• Regulatory exclusivity.
• Manufacturing readiness.
• Injunctions or appeal outcomes.

LINZESS received FDA approval in 2012 for irritable bowel syndrome with constipation and later approvals for chronic idiopathic constipation and pediatric use. The approved product is marketed in capsule strengths including 72 mcg, 145 mcg, and 290 mcg. [3][4]

What is the Orange Book status of US 8,802,628?

US 8,802,628 has been associated with LINZESS patent protection and is relevant to generic linaclotide capsule development. The FDA Orange Book should be treated as the controlling source for the current listing status, use codes, expiration date, and any delisting or listing changes. [2]

The patent's commercial significance depends on whether it is listed against the relevant LINZESS dosage forms and whether an ANDA applicant must certify to it. A formulation patent generally has greater relevance to an ANDA than a method-of-use patent when the patent claims the drug product itself.

For a Paragraph IV analysis, the applicant would normally need to address:

• Whether the proposed formulation contains calcium and leucine.
• Whether the relevant ingredients are present at the claimed ratio.
• Whether the product is a bead-containing capsule.
• Whether the claimed impurity profile is present.
• Whether the required stability or assay characteristics are met.
• Whether the patent claims are invalid, unenforceable, or not infringed.

Which companies are challenging LINZESS patent protection?

Public generic activity around LINZESS has involved ANDA applicants and patent litigation against Ironwood and its commercial partners. The relevant defendants have included generic pharmaceutical companies seeking approval for linaclotide capsules. Public docket activity and FDA approval records should be reviewed separately for each applicant because a Paragraph IV certification, a filed lawsuit, a settlement, and an approved ANDA are distinct events.

A company can challenge US 8,802,628 through:

• A Paragraph IV certification.
• A declaratory judgment action in limited circumstances.
• An invalidity or noninfringement defense after an infringement suit.
• An inter partes review, although formulation claims often present fact-intensive issues concerning formulation composition and stability.

A Paragraph IV notice does not itself establish that generic entry will occur. Under the Hatch-Waxman framework, a timely patent suit can trigger a 30-month stay of FDA approval, subject to statutory exceptions and court action. [5]

What patent litigation affects US 8,802,628?

The central litigation issues for this patent are likely to be formulation-specific rather than molecule-specific.

Likely infringement disputes

A patent holder would focus on:

• Calcium chloride or another calcium salt in the formulation.
• Free or formulation-associated leucine.
• The claimed molar ratio.
• Bead manufacture and capsule composition.
• Analytical evidence for impurity thresholds.
• Stability results under the claimed storage conditions.

Likely validity disputes

An ANDA applicant could challenge:

• Anticipation by earlier linaclotide formulations.
• Obviousness based on known peptide stabilization techniques.
• Written description and enablement for the full ratio and excipient scope.
• Indefiniteness of performance limitations.
• Lack of meaningful distinction between claimed and prior-art stability results.
• The dependency inconsistency in claim 22.
• Whether the claimed impurity limitations are adequately supported.

The combination of calcium and leucine may be defended as an unexpected stabilization system. The patent owner's strongest validity position would likely rely on comparative stability data showing that the claimed combination materially improves linaclotide purity or assay relative to formulations lacking calcium, leucine, or both.

How strong is the patent estate for LINZESS?

The estate is stronger as a layered formulation estate than as a single-patent barrier.

Protection layer	Strategic value
Linaclotide molecule and GC-C activity	Protects the active pharmaceutical ingredient, but timing depends on earlier patent terms
Calcium-plus-leucine composition	Directly targets a commercial formulation design
Specific calcium salts	Narrows design-around options
60:30:1 ratio	Creates strong exposure for a close formulation copy
Bead-containing capsule	Aligns with the marketed dosage form
Impurity limits	Supports analytical and quality-based enforcement
Stability and assay limits	May capture products with similar performance
Method-of-use claims	Can protect approved indications but may be more difficult to enforce against a label carve-out

The 8,802,628 patent is most valuable against a generic that copies the commercial formulation architecture. Its value is lower against a product using a different solid dosage platform, a different stabilization strategy, no leucine, a different calcium concentration, or a non-bead formulation.

What generic launch scenarios exist for linaclotide?

Scenario 1: Close formulation copy

A generic using linaclotide, calcium chloride, leucine, and a similar bead-containing capsule would face the highest risk. The 60:30:1 ratio claims and calcium chloride limitation would be central.

Scenario 2: Calcium-containing but leucine-free formulation

Removing leucine could avoid the principal composition claims, assuming leucine is not present as an excipient or processing residue. The product could still face other Orange Book patents or formulation claims.

Scenario 3: Leucine-containing but calcium-free formulation

Removing calcium would avoid claim 1 as written. The generic would need to confirm that calcium is not introduced through a filler, buffer, coating, or manufacturing step.

Scenario 4: Alternative solid formulation

A tablet, powder, multiparticulate, or capsule without the claimed calcium-leucine combination may reduce exposure to this patent. Other linaclotide patents could still apply.

