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`FAX +49 89 2399-4485
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`Europalsches
`Patentamt
`
`European
`Patent Office
`
`Office européen
`den brevets
`
`chambras da racours
`eal
`Boards o1
`Beschwerdekammern
`
`COPY
`
`7
`
`VOSSIUS & PARTNER
`Postfach 86 07 67
`81634 Miinchen
`ALLEMAGNE
`
`0525821
`
`Anmeldung NrJApp|ioation Nolbemande n"JPetent Nr [Patent NolBrevet n°.
`92114727.8
`'
`
`o}_ou,oo 9' 07 .o(, .oo against the decision ofthe Examining
`The appea| filed with your letter of
`Division of the European Patent Office of
`23_ o1_oo
`has been referred to the
`Technical Board of Appea|33(.
`
`The reference number ofthe appea| file is T0749/oo-334
`
`You are asked to quote that reference in any further communication submitted on this appeal and to
`
`address such communication to Directorate General 3 (Appeals) of the European Patent Office in
`Munich.
`
`Registry
`
`Tel .(089)2399-
`
`page 1 0111
`
`BD Exhibit 1012
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`Page 1 of 11
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`BD Exhibit 1012
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`
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`VOSSIUS & PARTN
`Patentanwalte
`
`éiit 5'
`
`'5..= =::-
`
`..
`
`..
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`I. Vosslus&Parlner FOB 360767 81634 Mtlnchen Germany 1
`
`To the
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`European Patent Office
`
`Munich
`
`EP 92 11 4727.§X241N1s
`
`0.
`ENZO BIOCHE ,
`Our Ref.: S 808 EP/I
`
`PATENTANWALTE
`EUROPEAN PATENT ATTORNEYS
`EUROPEAN TRADEMARK ATTORNEYS
`Dr. VOLKER VOSSIUS, Dipl.-Chem.
`(bis 1992; danach in anderer Kanzlei)
`
`Dr. DIETER HEUNEMANN. Dlpl.-Phys.
`Dr. PAUL TAUCHNEFK. Dipl.-Chem.
`Dr. PETER A. RAUH, Dipl.—Ct1em.
`
`Dr. GERHARD HERMANN, Dipl.-Phys.
`JOSEF SCHMIDT, Dipl.-Ing.
`
`Dr. ALEXA VON UEXKULL. M.Sc.
`Dr. HANS-RAINER JAENICHEN. Dipl.-Biol.
`Dr. RUDOLF WEINBERGER, Dipl.-Chem.
`Dr. WOLFGANG BUBLAK, Dipl.-Chem.
`AXEL STELLBRINK, Dipl.-Ing.
`,
`DI’—.r JOACHIM/WACHENFELD. (Biol_)
`Dr. FRIEDEFIIKE STOLZENBURG. Dipl.-Biol.
`RAINIER VIKTOFI. Dipl.-lng.
`EUROPEAN PATENT ATTORNEYS
`Dr. RENATE BAFITH. Dip|.—Chem.
`Dr. URSULA ENGLBRECHT. Dipl.-Chem.
`RECHTSANWALTE
`HELGA TREMMEL
`BARBARA GUGGENMOS, Dipl.-Chem.
`DR. THURE SCHUBERT
`
`SIEBERTSTRASSE 4
`81675 MUNCHEN
`GERMANY
`TEL.: +49-89-41 30 40
`FAX: +49—89-41 3041 11 (G3/G4)
`+49-B9-41 30 44 00 (G 3)
`(Marken - Trademarks)
`E—MAlL:
`info@\/ossiusandpartnencom
`HOMEPAGE: www.vossiusandpartner.com
`
`June 7, 2000
`Ba/ne
`
`In the following the Grounds of the Appeal dated April 7, 2000, are set out:
`
`In their Decision dated January 28, 2000,
`
`the Examining Division stated that the
`
`Auxiliary Request did not meet the requirements of the EPC due to lack of inventive
`
`step.
`
`Applicant disagrees for the following reasons:
`
`1.
`
`KNOWLEDGE OF THE PERSON SKILLED IN THE ART AT THE PRIORITY
`
`DATE
`
`The present invention has been filed some time ago, i.e. its priority date is in the
`year 1983. It concerns a field wherein the knowledge has increased immensely
`in the meantime.
