Synthego Corp v. Agilent Tech Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Synthego Corporation (Delaware)
  • Defendant: Agilent Technologies, Inc. (Delaware)
  • Plaintiff's Counsel: Weil, Gotshal & Manges LLP
• Case Identification: 5:21-cv-07801, N.D. Cal., 10/05/2021
• Venue Allegations: Venue is asserted in the Northern District of California because Defendant Agilent Technologies, Inc. maintains its corporate headquarters and principal place of business in the district.
• Core Dispute: Plaintiff Synthego seeks a declaratory judgment that its CRISPR-related RNA products and services do not infringe two of Defendant Agilent's patents concerning chemically modified guide RNAs.
• Technical Context: The case is centered on CRISPR gene-editing technology, where chemically modified guide RNAs (gRNAs) are critical for improving the stability and specificity of the editing process in research and therapeutic applications.
• Key Procedural History: The action follows a series of communications, initiated by Agilent on June 24, 2021, demanding that Synthego license Agilent's patents. Synthego alleges these communications and subsequent threats of "more formal legalistic processes" create a reasonable apprehension of an infringement suit. In the complaint, Synthego also states its intent to file petitions for inter partes review (IPR) to challenge the validity of the patents-in-suit, signaling a potential parallel challenge at the U.S. Patent and Trademark Office.

Case Timeline

Date	Event
2014-12-03	Earliest Priority Date for '034 and '001 Patents
2019-07-02	U.S. Patent No. 10,337,001 Issues
2021-01-26	U.S. Patent No. 10,900,034 Issues
2021-06-24	Agilent sends initial letter to Synthego demanding license
2021-10-05	Complaint for Declaratory Judgment Filed

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

U.S. Patent No. 10,900,034 - Guide RNA with Chemical Modifications (Issued Jan. 26, 2021)

The Invention Explained

• Problem Addressed: The patent's background section notes that developing guide RNAs (gRNAs) for CRISPR systems requires considerations of specificity (minimizing off-target effects), stability against degradation by enzymes, and efficient transferability into cells '034 Patent, col. 1:56-2:10 Naturally occurring gRNAs may be deficient in these areas, limiting their therapeutic and research potential '034 Patent, col. 1:56-62
• The Patented Solution: The invention addresses these problems by introducing specific chemical modifications into the gRNA structure '034 Patent, abstract These modifications, which can be made to the sugar, base, or phosphate backbone of the RNA, are designed to enhance stability and functionality without compromising the gRNA's ability to guide the Cas protein to its DNA target '034 Patent, col. 3:32-44
• Technical Importance: By improving the stability and specificity of gRNAs, these modifications facilitate the use of CRISPR-based technologies in more demanding environments, such as for the development of human therapeutics.

Key Claims at a Glance

• The complaint identifies claims requiring a synthetic CRISPR guide RNA with a 2'-O-methyl modification in the guide sequence Compl. ¶21 This corresponds to independent claim 1.
• Independent Claim 1 requires:
  • A synthetic CRISPR guide RNA comprising:
    • (a) a crRNA segment comprising (i) a guide sequence capable of hybridizing to a target sequence and (ii) a stem sequence; and
    • (b) a tracrRNA segment comprising a nucleotide sequence that is partially or completely complementary to the stem sequence.
  • Wherein the synthetic guide RNA has gRNA functionality (associating with a Cas protein and targeting the complex to the target sequence).
  • And comprises one or more modifications in the guide sequence, wherein the one or more modifications comprises a 2'-O-methyl.

U.S. Patent No. 10,337,001 - Guide RNA with Chemical Modifications (Issued Jul. 2, 2019)

The Invention Explained

• Problem Addressed: Similar to its related '034 patent, the '001 Patent addresses the need to improve the stability, specificity, and cellular delivery of gRNAs used in CRISPR systems '001 Patent, col. 1:52-2:11 The patent notes that unmodified gRNAs can be susceptible to nuclease degradation and may have off-target effects '001 Patent, col. 1:52-2:2
• The Patented Solution: The patent discloses chemically modified gRNAs that solve these issues. The invention involves placing one or more modified nucleotides near the 5' and/or 3' ends of the gRNA molecule to, for example, protect against degradation by cellular enzymes '001 Patent, col. 25:6-14 Figure 5B illustrates the general structure of a single guide RNA, a common format for synthetic gRNAs, which combines the crRNA and tracrRNA components into a single molecule '001 Patent, Fig. 5B
• Technical Importance: Modifying the ends of the gRNA provides a direct method to increase the molecule's lifespan within a cell, thereby improving the efficiency of gene editing for research and therapeutic purposes.

