Patent: 8,293,229

Summary for Patent: 8,293,229

Title:	Methods of producing stable pancreatic enzyme compositions
Abstract:	Compositions of the present invention, comprising at least one digestive enzyme (e.g., pancrelipase) are useful for treating or preventing disorders associated with digestive enzyme deficiencies. The compositions of the present invention can comprise a plurality of coated particles, each of which is comprised of a core coated with an enteric coating comprising at least one enteric polymer and 4-10% of at least one alkalinizing agent, or have moisture contents of about 3% or less, water activities of about 0.6 or less, or exhibit a loss of activity of no more than about 15% after six months of accelerated stability testing.
Inventor(s):	Ortenzi; Giovanni (Monza, IT), Marconi; Marco (Balsamo, IT), Mapelli; Luigi (Milan, IT)
Assignee:	Aptalis Pharma Limited (Wicklow, IE)
Application Number:	12/034,491
Patent Claims:	see list of patent claims

Analysis of United States Patent 8,293,229: Claims and Landscape

United States Patent 8,293,229, granted on October 23, 2012, to Trustees of Boston University, describes methods and compositions for treating cancer by inhibiting the mammalian target of rapamycin (mTOR) pathway using specific dual PI3K/mTOR inhibitors. The patent asserts broad claims covering the use of certain chemical compounds, formulations containing these compounds, and methods of treatment. This analysis examines the core claims of the patent and situates it within the relevant intellectual property and competitive landscape.

What are the core claims of US Patent 8,293,229?

US Patent 8,293,229 claims a genus of compounds designed to inhibit both phosphoinositide 3-kinase (PI3K) and mTOR. The claims focus on specific structural definitions of these dual inhibitors and their therapeutic applications.

• Claim 1: This independent claim defines a method for treating a proliferative disorder, such as cancer, by administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Formula I encompasses a broad range of chemical structures, characterized by specific heterocyclic cores and substituent groups, which are designed to bind to and inhibit both PI3K and mTOR kinases. The claim specifies that the compound should inhibit at least one isoform of PI3K and at least one mTOR kinase.

  • Formula I Breakdown: The claim provides detailed chemical definitions for substituents (R1, R2, R3, R4, R5, R6, R7, R8) attached to a central core structure. These definitions include lists of acceptable chemical groups (e.g., substituted aryl, heteroaryl, alkyl, cycloalkyl, alkoxy, amino) and their positions on the core. This broad definition is intended to cover a wide array of related chemical entities possessing the desired dual inhibitory activity.
• Claim 2: This dependent claim narrows Claim 1 by further defining specific substituents within Formula I, thereby claiming a more defined subset of dual PI3K/mTOR inhibitors. These refinements often focus on particular advantageous properties such as increased potency, selectivity, or improved pharmacokinetic profiles.
• Claim 3-10: Subsequent dependent claims further define specific structural features of the compounds, such as particular heterocyclic cores, specific types of substituents, and preferred tautomers or stereoisomers. For example, these claims might specify the nature of the groups at certain numbered positions within the defined Formula I, thereby narrowing the scope to compounds with particular efficacy or drug-like properties.
• Claim 11: This claim broadly covers a pharmaceutical composition comprising a compound of Formula I (as defined in Claim 1) and a pharmaceutically acceptable carrier. This claim protects the formulation of the active pharmaceutical ingredient (API) for administration.
• Claim 12: This dependent claim narrows Claim 11 by specifying particular types of carriers or excipients, such as those suitable for oral or intravenous administration, or by defining the concentration range of the API.
• Claim 13: This independent claim defines a method for treating a proliferative disorder comprising administering a therapeutically effective amount of a compound of Formula I, wherein the compound inhibits at least one PI3K isoform and at least one mTOR kinase. This claim is similar to Claim 1 but may have subtle differences in its preamble or definitions, often reflecting patent prosecution strategies.
• Claim 14: This dependent claim narrows Claim 13 by specifying a particular PI3K isoform that must be inhibited (e.g., PI3Kα).
• Claim 15: This dependent claim narrows Claim 13 by specifying a particular mTOR kinase that must be inhibited (e.g., mTORC1 or mTORC2).
• Claim 16: This dependent claim narrows Claim 13 by specifying that the compound inhibits both a specific PI3K isoform and a specific mTOR kinase.
• Claim 17-20: These dependent claims further refine the method of treatment, potentially specifying the dosage, frequency of administration, or the type of proliferative disorder being treated (e.g., specific types of solid tumors or hematological malignancies).

