Free Declaration - District Court of Delaware - Delaware

Case 1:07-cv-00385-GMS-LPS

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EXHIBIT

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE

FEBIT BIOTECH GMBH
1M Neuenheimer Feld 519

69120 Heidelberg, Germany

Civil Action No.

Plaintiff

JURY TRIAL DEMANDED
CODON DEVICES , INC. One Kendall Square Building 300 , Third Floor Cambridge , MA 02139

Defendant.

COMPLAINT
Plaintiff febit biotech GmbH (hereinafter " febit" ), through its undersigned attorneys ,
as

and for its Complaint against Defendant Codon Devices ,
alleges as follows:

Inc. (hereinafter " Codon

Devices

NATURE OF THE ACTION
This is an action arising under the patent laws of the United States (35 U.
C. gg

271 et seq. ) based upon Defendant Codon Devices ' infringement of u.S. Patent No. 6 586 211
B 1 entitled "

Method for Producing Polymers.

THE PARTIES

Plaintiff febit is a German corporation having its principal place of business at
Neuenheimer Feld 519 , 69120 Heidelberg, Germany.

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Upon information and belief,

Defendant Codon Devices , is a Delaware

corporation , having its principal place of business at One Kendall Square , Building 300 , Third
Floor , Cambridge , MA 02139.

JURISDICTION AND VENUE
This action for patent infringement

arises under the patent laws of the United

States , United States Code , Title 35.

This Court has subject matter jurisdiction over this action pursuant to 28 u.S.
gg 1331 and 1338(a).

This Court has personal jurisdiction over Defendant Codon Devices
Codon Devices is incorporated in Delaware.
Venue is proper in this district under 28 u.S. C.
gg 1391 and 1400.

because

THE PATENT-IN- SUIT
febit is the owner of the entire right , title and interest in and to u.S. Patent No.

586 211 Bl (hereinafter " the ' 211 patent" ), issued July

2003 , entitled " Method for Producing

Polymers. " The named inventors of this patent are Peer F. Stahler , Cord F. Stahler and Manfred

Muller. A true and correct copy of the ' 211 patent is attached to this Complaint as Exhibit A.
The independent claims ofthe ' 211 patent are:
Claim 1:

Method for synthesizing polymers , wherein said method comprises synthesizing a plurality of oligomeric building blocks by parallel synthesis steps , wherein each oligomeric building block is synthesized on a different area of a common support
detaching the plurality of

oligomeric building blocks from the support and

bringing the oligomeric building blocks into

contact with one another to

synthesize the polymer, and wherein said different areas of said common support are at least partially in fluid communication during synthesis.

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Claim 25:

Method for synthesizing polymers that are greater than 10 000 bp in length wherein said method comprises synthesizing a plurality of oligomeric building blocks by parallel synthesis steps , wherein each oligomeric building block is synthesized on a different area of a common support , detaching the plurality of oligomeric building blocks from the support and bringing the oligomeric building blocks into contact with one another to synthesize the polymer , and wherein said

different areas of said common support
communication during synthesis.

are at least partially in

fluid

COUNT I
(Infringement of the ' 211 Patent Pursuant to 35 U. C. ~ 271(g))
10.

The allegations of paragraphs 1- 9 above are repeated and re-alleged as if set forth

fully herein.
11.

Upon information and belief, Defendant Codon Devices manufactures and uses a

gene synthesis platform called the BioF ABQP platform.
12.

Upon information and belief, Defendant Codon Devices ' BioF AB~ platform , and

the methods it performs, synthesizes molecular biology devices such as DNA and protein clones

variant libraries and operon and operon variant libraries. More specifically, Codon Devices
BioF ABQP platform

is used to synthesize oligonucleotides ,
duplexes.

hybridize oligonucleotides into

duplexes and assemble genes from the

Codon Devices is currently

scaling the

platform to design and construct molecular biology devices hundreds of kilobases to megabases
in length.
13.

Upon information and belief, in 2005 , Defendant Codon Devices began offering

for sale and selling in the United States molecular biology devices made using its BioF AB
platform.
14.

Upon information and belief, Defendant Codon Devices continues to offer for sale

and sell in the United States molecular biology devices made using its BioF AB ~ platform.

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15.

Upon information and belief, Defendant Codon Devices s manufacturing process

to synthesize molecular biology devices using the BioFAB~ platform , if practiced in the United

States, infringes literally or under the doctrine of equivalents or will infringe literally or under
the doctrine of equivalents one or more claims of the ' 211 patent pursuant to 35 U.
16.
C. g 271(g).

Upon information and belief, Defendant Codon Devices ' offer for sale , sale or use

within the United States of its molecular biology devices made using its BioF AB~ platform
infringes literally or under the doctrine of equivalents , one or more claims of the ' 211 patent
pursuant to 35 U.
17.

C. g 271(g).

Upon information and belief, Defendant Codon Devices ' infringement of the ' 211

patent has been knowing and willful.
18.
Defendant Codon Devices '

infringement of the ' 211 patent has caused

and

continues to cause febit to suffer substantial money damages.
19.
Defendant Codon Devices '

infringement of the ' 211 patent has caused

and

continues to cause febit to suffer irreparable harm for which there is no adequate remedy at law.

COUNT II
(Infringement ofthe ' 211 Patent Pursuant to 35 U.
20.
c. ~ 271(a))

The allegations of paragraphs 1- 19 above are repeated and re-alleged as if set

forth fully herein.
21.

Upon information and belief, Defendant Codon Devices ' offer for sale , sale or use
platform

within the United States of its molecular biology devices made using its BioFAB ~

infringes literally or under the doctrine of equivalents , one or more claims of the ' 211 patent
pursuant to 35 U.
C. g 271(a).

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22.

On information and belief, Defendant Codon Devices ' infringement of the ' 211

patent has been knowing and willful.
23.
Defendant Codon Devices '

infringement of the ' 211 patent has caused

and

continues to cause febit to suffer substantial money damages.
24.
Defendant Codon Devices '

infringement of the ' 211 patent has caused

and

continues to cause febit to suffer irreparable hann for which there is no adequate remedy at law.

PRAYER FOR RELIEF
WHEREFORE , febit prays for a judgment:
Entering judgment that Defendant Codon Devices has infringed the ' 211 patent;

Entering a preliminary and permanent injunction enjoining Codon Devices and
their affiliates ,
subsidiaries , officers, directors , employees, agents , representatives , licensees

successors , assigns and all those acting for them or on their behalf, or acting in concert or privity with them , from committing further infringement of the ' 211 patent;
Awarding febit compensatory damages under 35 U. C. g 284;

Awarding febit treble damages for Codon Devices ' willful infringement; Awarding costs and reasonable attorney s fees in favor offebit; and
Awarding febit any further relief that this Court may deem appropriate.

