Who holds the patent for Linaclotide?

Introduction to Linaclotide

Linaclotide is a synthetic 14‐amino acid peptide that has emerged as a first‐in-class therapeutic agent primarily indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). Its unique structure and mechanism of action have made it a subject of extensive research and development, leading to an expansive and multifaceted patent portfolio. The innovation around linaclotide encompasses its molecule as well as numerous manufacturing, purification, formulation, and composition methods. 

Drug Overview and Uses

From a therapeutic standpoint, linaclotide is recognized for its ability to alleviate symptoms associated with constipation-related gastrointestinal disorders. It is administered orally and is available in multiple dosage forms, notably the capsules (72 mcg, 145 mcg, and 290 mcg) marketed under brand names such as LINZESS and CONSTELLA in different global markets. Clinically, linaclotide not only improves bowel movements by stimulating intestinal fluid secretion and accelerating gut transit but is also noted for its potential to reduce abdominal pain—an attribute that has been extensively validated in phase 2 and phase 3 clinical trials. Its mechanism of action is localized to the intestinal epithelium, where it acts as a guanylate cyclase-C (GC-C) agonist, a feature that minimizes systemic absorption and thereby reduces the risk of significant systemic adverse events.

Mechanism of Action

Linaclotide functions by binding to the GC-C receptors on the luminal surface of the intestinal epithelium. This binding results in an elevation of intracellular and extracellular cyclic guanosine monophosphate (cGMP) levels. The rise in cGMP then triggers chloride and bicarbonate secretion through the activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channels. This ionic secretion not only increases luminal fluid, which facilitates stool softening, but also accelerates intestinal transit, effectively addressing constipation. Additionally, linaclotide’s effect on extracellular cGMP is hypothesized to contribute to the modulation of afferent pain pathways in the gut, thereby attenuating abdominal pain, though the clinical relevance of this analgesic effect primarily rests on nonclinical models. 

Patent Information for Linaclotide

The intellectual property landscape for linaclotide is both extensive and complex. There is no single patent holder for all aspects of linaclotide; instead, multiple entities have secured rights over different facets of its discovery, synthesis, formulation, and commercialization. These patents span methods of synthesis, purification, manufacturing process optimizations, and even novel formulations such as delayed release and stable low-dose compositions.

Patent Holders

Different organizations hold patents for various innovations related to linaclotide, reflecting the multidisciplinary approaches and the evolution of production techniques over time. The patent holders include but are not limited to: 

- Hangzhou Xinhai Pharmaceutical Technology Co., Ltd.: This company has been granted patents covering specific preparation methods of linaclotide. For example, one patent describes a preparation method that utilizes cystine compounds with protective groups for directed disulfide bond formation, ensuring high purity and yield. 

- Jiangsu Notai Aosaino Biopharmaceutical Co., Ltd.: This entity holds patents primarily focusing on methods for purifying linaclotide, particularly through innovative HPLC techniques that significantly improve yield and purity in a one‐step purification process. 

- FRESENIUS KABI IPSUM S.R.L.: With a focus on process improvements, this company holds patents associated with oxidative folding methods that utilize aqueous solutions with fluorinated alcohol for the preparation of linaclotide.

- AURO PEPTIDES LTD.: AURO PEPTIDES LTD. is another important patent holder in this space, with patents covering processes that combine air and oxidizing agents to oxidize the linear peptide, followed by purification using RP-HPLC methods.

- Sichuan Qinghua University: Reflecting academic contributions to the field, a patent held by this institution describes a preparation method using a solid phase and liquid phase hybrid method that minimizes disulfide bond mispairing and reduces purification steps.

- CHEMI SPA: This company is responsible for patents emphasizing the production of high-purity linaclotide and its acetate salt, with stringent chromatographic purity specifications (≥99.9%) and innovative analytical methods such as ion-pairing chromatography.

- Chengdu Pinhe Technology Co., Ltd.: In its patent holdings, Chengdu Pinhe has described a linaclotide compound composition that combines the peptide with bifidobacteria for use in treating constipation diseases, representing a novel combined drug mode.

- IRONWOOD PHARMACEUTICALS, INC. and FOREST LABORATORIES HOLDINGS LIMITED: In the United States and certain other markets, the key composition of matter patents and formulation inventions (including low-dose stable formulations and delayed-release compositions) are predominantly held by IRONWOOD along with its partners such as FOREST LABORATORIES. These patents cover both the original linaclotide molecule and further improvements related to the oral capsule formulations. 

