Patent: 10,682,426

Summary for Patent: 10,682,426

Title:	Rabies vaccine
Abstract:	The present invention relates to an mRNA sequence, comprising a coding region, encoding at least one antigenic peptide or protein of Rabies virus or a fragment, variant or derivative thereof. Additionally the present invention relates to a composition comprising a plurality of mRNA sequences comprising a coding region, encoding at least one antigenic peptide or protein of Rabies virus or a fragment, variant or derivative thereof. Furthermore it also discloses the use of the mRNA sequence or the composition comprising a plurality of mRNA sequences for the preparation of a pharmaceutical composition, especially a vaccine, e.g. for use in the prophylaxis or treatment of Rabies virus infections. The present invention further describes a method of treatment or prophylaxis of rabies using the mRNA sequence.
Inventor(s):	Schnee; Margit (Constance, DE), Kramps; Thomas (Tubingen, DE), Stitz; Lothar (Rottenburg, DE), Petsch; Benjamin (Tubingen, DE)
Assignee:	CureVac AG (Tubingen, DE)
Application Number:	15/048,356
Patent Claims:	see list of patent claims

United States Patent 10,682,426: Rabies mRNA (GC-Enriched RAV-G) Landscape and Claim Scrutiny

US Patent 10,682,426 is directed to rabies prophylaxis or treatment using an mRNA encoding the rabies virus glycoprotein G (RAV-G). The core inventive axis is a GC-enriched coding region (relative to wild-type rabies G mRNA) while not modifying the encoded amino-acid sequence, combined with optional immunostimulatory or stability-oriented untranslated region (UTR) and 3' end elements (TOP-derived 5'UTR, histone stem-loop, globin/albumin-derived 3'UTR, poly(A), poly(C)), with optional co-administration of rabies immune globulin (RIG).

The patent is narrow in claims 2 to 17 (composition-detail dependent) but broad in claim 1 at the method level, because it covers any administration of such a GC-enriched, amino-acid-identical RAV-G mRNA, with optional RIG.

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What is the claim “center of gravity” in US 10,682,426?

Claim 1 defines the method in three mandatory blocks and several optional add-ons.

Mandatory elements (Claim 1)

1. Provide an mRNA with:

   • A coding region encoding rabies virus glycoprotein G (RAV-G).
   • Increased G/C content compared with the wild-type coding region’s G/C content.
   • No amino-acid sequence change relative to wild-type (synonymous coding).
   • The mRNA satisfies either:
     • (i) the mRNA is ≥95% identical to SEQ ID NO: 24, or
     • (ii) the mRNA includes a 5'-UTR element derived from the 5'UTR of a TOP gene.

2. Apply or administer the mRNA to a tissue or organism.

3. Optionally administer rabies immune globulin.

Why the structure matters

• The GC-enrichment concept is constrained by the “no amino-acid change” condition. That removes non-synonymous redesign and frames the novelty around codon-level modifications (and/or RNA-level properties linked to codon composition).
• Claim 1 includes a second path to coverage via TOP-derived 5'UTR, which functions as an alternative defining feature when the “≥95% identity to SEQ ID NO: 24” is not used.
• The “SEQ ID NO: 24” and TOP-UTR prong create two different claim coverage gates, which matters for both design-around and infringement analysis.

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How do dependent claims narrow or steer the scope?

Claims 2 to 17 specify composition features that, in practice, define the “practical infringement envelope” more than claim 1 alone.

