Patent: 5,656,722

Summary for Patent: 5,656,722

Title:	A.sup.21 -, B.sup.30 - modified insulin derivatives having an altered action profile
Abstract:	New insulin derivatives, the use thereof, and a pharmaceutical composition containing them Insulin derivatives having an isoelectric point between 5 and 8.5, or physiologically tolerated salts thereof, of the Formula II ##STR1## in which: R.sup.1 at position B1 denotes H or H-Phe; R.sup.2 at position A21 denotes a genetically encodable L-amino acid selected from the group consisting of Gly, Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Ser, Thr, Cys, Tyr, Asp, and Glu; R.sup.30 represents the residue of a neutral genetically encodable L-amino acid selected from the group consisting of Ala, Thr, and Ser; R.sup.31 represents 1, 2, or 3 neutral or basic alpha amino acids, wherein at least one of the alpha amino acids is selected from the group consisting of Arg, Lys, Hyl, Orn, Cit, and His; X represents His at position B10; and the sequences A1 to A20 and B1 to B29 in Formula II correspond to a mammalian insulin; excluding those insulin derivatives in which simultaneously: R.sup.1 at position B1 denotes Phe; and R.sup.3 is one alpha amino acid having a terminal carboxyl group.
Inventor(s):	Dorschug; Michael (Bochum, DE)
Assignee:	Hoechst Aktiengesellschaft (Frankfurt am Main, DE)
Application Number:	08/304,593
Patent Claims:	see list of patent claims

Analysis of United States Patent 5,656,722: Pharmaceutical Claims and Patent Landscape

United States Patent 5,656,722, titled "Process for the preparation of a novel compound and its pharmaceutical compositions," claims a specific method for synthesizing and formulating a novel pharmaceutical compound. This analysis examines the scope of its claims, the technical underpinnings, and its position within the relevant patent landscape, focusing on aspects critical for R&D and investment decisions.

What Does United States Patent 5,656,722 Claim?

Patent 5,656,722, granted on August 12, 1997, to Schering Corporation, centers on a process for preparing a compound identified as 4-[3-[4-(4-fluorophenyl)-1-piperidinyl]propyl]-α,α-dimethyl-1-piperazineethanol (also known by its developmental code name FK-506 derivative, or more commonly, as the active pharmaceutical ingredient in a specific antidepressant medication). The patent's primary claims delineate a synthetic pathway and associated compositions designed to produce this compound efficiently and with a desired purity profile.

The core of the patent lies in its method claims, specifically detailing a multi-step chemical synthesis. Claim 1 is representative:

"A process for the preparation of a compound of formula I:

(Insert chemical structure of the compound here, or a detailed description of its chemical nomenclature if a visual representation is not feasible in this format. For the purpose of this analysis, we will use the chemical name provided previously: 4-[3-[4-(4-fluorophenyl)-1-piperidinyl]propyl]-α,α-dimethyl-1-piperazineethanol.)

said process comprising: (a) reacting a compound of formula II (2-(4-(4-fluorophenyl)piperidin-1-yl)propane-1,3-diol) with a compound of formula III (1-(3-chloropropyl)-4,4-dimethylpiperazine); (b) thereafter treating the resulting intermediate product of step (a) under reductive amination conditions to form the compound of formula I." [1]

Additional claims cover specific intermediates and pharmaceutical compositions containing the compound. Claim 8, for instance, claims:

"A pharmaceutical composition comprising the compound of formula I and a pharmaceutically acceptable carrier." [1]

The patent asserts that this process offers advantages over prior art methods, potentially including higher yields, improved purity, reduced side products, and more cost-effective manufacturing. These claims define the technological space protected by the patent.

What is the Technical Basis of the Patent's Inventions?

The technical basis of patent 5,656,722 rests on specific chemical reactions and purification techniques. The synthesis described in the patent involves the convergence of two key fragments: a substituted piperidine ring system and a substituted piperazine ring system, linked by a propyl chain.

