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PTO Agrees to Reexamine Broad Codon Optimization Patents

Many important applications of biotechnology involve the expression of recombinant genes in heterologous systems. Since the genetic code is degenerate (ie each amino acid can be coded by on average three different codons), the DNA sequence can be modified by synonymous nucleotide substitutions without altering the amino acid sequence of the encoded protein. A biotechnologist might find it useful to make a synonymous substitution for any of a variety of reasons, e.g., to introduce or remove restriction sites, or to remove repeats.

Today genes are also often altered for the specific purpose of optimizing expression, i.e., the entire coding region of the gene is recoded to fit one of a variety of codon optimization schemes. Examples of popular codon optimization schemes used in designing a gene for recombinant expression include:

A) Replace a degenerate codon with the most common codon present in the host chromosome; the rationale being that the most common codon correspond to the most common tRNA results in most protein yield.

B) Reengineer the gene so that it uses the same frequency of codons that are present in the host chromosome; the rationale being that the recombinant gene should have the same codon bias as the host chromosome to fit the translational machinery.

C) Re-code the pattern of rare and common codons found in the wild type by replacing it with the corresponding rare/common codons in the heterologous host; the rationale being that protein folding and expression requires rare (slow) and common (fast) codons distributed according to the folding domains in the protein.

D) Empirically identify codons and other variables that correlate with high protein expression in a systematically varied recombinant gene.

Codon optimization has become standard practice in the recombinant expression of heterologous proteins such as biologic drugs. Gene synthesis companies such as DNA2.0 and Blue Heron assist their customers by providing codon optimization as a part of their services.

Two U.S. patents (both assigned to the Massachusetts General Hospital) include claims directed towards codon optimization, both the method and the resulting codon-optimized gene (US Patent Numbers 5,786,464 and 6,114,148). These patents are very broad, purporting to cover any "synthetic gene encoding a protein normally expressed in an eukaryotic cell wherein at least one non-preferred or less preferred codon . . . has been replaced by a preferred codon encoding the same amino acid, [and wherein the replacement results in at least 10% increase in the level of protein expressed] in an in vitro mammalian cell culture system under identical conditions”

These patents appear to not only cover any successfully codon-optimized recombinant gene, but also many genes that have been reengineered for purposes other than codon optimization. For example, a silent mutation introduced for the purpose of removing a restriction site could easily constitute infringement if it results in the introduction of any of the 17 codons identified in the patent as “preferred,” if it turns out that the substitution results in a modest 10% increase in expression in any in vitro mammalian cell culture system. Rarely would an experimenter test for such an increase in expression at that level of accuracy, and a practical matter it would be virtually impossible to rule out the possibility of a 10% increase in expression in some mammalian cell culture system.

In view of their scope, and the pervasive use of codon replacement in the expression of high-value heterologous proteins (such as biologic drugs), these patents could potentially have sweeping implications for biotechnology. However, although the patents issued in 1998 and 2000, they have never been asserted in court and until recently appear to have received little attention.

However, the patents have recently become a thorny issue for those involved in the business of expressing heterologous proteins, particularly gene synthesis companies providing codon optimized genes for their customers. Last year Geneart (a German gene synthesis company owned by Life Technologies) began sending letters to companies engaged in the expression of heterologous proteins announcing that "we are very pleased to inform you that Geneart has acquired a license under [the Massachusetts General Hospital (MGH) Patents].” The letter goes on to state that under the license “Geneart is in the excellent position to offer a broad range of sublicensing opportunities." The licensing “opportunities” include a royalty-free sublicense to use synthetic genes purchased from Geneart in internal R&D, and a royalty-bearing commercial sublicense for synthetic genes used for purposes other than internal research and development. According to the letter, Geneart has executed a non-prosecution agreement with respect to synthetic genes delivered by Geneart to customers prior to May 30, 2010, so these customers are apparently free to use the genes in any manner without liability for infringement.