Dependent claim map (what each adds)

• Claim 2: Full-length RAV-G protein encoding (not just fragments).
• Claim 3: RAV-G is from a rabies vaccine strain.
• Claim 4: mRNA includes:
  • 5'-CAP
  • poly(A)
  • optionally poly(C)
• Claim 5: poly(A) length about 25 to 400 adenosines.
• Claim 6: at least one histone stem-loop.
• Claim 7: includes a 3'-UTR element.
• Claims 8-12: 3'-UTR derived from stable mRNA genes; specific exemplars include:
  • albumin (generic and vertebrate albumin)
  • alpha-globin
  • beta-globin (listed)
  • tyrosine hydroxylase, lipoxygenase, collagen alpha (listed)
  • with Claim 12 specifically: 3'-UTR derived from SEQ ID NO: 18 (alpha-globin context).
• Claim 13: explicit architecture in 5'-to-3' direction:
  • 5'-CAP
  • coding region encoding RAV-G
  • 3'-UTR derived from alpha globin or albumin gene
  • poly(A)
  • poly(C)
  • histone stem-loop
• Claim 14: mRNA is the RNA sequence of SEQ ID NO: 24.
• Claims 15-17: 5'-UTR is TOP-derived, with granularity:
  • derived from TOP gene 5'UTR (Claim 15)
  • TOP gene encoding ribosomal protein (Claim 16)
  • TOP gene encoding ribosomal large protein (RPL) (Claim 17)

Net effect

• The patent simultaneously:
  • anchors claim coverage on a specific sequence (SEQ ID 24), and
  • provides fallback coverage through functional element provenance (TOP-derived 5'UTR and globin/albumin-derived 3'UTR motifs), plus standard mRNA manufacturing components (CAP, poly(A), poly(C), histone stem-loop).

This makes it likely that enforcement (if pursued) would focus on products that adopt globin/albumin 3'UTR + histone stem-loop + defined end structures, and/or molecules matching the exact sequences.

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What is the likely legal novelty theory: GC enrichment without amino-acid change?

The GC-enrichment requirement is framed as:

• increased G/C content of the coding region versus wild-type,
• while preserving the encoded amino-acid sequence.

This is a codon-optimization-style constraint with an emphasis on RNA property changes rather than protein changes. In litigation or validity analysis, the novelty theory would likely be tested against three categories of prior art:

1. Codon optimization generally

   • mRNA codon optimization while preserving amino-acid sequence.
   • If prior art already taught GC-modulation and maintained amino-acid identity, the claim may be treated as a routine optimization, unless the patent demonstrates a non-obvious technical effect or specific targeting of GC level to rabies RAV-G.

2. GC-content modulation specifically

   • Prior art can exist for tuning GC content to affect translation efficiency, stability, innate immune sensing, or antigen expression kinetics.

3. Rabies RAV-G mRNA formulations

   • Prior art for rabies mRNA vaccines with RAV-G, especially those using:
     • globin or albumin-derived 3'UTR,
     • histone stem-loop,
     • poly(A)/poly(C),
     • and possibly TOP-UTR or similar translational control elements.

The strongest novelty argument is not “GC enrichment exists,” but that:

• the patent specifies a GC-enriched rabies G coding region with synonymous amino-acid identity, and
• pairs that with a defined sequence identity threshold (≥95% identity to SEQ ID 24) and/or a specific TOP-UTR provenance and/or specific mRNA architecture elements.

That combination can be attacked as obvious if each element is independently known and the combination yields expected results.

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How does the patent position relative to mainstream mRNA design patterns?

Even without the full specification text, the dependent claims reveal a design pattern typical of “mRNA stability and translation enhancement”:

• 5'-CAP
• poly(A) within a defined length range
• optional poly(C)
• histone stem-loop (commonly used as a stability/translation-associated element)
• 3'-UTR derived from stable mRNA genes such as alpha-globin or albumin
• TOP-derived 5'UTR (ribosomal protein TOP motifs are linked to translational regulation)

US 10,682,426 therefore sits at the intersection of:

• rabies antigen selection (RAV-G),
• synonymous coding design (GC content modulation),
• and standardized mRNA regulatory elements (UTRs/end caps/stem-loop).

That intersection is where validity pressure is usually highest: the claim must show that the specific GC-enrichment plus the specific UTR provenance produces a technical effect not readily achieved by combinations of known pieces.

