Euro paisch es
`Pat ent amt
`
`Europea n
`Pat ent Off ice
`Offi ce e uro pfe n
`des brevet s
`
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`
`Smaggasgale, Gillian Helen
`WP Thompson
`55 Drury Lane
`London WC2B 5SQ
`ROYAUME-UNI
`
`t
`
`L
`
`7
`
`_J
`
`European Patent Offi ce
`80298 MUNI CH
`GERMAN Y
`Tel: +49 89 2399 0
`Fax: +49 89 2399 4465
`
`Formalities Officer
`Name: Hahn, Catriona
`Tel: +49 89 2399 - 7713
`or call
`+3 1 (0)70 340 45 00
`
`Substantive Examiner
`Name: Quirin, Katharina
`Tel: +49 89 2399 - 4742
`
`Application No.
`07 855 412 .8 - 1404
`
`Applicant
`DNA Genotek Inc.
`
`Ref.
`
`I GHS/P512005EP
`
`Date
`21.11.2013
`
`I
`
`Decision to refuse a European Patent application
`
`The Examining Division - at the oral proceedings dated 22.10 .2013 - has decided:
`
`European Patent application No. 07 855 412.8 is refused.
`
`Applicant/s:
`DNA Genotek Inc.
`Unit 200 , 29 Camelot Drive
`Ottawa, Ontario K2G 5W6
`CA
`
`Title
`STABILIZING COMPOSITIONS AND METHODS FOR
`EXTRACTION OF RIBONUCLEIC ACID
`
`The grounds for the decision are set out on the supplemental sheets annexed hereto.
`
`Means of redress
`
`This decision is open to appeal.
`Attention is drawn to the attached text of Articles 106 to 108 EPC and Rules 97 and 98 EPC.
`
`Registered letter with advice of delivery
`EPO Form 2007 12.0?TRI
`
`Page 1
`
`Spectrum Ex. 1013
`IPR Petition - USP 10,000,795
`
`

`

`Date 21.11 .2013
`
`Sheet 2
`
`Application No.: 07 855 412.8
`
`Examining Division:
`
`Chairman:
`2nd Examiner:
`1st Examiner:
`
`Leber, Thomas
`Dolce, Luca
`Quirin, Katharina
`
`Hahn, Catriona
`Formalities Officer
`Tel. No .: +49 89 2399-7713
`
`Enclosure(s) :
`
`8 page/s reasons (Form 2916)
`Form 2019
`
`to EPO postal service: 18.11 .13
`
`Registered letter with advice of delivery
`EPO Form 2007 12.0?TRI
`
`Page 2
`
`

`

`Datum
`Dme
`Date
`
`21. 11 . 2013
`
`Blatt
`Sheet
`Feuille
`
`1
`
`Anmelde-Nr:
`Application No : 0 7 8 5 5 412 . 8
`Demande n°:
`
`SUMMARY OF FACTS AND SUBMISSIONS
`
`I.
`
`The present European application EP 07 855 412.8 was filed on 05-10-2007
`under the PCT as application PCT/CA2007/001785 . It claims priority of the
`earlier applications US 60/828,563 filed on 06-10-2001, US 60/866,985 filed
`on 22-11-2006, and US 60/949,778 filed on 13-07-2007.The Applicant is DNA
`GENOTEK INC.
`
`II.
`
`The following documents have been discussed during examination:
`
`D1
`
`D2
`
`D3
`
`D4
`
`D5
`
`D6
`
`D7
`
`D8
`
`A 1
`
`A2
`
`WO 03/104251 A2
`
`DE 102 19 117 C1 (AD NAG EN AG [DE]) 30 October 2003
`
`US 2003/ 170694 A 1 (WALL DANIEL [US] ET AL) 11 September 2003
`
`YAMKOVAYA TV ET AL: "Isolation of total RNA from baker's yeast"APPLIED
`BIOCHEMISTRY AND MICROBIOLOGY, KLUWER ACADEMIC PUBLISHERS(cid:173)
`PLENUM PUBLISHERS , NE, vol. 42 , no. 1, 1 January 2006 (2006-01-01) , pages
`84-88, XP019293864
`
`OKUNO T ET AL: "RNA polymerase activity and protein synthesis in brome mosaic
`virus-infected protoplasts"VIROLOGY, ACADEMIC PRESS ,ORLANDO , US LNKD(cid:173)
`DOl :10.1016/0042-6822(79)90002-3 , vol. 99 , no . 2, 1 December 1979
`(1979-12-01) , pages 218-225 , XP023047707
`
`MOSER CLAUDIO ET AL: "Isolation of functional RNA from small amounts of
`different grape and apple tissues"MOLECULAR BIOTECHNOLOGY, HUMANA
`PRESS, INC, US LNKD- DOl:10.1385/MB:26:2:95, vol. 26, no. 2, 1 February 2004
`(2004-02-01 ) , pages 95-100, XP002526690
`
`US 2005/019814 A1 (LAUGHARN JAMES A [US] ET AL LAUGHARN JR JAMES
`A [US] ET AL) 27 January 2005 (2005-01-27)
`
`WO 99/00521 A1 (BIO RAD LABORATORIES [US]) 7 January 1999 (1999-01-07)
`
`p. 2-4 of the applicant's letter filed 17-10-2011 ; supporting technical information
`
`p. 1-6; supporting technical information filed with the letter dated 25-09-2013
`
`D1-D8 were cited by the Examining Division , A 1 and A2 were introduced by
`the Applicant with the letter dated 17-10-2011 and the telefax dated
`20-09-2013 , respectively.
`
`EPO Form 2916 01.91TRI
`
`Page 3
`
`