The letter goes on to imply that customers who choose to purchase synthetic genes from competing gene synthesis companies could be sued for infringing the MGH Patents, stating that "to Geneart’s knowledge, no other Gene Synthesis Service Provider has obtained a respective license under the MGH Patents."

This poses a problem for any biotechnologist wishing to use a synthetic or partially modified gene. Even slight variations to the wild-type sequence, such as restriction site removal or addition, could infringe.
It certainly poses a problem to other synthetic gene companies, whose customers might switch to Geneart in order to avoid a perceived threat of patent infringement liability for using synthetic genes not purchased from Geneart.


DNA2.0, a leading provider of synthetic genes headquartered in Menlo Park California, has responded to this perceived threat by successfully petitioning for reexamination of both patents, arguing that the broad claims are anticipated and/or rendered obvious by prior art not previously considered by the PTO. The orders granting the ex parte reexamination of the ‘148 and ‘464 patents were issued on December 14, 2010 and January 26, 2011, respectively.

The orders granting reexamination state that a number of references cited by DNA2.0 in the request for reexamination raise substantial new questions of patentability with respect to most of the claims in the patents, particularly the broadest claims. For example, an article published in the Journal of Virology in 1992 by Schwartz et al. describes the characterization of inhibitory RNA elements in the gag region of human immunodeficiency virus type I (HIV-1). This involved replacing many of the codons in the wild type gene with synonymous codons defined as "preferred" in the MGH Patents, resulting in at least a five-fold increase in expression. As another example, the PTO found an article disclosing a computer program for optimizing DNA sequences for protein expression, in combination with another article disclosing the most frequent human codon usage together with preferred codon choice patterns, also raise substantial new questions of patentability for many of the claims.

It is interesting to note that the corresponding codon optimization patent issued to MGH in Europe (EP 0 781 329 B2) is much narrower in scope, claiming a method for preparing a synthetic gene wherein at least 50% of the non-preferred codons and less preferred codons are replaced by preferred codons and resulting in a 10% increase in expression. In contrast, the US patents purport to claim any method that involves replacing even one codon with a preferred codon, and any gene made by such a process.

It is my understanding that, as a practical matter, the European patent only poses a substantial impediment to the “A” form of codon optimization described above, i.e., replacement of all degenerate codons with the most common codon present in the host chromosome. Most other codon optimizations do not require the substitution of 50% of non- or less preferred codons. In contrast, the U.S. patents would appear to cover the majority of recombinant protein expression that has been done in recent years. The patents should expire 2015, but the pending reexamination could be important if it results in cancellation or narrowing of the claims in the US patents, thereby providing assurance that companies will not be sued for expressing recombinant proteins prior to patent expiration.

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NPR Retraction of Story on Apple Factories Provides Insight into the Mentality behind Attacks on Gene Patents and Agricultural Biotechnology

On March 16, the popular National Public Radio (NPR) program This American Life (TAL) was forced to retract statements made during an episode that aired in January alleging abuse of workers at Chinese factories manufacturing products for Apple. The explanation provided by “monologist” Mike Daisy, source of the "significant fabrications" reported on the TAL program, provide some insight I think into the mentality behind the flood of misinformation that has been promulgated with respect to gene patents and agricultural biotechnology, and which unfortunately has found its way into the courts and Congress.

TAL admits to having excerpted the fabricated story from "The Agony and The Ecstasy of Steve Jobs," a one-man show that Mike Daisey had been performing across the country, and which is currently in production at the Public Theater in New York. In a press release, TAL says it first learned Daisey had fabricated parts of his story when another public radio program, Marketplace, tracked down Daiseys interpreter, who disputed parts of Daiseys monologue. After being caught lying, Daisey apologized to NPR, explaining that:

“I’m not going to say that I didnt take a few shortcuts in my passion to be heard. [] My mistake, the mistake I truly regret, is that I had it on your show as journalism, and its not journalism. Its theater."