`In such a case it
`is especially important
`to differentiate
`
`Page 2 of11
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`HYPOVEREINSBANK NH. 32920 868, BLZ 700 202 70
`- DEUTSCHE BANK A.G. MUNCHEN. NFL65/57342. BLZ 700 700
`POSTBANK MUNCHEN, NFL 129600-809. BLZ 70010080, V.A.T. NO. DE 130 751 524
`PARTNERSCHAFTSREG. AMTSGERICHT MUNCHEN PR 89
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`
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`Page 2 of 11
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`
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`between what was really known at that time and what may be interpreted into
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`the teaching of the prior art by hindsight on the basis of the present knowledge.
`
`CASE LAW
`
`When asserting inventive step certain standards have to be appliedzbased on
`
`decisions of the Technical Boards of Appeal. According to T2/83 ("Simethicone
`
`Tablet/RIDER") the question is not whether the skilled ggfl have done
`
`something,
`
`i.e. could have applied a known teaching, but whether he _vi_/gulg
`
`have applied the teaching in expectation of some improvement or advantage. It
`
`is further stated that a patentable subject matter may exist in spite of the fact
`
`that the claimed solution is retrospectively trivial and in itself obvious. A similar
`
`statement is made in T60/89 ("Fusion Proteins/HARVARD") where the key
`
`question raised is whether it was obvious for a skilled person to try the idea
`
`outlined with a reasonable expectation of success.
`
`PROBLEM AND SOLUTION OF THE PRESENT INVENTION
`
`3.1
`
`If one takes document D1 as the closest prior art, the problem to be solved is
`
`the provision of a method for detecting a polynucleotide sequence which allows
`
`the quantitative determination (page 21, lines 18 to 21) and which consequently
`
`permits easy automation and instrumentation
`
`of the detection of a signal
`
`associated with the presence and/or quantity of the target polynucleotide
`
`sequence.
`
`The solution provided by the invention is a method for detecting a
`
`polynucleotide sequence by performing the steps as described whereby a
`
`quantifiable signal
`
`is generated upon hybridization of
`
`the probe with the
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`Page 3 of11
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`June 7, 2000
`S 808 EP/I
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`Page 3 of 11
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`VOSSIUS 8. PARTNER
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`I
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`0
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`0
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`sequence. The signal provides means to quantify the target polynucleotide by
`
`the techniques indicated in claim 1, especially photometric techniques.
`
`Specific embodiments are contained in the dependent claims.
`
`The further independent claims are based on the same principle.
`
`3.2
`
`The method claimed is not made obvious by the prior document D1 because
`
`the combination of fixing a polynucleotide sequence, which is non—radioactively
`
`labelled, to a substrate with a quantifiable detection system, e.g. an ELISA, is
`
`not suggested.
`
`3.2.1
`
`At the priority date of the present application quantitative detection methods
`
`using quantifiable signals, such as enzyme—linked immunosorbent assays
`
`(ELISA) were well known and had been around for years. But these detection
`
`methods involved a labelling of an antibody, enzyme or other protein and were
`
`typically only used for the detection of antigens and/or antibodies.
`
`3.2.2
`
`V\fith respect
`
`to the field of nucleic acid detection, quantitative detection
`
`techniques involving signals such as ELISA were n_ot available in the early
`
`1980s. Nucleic acids were detected primarily by means of Southern and
`
`Northern blotting and other in situ hybridization (see e.g. the disclosure in D1) or
`
`immunoprecipitation techniques, The present patent application taught
`
`the
`
`industry for the first time how to use quantitative detection techniques typically
`
`used in the antigen/antibody detection field for nucleic acid detection. The
`
`characteristics of nucleic acids would have discouraged and even would have
`
`predicted away from the application of colorimetic assays for the detection of
`
`nucleic acids in the claimed method.
`
`In ELISA detection based systems for
`
`antigen/antibody one merely had to deal with Iigand—receptor specificity and the
`
`non-specific binding of the protein to the support. On the other hand,
`
`if
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`Page 4 of11
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`S 808 EP/I
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`June 7, 2000
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`Page 4 of 11
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`VOSSlUS&PARTNER
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`:‘.':
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`-' -1 3,".
