Spectrum Pharma Inc v. Sandoz Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Spectrum Pharmaceuticals, Inc. (Delaware) and University of Strathclyde (United Kingdom)
  • Defendant: Sandoz Inc. (Colorado)
  • Plaintiff’s Counsel: Lewis and Roca LLP; Marshall, Gerstein & Borun LLP
• Case Identification: 2:12-cv-00111, D. Nev., 01/20/2012
• Venue Allegations: Venue is alleged to be proper in the District of Nevada because Defendant Sandoz conducts systematic and continuous business in the district, including selling pharmaceutical products to Nevada residents.
• Core Dispute: Plaintiffs allege that Defendant’s filing of an Abbreviated New Drug Application (ANDA) to market generic levoleucovorin constitutes an act of infringement of a patent covering Plaintiffs' branded pharmaceutical product, Fusilev®.
• Technical Context: The technology relates to highly purified pharmaceutical compositions of the (6S) diastereoisomer of leucovorin, a compound used as a "rescue agent" to mitigate the toxic effects of methotrexate in cancer chemotherapy.
• Key Procedural History: This action was initiated under the Hatch-Waxman Act following a December 13, 2011 notification letter from Sandoz, in which Sandoz provided a Paragraph IV certification stating that U.S. Patent No. 6,500,829 is invalid, unenforceable, or will not be infringed by its proposed generic product. The patent-in-suit is listed in the FDA's "Orange Book" as covering the Fusilev® product.

Case Timeline

Date	Event
1986-09-03	’829 Patent Priority Date
2002-12-31	’829 Patent Issue Date
2008-03-07	FDA approves Plaintiff's Fusilev® NDA
2011-04-20	FDA approves Plaintiff's Fusilev® sNDA
2011-11-07	FDA grants Fusilev® orphan-drug exclusivity
2011-12-13	Sandoz sends Paragraph IV notification letter
2012-01-20	Complaint Filing Date

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

U.S. Patent No. 6,500,829 - Substantially Pure Diastereoisomers of Tetrahydrofolate Derivatives, issued December 31, 2002

The Invention Explained

• Problem Addressed: The patent’s background section explains that the cancer chemotherapy agent methotrexate requires a follow-up "rescue agent" called leucovorin to protect a patient's healthy cells (’829 Patent, col. 1:21-29). Leucovorin exists as a mixture of two molecular forms (diastereoisomers), but only one, the "(6S)" form, is therapeutically effective (’829 Patent, col. 1:57-64). The patent notes that prior methods for separating the useful (6S) form from the non-useful "(6R)" form were inefficient and resulted in low yields or products that were difficult to purify (’829 Patent, col. 2:12-24).
• The Patented Solution: The invention provides a process for producing a "substantially pure" form of the desired (6S) diastereoisomer. The process involves attaching a "chiral auxiliary group" to the mixed-isomer starting material, which creates new intermediate compounds that are more easily separated from one another, for example through solvent extraction. Once the desired intermediate is isolated, the auxiliary group is removed, yielding the highly pure (6S) diastereoisomer (’829 Patent, Abstract; col. 2:45-62). The patent claims the resulting high-purity pharmaceutical composition itself.
• Technical Importance: This approach provided a viable method for creating a leucovorin drug product containing almost exclusively the therapeutically active isomer, which could improve efficacy and potentially reduce side effects associated with the non-natural isomer (’829 Patent, col. 2:6-12).

Key Claims at a Glance

• The complaint asserts infringement of claims 1 and 2 (’829 Patent, col. 18:55-19:2; Compl. ¶23).
• Independent Claim 1:
  • A pharmaceutical composition for therapeutic use which consists essentially of a therapeutically effective amount sufficient for the treatment of human beings for methotrexate rescue or folate deficiency,
  • of a pharmaceutically acceptable compound which is a (6S) diastereoisomer selected from the group consisting of (6S) leucovorin (5-formyl-(6S)-tetrahydrofolic acid) and pharmaceutically acceptable salts and esters of (6S) leucovorin;
  • wherein the compound consists of a mixture of (6S) and (6R) diastereoisomers and consists of at least 92% by weight of the (6S) diastereoisomer, the balance of said compound consisting of the (6R) diastereoisomer;
  • in combination with a pharmaceutically acceptable carrier.
• The complaint focuses on claims 1 and 2 but contains general allegations that could implicate other claims (’829 Patent, col. 18:55-19:12; Compl. ¶25).

