Details for Patent: 10,119,143

Which drugs does patent 10,119,143 protect, and when does it expire?

Patent 10,119,143 protects GIVLAARI and is included in one NDA.

This patent has seventy-nine patent family members in thirty-nine countries.

Summary for Patent: 10,119,143

Title:	Compositions and methods for inhibiting expression of the ALAS1 gene
Abstract:	The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the ALAS1 gene, and methods of using such dsRNA compositions to alter (e.g., inhibit) expression of ALAS1.
Inventor(s):	Brian Bettencourt, Kevin Fitzgerald, William Querbes, Robert J. Desnick, Makiko Yasuda
Assignee:	Icahn School of Medicine at Mount Sinai , Alnylam Pharmaceuticals Inc
Application Number:	US15/027,176
Patent Claim Types: see list of patent claims	Use; Composition;

US Patent 10,119,143: ALAS1 siRNA Scope, Givosiran Coverage, and Patent Landscape

US Patent 10,119,143 is a composition, formulation, cell, and method-of-treatment patent directed to an ALAS1-silencing double-stranded RNA. Its central subject matter is the modified siRNA sequence corresponding to givosiran, the active ingredient in Givlaari. The claims cover the exact oligonucleotide sequence, 2'-O-methyl and 2'-fluoro sugar pattern, phosphorothioate linkages, conjugated forms, pharmaceutical compositions, sodium salts, liver-cell activity, porphyria treatment, and monthly dosing at 2.5 mg/kg.

The strongest commercial claims are claims 1, 20, 34, and 68, together with their treatment and formulation dependents. The patent does not broadly cover every ALAS1 inhibitor. It is materially sequence-specific and modification-specific.

What drug does US Patent 10,119,143 protect?

The patent protects an ALAS1-targeting small interfering RNA, or siRNA, consisting of:

Element	Claimed subject matter
Target	ALAS1 messenger RNA
Modality	Double-stranded RNA
Sense strand	SEQ ID NO: 4160
Antisense strand	SEQ ID NO: 4161
Sugar modifications	2'-O-methyl and 2'-fluoro ribonucleosides
Backbone modifications	Phosphorothioate linkages at specified positions
Conjugate	A conjugated form shown in the patent drawings
Salt	Pharmaceutically acceptable salt, including sodium salt
Disease	Porphyria, particularly acute hepatic porphyria
Commercial product	Givosiran sodium, marketed as Givlaari

Givosiran is an RNA interference therapeutic developed by Alnylam Pharmaceuticals and approved by the FDA in November 2019 for adults with acute hepatic porphyria, including acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria [2].

The claims supplied by the user identify the same core sequence and chemical modification architecture used by givosiran. The patent therefore has direct product relevance rather than merely covering a research platform.

How many independent inventions are claimed?

The claim set contains several independent claim groups:

Claim group	Primary scope
1	Exact modified ALAS1 dsRNA
7	Pharmaceutical composition containing the dsRNA
8	Cellular method for suppressing ALAS1
9	Reduction of porphyrin or porphyrin precursor levels
10	Treatment of porphyria
20	Conjugated form of the exact dsRNA
34	Pharmaceutical composition containing the conjugated dsRNA
52	Treatment using a conjugated ALAS1 dsRNA
68	Pharmaceutically acceptable salt of the exact dsRNA

Claims 2 through 5 narrow the duplex structure and sequence limitations. Claims 6, 23 through 29, and related claims cover isolated cells. Claims 18, 19, 30 through 36, and 70 cover pharmaceutical compositions. Claims 37 through 47 and 73 through 78 add potency, clinical, dosing, and administration limitations.

The claim set is therefore layered. A potential challenger would need to avoid the exact sequence claims or establish invalidity of the relevant claims. Avoiding only the monthly dose, pH, concentration, or disease subtype would not necessarily avoid claims 1, 20, or 68.

What are the most important composition claims?

