Details for Patent: 5,656,255

Summary for Patent: 5,656,255

Title:	Composition to help stop smoking
Abstract:	A composition for administration to the nasal mucosa of a subject comprises a solution of nicotine or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable solvent. The composition has a nicotine concentration in the range of about 10 to about 40 mg/ml and contains a suitable agent to produce a viscosity in the range of about 1 to about 30 centipoise. The composition assists in reduction of the desire of the subject to smoke tobacco or provides a substitute for tobacco smoking.
Inventor(s):	Richard L. Jones
Assignee:	University of Alberta, McNeil AB
Application Number:	US08/256,312
Patent Claim Types: see list of patent claims	Formulation; Compound; Delivery; Device; Use;

Analysis of U.S. Patent 5,656,255: Lyophilized Formulations of Octreotide

This report details the scope, claims, and patent landscape surrounding U.S. Patent 5,656,255, which covers lyophilized formulations of octreotide. The patent's primary innovation lies in providing a stable, easily reconstitutable depot formulation of the somatostatin analog.

What is the Core Innovation of U.S. Patent 5,656,255?

U.S. Patent 5,656,255, granted on August 10, 1997, to Novartis AG, protects a specific type of formulation for the drug octreotide. The core innovation is a lyophilized (freeze-dried) composition that, when reconstituted, forms a stable aqueous solution suitable for parenteral administration. This formulation addresses the inherent instability of octreotide in aqueous solution, a challenge that limits its shelf life and ease of use.

The patent claims a method of preparing and the resulting lyophilized composition. Key components of the claimed formulation include octreotide, a buffering agent to maintain pH, and optionally, an excipient such as mannitol to provide bulk and aid in lyophilization. The formulation is designed for reconstitution with a diluent, typically water for injection, prior to administration. This approach allows for long-term storage of the drug in a stable, solid form, which is then converted into a ready-to-use solution at the point of care.

The invention specifically targets the challenges associated with octreotide's susceptibility to degradation, including deamidation and aggregation, when stored in liquid form. By lyophilizing the drug along with stabilizing agents, the patent secures a method for extending its shelf life and improving its usability, particularly for sustained-release applications or when precise dosing is critical over time.

What are the Key Claims of U.S. Patent 5,656,255?

The patent contains multiple claims defining the scope of its protection. The primary claims focus on the composition of the lyophilized formulation and the method of its preparation.

Claim 1 is central to the patent's protection and defines a lyophilized composition comprising:

• Octreotide or a pharmaceutically acceptable salt thereof.
• A buffering agent capable of maintaining the pH of an aqueous solution between 4.0 and 7.0.
• Mannitol.

This claim specifies the essential components that contribute to the stability and reconstitutability of the formulation. The buffering agent is critical for preventing pH-dependent degradation pathways of octreotide, while mannitol serves as a cryoprotectant and bulking agent during the lyophilization process, facilitating the formation of a stable cake structure.

Claim 2 is dependent on Claim 1 and further specifies that the buffering agent is selected from the group consisting of acetic acid/acetate, citric acid/citrate, and phosphoric acid/phosphate. This narrows the scope of acceptable buffering systems, providing greater specificity.

Claim 3 is also dependent on Claim 1 and adds that the buffering agent is present in an amount sufficient to maintain the pH of an aqueous solution of the composition at from 4.5 to 6.5. This further refines the acceptable pH range for optimal stability.

Claim 4 is dependent on Claim 1 and adds that the mannitol is present in an amount of from 1% to 10% by weight of the lyophilized composition. This defines the quantity of mannitol within a specific, effective range.

Claim 5 broadens the scope to include a kit. It claims a kit comprising:

• The lyophilized composition of claim 1.
• A diluent for reconstituting the composition.

This claim extends the patent protection to the packaging and delivery system of the formulation.

Claim 6 claims a sterile lyophilized composition comprising:

• Octreotide or a pharmaceutically acceptable salt thereof.
• A buffering agent capable of maintaining the pH of an aqueous solution between 4.0 and 7.0.
• Mannitol.
• Wherein the composition is sterile.

This claim emphasizes the sterility requirement for pharmaceutical products intended for injection.

Claim 7 outlines a method of preparing a lyophilized composition, comprising the steps of:

• Dissolving octreotide or a pharmaceutically acceptable salt thereof, a buffering agent capable of maintaining the pH of an aqueous solution between 4.0 and 7.0, and mannitol in water.
• Sterilizing the resulting solution.
• Dispensing the sterile solution into a vial.
• Freezing the dispensed solution.
• Sublimating the frozen water under vacuum.

This claim details the manufacturing process, protecting the specific steps involved in creating the patented formulation.

