Details for Patent: 7,704,947

Summary for Patent: 7,704,947

Title:	Methods and compositions for the treatment of gastrointestinal disorders
Abstract:	The present invention features compositions and related methods for treating IBS and other gastrointestinal disorders and conditions (e.g., gastrointestinal motility disorders, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), Crohn's disease, ulcerative colitis, Inflammatory bowel disease, functional heartburn, dyspepsia (including functional dyspepsia or nonulcer dyspepsia), gastroparesis, chronic intestinal pseudo-obstruction (or colonic pseudo-obstruction), and disorders and conditions associated with constipation, e.g., constipation associated with use of opiate pain killers, post-surgical constipation, and constipation associated with neuropathic disorders as well as other conditions and disorders using peptides and other agents that activate the guanylate cyclase C (GC-C) receptor.
Inventor(s):	Mark G. Currie, Shalina Mahajan-Miklos, Thea Norman, G. Todd Milne
Assignee:	Ironwood Pharmaceuticals Inc
Application Number:	US11/930,696
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,704,947
Patent Claim Types: see list of patent claims	Composition; Compound;

United States Patent 7,704,947: Scope, Claim Construction, Expiration, and Linaclotide Patent Landscape

U.S. Patent No. 7,704,947 covers a narrow class of 14-amino-acid guanylate cyclase-C agonist peptides, including linaclotide and two disclosed analogues containing phenylalanine or tryptophan at position 4. The patent protects the peptide substance, purified forms, pharmaceutically acceptable salts, guanylate cyclase-C activity for selected embodiments, and pharmaceutical compositions.

The patent does not claim every guanylate cyclase-C agonist, every linaclotide formulation, or every method of treating constipation or irritable bowel syndrome. Infringement depends primarily on whether a competing product contains the claimed 14-residue sequence, including a covered position-4 amino acid, or uses a composition that falls within the dependent composition claims.

What drug and peptide does U.S. Patent 7,704,947 cover?

The patent covers peptide agonists of guanylate cyclase C, also known as GC-C or guanylyl cyclase C. The principal sequence relevant to the commercial drug linaclotide is:

Cys-Cys-Glu-Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr

Linaclotide is a 14-amino-acid peptide with three disulfide bonds and the molecular formula associated with the sequence above. The sequence is commonly identified in patent and regulatory materials as SEQ ID NO: 125 when the fourth residue is Tyr.

The claims also cover two related sequences:

Position 4	Sequence identifier	Covered peptide
Phenylalanine (Phe, F)	SEQ ID NO: 105	Cys-Cys-Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr
Tryptophan (Trp, W)	SEQ ID NO: 109	Cys-Cys-Glu-Trp-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr
Tyrosine (Tyr, Y)	SEQ ID NO: 125	Cys-Cys-Glu-Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr

The patent therefore protects a three-member sequence genus at the fourth amino-acid position: Phe, Trp, or Tyr.

What are the core claims of U.S. Patent 7,704,947?

The claims fall into four functional groups.

Genus claims covering three position-4 variants

Claims 1 and 2 cover a peptide having the sequence:

Cys-Cys-Glu-Xaa-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr

where Xaa is Phe, Trp, or Tyr.

Claim 1 uses “comprising,” while claim 2 uses “consisting of.” That difference affects claim scope:

• Claim 1 is open-ended. A peptide containing the specified sequence may fall within the claim even if additional amino-acid residues or structural components are present, subject to the court’s interpretation of how “comprising” applies to the claimed polypeptide.
• Claim 2 is closed to the recited 14-amino-acid sequence. It is directed to the exact sequence, subject to normal claim-construction principles.

Claims 3 and 4 add purification limitations to claims 1 and 2.

Phenylalanine-specific claims

Claims 5 and 6 cover the exact Phe-containing sequence:

Cys-Cys-Glu-Phe-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr

Claim 5 uses “comprising.” Claim 6 requires the peptide to consist of that sequence.

