DCT
4:17-cv-04405
Plexxikon Inc v. Novartis Pharma Corp
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Plexxikon Inc. (California)
- Defendant: Novartis Pharmaceuticals Corporation (Delaware)
- Plaintiff’s Counsel: Durie Tangri LLP; Young Basile Hanlon & Macfarlane, P.C.
- Case Identification: 4:17-cv-04405, N.D. Cal., 12/20/2017
- Venue Allegations: Venue is alleged to be proper as Defendant Novartis has regular and established places of business within the district, including facilities in San Carlos and Emeryville, and has committed acts of infringement in the district.
- Core Dispute: Plaintiff alleges that Defendant’s cancer drug Tafinlar® (dabrafenib) infringes two patents related to a class of selective BRAF kinase inhibitors.
- Technical Context: The technology involves small-molecule compounds designed to selectively inhibit mutated forms of the BRAF kinase, an enzyme linked to cell proliferation in certain cancers like metastatic melanoma.
- Key Procedural History: The complaint alleges a detailed history between Plaintiff and Defendant’s predecessor-in-interest, GlaxoSmithKline (GSK), involving confidential disclosure and material transfer agreements predating the development of the accused product. These allegations form the basis for claims of willful infringement based on alleged copying of the Plaintiff's core molecular structure. This filing is a Second Amended Complaint.
Case Timeline
| Date | Event |
|---|---|
| 2005-10-14 | Plexxikon and GSK enter into a Confidential Disclosure Agreement (CDA) |
| 2006-06-01 | Plexxikon and GSK sign a Material Transfer Agreement (MTA) |
| 2007-07-17 | Priority Date for ’640 and ’539 Patents |
| 2013-01-01 | GSK receives FDA approval for dabrafenib (Tafinlar®) |
| 2015-01-01 | GSK transfers its oncology portfolio, including Tafinlar®, to Novartis |
| 2016-06-16 | Application for ’640 Patent is published |
| 2016-10-18 | U.S. Patent No. 9,469,640 issues |
| 2017-03-02 | Application for ’539 Patent is published |
| 2017-08-03 | Original Complaint filed |
| 2017-12-19 | U.S. Patent No. 9,844,539 issues |
| 2017-12-20 | Second Amended Complaint filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 9,469,640 - Compounds and Methods for Kinase Modulation, and Indications Therefor
- Patent Identification: U.S. Patent No. 9,469,640, issued October 18, 2016.
The Invention Explained
- Problem Addressed: The complaint alleges that prior BRAF kinase inhibitors were not selective and inhibited many different types of RAF kinases, resulting in severe side effects that prevented the administration of doses high enough to be effective against cancer cells (Compl. ¶10).
- The Patented Solution: The invention is a class of compounds with a specific core molecular structure—identified in the complaint as a sulfonamide with its nitrogen attached to a halogenated phenyl—that allegedly allows them to bind selectively to the kinase produced by the mutated BRAF V600E gene (Compl. ¶11). This selectivity disrupts the mutated cancer cells' ability to metabolize energy while permitting higher, more effective dosing with fewer side effects (Compl. ¶¶9, 11). The patent specification describes compounds active on protein kinases for treating diseases associated with their aberrant activity (’640 Patent, col. 1:18-24).
- Technical Importance: This selective approach is described as a "true scientific breakthrough" that offered an effective treatment for metastatic melanoma, a disease for which treatment options were previously limited (Compl. ¶12).
Key Claims at a Glance
- The complaint asserts infringement of at least independent claim 1 and method claim 11 (’640 Patent, col. 152:11-15), and reserves the right to assert other claims (Compl. ¶¶20, 22, 45).
- Independent Claim 1 recites the following essential elements:
- A compound of formula Ia or a pharmaceutically acceptable salt thereof
- wherein L1 is a bond or —N(H)C(O)—
- each R¹ is optionally substituted lower alkyl or optionally substituted heteroaryl
- R² is hydrogen or halogen
- R⁴ is hydrogen
- R³ is optionally substituted lower alkyl or optionally substituted aryl
- m is 0, 1, 2, 3, 4, or 5
- Ar is a monocyclic heteroaryl containing 5 to 6 atoms wherein at least one atom is nitrogen
U.S. Patent No. 9,844,539 - Compounds and Methods for Kinase Modulation, and Indications Therefor
- Patent Identification: U.S. Patent No. 9,844,539, issued December 19, 2017.
The Invention Explained
- Problem Addressed: The technical problem addressed is identical to that described for the ’640 Patent: the need for selective BRAF kinase inhibitors to enable effective cancer treatment without dose-limiting side effects (Compl. ¶10).
