DCT
3:11-cv-02214
Isis Pharma Inc v. Santaris Pharma As Corp
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Isis Pharmaceuticals, Inc. (Delaware)
- Defendant: [Santaris Pharma A/S](https://ai-lab.exparte.com/party/santaris-pharma-as-corp) Corp. (Delaware) and Santaris Pharma A/S (Denmark)
- Plaintiff’s Counsel: McDermott Will & Emery LLP
- Case Identification: 3:11-cv-02214, S.D. Cal., 10/17/2014
- Venue Allegations: Plaintiff alleges venue is proper in the Southern District of California as Defendants conduct business in the State of California and have engaged in substantial and continuous contacts within the state.
- Core Dispute: Plaintiff alleges that Defendant’s antisense drug discovery services and products infringe patents related to chemically modified "gapmer" oligonucleotides and antisense compounds targeting the expression of beta-catenin and glioma-associated oncogene-2.
- Technical Context: The technology domain is antisense therapeutics, which uses synthetic nucleic acid strands (oligonucleotides) to bind to messenger RNA (mRNA) and inhibit the production of specific disease-causing proteins.
- Key Procedural History: The complaint notes that Defendant Santaris previously and unsuccessfully challenged Plaintiff's European Patent that stemmed from the same original application as the asserted ’199 Patent, which may be relevant to allegations of pre-suit knowledge and willfulness.
Case Timeline
| Date | Event |
|---|---|
| 1991-12-24 | U.S. Patent No. 6,326,199 Earliest Priority Date |
| 1999-06-25 | U.S. Patent No. 6,066,500 Priority Date |
| 2000-05-23 | U.S. Patent No. 6,066,500 Issue Date |
| 2001-07-17 | U.S. Patent No. 6,440,739 Priority Date |
| 2001-12-04 | U.S. Patent No. 6,326,199 Issue Date |
| 2002-08-27 | U.S. Patent No. 6,440,739 Issue Date |
| 2006-07-27 | Santaris announces agreement with Enzon Pharmaceuticals |
| 2007-12-19 | Santaris announces agreement with GlaxoSmithKline |
| 2009-08-24 | Santaris announces agreement with Shire PLC |
| 2011-01-04 | Santaris announces agreement with Pfizer, Inc. |
| 2014-10-17 | Second Amended Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 6,326,199 - "Gapped 2' Modified Oligonucleotides," Issued Dec. 4, 2001
The Invention Explained
- Problem Addressed: The patent describes a fundamental challenge in antisense drug design: oligonucleotides need to be modified for nuclease resistance and high binding affinity, but these same modifications often interfere with the ability of a cellular enzyme, RNase H, to recognize the oligonucleotide-mRNA duplex and cleave the target mRNA, which is a primary mechanism of action for antisense drugs (’199 Patent, col. 2:16-32).
- The Patented Solution: The invention proposes a chimeric or "gapmer" oligonucleotide structure. This design features a central segment ("gap") of DNA-like nucleotides (specifically, 2'-deoxy-erythro-pentofuranosyl) that is a substrate for RNase H. This gap is flanked on one or both sides by "wings" of modified nucleotides (e.g., with 2'-substituents) that provide enhanced nuclease resistance and binding affinity to the target mRNA (’199 Patent, col. 3:17-44; col. 4:45-50).
- Technical Importance: This gapmer design provides a platform solution that reconciles the conflicting requirements of stability, affinity, and enzymatic cleavage, creating a more potent and durable antisense therapeutic structure (Compl. ¶ 20).
Key Claims at a Glance
- The complaint asserts method claims (Compl. ¶ 20). Independent claim 11 is representative.
- Essential Elements of Independent Claim 11:
- A method of modifying a sequence-specific ribonucleic acid in a cell containing RNase H.
- Comprising contacting the cell with an oligonucleotide that has a sequence of nucleotides.
- Wherein at least one nucleotide is functionalized to increase nuclease resistance.
- Wherein a plurality of nucleotides have a substituent group to increase binding affinity.
- Wherein a plurality of nucleotides have 2'-deoxy-erythro-pentofuranosyl sugar moieties.
- The complaint does not explicitly reserve the right to assert dependent claims.
U.S. Patent No. 6,066,500 - "Antisense Modulation of Beta Catenin Expression," Issued May 23, 2000
The Invention Explained
- Problem Addressed: The patent background identifies the protein beta-catenin as a key mediator in cell signaling pathways whose overexpression or dysregulation is associated with the development of cancers, particularly colorectal cancer and melanomas (’500 Patent, col. 1:48-54). It notes a need for agents capable of inhibiting Beta catenin function (’500 Patent, col. 2:46-49).