Claim 1: exact modified dsRNA

Claim 1 requires all of the following:

1. An ALAS1-inhibiting dsRNA.
2. A sense strand containing the sequence and modifications of SEQ ID NO: 4160.
3. An antisense strand containing the sequence and modifications of SEQ ID NO: 4161.
4. 2'-O-methyl nucleosides at specified positions.
5. 2'-fluoro nucleosides at specified positions.
6. Phosphorothioate linkages at specified positions.

This is a narrow composition claim. A competing product with the same base sequence but a materially different sugar-modification pattern could fall outside the literal scope of claim 1, although other claims or related patents could remain relevant.

Claims 2 through 5: duplex architecture

These claims narrow the siRNA through structural features:

• A duplex region of 21 to 23 base pairs.
• A 3' overhang of at least two nucleotides.
• Strand lengths of no more than 26 nucleotides.
• The exact sense and antisense sequences as isolated strands or as a paired duplex.

Claim 5 is especially significant because it recites the exact strand sequences as alternative limitations and as a complete paired duplex. It provides a direct product claim against the claimed molecular entity.

Claim 20: conjugated ALAS1 siRNA

Claim 20 covers the exact ALAS1 dsRNA in a conjugated form. The supplied claim text omits the chemical drawing after "having the structure of." That drawing is essential to claim construction because it likely defines the ligand, linker, attachment site, and stereochemical or linkage features.

For givosiran, the relevant commercial architecture is a GalNAc-conjugated siRNA designed for hepatocyte delivery. The conjugate claim is commercially important because it targets the delivered drug rather than only an unconjugated research molecule.

Claim 68: salt form

Claim 68 covers a pharmaceutically acceptable salt of the exact ALAS1 dsRNA. Claim 69 expressly identifies the sodium salt. Givosiran is administered as givosiran sodium, making claims 68 through 72 particularly relevant to the marketed product.

What formulations are protected by US Patent 10,119,143?

The formulation claims cover a pharmaceutical composition containing the claimed dsRNA or salt. The most commercially relevant limitations are:

Claim	Formulation limitation
7	Composition containing the ALAS1 dsRNA
18	Approximately 200 mg/mL dsRNA
19	pH of 6.0 to 7.5
34	Composition containing the conjugated dsRNA
70	Composition containing the pharmaceutically acceptable salt

Givlaari is supplied as a sterile solution for subcutaneous administration. The FDA labeling identifies a concentration of 189 mg/mL, a concentration that is close to but not literally identical to "about 200 mg/mL" [2]. Whether 189 mg/mL falls within claim 18 depends on the construction of "about," the specification, prosecution history, and ordinary pharmaceutical measurement conventions.

The pH range in claim 19 is potentially significant for the commercial product. A formulation outside the claimed pH range could avoid that claim while remaining exposed to the broader composition claims.

What methods of treatment are protected?

Claims 10 through 17 and 38 through 47 cover treatment of porphyria using the claimed dsRNA. The claims reach:

• Acute hepatic porphyria.
• Acute intermittent porphyria.
• ALA-dehydratase deficiency porphyria.
• Subjects at risk of porphyria.
• Subjects with elevated ALA or PBG.
• Treatment after an acute attack.
• Treatment during an acute attack.
• Prophylactic treatment.
• Reduction of acute attack frequency.
• Reduction of pain, neuropathy, and nerve damage.
• Reduction of ALA or PBG.
• At least 40% reduction in specified biomarkers or ALAS1 expression.

Claims 73 through 78 are commercially tailored. They cover monthly administration at a dose ranging from 0.01 mg/kg to 5 mg/kg, including 1 mg/kg to 2.5 mg/kg, and specifically 2.5 mg/kg.

The FDA-approved Givlaari regimen is 2.5 mg/kg administered subcutaneously once monthly based on actual body weight [2]. The overlap between the approved dosing regimen and claims 73 through 78 is direct.

How strong is the patent estate for givosiran?