`

`Datum
`Dme
`Date
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`Blatt
`Sheet
`Feuille
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`Anmelde-Nr:
`Application No : 0 7 8 5 5 412 . 8
`Demande n°:
`
`Ill.
`
`IV.
`
`V.
`
`After the official communication dated 07-04-2011, summons to oral
`proceedings were issued on 15-05-2013. The oral proceedings were
`scheduled for 22-10-2013.
`
`With the telefax dated 20-09-2013, the Applicant submitted A2 and filed a new
`main request as well as an auxiliary request.
`
`Applicant thus requests the grant of a patent based on the following
`documents:
`
`MAIN REQUEST
`
`Description, Pages
`
`2, 5-51
`
`as published
`
`1, 3, 3a, 52, 53
`
`received on
`
`12-01-2011 with letter of
`
`4
`
`filed in electronic form on
`
`12-01-2011
`
`07-11-2011
`
`Claims, Numbers
`
`1-1 8
`
`filed with telefax on 20-09-2013
`
`Drawings, Sheets
`
`1 /19-19/19
`
`as published
`
`AUXILIARY REQUEST
`
`Description, Pages
`
`2, 5-51
`
`as published
`
`1, 3, 3a, 52 , 53
`
`received on
`
`12-01-2011 with letter of
`
`12-01-2011
`
`4
`
`filed in electronic form on
`
`07-11-2011
`
`Claims, Numbers
`
`1-18
`
`filed with telefax on 20-09-2013
`
`Drawings, Sheets
`
`1/19-19/19
`
`as published
`
`EPO Form 2916 01.91TRI
`
`Page 4
`
`

