United States Patent 10,111,900: Claims, Patent Scope, Validity Risks, and Commercial Landscape

US Patent 10,111,900 protects methods that combine a soluble yeast-derived beta-glucan, commonly associated with the investigational product Imprime PGG, with an anti-PD-1 antibody for cancer treatment and immune modulation. The patent is commercially relevant to combinations involving pembrolizumab or nivolumab, but it does not independently protect either antibody, beta-glucan composition, or an approved cancer indication.

The strongest infringement exposure is a clinical or commercial regimen that administers soluble beta-(1,3)/(1,6)-glucan and nivolumab or pembrolizumab to cancer patients. The principal validity risks are obviousness, written-description support for the broad cancer and anti-PD-1 genera, and the evidentiary sufficiency of the claimed immune-mechanism results.

What does US Patent 10,111,900 cover?

US 10,111,900 claims treatment and immune-modulation methods using two required therapeutic components:

A soluble beta-(1,6)-[poly-(1,3)-D-glucopyranosyl]-poly-beta-(1,3)-D-glucopyranose.
An anti-PD-1 antibody.

The beta-glucan structure corresponds to a soluble beta-glucan of the type used in Imprime PGG development. The claims are method claims, not composition claims. They require administration to a subject or a method-directed biological result.

Item	Patent information
Patent	US 10,111,900 B2
Issue date	October 30, 2018
Technology	Soluble beta-glucan plus anti-PD-1 cancer therapy
Principal assignee	Biothera Pharmaceuticals, Inc.
Claim type	Treatment, immune-stimulation, and tumor-microenvironment methods
Key antibody examples	Nivolumab and pembrolizumab
Key product association	Imprime PGG-type soluble beta-glucan
Earliest priority	March 2015, based on the published patent-family record
Nominal patent expiry	Approximately March 2036, subject to USPTO patent-term adjustment or other term changes
FDA status of beta-glucan component	Investigational; not an FDA-approved standalone cancer drug
Orange Book status	No identified Orange Book listing for US 10,111,900

The patent record should be used for the controlling priority and term-adjustment calculation. The nominal expiry date is based on the reported US filing and priority chronology, rather than an assumption that the issue date controls term.

What are the independent claims in US 10,111,900?

Claims 1, 16, and 19 are the principal independent claims.

Claim 1: cancer treatment

Claim 1 requires administering the soluble beta-glucan and an anti-PD-1 antibody to a subject with cancer. It is broad because the cancer is not limited in the independent claim.

The word "comprising" makes the claim open-ended. A regimen can include chemotherapy, radiation, targeted therapy, anti-CTLA-4 therapy, or other agents without necessarily falling outside the claim. Claim 15 narrows one embodiment by excluding IL-2 administration.

Claim 16: immune stimulation

Claim 16 covers administering the same two components to stimulate the subject's immune system against cancer cells. It is not limited to a named tumor type.

Claims 17 and 18 identify immune-cell and cytokine outcomes, including:

M1 macrophage activation;
N1 neutrophil activation;
NK-cell, T-cell, B-cell, or dendritic-cell activation;
interleukin-12;
interferon-gamma; and
tumor-necrosis factor alpha.

Claim 19: tumor-microenvironment modulation

Claim 19 covers administering the combination to remove immune suppression in the tumor microenvironment. Claim 20 specifies suppression of M2 macrophages, N2 neutrophils, myeloid-derived suppressor cells, or combinations of those cell populations.

These claims create a second infringement theory. A sponsor could face exposure even where its clinical protocol does not expressly describe the objective as cancer treatment, if the protocol administers both agents and produces the claimed immune-modulation result.

What dependent claim limitations matter commercially?

The dependent claims add indication, formulation, source, antibody-class, combination-agent, and mechanism limitations.

Claims	Limitation	Commercial significance
2	Melanoma, renal cell carcinoma, or lung cancer	Covers major checkpoint-inhibitor indications
3	Breast, pancreatic, colon, or B-cell lymphoma	Extends coverage into tumors with historically variable checkpoint response
4	Single formulation	Relevant to a fixed-combination product or co-formulated presentation
5	Separate formulations	Covers ordinary co-administration of two products
6-7	Yeast-derived beta-glucan, including Saccharomyces cerevisiae	Supports Imprime PGG-type manufacturing and sourcing
8	Immune-system stimulation	Functional confirmation of the mechanism
9-10	Non-complement-activating or complement-activating antibody	Covers both antibody-function categories
11	IgG4 anti-PD-1 antibody	Particularly relevant to pembrolizumab and nivolumab
12	Nivolumab or pembrolizumab	Highest practical relevance for current checkpoint combinations
13	Bavituximab, ipilimumab, or tremelimumab	Covers selected additional immunotherapy combinations
14	Tumor-targeting antibody	Broadens combination use beyond the named antibodies
15	No IL-2 administration	Preserves a beta-glucan/anti-PD-1 regimen without IL-2

Claims 4 and 5 are alternative product configurations. They do not require the beta-glucan and antibody to be in the same vial. A clinical program using separate intravenous or subcutaneous products may satisfy claim 5 if the other limitations are met.

