`
`Eumpiisches
`
` Patentamt
`
`European
`"w“ °'"“
`3:31;:an
`
`European Patent 0mm
`80298 MUNICH
`19EIVR3313 2399 o
`Fit: +49 39 2399 4465
`
`
`.
`.
`Application N0-1
`
`08 732 818.3
`
`Patent No.:
`
`EP-B-2 203 462
`
`Direct decision:
`
`D yes )fi no
`
`lnterlocutory decision in opposition proceedings (Art. 101(3)(a) and 106(2) EPC)
`
`The Opposition Division - at the oral proceedings dated 05.10.2016 - has decided:
`
`Account being taken of the amendments made by the patent proprietor during the opposition proceedings, the
`patent EP-B—2 203 462 and the invention to which it relates are found to meet the requirements of the
`Convention.
`
`The currently valid documents are:
`
`Auxiliary Request 1
`
`Description, Pages
`
`2-46
`
`of the patent specification
`
`Description, Paragraphs
`
`52
`
`handwritten amendments filed during Oral Proceedings on
`
`05-10-2016
`
`Claims, Numbers
`
`1, 2
`
`received on
`
`03—08-2016 with letter of
`
`03-08-2016
`
`The Grounds for the decision (Form 2916) are enclosed.
`
`Date /46 /1‘é
`
`0M -
`
`...r........t9. .....
`Chairman
`Tzschoppe, Dieter
`
`
`
`Legally qualified member
`Schauwecker, Mania
`
`.'
`
`..
`
`...
`
`.
`
`t Exami
`Gettins, M
`
`EPO Form 2339 (Sheet 1) 12.07TRI
`
`IPR2018-00119
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`Page 1 of38
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`I-MAK 1015
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`IPR2018-00119
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`Page 1 of 38
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`I-MAK 1015
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`Datum
`Date
`Date
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`31.10.2016
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`Blatt
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`1
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`Anmelde-Nr:
`Application No: 0 8 7 32 818. 3
`Demande n°:
`
`Facts and Submissions
`
`1
`
`The contested patent has the patent number EP2203462 and is based upon
`the application number 08732818 with the title "NUCLEOSIDE
`PHOSPHORAMIDATE PRODRUGS". The patent proprietor is Gilead
`Pharmasset LLC. The patent has 3 priority dates namely: 30.03.2007;
`24.10.2007 and 21.03.2008.
`
`2
`
`Claim 1 of the patent in suit is directed to the following racemate
`
`Claims 2-3 are directed to the enantiomers of this compound and have the
`following formulae:
`
`claim 2
`
`EPO Form 2916 01.91TRI
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`Demande n°:
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`claim 3
`
`Claims 4-6 relate to compositions corresponding to claims 1-3 respectively.
`
`3
`
`3.1
`
`3.2
`
`3.3
`
`3.4
`
`3.5
`
`3.6
`
`3.7
`
`3.8
`
`3.9
`
`A total of ten oppositions have been filed by the following opponents:
`
`Medecins du Monde (Opponent 1) on 10.02.2015;
`
`Mr H. H. Fleischer (Opponent 2) on 19.02.2015;
`
`Ellis IP Ltd. (Opponent 3) on 19.02.2015;
`
`Pharmaceutical Works Polpharma S.A. (Opponent 4) on 20.02.2015;
`
`Generics [UK] Ltd (Opponent 5) on 20.02.2015;
`
`Teva Pharmaceutical Industries Ltd; (Opponent 6) on 20.02.2015;
`
`Intellectual Property Services (IPS) (Opponent 07) on 23.02.2015;
`
`Stada Arzneimittel AG (Opponent 8) on 23.02.2015;
`
`ZBM Patents S.L. (Opponent 9) on 23.02.2015;
`
`3.10
`
`Actavis Group PTC ehf (Opponent 10) on 23.02.2015
`
`4
`
`The following documents have been cited:
`
`A 1 assignment of D1
`
`A2 assignment of D2
`
`A3 assignment of D3
`
`D1 US prov. appl. 60/909315 = 1st priority document of contested patent
`
`EPO Form 2916 01.91TRI
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`D2 US prov. appl. 60/982309 = 2nd priority document of contested patent