`

`Datum
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`VI.
`
`VI I.
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`21. 11 . 2013
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`Blatt
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`Anmelde-Nr:
`Application No : 0 7 8 5 5 412 . 8
`Demande n°:
`
`The requests and submissions were discussed with the First Examiner during
`the telefone conversations held on 27-09-2013 , 04-10-2013 , and 16-10-2013.
`The date for oral proceedings was maintained.
`
`With the telefax dated 21-10-2013, the Applicant indicated that he would not
`be represented at the oral proceedings. Oral proceedings took place on
`22-10-2013 in the absence of the Applicant. At the oral proceedings, the
`Examining Division decided to refuse the application for the reasons detailed
`infra.
`
`REASONS FOR THE DECISION
`
`1
`
`1 .1
`
`1.1 .1
`
`MAIN REQUEST (MR)
`
`Novelty (Articles 52(1 ), 54 EPC)
`
`The present application does not meet the requirements of Article 52(1) EPC
`because the subject-matter of claims 1, 6, 9, 10, and 13-15 is not new within
`the meaning of Article 54(1) and (2) EPC.
`
`1.1.2 Document D2 (cf. D2, claims 10-13; claims 1-6, 8) discloses a method for
`stabilizing RNA in a biological sample, wherein the method involves adding to
`the sample a stabilizing solution, i.e. forming a liquid mixture of the sample
`and a stabilizing composition.
`
`The stabilizing solution of D2 comprises:
`the anionic detergent Li-dodecyl sulfate,
`and further one or more of:
`10-500 mMol/I of the buffering agent Tris-HCI at pH 6.5-8.5
`100-3500 mMol/I LiCI
`1-100 mMol/I EDTA
`1-50mMol/l Dithiotreitol.
`
`1.1.2.1 The number of different stabilizing solutions, which can be obtained by
`selecting at least one among the four additional ingredients above, is limited
`to 15. Because of this small number, the skilled person would be aware of
`each of the possible combinations of ingredients, such that D2 is considered
`to disclose each of the corresponding 15 stabilizing solutions in an
`individualized form. In agreement with the notion that a selection from a single
`list of specifically disclosed elements does not confer novelty (cf. Guidelines,
`G-VI, 8 (i)), D2 thus discloses a stabilizing solution comprising the anionic
`detergent Li-dodecyl sulfate and 10-500 mMol/I of the buffering agent Tris-HCI
`
`EPO Form 2916 01.91TRI
`
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`
`at pH 6.5-8.5. The definition of the pH range for the buffering agent of from 6.5
`to 8.5 specifically discloses compositions comprising the anionic detergent Li(cid:173)
`dodecyl sulfate and 10-500 mMol/I of the buffering agent Tris-HCI at pH 6.5
`(cf. T666/89, reas. 4 and Guidelines, G-VI, 8(iii)). It is therefore concluded that
`in terms of its composition , the stabilizing solution of D2 falls under the
`wording of claim 1 of the MR.
`
`1.1.2.2 The skilled person knows that cell lysis occurs at the concentrations of up to
`5%, preferably 2% (w/v) of Li-dodecyl sulfate taught by D2 . This results in
`releasing soluble cellular components such as ribonucleic acid from the
`sample into the aqueous phase of the liquid mixture. It therefore is clear that
`the stabilizing solutions of D2 are for [i.e. suitable for, cf. Guidelines, F-IV,
`4.13] the purpose of extracting ribonucleic acids from a biological sample,
`when said stabilizing solution is mixed with said sample to form a liquid
`mixture.
`
`1.1 .2.3 The temperature at which the method of D2 should be performed is not
`explicitly mentioned in D2, which implies to the skilled reader that ambient, i.e.
`room , temperature is foreseen. This is confirmed by the working example
`provided by D2, which comprised incubation of a cell lysate as the biological
`sample with a stabilizing solution for various times at room temperature (cf.
`D2, p. 2, 1.66). It is hence clear from the teachings of D2 that the stabilizing
`solutions disclosed are also for [i.e. suitable for, cf. Guidelines, F-IV, 4.13] the
`purpose of storing ribonucleic acids from a biological sample such that the
`ribonucleic acid within said sample remains stable at room temperature, when
`said stabilizing solution is mixed with said sample to form a liquid mixture.
`
`A2, the experimental evidence submitted by the Applicant, does nothing to
`change this assessment of D2. The data submitted do not appear relevant for
`two reasons. First, the composition supposedly reflecting the teachings of D2
`was different with respect to the detergent used (sodium dodecyl sulfate
`instead of lithium dodecyl sulfate). Especially in view of D2's clear teaching to
`use Li dodecylsulfate (cf. D2, para. [0009]), the Examining Division cannot
`follow the Applicant's reasoning that both reagents were equivalent in the
`presence of a high concentration of LiCI. Second , the composition supposedly
`reflecting the teachings of D2 had a pH of 7.5 instead of 6.5. Moreover, the
`Examining Division cannot follow the Applicant's conclusions based on
`Figures 1-3 submitted. At least on the scanned copies available, no bona fide
`RNA bands, i.e. bands disappearing upon RNAse treatment, can be
`discerned. It is therefore considered that the data do not allow any conclusion
`on the performance of the RNA stabilizing solutions of D2.
`
`EPO Form 2916 01.91TRI
`
`Page 6
`
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`

