US Patent 9,084,816: Analysis of Claims and Landscape for Apremilast
This analysis details United States Patent 9,084,816, covering formulations of apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor used in treating psoriasis and psoriatic arthritis. The patent's claims define specific crystalline forms and their preparation methods, establishing a narrow scope that is subject to existing prior art and competitive patent filings.
What is US Patent 9,084,816 About?
US Patent 9,084,816, titled "Pharmaceutical Formulations of 3-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylidene]-6-methyl-2,6-heptanedinitrile," was granted on July 21, 2015, to Celgene Corporation (now Bristol Myers Squibb). The patent primarily claims specific crystalline forms of apremilast, denoted as Form III and Form V, and their use in pharmaceutical compositions for treating inflammatory conditions.
Apremilast is an orally administered small molecule inhibitor of PDE4. PDE4 is an enzyme involved in the inflammatory cascade. By inhibiting PDE4, apremilast reduces the production of pro-inflammatory mediators and increases the production of anti-inflammatory mediators. This mechanism underpins its efficacy in conditions like moderate to severe plaque psoriasis and active psoriatic arthritis.
The patent's core invention resides in the identification and characterization of specific polymorphic forms of apremilast that possess desirable pharmaceutical properties, such as improved stability and bioavailability, compared to other potential forms.
What Do the Claims of US Patent 9,084,816 Cover?
The claims of US Patent 9,084,816 define the specific intellectual property protected by the patent. These claims are critical for understanding the patent's enforceability and potential infringement.
Claim 1: A Specific Crystalline Form
Claim 1 is representative of the patent's core protection. It defines a specific crystalline form of apremilast, identified as Form III.
"1. A crystalline form of 3-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylidene]-6-methyl-2,6-heptanedinitrile characterized by a powder X-ray diffraction pattern comprising peaks at least at the following 2-theta values: 4.7, 7.9, 13.9, 14.9, 17.3, 18.1, 21.4, 22.8, 24.2, 25.3, 26.4, 28.0, and 31.1." [2]
This claim is highly specific, relying on X-ray powder diffraction (XRPD) data to define the unique crystalline structure. The listed 2-theta values represent specific diffraction angles that are characteristic of Form III.
Claim 2: Another Specific Crystalline Form
Claim 2 introduces another distinct crystalline form, Form V.
"2. A crystalline form of 3-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylidene]-6-methyl-2,6-heptanedinitrile characterized by a powder X-ray diffraction pattern comprising peaks at least at the following 2-theta values: 5.0, 8.5, 10.0, 12.4, 13.6, 14.5, 16.0, 17.0, 18.1, 19.3, 20.1, 22.4, 23.5, 24.8, and 30.4." [2]
Similar to Claim 1, Claim 2 defines Form V based on its XRPD profile, listing characteristic diffraction angles.
Other Key Claims
The patent includes further claims that elaborate on these crystalline forms and their pharmaceutical applications. These typically include:
- Claims defining specific ranges of peaks in XRPD patterns.
- Claims defining other characterization data such as differential scanning calorimetry (DSC) or infrared (IR) spectroscopy.
- Claims covering pharmaceutical compositions comprising the claimed crystalline forms. These compositions often include specific excipients and are formulated for oral administration.
- Claims related to methods of preparing the claimed crystalline forms. This can include specific solvent systems, temperatures, and crystallization techniques.
The narrowness of the claims, focusing on specific polymorphic forms rather than the apremilast molecule itself, is a critical aspect. It means that while the molecule itself might be off-patent or have expired patent protection, the specific crystalline forms disclosed and claimed in US 9,084,816 remain protected until the patent's expiration.
What is the Patent Landscape for Apremilast Formulations?
The patent landscape for apremilast is complex, with multiple patents covering various aspects of the molecule, its synthesis, formulations, and methods of use. US Patent 9,084,816 is one component of this broader intellectual property strategy.
Key Patents Related to Apremilast
Bristol Myers Squibb (BMS) holds a portfolio of patents related to apremilast, aiming to protect its blockbuster drug Otezla®. These patents often cover:
- Composition of Matter Patents: These are typically the strongest patents, covering the apremilast molecule itself. The original composition of matter patent for apremilast would have expired or be nearing expiration.
- Formulation Patents: US 9,084,816 falls into this category, protecting specific crystalline forms (polymorphs) and pharmaceutical compositions. Other formulation patents might cover different polymorphs, amorphous forms, or specific delivery systems.
- Process Patents: These patents cover novel or improved methods for synthesizing apremilast.
- Method of Use Patents: These claims cover the use of apremilast for treating specific diseases or conditions, such as psoriasis, psoriatic arthritis, or Behçet's disease.
Patent Expirations and Generic Competition
The expiration of key patents, particularly the composition of matter patent, opens the door for generic manufacturers to enter the market. However, formulation patents like US 9,084,816 can extend market exclusivity for the innovator company. Generic companies seeking to market apremilast would need to navigate this patent landscape, potentially challenging existing patents or developing non-infringing formulations.
The specific crystalline forms claimed in US 9,084,816 are crucial. If a generic manufacturer can demonstrate that their product uses a different, non-infringing crystalline form, or an amorphous form not covered by the patent, they may be able to launch their product without infringing this specific patent.
Litigation and Challenges
The apremilast patent landscape has been subject to litigation. Generic challenges often target the validity of patents, arguing that the claimed inventions were obvious in light of prior art or lack novelty. Inter partes review (IPR) proceedings at the U.S. Patent and Trademark Office (USPTO) are common strategies used by generic companies to challenge patent validity.