- The Patented Solution: The ’539 Patent claims a class of compounds with the same core molecular structure as the ’640 Patent, designed to selectively bind to and inhibit the kinase created by the BRAF V600E mutation (’539 Patent, Abstract; Compl. ¶¶11, 17).
- Technical Importance: As with the ’640 Patent, this technology provided a breakthrough treatment for certain forms of metastatic melanoma (Compl. ¶12).
Key Claims at a Glance
- The complaint asserts infringement of at least independent claim 1 and reserves the right to assert other claims (Compl. ¶¶27, 66).
- Independent Claim 1 recites the following essential elements:
- A compound of formula Ia or a pharmaceutically acceptable salt thereof
- wherein L1 is a bond or —N(H)C(O)—
- each R¹ is optionally substituted lower alkyl or optionally substituted heteroaryl
- R² is hydrogen or halogen
- R⁴ is hydrogen
- R³ is optionally substituted lower alkyl or optionally substituted aryl
- m is 0, 1, 2, or 3
- Ar is a monocyclic heteroaryl containing 5 to 6 atoms wherein at least one atom is nitrogen
III. The Accused Instrumentality
Product Identification
- The accused product is the drug dabrafenib, which Defendant markets under the trademark Tafinlar® (Compl. ¶7).
Functionality and Market Context
- Tafinlar® (dabrafenib) is a selective BRAF kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma and non-small cell lung cancer with a BRAF V600E mutation (Compl. ¶¶17-18, 24). The complaint alleges that Tafinlar® directly competes with Plaintiff's own selective BRAF kinase inhibitor, Zelboraf® (Compl. ¶17). The complaint includes a side-by-side comparison of molecular structures to allege that dabrafenib contains the same core molecular structure as Plaintiff's patented compounds, including a sulfonamide which binds to the kinase and a halogenated phenyl attached to the nitrogen of the sulfonamide (Compl. p. 16).
IV. Analysis of Infringement Allegations
’640 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| a compound of formula Ia | The overall molecular structure of dabrafenib | ¶21 | col. 3:5-15 |
| L1 is a bond | In dabrafenib, the Ar group is directly connected to the phenyl ring by a single bond, which the complaint alleges meets the "L1 is a bond" limitation. This is depicted in a diagram comparing the claimed formula to dabrafenib (Compl. p. 7). | ¶21 | col. 2:21-22 |
| each R¹ is optionally substituted lower alkyl or optionally substituted heteroaryl; and m is 2 | Dabrafenib has two R¹ substituents (m=2) on the Ar group: a pyrimidine group (an optionally substituted heteroaryl) and a methyl group (an optionally substituted lower alkyl). | ¶21 | col. 2:16-18 |
| Ar is a monocyclic heteroaryl containing 5 to 6 atoms wherein at least one atom is nitrogen | The complaint alleges that the core of dabrafenib's Ar group is a thiazole ring, which is a 5-atom monocyclic heteroaryl containing nitrogen and sulfur atoms. The complaint provides a diagram highlighting this thiazole ring as the claimed "Ar" group (Compl. p. 7). | ¶21 | col. 2:24-26 |
| R³ is optionally substituted aryl | Dabrafenib contains a difluorophenyl group, which is alleged to be an "optionally substituted aryl." | ¶21 | col. 2:23-24 |
| R², R⁴ are hydrogen | The corresponding positions on the dabrafenib molecule are occupied by hydrogen atoms. | ¶21 | col. 2:18-20 |
- Identified Points of Contention:
- Scope Questions: A central question for claim construction may be the relationship between the "Ar" group and its "R¹" substituents. The complaint posits that the thiazole ring in dabrafenib is the "Ar" group and the attached pyrimidine ring is an "R¹" substituent. A potential point of contention is whether the term "monocyclic heteroaryl" for the Ar group can be construed to serve as a scaffold for a large heteroaryl substituent like pyrimidine, or if the claim scope is more limited.
- Technical Questions: As this is a compound claim, the dispute will likely focus on structural identity rather than functional operation. The primary technical question is whether the specific chemical formula of dabrafenib meets every limitation of Claim 1, which will turn on the court's construction of the claim terms.