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Where are the key claim vulnerabilities (validity and enforcement)?

1) “G/C content increased” is likely a measurable but potentially non-limiting parameter

If the patent does not define a numeric delta (for example, “increase by X percentage points”), the phrase “increased compared with wild type” can be litigated on:

• what the baseline wild type coding sequence is,
• what window is used for measuring G/C,
• and whether “increased” includes marginal changes.

That tends to create validity risk if prior art already achieved any increase while maintaining amino-acid identity.

2) “Not modified compared with the coded amino-acid sequence of wild type”

This limits non-synonymous modifications. It also channels the claim into synonymous substitutions. For invalidity, prior art for codon optimization while preserving protein sequence can be highly relevant.

3) The “≥95% identity to SEQ ID NO: 24” prong may be narrow, but it provides an exact anchor

• It helps enforce against copies that match the sequence closely.
• It also introduces a design-around path: developers can aim below 95% identity while retaining functional equivalents (or preserve TOP-UTR instead of sequence identity).

4) Alternative coverage gate via TOP-UTR provenance

If a competitor uses GC-enriched RAV-G coding but avoids SEQ ID 24 identity, they can still land inside the claim if they include a TOP-derived 5'UTR as defined.

Conversely, if they avoid TOP-UTR provenance, they might avoid the claim even with GC-enriched coding, depending on how the patent interprets “increased G/C” plus any sequence identity requirement.

5) Dependent claims constrain end-structure architecture

A product that uses a different 3'UTR origin, omits histone stem-loop, uses a different poly(A) range, or excludes poly(C) would not meet specific dependent claims, though it may still satisfy claim 1 if claim 1’s alternative gates are met.

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Patent landscape assessment: what other players are likely in the vicinity?

The claim content points to shared knowledge areas rather than a single-company monopoly:

• mRNA vaccines for rabies using RAV-G are widely studied academically and commercially.
• Synonymous codon optimization is a general practice.
• Globin/albumin 3'UTRs, histone stem-loop, and poly(A)/poly(C) are recurring motifs in mRNA platform designs.
• TOP-UTR-derived elements are a known approach for translational regulation in mRNA constructs.

Given those overlaps, US 10,682,426 likely faces a dense background art environment. Enforcement, if any, would need to rely on:

• a close match to SEQ ID NO: 24 (most straightforward), and/or
• adoption of the specific TOP-UTR element provenance and the GC-enriched coding approach.

Without the patent specification, claim drawings, and the full list of SEQ IDs, it is not possible to map the landscape with the necessary precision to identify which specific patents most directly anticipate each limitation. Under the constraints here, no further landscape mapping can be produced from the provided information alone.

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What design-arounds are logically suggested by the claim text (without adding facts)?

The claims create explicit escape hatches:

1. Avoid the SEQ ID 24 “≥95% identity” route

   • If a competitor constructs an mRNA that preserves the antigen and the GC-enriched coding concept but diverges sufficiently from SEQ ID 24, it could avoid that pathway of claim 1.

2. Avoid TOP-UTR provenance

   • Claim 1 alternative coverage requires a TOP-derived 5'UTR element (as recited). Using a non-TOP 5'UTR architecture could avoid claim 1’s second alternative.

3. Break dependent-claim architecture elements

   • Dependent claims require specific components: histone stem-loop, globin/albumin-derived 3'UTR, poly(A) length range, and in Claim 13 the enumerated 5'-to-3' ordering.
   • Even if claim 1 is met (via either SEQ identity prong or TOP-UTR prong), a competitor can attempt to reduce exposure to dependent claims by using alternate UTR sources and/or different end structures.

4. Avoid co-administration of RIG

   • RIG is optional in claim 1. Eliminating RIG does not avoid claim 1 itself, but it may reduce specific treatment regimens that rely on claim language in dependent claim strategy or prosecution history.

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Practical infringement reading: when would a product be at highest risk?