Which products are most exposed to the patent?

The highest-risk products are investigational or commercial regimens that combine an Imprime PGG-type soluble beta-glucan with pembrolizumab or nivolumab.

Product or program	Potential relevance
Imprime PGG plus pembrolizumab	Directly aligned with claim 12 and claims 1, 4-8, 11, 16, and 19
Imprime PGG plus nivolumab	Directly aligned with claim 12 and the broad anti-PD-1 claims
Imprime PGG plus ipilimumab	Potentially within claim 13 if anti-PD-1 is also administered
Imprime PGG plus tremelimumab	Same limitation applies: claim 13 depends on claim 1, so anti-PD-1 remains required
Beta-glucan plus a non-PD-1 checkpoint inhibitor only	Generally outside the central claims unless an anti-PD-1 antibody is also administered
Insoluble or structurally different beta-glucan	Potentially outside the claims, depending on chemical identity and solubility
Anti-PD-L1 antibody without anti-PD-1	Not literally covered by the anti-PD-1 limitation

A regimen using ipilimumab alone is not covered by claim 13 because claim 13 depends on claim 1, which requires anti-PD-1 administration. The same applies to bavituximab and tremelimumab.

How strong is the patent estate for US 10,111,900?

The patent is strongest against the specific combination of soluble yeast beta-glucan and an anti-PD-1 antibody. It is weaker against products that alter the glucan structure, use a different immunomodulator, or separate the clinical administration from the claimed treatment context.

Strengths

Claim 1 reaches any cancer unless a narrower construction is adopted.
The "comprising" language permits additional treatment agents.
Claims 4 and 5 cover both co-formulation and separate administration.
Claim 12 identifies the two commercially important anti-PD-1 antibodies.
Claims 16 and 19 provide alternative immune-function theories.
Claims 17, 18, and 20 tie the combination to biologically measurable immune effects.
The yeast-source claims can support product identity and manufacturing evidence.

Weaknesses

The central beta-glucan nomenclature is chemically complex and may create claim-construction disputes concerning molecular structure, branching, molecular weight, and solubility.
The broad cancer language in claim 1 may be challenged under written-description and enablement standards if the specification does not support the full scope across tumor types and anti-PD-1 antibodies.
A challenger could argue that beta-glucan immune activation and PD-1 blockade were separately known and that their combination was an obvious immuno-oncology strategy.
Functional claims based on immune stimulation or removal of immune suppression may require proof that the accused regimen produces the claimed result.
The claims do not expressly require a synergistic response, a particular dose, treatment sequence, response rate, or biomarker threshold.

Patent validity is presumed under 35 U.S.C. § 282, but that presumption does not eliminate litigation risk. The grant record should be reviewed for examiner treatment of prior-art combinations, written-description amendments, and any terminal-disclaimer or patent-term-adjustment entries.

What prior-art issues could affect validity?

Obviousness

The most credible obviousness theory would combine:

prior art describing soluble beta-glucans as innate immune stimulators;
prior art describing PD-1 blockade for cancer;
pre-filing evidence suggesting that beta-glucan activation could convert an immunosuppressive tumor microenvironment into one more responsive to checkpoint inhibition.

A challenger would focus on whether a skilled person would have had a reasonable expectation that the specific soluble beta-glucan and anti-PD-1 combination would produce a clinically useful result. The patent owner would likely rely on unexpected immune-cell activation, changes in M1/M2 or N1/N2 populations, cytokine induction, and improved tumor-control data.

Written description and enablement

The patent claims all cancers in claim 1 but expressly lists only selected tumor categories in claims 2 and 3. The breadth of claim 1 may therefore be tested against the examples and disclosure in the specification.

The anti-PD-1 limitation also covers a broad antibody class, while claim 12 identifies nivolumab and pembrolizumab. The specification's disclosure of antibody formats, Fc functions, dosing, and treatment schedules will influence whether the genus claims are adequately supported.

Indefiniteness and claim construction

Potential disputes include:

the structural boundary of the beta-glucan;
the meaning of "soluble";
whether the glucan must be derived from yeast or may be produced by another process;
what constitutes "administering" the two agents;
whether immune stimulation must be measured;
whether "removing immune suppression" requires a demonstrated change in the tumor microenvironment; and
whether the antibody must directly bind PD-1 rather than affect the pathway indirectly.