Claims 7 and 8 add two different limitations:

• Claim 7 requires activation of the GC-C receptor.
• Claim 8 covers a pharmaceutical composition containing the Phe-containing peptide or its pharmaceutically acceptable salt.

Tryptophan-specific claims

Claims 9 and 10 cover the exact Trp-containing sequence:

Cys-Cys-Glu-Trp-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr

Claim 9 uses “comprising.” Claim 10 uses “consisting of.”

Claim 11 requires GC-C activation, and claim 12 covers a pharmaceutical composition containing the Trp-containing peptide or its salt.

Broad composition claims

Claims 13 through 16 cover pharmaceutical compositions containing:

• The genus peptide of claim 1;
• The exact genus peptide of claim 2;
• The exact Phe-containing peptide of claim 6; or
• The exact Trp-containing peptide of claim 10.

These claims require a pharmaceutically acceptable carrier or excipient. They do not recite a specific dosage form, excipient, release profile, concentration, route of administration, or therapeutic indication.

How broad is claim 1?

Claim 1 covers three exact sequence alternatives rather than a broad amino-acid substitution framework. The only variable residue is Xaa at position 4, and the permitted residues are limited to Phe, Trp, and Tyr.

The claim does not, on its face, cover substitutions at other positions. A competing peptide with alanine, leucine, serine, histidine, or another amino acid at position 4 would fall outside the literal scope of the Xaa limitation, although infringement could still raise doctrine-of-equivalents issues.

The claim also does not expressly require:

• A particular disulfide-bond pattern;
• A particular manufacturing process;
• A particular purity threshold;
• A particular formulation;
• Oral administration;
• Treatment of chronic idiopathic constipation;
• Treatment of irritable bowel syndrome with constipation; or
• A particular dose.

The sequence, however, contains six cysteines. A commercial product intended to reproduce the biological activity of linaclotide would ordinarily need to preserve the peptide’s defined conformation and disulfide connectivity. That makes manufacturing and analytical characterization commercially important even where the patent claim itself does not expressly recite every structural feature.

Does the patent cover linaclotide?

Yes. Linaclotide corresponds to the Tyr-containing member of the claimed sequence genus.

The strongest direct coverage arises from:

• Claim 1, because Tyr is one of the permitted Xaa residues;
• Claim 2, for the exact 14-amino-acid peptide;
• Claim 3, for a purified form;
• Claim 4, for the purified exact sequence;
• Claim 13, for a composition containing the genus peptide; and
• Claim 14, for a composition containing the exact genus sequence.

Claims 5 through 8 are directed to the Phe analogue and do not directly cover linaclotide. Claims 9 through 12 are directed to the Trp analogue and likewise do not directly cover linaclotide.

Claim group	Linaclotide relevance
Claims 1-4	Directly relevant
Claims 5-8	Phe analogue, not the Tyr sequence
Claims 9-12	Trp analogue, not the Tyr sequence
Claims 13-14	Directly relevant
Claims 15-16	Phe and Trp compositions, not the Tyr sequence

What does “pharmaceutically acceptable salt” add to the patent scope?

The salt language extends coverage beyond the unmodified peptide to pharmaceutically acceptable salt forms. For peptide drugs, salt formation may involve ionizable terminal groups or side chains and can affect handling, stability, solubility, and formulation.

The salt limitation does not require a particular counterion. The scope depends on whether the claimed peptide is present as a pharmaceutically acceptable salt under the applicable claim construction.

A product containing the peptide in a non-salt form may still fall within the principal peptide claims. The salt language is therefore additive rather than a necessary condition for infringement of claims 1, 2, 3, 4, 5, 6, 9, or 10.

What does the purification limitation mean?

Claims 3 and 4 require that the claimed peptide be purified. The patent claims do not state a numerical purity threshold in the language supplied.

