Patent: 10,001,483

Summary for Patent: 10,001,483

Title:	Methods for the treatment of Kaposi\'s sarcoma or KSHV-induced lymphoma using immunomodulatory compounds, and uses of biomarkers
Abstract:	Provided herein are uses of gene and protein biomarkers as a predictor of clinical sensitivity of Kaposi\'s sarcoma (KS) or Kaposi\'s sarcoma-associated herpesvirus (KSHV) induced lymphoma and patient response to treatment with an immunomodulatory compound. Further provided herein are methods for the treatment or management of Kaposi\'s sarcoma or KSHV-induced lymphoma with an immunomodulatory compound, alone or in combination with doxorubicin.
Inventor(s):	Yarchoan; Robert (Bethesda, MD), Zeldis; Jerome B. (Princeton, NJ), Polizzotto; Mark N. (New South Wales, AU), Davis; David A. (Bethesda, MD), Sereti; Irini (Washington, DC), Uldrick; Thomas S. (Washington, DC), Whitby; Denise (Frederick, MD), Khetani; Vikram (Short Hills, NJ)
Assignee:	Celgene Corporation (Summit, NJ) The United States of America, as Represented by the Secretary, Department of Health and Human Services (Washington, DC)
Application Number:	15/192,819
Patent Claims:	see list of patent claims

United States Patent 10,001,483: Claims, Patent Scope, and KSHV Lymphoma Exclusivity Analysis

US Patent 10,001,483 protects a biomarker-directed treatment method for Kaposi’s sarcoma-associated herpesvirus (KSHV)-induced lymphoma using pomalidomide, administered on a 21-days-on/7-days-off schedule. The patent does not claim pomalidomide as a chemical compound. Its commercial value depends on whether a product sponsor, physician, laboratory, or treatment protocol practices the combined elements of patient selection, MHC-I measurement, pomalidomide treatment, and the specified dosing cycle.

The patent is strongest against a deliberately designed KSHV lymphoma regimen that measures reduced MHC-I before prescribing pomalidomide. It is materially weaker against treatment that omits MHC-I testing, uses a different schedule, treats an unselected KSHV population, or relies on a different immunomodulatory agent.

What drug does US Patent 10,001,483 cover?

The compound depicted in the claims is pomalidomide, the immunomodulatory drug marketed in the United States as Pomalyst. Pomalidomide is a thalidomide analogue and is chemically distinct from lenalidomide, although the claims identify prior treatment with either thalidomide or lenalidomide as a patient characteristic.

Pomalidomide has the following relevant commercial attributes:

Item	Data
Active ingredient	Pomalidomide
Brand	Pomalyst
Sponsor and original patent holder	Celgene Corporation
Current major corporate owner	Bristol Myers Squibb, following the Celgene acquisition
FDA dosage form	Oral capsules
FDA-approved principal use	Multiple myeloma after at least two prior therapies, including lenalidomide and a proteasome inhibitor
Typical label schedule	4 mg once daily on Days 1 through 21 of a 28-day cycle
KSHV lymphoma status	Not an FDA-approved indication identified in the Pomalyst prescribing information
Patent type	Method of treatment and biomarker-selected use
Small-molecule pathway	ANDA, not biosimilar

The claim text does not cover every use of pomalidomide. It covers a specified use in KSHV-induced lymphoma, subject to the diagnostic and dosing limitations of the claims.

What are the independent and commercially important claims?

Claim 1 is the only independent claim. It contains four central limitations:

1. The patient has KSHV-induced lymphoma.
2. The patient is identified as sensitive to pomalidomide by measuring MHC-I in a biological sample.
3. Decreased MHC-I relative to a control indicates likely treatment sensitivity.
4. Pomalidomide is administered during a 28-day cycle consisting of 21 consecutive treatment days followed by seven days of rest.

The dependent claims narrow the disease, patient population, dose, route, formulation, prior treatment, and combination therapy.

