Source: s3://data.kl3m.ai/documents/govinfo/USCOURTS/USCOURTS-cand-3_07-cv-01427/USCOURTS-cand-3_07-cv-01427-16/pdf.json

Nature of Suit Code: 830
Nature of Suit: Patent
Cause of Action: 35:271 Patent Infringement

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United States District Court

For the Northern District of California

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IN THE UNITED STATES DISTRICT COURT

FOR THE NORTHERN DISTRICT OF CALIFORNIA

EXONHIT THERAPEUTICS S.A.,

a French societe anonyme, and

EXONHIT THERAPEUTICS, INC., a

Delaware corporation,

Plaintiff,

 v.

JIVAN BIOLOGICS, INC., a Delaware

corporation,

Defendant. /

No. C 07-01427 WHA

CLAIM CONSTRUCTION ORDER

INTRODUCTION

This is a claim construction order for United States Patent No. 6,881,571. This order

addresses one phrase selected for construction by the parties. A technology tutorial, as well as a

full round of briefing preceded this order. 

STATEMENT

This claim construction order comes after a convoluted and prolonged claim

construction briefing. Plaintiff Exonhit Therapeutics, Inc., is the assignee of the ’571 patent. In

their joint claim construction and prehearing statement, the parties identified four terms that

required construction. Defendant Jivan Biologics, Inc., then withdrew its proposed

constructions for all four claims and agreed to all constructions provided by plaintiffs. At this

time, defense counsel also indicated that its client was short on funds and no longer able to

afford a protracted litigation. Defendant then admitted that under the claim constructions

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agreed to that some of its products infringed the ’571 patent. At this point, it seemed as though

the only remaining loose end was to calculate a proper level of damages. With this in mind,

defendant was ordered to produce all documents necessary to calculate damages and to stipulate

to infringement. After the further discovery, however, the parties realized that there was still a

dispute over the scope of infringement due to a disagreement over the meaning of one of the

terms originally acquiesced to by defendant. Defendant was then allowed to withdraw its

stipulation to construction and challenge any term whose meaning remained in dispute. This

claim construction order ensued.

The patent itself is directed to a method for identifying and screening differences in gene

expression that are associated with physiological conditions. DNA consists of a long polymer

of simple units called nucleotides. Each nucleotide in human DNA has one of four

characteristic chemical structures, or bases: adenine, cystosine, guanine, or thymine. It is the

sequence of these bases that encodes information about the functioning of living organisms. 

The bases interact with one another to create a structure known as a double helix consiting of

two intertwined strands of DNA. These two strands are perfectly complementary to one

another, such that adenine bonds with thymine and cytosine bonds with guanine. 

Genes are specific regions in an organism’s DNA that contain the instructions necessary

to make proteins in a body. The first step in making a protein is copying the gene from DNA to

RNA, or ribonucleic acid, through a process called “transcription.” The initial RNA transcript

is known as pre-mRNA. While RNA is similar to DNA, its characteristic chemical structure

differs slightly in that the base thymine of DNA is replced by uracil in RNA. Although RNA is

capable of binding to DNA to form a double helix, it usually exists in a single strand. The

second step in making protein is physically cutting out portions of the pre-mRNA that are

unnecessary for the protein synthesis. This process known as “splicing” results in a shortened

RNA molecule, mRNA, which specifies the required structure to code the protein. The third

and final step in making protein is actually using the spliced RNA molecule to create the protein

in a process called “translation.” 

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The invention of the ’571 patent concerns the second step for making the protein, or

“splicing.” When the pre-mRNA is spliced certain portions of the sequence are cut out. The

term “intron” refers to those regions of the pre-MRNA that are spliced out of the transcription

process during the formation of the final mRNA molecule and ultimately not translated into a

protein. The term “exon” refers to those regions of the pre-mRNA that are transcribed during

the formation of the final mRNA molecule and ultimately used in the creation of the protein. 

The decision of which portions of the pre-mRNA to cut out and which to retain, however, may

vary. RNA can be spliced differently in different tissues or under different physiological

conditions (e.g., toxicity) to code for a variety of different proteins. This process is known as

“alternative splicing.”

