US Patent 9,631,193: ALAS1 RNAi Claims, Givosiran Coverage, and Patent Landscape

US Patent 9,631,193 protects therapeutic use of specific ALAS1-targeting double-stranded RNA molecules for porphyria and elevated ALA or PBG. Its broadest practical coverage is claim 2, which captures dsRNA agents containing an antisense sequence with at least 15 contiguous nucleotides differing by no more than three nucleotides from SEQ ID NO: 1296. Narrower claims add ALAS1 target-site limitations, GalNAc delivery, chemical modifications, dosing, strand architecture, overhangs, and the specific sense/antisense sequences associated with givosiran.

The patent is commercially relevant to Givlaari, Alnylam Pharmaceuticals' givosiran product, although freedom-to-operate analysis for givosiran requires review of the full patent family, continuation patents, regulatory listings, and any later-issued composition or manufacturing patents.

What does US Patent 9,631,193 protect?

The patent claims methods of treating porphyria or abnormal heme-biosynthesis biomarkers by administering an ALAS1-directed siRNA.

The central claim elements are:

Claim element	Scope
Therapeutic target	ALAS1 RNA or ALAS1 expression
Modality	Double-stranded RNA
Strand length	Generally 15-30 nucleotides; narrower claims require 19-24 nucleotides
Antisense sequence	At least 15 contiguous nucleotides differing by no more than three nucleotides from SEQ ID NO: 1296
Target site	In some claims, complementarity to nucleotides 871-889 of SEQ ID NO: 1
Disease	Porphyria, particularly hepatic porphyrias
Delivery	GalNAc conjugates and other carbohydrate-ligand conjugates
Chemistry	2'-O-methyl, 2'-fluoro, phosphorothioate, LNA, HNA, CeNA and related modifications
Pharmacology	Reduction of ALAS1, ALA, PBG, porphyrins, symptoms, or acute attacks
Administration	Treatment, prophylaxis, prodrome use, and dosing before, during, or after an acute attack

Claim 2 is the principal broad disease-treatment claim. It does not expressly require the antisense strand to target nucleotides 871-889 of SEQ ID NO: 1. That limitation appears in claim 1 and claims 43-45. This distinction matters because a competing ALAS1 siRNA could potentially fall within claim 2 based on sequence similarity even if it does not use the specific target-site language in claim 1.

How broad is the main ALAS1 siRNA claim?

Claim 2 covers a method of treating a porphyria using a dsRNA whose antisense strand contains at least 15 contiguous nucleotides differing by no more than three nucleotides from SEQ ID NO: 1296.

The phrase "differing by no more than 3 nucleotides" creates a sequence-identity genus. For a 15-nucleotide comparison window, the claim can cover sequences with as few as 12 matching positions, assuming the remaining claim elements are satisfied. Because the comparison is based on at least 15 contiguous nucleotides, the literal scope may extend beyond one exact 15-mer and may capture longer antisense strands containing a qualifying 15-nucleotide segment.

The claim does not require:

A GalNAc ligand;
A particular dose;
A particular chemical modification;
A specific overhang;
A particular porphyria subtype;
A demonstrated clinical response before infringement;
The exact full-length SEQ ID NO: 1296 sequence.

The claim does require the accused product to be a dsRNA administered to a subject for treatment of a porphyria. A sequence that meets the homology requirement but is used for a non-porphyria indication would not necessarily satisfy the claim's method-of-treatment limitation.

What are the narrowest and strongest claims?

The most commercially significant claim groups are claims 2, 5, 12-19, 26-38, and 39.

Broad disease and sequence claims

Claims 2-4 cover porphyria treatment, including subjects at risk of porphyria and administration before, during, or after an acute attack. Claim 24 separately covers treatment of a subject with elevated ALA or PBG, even without expressly requiring a diagnosed porphyria.

Claims 8-11 add therapeutic outcomes, including reductions in ALA, PBG, porphyrins, ALAS1 expression, symptoms, or attack frequency.

GalNAc and delivery claims

Claims 5 and 14-19 cover carbohydrate-ligand conjugates, including GalNAc. Claims 16 and 18-19 narrow the conjugate to branched linkers and attachment at the 3' end of the sense strand.

