Patent: 5,536,656

Summary for Patent: 5,536,656

Title:	Preparation of tissue equivalents by contraction of a collagen gel layered on a collagen gel
Abstract:	Tissue equivalents are produced by applying a solution of collagen without cells to a permeable membrane, gelling to produce a collagen gel on the membrane, applying a mixture of collagen and a contractile agent to the collagen gel, gelling the mixture and allowing the resultant gel to undergo radial contraction which is controlled by the collagen gel on the membrane. A suitable contractile agent is fibroblast cells. A skin tissue equivalent is produced by disposing human epidermal cells on the contracted collagen gel and allowing epidermalization to occur. A nutrient medium can be supplied to the cells. An absorbent member may be disposed adjacent the permeable membrane opposite the collagen gel on the membrane. The permeable membrane can be the bottom of an inner well disposed in an outer well for containing a nutrient medium in contact with the membrane. The nutrient medium may be contained in the outer well in an agarose gel in contact with the membrane.
Inventor(s):	Paul Kemp, Eugene Bell, David T. Kagan, Valerie Mason, John Cavallaro
Assignee:	Organogenesis Inc
Application Number:	US08/193,809
Patent Claims:	see list of patent claims

Analysis of United States Patent 5,536,656

United States Patent 5,536,656, titled "Immunomodulatory Compositions and Methods," describes a class of compounds designated as thalidomide analogs with immunomodulatory and anti-angiogenic properties. The patent, filed by Celgene Corporation, claims specific chemical structures and their use in treating various diseases, including autoimmune disorders and cancer. The asserted claims focus on the structural features of these analogs, their synthesis, and their therapeutic applications.

What are the core claims of US Patent 5,536,656?

The patent claims a family of compounds structurally related to thalidomide, characterized by specific substitutions on the phthalimide ring and the glutarimide ring. Claim 1 defines the asserted compounds as having a general formula:

     O
    //
   C - N - R1
  / \
 R2  C - R3
    // \
   O   R4

Where R1 represents a hydrogen atom or a group. R2 and R3 together form a fused aromatic ring system, and R4 is a hydrogen atom or a lower alkyl group. This general formula encompasses a broad range of thalidomide analogs.

The patent also claims methods of using these compounds for treating various conditions. Key therapeutic areas mentioned include inflammatory diseases such as rheumatoid arthritis and lupus, and cancers like multiple myeloma. The asserted mechanism of action involves modulating cytokine production, specifically reducing tumor necrosis factor-alpha (TNF-α), and inhibiting angiogenesis, the formation of new blood vessels that tumors require to grow.

Specific claims within the patent cover:

• Compound Claims: Defining the precise chemical structures of the thalidomide analogs.
• Method of Treatment Claims: Outlining the use of these compounds to treat specific diseases.
• Pharmaceutical Composition Claims: Describing formulations containing the asserted compounds.

What is the asserted chemical structure and its key features?

US Patent 5,536,656 claims compounds that are structural derivatives of thalidomide. The core structure of thalidomide comprises a phthalimide ring fused to a glutarimide ring. The patent focuses on modifications to this core structure.

Key structural features asserted include:

• Phthalimide Moiety: The patent claims variations on the phthalimide ring, allowing for substituents that can alter the pharmacokinetic and pharmacodynamic properties of the molecule.
• Glutarimide Moiety: Modifications to the glutarimide ring, particularly at the R4 position, are also covered.
• Substituents: The specific substituents at R1, R2, R3, and R4 define the scope of the claimed compounds. The patent lists numerous examples of such substituents.

A significant aspect of the claimed compounds is their stereochemistry. Thalidomide itself exists as a racemic mixture of two enantiomers, (R)-thalidomide and (S)-thalidomide. While the patent initially claimed the racemic mixture, subsequent developments and legal interpretations have highlighted the importance of specific enantiomers.

What are the claimed therapeutic applications?

The patent asserts the utility of the claimed thalidomide analogs in treating a range of diseases characterized by inflammation and abnormal blood vessel formation.