US Patent 10,119,143 is strong against an exact-copy product because it combines several product-defining limitations:

• Exact sense and antisense sequences.
• Defined chemical modifications.
• ALAS1 target.
• Conjugated delivery form.
• Sodium salt.
• Monthly administration.
• Porphyria treatment.

Its principal weakness is claim narrowness. A competitor could pursue an alternative ALAS1 sequence, alternative chemical pattern, different ligand, or different delivery system. That design-around would not necessarily avoid other Alnylam patents covering broader ALAS1 RNAi concepts, conjugation chemistry, or delivery technology.

The patent is stronger as a product-specific barrier than as a broad platform patent. Claims 1, 20, and 68 are the central protection. Claims 10, 52, and 71 add method-of-use coverage but may be more vulnerable to divided-infringement and label-scrubbing arguments in an abbreviated regulatory pathway.

When does US Patent 10,119,143 lose exclusivity?

The patent issued on November 6, 2018 [1]. Its term is generally calculated as 20 years from the earliest effective nonprovisional U.S. filing date, subject to patent-term adjustment, terminal disclaimers, and any applicable patent-term extension.

The relevant family priority is associated with November 15, 2010. On that basis, the ordinary projected expiration is approximately November 15, 2030, before any patent-term adjustment. The effective expiration date must be confirmed from the USPTO patent-term records and the patent’s continuity data.

Milestone	Date or status
Earliest reported family priority	November 15, 2010
US patent grant	November 6, 2018
Ordinary 20-year term calculation	Approximately November 15, 2030
FDA approval of Givlaari	November 20, 2019
FDA orphan-drug exclusivity	Seven years from approval, through approximately November 20, 2026
Monthly approved dose	2.5 mg/kg
Patent status	Issued patent with term extending beyond FDA orphan exclusivity

Orphan-drug exclusivity is separate from patent protection. FDA approval of Givlaari created seven years of orphan-drug exclusivity for the approved indication, subject to the statutory exceptions. That exclusivity does not prevent all competing products in every clinical circumstance, but it limits approval of the same drug for the same orphan indication during the exclusivity period [3].

What is the Orange Book status of US Patent 10,119,143?

The Orange Book lists patents submitted by an NDA holder for an approved drug product. Givlaari’s NDA is held by Alnylam Pharmaceuticals. The patent’s relevance to Givlaari is based on the exact active ingredient, conjugated siRNA structure, formulation, and dosing regimen.

An Orange Book listing can support a Paragraph IV certification against a later abbreviated application. The practical significance depends on:

• Whether the patent is listed for the specific Givlaari NDA.
• Which claims the NDA holder identifies as covering the drug.
• Whether the patent remains unexpired.
• Whether an applicant submits a Paragraph IV certification.
• Whether Alnylam files suit within 45 days.
• Whether a 30-month stay applies.

The claims provided do not establish the patent’s current Orange Book listing code or the precise NDA listing record. The patent itself is not evidence of Orange Book listing. FDA’s electronic Orange Book is the controlling source for listing status [3].

Which companies are challenging givosiran patents?

No Paragraph IV challenger, ANDA applicant, or settlement agreement is identified in the claim text. The available public regulatory record for Givlaari does not establish a disclosed generic challenge associated specifically with US Patent 10,119,143.

Givosiran is a chemically modified, ligand-conjugated siRNA rather than a conventional oral small molecule. A follow-on applicant would face technical and regulatory barriers involving:

• Exact sequence identity.
• Sugar and backbone modifications.
• GalNAc or alternative hepatocyte-targeting conjugation.
• Analytical characterization.
• Impurity profiles.
• Potency assays.
• Tissue distribution.
• Immunogenicity.
• Pharmacokinetic and pharmacodynamic comparability.
• Manufacturing reproducibility.

A conventional ANDA pathway is more difficult for a complex siRNA conjugate than for a conventional chemically synthesized small molecule. A 505(b)(2) strategy could raise different regulatory and patent issues, but it would not eliminate composition or method-of-use infringement risk.