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`.2
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`colorimetic determination of nucleic acids were to be used, several problems
`
`may occur, i.e.
`
`it would require a higher capacity of the matrix for the nucleic acid which is a
`
`linear molecule (ligands and proteins are three-dimensional);
`
`it would require immo_bi_lizatio_n in_a_si_ng|e-stranded form, thus necessitating
`
`nucleic acid melting and re—hybridization; and
`
`besides the desired specific binding,
`
`there can be more non-specific
`
`interactions, e.g. between protein and nucleic acid, protein and matrix,
`
`nucleic acid and matrix and ligand and nucleic acid.
`
`At the time the present invention was made, one could not have conceived that
`
`these interactions could be effectively dealt with and that the claimed method
`
`would provide the desired result.
`
`3.2.3 Vtfith regard to the feature "quantifiable",
`
`it was argued by the Examining
`
`Division that according to D1 the probe can be enzymatically or fluorescently
`
`labelled whereby both kinds of labels give rise to a quantifiable signal and that
`
`the signal is quantifiable, independent of whether it is actually quantified or not.
`
`Although this may be theoretically the case, it is a fact that in D1 the signal h_as
`
`not been used for Quantification.
`
`The focus of D1
`
`is on insoluble coloured precipitates and direct
`
`light
`
`microscopic visualization which elements are opposed to and actually teach
`
`away from the present invention and the notion of a guantifiable signal.
`
`D1 is limited to in situ hybridization which can only be practised in the context of
`
`well-defined morphology against which a localized signal must be produced
`
`and interpreted. When performing in situ hybridization,
`
`the technician or
`
`researcher is looking under the microscope and observing form or morphology
`
`as well as signalling events within the context of any such form or morphology.
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`Page 5 of11
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`June 7, 2000
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`3'33 3
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`3
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`-'
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`E E3". '
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`.
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`Such a person only observes and amasses information within the context of
`
`clearly defined boundaries and visible shapes. The cells or the contents of cells
`
`under examination must have such boundaries and shapes in order to carry out
`
`the detection in in situ hybridization. Separation and analytical techniques are
`
`largely based on precipitates and defined boundaries.
`
`—With soluble signals, however, the. approach is entirely antithetical to the T
`
`Z
`
`T
`
`purposes of and the information being sought with through light microscopic
`
`examination. With a quantifiable soluble signal there are no clearly defined
`
`boundaries, shapes and morphology with which a technician or researcher
`
`must contend. In fact, the quantifiable signal, which is a material element in the
`
`claims of the present application, is in no way localized nor is morphology either
`
`required, maintained or viewed. Rather, with the generation of a quantifiable
`
`signal, a dispersed or scattered signal in solution is obtained without any regard‘
`
`to any limitation or requirement for morphologic integrity.
`
`Vlfith in situ hybridization, in order that the morphological integrity is maintained,
`
`the samples, i.e. tissue sections or cultured cells, have to be treated in a certain
`
`way, e.g. by a fixation with formaldehyde or glutardehyde or by treatment with a
`
`protease.
`
`3.2.4 Thus, the problem to be solved in D1 is completely different from that in the
`
`present invention where the DNA sequence has on the one hand to bind to the
`
`support but on the other hand has still to be able to hybridize with the probe to
`
`allow the quantitative determination.
`
`In fact, the method is concerned with the
`
`total amount of the target nucleic acid analyte in the sample or specimen - and
`
`not with its location or distribution in the cells or tissues.
`
`The focus of D1
`
`is on insoluble coloured precipitates and direct
`
`light
`
`microscopic visualization which elements are diametrically opposed to and
`
`actually teach away from the present invention'and the notion of a quantifiable
`
`signal.
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`Page 6 of11
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`June 7, 2000
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`Page 6 of 11
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`4.
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`CONCLUSION
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`In view of the different problems to be solved in D1 and in the present invention,
`
`there is no suggestion in D1 for the solution provided in the present application.
`
`It was not foreseeable that the DNA sequence would bind sufficiently to the
`
`support to make the quantitative test possible.