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JURY DEMAND
febit demands a jury trial as to all issues that are triable by a jury in this action.

FEBIT BIOTECH GMBH

Date: June 15 ,

2007

By:

P. Clarkson ollins , Jr. (#739) Mary B. Matterer ( 2696)
MORRIS JAMES L

500 Delaware A enue , Suite 1500 Wilmington , Delaware 19801 302. 888. 6800
mmatterer~morrisi am

es. com

Mark Fox Evens Edward J. Kessler W. Blake Coblentz
STERNE, KESSLER , GOLDSTEIN & Fox PLLC

1100 New York Avenue , NW Washington , D. C. 20005- 3934 (202) 371- 2600
Attorneys for Plaintiff

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EXHIBIT

(*

""""""""""""""'"

""""""""

:"

,"

Case 1:07-cv-00385-GMS-LPS
(12)

111111111111111111111111111111111111111111111111111111111111111111111111111 Document 12-2 Filed 10/01/2007 Page 9 of 114

USO0658621lBl

United States Patent
Stahler et al.

(10) Patent No.

(45) Date

of Patent:
5/1989 9/1999 1/1990 6/1994 6/1995 3/1999 3/2000

US 6, 586, 211 Bl
Jul. 1

2003

(54) METHOD FOR PRODUCING POLYMERS (75) Inventors: Peer F. Stahler, Mannheim (DE); Cord
F. Stahler, Weinheim (DE); Manfred Muller, Schriesheim (DE)

(73) Assignee: FeBit Ferrarius Biotechnology GmbH
(DE)
Notice:

0316018 0385410 WO 90 00626 WO 94 12632 WO 95 17413 WO 99 14318 WO 0013017

alliER PUBLICATIONS
Stemmer W. P. C. et aI.

Subject to any disclaimer, the term of this

patent is extended or adjusted under 35
C. 154(b) by 0 days.

(21) Appl. No. :

09/869 332
PCT/EPOO/01356
26 ,

(22) PCT

Filed: Feb. 18 , 2000
2001

Single-step assembly of a gene and entire plasmid from large numbers of oligodeoxyribonucleotides , Gene , vol. 164 pp. 49-53 (1995). S. Rayner et al. MerMade: An oligodeoxyribonucleotide synthesizer for high throughput oligonucleotide production in dual 96-well plates" PCR Methods and Applications , US
Cold Spring Harbor,

NY vol. 8 ,

No. 7 Jul. 1 , 1998 pp.

(86) PCT No.

~ 371 (c)(I),

L E Sindelar and J M Jaklevic: High-throughput DNA
synthesis in a multichannel format Nucleic Acids Research , Oxford University Press , Surrey, vol. 23 , No. , Jan. 1
1995 , pp. 982-987.

741-747.

(2), (4) Date: Aug.

(87) PCT Pub. No. : WOOO/49142

(30) Foreign Application Priority Data
Feb. 19

PCT Pub. Date: Aug. 24, 2000

Jun. 24,

, 1999 (DE) ......................................... 19957116 (51) Int. CI.7 ........................... CUP 19/34; C12Q 1/68;
(52) U. S. CI. ......................... 435/91.1; 435/6; 536/23.

Aug. Aug. 27 , Nov. 26

, 1999 (DE) ......................................... 19907080 1999 (DE) ......................................... 199 28843 27, 1999 (DE) ......................................... 199 40752
1999 (yVO)

Lasbkari D A et al.: " An Automated Multiplex Oligonucleotide Synthesizer: Development of High-Throughput , LowCost DNA Synthesis" Proceedings of the National Academy of Sciences of USA, US , National Academy of Science. Washington , vol. 92 , No. 17, Aug. 15 , 1995 pp. 7912-7915.

* cited by examiner
Primary Examiner-Kenneth

PCT/EP99/06316
R. Horlick

com 21/02; C07H 21/04; G06F 19/00

Assistant Examiner-Teresa Strzelecka (74) Attorney, Agent, or Firm-Rothwell Figg, Ernst &
Manbeck, PC
(57)

(58)
(56)

536/24. 3; 702/19; 702/20 Field of Search ................... 435/91.1 6; 536/23. 536/24. 3; 702/19 , 20
References Cited

ABSTRACT

The invention relates to a method for producing polymers

in particular synthetic nucleic acid double strands of
optional sequence , comprising the steps:

S. PATENT DOCUMENTS
510 270 A * 4/1996 Fodor et al. 436/518 020 481 A * 2/2000 Benson et al. ............. 536/26. 238 884 B1 * 5/2001 Short et al. ................ 435/69.

(a) provision of a support having a surface area which contains a plurality of individual reaction areas, (b) location-resolved synthesis of nucleic acid fragments
having in each case different base sequences in several and (c) detachment of the nucleic acid fragments from individual reaction areas.
of the individual reaction areas ,

FOREIGN PATENT DOCUMENTS
0022242 0130166
1/1981 1/1985

26 Claims, 7 Drawing Sheets

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US 6, 586 211
METHOD FOR PRODUCING POLYMERS
DESCRIPTION The invention relates to a method for producing polymers,

in particular synthetic nucleic acid double strands of
optional sequence.

