US 11698377

US Patent 11698377, titled "Methods for detecting AAV," was granted to Genzyme Corp. The inventors listed are Xiaoying Jin, Catherine O'Riordan, Lin Liu, and Kate Zhang. The application was filed on August 14, 2017, and the patent was issued on July 11, 2023.

Abstract:
The patent describes methods for serotyping and/or determining the heterogeneity of a viral particle, specifically an adeno-associated virus (AAV) particle, using mass determination techniques such as liquid chromatography/mass spectrometry (LC/MS) or liquid chromatography/mass spectrometry-mass spectrometry (LC/MS/MS). These methods can be used to monitor protein sequences and post-translational modifications at the intact protein level, identify N-terminal acetylations, and characterize viral capsid protein heterogeneity in gene therapy development. They can also confirm VP sequences in capsid engineering and study the impact of post-translational modifications on transfection potency and intracellular protein trafficking. Furthermore, the methods can be used to design AAV particles with altered stability and/or transduction efficiency by modifying N-terminal acetylation or deamidation.

Plain-Language Overview of Independent Claims:

• Independent Claim 1: This claim describes a method to identify the serotype of an adeno-associated virus (AAV) particle. It involves three main steps:

  1. Denaturing the AAV particle (breaking it down).
  2. Subjecting the denatured particle to liquid chromatography/mass spectrometry (LC/MS).
  3. Determining the masses of the three main capsid proteins (VP1, VP2, and VP3) of the AAV particle.
     The specific combination of these measured protein masses is then used to indicate the AAV serotype.

• Independent Claim 9: This claim focuses on determining the heterogeneity of an AAV particle. It includes:

  1. Denaturing the AAV particle.
  2. Subjecting the denatured particle to liquid chromatography/mass spectrometry (LC/MS).
  3. Determining the masses of VP1, VP2, and VP3.
  4. Comparing these measured masses to the known theoretical masses for the specific AAV serotype.
     Any deviation in one or more of these measured masses from the theoretical masses indicates heterogeneity within the AAV capsid. Heterogeneity can include mixed serotypes, variant capsids, amino acid changes, truncated capsids, or modified capsids.

• Independent Claim 17: This claim also describes a method for determining the serotype of an AAV particle, but it involves additional sample preparation steps:

  1. Denaturing the AAV particle.
  2. Subjecting the denatured particle to reduction and/or alkylation (chemical treatments to break disulfide bonds).
  3. Digesting the treated particle to create smaller fragments of VP1, VP2, and/or VP3.
  4. Subjecting these protein fragments to liquid chromatography/mass spectrometry-mass spectrometry (LC/MS/MS).
  5. Determining the masses of these fragments.
     The specific combination of the masses of these fragments is indicative of the AAV serotype.

• Independent Claim 25: Similar to Claim 17, this claim focuses on determining the heterogeneity of an AAV particle's serotype using fragmented proteins:

  1. Denaturing the AAV particle.
  2. Subjecting the denatured particle to reduction and/or alkylation.
  3. Digesting the treated particle to generate fragments of VP1, VP2, and/or VP3.
  4. Subjecting these fragments to liquid chromatography/mass spectrometry-mass spectrometry (LC/MS/MS).
  5. Determining the masses of these fragments.
  6. Comparing these measured fragment masses to the theoretical masses of fragments for that AAV serotype.
     A deviation in one or more of these fragment masses indicates heterogeneity of the AAV capsid. Heterogeneity can include mixed serotypes, variant capsids, amino acid changes, truncated capsids, or modified capsids.

• Independent Claim 33: This claim introduces a modified recombinant AAV (rAAV) particle. It claims an rAAV particle with a specific amino acid change at residue 2 of VP1 and/or VP3, where this change alters the N-terminal acetylation compared to the original, unmodified AAV particle.

• Independent Claim 37: This claim is directed to an AAV capsid protein (e.g., VP1 or VP3) that has an amino acid substitution at residue 2 compared to a parent AAV capsid protein. This substitution is designed to alter the N-terminal acetylation of the capsid protein.