`D3 US prov. appl. 12/053015 = 3rd priority document of contested patent
`D4 WO2005/01 2327
`
`D5 Thesis entitled "Design, Synthesis and Biological Evaluation of Novel
`Nucleotide Prodrugs as Potential Anti-Hepatitis C Virus Agents" submitted by
`Plinio Perrone
`
`D6 Ma et al 2007, J. Biol. Chem. 282: pp29812-29820
`
`D7 Perrone et al 2007 J. Med. Chem. 50, pp1840-1849
`
`D7a Extract from website of J. Med. Chem. to confirm publication date of
`document D7
`
`D8 Poster presented at the 14th International Symposium on Hepatitis C
`Virus and Related Viruses which was held in Glasgow (Scotland) on 9-13
`September 2007
`
`D9 Murakami et al 2008 Antimicrob. Agents Chemother. 52:458-464
`
`D10 Clark et al 2005, J. Med. Chem. 48, pp5504-5508
`
`D11 Zemlicka 2002 Biochemica Acta 1587:276-286
`
`D 1 2 WO2005/00314 7
`
`D13 WO2008/121634 application document of contested patent
`
`D14 Lehsten et al, Org. Proces Res. Dev. 2002, 6, 819-822
`
`D15 WO2011/123645
`
`D16 Cahard et al, Mini-Reviews in Medicinal Chemistry, 2004, 4, pp:371-381
`
`D17 Jones et al., Mini review: Nucleotide Prodrugs. Antiviral Research 27
`(1995), pp. 1-17
`
`D18 Lee et al, Antimicrobial Agents and Chemotherapy 2005. pp 1898-1906
`
`D 1 9 WO 02/08241
`
`D20 McGuigan et al, J. Med. Chem, 2006, 49, pp 21 5-7226
`
`D21 Sofia et al. J, Med. Chem, 2010, 53, pp7202-7218
`
`D22 Abstract 100 "Design, synthesis, and Biological evaluation of Novel
`Nucleoside PPAs as Potential Anti-HGV Agents' presented at the 14th
`international Conference on Antiviral Research May 7-11, 2006
`
`D23 W02004/002999
`
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`D24 W02006/121820
`
`D25 W02006/012078
`
`D26 WO2006/065335
`
`D27 Gunic et al Bioorg & Med Chem. Letts 17(9) pp2456-2458 14.02.2007
`
`D28 US64 75985
`
`D29 WO03/000713
`
`D30 WO2007/020193
`
`D31 US2006/0241 064
`
`D32 WO2007 /095269
`
`D33 Ma et al "Characterization of the Intracellular metabolism of 3-D-2'(cid:173)
`deoxy-2'-fluoro-2'-C-methylcytidine .... " Antiviral Research 2007 74 A36
`Abstract 23
`
`D34 Evidence as to the priority date of D33 and D35
`
`D35 McGuigan et al "Sub Micromolar Inhibitors of HCV Generated from
`Inactive Nucleosides by Application of ProTide Technology" Antiviral
`Research 2007 7 4 A36 Abstract 24
`
`D36 McGuigan et al FEBS Letter (1994) 11-14
`
`D37 McGuigan et al, J. Med. Chem. 2005, pp3504-3515
`
`D38 Klumpp et al, J. Biol. Chem., 2006, vol. 281, pp3793-3799
`
`D40 US12/053015
`
`D42 Declaration of Dr Michael Sofia
`
`D43 Declaration of Dr Valentino Stella
`
`D44 Declaration of Professor John R. Thomas
`
`D45 Declaration of Dr Adrian Ray
`
`D45A Second Declaration of Dr Adrian Ray
`
`D46 Declaration of Dr Phillip Furman
`
`D47 Declaration of Dr William Delaney
`
`D48A Email exchange dated 14 May 2015 regarding publication date
`
`of D14
`
`D48B Email exchange dated 12 November 201 5 regarding the period
`
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`Application No: 0 8 7 32 818. 3
`Demande n°:
`
`of the Bar on Access of D14
`
`D48C Email exchange with Cardiff University Library
`
`D49 Ghany et at., AASLD Practice Guidelines, Hepatology, 49(4),
`
`2009, 1335-137 4
`
`D50 North et at., General Hospital Psychiatry, 2013, 35. 122-128
`
`D51 Klebl et al., Antiviral Chemistry and Chemotherapy, 2005, 16,
`
`69-90
`
`D52 De Francesco et al, Nature, 2005. 436, 953-960
`
`D53 Kaplan, Drug Discovery Today: Disease Mechanisms, 2006, 3(4),
`
`471-477
`
`D54 Wagner et al., Medical Research Reviews, 2000, 20(6), 417-451
`
`D55 Poster presented at 59th Annual Meeting for the American Association
`for the Study of Liver Diseases, 31 October to 4 November 2008, Furman et
`al.