- The Patented Solution: The patent discloses antisense compounds, specifically oligonucleotides, that are designed to be complementary to and hybridize with the nucleic acids that encode for beta-catenin. This binding is intended to interfere with the normal function of the beta-catenin nucleic acid, thereby inhibiting the expression (production) of the beta-catenin protein (’500 Patent, Abstract).
- Technical Importance: The invention provides a targeted molecular tool for reducing the production of a specific, well-established oncogene, offering a potential therapeutic approach for related cancers (Compl. ¶ 23).
Key Claims at a Glance
- The complaint asserts composition and method claims (Compl. ¶ 77). Independent claim 1 is representative.
- Essential Elements of Independent Claim 1:
- An antisense compound 8 to 30 nucleobases in length.
- Targeted to a region of human Beta catenin (specifically, the 3'-untranslated region, start codon, coding region, stop codon, or 5'-untranslated region).
- Wherein the compound specifically hybridizes with and inhibits the expression of human Beta catenin.
- The complaint does not explicitly reserve the right to assert dependent claims.
Multi-Patent Capsule
U.S. Patent No. 6,440,739 - "Antisense Modulation of Glioma-Associated Oncogene-2 Expression," Issued Aug. 27, 2002
- Technology Synopsis: The patent addresses the overexpression of glioma-associated oncogene-2 (GLI2), a protein associated with developmental syndromes and cancers (Compl. ¶ 24). The patented solution comprises antisense oligonucleotides that hybridize to the mRNA encoding GLI2, causing its destruction and thereby decreasing the production of the GLI2 protein (’739 Patent, Abstract).
- Asserted Claims: The complaint asserts infringement of the patent's composition and method claims (Compl. ¶ 83).
- Accused Features: The complaint alleges that Santaris sold to Enzon Pharmaceuticals, Inc. antisense compounds specifically designed to inhibit GLI2 production (Compl. ¶¶ 28, 55).
III. The Accused Instrumentality
Product Identification
- The accused instrumentalities are Santaris's antisense drug discovery services and the associated LNA (Locked Nucleic Acid)-containing "gapmer" oligonucleotide products (Compl. ¶¶ 25, 26).
Functionality and Market Context
- Santaris is alleged to engage in the business of selling these drug discovery services and products to pharmaceutical customers in the United States (Compl. ¶ 25). The services allegedly involve using LNA-containing gapmer antisense compounds in cell assays to identify potential gene targets or to screen oligonucleotides for their ability to inhibit protein production (Compl. ¶ 26). The complaint includes a diagram from a Santaris annual report illustrating this mechanism, which shows an "LNA antagonist" binding to mRNA and activating RNase H to degrade the mRNA (Compl. ¶ 26, p. 10). A second diagram, also from a Santaris report, shows the specific chemical structure of an LNA-DNA-LNA gapmer (Compl. ¶ 21, p. 8). Santaris is alleged to compete directly with Isis by selling these services and platform technology to pharmaceutical partners, including Enzon, Pfizer, Shire, and GlaxoSmithKline (Compl. ¶¶ 25, 44-68).
IV. Analysis of Infringement Allegations
U.S. Patent No. 6,326,199 Infringement Allegations
| Claim Element (from Independent Claim 11) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of modifying a sequence-specific ribonucleic acid in a cell... comprising contacting said cell with an oligonucleotide... | Santaris uses LNA-containing gapmer antisense compounds in cell assays and sells these methods to partners for use in target validation and screening. | ¶26, 27, 47 | col. 6:33-68 |
| ...where at least one of said nucleotides is functionalized to increase nuclease resistance... | The accused oligonucleotides employ phosphorothioate linkages to increase their stability in the presence of cellular nucleases. | ¶22 | col. 2:46-68 |
| ...where a plurality of the nucleotides have a substituent group located thereon to increase binding affinity... | The accused oligonucleotides incorporate Locked Nucleic Acid (LNA), a modified bicyclic ribose sugar ring that increases the binding affinity of the oligonucleotide to its target. | ¶22 | col. 3:17-30 |
| ...where a plurality of the nucleotides have 2'-deoxy-erythro-pentofuranosyl sugar moieties. | The middle of the accused oligonucleotides comprises a plurality of DNA-like nucleotides that serve to attract RNase H, which degrades the target mRNA. | ¶22, p. 9:1-3 | col. 2:20-27 |
U.S. Patent No. 6,066,500 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| An antisense compound 8 to 30 nucleobases in length... | Santaris sold and imported antisense oligonucleotides to Enzon Pharmaceuticals. | ¶28, 29 | col. 6:1-3 |
| ...targeted to a... region of human Beta catenin... | Santaris sold antisense compounds to Enzon specifically designed to inhibit beta-catenin production after Enzon nominated beta-catenin as a target under a commercial agreement. | ¶28, 51, 53 | col. 1:16-19 |
| ...wherein said antisense compound specifically hybridizes with and inhibits the expression of human Beta catenin. | The compounds sold by Santaris are alleged to be antisense compounds that inhibit beta-catenin production, consistent with the described mechanism of antisense technology. | ¶28, 54 | col. 2:46-49 |
Identified Points of Contention
- Legal Question: A central dispute concerns the applicability of the 35 U.S.C. § 271(e)(1) "safe harbor" exemption. The complaint argues that Santaris's sale of research tools and discovery services is a commercial enterprise not "solely for uses reasonably related to the development and submission of information" to the FDA, while Santaris may contend its activities fall within this exemption (Compl. ¶¶ 37-43).