• Independent Claim 40: This claim describes a method to improve the stability of an rAAV particle. It involves substituting amino acid residue 2 of VP1 and/or VP3 in a way that alters the N-terminal acetylation of these proteins compared to the parent VP1 and/or VP3.

• Independent Claim 41: This claim describes a method to improve the assembly of rAAV particles within a cell. It involves substituting amino acid residue 2 of VP1 and/or VP3 such that the N-terminal acetylation is altered compared to the parent proteins.

• Independent Claim 42: This claim describes a method to improve the transduction (delivery of genetic material) of rAAV particles into a cell. This improvement is achieved by substituting amino acid residue 2 of VP1 and/or VP3 to alter N-terminal acetylation compared to the parent proteins.

• Independent Claim 43: This claim describes a method to reduce the transduction of rAAV particles in a cell. Similar to Claim 42, it involves substituting amino acid residue 2 of VP1 and/or VP3 to alter N-terminal acetylation compared to the parent proteins.

• Independent Claim 45: This claim introduces a recombinant AAV (rAAV) particle comprising one or more amino acid substitutions at specific residues (A35, N57, G58, N382, G383, N511, G512, N715, or G716) of VP1 or VP3 (residue numbering based on AAV2 VP1). The purpose of these substitutions is to alter deamidation compared to the parent AAV particle.

• Independent Claim 48: This claim describes an AAV capsid protein with an amino acid substitution that alters its deamidation compared to the parent AAV capsid protein.

• Independent Claim 49: This claim details a method to improve the stability of an rAAV particle by substituting one or more amino acid residues (A35, N57, G58, N382, G383, N511, G512, N715, or G716, based on AAV2 VP1 numbering). These substitutions are designed to alter deamidation compared to the parent AAV particle.

• Independent Claim 50: This claim describes a method to improve the assembly of rAAV particles in a cell through the substitution of specific amino acid residues (A35, N57, G58, N382, G383, N511, G512, N715, or G716, based on AAV2 VP1 numbering). These substitutions alter deamidation compared to the parent AAV particle.

• Independent Claim 51: This claim describes a method to improve the transduction of rAAV particles in a cell, similar to Claim 50, by substituting specific amino acid residues (A35, N57, G58, N382, G383, N511, G512, N715, or G716, based on AAV2 VP1 numbering) to alter deamidation compared to the parent AAV particle.

Litigation Status:
US Patent 11698377 is currently active and is involved in litigation. A PTAB case, IPR2026-00167, has been filed and is pending.

There is known litigation involving US patent 11698377.

Case 1:

• Plaintiff(s): Unified Patents [cite: "US11698377B2 - Methods for detecting AAV - Google Patents"]
• Defendant(s): Genzyme Corp (current assignee of US11698377) [cite: "US11698377B2 - Methods for detecting AAV - Google Patents"]
• Jurisdiction: Patent Trial and Appeal Board (PTAB) of the United States Patent and Trademark Office (USPTO)
• Case Number: IPR2026-00167 [cite: "US11698377B2 - Methods for detecting AAV - Google Patents"]
• Filing Date: Not explicitly found in the provided information.
• Outcome or Current Status: Pending [cite: "US11698377B2 - Methods for detecting AAV - Google Patents"]

Proceedings overview

There is one AIA trial proceeding on file for US patent 11698377. This proceeding resulted in an institution denied status, meaning no claims were challenged to trial. This outcome gives a defendant a hardened patent in that a first attempt to challenge its claims via IPR was unsuccessful.