- Suzhou Tianma Pharmaceutical Group Tianji Biopharmaceutical Co., Ltd.: This company holds patents related to the preparation method of linaclotide that involve specific process parameters, such as pH control and fluidized bed coating granulation, which improve the stability and quality of the final product.

- ASTELLAS PHARMA, INC.: Through patents concerning granular pharmaceutical compositions, ASTELLAS has also secured rights on formulations that feature a damp-proofing function layer to ensure stability and prolonged shelf-life.

- Suzhou Zhonghua Pharmaceutical Industry Co., Ltd.: The company owns patents for capsule preparations that exhibit improved stability under both initial and storage conditions, marking its contribution in the alternative formulation strategies.

- Hantep BioPharmaceutical Group Co., Ltd.: This company holds patents that describe methods for preparing linaclotide using solid-liquid combination techniques that can efficiently avoid impurity generation and reduce production costs.

This diverse set of patent holders illustrates that the technological advancements around linaclotide are not owned by a single entity but rather by multiple companies and research institutions contributing various aspects of its overall production and formulation processes. 

Patent Numbers and Details

A closer look at the patent numbers provides further insight into the breadth of innovation and intellectual property protection surrounding linaclotide. The following details summarize several examples:

- CN113754735B: Granted to Hangzhou Xinhai Pharmaceutical Technology Co., Ltd., this patent describes a preparation method of linaclotide that ensures accurate disulfide bond formation, high product yield, and purity under mild oxidation conditions. The patent emphasizes the use of specific cystine protective groups and one-step directional bridging strategies.

- CN117946217A: This patent by Jiangsu Notai Aosaino Biopharmaceutical Co., Ltd. outlines a purification method using a microporous filter and HPLC with specific mobile phase compositions, significantly enhancing the throughput and efficiency of linaclotide production.

- WO2023144292A1: Filed by FRESENIUS KABI IPSUM S.R.L., this international patent application covers a process for linaclotide preparation employing oxidative folding in the presence of oxidants and a fluorinated alcohol in an aqueous system; it is designed to optimize the folding step to yield the target peptide.

- US11572386B2: Granted to AURO PEPTIDES LTD., this patent details a process for preparing linaclotide that uses a combination of air and oxidizing agents for the oxidation of the linear peptide, followed by RP-HPLC purification, thus addressing challenges in achieving consistent cyclic peptide formation.

- CN115894630A: This filing from Sichuan Qinghua University introduces a solid-liquid combination synthesis method that constructs three select disulfide bonds with reduced purification steps, resulting in an improved overall yield of linaclotide.

- WO2023110781A1: Issued to CHEMI SPA, this patent relates to a manufacturing process for linaclotide and its acetate salt, with a focus on attaining high chromatographic purity (≥99.9%) and minimal impurity levels through advanced analytical techniques.

- CN110935007B: This patent held by Chengdu Pinhe Technology Co., Ltd. discloses a linaclotide compound composition that incorporates bifidobacteria, indicating a combined therapeutic approach for constipation and related diseases.

- US20240075094A1: A patent filed by IRONWOOD PHARMACEUTICALS, INC. and FOREST LABORATORIES HOLDINGS LIMITED concerning low-dose stable formulations of linaclotide. This patent focuses specifically on the stability and formulation challenges, ensuring that the product retains efficacy and safety over time.

- US20230398173A1 and US20230142270A1: These patents, also held by IRONWOOD PHARMACEUTICALS, INC. in collaboration with FOREST LABORATORIES HOLDINGS LIMITED, deal with delayed release pharmaceutical compositions of linaclotide. They target modifications to the release profile of the active ingredient, ensuring that the therapeutic effects are sustained throughout the gastrointestinal tract.

- CN117482210A: Filed by Suzhou Tianma Pharmaceutical Group Tianji Biopharmaceutical Co., Ltd., this patent covers a fluidized bed coating granulation process aimed at improving the stability of linaclotide during storage and transportation.

- US20230113303A1: This innovation is assigned to ASTELLAS PHARMA, INC., describing granular pharmaceutical compositions that incorporate layers designed to protect the active ingredient from moisture, thus enhancing the product’s stability and shelf-life.

- CN114632141B: A patent granted to Suzhou Zhonghua Pharmaceutical Industry Co., Ltd. pertains to a capsule preparation that demonstrates enhanced stability based on rigorous testing under varied abbreviated humidity and temperature conditions.

- CN111499693B: Owned by Hantep BioPharmaceutical Group Co., Ltd., this patent outlines a solid-liquid combination method that improves the purity of the crude peptide, minimizes impurity peptides, and reduces the overall production cost.