Key Claims at a Glance

• The complaint identifies claims requiring a synthetic CRISPR guide RNA with modifications within five nucleotides of the 5'-end and/or 3'-end Compl. ¶25 This corresponds to independent claim 1.
• Independent Claim 1 requires:
  • A synthetic CRISPR guide RNA having at least one 5'-end and at least one 3'-end.
  • The synthetic guide RNA comprising (a) one or more modified nucleotides within five nucleotides from said 5'-end, or (b) one or more modified nucleotides within five nucleotides from said 3'-end, or (c) both.
  • Wherein said guide RNA comprises one or more RNA molecules and has gRNA functionality.
  • And wherein the modified nucleotide has a modification to a phosphodiester linkage, a sugar, or both.

III. The Accused Instrumentality

Product Identification

• The complaint identifies the "Synthego Accused Products" as Synthego's CRISPREVOLUTION line of Synthetic sgRNA kits, its Advanced RNA and CRISPR GMP sgRNA Manufacturing services, and its ECLIPSE genome editing services Compl. ¶1

Functionality and Market Context

• The accused products are synthetic single-guide RNAs (sgRNAs) and associated services for use in CRISPR-based gene editing Compl. ¶¶5-6 Synthego's platform is described as enabling the scalable development and manufacturing of these highly efficient sgRNAs Compl. ¶6
• The complaint alleges these products are used by scientists for research and the development of clinical therapeutics, with customers planning to use GMP-grade sgRNAs in preclinical and clinical trials (Compl. ¶¶4; Compl. ¶7). Synthego asserts that the sale and use of the accused products are "reasonably related to the development and submission of information to the Food and Drug Administration" (Compl. ¶¶7; Compl. ¶13; Compl. ¶25). This allegation forms the basis of Synthego's primary non-infringement defense.
• No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide a technical claim chart or a detailed element-by-element analysis of non-infringement. Instead, it asserts a broad legal defense of non-infringement under the safe harbor provision of 35 U.S.C. § 271(e)(1). The following table summarizes the non-infringement theory as presented.

'034 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A synthetic CRISPR guide RNA comprising (a) a crRNA segment... and (b) a tracrRNA segment...	The complaint asserts that the manufacture, use, and sale of the Synthego Accused Products are non-infringing acts under the safe harbor provisions of 35 U.S.C. § 271(e)(1) Compl. ¶21	¶21	col. 3:1-11
wherein the synthetic guide RNA has gRNA functionality comprising associating with a Cas protein and targeting the gRNA:Cas protein complex to the target sequence...	The complaint states the accused products are used for purposes reasonably related to the development and submission of information to the FDA or other regulatory bodies Compl. ¶13 Compl. ¶21	¶¶13; ¶21	col. 6:40-52
and comprises one or more modifications in the guide sequence, wherein the one or more modifications comprises a 2'-O-methyl.	Synthego argues that because the accused products' use falls under the § 271(e)(1) safe harbor, they do not infringe any valid claim of the patent, including claims requiring a 2'-O-methyl modification Compl. ¶21	¶21	col. 27:12-24

'001 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A synthetic CRISPR guide RNA having at least one 5'-end and at least one 3'-end, the synthetic guide RNA comprising (a) one or more modified nucleotides within five nucleotides from said 5'-end, or (b) one or more modified nucleotides within five nucleotides from said 3'-end, or (c) both (a) and (b);	The complaint asserts that the manufacture, use, and sale of the Synthego Accused Products are non-infringing acts under the safe harbor provisions of 35 U.S.C. § 271(e)(1) Compl. ¶25	¶25	col. 25:6-14
wherein said guide RNA...has gRNA functionality...	The complaint states the accused products are used for purposes reasonably related to the development and submission of information to the FDA or other regulatory bodies Compl. ¶13 Compl. ¶25	¶¶13; ¶25	col. 6:40-52
wherein the modified nucleotide has a modification to a phosphodiester linkage, a sugar, or both.	Synthego argues that because the accused products' use falls under the § 271(e)(1) safe harbor, they do not infringe any valid claim of the patent, including claims requiring the specified modifications Compl. ¶25	¶25	col. 7:40-10:55

