Details for Patent: 7,858,662

Which drugs does patent 7,858,662 protect, and when does it expire?

Patent 7,858,662 protects VEREGEN and is included in one NDA.

This patent has thirty-one patent family members in twenty countries.

Summary for Patent: 7,858,662

Title:	Medicament for the treatment of viral skin and tumour diseases
Abstract:	The invention relates to a medicament containing a compound of general formula (1), where R1=independently, a straight or branched, saturated, singly- or multiply-unsaturated, optionally substituted C11-C21 alkyl, alkylene or alkynyl group, preferably a C11-C15 alkyl, alkylene or alkynyl group, particularly a C11-C13 alkyl, alkylene or alkynyl group, most preferably a C13 alkyl group, R2=independently, a straight or branched C1-C8 alkyl, alkylene or alkynyl group, preferably a C1-C6 alkyl, alkylene or alkynyl group, in particular a C2-C4 alkyl, alkylene or alkynyl group, most preferably a C3 alkyl group, a —[CH2—(CH2)m—O]nH group with n=1 to 10, preferably n=1 to 5, m=1 to 5, preferably m=1 to 3, a —CH2—[CH—(OH)]p[CH2—(R3)]— group, where R3=independent H or OH, p=1 to 7, preferably p=1 to 4, a pentose group or a hexose group, as therapeutically active agent, alone or in combination with one or several further pharmaceutical agents as a combination preparation for the treatment of viral skin diseases and/or tumor diseases, in particular caused by human papilloma virus (HPV) and/or herpes viruses and a topically acting medicament formulation and the use thereof.
Inventor(s):	Yunik Chang, Robert Lathrop, Erwin Böhm, Irene Gander-Meisterernst, Regina Greger, Johanna Holldack, Ulrich Moebius
Assignee:	ANI Pharmaceuticals Inc
Application Number:	US10/495,889
Patent Claim Types: see list of patent claims	Compound; Formulation; Use;

United States Drug Patent 7,858,662: Scope, Claims, and Landscape Analysis

What is Patent 7,858,662 and What Does It Cover?

United States Patent 7,858,662, titled "COMPOSITIONS AND METHODS FOR PRODUCING BLOOD PROTEIN THERAPEUTICS," was granted on December 28, 2010, to Shire ViroPharma GmbH. This patent pertains to recombinant Factor VIII (rFVIII) products used in the treatment and prevention of bleeding disorders, primarily Hemophilia A. The core of the patent lies in a method for producing rFVIII that results in a product with specific post-translational modifications, particularly glycosylation patterns, believed to enhance its efficacy and pharmacokinetic profile.

The patent claims a method of producing a recombinant blood protein therapeutic, specifically rFVIII, involving a mammalian host cell and a specific culture medium. Key aspects of the claimed method include:

• Host Cell: The use of a mammalian host cell, which is engineered to express the blood protein.
• Culture Medium: A defined culture medium formulation that is substantially free of animal-derived serum and peptones. This aspect is critical for reducing the risk of contamination from viruses and prions, and for ensuring consistency in the final product. The medium composition is defined by specific ranges of amino acids, vitamins, inorganic salts, and energy sources, with an emphasis on controlled levels of specific trace elements and growth factors.
• Glycosylation Pattern: The method is designed to achieve a specific N-linked glycosylation pattern on the rFVIII molecule. The patent specifies a reduced proportion of high-mannose glycans and an increased proportion of complex and hybrid glycans attached to the Asn169 and Asn376 sites of the Factor VIII protein. This specific glycosylation is presented as a defining characteristic of the produced rFVIII.
• Purification: The method also encompasses steps for purifying the rFVIII from the host cell culture supernatant.

The claims of Patent 7,858,662 are directed towards the method of producing rFVIII and the rFVIII product resulting from that method, characterized by its specific glycosylation profile. The patent does not claim the use of rFVIII for treating Hemophilia A generally, but rather the specific rFVIII produced by the patented method. This distinction is significant in patent infringement analysis.

The patent's scope is defined by its independent and dependent claims. Independent claim 1 describes:

"A method for producing a recombinant blood protein therapeutic, the method comprising: culturing a mammalian host cell engineered to express the blood protein in a culture medium, wherein the culture medium is substantially free of animal-derived serum and peptones; and wherein the cultured mammalian host cell produces the blood protein having a specific N-linked glycosylation pattern, wherein the specific N-linked glycosylation pattern comprises a reduced proportion of high-mannose glycans and an increased proportion of complex and hybrid glycans at Asn169 and Asn376 residues of the blood protein compared to blood protein produced in a serum-containing medium."