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`Sheet
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`Demande n°:
`
`1.1.2.4 In summary, D2 discloses stabilizing solutions having the composition defined
`in claim 1 of the MR and being suitable for the purpose stated in said claim.
`The subject-matter of claim 1 of the MR is hence not new within the meaning
`of Article 54(1) and (2) EPC.
`
`1.1.2.5 Lithium dodecyl sulfate and Tris-HCI are among the components specified in
`dependent claims 6 and 10 of the MR (cf. D2 , claims 8, 13). Moreover, the
`specific endpoint of pH 6.5 disclosed by D2 falls in the ranges specified in
`dependent claim 9 of the MR (cf. D2 , claims 8, 13). The biological sample of
`D2 may be a sample comprising human or animal cells, i.e. a sample from a
`human (cf. D2, claim 10). At least the subject-matter of dependent claims 6,
`9, 10 and 15 is hence likewise anticipated by D2.
`
`1.1.3
`
`It is further noted that D1 (cf., e.g., D1, claims 15, 30, 41, and 42) likewise
`anticipates the subject-matter of claim 1 of the MR, the reasons being as
`follows.
`
`D1 teaches compositions for preserving and extracting nucleic acids from
`saliva, i.e. from a biological sample (cf. , e.g. , D1 , abstract). The compositions
`of D1 are explicitly suitable for preserving , when mixed with a mucin(cid:173)
`containing bodily fluid , the nucleic acids at room temperature under ambient
`conditions for extended periods of time (cf. , e.g. , D1 , p. 5, I. 1-3). In one
`embodiment, the composition of D1 comprises in an aqueous solution a
`chelating agent and a denaturing agent, where the pH of the composition is
`greater than 5.0 (cf., e.g. , D1 , p. 5, 1.12-15). D1 teaches that, for the
`preservation of RNA, it is desirable to use a pH from about 6.5 to about 6.8
`and that a buffer, such as BES, can be used to maintain the pH in a constant
`range (cf. , e.g. , D1 , p. 6, 1.3 O - p. 7, I. 2; p.14, I. 29-30). Urea, dodecyl sulfate,
`or an alcohol are taught as desirable denaturing agents (cf. , e.g. , p. 7, I. 5-6).
`Sodium dodecyl sulfate (SOS) is used as a denaturing agent in the specific
`examples 3 and 7 of D1 , thereby particularly highlighting the possibility to use
`this reagent.
`
`1.1.3.1 D1 thus discloses a composition for extracting and storing nucleic acid from a
`biological sample such that the nucleic acid within said sample remains stable
`at room temperature when said composition is mixed with said sample to form
`a liquid mixture. The skilled person understands from D1 that, if the nucleic
`acid to be preserved is a ribonucleic acid (RNA), the stabilizing composition
`should comprise in an aqueous solution a chelating agent and a denaturing
`agent, as well as a buffering agent at a pH of 6.5-6.8. The skilled person
`further understands that a particlular example of a suitable denaturing agent is
`dodecyl sulfate, e.g. sodium dodecyl sulfate. D1 thereby teaches a
`
`EPO Form 2916 01.91TRI
`
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`