Claim group	Subject matter	Commercial significance
Claim 1	KSHV lymphoma, reduced MHC-I biomarker, pomalidomide, 21/7 cycle	Core patent position
Claims 2-3	B-cell lymphoma and primary effusion lymphoma (PEL)	Most specific KSHV lymphoma application
Claim 4	Multicentric Castleman’s disease (MCD)	Extends beyond conventional lymphoma terminology
Claims 5 and 18	HIV-positive patients	Targets a major KSHV-associated population
Claims 6-7	Newly diagnosed, relapsed, refractory, or previously treated disease	Broad clinical-line coverage
Claims 8-9 and 19-20	Prior cytotoxic, radiation, immunomodulatory, interferon, local, thalidomide, or lenalidomide therapy	Captures heavily pretreated patients
Claims 10 and 21	Approximately 1-5 mg per day	Covers commercial pomalidomide dose ranges
Claims 11-13 and 22-24	Free base, oral use, capsule, or tablet	Aligns with Pomalyst commercial administration
Claim 25	PEL treated with 5 mg daily for 21 days followed by seven days of rest	Most protocol-specific claim
Claims 14-17 and 26-29	Doxorubicin, PD-1, PD-L1, or CTLA-4 inhibitor combinations	Covers combination development programs

Claims 3 and 25 are likely the most commercially relevant for a clinical program focused on PEL. PEL is a rare B-cell lymphoma closely associated with KSHV and often occurs in patients with HIV. Claim 25 adds the clearest operational regimen: oral pomalidomide at 5 mg per day for 21 consecutive days followed by seven days of rest.

What formulations and doses are protected?

Claims 10 and 21 cover approximately 1, 2, 3, 4, or 5 mg per day. Claims 11 through 13 and 22 through 24 cover the free base, oral administration, and capsule or tablet dosage forms.

The claims therefore overlap directly with the practical characteristics of pomalidomide products:

• oral administration;
• capsule or tablet delivery;
• low-milligram dosing;
• repeated 28-day cycles;
• 21 treatment days followed by seven rest days.

The formulation language does not appear to claim a particular excipient system, particle-size distribution, dissolution profile, coating, polymorph, or manufacturing process. A generic product using the same active ingredient and capsule presentation would not infringe merely because it uses the same dosage form. Infringement would require performance of the claimed treatment method.

A product sponsor could reduce exposure by using:

• a different dose;
• continuous administration;
• a different treatment cycle;
• a non-oral formulation;
• a regimen without the claimed MHC-I patient-selection step.

Those design choices could affect clinical usefulness and regulatory comparability, so they are not automatic freedom-to-operate solutions.

How strong is the MHC-I biomarker limitation?

The MHC-I limitation is the principal narrowing feature of claim 1. The method requires measuring a level of MHC-I in a patient sample and using a decreased level relative to a control to indicate likely pomalidomide sensitivity.

Claim construction issues

Several terms create potential claim-construction disputes:

• “measuring a level” does not specify a particular assay;
• “MHC-1” appears in the supplied claim text, while the conventional designation is MHC class I or MHC-I;
• “biological sample” is not limited to blood, tumor tissue, biopsy material, or another specific specimen;
• “control sample” is not expressly defined;
• “decreased level” has no stated numerical threshold;
• “indicates a likelihood” does not specify a required predictive accuracy;
• “sensitive to treatment” may be interpreted as a biological or clinical response standard.

The breadth of the assay language helps the patent reach different diagnostic platforms. It also creates vulnerability under 35 U.S.C. §112 if the specification does not adequately disclose representative assays, sample types, controls, thresholds, and a credible relationship between reduced MHC-I and pomalidomide response across the claimed disease populations.

Practical enforcement problem

The diagnostic step may be difficult to prove in a conventional prescribing case. A physician who administers pomalidomide without measuring MHC-I would not practice claim 1 as written. A laboratory that performs the test may practice one portion of the method, but method-of-treatment infringement typically requires analysis of who performs each claimed step and whether the steps are attributable to a single actor or jointly controlled.

The biomarker limitation therefore improves validity over an unrestricted “treat KSHV lymphoma with pomalidomide” claim but can reduce enforcement reach.

What disease populations are covered?

The claims cover a broad range of KSHV-associated disease settings, but their practical value differs by population.

Primary effusion lymphoma

PEL is the clearest target. Claims 3 and 18 through 29 specifically address PEL, HIV status, prior treatment, dose, route, formulation, regimen, and combinations.

The PEL claim set could cover a clinical protocol using:

• HIV-positive or HIV-negative patients;
• newly diagnosed or relapsed disease;
• patients previously treated with chemotherapy, radiation, lenalidomide, thalidomide, interferon, or local therapy;
• 5 mg oral pomalidomide on a 21/7 schedule;
• a checkpoint inhibitor or doxorubicin.