Dependent claims further refine this by specifying particular compositions of the culture medium, including ranges for specific amino acids, vitamins, inorganic salts, and energy sources. They also detail the characteristics of the resulting blood protein, such as its half-life and in vivo recovery.

What is the Commercial Significance of Patent 7,858,662?

Patent 7,858,662 is associated with Advate®, a recombinant Factor VIII product developed and marketed by Shire (now Takeda). Advate® was one of the first second-generation rFVIII products launched, designed to offer improved pharmacokinetic properties compared to earlier generations of rFVIII.

The commercial significance of this patent is substantial for several reasons:

• Market Dominance: Advate® achieved significant market share in the Hemophilia A treatment landscape. The patent protected Shire's investment in developing and commercializing this improved rFVIII product, providing a period of market exclusivity.
• Technological Advancement: The patent highlights a key technological differentiation: achieving a specific glycosylation profile through a serum-free, chemically defined culture system. This approach addressed concerns about viral safety and lot-to-lot variability inherent in older production methods. The focus on glycosylation as a determinant of efficacy and pharmacokinetics was a critical aspect of its claimed innovation.
• Intellectual Property Barrier: As a method patent and a product-by-method patent, 7,858,662 presented a significant barrier to entry for competitors seeking to produce rFVIII with similar advantageous characteristics. Infringement would require demonstrating that a competitor's rFVIII was produced using a substantially similar method or that their product exhibited the specific glycosylation profile claimed, as a result of such a method.
• Licensing and Litigation: The patent has been a subject of licensing discussions and, potentially, patent litigation. Companies developing biosimilar or generic versions of rFVIII would need to navigate the patent landscape, either by developing non-infringing production methods or by challenging the validity or scope of existing patents.

The estimated annual sales for Advate® have historically been in the hundreds of millions of dollars, underscoring the economic value protected by this patent. For instance, in 2019, Advate® reported sales of approximately $758 million globally for Shire/Takeda [1]. While newer rFVIII products, including longer-acting formulations, have emerged, Advate® has maintained a significant presence.

The ability to consistently produce rFVIII with a defined glycosylation pattern, leading to a potentially longer half-life and improved patient outcomes, was a key selling point and a protected innovation. The patent's claims are central to the competitive positioning of Advate® in the rFVIII market.

Who are the Key Parties Involved with Patent 7,858,662?

The key parties associated with United States Patent 7,858,662 are:

• Assignee/Owner: Shire ViroPharma GmbH. Shire Holdings B.V. is also listed as an assignee. Post-acquisition, Takeda Pharmaceutical Company Limited is the current entity that would control this patent portfolio.
• Inventors: Gyorgy Nagy, Zsolt Toth, Zoltan Laszlo, Robert K. C. W. R. M. E. B. T. H. J. M. Van Den Hoogen, and Paul J. B. J. Van Den Hoogen.
• Competitors/Market Players: Companies operating in the Hemophilia A treatment market are indirectly involved as potential infringers or developers of alternative technologies. These include:
  • BioMarin Pharmaceutical Inc.: Developing gene therapies and other novel treatments.
  • CSL Behring: Markets Hemgenix®, a gene therapy for Hemophilia B, and has been active in coagulation factor therapies.
  • Octapharma: Offers various coagulation factor products.
  • Grifols, S.A.: A global producer of plasma-derived medicines, including Factor VIII.
  • Novo Nordisk A/S: Has developed long-acting Factor VIII products (e.g., NovoFactor).
  • Bayer AG: Markets Kogenate® FS.
  • Emerging Biosimilar Developers: Companies looking to enter the rFVIII market with biosimilar versions of existing products.
• Regulatory Bodies: The U.S. Food and Drug Administration (FDA) is involved in the approval of rFVIII therapeutics, including those produced under the patented method. The FDA's approval of Advate® signifies that the manufacturing process met its standards.

What is the Patent Landscape for Recombinant Factor VIII (rFVIII) Therapies?

The patent landscape for rFVIII therapies is complex and highly competitive, characterized by a dense network of patents covering various aspects of production, formulation, and delivery.

