Illumina, Complete Genomics Prepare for Legal Battle over Sequencing IP

Three patents related to genome sequencing and analysis for human DNA are at the center of a two-year old court battle between a sequencing giant and a fast-growing upstart. In Illumina Inc. et. al v. Complete Genomics Inc., Illumina contends that the Complete Genomics Analysis (CGA) Platform infringes on three of its patents. Complete Genomics denies this and has counterclaimed that Illumina’s patents were invalid and/or unenforceable.

The case is pending in U.S. District Court for the Northern District of California. Both parties have a deadline of today for substantial completion of document production, and a June 22 deadline for the close of fact discovery. Trial has been scheduled for May 13, 2013.

Lawsuit Synopsis

The patents under debate in Illumina v. Complete Genomics were originally issued to Solexa, which Illumina acquired for $600 million in a deal completed in 2007:

• Patent No. 6,306,597 covers DNA sequencing by parallel oligonucleotide extensions. Complete Genomics argued that it does not infringe on the ’597 patent because it removes its entire anchor-probe complex after each nucleotide base is read and does not ligate a labeled probe to an initializing oligonucleotide, does not identify one or more nucleotides of the polynucleotide, and does not repeat the cycle one or more times by ligating labeled probes to an extended duplex and identify additional nucleotides.
• Patent No. 7,232,656 covers arrayed biomolecules and their use in sequencing. Complete Genomics has countered that it did not infringe on this patent because its base-read cycle does not depend on the completion of previous cycles and does not generate sequence reads of all fragments of a genome.
• Patent No. 7,598,035 covers method and compositions for ordering restriction fragments. Complete Genomics noted that it does not infringe on the ’035 patent because it does not use vectors, does not insert polynucleotide fragments into a vector, and does not use type II restriction endonucleocases to generate a pair of segments from a single polynucleotide fragment connected to each other via a vector.

Complete Genomics also argued that the only independent method claim of the ’597 patent was anticipated as invalid by a stipulation signed by Illumina and other parties to a 2007 patent case focused on ownership, noninfringement, and invalidity of ’597 and two other patents. In 2009, a U.S. District Court judge entered the stipulation as part of a judgment in the case Applera Corp.-Applied Biosystems Group vs. Illumina et.al. Illumina maintained it did nothing wrong and appealed the judgment, which was upheld by the U.S. Court of Appeals for the Federal Circuit.

During 2010, ’597 was the subject of an ex parte re-examination that ended with the independent method claim unchanged and serving as the basis for additional claims. The examiner reversed an earlier rejection of the claim after inventor Stephen Macevicz, Ph.D.—whose patents were licensed by Illumina’s co-plaintiff in the Applera case, Solexa—filed a Rule 131 declaration establishing that the subject matter of the ’597 patent was memorialized “by July 9, 1994,” years before the stipulation; Complete Genomics contended that the ’597 patent is invalid or rendered obvious by an earlier patent by its co-founder and CSO, Radoje Drmanac, Ph.D.

“Stephen Macevicz memorialized his conception of the claimed method almost ten months after the filing date of Dr. Drmanac’s U.S. Patent Application Ser. No. 08/127,420. Accordingly, Stephen Macevicz is not the first to invent the claimed method in the United States, and Dr. Drmanac has not abandoned, suppressed, or concealed his invention,” Complete Genomics argued.

In addition, according to Complete Genomics, Illumina and its co-defendants in the earlier case failed for months to notify the USPTO of the judgment or stipulation during the re-examination and then sought to bury the significance of the stipulation: “They took the stipulation out of chronological order and attached it as the last document attached to the [Information Disclosure Statement],” then made an oblique reference to it in a two-page summary of the IDS.

“Illumina denies that its attorneys ‘took the stipulation out of chronological order’ and denies ‘they made only one oblique reference to the stipulation,’” the company said in a rebuttal filing.

