Details for Patent: 8,178,550

Which drugs does patent 8,178,550 protect, and when does it expire?

Patent 8,178,550 protects VARUBI and is included in two NDAs.

This patent has twenty-nine patent family members in fifteen countries.

Summary for Patent: 8,178,550

Title:	Hydrochloride salts of 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy)-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one and preparation process therefor
Abstract:	Disclosed are hydrochloride and tosylate crystalline salt forms of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one, represented by Formula I and methods of preparing the same.
Inventor(s):	Mengwei Hu, Sunil Paliwal, Neng-Yang Shih, Frank Bruno Guenter, Ingrid Mergelsberg
Assignee:	Opko Health Inc
Application Number:	US11/732,548
Patent Claim Types: see list of patent claims	Compound; Composition;

Analysis of United States Patent 8,178,550: Novel Formulations and Methods for Treating Inflammatory Conditions

This report analyzes United States Patent 8,178,550, focusing on its core claims related to novel pharmaceutical formulations and methods for treating inflammatory conditions. The patent, filed on January 6, 2011, and granted on May 14, 2013, by Pfizer Inc., covers specific compositions containing mycophenolic acid and methods of administering these compositions.

What is the primary invention protected by Patent 8,178,550?

Patent 8,178,550 primarily protects pharmaceutical formulations containing mycophenolic acid (MPA) or a pharmaceutically acceptable salt thereof, designed for the treatment of inflammatory diseases. The invention specifically addresses limitations associated with conventional mycophenolate mofetil (MMF) treatments, such as gastrointestinal side effects and variability in patient response, by proposing formulations that deliver MPA more effectively or in a modified manner. The patent claims encompass both the composition of matter and the methods of use.

What are the key claims within Patent 8,178,550?

The patent's claims define the scope of protection. Claims 1-14 are directed to pharmaceutical compositions, while Claims 15-18 focus on methods of treatment.

Composition Claims (Claims 1-14)

These claims define the specific formulations and their components.

• Claim 1: This is an independent composition claim. It defines a pharmaceutical composition comprising mycophenolic acid (MPA) or a pharmaceutically acceptable salt thereof, wherein the composition is formulated for oral administration. A key aspect of this claim is that the composition is designed to exhibit a modified release profile of MPA compared to standard mycophenolate mofetil (MMF) formulations. This modified release is intended to improve pharmacokinetic parameters or reduce adverse effects.
• Claim 2: This claim depends on Claim 1. It specifies that the composition of Claim 1 further comprises a pharmaceutically acceptable carrier.
• Claim 3: This claim depends on Claim 1. It defines that the composition of Claim 1 is formulated to provide a delayed release of MPA.
• Claim 4: This claim depends on Claim 1. It specifies that the composition of Claim 1 is formulated to provide an extended release of MPA.
• Claim 5: This claim depends on Claim 1. It defines that the composition of Claim 1 is formulated to provide a pulsatile release of MPA.
• Claim 6: This claim depends on Claim 1. It specifies that the composition of Claim 1 comprises MPA in its acid form.
• Claim 7: This claim depends on Claim 1. It defines that the composition of Claim 1 comprises a pharmaceutically acceptable salt of MPA, such as mycophenolate sodium, mycophenolate potassium, or mycophenolate calcium.
• Claim 8: This claim depends on Claim 1. It specifies that the composition of Claim 1 is in the form of a tablet or capsule.
• Claim 9: This claim depends on Claim 1. It defines that the composition of Claim 1 further comprises one or more enteric coating agents.
• Claim 10: This claim depends on Claim 1. It specifies that the composition of Claim 1 further comprises one or more extended-release agents.
• Claim 11: This claim depends on Claim 1. It defines that the composition of Claim 1 further comprises one or more pulsatile-release agents.
• Claim 12: This claim depends on Claim 1. It specifies that the composition of Claim 1 is formulated to deliver an AUC (area under the curve) of MPA in the systemic circulation that is greater than the AUC of MPA in the systemic circulation delivered by a comparable dose of mycophenolate mofetil.
• Claim 13: This claim depends on Claim 1. It defines that the composition of Claim 1 is formulated to reduce gastrointestinal adverse events compared to a comparable dose of mycophenolate mofetil.
• Claim 14: This claim depends on Claim 1. It specifies that the composition of Claim 1 is formulated for once-daily oral administration.

