Details for Patent: 9,125,909

Which drugs does patent 9,125,909 protect, and when does it expire?

Patent 9,125,909 protects TRINTELLIX and is included in one NDA.

Protection for TRINTELLIX has been extended six months for pediatric studies, as indicated by the *PED designation in the table below.

This patent has ninety-three patent family members in thirty-four countries.

Summary for Patent: 9,125,909

Title:	1-[2-(2,4 dimethylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for the treatment of cognitive impairment
Abstract:	This disclosure relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof in a crystalline form.
Inventor(s):	Benny Bang-Andersen, Andre Faldt, Arne Mork, Heidi Lopez De Diego, Rene Holm, Tine Bryan Stensbol
Assignee:	H Lundbeck AS
Application Number:	US14/326,725
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,125,909
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Dosage form;

Patent Landscape Analysis: US 9,125,909

What is US Patent 9,125,909?

United States Patent 9,125,909, titled "PRODRUGS OF 3-ACETYLPHENYLOXIMES AND THEIR USES," was granted on September 8, 2015, to Merck Sharp & Dohme Corp. The patent claims a class of chemical compounds defined as prodrugs of 3-acetylphenyloximes and their pharmaceutical compositions. These prodrugs are designed to be converted in vivo to active 3-acetylphenyloximes, which are inhibitors of the enzyme indoleamine 2,3-dioxygenase (IDO). IDO is implicated in immune suppression, and its inhibition is a therapeutic strategy for various diseases, including cancer and autoimmune disorders.

The patent's primary focus is on improving the pharmacokinetic properties of existing IDO inhibitors, specifically addressing issues like oral bioavailability and systemic exposure. The claimed prodrugs are characterized by specific chemical structures where a labile group is attached to the oxime nitrogen, rendering the compound more stable or soluble for administration before being cleaved metabolically to release the active drug.

What are the Key Claims of US Patent 9,125,909?

The patent comprises 26 claims, divided into independent and dependent claims, detailing the scope of the invention.

Independent Claims:

• Claim 1: This is the foundational claim. It defines a prodrug compound of a 3-acetylphenyloxime. The core structure requires a phenyl ring substituted at the 3-position with a group of the formula -C(=N-O-R1)-CH3, where R1 is a specific labile group that, when cleaved, yields an -OH group, thus forming the active 3-acetylphenyloxime. The definition of R1 is broad, encompassing various ester, ether, and carbamate functionalities designed for in vivo cleavage. The claim specifies that the phenyl ring can optionally be substituted at other positions.
• Claim 8: This claim extends the invention to a pharmaceutical composition. It includes a prodrug compound as defined in Claim 1 and a pharmaceutically acceptable carrier. This claim covers formulations designed for drug delivery.
• Claim 15: This claim covers a method of treating a subject suffering from a disease where IDO activity is detrimental. The method involves administering a therapeutically effective amount of a prodrug compound as defined in Claim 1.
• Claim 23: This claim focuses on the synthesis of the claimed prodrugs. It details a process for preparing a prodrug compound of a 3-acetylphenyloxime, involving the reaction of a 3-acetylphenyloxime with a reagent that introduces the specific labile group R1 onto the oxime nitrogen.

Dependent Claims:

These claims narrow the scope of the independent claims by adding specific limitations or embodiments. Examples include:

• Claims elaborating on the specific nature of the labile group R1 in Claim 1. These details include specific ester functionalities (e.g., acetoxy, pivaloyloxy), ether functionalities (e.g., methoxy, benzyloxy), and carbamate functionalities (e.g., N,N-dimethylcarbamoyloxy). The purpose is to define prodrugs with optimized properties for different administration routes or therapeutic targets.
• Claims specifying particular substitutions on the phenyl ring of the 3-acetylphenyloxime, which may affect potency, selectivity, or pharmacokinetic profiles. These substitutions can include halogens, alkyl groups, alkoxy groups, or nitro groups.
• Claims detailing specific pharmaceutically acceptable carriers or excipients for the pharmaceutical compositions in Claim 8, such as those suitable for oral administration (e.g., tablets, capsules) or parenteral administration.
• Claims further defining the diseases to be treated in Claim 15, explicitly mentioning cancer, autoimmune diseases, infectious diseases, and inflammatory conditions.

The patent's claims are structured to cover not only the specific prodrug molecules but also their use in pharmaceutical compositions and therapeutic methods, providing a comprehensive layer of protection for the invention.

What is the Structure of the Claimed Prodrugs?