1. Technical Background of the Invention clonally in suitable organisms (cloning) and , after this Manipulation and construction of genetic elements such , for example , gene fragments, whole genes or regulatory 10 time-consuming step and isolation by appropriate methods regions through the development of DNA recombination is again available for manipulations such as , for example recombinations. However, the restriction enzyme cleavage technology, which is often also referred to as genetic engineering, led to a particular need for genetic engineering sites are a limiting factor in this method: each enzyme methods and further development thereof in the areas of recognizes a specific sequence on the (double-stranded) gene therapy, molecular medicine (basic research, vector 15 DNA, which is between three and twelve nucleotide bases in length , depending on the particular enzyme , and therefore development , vaccines , regeneration, etc. ). Important areas of application are also the development of active substances according to statistical distribution, a particular number of production of active substances in the context of the develcleavage sites at which the DNA strand is cut is present on each DNA element. CUtting the treated DNA into defined opment of pharmaceuticals, combinatorial biosynthesis (antibodies , effectors such as growth factors , neural 20 fragments , which can subsequently be combined to give the transmitters , etc. ), biotechnology (e. g. enzyme design desired sequence , is important for recombination. Suffipharming, biological production methods , bioreactors , etc. ciently different and specific enzymes are available for diagnostics (BioChips, receptors/antibodies , enzyme design, recombination technology up to a limit of 10-30 kilo base pairs (kbp) of the DNA to be cut. In addition , preliminary etc.) and environmental technology (specialized or custom microorganisms , production processes , cleaning-up, 25 work and commercial suppliers provide corresponding vectors which take up the recombinant DNA and allow cloning sensors, etc. (and thus propagation and selection). Such vectors contain 2. Prior Art suitable cleavage sites for efficient recombination and inteNumerous methods, first and foremost enzyme- based gration. methods, allow specific manipulation of DNA for different purposes. With increasing length of the manipulated DNA however, the rules of statistics give rise to the problem of All of said methods have to use available genetic material. multiple and unwanted cleavage sites. The statistical averSaid material is , on the one hand , well- defined to a large age for an enzyme recognition sequence of 6 nucleotide extent but allows , on the other hand , in a kind of " construcbases is one cleavage site per 4000 base pairs (46) and for 8 tion kit system " only a limited amount of possible combinucleotide bases it is one cleavage site per 65 000 (4!). nations of the particular available and slightly modified Recombination using restriction enzymes therefore is not elements. particularly suitable for manipulating relatively large DNA In this connection , completely synthetic DNA has so far elements (e. g. viral genomes , chromosomes, etc. played only a minor part in the form of one of these combinatorial elements , with the aid of which specific 40 Recombination by homologous recombination in cells is known , too. Here , if identical sequence sections are present modifications of the available genetic material are possible. on the elements to be recombined , it is possible to newly The known methods share the large amount of work assemble and manipulate relatively large DNA elements by required , combined with a certain duration of appropriate way of the natural process of homologous recombination. operations , since the stages of molecular biological and in particular genetic experiments such as DNA isolation, 45 These recombination events are substantially more indirect than in the case of the restriction enzyme method and manipulation , transfer into suitable target cells , propagation moreover, more difficult to control. They often give disrenewed isolation , etc. usually have to be repeated several tinctly poorer yields than the above- described recombinatimes. Many of the operations which come up can only tion using restriction enzymes. insufficiently be automated and accelerated so that the corresponding work remains time-consuming and laborA second substantial disadvantage is restriction to the intensive. For the isolation of genes, which must precede identical sequence sections mentioned which , on the one functional study and characterization of the gene product hand , have to be present in the first place and , on the other the flow of information is in most cases from isolated RNA hand , are very specific for the particular system. The specific (mRNA) via cDNA and appropriate gene libraries via comintroduction of appropriate sequences itself then causes
plicated screening methods to a single clone. The desired 55

plasmids , amplicons, viral or bacterial genomes , vectors) are first cut into fragments with defined ends by appropriate restriction enzymes. Depending on the composition of these ends, it is possible to recombine the fragments formed and to link them to form larger DNA elements (likewise enzymatically). For DNA propagation purposes, this is frequently carried out ii:1 a plasmid acting as cloning vector. The recombinant DNA normally has to be propagated

considerable difficulties.

An additional well-known method is the polymerase incomplete, so that further screening processes follow. chain reaction (PCR) which allows enzymatic DNA syntheFinally, the above- described recombination of DNA fragsis (including high multiplication) due to the bordering ments has only limited flexibility and allows, together with regions of the section to be multiplied indicating a DNA the described amount of work required , only fewopportu- 60 replication start by means of short , completely synthetic nities for optimization. In view of the variety and complexity DNA oligomers (" primers ). For this purpose, however in genetics, functional genomics and proteomics , i.e. the these flanking regions must be known and be specific for the study of gene product actions, such optimizations in parregion lying in between. When replicating the strand ticular are a bottleneck for the further development of however, polymerases also incorporate wrong nucleotides, modern biology. 65 with a frequency depending on the particular enzyme , so that A common method is recombination by enzymatic meththere is always the danger of a certain distortion of the ods (in vitro): here, DNA elements (isolated genomic DNA, starting sequence. For some applications , this gradual dis-

DNA which has been cloned in said clone is frequently

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US 6 586 211
tortion can be very disturbing. During chemical synthesis sequences such as, for example, the above-described restriction cleavage sites can be incorporated into the primers. This allows (limited) manipulation of the complete sequence. The multiplied region can now be in the region of approx. 30 5 kbp, but most of this DNA molecule is the copy of a DNA already present.

is synthesized on a support by parallel synthesis steps , is detached from the support and is brought into contact with
one another to synthesize the polymer. Preference is given to
synthesizing double-stranded nucleic acid polymers of at

least 300 bp, in particular at least 1000 bp in length. The

mixtures) which are too large and not required for PCR, while the variety in variants remains limited. polymer intermediate under hybridization conditions. FurSynthetic DNA Elements Since the pioneering work of Khorana (inter alia in: lS ther examples of suitable polymers are nucleic acid analogs and proteins. Shabarova: Advanced organic Chemistry of Nucleic Acids, In a particularly preferred embodiment , the invention VCH Weinheim;) in the 19608, approaches in order to relates to a method for producing synthetic DNA of any assemble double-stranded DNA with genetic or coding optional sequence and thus any known or novel functional sequences from chemically synthesized DNA molecules have repeatedly been described. State of the art here is 20 genetic elements which are contained in said sequence. This method comprises the steps genetic elements of up to approx. 2 kbp in length which are (a) provision of a support having a surface area which synthesized from nucleic acids. Chemical solid phase syncontains a plurality of individual reaction areas thesis of nucleic acids and peptides has been automated. (b) location-resolved synthesis of nucleic acid fragments Appropriate methods and devices have been described , for having in each case different base sequences in several example , in U. S. Pat. Nos. 4 353 989 and 5 112 575. of the individual reaction areas , and Double-stranded DNA is synthesized from short oligonucleotides according to two methods (see Holowachuk et (c) detachment of the nucleic acid fragments from individual reaction areas. aI. , PCR Methods and Applications , Cold Spring Harbor Laboratory Press): on the one hand , the complete double The base sequences of the nucleic acid fragments synthestrand is synthesized by synthesizing single-stranded nucleic 30 sized in individual reaction areas are preferably chosen such acids (with suitable sequence), attaching complementary that they can assemble to form a nucleic acid double strand hybrid. The nucleic acid fragments can then be detached in regions by hybridization and linking the molecular backbone step (c) in one or more steps under conditions such that a by, for example , ligase. On the other hand , there is also the plurality, i.e. at least some of the detached nucleic acid possibility of synthesizing regions overlapping at the edges fragments assemble to form a nucleic acid double strand as single-stranded nucleic acids , attachment by hybrid. Subsequently, the nucleic acid fragments forming hybridization , filling in the single-stranded regions via one strand of the nucleic acid double strand hybrid can at enzymes (polymerases) and linking the backbone. least partially be linked covalently to one another. This may In both methods , the total length of the genetic element is restricted to only a few thousand nucleotide bases due to , on be carried out by enzymatic treatment , for example using the one hand , the expenditure and production costs of 40 ligase , or/and filling in gaps in the strands using. DNA nucleic acids in macroscopic column synthesis and , on the polymerase. The method comprises within the framework of a modular other hand , the logistics of nucleic acids being prepared separately in macroscopic column synthesis and then comsystem the synthesis of very many individual nucleic acid strands which serve as building blocks and , as a result , a bined. Thus, the same size range as in DNA recombination 45 double-stranded nucleic acid sequence which can be more technology is covered. than 100 000 base pairs in length is generated , for example To summarize , the prior art can be described as a procein a microfluidic reaction support. dure in which , in analogy to logical operations, the available matter (in this case genetic material in the form of nucleic The highly complex synthetic nucleic acid which preferably consists of DNA is produced according to the method acids) is studied and combined (recombination). The result of recombination experiments of this kind is then studied and according to the following principle: first, relatively and allows conclusions , inter alia about the elements short DNA strands are synthesized in a multiplicity of employed and their combined effect. The procedure may reaction areas on a reaction support by. in situ synthesis.
therefore be described as (selectively) analytical and com-

