On November 26, 2019, in Merck Sharp & Dohme Corp. v. Wyeth LLC, the Federal Circuit vacated and remanded two final written decisions by the U.S. Patent and Trademark Office Patent Trial and Appeal Board finding claim 18 of U.S. Patent No. 8,562,999 to be nonobvious.  The '999 patent, which is directed to formulations for stabilizing polysaccharide-protein conjugate vaccines, is assigned to Wyeth LLC.

Polysaccharide-protein conjugate vaccines are derived from capsular polysaccharides present on the surface of certain disease-causing bacteria.  These capsular polysaccharides can be used by the human immune system to detect different serotypes (or strains) of a bacterial species.  Polysaccharide vaccines can be monovalent (comprising a single serotype) or multivalent (comprising multiple serotypes).  Because such capsular polysaccharides may have low immunogenicity, it is desirable to enhance the effectiveness of vaccines comprising such polysaccharides by conjugating the polysaccharides to a carrier protein with high immunogenicity.  As the '999 patent explains, however, polysaccharide-protein conjugate vaccines aggregate when exposed to silicone oil, which is commonly used as a lubricant in vaccine storage containers.  The '999 patent describes a formulation that inhibits silicone-induced aggregation by suspending the polysaccharide-protein conjugate in a mixture of a pH-buffered saline solution and an aluminum salt.  Claim 1 of the '999 patent (the sole independent claim) recites:

1.  A formulation comprising (i) a pH buffered saline solution, wherein the buffer has a pKa of about 3.5 to about 7.5, (ii) an aluminum salt and (iii) one or more polysaccharide-protein conjugates, wherein the formulation is comprised in a siliconized container means and inhibits aggregation induced by the siliconized container means.

Claim 18 of the '999 patent recites:

18.  The formulation of claim 1, wherein the one or more polysaccharide-protein conjugate comprises an S. pneumoniae serotype 4 polysaccharide conjugated to a CRM197 polypeptide, an S. pneumoniae serotype 6B polysaccharide conjugated to a CRM197 polypeptide, an S. pneumoniae serotype 9V polysaccharide conjugated to a CRM197 polypeptide, an S. pneumoniae serotype 14 polysaccharide conjugated to a CRM197 polypeptide, an S. pneumoniae serotype 18C polysaccharide conjugated to a CRM197 polypeptide, an S. pneumoniae serotype 19F polysaccharide conjugated to a CRM197 polypeptide, an S. pneumoniae serotype 23F polysaccharide conjugated to a CRM197 polypeptide, an S. pneumoniae serotype 1 polysaccharide conjugated to a CRM197 polypeptide, an S. pneumoniae serotype 3 polysaccharide conjugated to a CRM197 polypeptide, an S. pneumoniae serotype 5 polysaccharide conjugated to a CRM197 polypeptide, an S. pneumoniae serotype 6A polysaccharide conjugated to a CRM197 polypeptide, an S. pneumoniae serotype 7F polysaccharide conjugated to a CRM197 polypeptide and an S. pneumoniae serotype 19A polysaccharide conjugated to a CRM197 polypeptide.

Thus, claim 18 is directed to a formulation comprising thirteen different S. pneumoniae serotype polysaccharides conjugated to a CRM197 polypeptide.

Merck Sharp & Dohme Corp. petitioned for inter partes review of claims 1–6, 10, 11, 14, and 17–20 of the '999 patent.  The Board instituted review of all challenged claims in two parallel proceedings:  IPR2017-00378, in which claim 1 was challenged as obvious in view of International Publication No. WO 03/009869 ("Chiron"); Smith, Siliconization of Parenteral Drug Packaging Components (1988) ("Smith"); and International Publication No. WO 2004/071439 ("Elan"), and IPR2017-00380, in which claim 1 was challenged as obvious in view of Chiron and Annex I of the European Medicines Agency's European Public Assessment Report for Prevenar ("Prevenar").  In each proceeding, Merck challenged claim 18 as obvious in view of the above references in combination with Peña et al., 24 Pediatrika 47 (2004) ("Peña"), which discloses a study involving a 13-valent conjugate, but does not disclose conjugating the polysaccharides with the CRM197 protein as recited in claim 18.  In both proceedings, the Board found all of the challenged claims except claim 18 to be unpatentable as obvious.

Merck appealed the Board's decisions as to claim 18, arguing that the Board failed to provide a reasoned basis for upholding claim 18.  As discussed in the Federal Circuit's opinion, "[t]he Board's decision rests on its finding that the study discussed in Peña did not show that 'a formulation comprising each of the thirteen known serotypes conjugated to a CRM197 [protein] . . . was even considered, tried and successful.'"  However, the Court notes that:

Standing alone, this finding is insufficient to support a lack of motivation or a reasonable expectation of success.  Obviousness, unlike anticipation, does not require a prior art successful formulation.  See Par Pharm., 773 F.3d at 1198.  Here, there was conflicting evidence as to motivation and reasonable expectation of success—evidence not discussed by the Board.

That conflicting evidence included the testimony of Merck's expert, who testified that a skilled artisan would have found it obvious to select the thirteen conjugates recited in Peña, each conjugated to CRM197, for a polysaccharide-protein conjugate vaccine, and Wyeth's expert, who testified that Peña would not have lead a skilled artisan to conclude that the 7-valent conjugate vaccine of Prevenar could be expanded to the 13-valent pneumococcal polysaccharide single-carrier CRM197 conjugate vaccine of claim 18 with a reasonable expectation of success.  According to the panel, the parties' differences concerned whether a skilled artisan would have been dissuaded from using a single carrier protein, such as CRM197, for a 13-valent pneumococcal polysaccharide conjugate vaccine due to "immune interference," a phenomenon that may result in decreased immunogenicity in multivalent vaccines with a sole carrier protein.

Although Merck argued that the immune interference issue is irrelevant, the Court disagreed, stating that "this issue is relevant to whether a skilled artisan would have been motivated to conjugate the 13 serotypes with CRM197 as a sole carrier protein."  In vacating and remanding the Board's decisions, the panel indicated that "the Board simply did not address the evidence as to whether someone skilled in the art would have been motivated to combine the 13 serotypes into a CRM197 conjugate or whether the potential loss of immunogenicity would have dissuaded someone skilled in the art from making such a combination," and concluded that "the Board’s decision is too cryptic to survive judicial review."  The Federal Circuit therefore vacated the Board's obviousness findings with respect to claim 18, and remanded for further consideration of the parties' arguments and evidence as to the motivation to combine, reasonable expectation of success, and other issues such as secondary considerations.

Merck Sharp & Dohme Corp. v. Wyeth LLC (Fed. Cir. 2019)
Nonprecedential disposition
Panel: Chief Judge Prost and Circuit Judges Dyk and Wallach
Opinion by Circuit Judge Dyk