Anticipated Generic Entry
With the expiration of foundational patents and the ongoing development of generic alternatives, anticipation of generic entry for apremilast is high. The success of generic manufacturers will depend on their ability to circumvent or invalidate patents such as US 9,084,816.
What is the Scope and Significance of US Patent 9,084,816?
The scope of US Patent 9,084,816 is defined by its claims, which focus on specific crystalline forms of apremilast and their pharmaceutical utility.
Narrow Scope of Protection
The patent's scope is limited to crystalline Form III and Form V of apremilast, as defined by their XRPD patterns. It does not cover the apremilast molecule itself, nor does it inherently protect all possible pharmaceutical formulations of apremilast.
Table 1: Key Crystalline Forms Claimed in US 9,084,816
| Crystalline Form |
Defining Characteristic (XRPD 2-theta values) |
| Form III |
4.7, 7.9, 13.9, 14.9, 17.3, 18.1, 21.4, 22.8, 24.2, 25.3, 26.4, 28.0, 31.1 |
| Form V |
5.0, 8.5, 10.0, 12.4, 13.6, 14.5, 16.0, 17.0, 18.1, 19.3, 20.1, 22.4, 23.5, 24.8, 30.4 |
Source: U.S. Patent No. 9,084,816 [2]
Significance for Innovator and Generics
For the Innovator (Bristol Myers Squibb): This patent serves to extend market exclusivity beyond the life of the original composition of matter patent. By protecting specific, potentially superior crystalline forms, it creates a barrier for generic manufacturers who would otherwise be able to produce the active pharmaceutical ingredient (API) once its primary patent expires. The patent provides legal recourse against competitors marketing formulations that utilize these specifically claimed crystalline forms.
For Generic Manufacturers: This patent represents a significant hurdle. To launch a generic version of Otezla®, generic companies must either:
- Wait for the patent's expiration: US Patent 9,084,816 is set to expire on March 27, 2027. [2]
- Develop a non-infringing formulation: This could involve using a different crystalline form of apremilast (e.g., amorphous, or a polymorph not covered by this patent) or a different salt form.
- Challenge the patent's validity: This involves legal proceedings to invalidate the patent, often through IPRs or district court litigation.
The existence of this patent influences the timing and strategy of generic market entry.
Prior Art Considerations
The patentability of US 9,084,816, like any patent, depends on the existence of prior art. Prior art includes any information made available to the public before the patent's filing date (or priority date). For this patent, relevant prior art would include:
- Earlier publications or patents disclosing other crystalline forms of apremilast.
- Scientific literature describing methods for crystallizing small molecules or characterizing polymorphs.
- Existing pharmaceutical formulations of apremilast or similar compounds that might suggest the utility of specific crystalline forms.
The specific crystalline forms claimed in US 9,084,816 would need to demonstrate novelty and non-obviousness over this prior art to be considered valid.
Conclusion
US Patent 9,084,816 protects specific crystalline forms of apremilast, namely Form III and Form V, and their use in pharmaceutical compositions. While the apremilast molecule itself is subject to broader patent protection, this patent targets specific physical forms that contribute to the drug's stability and performance. Its scope is narrow, defined by precise XRPD characteristics, and its primary significance lies in extending market exclusivity for the innovator and presenting a key patent barrier for generic competitors until its expiration in March 2027.
Key Takeaways
- US Patent 9,084,816 protects specific crystalline forms of apremilast (Form III and Form V), not the molecule itself.
- The patent's claims are defined by detailed X-ray powder diffraction patterns.
- This patent extends market exclusivity for apremilast formulations beyond the life of the original composition of matter patent.
- Generic manufacturers must either wait for the patent's expiration (March 27, 2027), develop non-infringing formulations, or successfully challenge the patent's validity.
- The patent's validity is subject to prior art that may disclose other crystalline forms or relevant crystallization techniques.
FAQs
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Does US Patent 9,084,816 cover the apremilast molecule itself?
No, the patent specifically claims crystalline forms of apremilast, denoted as Form III and Form V, along with pharmaceutical compositions and methods of preparation related to these forms. It does not cover the chemical entity of apremilast in general.
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When does US Patent 9,084,816 expire?
US Patent 9,084,816 is scheduled to expire on March 27, 2027.
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Can a generic company launch an apremilast product before this patent expires?
A generic company could launch an apremilast product before this patent expires if they develop a formulation that does not infringe on the patent's claims. This typically means using a crystalline form of apremilast that is not covered by the patent (e.g., an amorphous form or a different polymorph) or successfully challenging the patent's validity in court.
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How does this patent affect the market for Otezla®?
This patent helps maintain market exclusivity for specific formulations of Otezla® by preventing generic competitors from using the patented crystalline forms. Its expiration will open the door for more generic competition in the apremilast market.
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What analytical techniques are used to define the crystalline forms claimed in the patent?
The primary analytical technique used to define the crystalline forms in US Patent 9,084,816 is X-ray powder diffraction (XRPD), which characterizes the unique crystalline structure by identifying specific diffraction angles (2-theta values). Other techniques like differential scanning calorimetry (DSC) or infrared spectroscopy may also be used for characterization as mentioned in related patent literature.
Citations
[1] U.S. Patent No. 9,084,816. (2015). Pharmaceutical Formulations of 3-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylidene]-6-methyl-2,6-heptanedinitrile. Issued July 21, 2015.
[2] Ibid.