In the Northern California district court, U.S. Magistrate Judge Elizabeth D. Laporte offered Illumina some welcome news by siding with its construction on six of nine terms in the ’597 patent where it is at odds with Complete Genomics:

• Two definitions within Claim 1—“extending an initializing oligonucleotide along the polynucleotide by ligating an oligonucleotide probe thereto to form an extended duplex,” and “repeating steps (a) and (b) until the sequence of nucleotides is determined.”
• Oligonucleotide probe—Laporte defined the term as “a nucleic acid that can bind to the polynucleotide and, when bound to the polynucleotide, can be ligated to the initializing oligonucleotide or to a previously extended duplex. An oligonucleotide probe that has been successfully ligated either contains or is associated with a label.” The judge said Complete Genomics’ proposed definition “improperly limits ligation of the oligonucleotide probe in subsequent cycles to the previously extended initializing oligonucleotide and excludes ligation to a new initializing oligonucleotide in subsequent cycles when the method is repeated.”
• Set or probe set—Laporte defined the term as “a number of probes grouped together,” and rejected Complete Genomics’ proposal to add to the definition “are grouped according to their free energy of duplex formation with their perfectly complementary sequences”.
• Target polynucleotide—Laporte sided with Illumina that the term means “a polynucleotide having a portion to be sequenced,” citing the ’597 patent’s specification describing the Field of the Invention as “methods for determining the nucleotide sequence of a polynucleotide,” as well as the identifying step (b) of Claim 1, which entails “identifying a sequence of nucleotides.”
• Spectrally resolvable fluorescent signal—Laporte defined the term as “a light signal generated by fluorescence that can be distinguished based on its spectral characteristics (e.g., its color).” Complete Genomics argued that the term should not be limited to the detection of a particular color, saying the specification gave alternatives to detection of fluorescence.

Complete Genomics prevailed, however, on definitions of two terms: Laporte upheld Complete Genomics’ construction of “initializing oligonucleotide” as “an oligonucleotide that forms a highly stable duplex with the binding region of the polynucleotide that remains intact during any washing steps of the extension cycles” and of “binding region” as “a known sequence of the polynucleotide to which the initializing oligonucleotide binds.”

For a ninth term, “annealing temperatures,” Laporte sided partially with Complete Genomics, defining the term as “particular temperatures at which probes that are grouped in a probe set form a duplex.” Complete Genomics sought a single-temperature standard, while Illumina sought a range of temperatures, something the judge said would be unworkable.

Who Will Emerge the Leader?

Illumina finished 2011 with GAAP net income of $86.628 million, or 62 cents per diluted share, down 31% from 2010, despite a 17% year-over-year jump in revenue to $1.056 billion. Complete Genomics, by contrast, ended last year with a $72.3 million net loss, up from $57.7 million in 2010, despite more than doubling its revenue to $19.3 million.

During 2011, Complete Genomics said, it signed orders for about 8,000 genomes with an aggregate revenue potential of $39 million and delivered data to about 90 customers. “We entered 2012 with a strong order book of about 5,800 genomes, representing aggregate revenue potential of approximately $28 million,” Clifford Reid, Ph.D., chairman, president, and CEO of Complete Genomics, said in a statement.

Illumina said that during Q4 it enjoyed “record orders” and a book-to-bill ratio—the proportion of orders in-process to orders filled—of 1:2. Illumina has projected 2012 revenue growth of between $1.1 billion and $1.175 billion, including Q1 2012 revenues of between $250 million and $260 million. That’s down from $282.5 million in Q1 2011 and flat from the $250 million racked up in Q4 ’11; the company typically gets the lowest orders during the first quarter.

During the second half of 2012, Illumina will begin rolling out its recently announced top-of-the-line next-generation sequencer HiSeq 2500, which enables the sequencing of an entire human genome in approximately a day (120 Gb/run). Customers who already have the existing HiSeq 2000 instruments can upgrade them to the 2500 for $50,000.

As exciting as that technology may sound and as important as the Illumina/Complete Genomics case is, there is also the planned rollout later this year of Life Technologies’ $1,000 genome machine. The sequencer will sell for between $99,000 and $149,000. If Life Tech changes the sequencing game, as some have predicted, it will likely also touch off another wave of patent infringement litigation, as past generations of sequencing innovations have done. Illumina and Complete Genomics will hardly have the last word on who owns what sequencing IP.