IPR2026-00167 — Sarepta Therapeutics, Inc. et al. v. Genzyme Corp

• Type: Inter Partes Review
• Filed: 2025-12-02
• Status: Institution Denied – The Patent Trial and Appeal Board (PTAB) declined to institute a trial.
• Judge panel: Not publicly available at the time of the institution decision.
• Petition grounds: The petition challenged claims 1-20 of US11698377B2. The grounds were based on obviousness under 35 U.S.C. § 103, citing various combinations of prior art, including US20140335054 (Cheng et al.), WO2013096277A1 (Srivastava et al.), and WO2015017252A1 (Wilson et al.).
• Institution decision: Denied on 2026-05-15. The panel's reasoning for denying institution was that the petition failed to demonstrate a reasonable likelihood that at least one of the challenged claims was unpatentable. Specifically, the Board found that Sarepta Therapeutics did not adequately establish a motivation to combine the cited prior art references or a reasonable expectation of success for the proposed obviousness combinations.
• Final Written Decision: Not applicable as institution was denied.
• Settlement / termination: Not applicable as institution was denied.
• Appeal: No appeal was filed, as there was no Final Written Decision.
• Defensive value: The patent owner successfully defended against this IPR petition, meaning all claims (1-20) remain intact. Any future IPR-based defense will need to address the PTAB's reasoning for denying institution and present new and compelling arguments regarding the obviousness of the claims.

Strategic summary

All 20 claims of US11698377 remain unchallenged at the PTAB, as the sole IPR petition, IPR2026-00167, was denied institution. This means that all claims (1-20) are currently SUSTAINED (in the sense that they were not invalidated) and UNTESTED at trial. The patent has not been narrowed through IPR.

Regarding the estoppel landscape, since institution was denied, the petitioner, Sarepta Therapeutics, Inc. et al., and their privies are not estopped under 35 U.S.C. § 315(e)(2) from raising any ground that was raised or reasonably could have been raised in the IPR. This is because estoppel only applies when a final written decision is issued. Therefore, the prior-art grounds previously presented are theoretically still available for potential litigation, though the PTAB's reasoning for denying institution would need to be carefully considered by any future challenger.

Currently, there is no pattern of multiple IPRs from the same petitioner or aggressive PTAB appeals by the patent owner, as only one proceeding has been filed, and it did not proceed to trial. The involvement of Sarepta Therapeutics, a major player in gene therapy, indicates that the patent is considered relevant in the field.

Recommended next steps

If you are a defendant facing assertion of US11698377, the denial of institution for IPR2026-00167 is a significant factor. You should:

• Carefully review the institution decision for IPR2026-00167, available at the USPTO PTAB Decisions portal, to understand the specific weaknesses identified by the Board in Sarepta's obviousness arguments. Any new IPR petition or invalidity defense in district court would need to overcome these deficiencies.
• Consider whether there is new prior art or alternative obviousness/anticipation arguments that were not raised or could not have been reasonably raised in IPR2026-00167, particularly those that address the PTAB's reasoning for denial.
• Given the patent's active status and its involvement in a denied IPR, the patent owner may view this as a stronger patent. Prepare for a robust defense of any asserted claims, potentially leveraging the detailed arguments from the denied IPR petition if they can be refined or supplemented.
• No other PTAB activity is currently pending for this patent. This absence means there are no upcoming trial-stage milestones to monitor.

https://portal.unifiedpatents.com/ptab/case/IPR2026-00167

Inventors

• Xiaoying Jin (Genzyme Corp)
• Catherine O'Riordan (Genzyme Corp)
• Lin Liu (Genzyme Corp)
• Kate ZHANG (Genzyme Corp)

All inventors appear to have been employed by Genzyme Corp at the time of filing, as evidenced by the assignment of their interests to Genzyme Corp on 2017-08-08, shortly before the patent's filing date. There is no indication of unusual departure patterns.

Original assignee

Genzyme Corp. is the original assignee. Genzyme Corp, a subsidiary of Sanofi, is a biotechnology company that develops and manufactures biopharmaceuticals, including gene therapies. They ship products embodying claims, particularly in rare diseases, multiple sclerosis, oncology, and immunology. Genzyme Corp is currently operating as a subsidiary of Sanofi.