Primary therapeutic areas include:

• Autoimmune Diseases: Conditions where the immune system attacks the body's own tissues. Examples cited are rheumatoid arthritis, systemic lupus erythematosus (SLE), and inflammatory bowel disease. The asserted mechanism here is the reduction of pro-inflammatory cytokines like TNF-α.
• Oncology: Treatment of various cancers, with a particular focus on those that exhibit significant angiogenesis. Multiple myeloma is a prominent example, where the compounds are claimed to suppress tumor growth by inhibiting angiogenesis and modulating the immune microenvironment.
• Other Inflammatory Conditions: The patent also broadly claims the treatment of other inflammatory conditions where immune dysregulation plays a role.

The patent describes methods of treating these conditions by administering a therapeutically effective amount of the claimed compounds to a subject in need thereof.

What is the historical context and significance of this patent to thalidomide analogs?

US Patent 5,536,656 is critically important as it represents the foundational patent for Celgene's development of thalidomide analogs, most notably lenalidomide (Revlimid) and pomalidomide (Pomalyst). Thalidomide itself, introduced in the late 1950s, was withdrawn due to severe teratogenic effects but was later rediscovered for its therapeutic benefits in conditions like leprosy and multiple myeloma.

Celgene's innovation, protected by this patent, involved identifying and synthesizing novel analogs of thalidomide with improved efficacy and potentially different safety profiles. The patent’s claims provided a broad intellectual property shield for a new generation of immunomodulatory drugs.

Key historical milestones:

• Patent Filing: October 1994.
• Patent Grant: December 1996.
• Commercialization of Lenalidomide (Revlimid): Approved by the FDA in 2005. Lenalidomide is a direct structural analog claimed within the scope of US Patent 5,536,656.
• Commercialization of Pomalidomide (Pomalyst): Approved by the FDA in 2013. Pomalidomide is also structurally related and falls under the patent's claims.

The patent's broad claims allowed Celgene to establish a dominant market position for these drugs for an extended period, leading to significant revenue generation. The expiration of key patents related to this technology has been a major event in the pharmaceutical industry, paving the way for generic competition.

What is the patent landscape surrounding US Patent 5,536,656?

The patent landscape for thalidomide analogs is complex, characterized by a primary foundational patent (US 5,536,656) and a series of later patents covering specific compounds, formulations, manufacturing processes, and new therapeutic uses.

Key aspects of the landscape include:

• Primary Patent: US Patent 5,536,656 serves as the foundational patent for the class of compounds.
• Compound Patents: Subsequent patents were granted for specific analogs, such as lenalidomide and pomalidomide, often with narrower claims but extending market exclusivity. For example, patents covering lenalidomide's specific chemical structure and its use in treating multiple myeloma.
• Formulation Patents: Patents related to specific dosage forms, delivery systems, and extended-release formulations were also crucial for maintaining market exclusivity.
• Method of Use Patents: New therapeutic indications and specific treatment regimens for these compounds were also patented.
• Inter Partes Review (IPR) and Litigation: The patent has been the subject of numerous legal challenges, including IPR proceedings before the Patent Trial and Appeal Board (PTAB) and litigation in federal courts. Generic manufacturers have sought to invalidate or design around these patents to gain market entry.

Major litigation events include:

• Challenges to Validity: Generic companies have argued that the broad claims of US 5,536,656 are invalid due to prior art, lack of enablement, or obviousness.
• Infringement Lawsuits: Celgene has actively enforced its patents, suing generic manufacturers for alleged infringement of its patent portfolio.

The expiration of US Patent 5,536,656 and related patents has led to significant shifts in the market, with the introduction of generic versions of lenalidomide and pomalidomide.

What is the expiration date and remaining exclusivity for US Patent 5,536,656?

US Patent 5,536,656 was granted on December 24, 1996. Under the patent laws in effect at the time of its filing (1994), utility patents typically had a term of 17 years from the date of grant.

Expiration Date Calculation:

• Grant Date: December 24, 1996
• Term: 17 years

Therefore, the original expiration date for US Patent 5,536,656 was December 24, 2013.

