Details for Patent: 10,138,270

Which drugs does patent 10,138,270 protect, and when does it expire?

Patent 10,138,270 protects KORSUVA and is included in one NDA.

This patent has fifty-three patent family members in twenty-seven countries.

Summary for Patent: 10,138,270

Title:	Synthetic peptide amides
Abstract:	The invention relates to synthetic peptide amide ligands of the kappa opioid receptor and particularly to agonists of the kappa opioid receptor that exhibit low P450 CYP inhibition and low penetration into the brain. The synthetic peptide amides of the invention conform to the structure of formula I: Pharmaceutical compositions containing these compounds are useful in the prophylaxis and treatment of pain and inflammation associated with a variety of diseases and conditions. Such treatable pain includes visceral pain, neuropathic pain and hyperalgesia. Inflammation associated with conditions such as IBD and IBS, ocular and otic inflammation, other disorders and conditions such as pruritis, edema, hyponatremia, hypokalemia, ileus, tussis and glaucoma are treatable or preventable with the pharmaceutical compositions of the invention.
Inventor(s):	Claudio D. Schteingart, Frédérique Menzaghi, Guangcheng Jiang, Roberta Vezza Alexander, Javier Sueiras-Diaz, Robert H. Spencer, Derek T. Chalmers, Robert Zhiyong Luo
Assignee:	Vifor Fresenius Medical Care Renal Pharma Ltd
Application Number:	US15/170,201
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,138,270
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Delivery; Dosage form;

United States Patent 10,138,270: Scope, Claim Construction, Expiration and Difelikefalin Patent Landscape

U.S. Patent No. 10,138,270 is a method-of-treatment patent directed to administering kappa-opioid-receptor agonist peptides for chronic kidney disease. Its commercially important subject matter is the use of difelikefalin, also known as CR845, in human dialysis patients, particularly by intravenous bolus after hemodialysis. The patent does not claim a general composition of matter for difelikefalin. Its principal value is indication, patient-population and dosing-route protection.

The patent creates meaningful risk for a product that uses difelikefalin to treat chronic kidney disease, end-stage renal disease or dialysis-associated patients. It is less likely to block unrelated kappa-opioid indications, non-difelikefalin molecules or products that do not practice the claimed treatment steps.

What does U.S. Patent 10,138,270 protect?

U.S. Patent 10,138,270 protects a method comprising administering a composition containing a defined class of synthetic peptide amides to a mammal with a kappa-opioid-receptor-associated chronic kidney disease.[1]

The claims have four principal layers:

Claim layer	Claims	Protected subject matter
Broad disease and peptide genus	1	Treatment of kappa-opioid-receptor-associated chronic kidney disease using a broad Markush peptide class
Kidney disease severity	2, 10, 12	End-stage renal disease
Dialysis population	3, 4, 9, 11	Dialysis patients, including hemodialysis patients
Human difelikefalin treatment	5-15	Human treatment using D-Phe-D-Phe-D-Leu-D-Lys-[omega(4-aminopiperidine-4-carboxylic acid)]-OH

The broad independent claim is a genus claim. It covers numerous substitutions at Xaa1 through Xaa4 and multiple heterocyclic, amidino, amino and substituted ring structures. The dependent claims narrow the protection to clinically recognizable treatment scenarios.

What molecule is identified in claims 6 through 15?

Claims 6 through 15 identify difelikefalin, the synthetic peptide used in KORSUVA.

The claimed structure is:

D-Phe-D-Phe-D-Leu-D-Lys-[omega(4-aminopiperidine-4-carboxylic acid)]-OH

Difelikefalin is a peripherally restricted, selective kappa-opioid-receptor agonist. KORSUVA injection received FDA approval in August 2021 for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis.[2]

The patent language uses the term "synthetic peptide amide," while the listed difelikefalin structure ends in "OH." The claim also expressly covers pharmaceutically acceptable salts, hydrates and acid salt hydrates. A product analysis must therefore evaluate the administered active moiety, salt form and any claim-relevant conversion or formulation characteristics.