’539 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| a compound of formula Ia | The overall molecular structure of dabrafenib | ¶28 | col. 3:15-25 |
| L1 is a bond | As alleged for the ’640 patent, the Ar group in dabrafenib is connected to the phenyl ring by a single bond. The complaint provides a diagram illustrating this connection (Compl. p. 11). | ¶28 | col. 2:23-24 |
| each R¹ is optionally substituted lower alkyl or optionally substituted heteroaryl; and m is 2 | Dabrafenib has two R¹ substituents (m=2) on the Ar group: a pyrimidine group (alleged to be an optionally substituted heteroaryl) and a methyl group (an optionally substituted lower alkyl). This value of m=2 falls within the claimed range of "0, 1, 2, or 3". | ¶28 | col. 2:24-25 |
| Ar is a monocyclic heteroaryl containing 5 to 6 atoms wherein at least one atom is nitrogen | As with the ’640 patent, the complaint alleges dabrafenib's thiazole ring is the claimed Ar group. The complaint provides a diagram highlighting this structural correspondence (Compl. p. 12). | ¶28 | col. 2:26-27 |
| R³ is optionally substituted aryl | Dabrafenib contains a difluorophenyl group, which is alleged to be an "optionally substituted aryl." | ¶28 | col. 2:25-26 |
| R², R⁴ are hydrogen | The corresponding positions on the dabrafenib molecule are occupied by hydrogen atoms. | ¶28 | col. 2:24-25 |
- Identified Points of Contention:
- Scope Questions: The points of contention are substantially similar to those for the ’640 Patent, focusing on whether dabrafenib's structure falls within the scope of the claim terms, particularly the "Ar" and "R¹" definitions. The narrower scope of "m" in Claim 1 of the ’539 patent (up to 3) compared to the ’640 patent (up to 5) does not create a point of contention for dabrafenib, which allegedly has m=2.
- Technical Questions: The infringement analysis will turn on structural mapping, and thus on claim construction, rather than on a dispute over the technical operation of the compound.
V. Key Claim Terms for Construction
The Term: "monocyclic heteroaryl" (the "Ar" group)
Context and Importance: The definition of this term is central to the infringement analysis. Plaintiff’s infringement theory depends on construing the thiazole ring within dabrafenib as the claimed "Ar" group, with the adjacent pyrimidine ring being an "R¹" substituent. Practitioners may focus on this term because Defendant could argue that "Ar" was intended to describe the entire aromatic system at that position, which in dabrafenib is not a single monocyclic ring.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification defines "heteroaryl" broadly to include five or six-membered rings like thiazole (’640 Patent, col. 48:51-64). The claim language for R¹ explicitly allows for a "heteroaryl" substituent, which could support Plaintiff's theory that a heteroaryl (pyrimidine) can be a substituent on the core "Ar" heteroaryl (thiazole).
- Evidence for a Narrower Interpretation: The specification's exemplary embodiments could be cited to argue that the inventors only contemplated simpler R¹ substituents (e.g., alkyl groups) on the Ar ring, not large, complex heteroaryl groups like pyrimidine.
The Term: "optionally substituted aryl" (the "R³" group)
Context and Importance: Infringement requires dabrafenib's difluorophenyl group to be an "optionally substituted aryl." The construction of this term will determine whether the specific substitutions on dabrafenib's phenyl ring are covered by the claim.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent specification provides a list of possible substituents that includes "halogen," which explicitly covers the fluoro-substituents on dabrafenib’s phenyl ring (’640 Patent, col. 14:47-65). This provides direct support for a construction that reads on the accused structure.
- Evidence for a Narrower Interpretation: A party could argue for a narrower construction if the specific examples in the patent do not disclose di-substituted phenyl rings at the R³ position, potentially suggesting that the inventors did not contemplate or enable such structures despite the broader definitional language.
VI. Other Allegations
- Indirect Infringement: The complaint alleges inducement of infringement against Novartis for both patents. The allegations are based on Novartis's marketing, sale, and promotion of Tafinlar®, including its Prescribing Information, Dosing Guides, and advertisements, which allegedly instruct and encourage healthcare providers and patients to use the drug in an infringing manner—specifically, for treating melanoma with the BRAF V600E mutation (Compl. ¶¶ 23-25, 56, 77).
- Willful Infringement: Willfulness is alleged for both patents. The claims are based on Novartis's alleged actual notice of the published patent applications, which are described as substantially identical to the issued patents (Compl. ¶¶ 50, 71). Crucially, the complaint also alleges that Novartis's predecessor, GSK, copied Plaintiff's technology after reviewing it under confidentiality and material transfer agreements, and that this knowledge of copying is imputed to Novartis (Compl. ¶¶ 30-43, 52, 73).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of structural interpretation: can the claim term "monocyclic heteroaryl" (Ar) be construed to cover dabrafenib's thiazole ring, while the attached pyrimidine ring is separately construed as an "optionally substituted heteroaryl" (R¹) substituent, as alleged by the Plaintiff? Or does this interpretation improperly divide a single, complex chemical group to fit the claim language?
- A key evidentiary question will be the history of development: what technical information did Plaintiff disclose to GSK under the 2005-2006 agreements, and does the evidence show that GSK used this information to develop dabrafenib? The answer will be central to the allegations of copying and a potential finding of willful infringement.