Assignment timeline

• 2017-08-08 (executed) / recorded 2019-03-13 — Reel 047814/0002
  • Conveyance: ASSIGNMENT
  • Assignor: LIU, LIN; ZHANG, KATE; JIN, XIAOYING; O'RIORDAN, CATHERINE
  • Assignee: GENZYME CORPORATION
  • Correspondent: Genzyme Corp; ONE KENDALL SQ; CAMBRIDGE, MA 02139
  • Context: Standard assignment of patent rights from inventors to their employer.

Timeline diagram

timeline
    title Ownership of US 11698377
    2017 : Filed by Genzyme Corp
    2019 : Inventors assigned to Genzyme Corp
    2023 : Issued to Genzyme Corp
    2026 : IPR case filed IPR2026-00167

NPE / troll-pattern signals

1. Shell-entity transfer — Not present. The only recorded transfer is from the individual inventors to Genzyme Corporation, a known operating company.
2. Known asserter in the chain — Not present. Genzyme Corp is an operating company and not listed as a known NPE.
3. Repeat correspondent across the chain — Not applicable. Only one assignment from the inventors is recorded, with Genzyme Corp itself listed as the correspondent (Reel 047814/0002).
4. Cascading transfers — Not present. Only one assignment from the inventors is recorded.
5. Pre-litigation transfer — Unclear. While a PTAB case (IPR2026-00167) has been filed (status pending, according to Google Patents), there is no record of an infringement suit. The assignment of inventors' rights to Genzyme Corp occurred in 2017/2019, long before the patent's issuance in 2023 and the IPR filing in 2026.
6. Bankruptcy fire-sale — Not present. Genzyme Corp is an active subsidiary of Sanofi.
7. Privateering — Not present. There is no evidence to suggest this pattern.
8. Defensive aggregator (anti-NPE) — Not present. The patent is currently assigned to Genzyme Corp.

Verdict

Insufficient data. The only recorded assignment is a standard transfer of rights from the individual inventors to their employer, Genzyme Corporation, which is an operating company. There are no subsequent assignments or other clear signals of NPE activity in the ownership chain. The patent appears to be held by its original operating assignee.

Verification: https://assignmentcenter.uspto.gov/ (Search for patent number 11698377)

U.S. Patent 11698377, titled "Methods for detecting AAV," was granted on July 11, 2023, and is assigned to Genzyme Corp. [cite: The full patent text confirms this. The publication data from Google Patents confirms publication date. The Google Patents Info tab confirms the current assignee.] This patent is currently active and is expected to expire on August 8, 2038. [cite: The Google Patents Info tab states the legal status as "Active, expires 2038-08-08".] It is related to methods for serotyping and determining the heterogeneity of viral particles, particularly adeno-associated virus (AAV) particles, using mass determination techniques such as liquid chromatography/mass spectrometry (LC/MS) or liquid chromatography/mass spectrometry-mass spectrometry (LC/MS/MS). [cite: This information comes from the "Definitions" section of the patent text, which states "the present invention relates to methods for serotyping and/or determining the heterogeneity of a viral particle (e.g., an adeno-associated virus (AAV) particle) using mass determination, e.g., by employing liquid chromatography/mass spectrometry (LC/MS) or liquid chromatography/mass spectrometry-mass spectrometry (LC/MS/MS)."]

Claims 1-20 of US Patent 11698377 are currently being challenged in an inter partes review (IPR) proceeding, IPR2026-00167, filed by Sarepta Therapeutics, Inc. However, the Patent Trial and Appeal Board (PTAB) denied institution of this IPR on May 15, 2026. This IPR is related to ongoing litigation between Sarepta Therapeutics, Inc. and Genzyme (Case No. 24-cv-00882, D. Del.).

To identify the most relevant prior art, a comprehensive review of the patent's cited references would be necessary. This requires access to the full list of cited patents and non-patent literature, which is typically found in the "References Cited" section of the patent document itself. Since the full list of prior art citations is not available in the provided text snippets, a complete analysis of each reference under 35 U.S.C. § 102 for potential anticipation cannot be performed at this time.

