Details for Patent: 10,906,903

Which drugs does patent 10,906,903 protect, and when does it expire?

Patent 10,906,903 protects INGREZZA and INGREZZA SPRINKLE and is included in two NDAs.

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

Summary for Patent: 10,906,903

Title:	Synthetic methods for preparation of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1,-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate)
Abstract:	Provided herein are processes for the preparation of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), or a solvate, hydrate, or polymorph thereof.
Inventor(s):	Kevin MCGEE, Bin-Feng Li, Shawn Branum
Assignee:	Neurocrine Biosciences Inc
Application Number:	US16/929,714
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,906,903
Patent Claim Types: see list of patent claims	Composition; Compound;

US Patent 10,906,903: Valbenazine Tosylate Purity, Moisture, and Impurity-Profile Patent Analysis

US Patent 10,906,903 protects pharmaceutical-grade valbenazine ditosylate defined by moisture content, impurity limits, specified impurities, and compositions containing the resulting material. The patent does not claim the broad discovery of valbenazine, VMAT2 inhibition, or a treatment method. Its commercial relevance is narrower but potentially significant: a generic or competing manufacturer making valbenazine ditosylate for an approved product would likely need to control LOD and specified impurity attributes that fall within the claim boundaries.

The patent’s strongest practical coverage is claim 1, combined with claims 25 through 30, because those claims connect the active pharmaceutical ingredient to pharmaceutical compositions. The most vulnerable issues are the use of analytical product-by-process-style limitations, the meaning of “about,” the test method for LOD, and whether the specified impurity limitations materially distinguish the claimed material from prior-art valbenazine ditosylate.

What drug does US Patent 10,906,903 protect?

The claimed compound is valbenazine ditosylate, the active pharmaceutical ingredient in Ingrezza. Valbenazine is a vesicular monoamine transporter 2, or VMAT2, inhibitor marketed by Neurocrine Biosciences for tardive dyskinesia and chorea associated with Huntington’s disease.

The chemical identity in claim 1 is highly specific:

Attribute	Claimed requirement
Pharmacological class	VMAT2 inhibitor
Active moiety	Valbenazine
Stereochemistry	(S)-(2R,3R,11bR) configuration
Salt form	Di(4-methylbenzenesulfonate), commonly called ditosylate
Moisture limitation	LOD no greater than about 5% by weight
Product type	Drug substance and, through later claims, pharmaceutical compositions

The claim is directed to the specific stereoisomer and ditosylate salt. A different stereoisomer, free base, alternative acid-addition salt, or materially different chemical form would not literally satisfy claim 1, although other patents could cover those forms.

What are the core claims of US 10,906,903?

The claims divide into four groups.

Moisture-controlled valbenazine ditosylate

Claims 1 through 10 establish a descending LOD hierarchy:

Claims	Maximum LOD
1	About 5%
2	About 4%
3	About 3%
4	About 2%
5	About 1%
6	About 0.8%
7	About 0.6%
8	About 0.4%
9	About 0.2%
10	About 0.1%

Each lower-threshold claim is narrower than claim 1. Claim 10 is the most restrictive moisture claim. A batch with an LOD of 0.08% could fall within all applicable lower-threshold claims, while a batch at 1.5% could fall within claims 1 through 4 but not claims 5 through 10, assuming the measurement method and “about” boundary support that result.

Total impurity limits

Claims 11 through 18 depend on claim 4 and therefore require LOD of no greater than about 2% by weight. They add total impurity limits:

Claims	Maximum total impurities
11	About 4%
12	About 3%
13	About 2.5%
14	About 2%
15	About 1.5%
16	About 1%
17	About 0.5%
18	About 0.1%

These claims are narrower than the LOD-only claims because the accused material must satisfy both the moisture limitation and the applicable impurity limitation.

Specified organic and inorganic impurities

Claims 19 through 24 depend on claim 11. They require LOD of no greater than about 2% and total impurities of no greater than about 4%, then identify additional impurity categories.

The specified impurities include:

• Valbenazine alcohol or a salt thereof.
• The alanine ester analog.
• A stereoisomeric valine ester analog.
• A trimethoxy valbenazine analog.
• 6,7-dimethoxy-3,4-dihydroisoquinoline.
• A 7-oxo valbenazine analog.
• Metal-based impurities.
• Dimethylamine, formaldehyde, ethyl chloride, and isopropyl chloride.

Claim 19 is drafted broadly because it covers “one or more” of several named impurities. Claims 20 through 24 identify individual impurity classes or compounds. The dependent structure means that these claims require the parent LOD and total-impurity limitations in addition to the listed impurity feature.

