Details for Patent: 8,486,973

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Which drugs does patent 8,486,973 protect, and when does it expire?

Patent 8,486,973 protects SUBSYS and is included in one NDA.

This patent has nine patent family members in nine countries.

Summary for Patent: 8,486,973

Title:	Sublingual fentanyl spray
Abstract:	The present invention is directed to sublingual formulations containing fentanyl, a pharmaceutically acceptable salt thereof, or derivative thereof, suitable for administration to a patient, and methods for treatment with the formulations.
Inventor(s):	S. George Kottayil, Venkat R. Goskonda, Zhongyuan Zhu, Linet Kattookaran, Neha Parikh
Assignee:	Btcp Pharma LLC
Application Number:	US12/221,333
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,486,973
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Delivery; Device;

US Patent 8,486,973: Fentanyl Sublingual Spray Claims, Exclusivity, Litigation and Patent Landscape

US Patent 8,486,973 protects a narrow fentanyl delivery platform rather than fentanyl generally. Its core combination is a propellant-free sublingual spray containing fentanyl, ethanol, propylene glycol and, optionally, water, with specified droplet size and human pharmacokinetic performance. The patent was assigned to Insys Therapeutics and is associated with Subsys, an FDA-approved fentanyl sublingual spray.

The strongest infringement risk arises where a competing product uses all of the following: a propellant-free sublingual spray, fentanyl at the claimed concentration, ethanol at 50% to 60% by weight, propylene glycol at 4% to 6% by weight, droplets with a mean diameter of at least approximately 10 microns, and pharmacokinetic results within the claimed ranges. The patent does not block fentanyl tablets, buccal films, nasal sprays, injectable products or sublingual products that fall outside the claimed formulation and delivery parameters.

What does US Patent 8,486,973 protect?

US Patent 8,486,973 protects three related subject matters:

1. A method of treating pain using a propellant-free fentanyl sublingual spray.
2. A method of manufacturing the spray by mixing fentanyl, purified water and dehydrated alcohol and loading the mixture into a sublingual delivery device.
3. A fentanyl spray that produces specified pharmacokinetic and droplet-size characteristics in humans.

The issued patent contains 20 claims. Claims 1, 19 and 20 are the principal independent claims. Claims 2 through 18 depend primarily from claim 1.

Claim group	Subject matter	Principal limitations
Claims 1-18	Treatment of pain	Fentanyl sublingual spray, propellant-free, specified formulation, droplet size and pharmacokinetics
Claim 19	Manufacturing method	Admix fentanyl, purified water and dehydrated alcohol; place mixture into sublingual delivery device
Claim 20	Treatment of pain	Fentanyl sublingual spray producing approximately 60% of maximum plasma concentration in about 10 minutes

The patent is formulation-specific and performance-specific. A product may contain fentanyl and be administered sublingually without infringing if it lacks one or more required claim limitations.

What are the key technical limitations in claim 1?

Claim 1 requires every element below:

Limitation	Claimed requirement
Therapeutic use	Treating pain
Active ingredient	Fentanyl or a pharmaceutically acceptable salt
Dosage form	Sublingual spray
Propellant	Propellant-free
Fentanyl content	Approximately 0.1% to 0.8% by weight
Ethanol	Approximately 50% to 60% by weight
Propylene glycol	Approximately 4% to 6% by weight
Droplet size	Mean diameter of at least approximately 10 microns
Pharmacokinetics	Mean Tmax of approximately 1.28 hours plus or minus 0.60 hours

The claimed Tmax range is approximately 0.68 to 1.88 hours if the "about" range is treated arithmetically. The claim does not require a single exact Tmax of 1.28 hours. It requires a formulation that, when administered under the relevant conditions, produces the claimed mean pharmacokinetic result.

The formulation ranges are cumulative. A competing spray containing 49% ethanol or 6.5% propylene glycol would have a potential non-infringement position on literal claim scope, subject to the interpretation of "about" and the doctrine of equivalents.

How do claims 2 through 18 narrow the patent scope?

Claims 2 through 18 add concentration, dose, pharmacokinetic and bioavailability limitations.

Fentanyl concentration and dose

Claims 2 and 3 cover fentanyl concentrations of approximately 1, 2, 4, 6 or 8 mg/mL. Claims 5, 7, 10, 13, 14 and 15 address specific doses, especially a 400-microgram dose.

At 4 mg/mL, a 400-microgram dose corresponds to approximately 0.1 mL of formulation. The claims also cover 100-, 200-, 600- and 800-microgram doses.