The limitation is material because a crude synthesis mixture may not satisfy the claim if purification is construed as a substantive limitation. A commercial active pharmaceutical ingredient, however, would ordinarily be isolated and purified before use in a drug product. As a result, claims 3 and 4 are commercially relevant even though they are narrower than claims 1 and 2.

Purity disputes would likely turn on:

• The patent specification;
• The ordinary meaning of “purified”;
• The purity level of the accused product;
• The presence of sequence-related impurities;
• The analytical method used; and
• The prosecution history.

What do claims 7 and 11 require?

Claims 7 and 11 require that the Phe or Trp peptide activate the GC-C receptor. These are functional limitations tied to specific sequence embodiments.

The claims do not identify a particular assay, potency threshold, concentration, or receptor-response measurement in the claim text provided. The specification and prosecution history would determine whether the limitation is interpreted broadly as any demonstrable activation or more narrowly by reference to an assay and activity level.

The GC-C limitation is not required by claims 1, 2, 5, 6, 9, or 10. A challenger therefore cannot avoid every sequence claim merely by disputing receptor activity.

What pharmaceutical formulations are protected?

The patent’s composition claims are broad. Claims 8, 12, and 13 through 16 require a covered peptide or salt plus a pharmaceutically acceptable carrier or excipient.

They do not require:

• An enteric coating;
• A specific tablet or capsule;
• A particular pH;
• A particular buffer;
• A specific stabilizer;
• A defined release time;
• A specific particle size;
• A particular dose;
• A particular dosing schedule; or
• A particular route of administration.

The composition claims could therefore reach a wide range of conventional pharmaceutical presentations containing the covered peptide. They are not limited to the commercial formulation of Linzess unless that formulation also falls within separate formulation claims in other patents.

What is the relationship between this patent and Linzess?

Linzess is the U.S. brand name for linaclotide, marketed by Ironwood Pharmaceuticals and AbbVie. The FDA approved Linzess in 2012 for adults with irritable bowel syndrome with constipation and chronic idiopathic constipation. FDA later expanded the label to include pediatric patients in specified age groups and indications. The approved product is an orally administered peptide drug that acts locally in the intestinal tract through GC-C activation. [2]

U.S. Patent 7,704,947 is a drug-substance and composition patent. It is distinct from later patents that may cover:

• Specific pharmaceutical formulations;
• Stability improvements;
• Dosing regimens;
• Pediatric use;
• Manufacturing processes;
• Crystalline or solid-state forms, where applicable; and
• Particular treatment methods.

A generic linaclotide applicant would need to assess the full Orange Book-listed patent set, not only U.S. Patent 7,704,947.

When does U.S. Patent 7,704,947 lose exclusivity?

The patent issued on April 27, 2010. Its effective expiration is governed by the patent-term calculation, including the earliest relevant nonprovisional filing date, any terminal disclaimer, patent-term adjustment, and any patent-term extension.

The patent is part of the linaclotide patent family and should be analyzed against the FDA’s Orange Book listing for Linzess and the USPTO’s official Patent Center and Patent Examination Data System records. The operative commercial date may differ from the nominal 20-year term if the patent received patent-term extension or if its term is subject to a terminal disclaimer.

A precise expiration date cannot be established from the claim text alone. The controlling sources are:

1. The face of U.S. Patent 7,704,947;
2. The patent’s continuity data;
3. The terminal-disclaimer record, if any;
4. USPTO patent-term adjustment and extension records; and
5. The FDA Orange Book entry for the approved linaclotide product.

What is the FDA and Orange Book status?

Linzess was approved under an NDA rather than a biologics license application. Linaclotide is a chemically synthesized peptide drug, so follow-on products generally proceed through the abbreviated new drug application pathway rather than the biosimilar pathway.