Spliced RNA can be used as a template to create matching DNA through a process

called “reverse transcription.” When a spliced mRNA molecule is reverse transcribed to create

a DNA sequence, the resulting DNA molecule is named “complementary DNA” or “cDNA.” 

cDNA is useful for scientists because it contains the same sequence as the spliced mRNA, but

with the properties of a DNA molecule. The mRNA can bind, or “hybridize,” with the cDNA to

form different chemical structures. The ’571 patent explains a method for identifying regions of

genetic code that may be spliced differently under varying physiological conditions. 

Alternative splicing events may be identified by analyzing the differences between hybridized

RNA or cDNA molecules obtained from various splicing events occurring under different

physiological conditions (col. 9:38–41).

When two samples of RNA or cDNA result from a differential splice they typically have

a majority of sequences in common, but because at least one of the samples has been spliced

differently than the other, the samples are not fully complementary. When such samples

hybridize with one another, the result is a partially hybridized fragment consisting of portions of

the sequence that have hybridized and portions for which have been retained in one strand and

spliced out in the other (Fig. 6A). The portions of the strand that have not hybridized, or

“loops,” may be identified and cloned (col.12:28–30).

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Cloning these loops creates structures that are complementary to alternative exons and

introns of the two samples used in the hybridization. These structures allow the junction

sequences formed by the deletion of an exon or intron at the splice site of the RNA or cDNA

missing the sequence to be identified (col. 8:57–62). Using this method for identifying

alternative splicing events allows the user to create a set of two types of probes, one to query

exons or introns and one that is specific to the junction (i.e., where the splicing event occurs)

formed by the spliced sequences. These probes allow the user to specify future alternative

splicing events by comparing the probes to the splicing events (col. 12:45–61).

Different probes may then be collected to form large libraries of sequences of nucleic

acids that represent qualitative differences occurring between two conditions created by varying

physiological conditions. The ’571 patent teaches the use of a probe (containing the library of

sequences) attached to a solid support, such as a membrane or chip, that can detect for any

given splicing event occurring in both the reference unspliced form of mRNA (i.e., the loop

portion) and the junction region between the two domains separated by the spliced form of the

mRNA (col. 16:10–18). When the probe is exposed to a sample containing an unknown gene

sequence, only those sequences that are complementary to the sequences of the probe will

hybridize. Those sequences that hybridize may then be tracked using known labeling

techniques in the prior art (col. 17:55–64). By identifying those sequences in the probe that

hybridize, the identity of the unknown gene sequence can be determined and the gene sequence

can be screened for the physiological condition (e.g., toxicity) that was used to develop the

probe library.

This action was filed on March 12, 2007, alleging that defendant infringed each of the

claims in the ’566 patent. A technology tutorial was held on January 9, 2008, but no claim

construction hearing was held. Trial is set for June 23, 2008. 

ANALYSIS

1. LEGAL STANDARD.

Claim construction is a matter of law to be decided by a judge, not a jury. Markman v.

Westview Instruments, Inc., 517 U.S. 370, 388 (1996). Courts must give words in the claims

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their ordinary and customary meaning, which “is the meaning that the term would have to a

person of ordinary skill in the art in question at the time of the invention.” Phillips v. AWH

Corp., 415 F.3d 1303, 1312–13 (Fed. Cir. 2005) (en banc). 

Where this ordinary and customary meaning is not immediately clear, courts must

primarily look to intrinsic evidence (i.e., the claims, the specification, and the prosecution

history) to determine the meaning. Id. at 1314. With respect to the specification, although a

difficult task, a court must distinguish “between using the specification to interpret the meaning

of a claim and importing limitations from the specification into the claim.” Id. at 1323. 

The latter is not permissible. 

Although courts have the discretion to consider extrinsic evidence, including expert and

inventor testimony, dictionaries and scientific treatises, such evidence is “less significant than

the intrinsic record in determining the legally operative meaning of claim language.” Id. at

1317 (citation omitted). “The construction that stays true to the claim language and most

naturally aligns with the patent’s description of the invention will be, in the end, the correct

construction.” Id. at 1315. “Nonetheless, any articulated definition of a claim term ultimately

must relate to the infringement questions it was intended to answer.” E-Pass Tech., Inc. v.

