Obviousness

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.