The Orange Book analysis should distinguish between:

Regulatory protection	Relevance
New chemical entity exclusivity	Initially delayed abbreviated approval eligibility
Patent listings	May support Paragraph IV litigation
Pediatric exclusivity	May extend applicable exclusivity or patent protection where granted
Formulation patents	May create additional launch barriers
Method-of-use patents	May affect labeled indications and carve-out strategy
Drug-substance patents	May block commercial manufacture or sale of the active peptide

U.S. Patent 7,704,947 is most relevant as a drug-substance and composition patent. Orange Book listing status, however, depends on FDA listing decisions and the patent information submitted for the NDA.

Have generic manufacturers challenged linaclotide patents?

Generic linaclotide competition has involved ANDA applicants and Paragraph IV certification risk. A Paragraph IV certification alleges that an Orange Book-listed patent is invalid, unenforceable, or would not be infringed by the proposed generic product.

The commercial consequences are substantial:

• A Paragraph IV notice can trigger Hatch-Waxman litigation.
• Filing suit within the statutory period can create a 30-month stay of FDA approval, subject to statutory exceptions.
• A settlement can establish a negotiated launch date before patent expiration.
• A successful invalidity or noninfringement judgment can remove the relevant patent barrier.
• A settlement may preserve other formulation or method-of-use barriers even if a drug-substance patent is defeated.

The relevant competitive diligence must identify each ANDA applicant, the patents challenged, the filing date of the litigation, the asserted claims, dismissal terms, and any agreed entry date. A patent-by-patent review is necessary because a settlement involving one patent does not necessarily resolve the full Linzess patent estate.

Is there biosimilar risk for linaclotide?

No conventional biosimilar pathway applies. Linaclotide is regulated as a drug under an NDA, not as a biological product under a BLA.

The competitive risk is therefore generic or follow-on peptide competition through an ANDA or, depending on product characteristics and FDA requirements, another drug application pathway. The key barriers are:

• Exact-sequence synthesis;
• Correct disulfide pairing;
• Peptide purity;
• Impurity profiling;
• Bioactivity and analytical comparability;
• Manufacturing scale;
• CMC documentation;
• Patent certification; and
• FDA approval of the proposed labeling.

Although linaclotide is a peptide, it does not automatically receive biologic exclusivity or require a biosimilar application.

How strong is the patent estate represented by U.S. Patent 7,704,947?

The patent is strong against an exact-sequence linaclotide product during its enforceable term because the core claims identify the active peptide by sequence. The principal strengths are:

• Direct coverage of the commercial Tyr sequence;
• Coverage of purified peptide;
• Coverage of pharmaceutically acceptable salts;
• Composition coverage;
• A genus claim covering three specified variants; and
• No requirement in the principal sequence claims to prove a particular therapeutic indication.

The principal limitations are:

• The sequence genus is narrow;
• Position 4 is limited to three amino acids;
• The patent does not expressly claim every formulation;
• The patent does not expressly claim every treatment method;
• “Purified” may create claim-construction issues in dependent claims; and
• Patent-term expiration eliminates the practical value of otherwise broad substance claims.

A generic linaclotide product with the exact Tyr sequence would face the highest direct infringement exposure. A modified peptide with a residue change outside the claimed set would present a stronger noninfringement position but could raise doctrine-of-equivalents and regulatory comparability issues.

How does this patent compare with formulation and method-of-use patents?

Patent category	Typical protected subject matter	Risk to generic
Drug-substance patent	Linaclotide sequence and analogues	High if exact sequence is used before expiry
Composition patent	Peptide plus carrier or excipient	High for covered formulations
Formulation patent	Enteric delivery, stability, release, or excipient system	Product-specific
Method-of-use patent	Treatment of constipation or IBS-C	Potentially avoidable through label carve-outs
Manufacturing patent	Synthesis, folding, oxidation, purification, or isolation	Process-specific
Regulatory exclusivity	FDA approval-based market protection	Time-limited and separate from patent validity

The patent supplied by the user is most important for the active peptide itself. It should not be treated as a complete statement of the Linzess exclusivity position.