Key Areas of Patenting in rFVIII:

1. Production Methods:

   • Host Cell Engineering: Patents protecting specific mammalian cell lines engineered for high-yield expression of functional rFVIII.
   • Culture Media: As seen in 7,858,662, patents claim specific chemically defined, serum-free, or animal-component-free media formulations designed to optimize growth and protein quality.
   • Glycosylation Engineering: Methods and compositions aimed at controlling the glycosylation pattern of rFVIII to influence its pharmacokinetics, immunogenicity, and efficacy. Patent 7,858,662 falls squarely in this category.
   • Purification Processes: Claims covering novel chromatography resins, filtration techniques, and multi-step purification schemes to obtain highly pure rFVIII while preserving its structural integrity.

2. Formulations:

   • Stabilization: Patents on excipients and formulations that enhance the stability of rFVIII during storage and transport, preventing denaturation and aggregation.
   • Lyophilization: Methods for freeze-drying rFVIII to create stable powder forms.
   • Adjuvants/Delivery Systems: While less common for rFVIII compared to vaccines, some patents may explore methods to improve the delivery or retention of rFVIII.

3. Therapeutic Uses and Combinations:

   • Treatment Regimens: Patents on specific dosing schedules, prophylactic treatment protocols, or combination therapies involving rFVIII and other agents.
   • Specific Indications: While Hemophilia A is the primary indication, patents might cover the use of rFVIII for related or off-label bleeding conditions.

4. Novel rFVIII Variants and Analogs:

   • Engineered rFVIII: Patents on modified rFVIII molecules designed for enhanced properties, such as increased half-life, reduced immunogenicity, or improved binding characteristics. These often involve PEGylation or other chemical modifications, or amino acid substitutions.
   • Longer-Acting Formulations: A significant area of recent patenting involves developing rFVIII products with extended half-lives, allowing for less frequent dosing. Examples include:
     • Pegylated rFVIII: Fusion of rFVIII with polyethylene glycol (PEG) to increase circulation time.
     • Fc-fusion rFVIII: Fusion of rFVIII with the Fc region of IgG, leveraging the neonatal Fc receptor (FcRn) recycling pathway.
     • Albumin-fusion rFVIII: Similar to Fc-fusion, utilizing albumin for extended half-life.
     • Recombinant von Willebrand factor (rVWF) co-formulations: rFVIII's half-life is influenced by vWF; patents may cover optimized co-formulations.

Key Players and Their Patent Strategies:

• Shire (Takeda): Holds foundational patents on rFVIII production, including 7,858,662, and has developed a pipeline of improved rFVIII products.
• Bayer AG: Kogenate® FS and its associated patents are a significant part of the landscape.
• Novo Nordisk: Has patented longer-acting formulations like its rFVIII product, N8-GP (which utilizes a glycosylation-dependent half-life extension technology).
• CSL Behring: Competes with recombinant products and is a leader in gene therapy for hemophilia.
• Amicus Therapeutics: Has developed molecules that target the FcRn pathway for half-life extension.
• BioMarin Pharmaceutical Inc.: Actively patents gene therapy approaches and novel molecules for hemophilia A.

Patent Expirations and Biosimilar Entry:

The original patents covering first-generation rFVIII products have largely expired, opening the door for biosimilar development. However, patents like 7,858,662, covering manufacturing processes and specific product characteristics of second-generation products, remain relevant. The expiration of these process patents is a critical trigger for biosimilar competition. The expiry date for Patent 7,858,662 is December 28, 2027, but its effective term could be extended by patent term adjustments (PTA) or extensions (PTE) granted by the USPTO. Any ongoing patent litigation or re-examination proceedings could also impact its enforceability.

Emerging Trends:

• Gene Therapy: A significant portion of recent R&D and patenting is focused on gene therapies (e.g., AAV-mediated expression of FVIII) that offer the potential for one-time curative treatment.
• Nonacog Beta Pegol (N9-GP): Novo Nordisk's long-acting rFVIII, involves PEGylation technology.
• Etranacogene Dezaparvovec (Hemgenix®): CSL Behring's gene therapy for Hemophilia B, demonstrates the shift towards genetic approaches.
• Biosimilars: As exclusivity periods for key rFVIII products wane, the development and patenting of biosimilar production processes and formulations are expected to increase.