How broad is independent claim 1?

Claim 1 is broad in chemical scope but narrow in therapeutic context.

Chemical breadth

The claim covers a large Markush genus defined by:

• Multiple D-amino-acid residues at Xaa1, Xaa2 and Xaa3.
• Multiple basic amino-acid or amino-acid-derived residues at Xaa4.
• Variable linker structures designated W.
• Nitrogen-containing four- to eight-membered heterocyclic ring systems.
• Substituents including alkyl, aryl, alkoxy, halogen, nitrile, amide, amidino, carboxylic-acid and sulfonamide groups.
• Fused, spiro and bridged ring systems.
• Pharmaceutically acceptable salts, hydrates, acid salt hydrates and N-oxides.

This type of claim is designed to capture related kappa-opioid peptide agonists, not only difelikefalin.

Therapeutic limitation

The claim requires treatment of a "kappa opioid receptor-associated chronic kidney disease." That limitation is material. A compound may fall within the chemical genus but avoid infringement if it is not administered for the claimed disease or if the relevant method does not satisfy the kappa-opioid-receptor-associated requirement.

Administration requirement

The claim requires administration of a composition comprising an effective amount of the peptide. Mere manufacture, possession or sale of the peptide is not necessarily within the literal scope of claim 1. Method-of-use infringement generally depends on the product's labeled indication, instructions, promotional conduct and the conduct of the administering party.

Which claims are most commercially important?

Claims 6 through 15 are the most commercially relevant because they identify difelikefalin and narrow the patient and administration profile.

Claim	Commercial limitation	Practical significance
6	Human patient; difelikefalin structure	Core human-use claim for the active peptide
7	Intravenous administration	Covers the approved injectable route
8	Intravenous bolus	Closely tracks post-dialysis administration practice
9	Post-dialysis administration	Targets hemodialysis workflow
10	End-stage renal disease	Further narrows claim 9
11	Human dialysis patient; post-dialysis difelikefalin	Broad post-dialysis human-use claim
12	End-stage renal disease	Narrows claim 11
13	Oral administration	Protects oral use of difelikefalin in the specified setting
14	Tablet	Covers an oral solid dosage form
15	Solution or suspension	Covers specified oral liquid dosage forms

Claims 7 through 12 have the strongest linkage to the approved KORSUVA product because KORSUVA is administered intravenously to adults undergoing hemodialysis. Claims 13 through 15 extend the estate beyond the currently approved injectable presentation and may have value for lifecycle development.

What patent protection does the patent provide for KORSUVA?

The patent provides indication and regimen protection for KORSUVA in dialysis-associated chronic kidney disease. It does not, standing alone, establish exclusive ownership of every use of difelikefalin.

The commercial protection can be divided into four categories:

1. The difelikefalin molecule may be protected by separate composition-of-matter patents.
2. Chronic kidney disease treatment may be protected by U.S. Patent 10,138,270 and related family members.
3. Intravenous, bolus and post-dialysis administration may be protected by dependent claims in this patent or related patents.
4. Injectable formulation, stability, manufacturing and dosage-form protection may be covered by separate patents.

A generic applicant would need to analyze the entire patent family and FDA Orange Book listings rather than rely on the expiration date or validity of U.S. Patent 10,138,270 alone.

When does U.S. Patent 10,138,270 lose exclusivity?

The patent's ordinary term is determined from its earliest effective nonprovisional filing date, subject to patent-term adjustment, terminal disclaimers and any applicable patent-term extension. A reliable expiration date requires review of the front page, continuity data and USPTO patent-term records.[3]

The patent is associated with the difelikefalin development program and was issued on November 27, 2018.[1] The patent should be analyzed as part of a family with expiration dates potentially extending into the late 2020s or 2029, depending on the earliest priority date and any terminal disclaimer.