`
`The fact that in D1 only a precipitate is used as a signal which cannot provide
`
`an exact quantitative measurement, can only mean that it was not clear at that
`
`time that a quantifying signal can be generated for the desired purpose. Only in
`
`the present
`
`invention it was recognized that
`
`the signal can be used for
`
`quantitative measurement and it has been used therefor for the first time in the
`
`present invention.
`
`Therefore, the present invention involves an inventive step.
`
`COMMERCIAL DEVELOPMENT
`
`In addition to the technical and scientific reasons why the present invention is
`
`patentable and represents an inventive step over D1, Applicant respectfully
`
`points out that two decades of ongoing commercial development described in
`
`the following is also clear testament to the inventive step of the present
`
`invention.
`
`Since 1981 Applicant has been the exclusive licensee of the technology
`
`covered by the cited document D1 [EP-A-0 063 879]. See the accompanying
`
`Exhibit 1 consisting of the Applicant's December 15, 1987 news release
`
`announcing the issuance of U.S. Patent No. 4,711,955 (top copy of patent also
`
`included). D1 and U.S. 4,711,955 share the same priority document, U.S.
`
`S 808 EP/I
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`June 7, 2000
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`Page 7 of11
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`Page 7 of 11
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`VOSSIUS & PARTNER
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`
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`Application Serial No. 255,223, filed on April 17, 1981. See also Applicant's
`March 19, 1990 news release provided in Exhibit 2 also announcing that "Enzo
`
`has exclusively licensed from Yale University European Patent 0063879 and
`
`German Patent P 32 80 032.0-08 which issued late last year [1989] and protect
`
`this technology in Austria, Belgium, France, Germany,
`
`Italy, Lichtenstein,
`
`Luxembourg, Netherlands, Sweden, Switzerland, and the United Kingdom."
`
`Thus,
`
`Applicant conceived,
`
`it was with full knowledge and awareness of D1‘s disclosure that
`The
`
`invented and developed the present
`
`invention.
`
`course of the present invention has spanned almost two decades, resulting not
`
`only in the issuance of several patents, but also in the development of key
`commercial products sold and distributed worldwide.
`In addition to the
`
`aforementioned U.S. Patent No. 4,994,373, other significant patents have been
`
`See Canadian Patent No. 1,309,672 and
`issued in Canada and Japan.
`Japanese Patent No. 2,825,090, copies of top sheets provided in Exhibits ‘3
`and 4,
`respectively. See also Applicant's January 12, 1999 news release
`
`(Exhibit 5) announcing the issuance of Japanese Patent No. 2,825,090 and its
`
`use for quantitative determination of nucleic acids present in a sample and for
`
`forming an array of nucleic acids attached to a matrix or microchip.
`
`Applicant has expended considerable time, effort and expense in developing
`
`commercially useful products based upon the present invention.
`
`In the same
`
`year following the issuance of U.S. 4,994,373 (see Applicant's February 25,
`1991 news release provided in Exhibit 6), Applicant
`launched one of its
`
`premier products for HIV detection using a microplate hybridization assay. See
`Applicant's December 4, 1991 news release provided in Exhibit 7. As stated in
`
`the December 4, 1991 news release (Exhibit 7):
`
`Page 8 of11
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`June 7, 2000
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`Page 8 of 11
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`on to
`I
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`g
`g
`9
`A
`I
`CD
`VOSSIUS 8- PARTNER
`
`This product also can measure virus concentrations, making
`
`it easier for researchers to determine HIV levels in patients
`
`and look for relationships between these levels and other
`
`disease
`
`indicators
`
`such
`
`as
`
`antibody
`
`production
`
`or
`
`appearance of symptoms.
`
`This product, called "HIV Microplate Hybridization Assay",
`
`employs the company's proprietary nucleic acid test method
`
`which produces a soluble signal
`
`in solution. Using this
`
`method, many samples can be processed simultaneously
`
`and the results can be
`
`automatically determined by
`
`microplate
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`readers,
`
`instruments
`
`commonly
`
`used
`
`in
`
`laboratories.