III. The Accused Instrumentality

Product Identification

• The accused instrumentalities are Sandoz's proposed "ready to use" vials of levoleucovorin in 175 mg and 250 mg dosage strengths, for which Sandoz seeks FDA approval via ANDA No. 203563 (Compl. ¶¶ 1, 16).

Functionality and Market Context

• Sandoz's product is a generic version of Plaintiffs' Fusilev® product (Compl. ¶1).
• The complaint alleges that by filing its ANDA, Sandoz has represented to the FDA that its proposed products have the same active ingredient, route of administration, dosage form, and strength as Fusilev® (Compl. ¶18).
• Sandoz’s ANDA is alleged to rely on data demonstrating the bioequivalence of its product to Fusilev® (Compl. ¶17). The purpose of the product is for use in indications such as the palliative treatment of advanced metastatic adenocarcinoma of the colon and rectum (Compl. ¶14).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

The complaint alleges that the act of filing the ANDA constitutes infringement under 35 U.S.C. § 271(e)(2) because the product Sandoz seeks to market would infringe the ’829 Patent if commercially sold (Compl. ¶24). The infringement theory is predicated on the assertion that Sandoz's generic product is bioequivalent to and has the same active ingredient as Fusilev®, which is covered by the asserted claims (Compl. ¶¶ 17-18).

’829 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A pharmaceutical composition for therapeutic use which consists essentially of a therapeutically effective amount sufficient for the treatment of human beings for methotrexate rescue or folate deficiency...	Sandoz's ANDA seeks approval for a generic levoleucovorin product, which is indicated for the same therapeutic uses as Fusilev®, including as a rescue agent following high-dose methotrexate therapy.	¶¶ 1, 10, 11, 18	col. 18:55-58
...of a pharmaceutically acceptable compound which is a (6S) diastereoisomer selected from the group consisting of (6S) leucovorin (5-formyl-(6S)-tetrahydrofolic acid) and pharmaceutically acceptable salts and esters of (6S) leucovorin...	The active ingredient in Sandoz's product is levoleucovorin, which is the nonproprietary name for the (6S) diastereoisomer of leucovorin. The ANDA represents that Sandoz's product contains this active ingredient.	¶¶ 10, 18, 22	col. 18:58-62
...wherein the compound consists of a mixture of (6S) and (6R) diastereoisomers and consists of at least 92% by weight of the (6S) diastereoisomer, the balance of said compound consisting of the (6R) diastereoisomer...	The complaint alleges that Sandoz's product will infringe this limitation. The basis for this allegation is that Sandoz's ANDA represents its product is bioequivalent to Fusilev®, which is covered by the patent, and therefore the product described in the ANDA necessarily meets the claimed purity threshold.	¶¶ 17, 18, 22, 24	col. 18:63-66
...in combination with a pharmaceutically acceptable carrier.	Sandoz's product is described as a "ready to use" solution for intravenous infusion, a formulation which by its nature includes pharmaceutically acceptable carriers.	¶¶ 16, 22	col. 18:67-68

• Identified Points of Contention:
  • Technical Question: A central factual dispute will concern the precise composition of the product described in Sandoz's ANDA. What evidence does Sandoz's ANDA provide regarding the purity of its levoleucovorin product and whether it meets the "at least 92% by weight" limitation required by claim 1? Sandoz's Paragraph IV certification suggests it will argue that its product does not meet this limitation (Compl. ¶19).
  • Scope Question: The infringement analysis may turn on the construction of "consists essentially of." Does this transitional phrase permit the presence of unlisted excipients or stabilizers in the Sandoz formulation without avoiding infringement? This raises the question of what the "basic and novel characteristics" of the invention are and whether any additional ingredients in the accused product materially affect them.