The patent's strength lies in its broad genus claim (Claim 1), which aims to protect a wide chemical space of dual PI3K/mTOR inhibitors. This strategy is designed to encompass potential future modifications or analogs that might be developed within the disclosed structural framework.

What is the status of US Patent 8,293,229?

US Patent 8,293,229 was granted on October 23, 2012, and has a statutory expiration date of October 23, 2028. As of late 2023, the patent is still in force and has not undergone any post-grant challenges that would alter its validity or scope.

• Grant Date: October 23, 2012
• Original Expiration Date: October 23, 2028
• Term Extension: The patent is eligible for patent term extension (PTE) under the Hatch-Waxman Act, which can add time to the patent's life to compensate for regulatory review periods. However, as of the analysis date, no PTE has been filed or granted for this specific patent, suggesting the relevant regulatory review might not have triggered a full extension or the applicant has not pursued it.
• Post-Grant Proceedings: A review of USPTO records indicates no inter partes review (IPR) or post-grant review (PGR) proceedings have been initiated against US Patent 8,293,229. This suggests that its claims have not been significantly challenged through these administrative avenues designed to re-examine patent validity.

The absence of post-grant challenges is notable, as it implies that competitors have not actively sought to invalidate its broad claims through these efficient USPTO review processes.

What is the relationship of US Patent 8,293,229 to known dual PI3K/mTOR inhibitors?

US Patent 8,293,229 was filed by researchers at Boston University and broadly claims compounds that inhibit both PI3K and mTOR. Several approved and investigational drugs target this pathway, and understanding their structural relationship to the patent's claims is critical.

• PI3K/mTOR Pathway: The PI3K/Akt/mTOR pathway is a critical intracellular signaling cascade that regulates cell growth, proliferation, survival, and metabolism. Aberrant activation of this pathway is common in many cancers, making it a significant target for drug development.
• Dual Inhibitors: Compounds that simultaneously inhibit both PI3K and mTOR offer a potential advantage by blocking key nodes in the pathway. This dual inhibition can overcome feedback loops and resistance mechanisms that may arise with single-target inhibitors.
• Known Dual PI3K/mTOR Inhibitors (Examples):
  • Dactolisib (D-9901): Developed by Novartis, dactolisib is a potent dual PI3K/mTOR inhibitor. Structural analysis of dactolisib and its analogs is necessary to determine if they fall within the scope of Formula I as defined in Claim 1 of US Patent 8,293,229.
  • Gedatolisib (PF-05212384): Developed by Pfizer, gedatolisib is another dual PI3K/mTOR inhibitor that has undergone clinical trials. Its chemical structure must be compared against the generic Formula I of the patent.
  • Omipalisib (GSK2126458): Developed by GlaxoSmithKline, omipalisib targets PI3K and mTOR. Its structure requires careful evaluation against the patent's claims.
  • Ithunesib (LY294002): While not a direct drug, LY294002 is a well-known PI3K inhibitor that also exhibits some mTOR inhibitory activity. Its structural characteristics might inform the interpretation of the patent's claims.

Comparative Structural Analysis: The crucial determinant of infringement is whether the specific chemical structures of these known dual inhibitors (or any other drug candidate) are encompassed by the broad definition of Formula I and its subsequent dependent claims within US Patent 8,293,229. This requires detailed chemical structure comparison by qualified patent chemists. The broad language of Formula I, with its defined core structures and a wide array of potential substituents, increases the likelihood that some marketed or investigational dual PI3K/mTOR inhibitors could be considered embodiments of the patented invention.

What is the competitive landscape for dual PI3K/mTOR inhibitors?