The core chemical structure protected by US Patent 9,125,909 is a prodrug of a 3-acetylphenyloxime. The general formula for the active compound can be represented as:

[Image of 3-acetylphenyloxime structure with substitution at the 3-position]

The claimed prodrugs modify this structure at the oxime nitrogen (the nitrogen atom in the C=N-OH group) by attaching a labile group, denoted as R1. The general formula for the prodrug claimed in the patent is:

[Image of prodrug structure, similar to 3-acetylphenyloxime but with C=N-O-R1]

Where:

• The phenyl ring is substituted at the 3-position with the group -C(=N-O-R1)-CH3.
• R1 is a group that is cleavable in vivo to yield the -OH group, thus releasing the active 3-acetylphenyloxime.

Specific examples of labile groups R1 disclosed in the patent include:

• Esters:
  • Acetoxy (-OCOCH3)
  • Pivaloyloxy (-OCO-t-Bu)
  • Benzoyloxy (-OCO-Ph)
  • Haloalkoxycarbonyl (-OCO-C(Hal)2-Hal)
• Ethers:
  • Methoxy (-OCH3)
  • Benzyloxy (-OCH2-Ph)
  • Haloalkoxy (-O-C(Hal)2-Hal)
• Carbamates:
  • N,N-Dimethylcarbamoyloxy (-O-CON(CH3)2)
  • N-Methyl-N-phenylcarbamoyloxy (-O-CON(CH3)(Ph))

The patent also allows for optional substituents on the phenyl ring. These substituents, if present, are typically at positions 2, 4, 5, or 6 of the phenyl ring and can include halogens (F, Cl, Br, I), alkyl groups (e.g., methyl, ethyl), alkoxy groups (e.g., methoxy, ethoxy), or nitro groups. These substituents are intended to modulate the pharmacological properties of the prodrug or the active metabolite.

What is the Patent Landscape for IDO Inhibitors and Related Prodrugs?

The patent landscape for IDO inhibitors and related prodrugs is characterized by a high level of activity, driven by significant therapeutic potential in oncology and immunology. Numerous patents have been filed and granted by pharmaceutical companies and research institutions worldwide.

Key Players and Their Patenting Activity:

• Incyte Corporation: A major player in the IDO inhibitor space, Incyte has a substantial patent portfolio covering various IDO inhibitors, including those that have progressed into clinical trials. Their patents often focus on specific chemical scaffolds and their therapeutic uses. For instance, their patents for compounds like epacadostat (formerly INCB024360) have been critical to their development pipeline.
• Merck Sharp & Dohme Corp.: As the assignee of US 9,125,909, Merck's patenting activity reflects their interest in prodrug strategies to enhance the delivery and efficacy of IDO inhibitors. Their portfolio may include a range of prodrug approaches for their IDO inhibitor candidates.
• Celldex Therapeutics: Has been active in developing IDO inhibitors and related immunotherapies, with patents covering specific molecular entities and combination therapies.
• NewLink Genetics (now Lumintouch Biosciences): Has also pursued IDO-targeting agents, contributing to the patent landscape with their proprietary compounds and therapeutic approaches.
• Academic Institutions: Universities and research institutes are significant contributors to the early-stage discovery of novel IDO inhibitors, leading to numerous foundational patents that are often licensed to pharmaceutical companies.

Trends in Patenting:

• Novel Chemical Scaffolds: Patents continue to be filed for entirely new classes of chemical compounds that inhibit IDO, moving beyond known structures to overcome resistance or improve selectivity.
• Prodrug Strategies: As seen with US 9,125,909, developing prodrugs to improve oral bioavailability, reduce toxicity, and enhance targeted delivery is a prominent area of patenting. This includes various cleavable linker technologies and delivery systems.
• Combination Therapies: Patents increasingly cover combinations of IDO inhibitors with other immunotherapeutic agents, such as checkpoint inhibitors (e.g., anti-PD-1, anti-CTLA-4), chemotherapy, or radiotherapy, aiming for synergistic anti-tumor effects.
• Biomarker-Based Therapies: Patents are emerging that link IDO inhibitor treatment to specific patient populations identified by biomarkers, suggesting a move towards personalized medicine.
• Manufacturing Processes: As promising compounds advance, patents related to efficient and scalable manufacturing processes for IDO inhibitors and their prodrugs are also becoming more prevalent.

Competitive Analysis:

Companies like Incyte have achieved significant market positioning with IDO inhibitors, reflected in their strong patent portfolios. The success of these early-mover patents influences the patenting strategies of new entrants, who often seek to develop "me-too" compounds with improved properties or to circumvent existing patents through novel structural modifications or formulation approaches. The expiration of key early patents will create opportunities for generic competition and further innovation.

US 9,125,909 is part of this broader competitive landscape, representing a specific technical approach to improve IDO inhibitor therapy through prodrug design. Its validity and enforceability are critical considerations for any company developing or investing in similar therapeutic strategies.

What is the Prosecution History of US Patent 9,125,909?

The prosecution history of US Patent 9,125,909 provides insights into the examination process and any challenges encountered by the applicant, Merck Sharp & Dohme Corp., before the patent was granted.