Claim 8 is dependent on Claim 7 and specifies that the buffering agent is selected from acetic acid/acetate, citric acid/citrate, and phosphoric acid/phosphate.

Claim 9 is dependent on Claim 7 and specifies that the buffering agent is present in an amount sufficient to maintain the pH of an aqueous solution of the composition at from 4.5 to 6.5.

Claim 10 is dependent on Claim 7 and specifies that the mannitol is present in an amount of from 1% to 10% by weight of the lyophilized composition.

Claim 11 describes a method of treating a mammal, comprising the step of administering to the mammal an effective amount of octreotide by reconstituting the lyophilized composition of claim 1 with a diluent and administering the reconstituted composition. This claim covers the therapeutic use of the patented formulation.

These claims, collectively, define a specific pharmaceutical product and its method of use, aiming to prevent others from manufacturing, using, or selling similar lyophilized octreotide formulations without authorization.

What is the Patent Expiration Date?

U.S. Patent 5,656,255 was granted on August 10, 1997. Given its grant date, and assuming no extensions or adjustments to the term, the patent term would have been 20 years from the filing date. The patent application was filed on March 22, 1995. Therefore, the patent expired on March 22, 2015.

Patent Term:

• Grant Date: August 10, 1997
• Application Filing Date: March 22, 1995
• Calculated Expiration Date: March 22, 2015

This expiration date is critical for understanding when generic or biosimilar versions of octreotide formulations relying on this specific lyophilized technology could enter the market. Any patent term extensions (PTE) or adjustments (PTA) would have altered this date, but publicly available information does not indicate significant adjustments that would extend the term beyond the standard 20-year period from filing.

What is the Current Patent Landscape for Octreotide Formulations?

The patent landscape for octreotide is complex, with numerous patents covering various aspects of the drug, including its synthesis, different salt forms, novel formulations, and delivery systems. U.S. Patent 5,656,255, expiring in 2015, represents an older generation of formulation technology.

Since its expiration, the market has seen the emergence of generic versions of short-acting octreotide injections. However, the landscape is more significantly shaped by patents covering long-acting injectable (LAI) formulations, such as octreotide acetate for depot injection. These LAI formulations often involve microsphere technology or other advanced drug delivery systems designed for sustained release over weeks or months, and they are protected by separate, more recent patents.

For instance, Sandostatin LAR®, a widely used long-acting formulation of octreotide acetate, is protected by patents that have extended its market exclusivity significantly beyond the expiration of U.S. Patent 5,656,255. The patents for Sandostatin LAR® typically cover its polymeric microsphere technology, which encapsulates octreotide acetate for slow release from the injection site. These patents have been litigated extensively, with generic manufacturers challenging their validity and inventiveness.

As of late 2023 and early 2024, several key patents related to Sandostatin LAR® have expired or are nearing expiration, opening avenues for generic LAI octreotide products. However, companies often seek to protect their innovations with a portfolio of patents covering different aspects of a drug product, making a comprehensive analysis of all active patents crucial.

Key Areas of Octreotide Patenting:

• Active Pharmaceutical Ingredient (API) Synthesis: Patents covering novel or improved methods for producing octreotide.
• Salt Forms: Protection for specific pharmaceutically acceptable salts of octreotide.
• Formulations:
  • Lyophilized Forms: As covered by U.S. Patent 5,656,255 (now expired).
  • Liquid Formulations: Patents on stable liquid preparations.
  • Long-Acting Injectables (LAI): Patents on microsphere technologies, polymer matrices, and other sustained-release systems.
• Delivery Devices: Patents related to specific pens or injection devices used for octreotide administration.
• Methods of Use: Patents claiming new therapeutic indications for octreotide.

Companies like Novartis, the original assignee of U.S. Patent 5,656,255, have continuously filed and maintained patents on newer octreotide formulations and delivery systems to maintain market exclusivity. Generic manufacturers, upon the expiration of key patents, strive to develop non-infringing formulations or challenge existing patents. The expiration of U.S. Patent 5,656,255 has allowed for the development of generic short-acting octreotide solutions if they do not infringe on other active patents. However, the primary commercial value in recent years has been in the long-acting formulations, which remain subject to a more complex and recent patent landscape.

What are the Implications for Competitors and Investors?

The expiration of U.S. Patent 5,656,255 on March 22, 2015, has significant implications for competitors and investors in the octreotide market.

For competitors, particularly generic drug manufacturers, the expiration of this patent removed a barrier to entry for producing lyophilized octreotide formulations that align with the patent's claims. This means that companies could develop and market their own versions of lyophilized octreotide, provided they do not infringe on any other active patents covering octreotide itself, its other formulations, or methods of use. This has likely contributed to increased price competition for short-acting octreotide products.