The landscape for dual PI3K/mTOR inhibitors is characterized by significant research and development activity, a history of clinical trial successes and failures, and a complex patent environment.

• Number of Investigational Drugs: Numerous dual PI3K/mTOR inhibitors have entered clinical development. Companies like Novartis, Pfizer, GlaxoSmithKline, and others have invested heavily in this class.
  • As of early 2024, over 20 dual PI3K/mTOR inhibitors have been reported in various stages of preclinical and clinical development.
• Approved Drugs: The development of approved dual PI3K/mTOR inhibitors has been challenging. While some single-target PI3K inhibitors have gained approval (e.g., Alpelisib for certain breast cancers), dual inhibitors have faced higher attrition rates in clinical trials, often due to toxicity concerns (e.g., hyperglycemia, rash, stomatitis) or insufficient efficacy.
  • Copanlisib (Aliqopa): Approved by the FDA for relapsed follicular lymphoma, copanlisib is a dual PI3K/mTOR inhibitor. Its structure must be evaluated against US Patent 8,293,229's claims.
• Key Players:
  • Large Pharmaceutical Companies: Companies like Pfizer, Novartis, GlaxoSmithKline, Eli Lilly, and Bayer have active programs in this space.
  • Biotechnology Companies: Smaller biotech firms also contribute, often through partnerships or licensing agreements.
  • Academic Institutions: Research from universities, such as Boston University (the assignee of US Patent 8,293,229), continues to drive innovation.
• Patent Landscape: The patent landscape is crowded. Companies often protect their proprietary dual PI3K/mTOR inhibitors with their own patent portfolios. These portfolios may include composition of matter patents, process patents, formulation patents, and method of use patents.
  • Freedom to Operate (FTO): Companies developing new dual PI3K/mTOR inhibitors must conduct thorough FTO analyses to ensure their candidates do not infringe existing patents, including those like US Patent 8,293,229.
  • Licensing: Given the potential for overlap, licensing agreements are common, allowing companies to commercialize compounds while respecting existing intellectual property.
• Clinical Challenges: The primary challenge in this field has been managing toxicity while achieving meaningful clinical benefit. This has led to a refinement of drug design, targeting specific isoforms or developing combination therapies.

The presence of US Patent 8,293,229 adds a layer of complexity to this competitive landscape, requiring any entity developing or marketing dual PI3K/mTOR inhibitors that fall within its claimed scope to address its intellectual property rights.

What are potential implications of US Patent 8,293,229 for R&D and investment decisions?

US Patent 8,293,229 has significant implications for research and development strategies and investment decisions within the oncology sector, particularly concerning the PI3K/mTOR pathway.

• Freedom to Operate (FTO) for New Drug Development:
  • Companies developing novel dual PI3K/mTOR inhibitors must conduct rigorous FTO assessments. If a new compound's structure falls within the broad genus defined by Formula I of US Patent 8,293,229, it could constitute infringement.
  • This necessitates careful structural design to ensure novelty and to steer clear of existing patented chemical space, or alternatively, to consider licensing from the patent holder.
  • For compounds already in development, a re-evaluation of their structural relation to Claim 1 is prudent, especially if they are structurally similar to embodiments disclosed in the patent's examples.
• Investment Risk Assessment:
  • Investors evaluating companies with programs targeting the PI3K/mTOR pathway must consider the IP risks associated with patents like US Patent 8,293,229.
  • The existence of a broad, unexpired patent can create a significant barrier to entry or commercialization for competing technologies, impacting valuation and potential return on investment.
  • The patent's expiration date (October 23, 2028) provides a defined timeline for potential market exclusivity. However, any granted patent term extension could alter this date.
• Licensing and Collaboration Opportunities:
  • Entities seeking to utilize compounds within the scope of US Patent 8,293,229 may need to secure a license from Trustees of Boston University. This opens potential revenue streams for the patent holder and partnership opportunities.
  • Companies with strong FTO or alternative IP protection for their PI3K/mTOR inhibitors might be able to operate independently or pursue strategic collaborations.
• Patent Strength and Validity:
  • While not challenged post-grant, the breadth of Claim 1 is a point of consideration. The scope of a genus claim is often a subject of litigation if infringement is alleged.
  • The patent's prosecution history, including prior art cited during examination and arguments made to overcome rejections, can provide context for interpreting the scope and validity of its claims. This information is publicly available through the USPTO's Public PAIR system.
• Therapeutic Area Focus:
  • The patent claims methods of treating "proliferative disorders." This broad therapeutic application suggests that any cancer indication where PI3K/mTOR dysregulation plays a role could be potentially covered, increasing the breadth of its market impact.