Together, these patent numbers and details provide a comprehensive view of how the patent landscape for linaclotide is segmented by innovation type, geographical coverage, and technological focus. Each patent contributes uniquely to the robust portfolio that covers everything from the molecule’s process chemistry to the final dosage forms delivered to patients.

Legal and Business Implications

The multi-faceted patent portfolio of linaclotide has significant implications for the legal and business landscapes of its commercial exploitation. Given that the patent rights are held by a diverse group of entities, including both established pharmaceutical companies and academic institutions, the competitive dynamics are complex and layered. Additionally, the licensing agreements and strategic partnerships formed based on these patents have a direct impact on market competitiveness and future innovation.

Licensing Agreements

One of the key aspects highlighted in various annual reports and industry analyses is the role of licensing in consolidating the market position of linaclotide. For instance, IRONWOOD PHARMACEUTICALS, INC., which holds core composition-of-matter patents in the United States, has entered into considerable licensing and collaboration agreements with other companies such as AbbVie and FOREST LABORATORIES HOLDINGS LIMITED. Such agreements ensure that while IRONWOOD holds the foundational patents on the molecule, partners in different geographic regions or with specialized manufacturing capabilities can contribute to the further development, regulatory approval, and commercialization of the product.

These licensing agreements typically cover not only the core molecule but also extend to process improvements, formulation innovations, and even new delivery modalities such as delayed release systems. Licensing and partnership strategies are crucial in a sector where extensive patent coverage (often involving multiple patents across different jurisdictions) plays a major role in determining market exclusivity. Notably, the agreements often feature options for milestone payments, royalties, and shared responsibilities in regulatory affairs, which affect business valuation and long-term market strategies.

Market Impact

The patent portfolio’s breadth directly translates into market power. A diverse patent landscape allows the patent holders to block or delay market entries by generic competitors effectively. For example, the composition-of-matter patents held by IRONWOOD Pharmaceuticals, combined with supplementary patents on formulation and manufacturing methods, create multiple layers of protection that generic manufacturers must navigate. This multi-layered patent strategy is part of a broader trend where patent clusters are used to prolong exclusivity, thereby ensuring higher returns on investment for the original developers.

Furthermore, the strategic alliances based on these patents have implications for market dynamics. Collaboration partners such as FOREST LABORATORIES, along with regional partnerships established in Europe (for example, with companies like AbbVie and Astellas in Japan), help ensure that linaclotide is marketed globally with robust legal backing. Such arrangements not only prolong the market exclusivity period through patent term extensions but also bolster the brand’s profile by leveraging the strengths of each partner in their respective markets. The business implications extend beyond mere market entry barriers; they also affect pricing strategies, reimbursement negotiations with health care systems, and long-term developmental investments in improving the product.

Future Prospects and Research

The current patent landscape for linaclotide suggests both significant ongoing research efforts and challenges related to patent expiration. Multiple stakeholders continue to innovate within their respective niches, ensuring that the pipeline for linaclotide-related products remains vibrant. From formulation innovations designed to improve stability to new methods of synthesis that reduce costs, the future of linaclotide is closely tied to its evolving intellectual property protection strategy.

Upcoming Patent Expirations

Patent expiration dates are pivotal for both innovators and potential generic entrants. For linaclotide, while some core patents—particularly the composition-of-matter patents—are still under extension in key markets like the United States (with IRONWOOD’s U.S. composition-of-matter patent extended to 2026 in some cases), other patents covering specific manufacturing processes or formulations may expire sooner. For instance, several patents filed by academic institutions and smaller companies (such as those from Hangzhou Xinhai Pharmaceutical Technology Co., Ltd. or Jiangsu Notai Aosaino Biopharmaceutical Co., Ltd.) have defined expiration dates that could potentially open the door for generic competition if sufficient alternatives for the manufacturing process are not developed.

In addition, the global nature of the patent portfolio means that while one jurisdiction’s patent may expire, others in Europe, Japan, or China may still be active, prolonging market protection. Companies involved in a broad array of patents often seek patent term extensions via regulatory frameworks such as the Hatch-Waxman Act in the United States, thus effectively prolonging market exclusivity and delaying generic entry. This strategy illustrates the importance of not only the original patents but also of accompanying patents that protect ancillary aspects of the product such as formulation and delivery systems.