The primers are prepared using automated solid phase synthesis and are widely available , but the configuration of all automatic synthesizers known to date leads to the production of amounts of primer DNA (umol-range reaction

nucleic acid polymers are preferably selected from genes, gene clusters, chromosomes , viral and bacterial genomes or sections thereof. The oligomeric building blocks used for synthesizing the polymer are preferably 5-150, particularly 10 preferably 5- , monomer units in length. In successive steps , it is possible to detach in each case partially complementary oligonucleotide building blocks from the support and to bring them into contact with one another or with the

This may take place ,

for example , using the supports

described in the patent applications DE 199 24 327. , DE binatorial. The prior art thus does not allow any systematic studies of 55 19940749.5, PCT/EP99106316 and PCT/EP99/06317. In this connection, each reaction area is suitable for the indiany combinations whatsoever. The modification of the combined elements is almost impossible. Systematic testing of

modifications is impossible.

vidual and specific synthesis of an individual given DNA sequence of approx. 10-100 nucleotides in length. These

DNA strands form the building blocks for the specific SUBJECT OF THE INVENTION AND OBJECT 60 synthesis of very long DNA molecules. The fluidic microACHIEVED TI-lEREWITI-I processor used here may carry reaction spaces specially It is intended to provide a method for directly converting designed for the application. digital genetic information (target sequence , databases, etc. The DNA synthesis itself is thus carried out by following into biochemical genetic information (nucleic acids) without the automated solid phase synthesis but with some novel making use of nucleic acid fragments already present. 65 aspects: the " solid phase " in this case is an individual The invention therefore relates to a method for producing reaction area on the surface of the support, for example the polymers , in which a plurality of oligomeric building blocks wall of the reaction space , i. e. it is not particles introduced

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586 211
light-dependent location- or/and time-resolved in situ syn-

into the reaction space as is the case in a conventional
synthesizer. Integration of the synthesis in a microfluidic

reaction support (e. g. a structure with optionally branched channels and reaction spaces) makes it possible to introduce the reagents and other components such as enzymes.
After synthesis , the synthesized building blocks are

thesis of the DNA strands, which in turn can be used as building blocks for the synthesis of longer DNA strands. This flexible synthesis allows free programming of the
individual building block sequences and thus also generation of any variants of the part sequences or the final sequence

detached from said reaction areas. This detachment process without the need for substantial modifications of system may be carried out location- or/and time-specifically for components (hardware). This programmed synthesis of the individual , several or all DNA strands. building blocks and thus the final synthesis products makes In a preferred variant of the method it is provided for a 10 it possible to systematically process the variety of genetic plurality of reaction areas to be established and utilized elements. At the same time , the use of computer-controlled

within a fluidic space or compartment so that the DNA
strands synthesized therein can be detached in one operation step and taken away from the compartment which fluidically connects the reaction areas. Subsequently, suitable combinations of the detached DNA

programmable synthesis allows automation of the entire process including communication with appropriate data-

15 With a given target sequence, the sequence of the individual building blocks can be selected efficiently, taking into account biochemical and functional parameters. After putting in the target sequence (e. g. from a database), an algorithm makes out suitable overlapping regions. Depending on

bases.

strands are formed. Single-stranded or/and double-stranded

building blocks are then assembled , for example , within a reaction space which may comprise one or more reaction
individual building blocks is chosen such that, when bring-

areas for the synthesis. Expediently, the sequence of the 20 the task , different

amounts of target sequences

can be

ing the individual building blocks into contact with one
another, regions complementary to one another are available at the two ends brought together, in order to make possible specific attachment of further DNA strands by hybridizing said regions. As a result , longer DNA hybrids are formed. The phosphorus diester backbone of these DNA hybrids may be covalently closed , for example by ligases , and possible gaps in the double strand may be filled in in a known manner

produced , either within one reaction support or spread over a plurality of reaction supports. The hybridization conditions
for formation of the hybrids , such as , for example

temperature , salt concentrations , etc. , are adjusted to the available overlap regions by an appropriate algorithm. Thus maximum attachment specificity is ensured. In a fully automatic version, it is also possible to take target sequence data directly from public or private databases and convert them

into appropriate target sequences. The products generated
30

enzymatically by means of polymerases. Single-stranded regions which may be present may be filled in by enzymes
(e. g. Klenow fragment) with the addition of suitable nucle-

may in turn be introduced
target cells.

optionally into appropriately

automated processes , for example into cloning in suitable

otides. Thus longer DNA molecules are formed. By bringing

Synthesis in stages by synthesizing the individual DNA

strands in reaction areas within enclosed reaction spaces also within reaction spaces it is in turn possible to generate longer 35 allows the synthesis of difficult sequences , for example those part sequences of the final DNA molecule. This may be done with internal repeats of sequence sections , which occur, for in stages, and the part sequences are put together to give ever example , in retroviruses and corresponding retroviral veclonger DNA molecules. In this way it is possible to generate tors. The controlled detachment of building blocks within

together clusters of DNA strands synthesized in this way

very long DNA sequences as completely synthetic molecules of more than 100,000 base pairs in length.