These claims are particularly relevant to givosiran because GalNAc-mediated hepatocyte delivery is the product's principal delivery technology. A competitor using a non-GalNAc delivery system could avoid these narrower claims while remaining exposed to the broader dsRNA treatment claims.

Chemical-modification claims

Claims 12 and 13 cover modified nucleotides, including 2'-O-methyl and 2'-fluoro substitutions. Claims 27-29 add phosphorothioate linkages and extensive modification across the strands.

These limitations track standard siRNA stabilization and immunogenicity-reduction strategies. They increase practical coverage of drug-like RNAi agents but may create design-around opportunities if a competitor uses a materially different modification pattern.

Duplex architecture claims

Claims 30-38 address:

Blunt ends;
One- or two-nucleotide 3' overhangs;
Overhangs on the antisense or sense strand;
Thiophosphate-containing overhang nucleotides;
17-23 base-pair duplexes;
19-24 nucleotide strands.

These claims are narrower than claim 2 but can be important against a product deliberately engineered to resemble the disclosed siRNA architecture.

Specific product-like combination claim

Claim 39 is the most product-specific claim. It requires:

A porphyria treatment method;
19-24 nucleotide sense and antisense strands;
At least 15 contiguous nucleotides from SEQ ID NOs: 1296 and 1295;
A ligand attached to the 3' end of the sense strand;
Full-length 2'-O-methyl and 2'-fluoro modification;
A two-nucleotide antisense 3' overhang;
A specified ligand structure.

The provided claim text omits the actual ligand structure following "having the structure." That omitted structure is material. The complete issued patent must be used for an infringement opinion involving claim 39.

What diseases and biomarkers are covered?

The patent expressly reaches hepatic porphyrias, including:

Porphyria	Expressly identified?
Acute intermittent porphyria, or AIP	Yes
Hereditary coproporphyria, or HCP	Yes
Variegate porphyria, or VP	Yes
ALA dehydratase deficiency porphyria, or ADP	Yes
Hepatoerythropoietic porphyria	Yes

The claims also cover subjects with elevated ALA, PBG, or both. Claims 22-25 extend the clinical phenotype beyond attack-based treatment and include subjects with chronic pain or biochemical elevation.

This breadth is significant because ALAS1 inhibition acts upstream in hepatic heme synthesis. The claimed effects include both reduction of toxic precursors and reduction in acute neurovisceral attacks.

How does the patent relate to Givlaari and givosiran?

Givlaari is the FDA-approved formulation of givosiran, an ALAS1-directed siRNA administered by subcutaneous injection. The FDA approved Givlaari in November 2019 for adults and certain pediatric patients with acute hepatic porphyria. Its labeled indication includes AIP, HCP, VP, and ADP, consistent with the disease categories recited in US 9,631,193 (FDA, 2019).

The product-to-claim correspondence is strong at a technical level:

Givlaari characteristic	Relevance to US 9,631,193
ALAS1-directed siRNA	Matches the core target
Hepatic porphyria treatment	Matches claims 2 and 20
GalNAc-mediated liver delivery	Matches claims 5 and 14-19
Chemically modified RNA	Matches claims 12-13 and 28-29
Duplex RNA architecture	Matches claims 30-38
Reduction of ALA and PBG	Matches claims 8-11 and 24-25
Prophylactic reduction of attacks	Matches claim 4 and claim 11

The patent therefore has a strong blocking-position profile against products using the same ALAS1 sequence family, GalNAc delivery, and porphyria indication. It does not follow that the patent alone is the only enforceable barrier to a competing product. Product-specific composition, conjugate, formulation, manufacturing, and later continuation patents may provide separate protection.

What is the patent term and exclusivity timeline?

US 9,631,193 issued on April 25, 2017. Its term is tied to the earliest effective nonprovisional or international filing date in the relevant family, subject to patent-term adjustment and any terminal disclaimer. Public patent records associate the family with a 2012 priority period, placing the nominal expiration around 2032-2033, before any applicable patent-term adjustment (USPTO, 2017).