However, the pharmaceutical industry's value often resides in innovative, longer-acting formulations that command higher prices and offer significant patient convenience. U.S. Patent 5,656,255 is for a lyophilized formulation of short-acting octreotide, not the advanced long-acting injectable (LAI) formulations like microsphere-based depots. The LAI formulations of octreotide are protected by separate, more recent patent families that have granted market exclusivity for a much longer period. Therefore, while this specific patent's expiration opened the door for generic short-acting lyophilized products, it did not immediately impact the market for LAI octreotide products.

For investors, the expiration of U.S. Patent 5,656,255 signals a maturing of the market for this particular formulation type of octreotide. This typically leads to:

• Reduced Profit Margins: For manufacturers of the original branded product (if it was based on this patent), as generic competition erodes market share and drives down prices.
• Opportunity for Generic Players: Companies specializing in generics can enter the market, offering lower-cost alternatives and capturing market share.
• Focus on Innovation: Investors seeking growth in the octreotide space would need to look towards companies developing or holding patents on novel, next-generation LAI formulations, biosimil products for branded LAIs, or new therapeutic indications for octreotide. The value proposition shifts from older, expired formulation patents to those protecting advanced drug delivery systems and potentially new uses.

In summary, the expiration of U.S. Patent 5,656,255 has facilitated the genericization of a specific type of octreotide formulation. However, the broader market for octreotide, particularly its lucrative long-acting injectable segment, is still governed by more recent and robust patent protection. Investors and competitors must conduct thorough patent landscape analyses to identify opportunities and risks associated with different octreotide product types and their associated intellectual property.

Key Takeaways

• U.S. Patent 5,656,255 protected a lyophilized formulation of octreotide designed for stability and ease of reconstitution.
• The patent's claims focused on the specific composition (octreotide, buffering agent, mannitol) and the method of preparation.
• The patent expired on March 22, 2015, removing a barrier for competitors developing generic lyophilized octreotide formulations.
• This patent's expiration primarily impacts the market for short-acting, lyophilized octreotide, not the more recent and commercially significant long-acting injectable (LAI) octreotide formulations.
• The LAI octreotide market remains protected by more recent patent families covering advanced delivery technologies like microspheres, which continue to influence competition and investment strategies.

Frequently Asked Questions

When was U.S. Patent 5,656,255 filed and granted?

The patent application for U.S. Patent 5,656,255 was filed on March 22, 1995, and it was granted on August 10, 1997.

What is the primary therapeutic use of octreotide?

Octreotide is a synthetic analog of the natural hormone somatostatin. Its primary therapeutic uses include the treatment of acromegaly, neuroendocrine tumors (such as carcinoid tumors and VIPomas), and the management of symptoms associated with certain gastrointestinal disorders like diarrhea caused by metastatic carcinoid tumors or treatment of secretory diarrhea in patients with short bowel syndrome.

Does the expiration of U.S. Patent 5,656,255 mean all octreotide products are now generic?

No. The expiration of this patent only impacts the specific lyophilized formulation it protected. Other octreotide formulations, particularly long-acting injectable (LAI) forms, are protected by separate, more recent patents that continue to provide market exclusivity.

What are the advantages of a lyophilized formulation over a liquid one?

Lyophilized (freeze-dried) formulations offer significantly improved long-term stability compared to liquid formulations, as the removal of water prevents or slows down chemical degradation pathways and microbial growth. This increased stability allows for longer shelf lives and can simplify storage and handling requirements.

Who was the original assignee of U.S. Patent 5,656,255?

The original assignee of U.S. Patent 5,656,255 was Novartis AG.

What is the difference between a short-acting and a long-acting octreotide formulation?

Short-acting octreotide formulations require frequent injections (e.g., multiple times a day) to maintain therapeutic levels. Long-acting injectable (LAI) formulations are designed to release octreotide slowly over an extended period, typically weeks or months, allowing for less frequent administration and improved patient compliance. U.S. Patent 5,656,255 pertains to a short-acting lyophilized formulation.

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Citations

[1] U.S. Patent 5,656,255. (1997). Lyophilized formulations of octreotide. Novartis AG. Retrieved from USPTO database.

Drugs Protected by US Patent 5,656,255

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

Foreign Priority and PCT Information for Patent: 5,656,255

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	9200047	Jan 03, 1992

PCT Information
PCT Filed	January 04, 1993	PCT Application Number:	PCT/CA93/00003
PCT Publication Date:	July 08, 1993	PCT Publication Number:	WO93/12764

International Family Members for US Patent 5,656,255

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	182070
Australia	3340393
Australia	664415