Pharmacokinetic limitations

The patent claims:

• Mean Cmax of approximately 0.813 ng/mL plus or minus 0.252 ng/mL for a 400-microgram dose.
• Mean Tmax values of approximately 1.12 hours for 100 micrograms, 1.04 hours for 200 micrograms, 0.97 hours for 400 micrograms, 0.987 hours for 600 micrograms and 1.06 hours for 800 micrograms.
• Approximately 60% of mean Cmax in 10 minutes.
• Approximately 86% of mean Cmax in 20 minutes.
• More than 80% of mean Cmax for approximately two hours.
• Mean AUClast of approximately 4.863 hour-ng/mL plus or minus 1.70821.
• Mean AUCinf of approximately 5.761 hour-ng/mL plus or minus 1.916.
• AUCextrap of approximately 10.26% plus or minus 5.66%.
• Bioavailability of approximately 71% plus or minus 16% based on AUClast.
• Geometric mean ln(Cmax) of approximately 0.7865 ng/mL.

These claims create narrower fallback positions. A challenger may avoid one dependent claim by failing to meet a specific Cmax or AUC value while still facing claim 1 if the broader formulation and Tmax limitations are met.

What is the scope of the manufacturing claim?

Claim 19 covers a manufacturing process requiring:

1. Fentanyl.
2. Purified water.
3. Dehydrated alcohol.
4. Admixing those components.
5. Placing the mixture into a sublingual delivery device.
6. A final formulation with the specified fentanyl, ethanol and propylene glycol ranges.
7. A mean Tmax of approximately 1.28 hours plus or minus 0.60 hours.
8. A mean aerodynamic particle size of at least approximately 10 microns upon delivery.

Claim 19 is narrower than a general formulation claim but creates a separate process-based infringement theory. A manufacturer could face process claim exposure even where its commercial product is evaluated through manufacturing records rather than only through finished-product testing.

The claim uses "mean aerodynamic particle size," while claim 1 uses "mean diameter." Those terms may create claim-construction disputes. Aerodynamic particle size incorporates particle density and aerodynamic behavior, while geometric droplet diameter is a physical size measurement. The distinction may matter for spray testing and infringement analysis.

What formulation is associated with Subsys?

Subsys is a fentanyl sublingual spray approved by the FDA for breakthrough pain in adults with cancer who are already receiving and tolerant to around-the-clock opioid therapy. The FDA approved Subsys in January 2012 under NDA 203826. Its approved strengths included 100, 200, 400, 600, 800 and 1,200 micrograms per spray, although the patent claims quoted here specifically recite strengths through 800 micrograms. [2]

The approved product uses a sublingual spray delivery system and is subject to the FDA’s Risk Evaluation and Mitigation Strategy for transmucosal immediate-release fentanyl products. The product label also limits use to opioid-tolerant adult patients because of fentanyl’s respiratory-depression risk. [2]

The patent’s claimed formulation ranges overlap the technical profile of Subsys. That overlap is commercially important because an ANDA applicant seeking approval for an equivalent fentanyl sublingual spray may need to address both formulation and method-of-use patent claims.

What is the Orange Book status of US Patent 8,486,973?

US Patent 8,486,973 has been associated with Subsys and its NDA listing in the FDA Orange Book. The patent’s relevance is tied to the approved fentanyl sublingual spray product, not to fentanyl products generally. [1]

The patent issued on July 30, 2013. Its earliest priority and patent-term history determine the statutory expiration date. Public patent records identify a December 2007 priority position for the relevant fentanyl spray technology, placing ordinary patent expiration in the late 2020s, subject to patent-term adjustment, terminal disclaimers and any applicable regulatory patent-term extension. [3]

Event	Date or period
Earliest relevant priority	December 2007
Patent issued	July 30, 2013
Ordinary 20-year term	Late 2027, subject to term calculation
FDA approval of Subsys	January 2012
Listed product	Subsys fentanyl sublingual spray
Regulatory pathway	NDA 203826

The precise expiration date should be determined from the USPTO patent-term calculation and the current Orange Book listing. A patent listing does not itself establish that every claim remains enforceable or that the patent is immune from invalidity challenges.

When does fentanyl sublingual spray lose exclusivity?

Fentanyl sublingual spray exclusivity depends on several separate rights:

• FDA orphan-drug exclusivity, if applicable to the approved indication.
• New chemical entity exclusivity, if applicable to the NDA.
• Patent exclusivity.
• Orange Book-listed method-of-use and formulation patents.
• Any pediatric exclusivity.
• Commercial or regulatory restrictions on generic labeling.