`
`D56 Pharmasset, Inc., Press Release of 31 July 2009
`
`D57 FDA Consumer Health Information Leaflet, July 2014, "Faster
`
`Easier Cures for Hepatitis C"
`
`D58 EMA Press release, 22 November 201 3 "European Medicines Agency
`recommends approval of sofosbuvir for the treatment of chronic hepatitis C"
`
`D59 Organic Stereochemistry, Michael J T Robinson, OUP, 2005, cover page
`and Sections 1 .4-1 .8
`
`D60 Organic Chemistry, Clayden et al., OUP, 2005, cover page and pages
`48-49
`
`D61 Inorganic Chemistry, Huheey et al, HarperCollins College Publishers,
`1993, cover page and pages 233-234
`
`D62 Roberts et al., Hepatology, 2006, 44 (S 2), S269
`
`D63 Strader et al., Hepatology, 2004, 39(4), 1147-1171
`
`D64 Furman et al., Antiviral Drugs: From Basic Discovery Through Clinical
`Trials, First Ed, 2011 , 305-315
`
`D65 Cole et al., Drugs of the Future, 2009, 34(4), 282-290
`
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`D66 Lawitz et al., Antimicrobial Agents and Chemotherapy, 2013, 57(3),
`1209-1217
`
`D67 Dykens et al., Future Drugs, 2007, 7(2), 161-175
`
`D67A Letter from the British Library confirming publication date of D67
`
`D68 FDA publication, June 2006, "Guidance for industry: Antiviral Product
`Development - Conducting and submitting virology studies to the agency"
`
`D69 Communication dated 15 July 2015 from Karen Winestock at the FDA
`
`D70 Feng et al., Antimicrobial Agents and Chemotherapy, 2015,
`
`published online 23 November 2015, ref no. AAC01922-15R1
`
`D71 Murakami et al., The Journal of Biological Chemistry, 2010,
`
`285(45), 34337-34347
`
`D72 Wedemeyer et al., Hepatology, 2013, 58(2), 524-537
`
`D73 Pockros et al., Hepatology, 2013, 58(2), 51 4-523
`
`D74 Pharmasset Press Release, 6 September 2011 , "Pharmasset
`Announces 91%SVR12 from the PROTON Trial in Subjects with Hepatitis C
`Genotype 1"
`
`D75 Nelson et al., Journal of hepatology, 2011 , 54, S544, Abstract 1372
`
`D76 Lalezari et al, Journal of Hepatology, 2011 . 54, S28, Abstract 61
`
`D77 Soriano et al, Expert Opinion on Pharmacotherapy, 2013, 14(9), 1161
`-1170
`
`D78 Kowdley et al., The Lancet, 2013, 381, 21002107
`
`D79 Lawitz et al., The New England Journal of Medicine, 2013, 368,
`1878-1887
`
`D80 World Health Organisation - Model List of Essential Medicines, August
`2015
`
`D81 Arnold et al, PLOS Pathogens, 2012. 8(11 ), e1003030
`
`D82 Dickinson et al, Chemical Principles, 1984, 4th Ed, pp9-1 O
`
`D83 T. L. Brown "Chemistry: The Central Science", 1994, 6th Ed, p50
`
`D84 Stuyver et al , Antiviral Chemistry & Chemotherapy, 2006, 17 (2),
`pp79-87
`
`D85 Wikipedia excerpt on "18s ribosomal RNA"
`
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`Application No: 0 8 7 32 818. 3
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`
`D86A Bibliographic record of D5 from Cardiff University Library
`
`D86B Email exchange with Cardiff University Library about the public
`availability of D5
`
`D87 Declaration of Prof. Ravicher
`
`D88 T0106/07
`
`D89 Second Declaration of Prof. John R. Thomas
`
`D90 Second Declaration of Prof. Ravicher
`
`5
`
`Opponent 1
`
`Opponent 1 (01) has cited the documents D1-D12 in the notice of opposition.