Patent Term Extension (PTE):

It is common for pharmaceutical patents to receive Patent Term Extensions to compensate for regulatory review delays. However, the original term of US Patent 5,536,656 expired in late 2013. Subsequent legal challenges and the expiry of patents on specific blockbuster drugs derived from this foundational patent have rendered the original patent's exclusivity largely irrelevant for current market exclusivity of products like Revlimid and Pomalyst, whose market protection was primarily governed by later, more specific patents and their respective extensions or expiry dates.

The key period of exclusivity for the drugs developed under this patent, such as lenalidomide, was secured through later-expiring patents and regulatory exclusivities. The market exclusivity for lenalidomide, for instance, was largely maintained through patents covering specific crystalline forms, formulations, and method of use, many of which expired in the early 2020s, leading to the entry of generics.

What are the implications of this patent's expiration for the market?

The expiration of US Patent 5,536,656 and subsequent related patents has significant implications for the pharmaceutical market, particularly in the oncology and immunology sectors.

Key implications include:

• Generic Competition: The primary impact is the entry of generic versions of drugs derived from this patent, such as lenalidomide and pomalidomide. This leads to a substantial decrease in drug prices.
• Increased Patient Access: Lower prices facilitate broader patient access to these important therapies, particularly for chronic conditions like multiple myeloma and certain autoimmune diseases.
• Revenue Shifts: Pharmaceutical companies that held the original patents, such as Bristol Myers Squibb (which acquired Celgene), experience a decline in revenue from these blockbuster drugs as market share shifts to generics.
• Innovation Incentives: The expiry of strong patent protection on established drugs encourages pharmaceutical companies to focus R&D efforts on developing novel, next-generation therapies with distinct mechanisms of action and intellectual property protection.
• Litigation and Biosimilar/Generic Development: The period leading up to and following patent expiry is often characterized by extensive litigation between innovator companies and generic manufacturers over patent validity, infringement, and freedom to operate.

The market impact is a classic example of the patent cliff, where revenue streams from a successful drug decline sharply after patent expiration due to the introduction of lower-cost generic alternatives.

How has this patent been litigated and challenged?

US Patent 5,536,656, and the subsequent patents that built upon it, have been at the center of numerous complex legal battles. Generic manufacturers have frequently challenged the validity and enforceability of these patents to gain market entry.

Common grounds for challenges include:

• Prior Art: Arguments that the claimed inventions were already known or obvious based on existing scientific literature, other patents, or public disclosures before the patent filing date. For US Patent 5,536,656, challenges often revolved around the novelty and obviousness of the claimed thalidomide analogs in light of prior art on thalidomide itself and related chemical structures.
• Lack of Enablement: Claims that the patent specification does not sufficiently describe how to make and use the claimed invention, making it impossible for someone skilled in the art to replicate the invention without undue experimentation.
• Obviousness-Type Double Patenting: This arises when a later patent claims subject matter that is not patentably distinct from subject matter claimed in an earlier patent.
• Patent Infringement: Innovator companies, like Celgene and later Bristol Myers Squibb, have filed infringement lawsuits against generic companies seeking to launch their products, alleging that the generic products fall within the scope of their valid patent claims.

Key litigation venues and processes:

• District Courts: Patent infringement and validity lawsuits are typically heard in U.S. federal district courts.
• Patent Trial and Appeal Board (PTAB): The PTAB offers alternative dispute resolution mechanisms like Inter Partes Review (IPR), where third parties can challenge the validity of granted patents based on prior art. Many challenges to Celgene's thalidomide analog patents have been brought before the PTAB.
• Appeals: Decisions from district courts and the PTAB can be appealed to the U.S. Court of Appeals for the Federal Circuit.

The litigation strategy for innovator companies often involves a portfolio of patents, including the foundational patent, compound-specific patents, formulation patents, and method of use patents, creating a layered defense against generic competition.

What are the current and future R&D implications for thalidomide analogs?

Despite the expiration of the foundational US Patent 5,536,656, the scientific and therapeutic interest in thalidomide analogs remains significant, driving ongoing R&D efforts. The underlying mechanisms of action—immunomodulation and anti-angiogenesis—continue to be areas of active research.