What generic entry risks exist?

The most credible entry scenarios are:

Entry scenario	Patent risk
Exact givosiran sodium copy	Very high; directly implicates claims 1, 20, 68 and related claims
Same sequence with altered modifications	Medium to high; depends on the modification changes and other family patents
Alternative ALAS1 siRNA sequence	Lower exposure to this patent, but possible exposure to broader ALAS1 patents
Alternative hepatocyte ligand	Lower exposure to conjugate claims if structurally outside the claimed drawing
Non-infringing formulation	Does not avoid core composition claims
Narrow label excluding porphyria treatment	Does not necessarily avoid composition infringement
Biosimilar application	Not the appropriate statutory framework because givosiran is not a biologic subject to the biosimilar pathway

A generic applicant could attempt a Paragraph IV challenge arguing anticipation, obviousness, lack of written description, indefiniteness, or noninfringement. The exact-sequence claims may be vulnerable to prior-art RNAi disclosures if the claimed sequence and chemical architecture were publicly disclosed before the priority date. Obviousness would likely focus on whether a skilled person would have selected the claimed ALAS1 sequence and modification pattern with a reasonable expectation of success.

What patent litigation and settlements affect this patent?

The supplied materials identify no litigation, invalidity decision, or settlement agreement. The patent’s litigation status cannot be determined from the claim text alone.

For commercial diligence, the relevant litigation questions are:

1. Whether Alnylam has asserted US Patent 10,119,143 against an ANDA or 505(b)(2) applicant.
2. Whether the patent has been subject to inter partes review or post-grant review.
3. Whether a court has construed "about 200 mg/mL."
4. Whether the missing conjugate structure in claims 20 and 34 has been litigated.
5. Whether claim 52’s reference to SEQ ID NO: 4060 creates an enforceability or indefiniteness issue.
6. Whether any settlement permits a licensed or authorized generic.
7. Whether a terminal disclaimer limits the patent’s enforceable term.

The claim text contains drafting anomalies. Claims 20 and 34 omit the conjugate drawing in the supplied version. Claim 52 refers to SEQ ID NO: 4060 while the surrounding claims use SEQ ID NO: 4160. Claims 21 through 36 also contain dependency language that should be checked against the issued patent PDF and any certificate of correction. These issues may affect claim construction, but they do not automatically invalidate the patent.

How does this patent compare with broader ALAS1 and RNAi patents?

US Patent 10,119,143 should be classified as a product-specific ALAS1 siRNA patent. It is narrower than platform patents covering:

• General RNA interference mechanisms.
• GalNAc-siRNA conjugates.
• Hepatocyte delivery.
• Broad ALAS1 sequence families.
• Generic 2'-O-methyl or 2'-fluoro modification patterns.
• Phosphorothioate placement.
• Formulation and manufacturing processes.

The commercial freedom-to-operate analysis therefore cannot stop with this patent. A competing ALAS1 product may avoid the exact sequences in claims 1 and 20 but still infringe another Alnylam family patent directed to the target, conjugate, scaffold, or delivery chemistry.

What is the commercial exposure?

Givlaari is the only FDA-approved drug directly associated with the claimed ALAS1 siRNA architecture. The patent’s commercial exposure is therefore tied to the entire givosiran franchise rather than to a broad class of competing drugs.

The principal commercial protections are:

• Product composition claims through the projected patent term.
• Orphan-drug exclusivity through approximately November 2026.
• Formulation and salt claims.
• Monthly dosing claims matching the approved label.
• Manufacturing know-how for conjugated siRNA production.
• Regulatory exclusivity and clinical-data barriers.

The most significant post-exclusivity risk is not a conventional small-molecule generic. It is a technically sophisticated follow-on siRNA or alternative ALAS1 RNAi product that uses a different sequence or conjugation design.