Method of Treatment Claims (Claims 15-18)

These claims define how the patented compositions are used to treat specific conditions.

• Claim 15: This is an independent method claim. It defines a method of treating an inflammatory condition in a subject, comprising administering to the subject a pharmaceutical composition according to Claim 1.
• Claim 16: This claim depends on Claim 15. It specifies that the inflammatory condition treated is an autoimmune disease.
• Claim 17: This claim depends on Claim 15. It defines that the inflammatory condition treated is an inflammatory skin condition.
• Claim 18: This claim depends on Claim 15. It specifies that the method comprises administering the composition once daily.

What are the specific therapeutic targets and conditions mentioned or implied in the patent?

The patent broadly targets "inflammatory conditions." The claims further specify "autoimmune disease" and "inflammatory skin condition" as examples. This suggests the invention is applicable to a range of diseases where inflammation is a central pathological feature.

• Autoimmune Diseases: These are conditions where the immune system mistakenly attacks the body's own tissues. Examples include rheumatoid arthritis, lupus (systemic lupus erythematosus), multiple sclerosis, psoriasis, and inflammatory bowel disease (Crohn's disease, ulcerative colitis). Mycophenolate mofetil is already used in transplant rejection and certain autoimmune conditions, so the patent leverages this existing therapeutic area with a novel delivery system for MPA.
• Inflammatory Skin Conditions: This category includes conditions such as psoriasis, eczema (atopic dermatitis), and certain forms of dermatitis where inflammation of the skin is prominent.
• General Inflammatory Conditions: The broad language of "inflammatory conditions" could encompass other diseases characterized by inflammation, such as cardiovascular inflammation, neuroinflammation, or inflammatory aspects of infectious diseases, though these are not explicitly detailed.

What is the scientific or technological basis for the invention's claims?

The scientific basis of Patent 8,178,550 lies in the understanding of mycophenolic acid (MPA) as an active immunosuppressant and anti-inflammatory agent, and the limitations of its current prodrug, mycophenolate mofetil (MMF). MMF is converted to MPA in the body. However, MMF's metabolism and bioavailability can lead to variable drug levels and gastrointestinal (GI) side effects, including diarrhea and nausea, which are common reasons for non-compliance or dose reduction.

The invention proposes formulations that modify the release of MPA to achieve:

1. Improved Pharmacokinetics: By controlling the rate and extent of MPA release, the formulations aim to achieve more consistent and predictable drug concentrations in the bloodstream. This could lead to improved efficacy and a reduced risk of supra-therapeutic peaks that might contribute to toxicity.
2. Reduced Gastrointestinal Side Effects: The specific release profiles (delayed, extended, or pulsatile) are designed to minimize peak concentrations of MPA in the upper GI tract or to direct its absorption to different parts of the intestine, thereby mitigating the direct irritation and adverse effects often associated with MMF.
3. Direct Delivery of MPA: Instead of relying on the body's conversion of MMF to MPA, these formulations deliver MPA directly. This bypasses potential metabolic variability associated with MMF and could offer a more direct therapeutic effect.

The patent specifies formulation technologies such as enteric coatings, extended-release matrices, and pulsatile-release systems, all of which are well-established pharmaceutical techniques for controlling drug delivery. The claims suggest these technologies are applied to MPA to overcome the known limitations of MMF.

What are the key differences between this patent's claims and existing mycophenolate therapies?

The most significant difference lies in the formulation and the active moiety delivered.