KSHV-associated multicentric Castleman’s disease

Claim 4 expressly includes MCD. MCD is not necessarily a lymphoma in ordinary clinical classification, creating a possible scope and written-description issue if the specification treats KSHV-induced lymphoma and MCD as distinct diseases without adequate support for the claimed overlap.

HIV-positive patients

Claims 5 and 18 narrow the population to HIV-positive patients. This limitation may have substantial clinical relevance because KSHV-associated malignancies are concentrated in immunocompromised populations. It does not require a particular HIV viral load, CD4 count, antiretroviral regimen, or degree of immune suppression.

When does US Patent 10,001,483 lose exclusivity?

The patent issued on June 19, 2018. Its expected basic patent term runs from the relevant nonprovisional filing date and generally expires 20 years from the earliest effective U.S. nonprovisional filing date, subject to patent-term adjustment, patent-term extension, terminal disclaimers, and any correction in the USPTO term calculation.

Public patent records associate the application with a priority period beginning in 2014. On that basis, the expected basic expiration is in January 2034, subject to the official USPTO patent-term calculation.

Event	Date or period
Earliest reported priority period	January 2014
U.S. patent grant	June 19, 2018
Expected basic term expiration	Approximately January 2034
Patent-term adjustment	Must be confirmed from the USPTO patent record
Patent-term extension	No extension is established by the claim text
Patent status	Issued U.S. method-of-use patent

Patent expiration should be distinguished from FDA regulatory exclusivity. Pomalyst’s regulatory exclusivity periods were separate from this patent and did not create a KSHV-specific approval. The relevant commercial barrier is therefore the enforceability of the method claims, not a KSHV indication exclusivity period.

What is the Orange Book status of US Patent 10,001,483?

US Patent 10,001,483 should not be treated as an automatic Orange Book barrier to generic pomalidomide.

The FDA Orange Book lists patents submitted by an NDA holder for an approved drug and approved uses. Pomalyst is approved for multiple myeloma, while the claims of US 10,001,483 are directed to KSHV-induced lymphoma and associated treatment regimens.

A method-of-use patent covering an unapproved indication may not provide the same Orange Book leverage as a patent claiming an approved indication. Its listing status must be evaluated against the FDA’s current patent-use-code records for Pomalyst. Even if listed, a generic applicant could use a section viii statement to carve out a patented indication where the product labeling and proposed use permit a lawful non-infringing launch.

Regulatory issue	Assessment
Drug substance approval	Pomalidomide is FDA-approved
KSHV lymphoma approval	Not established in the Pomalyst label
KSHV-specific FDA exclusivity	None established
Orange Book effect	Potentially limited because the patent claims an unapproved use
Generic pathway	ANDA with paragraph IV or section viii strategy, depending on listing and labeling
Biosimilar pathway	Not applicable

Are paragraph IV challenges likely?

A paragraph IV challenge would be relevant only if the patent is listed in the Orange Book in a manner that covers the proposed generic’s use or labeling. Because the patent claims a rare, unapproved KSHV indication, a generic applicant may avoid the claims through a section viii carve-out or by limiting its proposed labeling to non-KSHV uses.

A paragraph IV strategy would still be possible if:

• the patent is listed for Pomalyst;
• the generic labeling includes KSHV lymphoma;
• the applicant seeks approval for a use that falls within the claims;
• the applicant contests validity, enforceability, or infringement.

The principal invalidity theories would likely involve:

Anticipation and obviousness

Prior art could include:

• pomalidomide treatment of hematologic malignancies;
• thalidomide or lenalidomide treatment of KSHV disease;
• known MHC-I downregulation in KSHV-associated tumors;
• preclinical evidence linking MHC-I expression to immunomodulatory-drug response;
• known 21/7 dosing schedules for pomalidomide.

The strongest obviousness argument would combine known pomalidomide activity, known KSHV lymphoma biology, and an established clinical schedule. The patent holder would argue that the specific MHC-I selection rule and disease-specific response were not predictable.

Written description and enablement

The claims span KSHV-induced lymphoma, PEL, MCD, HIV-positive patients, multiple disease stages, multiple prior therapies, several combination agents, and a broad dose range. If the specification contains only limited examples, an accused infringer could argue that the disclosure does not support the full genus.

Indefiniteness

“Decreased level,” “control sample,” and “likelihood” may be challenged if the specification does not provide objective boundaries. The claim may be defensible if the patent describes suitable assays and establishes how a skilled person would determine reduced MHC-I.