The amount of individual building blocks which is assigning the overlapping regions on the individual building required for a long synthetic DNA molecule is dealt with in blocks. the reaction support by parallel synthesis of the building The high quality requirements necessary for synthesizing blocks in a location- or/and time-resolved synthesis process. very long DNA molecules can be met inter alia by using In the preferred embodiment , this parallel synthesis is car- 45 real- time quality control. This comprises monitoring the ried out by light-dependent location- or/and time-resolved location-resolved building block synthesis, likewise detachDNA synthesis in a fluidic microprocessor which is also ment and assembly up to production of the final sequence. described in the patent applications DE 199 24 327. , DE Then all processes take place , in a transparent reaction 19940 749.5 , PCT/EP99/06316 and PCT/EP99/06317. support. In addition , the possibility to follow reactions and The miniaturized reaction support here causes a reduction 50 fluidic processes in transmitted light mode , for example by in the amount of starting substances by at least a factor of CCD detection , is created. 1000 compared with a conventional DNA synthesizer. At the The miniaturized reaction support is preferably designed same time , an extremely high number of nucleic acid-double such that a detachment process is possible in the individual strands of defined sequence is produced. Only in this way is reaction spaces and thus the DNA strands synthesized on the it possible to generate a very large variety of individual 55 reaction areas located within these reaction spaces are building blocks , which is required for the synthesis of long detached individually or in clusters. In a suitable embodiDNA molecules , by using an economically sensible amount ment of the reaction support it is possible to assemble the of resources. The synthesis of a sequence of 100 000 base building blocks in reaction spaces in a process in stages and pairs , composed of overlapping building blocks of 20 nuclealso to remove building blocks , part sequences or the final otides in length , requires 10 000 individual building blocks. 60 product or else to sort or fractionate the molecules. This can be achieved using appropriately miniaturized The target sequence , after its completion , may be introequipment in a highly parallel synthesis process. duced as integrated genetic element into cells by transfer and For efficient processing of genetic molecules and systemthereby be cloned and studied in functional studies. Another atic inclusion of all possible variants it is necessary to possibility is to firstly further purify or analyze the synthesis produce the individual building block sequences in a flexible 65 product, a possible example of said analysis being sequencand economic way. This is achieved by the method prefering. The sequencing process may also be initiated by direct ably by using a programmable light source matrix for the coupling using an appropriate apparatus , for example using

the fluidic reaction spaces makes a synthesis of any 40 sequence possible , without problems being generated by

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a device described in the patent applications DE 199 24 327. , DE 199 40 749.5 , PCT/EP99/06316 and PCT/EP99/ 06317 (corresponding 35 U. c. ~371 application is U. patent application Ser. No. 09/763 914) for the integrated

It is possible to develop therewith extremely functionally integrated DNA molecules, unnecessary DNA regions being removed (minimal genes , minimal genomes).

synthesis and analysis of polymers It is likewise conceivable to isolate and analyze the generated target sequences after cloning. The method of the invention provides via the integrated genetic elements generated therewith a tool which , for the
further development of molecular biology, includes biologi-

The free combination of the genetic elements and also modifications of the sequence such as , for example , for adaptation to the expressing organism or cell type (codon
usage) are made possible as well as modifications of
the

cal variety in a systematic process. The generation of DNA molecules with desired genetic information is thus no longer the bottleneck of molecular biological work , since all molecules , from small plasmids via complex vectors to mini chromosomes , can be generated synthetically and are available for further work.

The production method allows generation of numerous different nucleic acids and thus a systematic approach for questions concerning regulatory elements , DNA binding sites for regulators , signal cascades , receptors , effect and interactions of growth factors , etc. The integration of genetic elements into a fully synthetic
complete nucleic acid makes it possible to further utilize

sequence for optimizing functional genetic parameters such , for example , gene regulation. 10 Modifications of the sequence for optimizing functional parameters of the transcript , for example splicing, regulation at the mRNA level, regulation at the translation level, and moreover, the optimization of functional parameters of the gene product, such as, for example , the amino acid sequence 15 (e. g. antibodies , growth factors , receptors, channels, pores transporters , etc.) are likewise made possible. On the whole , the system created by the method is extremely flexible and allows in a manner previously not available the programmed production of genetic material 20 under greatly reduced amounts of time, materials and work
needed.

Using the available methods, it has been almost imposknown genetic tools such as plasmids and vectors and thus sible to specifically manipulate relatively large DNA molto build on the relevant experience. On the other hand, this chromosomes for several hundred kbp, experience will change rapidly as a result of the intended 25 ecules of Even more complex (i. such as example. e. larger) viral genomes of optimization of available vectors , etc. The mechanisms more than 30 kbp (e. g. adenoviruses) are difficult to handle which, for example , make a plasmid suitable for propagation and to manipulate using the classical methods of gene in a particular cell type can be studied efficiently for the first technology.
time on the basis of the method of the invention.

appropriate DNA molthe DNA molecule into the final effector cells. For synthetiecules makes possible not only random composition of the 40 cally produced genes or gene fragments clonal propagation coding sequences and functional elements but also adaptain an intermediate host (usually E. coil) is no longer tion of the intermediate regions. This may rapidly lead to required. This avoids the danger of the gene product desminimal vectors and minimal genomes , whose small size in tined for the target cell exerting a toxic action on the turn generates advantages. As a result, transfer vehicles such intermediate host. This is distinctly different from the tox, for example , viral vectors can be made more efficient , for 45 icity of some gene products , which , when using classical example when using retroviral or adenoviral vectors. plasmid vectors, frequently leads to considerable problems In addition to the combination of known genetic for cloning of the appropriate nucleic acid fragments. sequences , it is possible to develop novel genetic elements Another considerable improvement is the reduction in which can build on the function of available elements. time and the reduction in operational steps to after the Especially for such developmental work, the flexibility of 50 . sequencing of genetic material , with potential genes found the system is of enormous value. being verified as such and cloned. Normally, after finding The synthetic DNA molecules are in each stage of the interesting patterns, which are possible open reading frames development of the method described here fully compatible (ORF), probes are used (e. g. by means ofPCR) to search in with the available recombination technology. For " tradicDNA libraries for appropriate clones which , however, need tional" molecular biological applications it is also possible to 'provide integrated genetic elements , for example by 55 not contain the whole sequence of the mRNA originally used in their production. In other methods, an expression gene appropriate vectors. Incorporation of appropriate cleavage library is searched by means of an antibody (screening). sites even of enzymes little used so far is not a limiting factor Both methods can be shortened very substantially using the for integrated genetic elements. method of the invention: if a gene sequence determined " IMPROVEMENTS IN COMPARISON WITH 60 silico " is present (i. e. after detection of an appropriate PRIOR ART pattern in a DNA sequence by the computer) or after This method makes it possible to integrate all desired decoding a protein Sequence , an appropriate vector with the functional elements as " genetic modules" such as , for sequence or variants thereof can be generated directly via example , genes, parts of genes, regulatory elements , viral programmed synthesis of an integrated genetic element and packaging signals, etc. into the synthesized nucleic acid 65 introduced into suitable target cells. molecule as carrier of genetic information. This integration The synthesis taking place in this way of DNA molecules leads to inter alia the following advantages: of up to several 100 kbp allows the direct complete synthesis