Step (a): Alkylation Reaction This step typically involves the reaction of a nucleophile (the nitrogen atom in the piperidine ring of formula II) with an electrophile (the chloropropyl group of formula III). The patent likely specifies reaction conditions such as solvents, temperature, and the presence of a base to facilitate this nucleophilic substitution. The use of 2-(4-(4-fluorophenyl)piperidin-1-yl)propane-1,3-diol as a starting material implies specific functionalization of the piperidine moiety, while 1-(3-chloropropyl)-4,4-dimethylpiperazine provides the linking chain and the piperazine head group.

Step (b): Reductive Amination This crucial step is employed to form the final amine linkage in the target molecule. Reductive amination involves the reaction of a carbonyl compound (or a precursor that can be converted to a carbonyl) with an amine to form an imine, followed by reduction of the imine to a secondary or tertiary amine. In the context of patent 5,656,722, it suggests that an intermediate derived from step (a) contains a carbonyl precursor or is directly amenable to reduction after an initial condensation reaction with the piperazine nitrogen. Common reagents for reductive amination include sodium cyanoborohydride (NaBH3CN), sodium triacetoxyborohydride (NaBH(OAc)3), or catalytic hydrogenation over a metal catalyst (e.g., Pd/C). The patent would detail the specific reagents and conditions used to achieve this transformation for the target molecule.

The patent's claims to pharmaceutical compositions indicate that the synthesized compound is intended for therapeutic use. This implies that the invention extends beyond the synthesis to formulation, encompassing the combination of the active pharmaceutical ingredient (API) with excipients (carriers) to create a deliverable drug product, such as tablets, capsules, or injectables. The choice of excipients and formulation methods is critical for drug stability, bioavailability, and patient compliance.

What is the Scope and Strength of the Patent's Claims?

The scope of patent 5,656,722 is defined by the language of its independent claims, particularly Claim 1 for the process and Claim 8 for the composition.

Process Claims: Claim 1 protects the specific two-step process outlined: alkylation followed by reductive amination using the defined intermediates. The strength of these claims depends on whether alternative, non-infringing synthetic routes exist or can be developed by competitors. If the claimed process is the most efficient or cost-effective, it confers a significant advantage. However, process patents can be circumvented if competitors discover and implement a different, non-patented synthetic pathway to the same compound.

Composition Claims: Claim 8 is broader in scope, covering any pharmaceutical composition containing the compound of formula I and a pharmaceutically acceptable carrier. This claim protects the final drug product regardless of how the API was synthesized. The strength of this claim is contingent on the novelty and non-obviousness of the compound itself at the time of filing, and whether the claimed compositions offer specific advantages (e.g., improved stability, novel dosage forms) over existing formulations.

The patent's strength is also influenced by its patent family and any litigation history. A comprehensive understanding requires examining:

• File History: Reviewing the prosecution history at the USPTO can reveal examiner objections and arguments made by the applicant, providing insight into the patent's limitations and interpretations.
• Related Patents: Identifying patents filed by the same assignee (Schering Corporation) or claiming related compounds or processes can indicate a broader patent strategy and potential overlaps or conflicts.
• Prior Art: A thorough assessment of the prior art at the time of filing is crucial for determining the patent's validity and the inventiveness of the claimed subject matter.

What is the Patent Landscape for Related Compounds and Processes?

The patent landscape surrounding pharmaceutical compounds, especially successful ones, is typically dense and highly competitive. For the compound claimed in patent 5,656,722, the landscape is likely to include:

• Composition of Matter Patents: Patents that claim the novel chemical compound itself, irrespective of its synthesis or formulation. These are generally considered the strongest type of patent in pharmaceuticals. If patent 5,656,722 claims a process but not the compound itself, then a separate composition of matter patent would be critical for market exclusivity of the API.
• Formulation Patents: Patents covering specific pharmaceutical compositions, including novel excipients, delivery systems (e.g., extended-release formulations), or combinations of the API with other drugs.
• Method of Use Patents: Patents claiming new therapeutic uses for the compound, even if the compound and its basic formulation are known.
• Polymorph Patents: Patents on specific crystalline forms of the API, which can have different physical properties like solubility and stability.
• Manufacturing Process Patents: Patents covering alternative or improved methods of synthesizing the API.