Eligibility

The claims combine a diagnostic observation with a treatment step and a defined dosing regimen. The treatment limitation is important under Section 101. A claim that merely observes a natural correlation would face greater eligibility risk, while a claim requiring administration of pomalidomide according to a specific regimen has a stronger argument that it integrates the biomarker into a therapeutic method.

What patent litigation affects the patent?

The patent’s principal litigation risk is likely to arise from a generic or specialty-pharma sponsor using pomalidomide in KSHV lymphoma, rather than from ordinary multiple myeloma commercialization.

There are three practical infringement scenarios:

Scenario	Likely exposure
Generic sells pomalidomide only for multiple myeloma	Low direct exposure unless labeling or promotional conduct reaches KSHV use
Sponsor conducts a KSHV trial using MHC-I selection and 21/7 dosing	High method-claim exposure
Physician uses pomalidomide off-label for KSHV lymphoma without MHC-I testing	Lower literal infringement risk under claim 1
Sponsor uses PEL, 5 mg, oral capsule, 21/7 regimen, and MHC-I testing	Highest overlap, particularly under claims 3 and 25
Sponsor combines pomalidomide with nivolumab or pembrolizumab after MHC-I testing	Potential overlap under claims 14-17 and 26-29

The combination claims do not claim checkpoint inhibitors independently. They require the underlying pomalidomide and KSHV lymphoma method. A checkpoint inhibitor company that does not administer pomalidomide would not practice the combination claims.

No settlement agreement, license, or litigation outcome is established by the claims themselves. The Celgene-Bristol Myers Squibb corporate transaction transferred Celgene’s portfolio context but was not a KSHV-specific license or settlement. [Bristol Myers Squibb, 2019]

What companies are challenging the patent?

The likely competitive parties are generic pomalidomide manufacturers and sponsors developing KSHV lymphoma therapies. A direct challenge would be economically difficult because KSHV-induced lymphoma and PEL are rare indications with limited near-term market size.

The most relevant potential challengers are:

• generic manufacturers seeking broad pomalidomide approval;
• oncology companies developing PEL or KSHV lymphoma programs;
• diagnostic companies whose MHC-I testing is integrated into treatment protocols;
• checkpoint inhibitor companies pursuing combination studies.

The patent’s rare-disease focus reduces the incentive for a standalone validity challenge. A challenge becomes more likely if a sponsor identifies a commercially meaningful KSHV indication or if the claims interfere with a trial design involving MHC-I selection and pomalidomide.

How does this patent compare with the broader pomalidomide estate?

US 10,001,483 is narrower than composition-of-matter or broad formulation patents covering pomalidomide.

Patent category	Scope	Relative strength
Composition of matter	Pomalidomide molecule and salts	Broadest chemical exclusion
Formulation	Capsules, excipients, release characteristics, solid forms	Product-focused
Multiple myeloma method	Pomalidomide treatment of approved disease	Commercially significant
KSHV method, US 10,001,483	Biomarker-selected KSHV lymphoma treatment	Narrow but disease-specific
Combination therapy	Pomalidomide plus checkpoint inhibitors or doxorubicin	Potentially valuable in trials
Manufacturing	Synthetic routes and intermediates	Can create supply-chain barriers
Diagnostic assay	MHC-I testing or response prediction	Dependent on test adoption and claim scope

The KSHV patent may remain legally relevant after broader pomalidomide composition patents expire because a later-expiring method patent can restrict a defined use. It does not, however, prevent generic supply for unrelated indications if the generic label and conduct avoid the patented use.

What manufacturing and geographic barriers exist?

The patent does not appear, from the supplied claims, to cover:

• synthesis of pomalidomide;
• a particular intermediate;
• a specific salt or polymorph;
• a capsule excipient system;
• a manufacturing plant;
• a diagnostic kit as a standalone product.

Its geographic scope is limited to the United States. Foreign family members would need separate analysis in Europe, Japan, China, Canada, Australia, and other jurisdictions. A U.S. patent cannot block manufacture and sale entirely outside the United States, although importation into the United States can create infringement exposure under 35 U.S.C. §271.

The principal non-patent barriers are clinical and regulatory:

• rarity of PEL and KSHV-associated MCD;
• difficulty enrolling HIV-positive and heavily pretreated patients;
• need to validate MHC-I testing;
• absence of an FDA-approved KSHV indication for pomalidomide;
• potential need for investigator-sponsored or orphan-disease development;
• uncertain commercial return relative to trial cost.

