TET Systems GmbH & Co KG v. Rejuvenate Bio Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: TET Systems GmbH & Co. KG (Germany)
  • Defendant: Rejuvenate Bio, Inc. (Delaware), Daniel Oliver, and Noah Davidsohn
  • Plaintiff’s Counsel: The Law Office of John F. Olsen
• Case Identification: 3:24-cv-01740, S.D. Cal., 09/30/2024
• Venue Allegations: Venue is based on Defendant Rejuvenate Bio, Inc. maintaining offices and conducting systematic and continuous business within the Southern District of California.
• Core Dispute: Plaintiff alleges that Defendants’ use of specific research tools and methods for gene therapy research infringes two patents related to tetracycline-regulated gene expression systems.
• Technical Context: The technology involves systems for inducibly controlling gene expression in eukaryotic cells, a foundational tool in biotechnology and pharmaceutical research for studying gene function and developing therapies.
• Key Procedural History: U.S. Patent No. RE49,583 is a reissue of U.S. Patent No. 8,383,364, suggesting the patent owner may have corrected an error in the original patent, potentially to broaden or clarify claim scope.

Case Timeline

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 9,181,556 - "Tetracycline Inducible Transcription Control Sequence," issued November 10, 2015

The Invention Explained

• Problem Addressed: The patent describes a need for tetracycline-dependent transcription control systems that offer "improved tight and reliable regulation," specifically seeking a system with low "basal activity" (i.e., minimal gene expression when turned "off") while retaining "high induction potential" when turned "on" (’556 Patent, col. 2:10-14).
• The Patented Solution: The invention is a specifically engineered DNA sequence (a promoter) that controls gene expression. It combines at least two tetracycline operator ("tetO") motifs, which act as binding sites for a regulatory protein, with a "minimal promoter" containing a TATA box and a binding site for a general transcription factor, TFIIB (’556 Patent, Abstract; col. 3:38-54). This specific architecture is designed to solve the problem of leaky expression and achieve precise control.
• Technical Importance: Achieving tight, inducible control over gene expression is critical for research and therapeutic applications, as unintended or "leaky" expression of a target gene can produce confounding experimental results or toxic effects in a patient (Compl. ¶8).

Key Claims at a Glance

• The complaint asserts independent claims 1 and 9 (Compl. ¶22).
• Claim 1 (product claim) covers:
  • A nucleic acid
  • having a sequence that is at least 90% identical to the sequence of any one of SEQ ID NO: 13, 14, 15, 16, or 17 (’556 Patent, col. 43:40-45).
• Claim 9 (method claim) covers:
  • A method for regulating the expression of a second nucleic acid sequence operatively linked to the nucleic acid of claim 1
  • by expressing a tetracycline-dependent transcriptional regulator in a host cell, animal, or plant
  • and modulating the concentration of tetracycline to regulate expression (’556 Patent, col. 43:50-64).
• The complaint also asserts dependent claims 2-5, 10, and 12 (Compl. ¶22).

U.S. Patent No. RE49,583 - "Inducible Expression Systems," issued July 18, 2023

The Invention Explained

• Problem Addressed: The patent addresses shortcomings in prior "reverse" tetracycline transactivators (rtTA), which are proteins that activate gene expression in the presence of an inducer like doxycycline (dox). These prior systems required high, potentially toxic concentrations of dox for activation and were not effectively activated by other tetracycline analogs (’583 Patent, col. 1:55-64).
• The Patented Solution: The invention provides improved rtTA proteins containing specific amino acid mutations at designated positions (e.g., positions 9, 19, 37, 56, etc.) (’583 Patent, col. 2:30-45). These mutations are disclosed to result in improved properties such as higher transcriptional activity, increased sensitivity to dox, and enhanced genetic stability.
• Technical Importance: Creating more sensitive and stable transactivators allows for the use of lower, safer doses of the inducing drug and expands the utility of the Tet-On system in research and therapeutic contexts, particularly in vivo (Compl. ¶17).

Key Claims at a Glance

• The complaint asserts independent claims 1, 14, 43, 55, and 80-83 (Compl. ¶22).
• Claim 1 (method claim) covers:
  • A method for inducibly expressing a nucleic acid sequence of interest
  • using an inducible gene expression system that comprises an rtTA
  • wherein the rtTA has a mutation in a codon at one or more specified amino acid positions (e.g., 9, 19, 37, 56, etc.) (’583 Patent, col. 61:35 - col. 62:49).
• Claim 14 (product claim) covers:
  • A synthetic or recombinant nucleic acid sequence
  • comprising an rtTA encoding nucleic acid sequence
  • which comprises a mutated codon at one or more specified amino acid positions (e.g., 9, 19, 37, 56, etc.) (’583 Patent, col. 63:25-34).
• The complaint also asserts dependent claims (Compl. ¶22).

