PTAB

IPR2018-01219

Pfizer Inc. v. Hoffman-La Roche Inc.

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1. Case Identification

2. Patent Overview

  • Title: Heavy Chain Mutant Leading to Improved Immunoglobulin Production
  • Brief Description: The ’225 patent describes nucleic acid sequences for producing recombinant immunoglobulins (antibodies). The technology addresses a problem where the naturally occurring, or "wild-type," nucleic acid sequence ("ggtaaa") encoding the C-terminal glycine-lysine dipeptide in human immunoglobulin heavy chains can create an unwanted splice site, leading to aberrant protein by-products and reduced expression. The patent claims specific alternative nucleic acid sequences that still encode the glycine-lysine dipeptide but eliminate the problematic splice site, thereby improving the expression of the desired immunoglobulin.

3. Grounds for Unpatentability

Petitioner asserted that the challenged claims are unpatentable as anticipated under 35 U.S.C. §102 and/or obvious under 35 U.S.C. §103 based on three primary prior art references, each of which allegedly discloses the key features of the invention.

Ground 1: Claims 1-3, 5, 10-12, and 20 are anticipated by and/or obvious over Denney.

  • Prior Art Relied Upon: Denney (Application # 2002/0160006).
  • Core Argument for this Ground: Petitioner argued that Denney, published over five years before the ’225 patent’s priority date, expressly discloses every limitation of the challenged claims, rendering them anticipated. In the alternative, Petitioner argued that Denney’s disclosures would have rendered the claims obvious to a person of ordinary skill in the art (POSA).
    • Prior Art Mapping: Petitioner asserted that Denney discloses nucleic acid sequences (SEQ ID NOs: 44 and 46) for IgG3 and IgG4 heavy chains, which fall within the scope of the claimed "IgG" class. Critically, Denney explicitly disclosed using the codon pair "ggcaag"—one of the specific sequences recited in claims 1 and 20 of the ’225 patent—to encode the terminal glycine-lysine dipeptide. Petitioner further mapped Denney's corresponding amino acid sequences (SEQ ID NOs: 45 and 47) as being identical to sequences claimed in the ’225 patent, thereby anticipating dependent claim 2. Denney was also shown to disclose the use of plasmids (anticipating claim 10) and transfection into isolated mammalian CHO cells (anticipating claims 11 and 12), as well as the complete method of transfecting, cultivating, and recovering the immunoglobulin (anticipating claim 20).
    • Motivation to Combine: For the alternative obviousness argument, Petitioner contended that Denney’s stated goal was to achieve high levels of immunoglobulin expression through codon optimization. This provided a clear motivation for a POSA to use Denney's disclosed sequences and methods to solve the exact problem of improving protein expression addressed by the ’225 patent.
    • Expectation of Success: A POSA would have had a high expectation of success because Denney explicitly stated it provided "improved methods" and because codon optimization was a routine and well-understood technique for improving protein expression in mammalian cells at the time.

Ground 2: Claims 1-5, 10-12, and 20 are anticipated by and/or obvious over Loetscher.

  • Prior Art Relied Upon: Loetscher (WO 2007/068429).
  • Core Argument for this Ground: Petitioner argued that Loetscher, which describes an antibody against amyloid beta, anticipates or renders obvious all challenged claims.
    • Prior Art Mapping: Petitioner alleged that Loetscher discloses a nucleic acid (SEQ ID NO: 23) encoding a human IgG1 heavy chain, which was optimized for recombinant protein production. This sequence used the codon pair "ggcaaa"—another specific sequence recited in claims 1 and 20—to encode the terminal glycine-lysine dipeptide. Loetscher’s corresponding amino acid sequence (SEQ ID NO: 6) was shown to be identical to a sequence claimed in the ’225 patent, anticipating dependent claim 2. Petitioner also asserted that Loetscher disclosed the use of plasmids containing the sequence, transfection into isolated CHO cells, and the full method of producing and recovering the antibody, anticipating claims 10-12 and 20.
    • Motivation to Combine: The motivation for the alternative obviousness ground was explicit, as Loetscher stated its disclosed heavy chain sequence was "optimized for recombinant production." This would have motivated a POSA to use Loetscher's teachings to improve immunoglobulin expression.
    • Expectation of Success: The expectation of success was argued to be high, given Loetscher's express statement that its sequence was optimized for this purpose and the general knowledge in the art regarding the reliability of codon modification techniques.

Ground 3: Claims 1-3, 5, 10-12, and 20 are anticipated by and/or obvious over Rosenthal.

  • Prior Art Relied Upon: Rosenthal (Application # 2006/0292152).
  • Core Argument for this Ground: Petitioner argued that Rosenthal, which describes monoclonal antibodies against amyloid beta, also anticipates or renders obvious the challenged claims.
    • Prior Art Mapping: Petitioner asserted that Rosenthal discloses a nucleic acid (SEQ ID NO: 13) encoding a human IgG2 heavy chain. This sequence used the codon pair "ggaaag"—a third specific sequence recited in claims 1 and 20—to encode the terminal glycine-lysine dipeptide. Rosenthal's corresponding amino acid sequence (SEQ ID NO: 11) was also shown to be identical to a sequence claimed in the ’225 patent. The petition further detailed how Rosenthal disclosed the use of the sequence in mammalian expression vectors (plasmids), transfection into isolated HEK 293 cells (a mammalian cell line), and the full method of expression and purification, anticipating the remaining challenged claims.
    • Motivation to Combine: For the alternative obviousness argument, Petitioner noted that Rosenthal used codon optimization to develop its heavy chain constant region and explicitly instructed the use of host cells "capable of over-expressing" the protein. This provided strong motivation to apply Rosenthal's teachings to improve protein expression.
    • Expectation of Success: A POSA would have reasonably expected success, reinforced by Rosenthal's teachings on codon usage and its instruction to use host cells capable of overexpression, both of which were standard and predictable approaches.

4. Key Claim Construction Positions

  • Petitioner argued that the preamble of independent method claim 20, "A method for improving the expression of an immunoglobulin in a mammalian cell," is not a claim limitation. It was contended that the preamble merely states the desired purpose or intended use of the invention, while the body of the claim recites a structurally complete method (transfecting, cultivating, recovering).
  • In the alternative, if the Board were to find the preamble limiting, Petitioner argued it should be construed to require "codon modification," as this is the only method described in the ’225 patent for achieving improved expression.

5. Key Technical Contentions (Beyond Claim Construction)

  • Petitioner argued that claims 1 and 20 are invalid on their face because they recite eight nucleic acid sequences that purportedly encode a glycine-lysine dipeptide, but two of the recited sequences ("ggaaca" and "ggcaac") are erroneous and do not encode glycine-lysine. Instead, they encode glycine-threonine and glycine-arginine, respectively.

6. Relief Requested

  • Petitioner requested the institution of an inter partes review and the cancellation of claims 1-5, 10-12, and 20 of Patent 8,314,225 as unpatentable.