Scenario 5: Post-expiration launch

A generic that cannot resolve the patent through litigation or settlement may target launch after May 28, 2029, subject to other patents and regulatory barriers.

Are biosimilar risks relevant to linaclotide?

No. Linaclotide is a chemically synthesized peptide drug, not a therapeutic protein regulated through the biosimilar pathway under the Public Health Service Act. Generic applicants generally pursue an ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act rather than a 351(k) biosimilar application.

The principal competitive threat is therefore an AB-rated generic linaclotide capsule, not a biosimilar. [4][5]

What manufacturing and IP barriers remain?

The formulation patent creates several technical barriers:

• Maintaining peptide stability during granulation or bead manufacture.
• Controlling moisture exposure.
• Controlling oxidation and hydrolysis.
• Uniformly distributing a microgram-level peptide dose.
• Achieving acceptable assay and content uniformity.
• Producing a reproducible calcium-to-leucine-to-linaclotide ratio.
• Matching dissolution and release characteristics.
• Packaging the product with suitable moisture protection and desiccant.

The manufacturing process itself may be protected by separate patents or trade secrets even if a generic designs around US 8,802,628. The absence of infringement of this patent would not establish freedom to operate across the full LINZESS patent estate.

How does US 8,802,628 compare with method-of-use patents?

US 8,802,628 claims the drug product. That makes it more directly relevant to an ANDA applicant than a method-of-use patent.

A method-of-use patent can sometimes be addressed through a section viii statement or a carved-out label if the patented indication is omitted and the remaining label does not encourage infringement. A composition patent generally cannot be avoided through label carving if the ANDA product itself contains the claimed formulation.

This distinction increases the commercial importance of 8,802,628 for a generic seeking approval for the same linaclotide capsule product.

Key Takeaways

• US 8,802,628 is a linaclotide formulation patent, not primarily a molecule patent.
• Claim 1 requires a solid oral composition containing linaclotide, calcium, leucine, and a pharmaceutical carrier.
• Calcium chloride is specifically claimed, and the 60:30:1 calcium:leucine:linaclotide ratio is a high-risk configuration.
• Bead-containing capsules are covered by claims 25 and 26 when the inherited composition and ratio limitations are met.
• Claims 8 through 19 add impurity, stability, chromatographic-purity, and assay limitations.
• The expected patent expiration date is May 28, 2029.
• Generic risk is highest for a close LINZESS formulation copy and lower for calcium-free, leucine-free, or materially different solid formulations.
• Linaclotide does not present a biosimilar pathway issue. The relevant pathway is an ANDA with possible Paragraph IV certification.
• Claim 22 contains a dependency and ratio-range inconsistency that may create a claim-construction dispute.
• The patent should be analyzed with the complete Orange Book listing and the broader LINZESS patent family before making a launch or licensing decision.

FAQs About US Patent 8,802,628 and Linaclotide

Does US 8,802,628 cover all linaclotide products?

No. It requires a solid oral composition containing both a calcium cation and leucine, in addition to linaclotide and a pharmaceutically acceptable carrier.

Can a generic avoid US 8,802,628 by using calcium phosphate instead of calcium chloride?

Not necessarily. Claim 2 expressly identifies calcium phosphate as a calcium source, and claim 1 is not limited to calcium chloride.

Does a tablet automatically avoid the bead-containing capsule claims?

A tablet may avoid claims 25 and 26 if it is not a bead-containing capsule. It could still infringe broader composition claims if it contains the required linaclotide, calcium, leucine, and other claimed elements.

What analytical evidence is relevant to claims 8 through 19?

Relevant evidence includes validated chromatographic purity testing, identification and quantification of the claimed degradation products, assay testing, stability protocols, storage packaging, humidity controls, temperature records, and lot-specific results.

Does expiration of US 8,802,628 permit immediate generic launch?

No. Immediate launch also depends on FDA approval, other unexpired Orange Book patents, litigation outcomes, settlement terms, regulatory exclusivity, and any applicable court order.

References

1. United States Patent and Trademark Office. (2014). US Patent No. 8,802,628 B2: Pharmaceutical compositions comprising linaclotide. https://patents.google.com/patent/US8802628B2/en

2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/

3. U.S. Food and Drug Administration. (2012). Linzess prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/

4. U.S. Food and Drug Administration. (2023). FDA approves first treatment for pediatric functional constipation and expands Linzess approval. https://www.fda.gov/

5. U.S. Food and Drug Administration. (2024). ANDA submissions: Amendments and requests for final approval to tentatively approved ANDAs. https://www.fda.gov/drugs/abbreviated-new-drug-application-anda/abbreviated-new-drug-application-anda-forms-and-resources

Drugs Protected by US Patent 8,802,628

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Abbvie	LINZESS	linaclotide	CAPSULE;ORAL	202811-001	Aug 30, 2012		RX	Yes	Yes					Y
Abbvie	LINZESS	linaclotide	CAPSULE;ORAL	202811-002	Aug 30, 2012		RX	Yes	No					Y

International Family Members for US Patent 8,802,628

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	073075
Argentina	118601
Australia	2009282446
Brazil	PI0917807