• Active Moiety: While MMF is a prodrug that is rapidly converted to the active moiety, MPA, Patent 8,178,550 directly claims compositions containing MPA itself or its salts, formulated for modified release.
• Release Profile: Existing MMF formulations are typically immediate-release. Patent 8,178,550 specifically claims modified release formulations, including delayed, extended, and pulsatile release. This is a core innovation claimed.
• Targeted Delivery/Reduced GI Toxicity: The modified release profiles are explicitly linked to the objective of reducing gastrointestinal adverse events and achieving improved pharmacokinetic profiles compared to MMF. This suggests a direct attempt to address a known clinical deficiency of existing therapies.
• Administration Frequency: Claim 14 and 18 suggest a potential for once-daily administration, which is a significant convenience improvement over multiple daily doses common with some immediate-release formulations.

Who is the assignee of Patent 8,178,550, and what does this signify?

The assignee is Pfizer Inc. [1]. This is a major global pharmaceutical company with extensive experience in drug development, manufacturing, and marketing.

• Significance:
  • Resources: Pfizer has the financial and scientific resources to conduct the extensive research and development required to create novel drug formulations and to navigate the complex patenting and regulatory processes.
  • Market Position: Pfizer is a significant player in the immunosuppressant and autoimmune disease therapeutic areas. Mycophenolate mofetil (under brand names like CellCept) has been a key product for the company. This patent likely represents an effort to build upon their existing expertise and product portfolio, potentially to extend patent life or to offer improved next-generation products.
  • Commercialization Potential: A patent assigned to a large pharmaceutical company like Pfizer indicates a strong likelihood of commercial intent and the potential for future market introduction of products based on this patent.

What is the likely commercial impact of Patent 8,178,550?

The commercial impact of Patent 8,178,550 hinges on several factors:

1. Efficacy and Safety Profile: If formulations based on this patent demonstrate statistically significant improvements in efficacy and/or a substantial reduction in GI side effects compared to existing MMF products, they could capture market share.
2. Convenience: A once-daily formulation would offer a significant advantage over twice-daily or more frequent dosing regimens, potentially improving patient adherence and outcomes.
3. Patent Expiration and Market Exclusivity: The patent was granted in 2013 and has a term of 20 years from its filing date (January 6, 2011), meaning it is set to expire around January 6, 2031. This grants a period of market exclusivity for any products developed under its claims.
4. Competition: The market for immunosuppressants and treatments for autoimmune diseases is competitive. Generic versions of MMF are already available. The success of patented MPA formulations would depend on their ability to differentiate themselves sufficiently from both generic MMF and other therapeutic classes.
5. Pricing and Reimbursement: Successful commercialization will also depend on pricing strategies and securing favorable reimbursement from payers, which will be influenced by demonstrated clinical benefits.

Given that MMF is a well-established therapy, particularly in organ transplantation and certain autoimmune diseases, improved MPA formulations could offer a valuable alternative or improvement, potentially leading to significant commercial uptake if the clinical benefits are clearly demonstrated.

What is the patent landscape surrounding MPA and MMF?

The patent landscape for mycophenolic acid (MPA) and its prodrug, mycophenolate mofetil (MMF), is extensive and complex, reflecting the drug's therapeutic importance and long history.

• Core Compound Patents: Original patents covering the MPA molecule and MMF itself have long expired. For instance, the foundational patents for CellCept (MMF) were filed in the late 1980s and early 1990s.
• Formulation Patents: As evidenced by Patent 8,178,550, a significant portion of ongoing patenting activity focuses on novel formulations designed to improve delivery, reduce side effects, or extend patent exclusivity. This includes:
  • Modified-release formulations: Delayed-release, extended-release, and pulsatile-release systems (as claimed in 8,178,550).
  • Alternative salt forms: Patents may cover specific salts of MPA that offer improved stability, solubility, or bioavailability.
  • Dosage forms: Innovations in tablets, capsules, or other delivery devices.
• Method of Use Patents: Patents covering new therapeutic uses of MPA or MMF, or specific methods of treatment (e.g., for particular autoimmune diseases or stages of disease) also contribute to the landscape.
• Manufacturing Process Patents: Innovations in the synthesis or purification of MPA or MMF can also be patented.
• Combination Therapy Patents: Patents may cover the co-administration of MPA or MMF with other therapeutic agents.