shortening up to the last stage of cloning a gene: the gene or possible to detect the entire combination space of genetic the genes are synthesized as DNA molecule and then (after elements. Thus , in addition to the at the moment rapidly suitable preparation such as purification , etc.) introduced developing higWy parallel analysis (inter alia on DNA arrays directly into target cells and the result is studied. The or DNA chips), the programmed synthesis of integrated genetic elements is created as a second important element. 35 multi-stage cloning process which is mostly carried out in microorganisms such as E. coli (e. g. DNA isolation, Only both elements together can form the foundation of an purification , analysis , recombination , cloning in bacteria, efficient molecular biology. isolation , analysis, etc. ) is thus reduced to the last transfer of The programmed synthesis of

This efficient study of large numbers of variants makes it 30

The method of the invention

leads to a considerable

).
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US 6 586 211 Bl
of viral genomes , for example adenoviruses. These are an important tool in basic research (inter alia gene therapy) but
due to the size of their genome (approx. 40 kbp), are difficult to handle using classical genetic engineering methods. As a

reaction areas and, secondly, the synthesis by programmable light- dependent individualization of the reaction areas. In both variants, synthesis is carried out in a microfluidic

gene can be synthesized and made available.

reaction support. The design of this reaction support may provide in the system for the bringing together in stages the detached synthesis products, i.e. building blocks, by collectoptimization in particular is greatly limited. This limitation ing the nucleic acid strands , after detaching them , in approis removed by the method of the invention. priate reaction areas and the assembly taking place there. The method leads to integration of the synthesis , detachGroups of such assembly areas may then for their part be ment of synthesis products and assembly to a DNA molecule being carried out in one system. Using production methods 10 brought into contact again with one another so . that during the course of a more or less long cascade the final synthesis of microsystem technology, it is possible to integrate all products are produced: genetic information carriers in the necessary functions and process steps up to the purification form of DNA molecules. The following variants are suitable of the final product in a miniaturized reaction support. These here: Either synthesis, detachment and assembly are carried may be synthesis areas, detachment areas (clusters), reaction out chronologically but spatially integrated in a microfluidic spaces , feeding channels , valves, pumps, concentrators, 15 reaction support or synthesis , detachment and assembly are fractionation areas , etc. carried out partially in parallel in one or more microfluidic reaction supports. It is furthermore possible that the microfPlasmids and expression vectors may be prepared directly luidic reaction support contains only reaction areas for the for sequenced proteins or corresponding part sequences and programmed synthesis and that subsequently detachment the products may be analyzed biochemically and functionally, for example by using suitable regulatory ele- 20 and elution into a reaction vessel for the assembly are carried out. ments. This omits the search for clones in a gene library. In the case of very large DNA molecules, synthesis Correspondingly, ORFs from sequencing work (e. g. Human detachment and assembly can be supplemented by condenGenome Project) can be programmed directly into approsation strategies which prevent break-up of the molecules. priate vectors and be combined with desired genetic eleThis includes , for example , the use of histones (nuclear ments. An identification of clones , for example by compliproteins which make condensation of the chromosomes in cated screening of cDNA libraries , is removed. Thus, the the nucleus possible in eukaryotes), the use of topoiflow of information from sequence analysis to function some rases (enzymes for twisting DNA in eukaryotes and analysis has been greatly reduced , because on the same day prokaryotes) or the addition of other DNA-binding, stabion which an ORF is present in the computer due to analysis lizing and condensing agents or proteins. Depending on the of primary data , an appropriate vector including the putative 30 design of the reaction support , this may take place by

result, the rapid and economic generation

of variants for 5

integrating the condensation reaction in another reaction

Compared with conventional solid-phase synthesis for obtaining synthetic DNA, the method according to the
invention is distinguished by a small amount of material needed. In order to produce thousands of different building blocks for generating a complex integrated genetic element of several 100 000 kbp in length, in an appropriately paral-

chamber provided therefor or by addition during the combination and assembly in stages of the building blocks. The free choice of sequence is of essential importance for

lelized format and with appropriate miniaturization (see exemplary embodiments), a microfluidic system needs
markedly fewer starting substances for an individual DNA oligomer than a conventional solid-phase synthesis apparatus (when using a single column). Here , microliters compare with the consumption of milliliters , i.e. a factor of 1000.
Taking into account the newest findings in immunology, the presented method allows an extremely efficient and rapid vaccine design (DNA vaccines).

the controlled and efficient building block assembly in stages to the final product. For the choice of overlapping complementary ends influences the specificity of the assem40 concentration, temperature , etc.

(salt When providing a sequence for the gene of interest and after automatic or
overall biochemical conditions

bly and the

manual selection of the other genetic elements (regulatory

EXEMPLARY EMBODIMENTS
To carry out the method, the present invention requires the
provision of a large

number of nucleic acid molecules usually DNA, whose sequence can be freely determined.

These building blocks must have virtually 100% identical sequences within one building block species (analogously to

regions , resistance genes for cloning, propagation signals etc. ) for determination of the final product (e. g. a plasmid 45 vector), the provided sequence is fragmented into suitable building blocks which are then synthesized in the required number of reaction supports. The fragments or their overlap regions to be hybridized are chosen such that the conditions for hybridizing are as similar as possible (inter alia GC : AT 50 ratio , melting points , etc. Further extension of the system provides for elements for purification and isolation of the product forming, which are likewise designed by microfluidics or microsystem technology. Said elements may be , for example , methods in which
55

the synthesis performance of conventional synthesizers). Only higWy parallel synthesis methods are suitable for
generating the required variance. In order for the system to be able to work flexibly and , despite the necessary multiplicity of different building blocks to be synthesized , to

the final double-stranded DNA after its synthesis

using

fluorescent synthons must have a particular total fluores-

cence. When using proteins with condensing action , these proteins , where appropriate , may also carry a fluorescent

label which is preferably detectable separately (reference require as little space and as few reagents as possible , the 60 signal). It is then possible to sort the mixture of final reaction method is preferably carried out in a microfluidic system product in the reaction support structures according to within which the individual sequences are produced in a fluorescence (see Chou et al. , Proceedings of the National determinable form. Two types of programmed synthesis are Academy of Science PNAS 96:11-13, 1999). Thus a suffisuitable for systems of this kind , which are also described in cient quality is achieved in order to directly provide a the patent applications DE 199 24327. 1, DE 199 40 749.5 65 product for further work. PCT/EP99/06316 and PCT/EP99/06317: these are first the Information from sequencing projects, which is present in synthesis by programmable fluidic individualization of the databases, may be studied for genes fully automatically

. .