For Subsys, the principal long-term barrier has been patent protection rather than the initial FDA exclusivity period. The patent term extends materially beyond the 2012 approval date. Generic entry before patent expiry would generally require a Paragraph IV certification, a successful patent challenge, a settlement permitting entry, or an agreement to launch after the relevant patent expires.

Which companies have challenged the Subsys patent estate?

Public records have associated generic competition with ANDA activity concerning fentanyl sublingual spray. The relevant parties may include generic manufacturers filing ANDAs and Insys or related patent owners defending Orange Book-listed rights.

A Paragraph IV certification would allege that the listed patent is invalid, unenforceable or not infringed. The patent owner generally has 45 days after receiving notice to file an infringement action. A timely action can trigger a 30-month stay of FDA approval under the Hatch-Waxman framework, subject to statutory exceptions and court rulings. [4]

The claim set creates several likely challenge theories:

Lack of written description or enablement

A challenger could argue that the specification does not support the full combination of broad formulation ranges, droplet size and numerous human pharmacokinetic outcomes across all claimed doses.

Indefiniteness

Potential targets include:

• "About"
• "Substantially dose proportional"
• "Effective amount"
• "Mean diameter"
• "Mean aerodynamic particle size"
• The relationship between "Tmax" and time to 60% of maximum plasma concentration

Obviousness

A challenger could combine known fentanyl formulations, ethanol-based sublingual delivery systems, propylene glycol excipients, metered spray devices and prior pharmacokinetic data.

Infringement by testing

Many dependent claims require human pharmacokinetic data. A patent owner may need to establish infringement through bioequivalence studies, clinical testing, product characterization or regulatory submissions. Formulation limitations are generally easier to test than patient-treatment limitations, although induced-infringement theories can make approved labeling important.

How strong is the patent estate?

The estate has moderate strength against close copies and weaker strength against materially different delivery systems.

Risk category	Assessment
Direct copy of Subsys formulation	High
Same excipient ranges but different spray device	Moderate to high
Fentanyl sublingual tablet	Low under these claims
Fentanyl buccal film	Low under these claims
Fentanyl nasal spray	Low under these claims
Spray with non-propellant delivery but different excipients	Moderate
Spray with ethanol or propylene glycol outside the ranges	Reduced literal infringement risk
Product reproducing claimed PK profile	Increased risk
Manufacturing process using different mixing steps	Reduced claim 19 risk
Product approved for non-pain indication	Reduced claim 1 and claim 20 risk, but not necessarily eliminated

The patent’s strongest feature is the combination of formulation and delivery-performance limitations. Its weakness is that several limitations depend on measured clinical or particle-size results, which can create reproducibility and claim-construction disputes.

What generic launch scenarios exist?

Scenario 1: Launch after patent expiration

This is the lowest litigation-risk path. The generic sponsor avoids an early patent challenge but loses years of market opportunity.

Scenario 2: Paragraph IV challenge

The sponsor seeks approval before patent expiration and argues invalidity or non-infringement. The risk is a patent suit, a potential 30-month stay, litigation expense and delayed approval.

Scenario 3: Formulation design-around

A sponsor may use a different excipient ratio, droplet-size profile, spray mechanism or dosage form. This approach reduces literal infringement risk but may create new bioequivalence and regulatory problems.

Scenario 4: Label carve-out

If the patent claims a method of use that can be removed from the generic label, a section viii statement may avoid certification for that use. The practical value is limited where the patented use is central to the product’s approved indication or where the formulation claims remain.

Scenario 5: Settlement

A settlement could establish an agreed generic launch date, licensing terms or supply arrangement. Any agreement involving a generic entrant may receive antitrust scrutiny and may be reported to the FTC under applicable law.

What other technologies compete with the patent?

The competitive landscape includes several fentanyl delivery platforms:

Technology	Representative product or platform	Relationship to US 8,486,973
Sublingual spray	Subsys	Direct commercial technology associated with the patent
Buccal tablet	Fentora	Different dosage form and absorption route
Buccal film	Onsolis	Film-based delivery, not spray
Sublingual tablet	Abstral	Solid dosage form
Nasal spray	Lazanda	Intranasal delivery
Transmucosal lozenge	Actiq	Lozenge delivery
Injectable fentanyl	Generic injectable products	Different administration route

The patent does not control the fentanyl molecule, opioid analgesia or all transmucosal delivery. Its commercial reach depends on whether the competing product reproduces the sublingual spray architecture and the claimed formulation profile.

What revenue exposure is tied to the patent?