`In the notice of opposition the patent was opposed for lack of novelty, lack of
`inventive step, insufficient disclosure and added subject matter. Objections
`were made against claims 2-3, 5-6 under Art. 123 (2) EPC. An objection
`under Art. 83 was made against claims 2-3 and 5-6 since the opposed patent
`does not disclose any stereospecific method of synthesis and/or of
`purification of the compounds of claims 2-3. The question of priority was
`discussed. At the time of filing of the application the Patentee was
`Pharmasset Inc. Opponent 1 considers that Pharmasset cannot be
`considered to be the successor in title of the inventors and that accordingly
`none of the claimed matter is entitled to the priority data of any of D1-D3. A
`novelty objection was made against claim 1 based on D4 - this objection is
`not linked to the entitlement of the priority date. An inventive step objection
`was made against claims 1-6 using D5 or D7 as the closest prior art and
`combining this with D6 or D8 or D9. If the priority date is held to be valid an
`inventive step objection is made based on D4 or D10 in combination with D5
`or D7. 01 filed further arguments with the letter of 04.08.2016 and cited
`D86A, D86B and D87. 01 disagreed with the choice of D53 as the closest
`prior art and objected to the auxiliary requests under Art. 84 EPC. With the
`letter of 29.09.2016 01 commented on the Patentee's letter of 02.09.2016
`and submitted D90.
`
`6
`
`Opponent 2
`
`Opponent 2 (02) has cited the documents D1, D4,D6-D8 D10, D12-D13,
`D16-D25 in the notice of opposition. Claims 1-6 are said to not be entitled to
`the priority of D1. Claims 2-3 and 5-6 are attacked under Art. 123 (2) and Art.
`83 EPC. An inventive step objection is made against claims 1-6 using D1 Oas
`
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`
`the closest prior art. The objection uses D10 on its own or in combination with
`any one of D7, D16, D18-D20. A further objection uses D8 as the closest prior
`art. For claims 2-3 D4 is also used. 02 filed additional arguments under Art.
`123 (2), 83, inventive step and priority with the letter of 03.08.2016 and
`submitted D84-D85.
`
`7
`
`Opponent 3
`
`Opponent 3 (03) has cited the documents D6, D7, D9, D10 and D13-D15 in
`the notice of opposition. In the notice of opposition the patent was opposed
`for lack of inventive step, added subject matter and Art. 83 EPC. Objections
`were made against claims 2-3, 5-6 under Art. 123 (2) EPC. An objection
`under Art. 83 EPC was made against claims 1-6 since the opposed patent
`does not disclose enough details of how to obtain the compound of claim 1 or
`the compounds of claims 2-3. The question of priority was discussed.
`Opponent 2 considered that claims 1 and 4 are not entitled to the priority of
`D1 and that claims 2, 3, 5-6 are not entitled to the priority of any of D1 -D3.
`For claims with an invalid priority claim D7 (closest prior art) and D6 were
`used in an inventive step objection or D9 (closest prior art) and D7. If the
`priority claim is held to be valid an inventive step objection is made using D10
`(closest prior art) in combination with D7. A lack of inventive step objection
`was also made based on the fact that the alleged antiviral activity of claims
`2-3 has not been substantiated and that these claims do not solve any
`problems, but merely represent compounds without any technical effect. 03
`confirmed that he would not attend the O.P. in the letter of 19.07.2016.
`
`8
`
`Opponent 4
`
`Opponent 4 (04) has cited the documents D4, D7, and D25-D32 in the notice
`of opposition. Objections are made against the enantiomers under Art. 123
`(2) and Art. 83 EPC. Claims 1-6 are attacked as lacking an inventive step.
`The objection makes particular reference to D7 and D12. 04 filed further
`arguments with the letter of 04.08.2016 and submitted D88.
`
`9
`
`Opponent 5
`
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`The text in the notice of opposition is by the same representative as for 04
`and appears to be identical. The same objections as for 04 therefore apply.
`05 filed arguments with the letter of 04.08.2016 and submitted D88. The text
`appears to be the same as that filed by Opponent 4 on the same day.
`
`10
`
`Opponent 6
`
`Opponent 6 (06) has cited i.a. the documents D4, D7, D10, D12, D16, D18
`and D25-D36. An inventive step objection has been made against claims 1-6
`using D7 or D33 as the closest prior art. 06 filed arguments Re inventive step
`with the letter of 03.08.2016 and submitted D7a. Auxiliary requests were
`objected to.