III. The Accused Instrumentality

Product Identification

• The accused instrumentalities are the research tools, processes, and methods used by Defendants, as described in a January 2023 scientific paper titled “Gene Therapy Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Relate Changes in Aged Mice” (Compl. ¶20).

Functionality and Market Context

• The complaint alleges that in their research, Defendants used key components of Plaintiff's "Tet-On 3G System" to achieve inducible gene expression. Specifically, Defendants are alleged to have used a "PTRE3G promoter" to control the expression of certain "Yamanaka factors" in transgenic mice, and a transactivator protein called "rtTA4" to activate that promoter in the presence of an inducer (Compl. ¶20). The complaint frames this use as part of research into "novel therapies to treat aging and age-related diseases" (Compl. ¶2).
  No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

• ’9,181,556 Infringement Allegations

• ’RE49,583 Infringement Allegations

• Identified Points of Contention:
  • Factual/Evidentiary Questions: The central dispute appears to be factual rather than one of claim scope. The complaint makes direct assertions of infringement but does not include the sequence data for the accused "PTRE3G promoter" or "rtTA4" transactivator. Key questions will therefore be:
    • What is the nucleotide sequence of the "PTRE3G promoter" used by Defendants, and does it meet the "at least 90% identical" limitation of claim 1 of the ’556 Patent?
    • What specific modification(s) exist in the "rtTA4" transactivator, and do they correspond to any of the amino acid mutations recited in the asserted claims of the ’583 Patent?
  • Scope Questions: Should the evidence show that "rtTA4" contains a mutation at a position not explicitly listed in the asserted claims, a question may arise as to whether Defendants' transactivator is truly a "modified version" of Plaintiff's proprietary technology in a legally relevant sense, or if it constitutes a distinct, non-infringing design.

V. Key Claim Terms for Construction

• The Term: "at least 90% identical" (’556 Patent, Claim 1)

  • Context and Importance: This term defines the boundary of the patent monopoly for the claimed nucleic acid sequences. The infringement analysis for the ’556 Patent will hinge on a factual comparison of the accused promoter's sequence against the patent's reference sequences, calculated according to the established legal and scientific meaning of "percent identity." Practitioners may focus on this term because seemingly small differences in sequence could be dispositive of infringement.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent does not appear to define the term in a way that limits the standard technical meaning, which could support the application of commonly used sequence alignment algorithms.
    • Evidence for a Narrower Interpretation: The specification provides specific examples of sequences (SEQ ID NOs 13-17) that embody the invention. A defendant may argue that the 90% identity must be assessed in a way that preserves the core functional elements described as critical in the specification, such as the distinct operator and minimal promoter regions.

• The Term: "a mutation in a codon at rtTA amino acid position [X]" (’583 Patent, Claims 1, 14)

  • Context and Importance: The claims of the ’583 Patent are defined by the presence of mutations at specific locations within the rtTA protein sequence. The infringement analysis depends entirely on identifying such a mutation in the accused "rtTA4" transactivator. The numbering of amino acid positions is only meaningful relative to a reference sequence.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The claims list a wide array of possible mutation sites, suggesting an intent to cover numerous modified versions of rtTA.
    • Evidence for a Narrower Interpretation: The specification provides a reference sequence for rtTA in Figure 19 (’583 Patent, col. 4:60-64, FIG. 19). The patent's disclosure is grounded in this specific sequence, and a court would likely construe the positional numbering of the claims (e.g., "position 9") by aligning an accused sequence with this reference.

VI. Other Allegations

• Indirect Infringement: The complaint alleges that the individual defendants, Daniel Oliver (CEO) and Noah Davidsohn (CSO), actively participated in the infringing experiments and/or knowingly induced others at Rejuvenate Bio to infringe the patents (Compl. ¶21). Defendant Davidsohn is identified as the corresponding author on the scientific paper at issue (Compl. ¶21).
• Willful Infringement: The prayer for relief seeks a declaration that infringement has been willful, which would permit an award of enhanced damages (Prayer ¶(b), (e)). The factual basis appears to be the allegation that Defendants are not licensees and are not an academic or non-profit entity that might otherwise receive a cost-free license from TET, implying they knew or should have known their use of the "Tet Technology" was unlicensed and infringing (Compl. ¶23).

VII. Analyst’s Conclusion: Key Questions for the Case

This case appears to turn less on complex claim construction issues and more on straightforward factual evidence that is not yet present in the complaint. The central questions for the court will likely be:

• A primary issue will be one of evidentiary proof: can Plaintiff produce definitive sequence evidence demonstrating that the "PTRE3G promoter" used by Defendants falls within the "90% identical" scope of the ’556 Patent's claims?
• A second core evidentiary question will be one of structural identity: what is the specific amino acid sequence of the accused "rtTA4" transactivator, and does it contain one or more of the specific mutations at the specific positions required by the asserted claims of the ’583 Patent?
• A third question will relate to liability for inducement: assuming infringement by the corporation is found, what specific actions did the individual defendants take that demonstrate the requisite knowledge and intent to encourage the company's infringement?