Claims 17, 18, and 20 are more vulnerable to factual disputes because they recite biological outcomes. Claims 1 and 12 are more straightforward infringement targets because they focus on the administered agents.

What is the FDA and Orange Book status?

The patent does not create FDA approval. Nivolumab and pembrolizumab are FDA-approved anti-PD-1 antibodies for multiple indications, but the combination with the claimed soluble beta-glucan remains a separate regulatory proposition.

The FDA-approved products include:

Opdivo, nivolumab, marketed by Bristol Myers Squibb;
Keytruda, pembrolizumab, marketed by Merck & Co.; and
related approved checkpoint combinations involving other agents.

The beta-glucan combination is not converted into an approved therapy merely because the antibody component is approved. A sponsor would need clinical and regulatory support for the combination, including manufacturing, dosing, safety, efficacy, and indication-specific evidence.

US 10,111,900 is not an ordinary Orange Book patent for an approved small-molecule drug. Orange Book listing depends on submission by the relevant NDA holder and on whether the patent claims the approved drug, formulation, or approved method of use. A third-party combination-method patent generally does not become an Orange Book obstacle to an ANDA for pembrolizumab or nivolumab. It could, however, create separate patent exposure for a sponsor that markets the patented combination.

When does US 10,111,900 lose exclusivity?

The patent issued on October 30, 2018. Based on the reported 2015 priority chronology, the nominal expiration is approximately March 2036. The controlling date is the USPTO-calculated patent term, including any patent-term adjustment, terminal disclaimer, patent-term extension, or correction.

The patent's practical exclusivity is narrower than the calendar term because:

the beta-glucan component is not an FDA-approved standalone oncology drug;
anti-PD-1 antibodies may be used outside the claimed combination;
a competitor may design around the claimed beta-glucan structure;
the claims are directed to administration and treatment, not a monopoly over all checkpoint therapy; and
clinical development failure could prevent meaningful commercial use before patent expiry.

Are there Paragraph IV challenges?

A conventional Paragraph IV challenge to US 10,111,900 is unlikely to be the primary pathway because the patent is not an Orange Book-listed patent for an approved beta-glucan/anti-PD-1 combination product.

A generic applicant filing an ANDA for pembrolizumab or nivolumab would not ordinarily trigger a Paragraph IV certification to this patent unless the patent were listed for the relevant approved product and method. A biosimilar applicant follows the Public Health Service Act pathway rather than the Hatch-Waxman ANDA pathway. The patent could still be asserted in district court against a biosimilar sponsor, but the procedural posture would not be a standard Paragraph IV challenge tied to an Orange Book listing.

What biosimilar and generic entry risks exist?

Pembrolizumab and nivolumab

The principal biologic-entry risk concerns biosimilars to pembrolizumab and nivolumab, not generic copies of the beta-glucan combination. A biosimilar entrant could avoid direct exposure by declining to seek or market the combination indication, depending on the scope of the approved label and the patent owner's enforcement theory.

Beta-glucan products

A competing beta-glucan product may design around the patent by changing:

the source organism;
branching pattern;
molecular-weight distribution;
degree of solubility;
purification process;
formulation;
dosing route; or
combination partner.

Those changes require chemical and clinical equivalence analysis. A product that remains within the claimed structural definition and is administered with an anti-PD-1 antibody may still face infringement risk even if it is sold under a different brand.

What manufacturing and geographic barriers apply?

The patent covers use of the beta-glucan in treatment, not every manufacturing method for producing it. Manufacturing freedom-to-operate therefore requires a separate review of composition, purification, molecular-weight, formulation, and process patents in the relevant family.

Geographically, US 10,111,900 can be enforced only for conduct within US patent jurisdiction. Foreign counterpart patents may create parallel risk in Europe, Japan, China, Canada, and other jurisdictions, but foreign scope, prosecution history, term, and enforceability must be assessed separately. A global clinical trial can create country-specific exposure if the combination is administered in a jurisdiction where a corresponding patent remains enforceable.

Which companies are relevant to the competitive landscape?

Company	Relevant asset or role	Patent impact
Biothera Pharmaceuticals	Developer and patent holder associated with Imprime PGG	Core owner of the beta-glucan/checkpoint combination position
Merck & Co.	Keytruda, pembrolizumab	Potential commercial partner, licensee, or combination sponsor
Bristol Myers Squibb	Opdivo, nivolumab	Potential combination sponsor or enforcement target
AstraZeneca	Imfinzi, durvalumab	PD-L1 rather than PD-1; generally outside the literal core claims absent anti-PD-1 co-administration
Roche/Genentech	Tecentriq, atezolizumab	Same PD-L1 distinction
Other oncology developers	Combination trials using checkpoint inhibitors and innate immune agonists	Potential design-around and competitive threat

The key strategic distinction is between a beta-glucan/anti-PD-1 product and broader innate-immunity/checkpoint programs. US 10,111,900 does not block all combinations of immune agonists with checkpoint inhibitors.