The practical loss-of-exclusivity date for KORSUVA is not necessarily the expiration date of this patent. FDA approval may be protected by:

• Composition-of-matter patents.
• Method-of-use patents.
• Formulation patents.
• Patent-term adjustment.
• Pediatric exclusivity.
• Approved-label limitations.
• Litigation settlements that impose a later generic launch date.

A commercial exclusivity model should therefore use patent-by-patent dates from the current Orange Book and USPTO records.[3,4]

What is the Orange Book status of U.S. Patent 10,138,270?

The FDA Orange Book identifies patents submitted by an NDA holder for an approved drug and its approved uses. Orange Book listing status is product-specific and can change through patent-listing updates, delistings and FDA review.[4]

For KORSUVA, the relevant diligence question is whether U.S. Patent 10,138,270 is listed against the approved KORSUVA injection NDA and whether the listed claims cover the approved indication. A method patent that covers the approved chronic kidney disease use can support a Paragraph IV challenge and may trigger the statutory 30-month stay if the patent is properly listed and the NDA holder files suit within the applicable period.[5]

The patent's existence alone does not establish Orange Book listing. Orange Book status must be verified against the current FDA publication and the applicable NDA patent listing information.

What Paragraph IV challenges could target this patent?

An ANDA applicant seeking approval for a difelikefalin product could submit a Paragraph IV certification asserting that a listed patent is invalid, unenforceable or not infringed.[5]

Potential theories against U.S. Patent 10,138,270 include:

Noninfringement

A generic applicant could attempt to avoid infringement by:

• Omitting the chronic kidney disease indication from its label.
• Avoiding dialysis or post-dialysis instructions.
• Limiting the label to a use not covered by the patent.
• Arguing that the proposed product is not the claimed peptide or salt.
• Challenging whether the label instructs administration in a manner meeting the claims.

Label carving is constrained when the patented use is central to the approved product. FDA approval, prescribing information and promotional activity would be important evidence.

Invalidity

The principal invalidity theories would be:

• Lack of written description across the broad Markush genus.
• Lack of enablement for the full breadth of the peptide and heterocycle combinations.
• Anticipation by prior kappa-opioid peptide patents or publications.
• Obviousness based on known kappa-opioid agonists and dialysis-related treatment literature.
• Indefiniteness in terms such as "kappa opioid receptor-associated" or in the structural definition of the genus.

The narrower difelikefalin claims generally present a stronger written-description and enablement position than claim 1 because they identify a specific compound and administration setting.

What patent litigation affects difelikefalin?

The principal litigation risk is an ANDA challenge directed at KORSUVA and its listed patents. A Paragraph IV notice would require the NDA holder or patent owner to assess suit within the statutory period. A timely infringement action can delay FDA approval for up to 30 months, subject to court action and statutory exceptions.[5]

The relevant litigation questions are:

Issue	Business impact
Whether the patent is Orange Book listed	Determines Paragraph IV relevance
Whether the ANDA label includes dialysis-associated pruritus	Determines method-of-use exposure
Whether the generic seeks a carve-out	May narrow infringement risk
Whether the patent has a terminal disclaimer	May align its expiration with another family patent
Whether settlement includes a launch date	Determines actual market entry
Whether the patent survives claim construction	Determines injunction and settlement leverage

No separate biosimilar pathway applies to difelikefalin. Difelikefalin is a synthetic peptide drug, not a biologic approved under the Public Health Service Act. A competing applicant would generally pursue an ANDA or another drug application pathway, not a biosimilar application under section 351(k).[6]

How strong is the patent estate for difelikefalin?

The estate is strongest where the product, indication and administration route overlap:

• Difelikefalin.
• Human patients.
• Chronic kidney disease.
• Hemodialysis.
• Intravenous administration.
• Post-dialysis dosing.

The estate is weaker against:

• A structurally different kappa-opioid agonist.
• A non-CKD indication.
• A product with an approved label that omits the patented use.
• A route or dosage form not covered by an enforceable claim.
• A product supported by a successful written-description or enablement challenge to the genus claim.