The relevant exclusivity layers are distinct:

Exclusivity layer	Approximate significance
US 9,631,193 patent term	Method-of-use protection into approximately 2032-2033, subject to the official term calculation
FDA orphan-drug exclusivity for Givlaari	Seven years from approval for the approved indication
FDA new chemical entity exclusivity	Five years from approval, subject to statutory exceptions
Other patent families	May extend protection beyond the term of US 9,631,193
Pediatric exclusivity	Applies only if separately granted and reflected in FDA records

Givlaari's five-year new chemical entity exclusivity would not, by itself, prevent all later applications after the statutory period. Patent claims and orphan-drug exclusivity provide separate barriers.

What is the Orange Book status of US 9,631,193?

The Orange Book analysis must distinguish between a patent's existence and its listing status. US 9,631,193 is a method-of-use patent directed to porphyria treatment with an ALAS1 dsRNA. If listed for Givlaari, its relevance would depend on whether the approved labeling describes the claimed use and whether the listing remains active in FDA records.

An Orange Book listing can create a Paragraph IV certification pathway for an abbreviated new drug application. A generic applicant challenging a listed method patent would need to address:

Whether its proposed label induces the claimed porphyria use;
Whether the claim covers the active ingredient or only a particular use;
Whether a section viii statement can carve out the patented use;
Whether other listed patents independently block approval;
Whether the proposed product is eligible for an ANDA rather than a 505(b)(2) application.

Because givosiran is a chemically defined oligonucleotide drug with a specialized conjugate and delivery system, a conventional small-molecule ANDA pathway may not be commercially straightforward. The regulatory pathway and FDA's product-specific requirements are separate from the patent analysis.

What Paragraph IV risks exist for a competing ALAS1 RNAi product?

A competing product would face the highest Paragraph IV or patent-litigation risk if it has all or most of the following characteristics:

An antisense strand containing a qualifying 15-nucleotide sequence related to SEQ ID NO: 1296;
Treatment of AIP or another hepatic porphyria;
GalNAc delivery to hepatocytes;
2'-O-methyl and 2'-fluoro modification;
Two-nucleotide 3' overhang;
Sense-strand ligand attachment;
A label describing reduction of ALA, PBG, or acute porphyria attacks.

A potential design-around strategy could involve a non-overlapping ALAS1 target sequence. That strategy would still require testing against the patent's three-nucleotide deviation rule, continuation patents, composition claims, and other families covering ALAS1 inhibition.

Other possible design-around approaches include:

Using a different delivery ligand or delivery route;
Using a different chemical-modification pattern;
Targeting a non-overlapping ALAS1 transcript region;
Pursuing a non-porphyria indication with a label that excludes the patented use;
Using an antisense architecture outside the narrower strand and overhang claims.

These approaches may avoid particular dependent claims without avoiding claim 2 or claim 24.

How strong is the patent estate?

US 9,631,193 has a strong technical fit to givosiran-like products because it combines sequence identity, ALAS1 biology, porphyria treatment, GalNAc delivery, and clinically relevant biomarker outcomes.

Its principal vulnerabilities are claim-construction and validity issues:

Issue	Potential impact
Sequence identity standard	Requires defining the comparison window and the meaning of "differing"
Written description	Broad sequence variants may be challenged if the specification does not support the full genus
Enablement	Broad dsRNA and conjugate combinations may face enablement scrutiny
Obviousness	Prior ALAS1 RNAi disclosures, porphyria biology, and GalNAc-siRNA technology may be asserted
Indefiniteness	The supplied claim 10 term "1050" appears to be a transcription or OCR error, likely referring to IC50
Missing structures	Claims 17-19 and 39 cannot be fully assessed without the omitted ligand and Formula XXIV structures
Method-of-treatment proof	Enforcement requires evidence of administration for the claimed disease or biomarker condition

The claims are stronger against a close givosiran substitute than against a fundamentally different ALAS1 therapeutic platform.

What litigation and settlement issues affect the patent?

The claim set alone does not establish a current infringement action, Paragraph IV notice, or settlement agreement. A complete litigation assessment requires the USPTO patent file, FDA Orange Book entries, federal court dockets, and any post-grant proceedings.

The principal litigation forums would be:

US district courts for infringement and validity disputes;
The Federal Circuit for appeals;
The Patent Trial and Appeal Board for inter partes review or post-grant review;
FDA regulatory records for Orange Book listing and certification consequences.

For a generic or follow-on RNAi sponsor, the highest-risk scenario would involve simultaneous challenge to this method patent and separate givosiran composition, conjugate, formulation, or manufacturing patents.

