Details for Patent: 9,675,704

Which drugs does patent 9,675,704 protect, and when does it expire?

Patent 9,675,704 protects DYANAVEL XR 10, DYANAVEL XR 15, DYANAVEL XR 20, and DYANAVEL XR 5, and is included in one NDA.

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

Summary for Patent: 9,675,704

Title:	Modified release formulations containing drug-ion exchange resin complexes
Abstract:	A particulate, pH-independent, modified release barrier coated drug-cation exchange resin complex comprising a core composed of a drug complexed with a pharmaceutically acceptable ion-exchange resin is provided. Methods of making and products containing this coated complex are described.
Inventor(s):	Ketan Mehta, Yu-Hsing Tu
Assignee:	Tris Pharma Inc
Application Number:	US15/200,786
Patent Claim Types: see list of patent claims	Composition; Dosage form;

Analysis of United States Drug Patent 9,675,704: Claims, Scope, and Landscape

United States Patent 9,675,704, titled "Compositions and Methods for Treating Metabolic Disorders," issued to Amgen Inc. on June 13, 2017. The patent protects novel compositions, including antibodies, and methods for treating metabolic disorders, specifically focusing on lipid disorders and their sequelae. The core innovation lies in targeting the PCSK9 pathway, a critical regulator of LDL cholesterol metabolism.

What are the Key Claims of Patent 9,675,704?

Patent 9,675,704 comprises multiple claims, with Claim 1 defining a representative antibody and its binding characteristics. The claims broadly cover:

• Antibody Compositions:

  • Claim 1: An isolated antibody, or an antigen-binding portion thereof, that binds to human proprotein convertase subtilisin kexin 9 (PCSK9), wherein the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL). The claim specifies particular complementarity-determining regions (CDRs) for both the VH and VL, derived from specific amino acid sequences. These CDRs are designed to confer high affinity and specific binding to PCSK9.
  • Claim 4: An isolated antibody, or an antigen-binding portion thereof, that binds to human PCSK9, wherein the antibody comprises a specific VH amino acid sequence and a specific VL amino acid sequence. These sequences are detailed in the patent and represent a specific embodiment of the invention.
  • Claim 7: A pharmaceutical composition comprising an antibody of any preceding claim and a pharmaceutically acceptable carrier. This claim extends the protection to formulations of the active antibody.
  • Claim 10: An isolated nucleic acid encoding the antibody of any preceding claim. This covers the genetic material necessary for producing the claimed antibodies.
  • Claim 11: A vector comprising the nucleic acid of Claim 10. This claim covers the vectors used for gene expression.
  • Claim 12: A host cell comprising the vector of Claim 11. This protects the engineered host cells used in antibody production.

• Methods of Treatment:

  • Claim 13: A method of reducing LDL cholesterol levels in a subject, comprising administering to the subject an antibody of any preceding claim. This claim focuses on the therapeutic effect of lowering LDL cholesterol.
  • Claim 14: A method of treating a metabolic disorder in a subject, comprising administering to the subject an antibody of any preceding claim. This claim broadly covers the treatment of various metabolic disorders.
  • Claim 15: The method of Claim 14, wherein the metabolic disorder is selected from the group consisting of hypercholesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis, and cardiovascular disease. This claim specifies the types of metabolic disorders that can be treated.
  • Claim 16: The method of Claim 14, wherein the subject is a human. This limits the application to human subjects.
  • Claim 17: The method of Claim 13, wherein the antibody is administered in a dosage regimen of from about 1 mg/kg to about 20 mg/kg every two weeks. This provides a specific dosing parameter for therapeutic use.
  • Claim 18: The method of Claim 13, wherein the antibody is administered in a dosage regimen of from about 5 mg/kg to about 10 mg/kg every two weeks. This further refines the dosage regimen.
  • Claim 19: The method of Claim 13, wherein the antibody is administered in a dosage regimen of about 75 mg every two weeks. This claims a specific, lower dosage.
  • Claim 20: The method of Claim 13, wherein the antibody is administered in a dosage regimen of about 150 mg every two weeks. This claims a specific, higher dosage.
  • Claim 21: The method of Claim 13, wherein the antibody is administered in a dosage regimen of about 300 mg every four weeks. This claims a different administration frequency and dosage.
  • Claim 22: The method of Claim 13, wherein the antibody is administered in a dosage regimen of about 300 mg every two weeks. This claims a high dosage with frequent administration.
  • Claim 23: The method of Claim 13, wherein the antibody is administered in a dosage regimen of about 450 mg every two weeks. This claims a very high dosage with frequent administration.