The broad genus claim creates potential blocking value, but it also creates litigation exposure because broad Markush claims are more vulnerable to written-description and enablement attacks than claims directed to a single disclosed compound.

What formulation patents and manufacturing barriers matter?

U.S. Patent 10,138,270 is principally a treatment-method patent. It does not, based on the supplied claims, claim:

• A specific injectable excipient system.
• A vial or prefilled syringe.
• A particular concentration.
• A defined pH or buffer.
• A manufacturing process.
• A purification process.
• A crystalline form.
• A specific impurity profile.

Those protections must be located in separate patents or applications.

Manufacturing remains commercially relevant because difelikefalin is a stereochemically defined peptide requiring control of:

• D-amino-acid configuration.
• Sequence integrity.
• Coupling and deprotection impurities.
• Peptide aggregation.
• Residual solvents and reagents.
• Sterility and endotoxin levels for injection.
• Salt or hydrate form.
• Batch-to-batch potency.

These issues create regulatory and quality barriers but do not automatically create patent infringement. A generic peptide manufacturer would need to address both ANDA chemistry, manufacturing and controls requirements and the patent estate.[7]

How does U.S. Patent 10,138,270 compare with composition patents?

Protection type	Typical scope	Relevance to difelikefalin
Composition of matter	Peptide structure and salts	Broadest product control
Method of treatment	Disease, patient and use	Core subject of U.S. 10,138,270
Route and regimen	IV, bolus, post-dialysis, oral	Stronger overlap with the approved label
Formulation	Excipients, concentration, stability	May extend protection beyond molecule expiry
Manufacturing	Synthesis, purification, sterilization	Raises technical entry barriers
Regulatory exclusivity	FDA statutory exclusivity	Independent of patent validity

A generic can avoid one patent while remaining blocked by another. Conversely, expiration of a composition patent does not guarantee immediate entry if a listed method or formulation patent remains enforceable.

What licensing deals affect the commercial landscape?

Cara Therapeutics developed difelikefalin and commercialized KORSUVA in the United States. Vifor Pharma obtained rights associated with commercialization outside the United States, and Vifor was later acquired by CSL.[8] Licensing arrangements can affect who owns, prosecutes, enforces or settles patent rights, but they do not change the claim scope of U.S. Patent 10,138,270.

The relevant commercial parties include:

• Cara Therapeutics, the originator and U.S. rights holder associated with KORSUVA.
• Vifor Pharma, a former commercialization partner.
• CSL, following its acquisition of Vifor.
• Potential generic peptide manufacturers and ANDA sponsors.

What generic entry risks exist?

The likely entry scenarios are:

Scenario 1: Full-label ANDA

The applicant seeks approval for the same dialysis-associated CKD indication. This creates the highest risk of Paragraph IV litigation and a 30-month stay if the statutory requirements are met.

Scenario 2: Carved-out label

The applicant removes patented CKD or dialysis-related use language. This may reduce method-of-use infringement exposure but can limit commercial utility and trigger disputes over induced infringement.

Scenario 3: Alternative formulation

The applicant develops a different injectable or oral formulation. This may avoid formulation claims but remains exposed to composition and method claims.

Scenario 4: Alternative kappa-opioid peptide

A structurally distinct peptide may avoid the difelikefalin-specific claims but could remain within claim 1's broad Markush genus. The applicant would need a detailed claim chart against every structural limitation.

Scenario 5: Post-expiry launch

The applicant accepts the patent estate and targets launch after the latest enforceable patent, settlement date or regulatory exclusivity period.

Geographic coverage and international relevance

U.S. Patent 10,138,270 provides protection only in the United States. Related patent-family members may exist in Europe, Japan, Canada, Australia and other jurisdictions, but national claims, prosecution histories and expiration dates can differ.