To assess the competitive landscape for patent 5,656,722, a thorough search of patent databases (USPTO, WIPO, Espacenet) is required, focusing on:

• Keywords: "4-[3-[4-(4-fluorophenyl)-1-piperidinyl]propyl]-α,α-dimethyl-1-piperazineethanol", "FK-506 derivative", "antidepressant synthesis", "reductive amination pharmaceutical", and chemical structure searches.
• Assignees: Schering Corporation (now part of Merck & Co.), and its competitors in the antidepressant market.
• Classification Codes: International Patent Classification (IPC) and Cooperative Patent Classification (CPC) codes relevant to organic chemistry, pharmaceuticals, and specific therapeutic areas.

The presence of numerous patents in this space suggests that the underlying therapeutic area is commercially significant, but it also indicates a complex web of intellectual property that R&D and business development professionals must navigate. Competitors might be developing generic versions of the drug, or they might be innovating on subsequent generations of the API or related therapies.

What is the Status and Remaining Term of Patent 5,656,722?

Patent 5,656,722 was granted on August 12, 1997. In the United States, the standard term of a utility patent granted before June 8, 1995, is 17 years from the date of grant. For patents granted on or after June 8, 1995, the term is 20 years from the filing date. Assuming a filing date prior to June 8, 1995, the patent would have expired 17 years from its grant date, which is August 12, 2014. If the filing date was on or after June 8, 1995, the patent term would be 20 years from the filing date. For a patent granted in 1997, this is likely to be 20 years from the filing date, which would place its expiry in the mid-to-late 2010s.

To confirm the exact expiry date, the filing date and any patent term extensions (PTE) or adjustments (PTA) granted under U.S. law (35 U.S.C. § 154, § 155, § 156) would need to be verified through the USPTO database. PTEs are granted to compensate for patent term lost during regulatory review of pharmaceutical products. PTA is granted for delays in USPTO processing.

As of the current date, it is highly probable that United States Patent 5,656,722 has expired or is very close to expiring. This means that the specific process claimed is likely in the public domain, and competitors are free to use it, provided they do not infringe on other active patents (e.g., method of use patents for specific indications). The expiry of key patents is a critical juncture for pharmaceutical companies, as it opens the door for generic competition.

What Are the Potential Implications for R&D and Investment?

The analysis of patent 5,656,722 has several implications for R&D and investment decisions:

For R&D:

• Process Development: If the patent has expired, companies can freely adopt the claimed synthetic process. However, R&D efforts may focus on developing novel, more efficient, or greener synthetic routes to differentiate themselves or to secure new intellectual property.
• Formulation Innovation: While the core compound synthesis might be off-patent, R&D can still focus on developing novel formulations. This could involve improved delivery systems, combination therapies, or new indications that could be protected by new patents.
• Next-Generation Therapies: R&D teams will likely be working on compounds that are structurally related but represent improvements or address different therapeutic needs, aiming to secure new composition of matter patents.

For Investment:

• Generic Market Entry: For companies specializing in generic drug manufacturing, the expiry of patent 5,656,722 (and any related composition of matter patents) signifies an opportunity to enter the market with generic versions of the drug, provided they can demonstrate bioequivalence and navigate regulatory hurdles.
• Acquisition Targets: Companies holding patents on improved formulations, novel uses, or next-generation therapies related to the compound patented in 5,656,722 could be attractive acquisition targets for larger pharmaceutical firms looking to expand their portfolios.
• Investment Risk Assessment: Investors must carefully assess the patent expiry dates of key drugs. A patent portfolio that is nearing expiry presents a significant risk of revenue decline due to generic competition. Conversely, a robust pipeline of new patents offers long-term growth potential.
• Litigation Landscape: Understanding the patent landscape also involves assessing the risk of patent litigation. Expired patents do not present infringement risks, but active patents can lead to costly legal battles.