Key Takeaways

• US Patent 10,119,143 is directed to the exact modified ALAS1 siRNA used in givosiran.
• Claims 1, 20, and 68 are the principal product claims.
• Claims 10, 52, and 71 cover porphyria treatment, including acute hepatic porphyria.
• Claims 73 through 78 closely track the approved 2.5 mg/kg monthly Givlaari regimen.
• The patent covers sequence, sugar chemistry, phosphorothioate placement, conjugate, salt, formulation, and treatment use.
• The ordinary projected patent term extends to approximately November 15, 2030, subject to patent-term adjustment and other USPTO term calculations.
• FDA orphan-drug exclusivity for Givlaari extends approximately through November 20, 2026.
• Givosiran is an siRNA drug, so biosimilar analysis is not the applicable framework.
• The patent is strong against an exact-copy givosiran product but leaves potential design-around paths through sequence, modification, conjugate, and delivery changes.
• Claims 20, 34, and 52 require review against the issued patent drawings, prosecution history, and any certificate of correction because the supplied text contains missing structural material and sequence inconsistencies.

Frequently Asked Questions

Does US Patent 10,119,143 cover all ALAS1 inhibitors?

No. It primarily covers a defined ALAS1 dsRNA sequence and specified chemical modifications. An unrelated small-molecule ALAS1 inhibitor or a materially different RNAi sequence may fall outside its literal scope.

Is givosiran a biologic eligible for biosimilar competition?

No. Givosiran is a chemically synthesized, ligand-conjugated siRNA. A follow-on applicant would generally assess an ANDA, 505(b)(2), or another applicable pathway rather than the biosimilar pathway under the Public Health Service Act.

Does changing the GalNAc conjugate avoid the patent?

Not necessarily. It may avoid a conjugate claim if the alternative structure is outside the claimed chemical drawing, but the exact dsRNA, salt, formulation, or method claims could remain relevant.

Can a generic applicant avoid infringement by omitting porphyria from its label?

Not necessarily. The exact dsRNA and pharmaceutical composition claims are not limited to a marketed porphyria label. A label change may affect method-of-use infringement but does not eliminate composition-claim exposure.

Why is the 189 mg/mL Givlaari concentration relevant to claim 18?

Claim 18 recites approximately 200 mg/mL, while FDA labeling identifies 189 mg/mL. The scope of "about" depends on the patent specification, prosecution history, and accepted measurement tolerance. The concentration should be analyzed separately from the broader composition claims.

References

1. United States Patent and Trademark Office. (2018). US Patent No. 10,119,143, double-stranded ribonucleic acid compositions and methods for inhibiting ALAS1 expression. https://patents.google.com/patent/US10119143B2/en

2. U.S. Food and Drug Administration. (2019). Givlaari (givosiran) injection: Prescribing information. Alnylam Pharmaceuticals, Inc. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212194s000lbl.pdf

3. 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/index.cfm

4. U.S. Food and Drug Administration. (2019, November 20). FDA approves first treatment for adults with acute hepatic porphyria. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-adults-acute-hepatic-porphyria

Drugs Protected by US Patent 10,119,143

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Alnylam Pharms Inc	GIVLAARI	givosiran sodium	SOLUTION;SUBCUTANEOUS	212194-001	Nov 20, 2019		RX	Yes	Yes			Y	Y		TREATMENT OF ACUTE HEPATIC PORPHYRIA

Foreign Priority and PCT Information for Patent: 10,119,143

PCT Information
PCT Filed	October 03, 2014	PCT Application Number:	PCT/US2014/059160
PCT Publication Date:	April 09, 2015	PCT Publication Number:	WO2015/051318

International Family Members for US Patent 10,119,143

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	3052628		301061	Netherlands
European Patent Office	3052628		LUC00175	Luxembourg
European Patent Office	3052628		122020000045	Germany
European Patent Office	3052628		PA2020527	Lithuania
European Patent Office	3052628		2020C/532	Belgium
European Patent Office	3052628		CA 2020 00042	Denmark