The U.S. claim's dialysis-specific structure may be particularly relevant in markets where difelikefalin is approved for chronic kidney disease-associated pruritus. International freedom-to-operate analysis must account for:

• National phase status.
• Granted claims.
• Opposition or post-grant proceedings.
• Supplementary protection certificates.
• Local patent-term adjustments.
• Country-specific medical-use claim formats.
• Local rules governing skinny labels and induced infringement.

Key Takeaways

• U.S. Patent 10,138,270 is a method-of-treatment patent, not the primary composition-of-matter patent for difelikefalin.
• Its strongest commercial claims cover human dialysis patients receiving difelikefalin for chronic kidney disease.
• Claims 7 through 12 closely track intravenous, bolus and post-dialysis use.
• Claims 13 through 15 extend protection to oral tablet, solution and suspension formats.
• The broad Markush claim has substantial chemical breadth but greater written-description and enablement exposure than the compound-specific claims.
• A difelikefalin ANDA would likely require a Paragraph IV analysis if the patent is listed against KORSUVA.
• Difelikefalin is not subject to the biosimilar pathway; generic entry would generally proceed through an ANDA or another drug application route.
• Actual market entry depends on the complete Orange Book listing, related composition and formulation patents, terminal disclaimers, patent-term calculations and any settlement agreement.
• The commercially relevant protection is the combined patent estate, not U.S. Patent 10,138,270 in isolation.

FAQs

Does U.S. Patent 10,138,270 cover all uses of difelikefalin?

No. The claims require treatment of a kappa-opioid-receptor-associated chronic kidney disease or a narrower dialysis-related condition. They do not, on their face, cover every indication or administration of difelikefalin.

Can a generic sell difelikefalin after the composition patent expires?

Not necessarily. A generic may remain exposed to listed method-of-use, formulation, process or dosage-form patents. The approved label and any Paragraph IV litigation would determine practical entry risk.

Does an oral difelikefalin product fall within the patent?

Claims 13 through 15 expressly cover oral administration, including tablets, solutions and suspensions, when the other claim limitations are met.

Is post-dialysis administration required for every asserted claim?

No. Claim 7 requires intravenous administration, while claim 8 adds bolus administration. Claims 9 through 12 add post-dialysis limitations. Claim 6 is broader than those claims because it does not itself require a particular route.

Is U.S. Patent 10,138,270 a formulation patent?

No. The supplied claims primarily cover therapeutic use and administration conditions. They do not recite a specific excipient, concentration, container, buffer or manufacturing process.

References

1. U.S. Patent No. 10,138,270. (2018). Methods of treating chronic kidney disease. United States Patent and Trademark Office.
2. U.S. Food and Drug Administration. (2021). KORSUVA (difelikefalin) injection prescribing information.
3. United States Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation resources.
4. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book.
5. U.S. Food and Drug Administration. (n.d.). Abbreviated new drug application submissions and patent certifications.
6. U.S. Food and Drug Administration. (n.d.). Biosimilars and interchangeable biosimilars.
7. U.S. Food and Drug Administration. (2019). Guidance for industry: ANDAs for certain highly purified synthetic peptide drug products that refer to listed drugs of recombinant or non-recombinant origin.
8. CSL Limited. (2022). Acquisition of Vifor Pharma completed.

Drugs Protected by US Patent 10,138,270

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Vifor Intl	KORSUVA	difelikefalin acetate	SOLUTION;INTRAVENOUS	214916-001	Aug 23, 2021		RX	Yes	Yes	10,138,270					TREATMENT OF MODERATE-TO-SEVERE PRURITUS ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD-AP) IN ADULTS UNDERGOING HEMODIALYSIS (HD)

International Family Members for US Patent 10,138,270

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2064228		301199	Netherlands
European Patent Office	2064228		CA 2022 00045	Denmark
European Patent Office	2064228		PA2022522	Lithuania
European Patent Office	2064228		LUC00282	Luxembourg
European Patent Office	2064228		2022C/546	Belgium