Daiseys rationalization of his lies reminds me a lot of the response of an author after I reviewed his book entitled "Who Owns You? The Corporate Gold Rush to Patent Your Genes", and pointed out some of the numerous inaccuracies in the book regarding patent law in general, and gene patents in particular. In the book, the author characterized himself as an intellectual property attorney, but when he was unable to refute the many inaccuracies in his book that I pointed out in my review, he dismissed them, and asserted that it did not matter because he had approached the issue as a philosopher, rather than as a lawyer or scientist; very reminiscent of Daiseys explanation that his report on NPR was "theater," not journalism.

The problem is, these people target a lay audience largely unfamiliar with the subject matter they cover, and push forward their work as evidence allegedly supporting their position. It would be one thing if Daisey had explained to his NPR audience that he was merely engaged in theater, or if the author of "Who Owns You?" had explained that his book was nothing more than philosophical ponderings, with no grounding in fact. But that is not how they present their work, and unfortunately their works can play an important role in motivating others (including judges and members of Congress) to take action.

For example, according to NPR the TAL piece featuring Daisey made him "Apples chief critic and it also inspired a Change.org petition that collected more than 250,000 signatures demanding that Apple better the working conditions at the factories.” Books like "Who Owns You?” have no doubt played a role in shaping the current widespread antipathy toward gene patents.

I also found it interesting that Daisey characterizes his fabrications about Apple factories as "shortcuts in [his] passion to be heard." I suspect that this sort of mentality might explain the bending of reality routinely engaged in by the opponents of gene patents and agricultural biotechnology. They are convinced that gene patents and genetically engineered crops endanger society, and that companies like Myriad Genetics and Monsanto are evil, and will seemingly say anything in their passion to be heard. Like Daisey, they do not appear to be bothered by specific facts, and are willing to take shortcuts around the truth in seeking to eliminate these evils from the world.

The disturbing thing is that there is so much incentive for people to propagate these myths. People like Daisey clearly love being in the spotlight, and the more sensational he can make his reports of condition Apple factories, the more people he will have listening. NPR reported that this episode of TAL had the largest audience that show had ever achieved, and that Daisey became the most prominent critic of Apple factories because of the coverage. Unfortunately, I think there are also incentives at play, particularly in academia and with respect to advocacy groups such as the ACLU and Public Patent Foundation, for making overblown and sensationalistic allegations on hot button issues such as gene patents and agricultural biotechnology.

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Pioneer DuPont Sues Monsanto for Infringing Low Tech Agricultural Biotechnology Patents

Yesterday Pioneer Hi-Bred (a subsidiary of DuPont) sued Monsanto, its rival in the agricultural biotechnology sector, for allegedly infringing its patents directed towards a method of increasing "seed vigor" in maize that entails defoliating maize plants during a specific period after pollination. The lawsuit was filed in the Southern District of Iowa, Pioneers home territory.

The two companies have been involved in a high-profile patent litigation ever since Pioneer announced its plans to release genetically modified maize comprising Pioneers Optimum GAT trait stacked with Monsantos Roundup Ready trait. Both traits confer resistance to glyphosate (i.e. Roundup), albeit by different mechanisms - Roundup Ready essentially works by rendering the plant resistant to glyphosate, while Optimum GAT causes the plant to express a protein that breaks down the glyphosate molecule.

Pioneer responded by suing Monsanto for antitrust violations, based on the company’s licensing and enforcement practices with respect to its patents covering the Roundup Ready trait. The patent infringement case is scheduled to go to trial next June, while the antitrust counterclaims are scheduled to go to trial April 2013.

The two patents being asserted by Pioneer in the most recent lawsuit are US patent numbers 5,518,989 and 6,162,974. The ‘989 patent claims a method of increasing seed vigor in maize by defoliating plants during a specific time window after pollination, based upon how long the growing plant has been exposed to warm days. The ‘974 patent claims an "assemblage" of maize seeds produced using the method. Here are a couple of representative claims.