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(computer-assisted). Identified or putative genes (ORFs) are
converted into completely
an ass.embled do~ble-stranded nucleic acid hybrid 62

~y~e 63 (e. g. ligases) for the covalent linkage of the contain , where appropriate , regulatory and other genetic bmldmg blocks of the nucleic acid hybrid 85 , a linear covalently linked nucleic acid double strand 65 and a elements which seem suitable , so that, for example , one or more vectors are generated. The product is either made 5 circular closed nucleic acid double strand 66 (e. g. vector). The reference number 64 represents a reaction of the available (e. g. as pure DNA) or directly introduced to enzymes with the nucleic acid hybrid. functional studies , inter alia by transfer into suitable target What is claimed is: cells. The information may come from public databases, 1. Method for synthesizing polymers , wherein said from work of decentralized users or from other sources , for example the method described in the patent applications DE 10 m ~th~d comprises synthesizing a plurality of oligomeric bmldmg blocks by parallel synthesis steps , wherein each 199 24 327. 1 and DE 199 40 749.5. oligomeric building block is synthesized on a different area It may be of interest that a variance of randomized of a common support, detaching the plurality of oligomeric sequence occurs at a particular site or sites of the target
synthetic DNA which may
~q~ence. example is the testing of variants of a binding sIte mto whIch , for example over an area of 20 amino acids
e. 60 nucleotides , random variations of nucleotides wer incorporated. This may take place in an embodiment in that du~g the synthesis process , after activating a reaction area

building blocks from the support and bringing the oligo-

a mIXture of synthons is added so that all added synthons can

hybridize in a statistically distributed manner. A modification of this process may provide for DNA building blocks of different length to be used at a particular position of the target sequence , for example by producing different building

blocks on different reaction areas, which show the same sequence for overlapping and hybridization.
BRIEF DESCRIPTION OF TIlE DRAWINGS
~G. ~ shows

synthesize the polymer, and wherein said different areas of said common support are at least partially in fluid communication during synthesis. 2. Method according to claim 1 , wherein double-stranded 20 nucleic acid polymers of at least 300 bp in length are synthesized. 3. A method according to claim 1 , wherein the polymers are nucleic acid polymers which are selected from the group consisting of genes or sections thereof, gene clusters or 25 sections thereof, chromosomes or sections thereof, and viral
and bacterial genomes or sections thereof. 4. Method according to claim 1 , wherein the oligomeric

15 meric building blocks into contact with one another to

a vertical section of a reaction support 30

whIch IS

orthogonal to the microchannels 33 present

building blocks are from 5 to 150 monomer units in length. 5. Method according to claim 1 , wherein partially com30 plimentary oligonucleotide building blocks are detached

thereon , which are separated from one another by walls 32.
The bottom 31 of the reaction support is transparent.

from the support and are brought into contact with one

Furthermore , a single-stranded nucleic acid 10 with the designation of the 5' and 3' ends according to convention is depicted diagrammatically. These are depicted as lOa with the . 3' end covalently bound to the reaction support 30 by solId-phase synthesis. A light source matrix 20 with a light source and a controllable illumination exit facing the reaction support 30 is likewise depicted.

another or with a polymer intermediate under hybridization conditions in successive steps. 6. Method according to claim 1 for producing synthetic nucleic acid double strands, wherein said method comprises
the steps:

(a) providing a support having a surface area which

AG. 2 shows a top view of reaction support 30 with
reaction areas 12 and the walls 32 between the microchannels 33. The arrows indicate the direction of flow. AG. 3 shows , similar to AG. , a vertical section through the reaction support 30 , with the single-stranded nucleic

contains a plurality of individual reaction areas (b) synthesizing nucleic acid fragments in a locationresolved manner, wherein said nucleic acid fragments

comprise different base sequences ,

as compared to

other nucleic acid fragments, in several of the individual reaction areas , and (c) detaching the nucleic acid fragments from the indi45

acids in the microchannel 33 being detached. , AG. 4 again depicts a top view of the reaction support 30 with the single-stranded nucleic acids in the microchannel
33 being detached.

vidual reaction areas.
7. Method according to claim 6 , wherein the base
sequences of the nucleic acid fragments synthesized

AG. 5 shows a top view of the arrangement

individual reaction areas are chosen such that they can
of micro-

channels with fluidic reaction spaces 50 , which contain the m IVI u reactIOn areas, and reaction chambers , where a

part sequence is assembled. In the reaction space 54 all
microchannels within a reaction support are brought

assemble to form a nucleic acid double strand hybrid. 8. Method according to claim 6 wherein the nucleic acid fragments according to step (c) are detached in one or more steps under conditions such that a plurality of the detached
nucleic acid fragments assemble to form a nucleic acid

together. The final synthesis product is assembled there , too, and is removed through exit 55. The reference numbers 51a

double strand hybrid.

indicate the representations of a reaction chamber which are shown in enlarged form in FIG. 6 and FIG. 7 and
and 51b

9. Method according to claim 8 , wherein several nucleic acid fragments which form one strand of the nucleic acid
double strand hybrid are linked covalently to one another.

FIG. 8. The arrows again signal the direction of flow.

AG. 6 shows an enlarged
chamber 51a

representation of a reaction

after a microchannel with detached single-

stranded nucleic acids.

AG. 7 shows an enlarged representation of a reaction
chamber 51a after a microchannel with a double-stranded hybrid 60 composed of two attached complementary nucleic

acid single strands. AG. 8 shows an
chamber 51b

enlarged representation of a reaction

10. Method according to claim 9 , wherein the covalent linking includes treatment with ligase or/and filling in gaps 60 in the strands using DNA polymerase. 11. Method according to claim 6 , wherein the sequence comprises at one or more position recognition sequences for specific interaction with other molecules. 12. Method according to claim 6 , wherein the sequence of the nucleic acid double strands is a naturally occurring sequence , a not naturally occurring sequence or a combination of these two.

after bringing together two microchannels with

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13. Method according to claim 6 , wherein the sequence is taken from a database , a sequencing experiment or a device for the integrated synthesis and analysis of polymers. 14. Method according to claim 1, wherein the oligomeric

