Merck Sharp & Dohme Corp. v. GlaxoSmithKline Biologicals SA

1. Case Identification

• Case #: IPR: Unassigned
• Patent #: 9,265,839
• Filed: June 11, 2018
• Petitioner(s): Merck Sharp & Dohme Corp.
• Patent Owner(s): GlaxoSmithKline Biologicals S.A.
• Challenged Claims: 1-10

2. Patent Overview

• Title: Process for Conjugating a Bacterial Saccharide
• Brief Description: The ’839 patent describes a process for making vaccine components by conjugating a bacterial saccharide to a carrier protein. The claimed invention specifically involves using a low concentration of periodate (0.001-0.7 molar equivalents) to activate the S. pneumoniae capsular saccharide 6B, purportedly to reduce the "sizing effect" (i.e., fragmentation or size reduction of the saccharide) that occurs during the activation step.

3. Grounds for Unpatentability

Ground I: Anticipation over WO'376 - Claims 1-10 are anticipated by WO’376

• Prior Art Relied Upon: WO’376 (PCT Publication # WO 2004/043376A2).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that WO’376, which was not considered during prosecution, discloses every element of the challenged claims. Specifically, Example 4 of WO’376 describes a method for conjugating bacterial saccharides, including the claimed S. pneumoniae serotype 6B. This example allegedly discloses reacting the saccharide with 0.27 molar equivalents (MEq) of periodate, a value falling squarely within the claimed 0.001-0.7 MEq range. Furthermore, WO'376 allegedly teaches performing this reaction in a 100 mM phosphate buffer (within the claimed 1-100 mM range), mixing the activated saccharide with a carrier protein (pneumolysin), and reacting the mixture with a reducing agent to form the conjugate.
  • Key Aspects: Petitioner contended that the preamble phrase "reducing the sizing effect" is either a non-limiting statement of intended purpose or is inherently disclosed. The use of a lower periodate concentration, as taught in WO'376, would naturally and necessarily result in less saccharide degradation compared to higher concentrations, thereby achieving the "reducing the sizing effect" outcome.

Ground II: Obviousness over Core Vaccine Literature - Claims 1-10 are obvious over WO’376 in view of Frasch and Lees

• Prior Art Relied Upon: WO’376 (PCT Publication # WO 2004/043376A2), Frasch (a 2009 Vaccine journal article), and Lees (a 2008 book chapter on conjugation chemistry).
• Core Argument for this Ground:
  • Prior Art Mapping: This ground asserted that even if WO’376 does not explicitly teach "reducing the sizing effect," the combination with Frasch and Lees renders the invention obvious. WO’376 provided the complete base process for creating the 6B conjugate. Frasch and Lees, representing the state of the art, explicitly taught that periodate activation was a common but known-to-be-harsh method that could degrade saccharides (the "sizing effect"), fragmenting them and potentially reducing immunogenicity by destroying important epitopes.
  • Motivation to Combine: A Person of Ordinary Skill in the Art (POSA) practicing the method in WO’376 would have been motivated to consult general knowledge references like Frasch and Lees to understand and optimize the process. These references taught that using milder conditions, including lower periodate concentrations, was a well-known strategy to minimize saccharide degradation and preserve the structural integrity and immunogenicity of the final conjugate.
  • Expectation of Success: A POSA would have had a reasonable expectation of success in applying the principles from Frasch and Lees to the WO'376 process. The principle that lower reactant concentrations lead to less degradation was a fundamental concept in chemistry, and optimizing periodate levels was described as a routine part of developing conjugate vaccines.

Ground III: Obviousness of Dependent Claims - Claim 4 is obvious over WO’376, Frasch, and Lees in further view of GSK 2009 PCT

• Prior Art Relied Upon: The combination from Ground II, plus GSK 2009 PCT (PCT Publication # WO 2009/000825A2).

• Core Argument for this Ground:

  • Prior Art Mapping: Claim 4 adds the limitation that the saccharide has an average molecular weight of 1-1100 kDa after the activation step. Petitioner argued this was obvious over the primary combination in view of GSK 2009 PCT. This reference, attributed to the Patent Owner, explicitly teaches that for saccharide conjugate vaccines to have a good immune response, the pre-conjugation saccharide should have a larger size, disclosing preferred ranges such as 100-1000 kDa and 150-500 kDa.
  • Motivation to Combine: A POSA seeking to create an effective vaccine using the base process would be motivated to ensure the saccharide maintained a size known to be immunogenic, as taught by GSK 2009 PCT. This reference provided the direct motivation and a known target size range, making the selection of a saccharide within the claimed 1-1100 kDa range an obvious design choice.

• Additional Grounds: Petitioner asserted additional obviousness challenges against other dependent claims. These grounds followed a similar logic, combining the core references (WO'376, Frasch, Lees) with an additional reference to teach a specific limitation. For instance, Prevnar (a 2009 Physicians' Desk Reference entry) was added to teach the use of CRM197 as a carrier protein (Ground IV for claim 5), and GSK 2009 PCT was added to teach mixing the final conjugate with other free S. pneumoniae proteins (Ground V for claim 9).

4. Key Claim Construction Positions

• "reducing the sizing effect": Petitioner argued this preamble term is not a limitation on the claims. It was presented as merely stating the intended purpose or a natural result of performing the claimed steps (specifically, using a low periodate concentration), as the body of the claim fully sets forth the process. Alternatively, if found to be limiting, Petitioner asserted it should be construed by its plain meaning as "decreasing the reduction in the size of the bacterial saccharide."
• "molar equivalents": Petitioner proposed this term be construed as "the ratio of moles of periodate to the moles of saccharide repeating unit." This construction was asserted as critical to the anticipation analysis, as it allows for the calculation of the MEq value in WO'376's Example 4, showing it falls within the claimed range.

5. Key Technical Contentions (Beyond Claim Construction)

• Claimed Range is Not Critical and Lacks Unexpected Results: A central contention was that the claimed periodate range of 0.001-0.7 MEq was not critical and was chosen simply to avoid prior art disclosed during prosecution (which used 0.8-1.2 MEq). Petitioner argued that the Patent Owner's evidence of "unexpected results" (i.e., reduced sizing effect) was flawed because it merely showed a continuous, expected trend where less periodate causes less degradation. The experiments presented during prosecution were allegedly based on improper ad-hoc comparisons (e.g., comparing results from reactions in water versus a buffer) and did not demonstrate any surprising effect specific to the claimed range.

6. Relief Requested

• Petitioner requested the institution of an inter partes review and the cancellation of claims 1-10 of the ’839 patent as unpatentable.