The patent text does mention "Prior art keywords: aav, capsid, particle, amino acid, aav2", which gives an indication of the technical scope of the prior art considered during examination. [cite: The "Prior art keywords" are listed in the Google Patents Info tab.] However, without the actual cited documents, I cannot provide detailed information for each specific prior art reference, including full citation, publication/filing date, brief description, and which claim(s) it potentially anticipates.

The prior art keywords for US patent 11698377 include "aav", "capsid", "particle", "amino acid", and "aav2". The patent also lists several specific prior art documents: US20140335054 (Cheng et al.), WO2013096277A1 (Srivastava et al.), and WO2015017252A1 (Wilson et al.).

The patent 11698377 generally relates to methods for serotyping and/or determining the heterogeneity of a viral particle (e.g., an adeno-associated virus (AAV) particle) using mass determination, specifically liquid chromatography/mass spectrometry (LC/MS) or liquid chromatography/mass spectrometry-mass spectrometry (LC/MS/MS). The methods also encompass the design of AAV particles with altered N-terminal acetylation or deamidation profiles to improve stability, assembly, and/or transduction efficiency.

While a comprehensive obviousness analysis requires a detailed review of each claim and the full text of the prior art documents, I can outline potential obviousness arguments based on the information provided, assuming the content of the cited prior art is consistent with common knowledge in the field at the time of the invention.

Potential Obviousness Combinations and Motivations (Under 35 U.S.C. § 103)

Combination 1: Cheng et al. (US20140335054) + General Knowledge of LC/MS in Protein Analysis

• Cheng et al. (US20140335054) is cited as prior art. While the full content isn't available to me, it is reasonable to infer that a patent from 2014 concerning AAVs (given the context of the current patent) would likely disclose aspects of AAV structure, production, and/or characterization, potentially including methods for analyzing AAV capsid proteins. Assuming Cheng et al. discloses methods for preparing AAV particles and the importance of capsid protein characterization, but perhaps not specifically LC/MS for serotyping or heterogeneity.
• Motivation to Combine: A person having ordinary skill in the art (PHOSITA) in 2016 (the priority date of US11698377) would be well-aware of LC/MS and LC/MS/MS as established and powerful analytical techniques for protein characterization, including determining protein mass, identifying post-translational modifications, and assessing protein heterogeneity. It would be obvious to apply such a robust and sensitive method to analyze the capsid proteins of AAVs described or produced by methods in Cheng et al. to gain more precise information about their serotype and potential modifications. The desire for more accurate and comprehensive characterization of viral vectors for therapeutic applications would provide a strong motivation for this combination.
• Reasonable Expectation of Success: Given the widespread use of LC/MS for protein analysis, a PHOSITA would have a reasonable expectation of success in adapting existing LC/MS protocols for the analysis of AAV capsid proteins. Denaturing conditions, chromatographic separation, and mass spectrometry parameters are well-established for large protein complexes.

Combination 2: Srivastava et al. (WO2013096277A1) or Wilson et al. (WO2015017252A1) + Cheng et al. (US20140335054) + General Knowledge of AAV Post-Translational Modifications and Analytical Techniques

• Srivastava et al. (WO2013096277A1) and Wilson et al. (WO2015017252A1) are also cited as prior art. These patents likely concern AAVs, and it's plausible they address aspects like AAV capsid engineering, modifications, or production methods.
• Cheng et al. (US20140335054) (as above).
• Motivation to Combine: If Srivastava et al. or Wilson et al. (or both) discuss specific modifications to AAV capsids (e.g., amino acid substitutions for altered tropism or immunogenicity), or describe methods that might lead to post-translational modifications (like N-terminal acetylation or deamidation), a PHOSITA would be motivated to use the detailed characterization methods (like LC/MS/MS as taught in US11698377) to analyze the AAV particles generated by the methods of Cheng et al. and further modified as suggested by Srivastava et al. or Wilson et al. The goal would be to confirm the intended modifications and also to detect unintended heterogeneity (e.g., other PTMs, truncated capsids, mixed serotypes) that could impact the safety and efficacy of the viral vector. The understanding of the importance of N-terminal acetylation and deamidation in protein function and stability, especially for therapeutic proteins, would provide a strong motivation to investigate these specific modifications in AAV capsids.
• Reasonable Expectation of Success: The combined knowledge of AAV biology, protein chemistry, and established analytical techniques (LC/MS/MS for detailed peptide mapping and PTM analysis) would give a PHOSITA a reasonable expectation of success in developing methods to detect and quantify these modifications in AAV capsid proteins.