22. Method according to claim 1 , wherein partially complimentary oligonucleotide building blocks are detached

from the support and are brought into contact with (1) one another or with second partially complimentary oligonuclebuilding blocks are synthesized by location- or/and time- 5 otide building blocks to form a polymer intermediate or (2) with a polymer intermediate under hybridization conditions resolved illumination by means of a programmable light to form an advanced polymer intermediate , and thereafter source matrix. third partially complimentary oligonucleotide building 15. Method according to claim 1 , wherein the synthesizblocks are detached and brought into contact with (1) fourth ing step is a location- or/and time-resolved synthesis of the oligomeric building blocks in a microfluidic reaction support 10 partially complimentary oligonucleotide building blocks or with third partially complimentary oligonucleotide building having one or more fluidic reaction compartments and one blocks to form a polymer intermediate or (2) with a polymer or more reaction areas within a fluidic reaction compartintermediate under hybridization conditions, to form an ment. advanced polymer intermediate , and these steps are 16. Method according to claim 1, wherein the oligomeric repeated. building blocks contain nucleotides occurring in nature 23. Method according to claim 11 , wherein the other modified nucleotides or mixtures thereof. molecules are selected from the group consisting of proteins 17. Method according to claim 1, wherein said oligomeric nucleic acids , pep tides, pharmaceuticals , saccharides , lipids building blocks contain synthesis building blocks carrying hormones , and organic compounds. labeling groups for subsequent detection of the polymer. 24. Method according to claim 20 , wherein the other 18. Method according to claim 17 , wherein the labeling functional molecules are selected from the group consisting groups are detectable in a light- dependent manner. of histones or topoisomerases. 19. The method of claim 1, wherein said method further 25. Method for synthesizing polymers that are greater comprises stabilizing, condensing and/or topologically than 10 000 bp in length , wherein said method comprises manipulating a nucleic acid double strand or nucleic acid synthesizing a plurality of oligomeric building blocks by double strand precursor during or following the assembly of 25 parallel synthesis steps , wherein each oligomeric building the nucleic acid double strand. block is synthesized on a different area of a common 20. A method according to claim 19 , where the support , detaching the plurality of oligomeric building stabilization , condensation or/and topological manipulation blocks from the support and bringing the oligomeric buildis carried out by functional molecules selected from the ing blocks into contact with one another to synthesize the group consisting of histones , topoisomerases, DNA-binding 30 polymer, and wherein said different areas of said common agents, DNA-binding proteins , DNA-stabilizing agents support are at least partially in fluid communication during DNA-stabilizing proteins , DNA-condensing agents and synthesis. DNA-condensing proteins. 26. Method according to claim 1 , wherein the oligomeric 21. Method according to claim 1 , wherein doublebuilding blocks are from 5 to 30 monomer units in length. stranded nucleic acid polymers of at least 1000 bp in length 35

15

are synthesized.

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EXHIBIT

Case 1:07-cv-00385-GMS-LPS
~ AD 120 (Rev. 3/04)
Mail Stop 8

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TO:

REPORT ON THE

Director of the U. S. Patent and Trademark Office O. Box 1450 Alexandria , VA 22313- 1450

FILING OR DETERMINATION OF AN ACTION REGARDING A PATENT OR TRADEMARK
on the following

In Compliance with 35 V. C. ~ 290 and/or 15 V. C. ~ 1116 you are hereby advised that a court action has been
filed in the V. S.
DOCKET NO. 07- 385 PLAINTIFF
District Court

Delaware

Patents or

Trademarks:

DATE FILED 6/15/07

S. DISTRICT COURT

DISTRICT OF DELAWARE
DEFENDANT

febit biotech GmbH

Codon Devices Inc.

PATENTOR
586 211 Bl

DATE OF PATENT
7/1/2003

HOLDER OF PATENT OR TRADEMARK FeBit Ferrarius Biotechnology GmbH

In the above----entitled case , the following patent(s)/ trademark(s) have been included:

DATE INCLUDED

INCLUDED BY
0 Amendment
0 Answer

Cross Bill

Other Pleading

PATENTOR
TRADEMARK NO.

DATE OF PATENT OR TRADEMARK

HOLDER OF PATENT OR TRADEMARK

In the above----entitled case , the following decision has been rendered or judgement issued:

DECISION/JUDGEMENT

CLERK

(BY) DEPUTY CLERK

DATE
6/15/07

PETER T. DALLEO , CLERK OF COURT

Copy I-Upon initiation of action , mail this copy to Director Copy 3-Upon termination of action, mail this copy to Copy 2-Upon filing document adding patent(s), mail this copy to Director Copy 4-Case file copy

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EXHIBIT

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'Rip FinstlSVIWGM/US 07/24/200712:36 PM

To mevens~skgf. eom
ee jblumenfeld~mnat.eom , mmatterer~morrisjames. eom

edward. reines~weil. eom
bee

Subject febit v. Codon

Dear Mark -

Thanks for returning my call and for agreeing to a 30- day extension for Codon to respond to febit biotech' complaint. Per our discussion , I'll ask our local counsel Jack Blumenfeld (cc d on this email) to work with
your local counsel (who I understand is Mary Matterer) to prepare and file a stipulation extending the deadline for Codon to answer or otherwise respond to the complaint from July 30 to August 30.
We look forward to receiving your letter regarding ownership of the patent- in-suit this Friday, July 27.

Best regards
Rip Finst Weil , Gotshal & Manges LLP Silicon Valley Office 201 Redwood Shores Parkway Redwood Shores , CA 94065 650-802- 3220 office 650- 802- 3100 fax
c:::

END::-

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EXHIBIT

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - :;.

-----

- - --

------

, "

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Mark F. Evens
c::MEVENS(Qjskgf. com==-

To -Rip. Finst(QjweiLeom
ee jblumenfeld(Qjmnateom , mmatterer(Qjmorrisjames. eom

ViII
Rip,

07/27/200701 :43 PM

edward. reines(Qjweil. eom
bee
c::EKESSLER(Qjskgf. eom=-

Ed

Kessler Blake Coblentz"

Subject RE:

febit v. Codon

I did not receive the translation. I should get it Monday and will then forward it to you for review.
Mark Fox Evens

Director

Sterne, Kessler , Goldstein & Fox PLLC 1100 New York Ave., NW Washington, DC 20005

202- 772- ~888 (direct) 202- 371- 2540 (fax) 202- 371- 2600 (reception)
Original Message-

From: Rip. Finst~weil. com (mailto: Rip. Finst~weil.
edward. reines~weil. com

com)

Sent: Tuesday, July 24, 2007 3:37 PM To: Mark F. Evens Cc: jblumenfeld~mnat. com; mmatterer~morrisjames. com;
Subject: febit v. Codon

Dear Mark Thanks for returning my call and for agreeing to a 30- day extension for Codon to respond to febit biotech I s our discussion, I'll ask our local counsel Jack Bl