What generic launch scenarios exist?

Three practical scenarios dominate:

1. Launch after patent expiry. The generic applicant waits until all enforceable substance and composition barriers expire or are resolved.
2. Settlement-based early launch. The applicant receives a negotiated entry date from the patent holder before the latest asserted patent expiry.
3. Litigation victory. The applicant launches after prevailing on invalidity, unenforceability, or noninfringement.

A fourth possibility is a design-around using a sequence outside the claimed Phe/Trp/Tyr set. That strategy would have to address whether the redesigned peptide remains therapeutically and regulatorily equivalent to linaclotide.

Key Takeaways

• U.S. Patent 7,704,947 claims a 14-amino-acid GC-C agonist peptide genus with Phe, Trp, or Tyr at position 4.
• Linaclotide is the Tyr-containing embodiment and is directly implicated by claims 1 through 4 and 13 through 14.
• Claims 5 through 8 cover the Phe analogue; claims 9 through 12 cover the Trp analogue.
• The patent covers peptide substance, purified peptide, pharmaceutically acceptable salts, and pharmaceutical compositions.
• It does not, based on the supplied claims, recite a specific dosage form, excipient system, treatment indication, manufacturing process, or release profile.
• Linaclotide is an NDA drug, not a biologic. Follow-on competition is principally a generic ANDA issue, not a biosimilar issue.
• The commercial freedom-to-operate analysis must include all Orange Book-listed Linzess patents, FDA exclusivity, Paragraph IV certifications, litigation settlements, and any formulation or method-of-use patents.
• The exact effective expiration date must be taken from the official USPTO and FDA records because patent-term adjustment, patent-term extension, and terminal-disclaimer data can alter the nominal term.

FAQs

Does U.S. Patent 7,704,947 cover the commercial linaclotide sequence?

Yes. Linaclotide contains Tyr at the variable fourth position and falls within the sequence genus of claim 1 and the exact-sequence coverage of claims 2 and 14.

Does the patent cover a linaclotide tablet with any excipient?

Potentially, if the tablet contains a covered peptide or salt and the excipient is pharmaceutically acceptable. Claims 8 and 13 through 16 are composition claims, but the applicable claim depends on whether the product contains the Tyr, Phe, or Trp embodiment.

Can a generic avoid the patent by changing the disulfide bonds?

Changing disulfide connectivity could support a noninfringement argument, but it may also eliminate the structure and activity required for a commercially viable linaclotide equivalent. The outcome would depend on claim construction, product characterization, and the doctrine of equivalents.

Is a Phe-containing peptide the same drug as linaclotide?

No. The Phe analogue is a separate sequence embodiment. It is covered by claims 5 through 8 but is not the commercial Tyr-containing linaclotide sequence.

Are manufacturing patents more important after the sequence patent expires?

They can be. After expiry of a core drug-substance patent, process patents may remain relevant if the generic uses the patented synthesis, folding, oxidation, purification, or isolation process. Their practical value depends on whether noninfringing manufacturing routes are available.

References

1. United States Patent and Trademark Office. (2010). U.S. Patent No. 7,704,947, peptides as guanylate cyclase C agonists.
2. U.S. Food and Drug Administration. (2023). Linzess (linaclotide) prescribing information.
3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
4. U.S. Food and Drug Administration. (2024). Approved drug product exclusivity and patent information.
5. United States Patent and Trademark Office. (2024). Patent Center and patent term adjustment information.

Drugs Protected by US Patent 7,704,947

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 7,704,947

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1594517		300593	Netherlands
European Patent Office	1594517		C300593	Netherlands
European Patent Office	1594517		CA 2013 00026	Denmark
European Patent Office	1594517		PA2013013	Lithuania
European Patent Office	1594517		92200	Luxembourg
European Patent Office	1594517		1390024-6	Sweden
European Patent Office	2246360		C300594	Netherlands