3Com Corp., 473 F.3d 1213, 1219 (Fed. Cir. 2007) (citing Wilson Sporting Goods Co. v.

Hillerich & Bradsby Co., 442 F.3d 1322, 1326 (Fed. Cir. 2006)). 

2. DISPUTED CLAIM TERM.

Plaintiffs and defendant have stipulated to all but one phrase: “region of variability.” 

The other terms whose meaning have been stipulated to have not been vetted by the Court and

should not be considered authoritative for any future litigation involving the patent. Claim 1 is

representative of the entirety of claims asserted. It recites (col. 49:40–63):

A device for identifying at least one differentially spliced

gene product,

wherein said device comprises a solid support

material and single-stranded oligonucleotide of

between 5 and 100 nucleotides in length attached to

said support material,

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wherein said oligonucleotides comprise at least a

first and a second oligonucleotide molecule

arranged serially on the support material,

wherein said first oligonucleotide molecule

comprises a first sequence that is complementary to

and specific for an exon or an intron of a first gene,

and wherein said first sequence corresponds to a

region of variability in at least one product of said

first gene due to differential splicing,

and wherein said second oligonucleotide molecule

comprises a second sequence that is complementary

to and specific for an exon-exon or exon-intron

junction region of said first gene,

and wherein said second sequence corresponds to a

region of variability in at least one product of said

first gene due to differential splicing, said device

allowing, when contacted with a sample containing

at least said device allowing, when contacted with a

sample containing at least one nucleic acid

molecule under conditions allowing hybridization to

occur, the determination of the presence or absence

of said differentially spliced gene product. 

A. “Region of Variability.”

Plaintiffs propose that “region of variability” should mean “a segment of DNA within a

gene or gene product that serves one role (exon, intron, exon-intron junction or exon-exon

junction) with respect to one isoform of the gene product and a different role with respect to

another isoform of the gene product.” Defendant objects to the inclusion of “exon-intron

junction or exon-exon injunction” in the definition of the types of roles that the segment used on

the probe may take on.

The term “region of variability” is meant to convey that a given segment of a gene may

serve different roles depending on how that gene is spliced in the resulting isoform of the gene

product. Segments of DNA are retained in some gene product isoforms and spliced out of

others. Some isoforms of the gene may include the sequence (e.g., exon), while other isoforms

of the gene may have cut the sequence out (e.g., intron). Accordingly, the role of the given

segment varies with respect to the differing isoforms of the gene product, giving rise to a region

of variability.

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The only question is whether this region of variability includes exon-intron junctions or

exon-exon junctions as argued by plaintiffs. This order finds that it does. The specification

explains, “[t]his variant is advantageous in that it reveals not only alternative introns and exons

but also, and within a same nucleic acid library, specific junctions formed by deletion of and

exon or an intron” (col. 8:61–63). The specification further teaches (col. 12:50–55):

Cloning these fragments generates an alternative splicing

library in which, for each splicing event, positive and

negative fingerprints are present. This library therefore

gives access not only to alternative exons and introns but

also to the specific junctions formed by the excision of

these spliced sequences.

In this respect, the specification specifically recognizes that the libraries created to screen for

specific physiological conditions include the specific sequences associated with specific

junctions created by the splicing event. The specific sequences screened for may be an intron in

one isoform of a gene or an extron in another isoform of a gene depending on the splicing event. 

These same sequences may also be junctions in yet another isoform of the same gene. It is

these variations that give rise to a “region of variability.” Defendant points to no language from

the claims, specification, or any expert testimony that suggests that the region of variability

should be limited to only introns and exons. 

Accordingly, this order finds that “region of variability” means “a segment of DNA

within a gene or gene product that serves one role (exon, intron, exon-intron junction or exonexon junction) with respect to one isoform of the gene product and a different role with respect

to another isoform of the gene product.” 

CONCLUSION

This claim construction order will govern for the remainder of this action. 

IT IS SO ORDERED.

Dated: March 7, 2008. 

WILLIAM ALSUP

UNITED STATES DISTRICT JUDGE

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