• Identified Points of Contention:
  • Legal Question: The central dispute presented in the complaint is not technical but legal: Does Synthego's business of developing and selling synthetic gRNAs to researchers for use in preclinical and clinical therapeutic development constitute acts "reasonably related to the development and submission of information" to the FDA, thereby qualifying for the § 271(e)(1) safe harbor from infringement? (Compl. ¶¶13; Compl. ¶21; Compl. ¶25).
  • Technical Question: Should the court find that the safe harbor does not apply, a secondary question will be whether Synthego's products technically meet the limitations of the asserted claims. The complaint does not provide sufficient detail for analysis of this point, but it raises the question of what evidence will show whether the accused products contain the specific 2'-O-methyl modifications ('034 Patent) or the specific terminal modifications ('001 Patent) as claimed.

V. Key Claim Terms for Construction

The complaint does not propose any claim constructions, as its primary argument rests on a statutory exemption from infringement. However, based on the patent claims, the following terms may become central to a technical infringement analysis.

• Term: "gRNA functionality" (from Claim 1 of '034 Patent; Claim 1 of '001 Patent)

  • Context and Importance: This term defines the baseline capability a modified RNA must possess to be infringing. The scope of "functionality" is critical, as a defendant could argue its modified RNA, while structurally similar, lacks a required function or operates differently. Practitioners may focus on this term to dispute whether an accused product performs the same function in the same way as the claimed invention.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification provides a list of functions, stating that a gRNA with "gRNA functionality" is one that has "one or more of the functions of naturally occurring guide RNA" '001 Patent, col. 6:40-44 This disjunctive "one or more" language may support a broader reading where not all natural functions are required.
    • Evidence for a Narrower Interpretation: The claim language itself specifies that functionality comprises "associating with a Cas protein and targeting the gRNA:Cas protein complex to a target polynucleotide" '001 Patent, claim 1 A party could argue that this defines the complete and required scope of functionality, excluding other potential activities.

• Term: "guide sequence" (from Claim 1 of '034 Patent)

  • Context and Importance: This term defines the part of the gRNA that directs it to the DNA target. The '034 patent claims a modification "in the guide sequence." The precise boundaries of this sequence are therefore critical for determining if a modification falls inside or outside this limitation.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The term is broadly defined as being "capable of hybridizing to a target sequence" '034 Patent, claim 1, which could be argued to encompass any portion of the gRNA that participates in target binding.
    • Evidence for a Narrower Interpretation: The patent provides examples of guide sequences of specific lengths, such as 20 nucleotides '034 Patent, col. 7:59-63 A party could argue that this creates a narrower definition, potentially excluding modifications in nucleotides that are adjacent to but not part of this core 20-nt region.

VI. Other Allegations

The complaint, being a declaratory judgment action for non-infringement, does not contain allegations of indirect or willful infringement by the patent holder, Agilent. These allegations would typically be brought by the patent holder in a direct infringement suit against the accused infringer, Synthego.

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

This case is a preemptive action by an accused infringer and presents a distinct set of strategic questions for the court, revolving less around technical infringement and more around statutory and procedural issues.

1. The Safe Harbor Question: The primary issue is the applicability of the 35 U.S.C. § 271(e)(1) safe harbor. Can the commercial sale of research-use-only and GMP-grade gene editing tools, which are used by customers for developing information for submission to the FDA, be considered "reasonably related" to such submissions? The court's decision on this threshold legal question could be dispositive.

2. The Procedural and Validity Question: A significant secondary issue is the interplay between this district court action and Synthego's stated intent to file inter partes review (IPR) petitions against the patents. Will the court stay this case pending the outcome of the IPRs, as Synthego intends to request? The IPRs will directly challenge the validity of the patents, and their institution and final outcome will critically impact the scope and relevance of the infringement dispute.

3. The Technical Infringement Question: If the safe harbor defense fails and the patents survive IPR challenges, the case will turn on a fundamental question of technical correspondence: does the evidence show that Synthego's accused sgRNA products contain the exact chemical modifications-a 2'-O-methyl modification in the guide sequence ('034 Patent) and a sugar or backbone modification within five nucleotides of the 5' or 3' end ('001 Patent)-as required by the asserted claims?