Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.

1. Case Identification

• Case #: IPR2016-00204
• Patent #: RE38,551
• Filed: November 23, 2015
• Petitioner(s): Argentum Pharmaceuticals LLC
• Patent Owner(s): Research Corporation Technologies, Inc.
• Challenged Claims: 1-13

2. Patent Overview

• Title: Anticonvulsant Enantiomeric Amino Acid Derivatives
• Brief Description: The ’551 patent is directed to anticonvulsant amino acid derivatives, their therapeutic compositions, and methods of use. The claims cover compounds in the R configuration, with claim 8 specifically reciting (R)-N-Benzyl 2-Acetamido-3-methoxypropion-amide, known as R-lacosamide.

3. Grounds for Unpatentability

Ground 1: Claims 1-13 are Anticipated by or Obvious over LeGall in view of the ’729 patent

• Prior Art Relied Upon: LeGall (a 1987 master's thesis) and Patent 5,378,729 (’729 patent).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that LeGall anticipates claims 1 and 3-8 under 35 U.S.C. §102(b). LeGall explicitly discloses racemic lacosamide (compound 107e), which Petitioner asserted meets the limitation of independent claim 1 for "a compound in the R configuration" because 50% of the racemate consists of the R-isomer. For the remaining claims, Petitioner asserted they are obvious under 35 U.S.C. §103. LeGall discloses the core compound, while the ’729 patent, which discloses a genus of compounds covering lacosamide, teaches the remaining elements for the dependent claims. Specifically, the ’729 patent teaches formulating such compounds into therapeutic compositions (claim 10) and using them in methods of treating central nervous system (CNS) disorders (claims 11-13).
  • Motivation to Combine: A POSA would combine the teachings because both references concern the same class of anticonvulsant compounds. LeGall identifies racemic lacosamide as a promising analogue for development. Both LeGall and the ’729 patent expressly state a preference for the R-isomer over the S-isomer or the racemate, noting it is significantly more active and less toxic. This provides a clear motivation to isolate the R-isomer from the racemic mixture disclosed in LeGall to achieve the "substantially enantiopure" compound of claims 2 and 9.
  • Expectation of Success: A POSA would have had a high expectation of success in isolating the R-isomer, as both the ’551 patent itself and the ’729 patent acknowledge that separating racemic mixtures into individual isomers was achievable using standard, well-known techniques like chiral chromatography.

Ground 2: Claims 1-9 are obvious over Choi in view of Kohn 1991

• Prior Art Relied Upon: Choi (a 1995 journal article) and Kohn 1991 (a 1991 journal article).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner's argument centered on a lead compound modification strategy. Choi disclosed a hydroxymethyl compound (compound 2d) as a useful synthetic intermediate for preparing bioactive amino acid derivatives. This compound is structurally very similar to lacosamide.
  • Motivation to Combine: A POSA would select Choi’s hydroxymethyl compound as a lead compound due to its synthetic utility and structural similarity to other active compounds. Kohn 1991 provided the motivation to modify this lead compound, teaching a key structure-activity relationship: anticonvulsant activity dramatically increases when an oxygen atom is "functionalized" and located two atoms away from the α-carbon. A POSA would be motivated to apply this teaching by converting the hydroxyl group (-CH2OH) of Choi’s compound 2d to a methoxy group (-CH2OCH3), which is the simplest functionalization, thereby arriving directly at lacosamide.
  • Expectation of Success: The required chemical conversion—a Williamson ether synthesis—is a routine and predictable procedure in organic chemistry. The ’551 patent itself employs this exact reaction, confirming its feasibility and a POSA's high expectation of success.

Ground 3: Claims 1-9 are obvious over Kohn 1991 in view of Silverman

• Prior Art Relied Upon: Kohn 1991 (a 1991 journal article) and Silverman (a 1992 textbook).

• Core Argument for this Ground:

  • Prior Art Mapping: This ground presented an alternative lead compound argument. Kohn 1991 disclosed a series of anticonvulsant compounds, with the methoxyamino compound (compound 3l) being the most potent. A POSA would select this highly potent compound as a lead for further optimization.
  • Motivation to Combine: Petitioner argued a POSA would be motivated to modify the lead compound's methoxyamino moiety (-NHOCH3) because it is uncommon in pharmaceuticals and could present synthetic or stability issues. The Silverman reference taught the well-known principle of bioisosterism, which provides a rationale for replacing a secondary amino group (-NH-) with a methylene group (-CH2-). A POSA would apply this established drug design strategy to replace the -NH- in the lead compound's methoxyamino group, resulting in a methoxymethyl group (-CH2OCH3) and thereby arriving at lacosamide.
  • Expectation of Success: This bioisosteric replacement was a common technique for improving pharmacokinetic properties. Data in Kohn 1991 itself suggested that such a replacement would be expected to retain the high potency of the lead compound, giving a POSA a strong expectation of success.

• Additional Grounds: Petitioner asserted an additional obviousness challenge (Ground 4) based on modifying the methyl compound from Cortes (1985) using the structure-activity relationships taught in Kohn 1991, but this relied on a similar lead-compound modification theory.

4. Key Claim Construction Positions

• "A Compound in the R Configuration" (Claim 1): Petitioner argued this phrase should be given its broadest reasonable interpretation to cover any compound containing the R-isomer, whether it is substantially pure or mixed with the S-isomer (i.e., a racemic mixture). This construction is critical for the anticipation argument (Ground 1A), as it allows LeGall’s disclosure of racemic lacosamide to meet the limitations of claim 1.
• "Therapeutic Composition" (Claim 10): Petitioner contended that this phrase, appearing in the preamble of claim 10, is a non-limiting statement of intended use. The body of the claim recites a structurally complete invention (an anticonvulsant compound and a pharmaceutical carrier), so the preamble term does not add a separate limitation to the claim.

5. Arguments Regarding Discretionary Denial

• Petitioner argued that the Board should not decline to institute review under 35 U.S.C. §325(d). The petition asserted that it was not a "second bite" at the apple concerning a prior IPR (IPR2014-01126) because the Patent Owner in that case avoided a decision on the merits of the LeGall reference by successfully arguing it was not proven to be prior art. Petitioner presented new evidence of LeGall's prior art status, including an admission by the Patent Owner in district court litigation. Furthermore, Grounds 2, 3, and 4 were entirely new and had never been presented to the Board.

6. Relief Requested

• Petitioner requested that the Board institute an inter partes review and cancel claims 1-13 of Patent RE38,551 as unpatentable.