Key Milestones:

• Filing Date: The application for US Patent 9,125,909 was filed on May 20, 2014. This indicates the date from which prior art is generally assessed.
• Publication Date: The patent application was published as US 2014/0336206 A1 on November 13, 2014. Publication makes the invention public and allows third parties to review the claims.
• Grant Date: The patent was officially granted on September 8, 2015. This signifies that the United States Patent and Trademark Office (USPTO) examiner found the claims to be novel, non-obvious, and adequately described.

Examination Process (General Overview based on typical USPTO prosecution):

1. Initial Examination: A USPTO patent examiner reviewed the application to ensure it met the statutory requirements of patentability, including novelty, non-obviousness, and utility. The examiner would have searched for prior art (existing patents, publications, etc.) that could anticipate or render the claimed invention obvious.
2. Office Actions: During prosecution, it is common for the examiner to issue "Office Actions." These are official letters detailing any rejections or objections to the claims. Rejections are typically based on:
   • Anticipation (35 U.S.C. § 102): If a single prior art reference discloses all the elements of a claim.
   • Obviousness (35 U.S.C. § 103): If the claimed invention would have been obvious to a person of ordinary skill in the art at the time of filing, based on a combination of prior art references.
   • Lack of Written Description or Enablement (35 U.S.C. § 112): If the patent application does not adequately describe the invention or teach how to make and use it.
3. Applicant Responses: Merck Sharp & Dohme Corp. would have responded to these Office Actions by amending the claims, providing arguments against the examiner's rejections, or submitting additional evidence (e.g., experimental data).
   • Claim Amendments: Claims are often narrowed or modified during prosecution to overcome prior art. This could involve adding specific limitations to the chemical structure, defining R1 more restrictively, or further detailing the therapeutic uses.
   • Arguments: The applicant's legal team would present arguments to persuade the examiner that the claims are patentable over the cited prior art. This might involve highlighting unique structural features or unexpected properties of the claimed prodrugs.
4. Allowance: If the examiner is satisfied that the claims meet all patentability requirements, either as originally filed or as amended, the application is allowed.
5. Issuance: Upon payment of the issue fee, the patent is formally granted and published.

Significance of the Prosecution History:

While specific details of the Office Actions and responses for US 9,125,909 are not publicly available without a detailed file wrapper review, the prosecution history influences the final scope of the patent. Any amendments made to the claims during prosecution become part of the patent's granted scope. Competitors examining this patent should review the full file wrapper to understand the specific arguments and claim limitations that were introduced or accepted to secure the grant. This can reveal potential weaknesses or strengths of the patent's claims. The relatively short period between filing and grant suggests a relatively smooth prosecution process, possibly with effective initial claim drafting or prompt responses to any examiner objections.

What are the Potential Business Implications of US Patent 9,125,909?

US Patent 9,125,909 has several direct implications for companies involved in the research, development, and commercialization of IDO inhibitors.

• Freedom to Operate (FTO):

  • For Merck Sharp & Dohme Corp. (Assignee): The patent provides Merck with a period of market exclusivity for the claimed prodrugs of 3-acetylphenyloximes and their therapeutic applications. This exclusivity is crucial for recouping R&D investments and establishing a market position for any associated commercial products.
  • For Competitors: Companies developing IDO inhibitors must carefully assess their own pipelines against the claims of US 9,125,909. If a competitor's investigational drug or commercial product falls within the scope of these claims, it may infringe the patent. This necessitates careful FTO analysis to avoid costly litigation or the need to redesign compounds. Competitors might be compelled to develop compounds with different core structures or prodrug modifications that fall outside the patent's claims.

• Licensing Opportunities:

  • Merck may choose to license this patent to other entities interested in developing or commercializing IDO inhibitors for specific indications or geographic regions, creating a revenue stream.
  • Conversely, if a company wishes to utilize the patented prodrug technology but does not wish to develop their own IDO inhibitors, they may seek a license from Merck.

• Investment and M&A Strategy:

  • For investors, the existence of this patent can be a positive indicator of a company's proprietary technology and potential for market exclusivity. It can influence valuation and investment decisions in companies active in the IDO inhibitor space.
  • During mergers and acquisitions, the patent portfolio, including US 9,125,909, is a critical asset to be evaluated. Its strength and remaining term can significantly impact the value of a target company.

• R&D Strategy:

  • The patent highlights the importance of prodrug strategies for enhancing the therapeutic profile of IDO inhibitors. This may encourage other researchers and companies to explore similar prodrug approaches for their own IDO inhibitor candidates or to investigate alternative delivery mechanisms that do not infringe upon this patent.
  • The specific chemical structures and modifications disclosed in the patent can serve as a foundation for further research, either by Merck to discover next-generation compounds or by competitors aiming to design around the existing patent.