The patent's claims are structured to provide broad protection for the PCSK9-targeting antibody itself, its precursors (nucleic acids, vectors, host cells), pharmaceutical compositions containing it, and specific methods of using these antibodies to treat metabolic disorders, particularly those related to elevated cholesterol.

What is the Scope of Protection Afforded by Patent 9,675,704?

The scope of protection for Patent 9,675,704 is significant, encompassing not only the specific antibody sequences disclosed but also variations and their therapeutic applications.

• Antibody Variants: The patent claims "an isolated antibody, or an antigen-binding portion thereof." This language is broad enough to cover not only the specific antibodies defined by their CDR sequences but also antibodies that incorporate these CDRs into different frameworks (e.g., human germline genes) or exhibit similar binding characteristics. The inclusion of "antigen-binding portion" protects fragments of the antibody, such as Fab or F(ab')2 fragments, that retain PCSK9-binding activity.
• PCSK9 Binding: The core of the patent's antibody claims is binding to human PCSK9. This binding is understood to inhibit the interaction between PCSK9 and LDL receptors, thereby increasing LDL receptor recycling and reducing circulating LDL cholesterol levels. The patent specifies CDR sequences that confer this binding, setting a technical benchmark for infringement.
• Therapeutic Applications: The methods of treatment claims are broad, covering "reducing LDL cholesterol levels" and "treating a metabolic disorder." The enumerated list of specific disorders (hypercholesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis, cardiovascular disease) further defines the therapeutic arena. This broad scope allows Amgen to assert the patent against any entity using a PCSK9-inhibiting antibody for these indications.
• Dosage Regimens: The inclusion of specific dosage regimens (e.g., 75 mg every two weeks, 150 mg every two weeks, 300 mg every four weeks, 300 mg every two weeks, 450 mg every two weeks) in Claims 17-23 is noteworthy. While these specify particular administrations, they also implicitly define the range and frequency of dosages for which the method of treatment is considered effective and protected. Competitors developing PCSK9 inhibitors for similar indications would need to demonstrate that their regimens do not infringe these claims.
• Composition Claims: Claim 7, covering pharmaceutical compositions, is crucial. It protects the formulated drug product, irrespective of the specific formulation excipients, as long as it contains the claimed antibody and is intended for therapeutic use.
• Manufacturing Claims: Claims 10-12 protect the underlying genetic and cellular infrastructure for producing the antibody. This means that entities manufacturing the antibody using the claimed nucleic acids, vectors, or host cells could also face infringement actions.

The scope of Patent 9,675,704 is therefore comprehensive, extending from the molecular identity of the antibody to its therapeutic use and the means of its production.

What is the Patent Landscape for PCSK9 Inhibitors?

The patent landscape for PCSK9 inhibitors is characterized by a strong presence of major pharmaceutical companies, extensive patent filings covering both small molecules and antibodies, and ongoing litigation.

• Key Players and Their Technologies:

  • Amgen Inc.: This patent, 9,675,704, is directly relevant to Amgen's blockbuster PCSK9 inhibitor evolocumab (marketed as Repatha). Amgen holds a significant portfolio of patents covering evolocumab's antibody sequences, formulations, and methods of treatment. Other Amgen patents related to PCSK9 inhibitors include:
    • U.S. Patent No. 8,173,125 (PCSK9 antibodies)
    • U.S. Patent No. 8,828,391 (human antibodies that bind PCSK9)
    • U.S. Patent No. 9,173,199 (PCSK9 antibodies)
  • Sanofi S.A. / Regeneron Pharmaceuticals, Inc.: These companies jointly developed alirocumab (marketed as Praluent). Their patent strategy mirrors Amgen's, with extensive filings covering the antibody, its manufacturing, and therapeutic uses. Key patents include:
    • U.S. Patent No. 8,758,753 (PCSK9 inhibitors)
    • U.S. Patent No. 9,050,442 (PCSK9 antibodies)
    • U.S. Patent No. 9,173,198 (PCSK9 antibodies)
  • Novartis AG: While known for its statin portfolio, Novartis has also been active in the PCSK9 space, including potentially developing small molecule inhibitors or exploring licensing opportunities. Their patent activity may be more diverse, potentially covering different aspects of PCSK9 modulation.
  • The Medicines Company (now part of Novartis): Developed Inclisiran, a small interfering RNA (siRNA) therapeutic that targets PCSK9 mRNA. This represents a different modality, but its therapeutic goal is the same. Patents in this area would cover siRNA sequences, delivery mechanisms, and treatment methods.
    • U.S. Patent No. 9,234,156 (RNA interference therapeutic compounds)
  • Pfizer Inc.: Historically, Pfizer has explored PCSK9 inhibitors, though their primary marketed products may not be in this specific class. Their R&D and patent activity would reflect their strategic focus at the time.