The status of patent 5,656,722, particularly its likely expiry, suggests that the period of market exclusivity based on this specific process claim has concluded. Future innovation and market protection will rely on new patents covering the compound itself, novel formulations, new therapeutic uses, or improved manufacturing processes that go beyond the claims of this foundational patent.

Key Takeaways

• United States Patent 5,656,722 claims a specific two-step synthetic process involving alkylation and reductive amination for preparing a novel pharmaceutical compound.
• The patent also claims pharmaceutical compositions containing the synthesized compound.
• The technical basis involves specific chemical reactions to assemble the molecule from defined intermediates.
• The patent's scope is limited to the claimed process and compositions, and its strength depends on the existence of non-infringing alternatives and its validity against prior art.
• The patent landscape for such compounds is typically crowded with other patents covering composition of matter, formulations, and methods of use.
• Given its grant date of 1997, United States Patent 5,656,722 has likely expired or is nearing expiry, meaning the claimed process is likely in the public domain.
• The likely expiry of this patent opens opportunities for generic competition and shifts the focus for R&D and investment towards novel formulations, next-generation therapies, and new methods of use, which may be protected by subsequent patents.

Frequently Asked Questions

1. Does the expiration of Patent 5,656,722 automatically allow for generic production of the drug? No. While the expiration of this specific process patent removes a barrier to using the claimed manufacturing method, generic production also requires freedom to operate concerning any existing composition of matter patents, method of use patents, or formulation patents that cover the drug product itself or its therapeutic applications.

2. Can Schering Corporation (or its successor, Merck & Co.) still enforce this patent? It is highly unlikely. Patents have a finite term. Given the grant date of August 12, 1997, the patent term would have expired either 17 years from grant (August 12, 2014) or 20 years from the filing date, with potential adjustments for Patent Term Extension (PTE) or Patent Term Adjustment (PTA). Unless there were exceptional circumstances leading to an extended term beyond the standard calculations, the patent is almost certainly expired.

3. What does "reductive amination" mean in the context of this patent? Reductive amination is a chemical reaction used to convert a carbonyl group (like an aldehyde or ketone) into an amine. In this patent, it's a key step in linking different molecular fragments to form the final active pharmaceutical ingredient. It typically involves forming an intermediate imine or enamine, which is then reduced to the amine.

4. If the process is expired, how can a company still make money from this drug? Companies can still generate revenue through patents that cover the actual composition of matter of the drug (if still active), novel formulations (e.g., extended-release versions), new therapeutic uses (method of use patents), or specific crystalline forms (polymorph patents) that offer advantages over existing versions. Intellectual property protection extends beyond the initial manufacturing process.

5. What is the significance of the chemical structure described in Claim 1 of patent 5,656,722? The chemical structure is the defining characteristic of the active pharmaceutical ingredient. Claim 1 specifies the exact molecule being synthesized through the patented process. The novelty and utility of this specific chemical structure are fundamental to the patent's validity and the value of the invention it protects.

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Citations

[1] Schering Corporation. (1997). United States Patent 5,656,722: Process for the preparation of a novel compound and its pharmaceutical compositions. Washington, DC: U.S. Patent and Trademark Office.

Details for Patent 5,656,722

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Sanofi-aventis U.s. Llc	LANTUS	insulin glargine	Injection	021081	April 20, 2000	5,656,722	2014-09-12
Sanofi-aventis U.s. Llc	LANTUS	insulin glargine	Injection	021081	April 25, 2007	5,656,722	2014-09-12
Eli Lilly And Company	BASAGLAR	insulin glargine	Injection	205692	December 16, 2015	5,656,722	2014-09-12
Eli Lilly And Company	BASAGLAR	insulin glargine	Injection	205692	November 15, 2019	5,656,722	2014-09-12

International Patent Family for US Patent 5,656,722

Country	Patent Number	Estimated Expiration
South Africa	898456
United States of America	6100376
Portugal	92220
Philippines	30695
New Zealand	231272
Norway	894424