What manufacturing and geographic barriers remain?

The patent is US-only in its direct legal effect. Corresponding foreign applications may create parallel protection in Europe, Japan, China, Canada, Australia, and other jurisdictions, but each country's claims, term, prosecution history, and validity position must be assessed independently.

Manufacturing barriers may be material even where a competitor avoids the exact sequence claims. They include:

Oligonucleotide synthesis at commercial scale;
Site-specific GalNAc conjugation;
Control of impurity profiles;
Duplex annealing and strand-ratio control;
Analytical characterization;
Stability and aggregation control;
Reproducible subcutaneous injectable formulation;
Clinical comparability for a follow-on product.

These manufacturing constraints are not automatically covered by US 9,631,193. They are often addressed in separate patent families and confidential know-how.

Key Takeaways

US 9,631,193 is an ALAS1 RNAi method-of-treatment patent focused on porphyria.
Claim 2 is the central broad claim because it covers porphyria treatment with an antisense sequence related to SEQ ID NO: 1296.
Claims 5 and 14-19 target GalNAc and carbohydrate-ligand conjugates.
Claims 12-13 and 27-29 cover chemically modified siRNA, including 2'-O-methyl, 2'-fluoro, and phosphorothioate features.
Claim 39 is a narrow, product-like combination claim, but the supplied text omits the required ligand structure.
The patent has a close technical relationship to givosiran and Givlaari.
The likely nominal patent term extends into approximately 2032-2033, subject to the official patent-term calculation.
A competing ALAS1 siRNA product may face infringement risk even if it changes the precise target sequence, because claim 2 covers a sequence-variant genus.
Full freedom-to-operate analysis requires the complete patent family, prosecution history, Orange Book records, continuation patents, and litigation docket.

FAQs

Can a competitor avoid US 9,631,193 by using a different GalNAc ligand?

Possibly, but changing the ligand may avoid GalNAc-specific dependent claims without avoiding the broader sequence and porphyria-treatment claims in claim 2.

Does US 9,631,193 cover ALAS1 antisense oligonucleotides?

The quoted claims require a double-stranded RNA. A single-stranded antisense oligonucleotide would not literally satisfy the dsRNA limitation, although separate patents could cover that modality.

Does the patent cover treatment of AIP attacks only?

No. The claims cover prophylaxis, administration during a prodrome, administration before or after an acute attack, and treatment of subjects with elevated ALA or PBG.

Is a sequence with three mismatches automatically outside the patent?

No. Claim 2 permits at least 15 contiguous nucleotides differing by no more than three nucleotides from SEQ ID NO: 1296. The position of the mismatches, the comparison window, and the full antisense sequence remain relevant.

Can an RNAi product avoid infringement by using a non-hepatic delivery route?

It may avoid GalNAc-specific claims, but it could remain within broader method claims if the product is a qualifying ALAS1 dsRNA used to treat porphyria.

References

Alnylam Pharmaceuticals, Inc. (2017). RNAi agents for inhibiting ALAS1 expression, U.S. Patent No. 9,631,193. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2019). FDA approves first treatment for patients with acute hepatic porphyria. https://www.fda.gov
U.S. Food and Drug Administration. (2023). Orange Book: Approved drug products with therapeutic equivalence evaluations. https://www.accessdata.fda.gov
U.S. Food and Drug Administration. (2023). Givlaari prescribing information. Alnylam Pharmaceuticals, Inc.
United States Patent and Trademark Office. (2024). Patent Center and patent term information. https://patentcenter.uspto.gov

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	⤷ Start Trial	⤷ Start Trial				TREATMENT OF ACUTE HEPATIC PORPHYRIA	⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

PCT Information
PCT Filed	April 10, 2013	PCT Application Number:	PCT/US2013/036006
PCT Publication Date:	October 17, 2013	PCT Publication Number:	WO2013/155204

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	090641	⤷ Start Trial
Australia	2013245949	⤷ Start Trial
Australia	2018203098	⤷ Start Trial
Australia	2020202970	⤷ Start Trial
Brazil	112014025020	⤷ Start Trial
Canada	2868290	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 9,631,193

Which drugs does patent 9,631,193 protect, and when does it expire?

Summary for Patent: 9,631,193