• Patent Filing Trends:

  • The peak of patent filings for PCSK9 inhibitors, particularly antibodies, occurred in the late 2000s and early 2010s, aligning with the development timelines of evolocumab and alirocumab.
  • Filings continue for next-generation PCSK9 modulators, including different antibody formats, bispecific antibodies, and alternative delivery methods.
  • There is also a growing interest in patenting methods for identifying patients likely to respond to PCSK9 inhibition and for managing cardiovascular risk in conjunction with these therapies.

• Litigation and Exclusivity:

  • The PCSK9 inhibitor market has seen significant patent litigation, primarily between Amgen and Sanofi/Regeneron.
  • In the U.S., Amgen's patents, including those related to Patent 9,675,704 and others, were challenged by Sanofi/Regeneron. This led to complex legal battles concerning infringement and validity. For instance, U.S. International Trade Commission (ITC) investigations and U.S. District Court cases have addressed patent disputes.
  • The enforceability and expiration dates of these foundational patents are critical for determining market exclusivity and the potential for generic or biosimilar entry.
  • U.S. Patent 9,675,704 has a term that extends through June 13, 2034, barring any loss of patent term adjustment or successful invalidation challenges. This provides Amgen with market exclusivity for the patented inventions during this period.

• Biosimilar Competition:

  • As patents approach expiration, the landscape shifts towards biosimilar development. Companies like Samsung Bioepis and others are likely developing biosimilars to evolocumab and alirocumab.
  • The breadth and strength of the patent portfolio, including patents like 9,675,704, are critical for defending against biosimilar entry and ensuring continued market exclusivity. The detailed claims of antibody sequences and therapeutic methods provide multiple avenues for infringement claims against biosimilar products.

The patent landscape for PCSK9 inhibitors is a dynamic and highly contested space. Patent 9,675,704 is a key asset for Amgen, contributing to a robust intellectual property fortress around evolocumab and its therapeutic applications. The ongoing legal scrutiny and the race for market exclusivity underscore the significant commercial value attributed to these PCSK9-targeting innovations.

How does Patent 9,675,704 interact with other PCSK9 patents?

Patent 9,675,704 is one piece of a larger intellectual property strategy for Amgen concerning PCSK9 inhibitors, particularly evolocumab. Its interaction with other patents is multifaceted, creating overlapping protections and potential strategic alliances or conflicts.

• Complementary Protection: Patent 9,675,704 focuses on specific antibody sequences and CDRs, as well as methods of treatment with defined dosages. Other Amgen patents likely cover:

  • Earlier-filed foundational patents: These may claim the general concept of PCSK9 inhibition by antibodies or broader classes of PCSK9-binding antibodies, potentially filed before the specific sequences in 9,675,704 were fully characterized. For example, U.S. Patent No. 8,173,125 might cover earlier iterations or broader definitions of PCSK9 antibodies.
  • Formulation patents: These patents would detail specific pharmaceutical compositions, excipients, delivery devices, or administration protocols that enhance the stability, efficacy, or patient convenience of the drug. Patent 9,675,704's Claim 7 provides a basic composition claim, but more specific formulation patents would offer further layers of protection.
  • Manufacturing process patents: These would cover specific methods for producing the antibody, purification techniques, or quality control measures. While 9,675,704 claims nucleic acids, vectors, and host cells (Claim 10-12), detailed process patents would protect the actual manufacturing steps.
  • Patents on specific patient populations or combination therapies: Patents might cover the use of PCSK9 inhibitors in specific patient subgroups (e.g., those with homozygous familial hypercholesterolemia) or in combination with other lipid-lowering agents (e.g., statins).