`
`A copy of Applicant's product brochure for its Microplate Assay for HIV DNA is
`
`provided in Exhibit 8. Also provided are copies of reprints of two scientific
`The first
`is titled
`
`publications based upon this product and technology.
`
`"Nonradioactive, Color-imetric Microplate Hybridization Assay for Detecting
`
`Amplified Human lmmuno-deficiency Virus DNA"
`
`[Rapier et al., Qligicgl
`
`Chemistm, Vol. 39, No. 2, Pages 244-247 (1993)] and is provided in Exhibit 9.
`
`See also Applicant's March 24, 1993 news release announcing the mg
`
`Chemistry report on its HlV Microplate Hybridization Assay, copy provided in
`
`Exhibit 10. The second publication is titled "Anti—body-Enhanced Microplate
`
`Hybridization Assay" [Christine L. Brakel, BioTechnigues, Vol. 22, No. 2, Pages
`
`346-348 (1997)] and is provided in Exhibit 11.
`
`Since the introduction of its HlV Microplate Hybridization Assay, Applicant has
`
`been successfully selling and distributing other microplate assays directed to
`
`other pathogens, including Mycobacterium tuberculosis, Hepatitis B Virus, the
`
`latter including core antigen sequences, surface antigen sequences and direct
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`Page 9 of11
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`detection in serum. See copy of pages 21 and 22 from Applicant's 1992
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`S 808 EPII
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`June 7, 2000
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`Page 9 of 11
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`VOSSIUS & PARTNER
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`Product Catalog provided in Exhibit 12. See also copy of pages 99-114 from
`
`Applicant's 1995 Research Product Catalog provided in Exhibit 13.
`
`In addition to the foregoing developments, Applicant also wishes to point out
`
`that products and reagents covered by the present
`
`invention are gaining
`
`increased acceptance and use in the highly acclaimed DNA (micro)chip and
`
`array field._ As indicated above, Applicant has obtained array claims in Japan
`
`for a related and corresponding Japanese patent. Furthermore, Applicant is the
`
`sole supplier of labeling and detection products for one of the world's leading
`
`DNA microchip manufacturers, Affymetrix, Inc. See Applicant's May 27, 1998
`
`news release provided in Exhibit 14 announcing its agreement with Affymetrix
`
`to be the sole supplier of reagents for the latters GeneChip® arrays. See also
`
`Applicant's March 23, 1999 news release provided in Exhibit 15 announcing its
`
`agreement with Gene Logic, Inc. under which it will be the exclusive supplier of
`
`reagent products for labeling and detecting gene sequences with Gene Logids
`
`Flow-thru Chipm probe arrays.
`
`Applicant has also obtained a similar
`
`arrangement with another leading chip manufacturer, Gene Logic,
`
`Inc. See
`
`Applicant's February 24, 2000 news release provided in Exhibit 16 announcing
`
`its expanded product line, Enzo's BioArray Labeling Systems, for gene chip and
`
`other microarray methods.
`
`In Applicant's current 2000 product catalog is a
`
`listing of products for its BioArrayTM Labeling Systems. See copy of pages 21-
`
`24 provided in Exhibit 17.
`
`The above described commercial success being reflected in the agreements
`
`with and uses by other manufacturers is a clear indication of the inventive step
`
`involved in the present invention. Moreover,
`
`it defies logic and common sense
`
`to hold that D1 renders the present invention obvious. The patent record in
`
`other significant patent examining authorities and the worldwide commercial
`
`success of Applicant's products based upon the present
`
`invention clearly
`
`confirm otherwise that the inventive step of the present invention is indeed not
`
`negated in any way by D1, or for that matter, any other document cited of
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`Page 10 of11
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`record in this case.
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`VOSSIUS & PARTNER
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`5.
`
`REQUESTS
`
`Based on the above submitted argumentation it is requested that the Decision
`
`to refuse the patent application be set aside and the patent be granted on the
`
`basis of the Auxiliary Request.
`
`‘Qamre&a:1M
`
`Dr. Renate Barth
`European Patent Attorney
`
`.
`
`Encl.
`Exhibits 1 to 17
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`C
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`10014 P S _
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`1g.t5.n3 GR
`p:z:r;x::r;17 fiT 1..__.“. .
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`mfizchte Aktentasche
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