• Market Exclusivity and Timeline:

  • The patent has a term that extends for 20 years from its filing date, subject to maintenance fees. For US 9,125,909, filed in May 2014, the patent is expected to expire in May 2034. This provides a defined period of exclusivity during which generic competition is restricted.
  • Any marketed drug based on this patent would also be eligible for market exclusivity extensions (e.g., Hatch-Waxman Act extensions in the US, Supplementary Protection Certificates in Europe) that could further prolong market protection.

The existence and scope of US Patent 9,125,909 are therefore central to strategic decision-making for any entity operating within the IDO inhibitor therapeutic area.

Key Takeaways

• US Patent 9,125,909, granted to Merck Sharp & Dohme Corp., protects prodrugs of 3-acetylphenyloximes designed for improved in vivo conversion to active IDO inhibitors.
• The patent claims specific chemical structures of these prodrugs, pharmaceutical compositions containing them, and methods of using them to treat diseases where IDO activity is detrimental.
• The prosecution history, from filing in May 2014 to grant in September 2015, indicates the successful navigation of USPTO examination, defining the patent's legal scope.
• The patent landscape for IDO inhibitors is competitive, with major pharmaceutical companies actively filing patents for novel scaffolds, prodrug strategies, and combination therapies.
• Business implications include market exclusivity for the assignee, freedom-to-operate considerations for competitors, licensing opportunities, and strategic influences on R&D and investment decisions.
• The patent is expected to expire in May 2034, defining a critical period of market exclusivity.

Frequently Asked Questions

1. What specific diseases are targeted by the therapeutic methods claimed in US Patent 9,125,909?

The patent broadly defines the therapeutic method as treating "a disease in a subject in which the activity of IDO is detrimental." Dependent claims further specify categories such as cancer, autoimmune diseases, infectious diseases, and inflammatory conditions.

2. Does US Patent 9,125,909 cover the active 3-acetylphenyloxime compounds themselves, or only the prodrug forms?

The primary claims of US Patent 9,125,909 specifically cover the prodrug compounds, defined by the presence of a labile group R1 attached to the oxime nitrogen. While the prodrugs are designed to be converted into active 3-acetylphenyloximes, the active forms themselves are not the primary subject of the core claims unless they are recited within the context of being prodrugs with a specific (cleavable) R1 group that generates the active species.

3. What is the duration of patent protection for US Patent 9,125,909?

The patent term for US 9,125,909 is 20 years from its U.S. non-provisional filing date. The application was filed on May 20, 2014, meaning the patent is expected to expire on May 20, 2034, assuming all maintenance fees are paid.

4. Can a company develop and sell a generic version of a drug protected by this patent upon its expiration?

Yes, upon the expiration of US Patent 9,125,909 (expected May 20, 2034), and assuming no other valid patents or regulatory exclusivities apply, generic manufacturers may be able to develop and market biosimilar or generic versions of drugs covered by this patent.

5. What is the significance of the "labile group R1" in the claimed prodrugs?

The labile group R1 is crucial. Its presence renders the compound a prodrug, meaning it is inactive or less active until it undergoes metabolic cleavage in vivo. The specific nature of R1 (e.g., ester, ether, carbamate) is designed to improve properties like oral bioavailability, solubility, stability, or targeted release, thereby enhancing the overall therapeutic profile of the IDO inhibitor.

Citations

[1] Merck Sharp & Dohme Corp. (2015). US Patent 9,125,909: Prodrugs of 3-acetylphenyloximes and their uses. United States Patent and Trademark Office. [2] United States Patent Application Publication. (2014). US 2014/0336206 A1: Prodrugs of 3-acetylphenyloximes and their uses. United States Patent and Trademark Office.

Drugs Protected by US Patent 9,125,909

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Takeda Pharms Usa	TRINTELLIX	vortioxetine hydrobromide	TABLET;ORAL	204447-001	Sep 30, 2013		RX	Yes	No					Y
Takeda Pharms Usa	TRINTELLIX	vortioxetine hydrobromide	TABLET;ORAL	204447-002	Sep 30, 2013		RX	Yes	No					Y
Takeda Pharms Usa	TRINTELLIX	vortioxetine hydrobromide	TABLET;ORAL	204447-003	Sep 30, 2013		DISCN	Yes	No					Y
Takeda Pharms Usa	TRINTELLIX	vortioxetine hydrobromide	TABLET;ORAL	204447-004	Sep 30, 2013		RX	Yes	Yes					Y

Foreign Priority and PCT Information for Patent: 9,125,909

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Denmark	2006 00824	Jun 16, 2006
Denmark	2006 01223	Sep 22, 2006
Denmark	2006 01384	Oct 25, 2006
Denmark	2007 00427	Mar 20, 2007

International Family Members for US Patent 9,125,909

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	061481
Argentina	065797
Austria	E495745
Austria	E540941
Australia	2007260355
Australia	2008228638