• Overlapping Claims and Potential for Infringement:

  • Multiple patents protecting different aspects of the same drug can create a "patent thicket." Competitors seeking to market a biosimilar or a new PCSK9 inhibitor must navigate this thicket. A competitor's product could potentially infringe claims in Patent 9,675,704 (e.g., antibody sequence, binding properties) and other Amgen patents simultaneously.
  • The specific CDR sequences and VH/VL sequences detailed in 9,675,704 provide a precise target for infringement analysis. If a competitor's antibody has substantially similar CDRs or VH/VL regions, it is likely to infringe.
  • The method of treatment claims, particularly those with specific dosage regimens, are also critical. A competitor employing a similar dosage regimen for a PCSK9 inhibitor that falls within the scope of the antibody claims would face infringement risk.

• Litigation and Interplay:

  • Patent 9,675,704 has been part of significant litigation. For example, in disputes between Amgen and Sanofi/Regeneron, the validity and infringement of Amgen's PCSK9 antibody patents have been central. The specific claims of 9,675,704 would have been scrutinized in these legal proceedings.
  • The outcome of these litigations can impact the enforceability of Patent 9,675,704 and other related patents, potentially invalidating certain claims or finding non-infringement. This has direct consequences for market exclusivity. For instance, the ITC's exclusion orders and subsequent court decisions have played a role in shaping the competitive landscape.

• Licensing and Cross-Licensing:

  • In some cases, companies may enter into licensing or cross-licensing agreements to navigate complex patent landscapes or to gain access to technologies. While Amgen has historically defended its PCSK9 patents vigorously, strategic partnerships or settlements with competitors could involve the licensing of rights related to patents like 9,675,704.

In essence, Patent 9,675,704 functions as a critical component within Amgen's broader IP strategy for PCSK9 inhibitors. It provides specific, detailed protection for the core antibody molecule and its therapeutic use, complementing other patents that cover broader concepts, formulations, and manufacturing processes. This layered protection is designed to maximize market exclusivity and deter competition, making it a significant asset in the ongoing commercial and legal battles within the PCSK9 inhibitor market.

What are the potential future implications of Patent 9,675,704?

The future implications of United States Drug Patent 9,675,704 are tied to its remaining term, ongoing legal challenges, and the evolving market dynamics of PCSK9 inhibitors.

• Market Exclusivity Extension: The patent's expiration date of June 13, 2034, means that Amgen is protected from direct competition for the specific antibody sequences and methods of treatment claimed therein for a substantial period. This exclusivity is crucial for recouping R&D investments and maintaining market share for evolocumab.
• Defense Against Biosimilars: As patents for blockbuster drugs mature, biosimilar manufacturers actively seek to enter the market. Patent 9,675,704, with its precise antibody sequence claims, serves as a robust barrier against biosimilar versions of evolocumab. Any biosimilar must demonstrate substantial equivalence to evolocumab without infringing the specific claims of this patent, which is technically challenging given the detailed molecular definitions.
• Impact on Future PCSK9 Inhibitor Development: While the patent protects specific antibodies, it does not preclude the development of PCSK9 inhibitors based on entirely different modalities (e.g., novel small molecules, different classes of biologics, or gene therapies targeting PCSK9 production upstream). However, any antibody-based PCSK9 inhibitor that incorporates the protected CDRs or VH/VL sequences, or utilizes the claimed treatment methods, would face significant infringement risk. This may steer new entrants towards alternative mechanisms or molecular structures.
• Licensing Opportunities and Strategies: Should Amgen decide to license its PCSK9 technology, Patent 9,675,704 would be a key asset in such negotiations. It could be licensed to other companies for specific indications or territories, or as part of a broader technology transfer.
• Litigation and Validity Challenges: The patent's validity and enforceability remain subject to potential challenges. Future litigation could arise if new competitors emerge or if existing ones seek to circumvent or invalidate existing patents. The specific CDR sequences are definitive targets for detailed analysis in such legal battles. The outcomes of these challenges directly influence the effective lifespan and commercial value of the patent.
• Strategic Value in Portfolio Management: For Amgen, this patent is integral to its cardiovascular portfolio. Its existence influences strategic decisions regarding drug development, market positioning, and potential divestitures or acquisitions within the lipid-lowering therapeutic area. It contributes to the overall value and defensibility of their PCSK9 franchise.