`
`11
`
`Opponent 7
`
`Opponent 7 (07) has cited the documents D1-D3, D6, D7, D9, D10, D30 and
`D38. An objection was made against claims 2-3 and 5-6 under Art. 123 (2)
`and Art. 83 EPC. Claims 1-6 of the contested patent are said to not be
`entitled to any of the priorities D1 -D3 for formal (as already outlined by 01)
`and substantive reasons. An inventive step objection against claims 1-6 was
`made on the basis of combinations of D6, D7, D9, D10, D30 and D38.
`
`12
`
`Opponent 8
`
`Opponent 8 (08) has cited the documents A 1, D4, D6-D11, D18 and D37. An
`objection was made against claims 2-3 and 5-6 under Art. 123 (2) and Art. 83.
`Claims 1-6 of the contested patent are said to not be entitled to any of the
`priorities D1-D3 for formal (as already outlined by 01) and substantive
`reasons. Claims 2-3 are considered to lack an inventive step since the
`problem to be solved- provision of anti-HGV agents has not been shown to
`have been solved. An inventive step objection against claims 1-6 is made on
`the basis of combinations of D4, D6-D11, D18 and D37. 08 filed arguments
`with the letter of 04.08.2016 Re novelty vis-a-vis D4 and inventive step using
`D4, D6, D9, D10 with D7, D18, D37.
`
`13
`
`Opponent 9
`
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`Demande n°:
`
`Opponent 9 (09) has cited the documents D1-D3, D6-D10 and D16. An
`objection was made against claims 2-3 and 5-6 under Art. 123 (2) and Art. 83.
`Claims 2-3 and 5-6 are said to not be entitled to any of the priorities D1-D3 for
`formal (as already outlined by 01) and substantive reasons while claims 1
`and 4 are not entitled to the first priority. Claims 2-3 are considered to lack an
`inventive step since the problem to be solved- the provision of anti-HGV
`agents has not been shown to have been solved. If D1 is a valid priority an
`inventive step objection is made based on D7 and D10. If it is considered that
`the patent is not entitled to the priority of D1, an inventive step objection
`against claims 1-6 is made on the basis of D7 in combination with one of D8,
`D9 or D16. 09 confirmed that he would not attend the O.P. with the letter of
`07.09.2016.
`
`14
`
`Opponent 10
`
`Opponent 10 (010) has cited the documents A 1-A3, D4, D6-D8, D10-D12,
`D16 and D37. An objection was made against claims 2-3 and 5-6 under Art.
`123 (2) and Art. 83 EPC. Claims 1-6 of the contested patent are said to not be
`entitled to any of the priorities D1 -D3 for formal (as already outlined by 01)
`and substantive reasons. A novelty objection against claims 1 and 4 was
`made based on D4. If D1 is a valid priority an inventive step objection is made
`based on D10 and D12 and the lack of evidence of the anti-HGV activity with
`particular reference to D11 and D16. If it is considered that the patent is not
`entitled to the priority of D1, D8 is considered to be the closest prior art and,
`in combination with any of D7, D16 or D37, is the basis for an inventive step
`objection against claims 1-6.
`
`15
`
`Patentee
`
`The Patentee replied on 11.12.2015 and submitted nine auxiliary requests.
`The Patentee cited documents D42-D81. The Patentee considered that D5
`was not made available until March 2009 and therefore considers that D5 is
`not prior art. Support for this is said to be provided by D48B. The claimed
`compound is said to have a unique combination of structural properties
`leading to a nucleotide analogue NS5B inhibitor with potent HCV activity, low
`toxicity and can be administered orally. Re Art. 123 (2) EPC claims 2-3 are
`said to be supported by entry IX-25-2 on page 254 which should be
`interpreted in the light of page 99, line 1 Oto page 100, line 5. T1046/97 and
`T658/91 were evaluated. The issues of sufficiency and entitlement to priority
`
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`were addressed. Novelty and inventive step were also discussed with D53 as
`the closest prior art. The patent is said to be inventive because of its
`unexpected anti-HGV activity or on account of its improved anti-HGV activity.
`Arguments were submitted on 03.08.2016 as were further auxiliary requests.
`New auxiliary requests 2-11 were filed which replaced the previous auxiliary
`requests and whereby only auxiliary requests 2 and 8 differ from the previous
`auxiliary requests. Documents D45a, D82 and D83 were cited. The main
`arguments related to inventive step and considered D4, D7, D10 and D12.