Subsys was a major revenue product for Insys before the company’s financial collapse and criminal investigations involving opioid promotion. Insys reported hundreds of millions of dollars in annual revenue during the product’s commercial peak, with Subsys representing the company’s principal product revenue. [5]

Revenue exposure declined as a result of payer restrictions, regulatory scrutiny, litigation, loss of market access and competitive pressure. The patent remained commercially relevant because it protected the product architecture, but patent protection alone could not preserve sales in the face of reimbursement and compliance problems.

For a potential licensee or generic challenger, the key commercial variables are:

• Remaining patent term.
• Current FDA approval and marketing status.
• Prescriber restrictions.
• Reimbursement coverage.
• Existing opioid-tolerant patient population.
• Availability of competing fentanyl dosage forms.
• Regulatory scrutiny of immediate-release transmucosal fentanyl products.

Key Takeaways

• US Patent 8,486,973 is a narrow fentanyl sublingual spray patent.
• Claim 1 requires a cumulative combination of fentanyl, ethanol, propylene glycol, propellant-free delivery, minimum droplet size and human Tmax.
• Claims 2 through 18 add specific concentrations, doses, Cmax, AUC, Tmax and bioavailability parameters.
• Claim 19 separately protects a manufacturing process involving fentanyl, purified water and dehydrated alcohol.
• Claim 20 focuses on rapid achievement of approximately 60% of maximum plasma concentration.
• The patent is associated with Subsys, FDA-approved under NDA 203826.
• The relevant patent term extends into the late 2020s based on the public priority and issuance history.
• A generic sponsor would likely face Paragraph IV, formulation design-around, post-expiration launch or settlement options.
• The patent presents the greatest risk to a close copy of the Subsys formulation and spray device.
• Fentanyl tablets, buccal films, nasal sprays and injectable products generally fall outside the literal scope of these claims.

FAQs

Does US Patent 8,486,973 cover all fentanyl sprays?

No. It covers sprays that satisfy the specific sublingual, propellant-free, formulation, droplet-size and pharmacokinetic limitations in the claims.

Can a fentanyl nasal spray infringe this patent?

A fentanyl nasal spray would generally avoid the express sublingual limitation. It could still require analysis of other patents covering fentanyl formulations, devices or methods.

Does using a different ethanol concentration avoid infringement?

It may reduce literal infringement risk, but the answer depends on whether the concentration falls within the proper construction of "about" and whether the doctrine of equivalents applies.

Are the pharmacokinetic claims difficult to enforce?

They can be. Enforcement may require reliable human pharmacokinetic evidence, validated testing and proof that the accused product produces the claimed results under comparable conditions.

Is Subsys still protected after FDA exclusivity ends?

FDA marketing exclusivity and patent protection are separate rights. The end of regulatory exclusivity does not necessarily terminate a valid Orange Book-listed patent.

References

1. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/
2. U.S. Food and Drug Administration. (2012). Subsys fentanyl sublingual spray prescribing information. NDA 203826.
3. United States Patent and Trademark Office. (2013). U.S. Patent No. 8,486,973, Fentanyl spray formulation.
4. U.S. Food and Drug Administration. (2023). ANDA submissions: Patent certification and 30-month stay provisions.
5. Insys Therapeutics, Inc. (2016). Annual report on Form 10-K for the fiscal year ended December 31, 2015. U.S. Securities and Exchange Commission.

Drugs Protected by US Patent 8,486,973

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Btcp Pharma	SUBSYS	fentanyl	SPRAY;SUBLINGUAL	202788-001	Jan 4, 2012		DISCN	Yes	No						TREATMENT OF PAIN
Btcp Pharma	SUBSYS	fentanyl	SPRAY;SUBLINGUAL	202788-002	Jan 4, 2012		DISCN	Yes	No						TREATMENT OF PAIN
Btcp Pharma	SUBSYS	fentanyl	SPRAY;SUBLINGUAL	202788-003	Jan 4, 2012		DISCN	Yes	No						TREATMENT OF PAIN
Btcp Pharma	SUBSYS	fentanyl	SPRAY;SUBLINGUAL	202788-004	Jan 4, 2012		DISCN	Yes	No						TREATMENT OF PAIN
Btcp Pharma	SUBSYS	fentanyl	SPRAY;SUBLINGUAL	202788-005	Jan 4, 2012		DISCN	Yes	No						TREATMENT OF PAIN
Btcp Pharma	SUBSYS	fentanyl	SPRAY;SUBLINGUAL	202788-006	Aug 30, 2012		DISCN	Yes	No						TREATMENT OF PAIN

International Family Members for US Patent 8,486,973

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2008282743
Canada	2698749
Denmark	2180844
European Patent Office	2180844
Spain	2668366
Norway	2180844