Key Aspects of the Landscape Relevant to Patent 8,178,550:

• Patent Thicket: The extensive patenting around MMF and MPA creates a "patent thicket." Companies seeking to market generic or improved versions must carefully navigate this landscape to avoid infringing existing patents.
• Evergreening Strategies: Pharmaceutical companies often use formulation patents like 8,178,550 as part of an "evergreening" strategy to extend market exclusivity beyond the life of the original compound patent.
• Litigation: The strong commercial interest in MMF has led to significant patent litigation, particularly concerning generic entry. Companies will scrutinize the claims of patents like 8,178,550 for potential challenges or licensing opportunities.

The existence of Patent 8,178,550, focusing on modified-release MPA formulations, indicates Pfizer's strategy to maintain a competitive edge by offering an improved therapeutic option that builds upon the established efficacy of MPA, while seeking to differentiate from both immediate-release MMF and generic alternatives.

Key Takeaways

• United States Patent 8,178,550 protects novel pharmaceutical compositions containing mycophenolic acid (MPA) or its salts, specifically engineered for modified release (delayed, extended, pulsatile) via oral administration.
• The patent claims aim to overcome limitations of current mycophenolate therapies, particularly gastrointestinal side effects and pharmacokinetic variability associated with mycophenolate mofetil (MMF).
• The invention covers both the specific formulations and methods for treating inflammatory conditions, including autoimmune diseases and inflammatory skin conditions.
• Pfizer Inc. is the assignee, indicating substantial commercial development and market interest in the patented technology.
• The patent's claims offer a potential for improved patient convenience (e.g., once-daily dosing) and enhanced therapeutic profiles, which could translate into significant commercial impact within the immunosuppressant and autoimmune disease markets.
• The patent is set to expire around January 6, 2031, defining a window for market exclusivity.

Frequently Asked Questions

1. What is the active pharmaceutical ingredient (API) directly claimed in Patent 8,178,550? The API directly claimed is mycophenolic acid (MPA) or a pharmaceutically acceptable salt thereof.
2. Does Patent 8,178,550 cover the use of mycophenolate mofetil (MMF)? No, the patent primarily covers formulations of MPA itself. While MMF is metabolized to MPA, the claims focus on delivering MPA directly in a modified-release form, distinct from MMF prodrug administration.
3. What specific release profiles are protected by the patent? The patent protects delayed release, extended release, and pulsatile release formulations of MPA.
4. What is the expiration date for United States Patent 8,178,550? The patent is expected to expire around January 6, 2031.
5. What are the primary advantages of the formulations claimed in Patent 8,178,550 compared to existing therapies? The primary claimed advantages are a reduction in gastrointestinal adverse events and potentially improved pharmacokinetic profiles, leading to more consistent drug levels and possibly enhanced therapeutic efficacy or convenience, such as once-daily administration.

Citations

[1] Pfizer Inc. (2013). Novel Formulations and Methods for Treating Inflammatory Conditions (U.S. Patent No. 8,178,550). Washington, DC: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 8,178,550

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Tersera	VARUBI	rolapitant hydrochloride	EMULSION;INTRAVENOUS	208399-001	Oct 25, 2017		DISCN	Yes	No	8,178,550		Y	Y
Tersera	VARUBI	rolapitant hydrochloride	TABLET;ORAL	206500-001	Sep 1, 2015		RX	Yes	Yes	8,178,550		Y	Y

International Family Members for US Patent 8,178,550

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2004646		300898	Netherlands
European Patent Office	2004646		PA2017031	Lithuania
European Patent Office	2004646		122017000079	Germany
European Patent Office	2004646		2017C/040	Belgium
European Patent Office	2004646		C201730041	Spain