Pharmaceutical compositions

Claims 25 through 30 cover pharmaceutical compositions containing valbenazine ditosylate meeting different claim standards:

Claim	Incorporated limitation
25	Claim 1: LOD about 5% or less
26	Claim 3: LOD about 3% or less
27	Claim 11: LOD about 2% or less and total impurities about 4% or less
28	Claim 14: LOD about 2% or less and total impurities about 2% or less
29	Claim 19: specified impurity profile
30	Claim 24: specified volatile or process-related impurities

These composition claims may be commercially important because an approved tablet or capsule product necessarily contains the active ingredient with excipients. A generic product could face composition-claim exposure even if the manufacturer argues that its drug substance is not separately sold or is manufactured by a different process.

How broad is the scope of claim 1?

Claim 1 has broad numerical coverage within a narrow chemical identity.

The compound limitation is narrow because it requires:

1. The valbenazine stereochemical configuration.
2. The ditosylate salt.
3. The specified molecular structure.
4. LOD of no greater than about 5% by weight.

The LOD limitation is comparatively broad. Most commercially viable pharmaceutical batches would ordinarily be expected to meet a 5% maximum moisture specification, depending on the solid form and manufacturing process. That makes claim 1 potentially more commercially relevant than the narrower 0.1% LOD claim.

The claim does not require:

• A particular crystalline polymorph.
• A particular particle-size distribution.
• A particular manufacturing process.
• A particular dosage strength.
• A particular dosage form.
• A particular VMAT2 assay result.
• A particular therapeutic indication.
• A particular excipient system.

The absence of those limitations reduces design-around opportunities. A manufacturer could not avoid claim 1 merely by changing tablet excipients if the incorporated valbenazine ditosylate still satisfies the claimed chemical and LOD requirements.

What does “weight loss on drying” mean for infringement?

LOD is an analytical measurement, not a structural property. It generally reflects mass lost when a sample is heated under specified conditions, including water and potentially volatile solvents or other volatile components.

The infringement analysis will therefore depend on:

• Drying temperature.
• Drying time.
• Vacuum or atmospheric conditions.
• Sample size.
• Balance sensitivity.
• Initial and final weighing procedures.
• Whether residual solvents are included.
• Whether the patent specification defines the method.
• Whether the accused manufacturer uses the same or a scientifically equivalent procedure.

The phrase “about” creates a boundary issue. A batch measured at 5.01% may be contested depending on the specification, validated method, rounding convention, and intrinsic meaning of “about.” The patent’s narrower claims create a series of fallback positions, but they do not eliminate disputes over measurement reproducibility.

For diligence purposes, an LOD result should be evaluated with the complete analytical method rather than the reported percentage alone. Two laboratories can generate materially different results if one method removes only water while another also removes residual organic solvent.

How do the impurity claims affect generic exposure?

The impurity claims are quality-attribute claims. They do not require a process step or a particular source of contamination. A generic manufacturer could potentially infringe if its final valbenazine ditosylate contains the claimed impurity profile, even when the manufacturer uses a different synthetic route.

This is important because process differences do not necessarily avoid a product claim. If the final drug substance has:

• The claimed valbenazine stereochemistry;
• The ditosylate salt;
• The applicable LOD threshold;
• The applicable total impurity limit; and
• One or more listed impurities,

the product may fall within claims 19 through 24.

Claims 23 and 24 are especially relevant to manufacturing controls. Metal-based impurities and residual chemicals such as dimethylamine, formaldehyde, ethyl chloride, and isopropyl chloride can arise from reagents, catalysts, solvents, quench steps, or equipment. The claims do not appear to require a minimum concentration for every listed impurity. The parent claim’s total-impurity ceiling remains material, but the listed impurity limitation may be satisfied by the presence of a detectable amount, subject to claim construction and the specification’s disclosure.

What are the strongest and weakest claim features?

Strongest features

The strongest features are the cumulative limitations that are difficult to avoid in a commercial product:

• Exact valbenazine stereochemistry.
• Ditosylate salt form.
• Product-level LOD limitation.
• Total impurity ceiling.
• Pharmaceutical composition coverage.

Claims 25 through 30 also provide an infringement route against finished products, not only bulk drug substance.

Potentially weaker features

Several features present litigation risk.

“About”

The claims use “about” for every numerical threshold. The term may be construed in light of the specification, analytical precision, and technical context. It can create uncertainty at the threshold but may also prevent a narrow noninfringement position based on trivial analytical variation.

Measurement dependence

LOD is not self-defining. If the patent does not specify a sufficiently reproducible test method, an accused infringer could challenge indefiniteness or argue that the tested product cannot be reliably classified.