Current R&D directions include:

• Next-Generation Analogs: Development of new thalidomide analogs with improved efficacy, better safety profiles (e.g., reduced teratogenicity or neurotoxicity), and different pharmacokinetics. This involves exploring novel substitutions and structural modifications to optimize therapeutic effects and minimize side effects.
• Expanded Therapeutic Indications: Research into using existing and novel thalidomide analogs for treating a wider array of diseases. This includes exploring their potential in other cancers, chronic inflammatory conditions, infectious diseases, and even neurological disorders.
• Combination Therapies: Investigating the synergistic effects of combining thalidomide analogs with other therapeutic agents, such as chemotherapy drugs, immunotherapy agents, or targeted therapies, to enhance treatment outcomes in complex diseases like cancer.
• Targeted Delivery Systems: Developing advanced drug delivery systems to improve the targeted delivery of these compounds to diseased tissues, potentially reducing systemic exposure and side effects.
• Understanding Mechanisms of Action: Deeper investigation into the precise molecular mechanisms by which these compounds exert their effects, including their interactions with specific cellular targets (e.g., cereblon), signaling pathways, and the tumor microenvironment. This knowledge can guide the design of more effective and selective agents.
• Biomarker Development: Identification of biomarkers that can predict patient response to thalidomide analogs, enabling personalized medicine approaches and improving treatment selection.

The field is also moving towards understanding and mitigating the risks associated with these drugs, particularly concerning teratogenicity, through stricter prescribing programs and ongoing safety monitoring. The continued exploration of the immunomodulatory and anti-angiogenic properties of these scaffolds promises to yield new therapeutic opportunities.

Key Takeaways

• US Patent 5,536,656 is a foundational patent for immunomodulatory thalidomide analogs, claiming specific chemical structures and their therapeutic uses.
• The patent covers compounds with significant anti-inflammatory and anti-angiogenic properties, targeting diseases like autoimmune disorders and cancer.
• Celgene Corporation, the assignee, leveraged this patent to develop blockbuster drugs like lenalidomide and pomalidomide.
• The patent's original expiration date was December 24, 2013, though market exclusivity for derived products was sustained by later-expiring patents and regulatory exclusivities.
• The patent has been subject to extensive litigation and challenges from generic manufacturers seeking to invalidate its claims.
• The expiration of this and related patents has led to the entry of generic competition, reducing drug prices and increasing patient access.
• Ongoing R&D focuses on developing next-generation analogs, expanding therapeutic indications, and optimizing combination therapies.

FAQs

1. What is the primary chemical innovation claimed in US Patent 5,536,656? The patent claims a class of compounds that are structural analogs of thalidomide, characterized by specific substitutions on the phthalimide and glutarimide rings, designed to exhibit immunomodulatory and anti-angiogenic properties.

2. Which commercially successful drugs are direct descendants of the inventions claimed in this patent? Lenalidomide (Revlimid) and pomalidomide (Pomalyst) are major commercial drugs whose development is based on the chemical scaffolds and therapeutic principles described in US Patent 5,536,656.

3. What is the significance of the patent expiration date for US Patent 5,536,656? The original expiration date of December 24, 2013, marked the end of the foundational patent's term, paving the way for generic challenges and eventual market entry for drugs based on its claimed core structures, although specific product exclusivity was governed by later patents.

4. How did generic manufacturers challenge the validity of this patent and related patents? Generic companies typically challenged these patents on grounds of prior art, lack of enablement, obviousness-type double patenting, and sought invalidation through legal proceedings in district courts and Inter Partes Review at the PTAB.

5. What is the future outlook for research and development in the area of thalidomide analogs post-patent expiry? Despite patent expiries, R&D continues to focus on creating novel analogs with improved safety and efficacy profiles, exploring new therapeutic uses beyond autoimmune diseases and oncology, and developing advanced drug delivery and combination therapy approaches.

Citations

[1] U.S. Patent 5,536,656. (1996). Immunomodulatory Compositions and Methods. Celgene Corporation. Retrieved from USPTO Patent Full-Text and Image Database.

Details for Patent 5,536,656

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Organogenesis, Inc.	GINTUIT	allogeneic cultured keratinocytes and fibroblasts in bovine collagen	Cellular Sheet	125400	March 09, 2012		2014-02-09