`Datum
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`Feuille
`
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`
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`Demande n°:
`
`composition comprising the anionic detergent dodecyl sulfate and a buffering
`agent at a pH of 6.5-6.8 , which composition is for [i.e. suitable for, cf.
`Guidelines, F-IV, 4.13] the purpose stated in claim 1 of the MR. With the
`narrower pH range defined by 01 falling fully within the pH range specified in
`claim 1 of the MR, the subject-matter of said claim is not new within the
`meaning of Article 54(1) and (2) EPC.
`
`1.1.3.2 A 1, the experimental evidence submitted by the Applicant, does nothing to
`change the above assessment of 01 , because the data submitted only relate
`to the composition disclosed in Example 7 of 01 , which had a pH of 8.0.
`
`2
`
`2.1
`
`2.1 .1
`
`AUXILIARY REQUEST (AR)
`
`Amendments (Article 123(2) EPC)
`
`The AR fails to fulfill the requirements of Article 123(2) EPC, the reasons
`being as follows.
`
`2.1 .1.1 Claim 1 of the AR was amended by introducing a concentration range of the
`anionic detergent, namely from 4% to 16% (w/v). Applicant indicated p. 11 , I.
`4-6 of the application as filed as a basis for said amendment. However, the
`passage in question only cites specific embodiments of the compositions
`claimed, namely a composition comprising 16%, 12%, or 8% SOS and 50mM
`COTA at pH 6.2. Other specific embodiments disclosed on the same page
`relate to 4% SOS and 50 mM COTA pH 6.2 (cf.p. 11 , I. 1-2) and to 4% or 8%
`Sarkosyl , 50mM COTA pH 6.6.
`
`The applicant hence attempts to extract a specific feature in isolation from an
`originally disclosed combination of features and to use this to delimit claimed
`subject-matter. It is established practice to consider such an amendment only
`allowable under Article 123(2) EPC, if no structural and functional relationship
`exists between the features (cf. Guidelines, H-V, 3.2.1 and, e.g. , T1067/97,
`T1408/04). In the present case, however, the suitable concentration of an
`anionic detergent is linked to the nature of the specific detergent used.
`Moreover, as micelle formation by detergents is well known to be dependent
`on ionic strength and pH, the ski lied person would consider that the specific
`concentration of SOS and Sarkosyl disclosed cannot be transferred in
`isolation and irrespective of the specific buffer and pH used. Hence, the skilled
`person would not conclude from reading the above passages that the
`compositions of the present application can comprise any detergent at a
`
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`concentration of 4%-16% (w/v) , irresgective of the buffering agent and in a
`broader gH range . Claim 1 of the AR thus represents an unallowable
`intermediate generalization over the passages of the description cited above.
`
`2.1 .1.2 Having regard at the application as a whole, no other basis for the
`amendment could be found in the application as originally filed. Claim 1 of the
`AR hence violates the provisions of Art. 123(2) EPC.
`
`2.1.1.3 The same objection applies to independent claims 2 and 18 of the AR.
`
`3
`
`3.1
`
`3.1 .1
`
`FINAL REMARKS NOT PART OF THE DECISION
`
`For the sake of completeness, it is noted that D1 is also considered relevant
`to the novelty of claims 6, 9,10, 13-15 and 18 of the MR.
`
`SOS and BES are among the components specified in dependent claims 6
`and 10 of the MR. Moreover, the pH range of 6.5-6 .8 disclosed by D1 is
`specified in dependent claim 9 of the MR. The biological sample of D1 may
`be a sample comprising human saliva (cf. , e.g. , D1 , abstract and example 1 ),
`i.e. a bodily fluid from a human. Thus, the subject-matter of claims 6, 9,10,
`and 13-15 of the MR is not new within the meaning of Article 54(1) and (2)
`EPC.
`
`3.1 .2 Claim 18 of the MR relates to an RNA storage kit comprising:
`a) a composition according to any one of claims 1, or 6 to 17 of the MR, and
`b) instructions for use thereof.
`Said instructions for use have no technical effect themselves on the
`composition contained in the kit. Rather, the technical effect of the
`composition, namely RNA stabilization , "results from its intrinsic chemical
`nature and independently of the given instructions". Therefore, in line with T
`553/02 (cf. reasons 1.2.2 and 1.3), the instructions for use are considered
`mere representations of information , i.e. a non-technical feature, which does
`not limit the scope of claim 18 and does "not have to be considered in the
`evaluation of novelty". Claim 18 hence relates to an RNA storage kit
`comprising a composition according to any one of claims 1, or 6 to 17 of the
`MR. This subject-matter is anticipated by D1, the reasons being as follows.
`
`D1 teaches kits comprising a collection device for saliva, wherein the device
`contains a composition according to D1 (cf. D1 , p. 24, I. 25-30) . As set out in
`items 1.1.3 and 3.1.1 above, D1 discloses compositions according to claims 1,
`6, 9,10, and 13-15 of the MR. Consequently, D1 discloses a kit comprising a
`composition according to any one of claims 1, or 6-17 of the MR. Said kit
`would appear suitable for RNA storage, i.e. be an RNA storage kit, since its
`
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`contents are explicitly intended "for stablilizing , preserving , or facilitating the
`recovery of nucleic acids from a biological sample by using the device to bring
`a biological sample into contact with the composition" (cf. p. 24, I. 25-30).
`Thus, the subject-matter of claim 18 of the MR is not new within the meaning
`of Article 54(1) and (2) EPC.
`
`DECISION
`
`Since none of the requests on file meets the requirements of the EPC, the application
`is refused (Article 97(2) EPC).
`
`EPO Form 2916 01.91TRI
`
`Page 10
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`