What patent litigation or settlement activity affects the patent?

The cited public patent records do not establish a reported final US district-court judgment, PTAB final written decision, or publicly documented settlement that invalidates or materially narrows US 10,111,900. The patent remains enforceable unless a court, the PTAB, or a later USPTO proceeding changes that position.

A freedom-to-operate review should examine:

the full US prosecution history;
continuation and divisional applications;
foreign counterparts;
assignments and security interests;
post-grant proceedings;
clinical-trial sponsors;
license agreements involving Imprime PGG; and
any confidential settlement or field-of-use restrictions.

Key Takeaways

US 10,111,900 is a combination-treatment patent, not a patent on pembrolizumab, nivolumab, or beta-glucan generally.
Its commercial center is soluble yeast-derived beta-glucan, particularly Imprime PGG-type material, administered with pembrolizumab or nivolumab.
Claim 1 is broad because it covers treatment of a subject with cancer without limiting the cancer type.
Claims 16 and 19 create alternative enforcement theories based on immune stimulation and tumor-microenvironment suppression.
The strongest validity challenges are obviousness, written description, enablement, and construction of the beta-glucan structure.
The patent is not expected to create a conventional Paragraph IV barrier for ordinary ANDA filings directed to Keytruda or Opdivo.
Biosimilar sponsors may face combination-use risk even where the antibody itself is not covered by this patent.
The nominal patent term extends to approximately March 2036, subject to the official USPTO term calculation.
No identified public final decision currently removes the patent's enforceability.
Commercial value depends heavily on successful FDA development of the beta-glucan/anti-PD-1 combination.

FAQs

Does US 10,111,900 cover pembrolizumab by itself?

No. The claims require administration of the soluble beta-glucan together with an anti-PD-1 antibody. Pembrolizumab monotherapy is outside the claims.

Does the patent cover nivolumab plus ipilimumab?

Not by itself. Claim 13 depends on claim 1, so the regimen must also include the claimed soluble beta-glucan and an anti-PD-1 antibody. Nivolumab plus ipilimumab without beta-glucan is outside this patent.

Can a competitor avoid the patent by using a PD-L1 antibody?

Potentially. The claims recite an anti-PD-1 antibody, not an anti-PD-L1 antibody. A regimen using only atezolizumab, durvalumab, or avelumab may avoid literal infringement, subject to claim construction and equivalents analysis.

Is Imprime PGG an FDA-approved cancer drug?

No. Imprime PGG has been developed as an investigational soluble beta-glucan immunomodulator. The FDA approvals for pembrolizumab and nivolumab do not approve the beta-glucan combination.

Does a single-vial combination create more patent risk than separate administration?

Both configurations are expressly addressed. Claim 4 covers a single formulation, while claim 5 covers separate formulations. The patent therefore targets the therapeutic combination rather than only a fixed-dose product.

References

Biothera Pharmaceuticals, Inc. (2018). US Patent No. 10,111,900 B2: Methods of treating cancer using soluble beta-glucan and anti-PD-1 antibody. United States Patent and Trademark Office.
United States Patent and Trademark Office. (n.d.). Patent Center: US10,111,900. https://patentcenter.uspto.gov/
U.S. Food and Drug Administration. (2024). Drugs@FDA: FDA-approved drugs. https://www.accessdata.fda.gov/scripts/cder/daf/
U.S. Food and Drug Administration. (2024). Purple Book: Database of licensed biological products. https://purplebooksearch.fda.gov/
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book-data-files
35 U.S.C. §§ 101, 112, 271, 282. (2024). United States Code.
37 C.F.R. §§ 1.701-1.705. (2024). Patent term adjustment and patent term extension regulations.

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bristol-myers Squibb Company	YERVOY	ipilimumab	Injection	125377	25-Mar-11	10,111,900	2036-12-21
Merck Sharp & Dohme Llc	KEYTRUDA	pembrolizumab	For Injection	125514	September 04, 2014	10,111,900	2036-12-21
Msd International Business Gmbh	KEYTRUDA	pembrolizumab	For Injection	125514	4-Sep-14	10,111,900	2036-12-21
Merck Sharp & Dohme Llc	KEYTRUDA	pembrolizumab	Injection	125514	January 15, 2015	10,111,900	2036-12-21
>Applicant	>Tradename	>Biologic Ingredient	>Dosage Form	>BLA	>Approval Date	>Patent No.	>Expiredate

Patent: 10,111,900

Summary for Patent: 10,111,900