Earlier, the International Trade Commission (ITC) ruled that the importation and sale of certain lysine feed products did not violate section 337 of the Tariff Act of 1930 as amended, 19 U.S.C. § 1337. The Commission found that (1) the asserted claims of Ajinomoto’s U.S. Patents 5,827,698 and 6,040,160 are invalid under 35 U.S.C. § 112 for failure to comply with the best mode requirement and (2) the ’698 patent is unenforceable due to inequitable conduct. The U.S. Court of Appeals for the Federal Circuit agreed.  Ajinomoto v. ITC (09-1081).

The ’698 and ’160 patents relate to improved methods of producing L-lysine (“lysine”) by cultivating Escherichia bacteria that have been genetically engineered to produce and accumulate greater quantities of lysine than naturally occurring (or wild- type) bacterial strains. Lysine is an essential amino acid, which means that most animals cannot synthesize it but must obtain it directly from their diets. Consequently, feed producers and farmers regularly add lysine as a necessary dietary supplement to low-protein grass feed for livestock. To supply lysine, the industry employs microorganisms such as Escherichia coli that can synthesize lysine from a carbon source (e.g., a sugar such as glucose) through a well- known biosynthetic pathway.

The patents involved in this case alter two mechanisms that contribute to E. coli’s limited lysine production. The first mechanism, known as “feedback inhibition,” is triggered by lysine itself. Specifically, when sufficient lysine is present to meet the organism’s needs, lysine inhibits its own production by inhibiting the activity of certain of its biosynthetic enzymes. At the same time, E. coli also employ enzymes, called lysine decarboxylases, which break down any extra lysine produced into a non-nutritious byproduct. Both mechanisms—feedback inhibition and lysine degradation—keep E. coli from accumulating excess lysine.

Scientists at Ajinomoto disrupted the lysine degradation limitation imposed on lysine production by engineering an E. coli with a mutant lysine decarboxylase gene. Specifically, the ’698 patent, entitled “Lysine Decarboxylase Gene and Method of Producing L-Lysine,” discloses the identification of the lysine decarboxylase gene ldc and the creation of an E. coli strain with mutations in ldc that reduce or eliminate lysine decarboxlyase activity. Asserted claim 15 of the ’698 patent covers a method of producing lysine by cultivating E. coli with mutant ldc and collecting the accumulated lysine:

A method for producing L-lysine, comprising:  cultivating an isolated microorganism belonging to the genus Escherichia, wherein the microorganism contains a [mutant lysine decarboxylase] in a liquid medium, thereby producing the L-lysine and accumulating the L-lysine in the liquid medium, and collecting the L-lysine produced and accumulated in step (a), wherein the microorganism belongs to the species Escherichia coli.

The’160 patent, entitled “Method of Producing L-Lysine by Fermentation,” discloses the creation of an E. coli strain with at least one of two mutations in dapA, the gene encoding the biosynthetic enzyme dihydrodipicolinate synthase (“DDPS”). The mutations release DDPS from the feedback inhibition imposed by excess lysine, and result in an E. coli strain that produces greater amounts of lysine than wild-type strains. Asserted claim 15 of the ’160 patent covers a method of producing lysine by cultivating E. coli that contain mutant dapA and collecting the accumulated lysine:

A method of producing L-lysine, comprising: cultivating a bacterium belonging [to] the genus Escherichia which is transformed with a DNA coding for a dihydrodipicolinate synthase originating from a bacterium belonging to the genus Escherichia and having mutation to desensitize feedback inhibition of L-lysine, wherein the mutation is selected from the group consisting of [a mutation to replace the alanine residue at the 81st position and/or a mutation to replace the histidine residue at the 118th position] in a suitable culture medium, producing and accumulating L- lysine in the culture thereof, and collecting L-lysine from the culture.

Both patents disclose certain E. coli host strains for practicing the claimed inventions. The ’698 patent describes a two-step process of producing a mutant ldc host strain. In contrast to the disclosure in the specification, it is undisputed that the actual strain used by the inventors had two additional genetic alterations made to it before the addition of mutant ldc. The inventors identified this strain as WC80.

Similarly, the ’160 patent discloses two host strains, B-399 and W3110(tyrA), into which the inventors introduced mutant dapA. Yet, before filing the Japanese application from which the ’160 patent claims priority, the inventors characterized a different strain, AE-70, as their best lysine producer.

After Ajinomoto filed a complaint at the ITC, the Administrative Law Judge (ALJ) found that the asserted claims were invalid for multiple violations of the best mode requirement of 35 U.S.C. § 112, first paragraph, and that both patents were unenforceable for inequitable conduct because of those best mode violations.

The ALJ concluded that the inventors had violated the best mode requirement by (1) concealing their preferred and only host strain, WC80-1 96S, via a misrepresentation of the steps actually performed to create a mutant ldc host strain; (2) concealing sucrose as their preferred carbon source, which materially affects achieving the claimed invention; and (3) submitting data associated with fictitious host strains in support of the best mode. Similarly, with regard to claim 15 of the ’160 patent, the ALJ concluded that the inventors had violated the best mode requirement by (1) concealing their preferred host strain, AE-70, and (2) submitting fictitious data in support of the best mode.

Section 112 of the Patent Act provides that the patent specification “shall set forth the best mode contemplated by the inventor of carrying out his invention.” Known as the best mode requirement, it comprises part of the quid pro quo of the patent grant, prohibiting inventors from receiving the benefit of the right to exclude while at the same time concealing from the public preferred embodiments of their inventions. To satisfy the best mode requirement, an inventor must disclose the preferred embodiment of his invention as well as preferences that materially affect the properties of the invention.

Determining compliance with the best mode requirement is a two-prong inquiry. First, the court must determine whether, at the time the patent application was filed, the inventor possessed a best mode of practicing the claimed invention. Second, if the inventor has a subjective preference for one mode over all others, the court must then determine whether the inventor “concealed” the preferred mode from the public.

The Federal Circuit held:

By defining the invention to include the host strains, we do not read the Commission’s decision as requiring the disclosure of any and all preferences related to the production of lysine, as Ajinomoto claims. The Commission simply defined the scope of the claimed invention to include “cultivating a bacterium” as recited by the asserted claims. Also, the Commission did not, as Ajinomoto asserts, require the disclosure of all subject matter having to do with the claim term “bacterium.” The Commission simply required the disclosure of the preferred and, for the ’698 patent, only bacterial strain that the inventors used to practice the claimed invention.

[W]e disagree with Ajinomoto’s interpretation of the Commission’s opinion and the law. First, the Commission’s opinion did not, as Ajinomoto contends, find that the inventors concealed the method of creating the host strain into which they later introduced an ldc mutation. Rather, the Commission found that the inventors concealed the identity of the preferred host strain, and specifically that other genetic alterations, including a lysC variant and sucrose utilization genes, had been introduced (by whatever method) into the only host strain used to practice the claimed invention. Cf. Ajinomoto Co. v. Archer-Daniels-Midland Co., 228 F.3d 1338, 1347 (Fed. Cir. 2000) (finding no best mode violation when one of skill in the art would know that the identified preferred host strain contained another genetic alteration).

Second, the best mode requirement cannot be satisfied by the deposit of a non- preferred strain. It is undisputed that the host strain deposited by Ajinomoto lacked the sucrose utilization genes and thus was not the host strain into which the inventors inserted an ldc mutation. Furthermore, while the deposited strain contained the lysC variant, the specification contains no disclosure of that fact, and one of skill in the art would not know that the strain had such an alteration. As such, the deposit failed to enable one of skill in the art to practice the inventors’ preferred embodiment and thus concealed the best mode.

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