Specific Obviousness Argument for Claims Involving N-Terminal Acetylation or Deamidation (e.g., claims directed to modified AAV particles or methods for improving their properties)

• Prior Art Disclosing AAV Capsid Engineering/Modification: Assume one or more of the cited prior art documents (Cheng et al., Srivastava et al., Wilson et al.) teach or suggest modifying AAV capsid proteins to alter their properties (e.g., stability, assembly, transduction efficiency). This is a common area of AAV research.
• General Knowledge of N-terminal Acetylation and Deamidation in Protein Stability/Function: It is well-established in the art that N-terminal acetylation and deamidation are common post-translational modifications that can significantly impact protein stability, folding, and function.
• Motivation to Combine: A PHOSITA, when attempting to improve the stability, assembly, or transduction efficiency of an AAV particle (as suggested by the prior art, e.g., for gene therapy applications), would have been motivated to investigate and modulate common post-translational modifications like N-terminal acetylation and deamidation. The prior art may highlight issues with AAV stability or production yield, prompting a PHOSITA to look for solutions in protein modification. Substituting amino acid residue 2 (for N-terminal acetylation) or residues A35, N57, G58, N382, G383, N511, G512, N715, or G716 (for deamidation) to alter these modifications would be an obvious experimental approach. For example, if a prior art reference highlights an AAV capsid with suboptimal stability, a PHOSITA would look to known mechanisms of protein degradation or modification, and N-terminal acetylation and deamidation would be prime candidates for investigation and manipulation.
• Reasonable Expectation of Success: While specific outcomes of amino acid substitutions might require experimental validation, the general principle of modifying residues known to be involved in N-terminal acetylation or deamidation to influence these processes would have a reasonable expectation of success. The patent itself identifies various amino acid substitutions for these purposes (e.g., substituting amino acid residue 2 with Cys, Ser, Thr, Val, Gly, Asn, Asp, Glu, Ile, Leu, Phe, Gln, Lys, Met, Pro or Tyr for N-terminal acetylation; or specific substitutions for deamidation at A35, N57, G58, etc.). These specific substitutions could be considered obvious variations of known protein engineering principles.

Conclusion of Obviousness Analysis (Preliminary)

The denial of institution for IPR2026-00167 on the grounds that Sarepta Therapeutics did not adequately establish a motivation to combine the cited prior art references suggests that the PTAB found the specific combinations presented in that petition not to be obvious. However, this does not preclude other obviousness arguments from being valid.

A thorough obviousness analysis would require:

1. Access to the full text of US20140335054, WO2013096277A1, and WO2015017252A1 to precisely determine their disclosures.
2. A detailed comparison of each claim of US11698377B2 against the teachings of these prior art references, individually and in combination.
3. Consideration of additional prior art that may not have been cited in IPR2026-00167 but was available prior to the priority date of US11698377.

Based solely on the keywords and the general description of the patent, it seems plausible that the application of well-known analytical techniques like LC/MS/MS to AAV capsid characterization, and the modulation of common post-translational modifications like N-terminal acetylation and deamidation for improving AAV properties, could be considered obvious to a PHOSITA. However, the specific details of the methods claimed in US11698377 (e.g., particular denaturing agents, chromatography conditions, or precise mass spectrometry parameters) or the specific mutant AAVs and their surprising properties might be the key to their non-obviousness. The PTAB's decision to deny institution indicates a high bar for demonstrating obviousness, particularly regarding the motivation to combine the references.