New Research and Developments

Ongoing research is actively expanding the applications and formulations of linaclotide. Several patents in the portfolio reflect a continuous effort to improve the product’s stability, minimize adverse effects, and even explore novel therapeutic indications. For instance, newer patents focusing on delayed release formulations and low-dose stable formulations are examples of how the technology around linaclotide is being refined to optimize its clinical performance and patient compliance.

Furthermore, research initiatives are extending beyond formulation improvements to encompass novel therapeutic applications. One particularly innovative patent explores the potential of linaclotide in treating viruses belonging to the coronaviridae family by identifying binding sites using pharmacophore models. Although this represents a significant departure from the conventional gastrointestinal indications, it underscores the broad potential of the peptide based on its molecular interactions. This type of innovative research portends further developments in the use of linaclotide or derivatives thereof in indications beyond just IBS-C and CIC.

Additional research is being pursued in the areas of improved solid state formulations and alternative administration methods that might further enhance the drug’s efficacy while reducing the incidence of typical adverse events such as diarrhea. Academic contributions, as seen in patents and publications from institutions such as Sichuan Qinghua University and through various published papers, also continue to feed into the active research pipeline, potentially offering new manufacturing methods or novel ways to mitigate adverse effects.

Given these ongoing research efforts, the patent portfolio is likely to expand further, with additional filings anticipated that cover new indications, novel formulations, and breakthrough manufacturing methods. This continuous stream of innovation ensures that even as certain patents near expiration, the overall intellectual property landscape remains robust, thus keeping the competitive edge intact for the patent holders.

Conclusion

In conclusion, the patent landscape for linaclotide is inherently complex and multifaceted, reflecting both its clinical importance and the broad range of scientific innovations that have been applied to its development and commercialization. There is no single patent holder for linaclotide; rather, the overall portfolio is shared among various entities, each owning distinct patents that cater to different aspects of the drug’s life cycle:

- Hangzhou Xinhai Pharmaceutical Technology Co., Ltd. and Jiangsu Notai Aosaino Biopharmaceutical Co., Ltd. are focused on innovative preparation and purification methods. 
- FRESENIUS KABI IPSUM S.R.L. and AURO PEPTIDES LTD. hold patents that refine the oxidation and folding processes critical to achieving the desired peptide structure. 
- Academic institutions like Sichuan Qinghua University contribute with novel synthesis strategies that improve yield and reduce costs. 
- CHEMI SPA enhances manufacturing quality with high purity specifications. 
- Chengdu Pinhe Technology Co., Ltd. has introduced innovative combined formulations using bifidobacteria. 
- IRONWOOD PHARMACEUTICALS, INC. (in collaboration with FOREST LABORATORIES HOLDINGS LIMITED) serves as the primary holder for core composition-of-matter and advanced formulation patents, particularly in the United States, underlining the commercial backbone of linaclotide’s global market presence. 
- Additional contributions by Suzhou Tianma Pharmaceutical Group Tianji Biopharmaceutical Co., Ltd., ASTELLAS PHARMA, INC., Suzhou Zhonghua Pharmaceutical Industry Co., Ltd., and Hantep BioPharmaceutical Group Co., Ltd. further consolidate the range of protected technologies that underlie the manufacturing, stabilization, and delivery of linaclotide.

Legally and commercially, this layered and diverse patent portfolio not only safeguards the innovation of the original molecule but also extends the product’s exclusivity through successive process and formulation patents, rigorous licensing agreements, and strategic global partnerships. This multi-dimensional protection significantly impacts market entry strategies, pricing, and long-term profitability. Moreover, ongoing research and new patent filings indicate that while some patents are approaching expiration, continuous innovation is likely to keep the competitive edge alive for current patent holders.

Thus, in response to the question, "Who holds the patent for Linaclotide?"—the answer is multifaceted: while IRONWOOD PHARMACEUTICALS, INC. (in alliance with partners like FOREST LABORATORIES HOLDINGS LIMITED) is the key holder of the composition-of-matter and major formulation patents, a number of other companies and research institutions also hold important patents covering various preparation, purification, manufacturing, and formulation innovations related to linaclotide. This collective intellectual property portfolio underscores a collaborative and competitive landscape that is central to the continued success and evolution of linaclotide as a therapeutic agent.

In summary, the patent holders for linaclotide come from diverse sectors—ranging from established pharmaceutical companies to academic research institutions—with IRONWOOD Pharmaceuticals, Inc. playing a central role in the core patented technology used in major markets. This multi-holding environment not only enhances the drug’s market protection but also drives innovation, ensuring that linaclotide remains a clinically and commercially viable treatment option for gastrointestinal disorders well into the future.

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