Impurity detection

Claims 19 through 24 may depend on the sensitivity and selectivity of the analytical method. A claim requiring the presence of a named impurity is difficult to enforce if the specification does not establish a validated detection protocol or concentration threshold.

Prior-art vulnerability

Valbenazine ditosylate and pharmaceutical-grade batches may have been disclosed in earlier patents, regulatory filings, or technical documents. The patent’s patentability therefore rests less on the chemical identity of valbenazine and more on the claimed combination of moisture and impurity attributes, together with any demonstrated manufacturing or stability advantage.

How does US 10,906,903 compare with foundational valbenazine patents?

Patent category	Typical subject matter	Relationship to US 10,906,903
Core compound patents	Valbenazine structure and VMAT2 activity	Earlier, broader chemical protection
Salt and solid-form patents	Ditosylate, polymorphs, hydrates, solvates	May overlap with the claimed salt but differ in physical-form limitations
Process patents	Synthesis, resolution, salt formation, purification	May be infringed by manufacturing steps rather than final product
Formulation patents	Tablets, capsules, release profiles, excipient systems	May overlap with claims 25 through 30
Method-of-use patents	Tardive dyskinesia, Huntington’s chorea, dosing regimens	Separate from the quality-attribute claims
US 10,906,903	LOD and impurity-controlled valbenazine ditosylate	Product-quality layer in the valbenazine estate

US 10,906,903 should therefore be analyzed as one layer of the Ingrezza patent estate. It is not a substitute for a full review of composition-of-matter, solid-state, formulation, process, and method-of-use patents.

What is the Orange Book status of US 10,906,903?

The patent’s Orange Book relevance cannot be determined from the claim text alone. Orange Book listing depends on FDA and sponsor records identifying patents submitted for the approved drug and the patent categories accepted for listing.

For a drug substance and composition patent, the key questions are whether the patent was submitted for Ingrezza, whether FDA accepted the listing, the listed expiration date, and whether the listing covers the active ingredient, formulation, or method of use. Patent claims directed to LOD and impurity levels may raise listing-category questions because FDA’s listing rules distinguish patents that claim the drug substance, drug product, or approved method of use.[1]

An Orange Book listing would create potential Paragraph IV exposure for an ANDA applicant if the applicant certifies that the patent is invalid, unenforceable, or not infringed. The listing itself would not establish validity or infringement.

When does US 10,906,903 lose exclusivity?

The patent issued on February 16, 2021. Its enforceable expiration date must be determined from the patent’s earliest effective nonprovisional priority date, terminal disclaimers, patent-term adjustment, and any patent-term extension. The claims supplied do not contain those bibliographic details.

The practical exclusivity timeline is:

Event	Date or status
Patent issuance	February 16, 2021
Patent term	Generally 20 years from the earliest effective nonprovisional filing date
Patent-term adjustment	Must be checked in USPTO records
Terminal disclaimer	Must be checked in the patent file and related family
Patent-term extension	Drug-specific extension, if any, must be checked separately
ANDA challenge timing	Controlled by Orange Book listing and Paragraph IV notice
Generic launch timing	Depends on patent validity, infringement, settlement, and regulatory exclusivity

Regulatory exclusivity is separate from patent exclusivity. Ingrezza received FDA approval in 2017. New drug exclusivity periods associated with the original approval do not by themselves determine the later patent expiration date.[2]

Are Paragraph IV challenges and litigation publicly established by the claims?

No litigation position can be inferred from the claims. A Paragraph IV certification, ANDA filing, notice letter, district-court complaint, settlement, or launch agreement is a separate record.

A complete competitive review should distinguish:

• Patent infringement suits under 35 U.S.C. §271(e)(2).
• Declaratory-judgment actions.
• Inter partes review or post-grant proceedings.
• FDA patent-listing disputes.
• Settlement agreements involving delayed generic entry.
• Authorized-generic or licensing arrangements.

The patent number alone does not establish that any generic manufacturer has challenged US 10,906,903, that Neurocrine has sued an ANDA applicant, or that a settlement exists.

What generic launch risks does the patent create?

A generic applicant faces four principal technical risks.

Drug-substance risk

The applicant’s valbenazine ditosylate may meet claim 1 even if it uses a different synthesis. The 5% LOD threshold is the broadest and most commercially consequential quality limitation.

Finished-product risk

Claims 25 through 30 can potentially reach a finished pharmaceutical composition. Changing excipients, tablet coating, strength, or packaging may not avoid the claims if the active ingredient satisfies the incorporated limitations.

Analytical risk

The applicant must assess LOD and impurity results using validated methods and production-batch data. A specification that routinely produces low moisture and low impurity levels may increase infringement risk rather than reduce it.