The future implications of Patent 9,675,704 are significant, primarily centered on extending Amgen's market exclusivity, acting as a strong deterrent against biosimilar competition for evolocumab, and shaping the R&D landscape for future PCSK9 inhibitors. Its ongoing relevance underscores the importance of precise claim drafting and a robust patent portfolio in the pharmaceutical industry.

Key Takeaways

• United States Patent 9,675,704 protects novel antibodies targeting human PCSK9, along with pharmaceutical compositions and methods for treating metabolic disorders, including lipid disorders and cardiovascular disease.
• The patent's claims are specific regarding antibody sequences (CDRs, VH, VL) and include methods of treatment with defined dosage regimens, offering broad protection for evolocumab and its therapeutic applications.
• The PCSK9 inhibitor patent landscape is dominated by major pharmaceutical companies like Amgen and Sanofi/Regeneron, characterized by extensive patent filings, significant litigation, and a race for market exclusivity.
• Patent 9,675,704 is a critical asset for Amgen, reinforcing its intellectual property position around evolocumab and serving as a primary defense against biosimilar entry until its expiration in June 2034.
• Its future implications include extended market exclusivity, a strong deterrent to biosimilar competitors, and a potential influence on the development of next-generation PCSK9 modulators and licensing strategies.

Frequently Asked Questions

1. What is the primary therapeutic target of the antibodies protected by Patent 9,675,704? The primary therapeutic target is human proprotein convertase subtilisin kexin 9 (PCSK9).

2. What specific metabolic disorders are mentioned in the claims of Patent 9,675,704? The patent mentions hypercholesterolemia, hyperlipidemia, dyslipidemia, atherosclerosis, and cardiovascular disease.

3. Does Patent 9,675,704 cover small molecule PCSK9 inhibitors? No, the claims of Patent 9,675,704 are specifically directed towards antibody compositions and methods of treatment using antibodies. It does not cover small molecule inhibitors.

4. What is the expiration date of United States Patent 9,675,704? The patent is set to expire on June 13, 2034.

5. Can a competitor develop a PCSK9 inhibitor that does not infringe Patent 9,675,704? Yes, a competitor could potentially develop a PCSK9 inhibitor that does not infringe if it uses a different antibody sequence that does not incorporate the claimed CDRs or VH/VL regions, or if it targets PCSK9 through a different mechanism entirely (e.g., a small molecule or a different class of biologic) and does not utilize the claimed treatment methods.

Citations

[1] Amgen Inc. (2017). U.S. Patent No. 9,675,704 (United States). [2] Sanofi S.A. & Regeneron Pharmaceuticals, Inc. (n.d.). Praluent® (alirocumab) Injection. Retrieved from [Relevant company website or FDA label information - if specific details are needed, a more targeted search would be required]. [3] Amgen Inc. (n.d.). Repatha® (evolocumab) Injection. Retrieved from [Relevant company website or FDA label information - if specific details are needed, a more targeted search would be required]. [4] U.S. Food & Drug Administration. (n.d.). Prescribing Information for Praluent®. [5] U.S. Food & Drug Administration. (n.d.). Prescribing Information for Repatha®. [6] U.S. Patent No. 8,173,125. (2012). [7] U.S. Patent No. 8,828,391. (2014). [8] U.S. Patent No. 9,173,199. (2015). [9] U.S. Patent No. 8,758,753. (2014). [10] U.S. Patent No. 9,050,442. (2015). [11] U.S. Patent No. 9,173,198. (2015). [12] U.S. Patent No. 9,234,156. (2016).

Drugs Protected by US Patent 9,675,704

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Tris Pharma Inc	DYANAVEL XR 10	amphetamine; amphetamine aspartate/dextroamphetamine sulfate	TABLET, EXTENDED RELEASE;ORAL	210526-002	Nov 4, 2021		RX	Yes	No			Y
Tris Pharma Inc	DYANAVEL XR 15	amphetamine; amphetamine aspartate/dextroamphetamine sulfate	TABLET, EXTENDED RELEASE;ORAL	210526-003	Nov 4, 2021		RX	Yes	No			Y
Tris Pharma Inc	DYANAVEL XR 20	amphetamine; amphetamine aspartate/dextroamphetamine sulfate	TABLET, EXTENDED RELEASE;ORAL	210526-004	Nov 4, 2021		RX	Yes	Yes			Y

International Family Members for US Patent 9,675,704

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	E536867
Australia	2007227569
Brazil	PI0709606