Highest risk generally occurs when a rabies mRNA candidate has all of the following:

• Antigen matches: rabies glycoprotein G (RAV-G), ideally full-length and from a vaccine strain (claims 2 and 3).
• Coding region: GC-enriched relative to wild-type coding region while keeping the amino-acid sequence identical.
• Sequence match: near-matching the patent’s SEQ ID NO: 24 (claim 1’s 95% identity pathway and claim 14 direct hit).
• 5'UTR: TOP-derived 5'UTR (claim 1 alternative; claims 15-17 specify ribosomal protein/RPL context).
• mRNA feature set: includes the CAP/poly(A) constructs and commonly added elements (histone stem-loop, poly(C), globin/albumin-derived 3'UTR) as specified in dependent claims.

Any product that does not meet the SEQ identity threshold and does not use TOP-derived 5'UTR would reduce risk substantially at the claim 1 level, even if it shares GC enrichment for RAV-G.

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Key Takeaways

• US 10,682,426 claims rabies prophylaxis/treatment with an mRNA encoding RAV-G where the coding region’s GC content increases versus wild-type without changing the amino-acid sequence.
• Claim 1 is enforced through two alternative gates: (a) ≥95% identity to SEQ ID NO: 24 or (b) a TOP-gene-derived 5'UTR element.
• Dependent claims tighten scope using standard mRNA build blocks and provenance-specific UTR elements: histone stem-loop, alpha-globin/albumin-derived 3'UTR, and TOP-derived 5'UTR details, plus defined poly(A) length and optional poly(C).
• The strongest vulnerability for validity is that the invention combines elements that are common in mRNA platforms (CAP, poly(A), histone stem-loop, globin/albumin 3'UTR, synonymous codon optimization). The claim likely survives only if the GC-enrichment for rabies RAV-G plus the specified sequence/UTR provenance yields a non-obvious technical outcome over close background art.

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FAQs

1. Is RIG required for infringement under claim 1?
No. Rabies immune globulin is “optionally” administered in claim 1.

2. What makes claim 1 broader than the dependent claims?
Claim 1 covers any administration of a GC-enriched, amino-acid-identical RAV-G mRNA that satisfies either the SEQ ID NO: 24 identity threshold or the TOP-derived 5'UTR requirement.

3. What are the two alternative coverage gates in claim 1?
(1) mRNA is at least 95% identical to SEQ ID NO: 24; or (2) mRNA contains a 5'-UTR derived from a TOP gene.

4. Do dependent claims require the same mRNA architecture?
They add limitations. For example, claim 13 specifies a particular 5'-to-3' element ordering including CAP, RAV-G coding region, alpha-globin/albumin 3'UTR, poly(A), poly(C), and histone stem-loop.

5. How can a competitor reduce risk based on the literal claim language?
Avoid matching SEQ ID NO: 24 above the identity threshold and avoid including a TOP-derived 5'UTR; also choose different 3'UTR/histone stem-loop/poly(A) parameters to fall outside dependent-claim limitations.

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References

[1] United States Patent 10,682,426.

Details for Patent 10,682,426

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bavarian Nordic A/s	RABAVERT	rabies vaccine	For Injection	103334	October 20, 1997	10,682,426	2036-02-19
Sanofi Pasteur Sa	IMOVAX RABIES	rabies vaccine	For Injection	103931	February 04, 2000	10,682,426	2036-02-19
Octapharma Pharmazeutika Produktionsges.m.b.h.	OCTAGAM	immune globulin intravenous (human)	Injection	125062	May 21, 2004	10,682,426	2036-02-19
Octapharma Pharmazeutika Produktionsges.m.b.h.	OCTAGAM	immune globulin intravenous (human)	Injection	125062	March 26, 2007	10,682,426	2036-02-19
Octapharma Pharmazeutika Produktionsges.m.b.h.	OCTAGAM	immune globulin intravenous (human)	Injection	125062	July 11, 2014	10,682,426	2036-02-19