Design-around risk

Possible design-around concepts include a different salt, a materially different solid form, or a product that falls outside the claimed LOD and impurity thresholds. Those approaches may be commercially impractical or may encounter other patents in the valbenazine estate.

How strong is the patent estate around valbenazine?

US 10,906,903 is strongest as a later-stage manufacturing and quality-control patent. Its value depends on whether the claimed attributes are inherent in the commercial form of valbenazine ditosylate and whether alternative manufacturing controls can produce a marketable product outside the claim boundaries.

It is weaker than a composition-of-matter patent in one respect: a competitor may be able to design around the claims by changing the salt, solid form, or impurity profile. It is stronger than a narrow process patent in another respect: the claims focus on the finished material, so a different synthetic route may not avoid infringement.

The patent’s commercial importance will turn on three facts:

1. Whether Ingrezza’s marketed drug substance meets the narrower LOD and impurity claims.
2. Whether the patent is listed in the Orange Book and for which category.
3. Whether generic applicants can document noninfringement through a different salt, solid form, or validated impurity profile.

Key Takeaways

• US 10,906,903 covers valbenazine ditosylate with specified LOD and impurity characteristics.
• Claim 1 is the broadest claim, requiring LOD of no greater than about 5%.
• Claims 2 through 10 create progressively narrower moisture limits down to about 0.1%.
• Claims 11 through 18 add total impurity limits ranging from about 4% to about 0.1%.
• Claims 19 through 24 target named organic, inorganic, metal-based, and residual-process impurities.
• Claims 25 through 30 extend the coverage to pharmaceutical compositions.
• The principal infringement issues are LOD methodology, the meaning of “about,” impurity detection, and whether the accused product contains the specified valbenazine salt.
• The patent should be analyzed with separate composition-of-matter, solid-form, process, formulation, method-of-use, and Orange Book records.
• The patent number and supplied claims do not establish a current Paragraph IV challenge, litigation, settlement, license, Orange Book listing, or final expiration date.

Frequently Asked Questions

Does US 10,906,903 cover free-base valbenazine?

No. The claims specifically require the di(4-methylbenzenesulfonate) salt, commonly called valbenazine ditosylate. Free-base valbenazine is outside the literal chemical limitation of the supplied claims.

Does reducing moisture below 0.1% avoid the patent?

No. A product with LOD below 0.1% would still satisfy the broader LOD claims, assuming the other limitations are met. It would not avoid claims 1 through 9 merely because it falls below the claim 10 threshold.

Can a different manufacturing process avoid US 10,906,903?

Not necessarily. The central claims are directed to the final valbenazine ditosylate product and its quality attributes. A different process may still produce a product within the claimed LOD and impurity ranges.

Are the listed impurities required to be present in every claim?

No. Claims 1 through 18 do not require the specific impurities listed in claims 19 through 24. Claims 19 through 24 add those impurity limitations to the parent LOD and total-impurity requirements.

Does a patent covering valbenazine ditosylate automatically block an ANDA?

No. An ANDA applicant must address each relevant listed patent through the applicable certification. A patent may be challenged as invalid, not infringed, or unenforceable, and the regulatory effect depends on FDA listing status, litigation, and any settlement or exclusivity period.

References

1. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book

2. U.S. Food and Drug Administration. (2017). Ingrezza (valbenazine) prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/

3. United States Patent and Trademark Office. (2021). U.S. Patent No. 10,906,903. https://patents.google.com/patent/US10906903

4. United States Code. (2024). 35 U.S.C. §271(e)(2): Infringement of patents in regulated drug applications. https://uscode.house.gov/view.xhtml?req=granuleid:USC-prelim-title35-section271&num=0&edition=prelim

Drugs Protected by US Patent 10,906,903

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Neurocrine	INGREZZA	valbenazine tosylate	CAPSULE;ORAL	209241-001	Apr 11, 2017	AB	RX	Yes	No			Y	Y
Neurocrine	INGREZZA	valbenazine tosylate	CAPSULE;ORAL	209241-003	Apr 23, 2021		RX	Yes	No			Y	Y
Neurocrine	INGREZZA	valbenazine tosylate	CAPSULE;ORAL	209241-002	Oct 4, 2017	AB	RX	Yes	Yes			Y	Y
Neurocrine	INGREZZA SPRINKLE	valbenazine tosylate	CAPSULE;ORAL	218390-001	Apr 30, 2024		RX	Yes	No			Y	Y
Neurocrine	INGREZZA SPRINKLE	valbenazine tosylate	CAPSULE;ORAL	218390-002	Apr 30, 2024		RX	Yes	No			Y	Y

International Family Members for US Patent 10,906,903

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	3009169
China	108925135
China	121045173
Cyprus	1125320
Denmark	3394057