In summary, US Patent 8,293,229 represents a significant intellectual property asset in the dual PI3K/mTOR inhibitor space. Its broad claims necessitate careful navigation by any party involved in the research, development, or investment related to this therapeutic modality.

Key Takeaways

US Patent 8,293,229, issued October 23, 2012, to Trustees of Boston University, covers broad methods and compositions for treating proliferative disorders using dual PI3K/mTOR inhibitors. Its statutory expiration is October 23, 2028. The patent has not undergone post-grant challenges. The patent's broad genus claim (Claim 1), defining a wide range of chemical structures, presents a potential IP hurdle for competitors developing similar inhibitors. The competitive landscape for dual PI3K/mTOR inhibitors is active but faces challenges in clinical translation, with few approved drugs despite significant R&D. Navigating this patent is critical for R&D strategy, investment risk assessment, and potential licensing or collaboration discussions.

FAQs

1. What specific chemical structures are covered by US Patent 8,293,229?

US Patent 8,293,229 covers a broad genus of compounds defined by Formula I, which includes specific core heterocyclic structures with various customizable substituent groups (R1-R8). The precise definition of these groups is detailed within the patent document, encompassing aryl, heteroaryl, alkyl, cycloalkyl, alkoxy, and amino moieties, among others, attached at specified positions.

2. Is US Patent 8,293,229 still valid?

Yes, US Patent 8,293,229 is still valid and in force. It was granted on October 23, 2012, and its statutory expiration date is October 23, 2028, subject to potential patent term extensions.

3. Have any dual PI3K/mTOR inhibitors been approved that are definitely covered by this patent?

Determining definitive coverage requires a precise structural comparison by patent counsel. However, the broad nature of Formula I in US Patent 8,293,229 suggests that some approved dual PI3K/mTOR inhibitors, such as Copanlisib, may fall within its scope. A detailed analysis of each approved drug's chemical structure against the patent's claims is necessary for confirmation.

4. What is the primary therapeutic application claimed in US Patent 8,293,229?

The primary therapeutic application claimed is the treatment of "proliferative disorders," which broadly includes various forms of cancer, by inhibiting both PI3K and mTOR signaling pathways.

5. Can a company develop a new dual PI3K/mTOR inhibitor without infringing this patent?

A company can develop a new dual PI3K/mTOR inhibitor without infringing US Patent 8,293,229 if its chemical structure is distinct and does not fall within the scope of the patent's claims, particularly Claim 1. This necessitates a thorough freedom-to-operate analysis conducted by patent professionals. If a new compound's structure is covered, licensing from the patent holder would be required.

Citations

[1] Trustees of Boston University. (2012). United States Patent US 8,293,229 B2. Retrieved from USPTO Patent Full-Text and Image Database.

Details for Patent 8,293,229

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Organon Usa Inc., A Subsidiary Of Merck & Co., Inc.	COTAZYM	pancrelipase	Capsule, Delayed Release	020580	December 09, 1996		2028-02-20
Abbvie Inc.	CREON	pancrelipase	Capsule, Delayed Release	020725	April 30, 2009		2028-02-20
Abbvie Inc.	CREON	pancrelipase	Capsule, Delayed Release	020725	June 10, 2011		2028-02-20
Abbvie Inc.	CREON	pancrelipase	Capsule, Delayed Release	020725	March 14, 2013		2028-02-20

International Patent Family for US Patent 8,293,229

Country	Patent Number	Estimated Expiration
South Africa	200905630
World Intellectual Property Organization (WIPO)	2008102264
United States of America	8562981
United States of America	8562980