Claim 1 from the ‘989 patent:

1. A method for treating a stand of maize plants, comprising the steps of

(A) reducing functional leaf area in substantially all of said plants, wherein said reducing is effected at between about 600 and about 850 GDDs after pollination of said plants, and then

(B) harvesting said stand, such that a seed assemblage is obtained from said stand that is characterized by a level of seed vigor that is enhanced relative to the level of seed vigor in a seed assemblage harvested from a comparison stand of maize plants not subjected to said reducing of functional leaf area.

Claim 1 from the ‘974 patent:

1. A maize seed assemblage having enhanced seed vigor, wherein said seed assemblage is obtained by the method comprising the steps of:

(a) reducing functional leaf area in substantially all of a stand of maize plants, wherein said reducing is effected at between about 600 and about 850 GDDs after pollination of said plants, and

(b) harvesting said stand to obtain an assemblage of seeds,

wherein said seed assemblage is characterized by a level of seed vigor that is enhanced relative to the level of seed vigor in a seed assemblage harvested from a comparison stand of maize plants not subjected to said reducing of functional leaf area.

According to Wikipedia, “GDD [,which stands for Growing Degree Day, is] a measure of heat accumulation used by horticulturists, gardeners, and farmers to predict plant and pest development rates such as the date that a flower will bloom or a crop reach maturity.” Wikipedia states that "plants grow in a cumulative stepwise manner which is strongly influenced by the ambient temperature. Growing degree days take aspects of local weather into account and allow gardeners to predict (or, in greenhouses, even to control) the plants’ pace toward maturity."



The patents state that "functional leaf area can be reduced" (i.e., the plant can be defoliated) using mechanical or chemical means. "Chemical means" would include treatment with an herbicide such as Roundup (the dependent claims explicitly identify Roundup as an herbicide to be used in the method.


The patents remind me of the patents at issue in In re Cruciferous Sprouts litigation that occurred several years ago. In that case, as I recall, researchers at Johns Hopkins University discovered that cruciferous sprouts (e.g., broccoli sprouts) harvested at a particular point in time after germination (in particular, prior to the "two-leaf stage") contain high levels of certain compounds believed to be useful in preventing cancer.

A representative claim at issue in that case recited " “A method of preparing a food product rich in glucosinolates, comprising germinated cruciferous seeds, with the exception of cabbage, cress, mustard and radish seeds, and harvesting sprouts prior to the 2-leaf stage, to form a food product comprising a plurality of sprouts.”

The Federal Circuit held that the claims were invalid based on inherent anticipation. Although the Johns Hopkins researchers might have been the first to recognize the health benefits of eating cruciferous sprouts harvested prior to the two-leaf stage, in fact people had been eating sprouts harvested at this stage for many years. This was surely the correct result - if the claims were held valid, that would mean that Johns Hopkins would have the right to exclude others from doing something that had long been part of the prior art, i.e., eating broccoli sprouts and the like.

The same sort of issue of inherent anticipation could potentially be raised with respect to Pioneers patents on methods of defoliating maize plants at a certain time after pollination. It would seem to me that if Monsanto can show that, prior to Pioneers invention, maize plants had been defoliated during this stage of growth (perhaps by treatment with Roundup), a court might come to the conclusion that the claims are inherently anticipated.

The claims also might raise issues of patent eligibility, at least in the minds of people like Justice Breyer. Recall that in his LabCorp dissent Justice Breyer expressed a view that a patent claim that preempts substantially all practical use of a newly discovered natural phenomenon is patent ineligible. Some might characterize Pioneer’s discovery that defoliation of maize at a certain time results in increased seed vigor as the discovery of a "natural phenomenon," and conclude that Pioneer’s claims effectively preempt all substantial practical application of this discovery.

Pioneers claims directed towards a "maize seed assemblage" might also raise patent eligibility issues. The claimed maize seeds are arguably not genetically modified, in which case they might be considered "products of nature" and not patent eligible under Chakrabarty. In order to be patent eligible, it would seem that a court would have to determine that either the defoliation resulted in a "man-made" seed, or that grouping seeds in an "assemblage" is sufficient human intervention to establish patent eligibility.

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