V. Key Claim Terms for Construction

• The Term: "consists essentially of"

  • Context and Importance: This term sets the scope of the composition claim. Unlike the open-ended "comprising," it limits the claim to the specified ingredients and those that do not materially affect the "basic and novel characteristics" of the invention. The outcome of the infringement analysis could depend on whether any additional excipients in Sandoz's formulation are deemed to materially affect the invention's characteristics, which appear to relate to achieving high therapeutic purity. Practitioners may focus on this term because Sandoz could design a formulation with additional substances and argue they materially alter the claimed composition.
  • Intrinsic Evidence for a Broader Interpretation: The patent's specification focuses heavily on the process of separating the (6S) and (6R) isomers to achieve high purity (’829 Patent, col. 2:45-62). A party may argue that as long as additional ingredients are inert and do not interfere with the therapeutic function of the high-purity (6S) isomer, they do not materially affect the invention's core characteristics.
  • Intrinsic Evidence for a Narrower Interpretation: The patent claims a specific composition with a defined purity ratio (’829 Patent, col. 18:63-66). A party could argue that this high-purity composition itself is the basic and novel characteristic, and the introduction of any other active or stabilizing agent not recited in the claim would materially alter it.

• The Term: "at least 92% by weight of the (6S) diastereoisomer"

  • Context and Importance: This quantitative limitation is the defining feature of the claimed composition's purity. Infringement will be determined by whether the product specified in Sandoz's ANDA is required to meet this precise numerical threshold. Sandoz's non-infringement defense may rest on an argument that its product specifications fall below this 92% floor.
  • Intrinsic Evidence for Interpretation: The patent specification provides an example of achieving this exact purity level through the disclosed separation process, stating a "2nd crop" of the desired isomer is "92% isomerically pure" (’829 Patent, Fig. 4). The claims further recite compositions of "greater than 95%" and "about 92%," underscoring that high, specific purity is central to the invention (’829 Patent, col. 18:63-19:2). This may support a strict interpretation of the numerical limit as an essential element of the claim.

VI. Other Allegations

• Indirect Infringement: The complaint alleges infringement under 35 U.S.C. § 271(b) and (c) (Compl. ¶25). Allegations supporting inducement (271(b)) are based on Sandoz seeking approval to market its product with proposed labeling that is the "same or substantially the same" as that for Fusilev® (Compl. ¶18). This act suggests Sandoz's intent for healthcare providers to use the generic product for the patented therapeutic methods.
• Willful Infringement: The complaint does not use the word "willful" but does request treble damages and attorneys' fees for an "exceptional case" (Compl. ¶¶ 28, Prayer for Relief ¶¶ G, H). The factual basis for this is Sandoz's alleged knowledge of the ’829 Patent, evidenced by the patent's listing in the FDA's Orange Book and Sandoz's December 13, 2011 notification letter explicitly referencing the patent (Compl. ¶¶ 15, 19).

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

• An Evidentiary Question of Purity: Will the product specifications contained within Sandoz's confidential ANDA filing demonstrate that its proposed generic product is required to meet the "at least 92% by weight of the (6S) diastereoisomer" limitation of the asserted claims?
• A Definitional Question of Scope: Will the court determine that the "basic and novel characteristics" of the invention under the phrase "consists essentially of" are limited only to the purity ratio of the (6S) and (6R) isomers, or will additional excipients in Sandoz's formulation be found to materially alter those characteristics and thereby avoid infringement?
• A Question of Validity: Sandoz's Paragraph IV certification raises the issue of invalidity. A central question for the court will be whether Sandoz can present clear and convincing evidence that the asserted claims are invalid, likely on grounds of obviousness in view of prior art methods for separating chemical isomers.