- Evidentiary Question: The infringement allegations for the ’500 and ’739 Patents rely on activities performed under commercial agreements, such as with Enzon Pharmaceuticals. A key question will be what evidence discovery yields to show that the specific oligonucleotide compounds delivered under these agreements meet each limitation of the asserted claims (Compl. ¶¶ 30, 32).
V. Key Claim Terms for Construction
’199 Patent
- The Term: "a plurality of... 2'-deoxy-erythro-pentofuranosyl sugar moieties"
- Context and Importance: This term defines the essential "gap" that enables RNase H cleavage. The scope of "plurality" (i.e., how many nucleotides are required) is critical to determining whether an accused gapmer infringes, as the length of the gap dictates the efficiency of the antisense mechanism. Practitioners may focus on this term because the functionality of the invention depends on the gap being long enough to be recognized by RNase H.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The plain meaning of "plurality" is simply "more than one." The patent claims do not specify a minimum number.
- Evidence for a Narrower Interpretation: The specification suggests that a certain minimum number of such nucleotides is required for the invention to function as intended, stating a preference for "at least 3 of said... β-nucleosides, more preferably at least 5" (’199 Patent, col. 4:41-44). This may support an argument that "plurality" should be construed to mean a number sufficient to induce effective RNase H cleavage.
’500 Patent
- The Term: "inhibits the expression of human Beta catenin"
- Context and Importance: This functional language defines what the accused compound must do. The dispute may center on the required degree of inhibition. Practitioners may focus on this term to dispute whether any observed reduction in expression is sufficient to meet the claim limitation, or if a more substantial, therapeutically relevant level of inhibition is required.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The claim language does not quantify the level of inhibition. Any statistically significant reduction in beta-catenin mRNA or protein levels could be argued to meet the plain meaning of "inhibits."
- Evidence for a Narrower Interpretation: The background section discusses beta-catenin's role in tumorigenesis and the need for therapeutic agents, which may suggest that "inhibits" should be construed in a therapeutic context, implying a level of inhibition sufficient to have a biological effect (’500 Patent, col. 2:2-10).
VI. Other Allegations
- Indirect Infringement: The complaint alleges that Santaris induced infringement of the ’199 Patent by providing its pharmaceutical partners with the "know-how and materials" necessary to practice the patented methods, with the intent that its partners would perform the infringing acts in the United States (Compl. ¶ 33).
- Willful Infringement: Willfulness is alleged for all three patents-in-suit (Compl. ¶¶ 73, 79, 85). The allegations are based on pre-suit knowledge, supported by the specific assertion that Santaris had knowledge of the ’199 Patent "at least prior to 2006" and unsuccessfully challenged its European equivalent (Compl. ¶ 33).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central legal issue will be the scope of the safe harbor: Does the sale of platform technology and drug discovery services, as alleged here, constitute a commercial enterprise outside the protection of 35 U.S.C. § 271(e)(1), or are these activities "solely for uses reasonably related" to submitting data to the FDA, and therefore exempt from infringement?
- A key evidentiary question will be one of technical proof: As the allegations concerning the ’500 and ’739 patents are based on activities under contract with third parties, the case will likely turn on whether discovery produces evidence that the specific antisense compounds delivered by Santaris actually possess the chemical structures and target specificity required by the patent claims.
- The infringement analysis of the ’199 platform patent will raise a question of structural scope: Can the claims, which recite a gapmer structure with wings containing a general "substituent group" for increasing affinity, be construed to cover Santaris's specific use of Locked Nucleic Acid (LNA), a bicyclic sugar modification that was a distinct and separately developed technology for enhancing affinity?