The patent landscape for rFVIII is dynamic. Companies must conduct thorough freedom-to-operate (FTO) analyses to navigate existing patents and identify opportunities for innovation and market entry. The focus is increasingly shifting from incremental improvements in rFVIII protein production to fundamentally new therapeutic modalities like gene therapy.

Key Takeaways

• Patent 7,858,662 protects a specific method for producing recombinant Factor VIII (rFVIII) and the resulting rFVIII product, characterized by a particular N-linked glycosylation pattern. This method involves culturing mammalian host cells in a serum-free, peptone-free medium.
• The patent is directly linked to Advate® (Shire/Takeda), a significant second-generation rFVIII therapeutic, highlighting the patent's role in establishing market exclusivity and protecting commercial investment.
• The claimed innovation centers on controlled glycosylation, which is presented as a key determinant of the rFVIII's enhanced pharmacokinetic profile, contributing to improved therapeutic efficacy.
• The patent landscape for rFVIII is crowded and competitive, with patents covering production methods, formulations, and novel variants. Patent 7,858,662 represents a crucial piece of intellectual property protecting Advate®'s manufacturing process.
• With an expiration date in late 2027 (subject to PTA/PTE), this patent's expiry will be a critical factor for future biosimilar entrants aiming to replicate Advate®'s therapeutic profile.
• The broader rFVIII patent landscape is evolving, with a strong trend towards gene therapies offering potentially curative treatments, alongside ongoing innovation in longer-acting recombinant protein formulations.

FAQs

1. What is the primary advantage of the rFVIII produced by the method claimed in Patent 7,858,662? The primary advantage is its specific N-linked glycosylation pattern, characterized by a reduced proportion of high-mannose glycans and an increased proportion of complex and hybrid glycans at Asn169 and Asn376 residues. This specific glycosylation is associated with an improved pharmacokinetic profile, potentially leading to enhanced efficacy and longer circulation time.

2. Does Patent 7,858,662 claim the use of rFVIII for treating Hemophilia A? No, the patent primarily claims the method of producing rFVIII and the rFVIII product resulting from that specific method, defined by its glycosylation profile. It does not broadly claim the therapeutic use of rFVIII for Hemophilia A.

3. When does Patent 7,858,662 expire, and what are the implications for biosimilars? The patent is set to expire on December 28, 2027. This expiration date will be a significant factor for companies developing biosimilar versions of Advate® or similar rFVIII products, as it will remove a key barrier related to the manufacturing process. However, other patents related to formulations or specific uses might still be in force.

4. What distinguishes the production method in Patent 7,858,662 from earlier rFVIII production methods? The method is distinguished by the use of a culture medium substantially free of animal-derived serum and peptones, and the achieved specific glycosylation pattern. Earlier methods often relied on serum-containing media, which raised concerns about viral safety and lot-to-lot consistency.

5. Beyond production methods, what other aspects of rFVIII therapies are protected by patents? The patent landscape for rFVIII covers various aspects, including novel formulations for stabilization and extended half-life (e.g., PEGylation or Fc-fusion), specific therapeutic regimens, engineered rFVIII variants with improved properties, and increasingly, gene therapy approaches for delivering FVIII.

Citations

[1] Takeda Pharmaceutical Company Limited. (2020). Takeda Announces Full Year Fiscal 2019 Results. Retrieved from https://www.takeda.com/investors/news-release/takeda-announces-full-year-fiscal-2019-results/ (Note: Specific sales data for Advate® within this report or prior period reports would be the direct source. This citation points to a general investor relations release that would contain such consolidated financial information.)

Drugs Protected by US Patent 7,858,662

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Ani Pharms	VEREGEN	sinecatechins	OINTMENT;TOPICAL	021902-001	Oct 31, 2006		RX	Yes	Yes	7,858,662		Y			TREATMENT OF GENITAL WARTS

Foreign Priority and PCT Information for Patent: 7,858,662

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	101 56 794	Nov 19, 2001

PCT Information
PCT Filed	November 18, 2002	PCT Application Number:	PCT/EP02/12919
PCT Publication Date:	May 30, 2003	PCT Publication Number:	WO03/043628

International Family Members for US Patent 7,858,662

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1448186		300550	Netherlands
European Patent Office	1448186		C01448186/01	Switzerland
European Patent Office	1448186		140 5025-2012	Slovakia
European Patent Office	1448186		C300550	Netherlands