What generic launch risks exist?

A generic manufacturer can likely launch pomalidomide for non-KSHV indications if it lawfully omits the patented KSHV use from labeling and avoids active promotion of that use. Risk rises if the manufacturer:

• includes KSHV lymphoma in labeling;
• supplies a protocol specifically designed for the patented regimen;
• markets 5 mg capsules for the claimed PEL regimen;
• provides MHC-I testing instructions linked to pomalidomide treatment;
• funds or directs a trial that practices the claimed method.

The patent is therefore more important as a clinical-development constraint than as a broad generic barrier.

Key Takeaways

• US 10,001,483 is a method-of-treatment patent directed to pomalidomide in KSHV-induced lymphoma.
• Claim 1 requires reduced MHC-I measurement, a sensitivity determination, pomalidomide treatment, and a 21/7 cycle.
• Claims 3 and 25 are the most commercially specific claims for PEL.
• The patent does not claim pomalidomide itself, a generic capsule, or the drug’s manufacturing process.
• The expected basic patent term runs to approximately January 2034, subject to the official USPTO term calculation.
• The patent is not equivalent to FDA exclusivity and does not automatically block generic pomalidomide for multiple myeloma.
• Paragraph IV exposure depends heavily on Orange Book listing and proposed generic labeling.
• Key validity issues include obviousness, enablement, written description, indefiniteness, and the predictive value of MHC-I reduction.
• The highest infringement risk arises from a sponsor running a U.S. PEL or KSHV lymphoma program with MHC-I selection and 5 mg pomalidomide on a 21/7 schedule.
• Biosimilar risk is irrelevant because pomalidomide is a small molecule regulated through the ANDA pathway.

FAQs

Does US Patent 10,001,483 cover lenalidomide?

No. The claims identify prior treatment with lenalidomide or thalidomide, but the claimed treatment compound is pomalidomide.

Does the patent cover all patients with primary effusion lymphoma?

No. The claimed method requires the other elements of the relevant claim, including pomalidomide administration. Claim 1 also requires MHC-I measurement showing a decreased level relative to a control.

Can a generic sell pomalidomide after the composition patent expires?

Potentially, yes, for non-KSHV uses if the generic approval, labeling, and commercial conduct avoid the patented KSHV treatment method.

Is an MHC-I test itself patented by US 10,001,483?

The supplied claims do not claim an MHC-I diagnostic kit as a standalone product. They require MHC-I measurement as part of a treatment method.

Does combining pomalidomide with pembrolizumab fall within the patent?

It may fall within claims 14 through 17 or 26 through 29 when the treatment is for KSHV-induced lymphoma and the other claimed limitations, including the MHC-I selection and pomalidomide regimen, are practiced.

References

Bristol Myers Squibb. (2019). Bristol Myers Squibb completes acquisition of Celgene. https://www.bms.com

Food and Drug Administration. (2024). Pomalyst (pomalidomide) prescribing information. U.S. Department of Health and Human Services. https://www.accessdata.fda.gov

Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. U.S. Department of Health and Human Services. https://www.fda.gov

United States Patent and Trademark Office. (2018). United States Patent No. 10,001,483: Methods of treating KSHV-induced lymphoma. https://patents.google.com

United States Code. (2024). 35 U.S.C. §§ 101, 112, 154, 271, and 282. Government Publishing Office. https://uscode.house.gov

Details for Patent 10,001,483

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Llc	KEYTRUDA	pembrolizumab	For Injection	125514	September 04, 2014	10,001,483	2036-06-24
Msd International Business Gmbh	KEYTRUDA	pembrolizumab	For Injection	125514	4-Sep-14	10,001,483	2036-06-24
Merck Sharp & Dohme Llc	KEYTRUDA	pembrolizumab	Injection	125514	January 15, 2015	10,001,483	2036-06-24
Msd International Business Gmbh	KEYTRUDA	pembrolizumab	Injection	125514	15-Jan-15	10,001,483	2036-06-24
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	22-Dec-14	10,001,483	2036-06-24
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	4-Oct-17	10,001,483	2036-06-24

International Patent Family for US Patent 10,001,483

Country	Patent Number	Estimated Expiration
European Patent Office	3313818
Spain	2970117
Hungary	E065109
Japan	2018527302
Slovenia	3313818
United States of America	2016377621