`For subject matter entitled to the priority of D1 D53 is the closest prior art. If
`the current application is not entitled to the priority of D1, D8 and D7/D16/
`D18-20 and D37 have been considered. If priority D1 and D2 are not valid D9
`or D9 and D18/D30/D37 are considered. The Patentee considered that
`D86A, D86B and D87 were late filed and should not be allowed into the
`proceedings. Further arguments on the citability of D5 and priority were filed
`on 02.09.2016 and D48G and D89 were cited. A consolidated list of
`documents was filed.
`
`16
`
`16.1
`
`A brief summary of the Auxiliary Requests prior to the O.P. is as follows. The
`numbering 1 to 3 relates to the racemate of claim 1 (of the main request) and
`the enantiomers of claims 2-3 respectively.
`
`Aux Req 1: 1 is claimed. The enantiomers are not claimed in structural terms
`any more, but are now the "slow eluting isomer" and the "fast eluting isomer"
`obtainable under specific chromatographic conditions.
`
`16.2
`
`Aux Req 2: 1 and 2 are claimed
`
`16.3
`
`Aux Req 3: Only 1 is claimed
`
`16.4
`
`Aux Req 4: Only 2 is claimed
`
`16.5
`
`Aux Req 5: Only slow eluting isomer is claimed.
`
`16.6
`
`Aux Req 6: 1-3 claimed and pharmaceutically acceptable medium specified.
`
`16.7
`
`16.8
`
`Aux Req 7: 1 claimed as are slow and fast eluting isomers and
`pharmaceutically acceptable medium specified
`
`Aux Req 8: 1 and 2 claimed and pharmaceutically acceptable medium
`specified
`
`16.9
`
`Aux Req 9: 1 claimed and pharmaceutically acceptable medium specified
`
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`Application No: 0 8 7 32 818. 3
`Demande n°:
`
`16.10 Aux Req 10: 2 claimed and pharmaceutically acceptable medium specified
`
`16.11 Aux Req 11 slow eluting isomer and pharmaceutically acceptable medium
`defined
`
`17
`
`18
`
`The parties were summoned to Oral Proceedings. In accordance with Rule
`116 (1) EPC all parties were informed that any written submissions (new
`documents, new claims etc) should be submitted at the very latest two
`months before the oral proceedings.
`
`Oral proceedings were held on 04-05.10.2016. The opposition division
`decided that the main request did not meet the requirements of Art. 123(2)
`EPC. The auxiliary request 1 was found to meet the requirements of the
`European Patent Convention.
`
`Reasons for the Decision
`
`Main Request
`
`Art 123 (2) EPC amendments
`
`19
`
`No objections were made against the racemate of claim 1 and its composition
`in claim 4. All objections were directed against the enantiomers of claims 2-3
`and their compositions in claims 5-6.
`
`19.1
`
`The racemate of claim 1 is disclosed as example 25 - see e.g. page 683 or
`claim 2 of the original application (D13).
`
`19.2
`
`The Patentee indicated the following passages in D13 as disclosure for the
`two enantiomers: Formula IX-25-2 on page 683 in combination with pages
`99-100, example 25 and claim 2 which discloses example 25 and "its
`stereoisomer". The relevant passage referred to in pages 99-100 reads:
`
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`Datum
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`19.3
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`31.10.2016
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`Application No: 0 8 7 32 818. 3
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`
`" In each of the presented tables, the phosphoramidate substituent containing
`the substituents R38 and R3b are depicted without reference to stereochemical
`structure (cf. structures 1-1, 1-3, 1-5, 1-7, and 1-9 above). It is contemplated
`that the compounds recited below embody compounds in which R38 projects
`toward the viewer while ff3b projects away from the viewer (cf. structures 1-2,
`1-4, 1-6, 1-8, and 1-1 OJ. Moreover, it is contemplated that the compounds
`recited below also embody compounds in which R38 projects away from the
`viewer while R3b projects towards the viewer. Not meant to be limiting,
`however, it is contemplated that preferred compounds are those in which R38
`projects towards the viewer and R3b projects away from the viewer such that
`the natural L-amino acid (SJ-configuration is presented. Additionally, the
`inventors recognize that the phosphorus atom of the phosphoramidate moiety
`is another source of chirality. Although the structures below do not specifically
`depict chirality at phosphorus, the inventors recognize that stereochemical
`configurations are possible such that in a staggered (or zig-zag) line structure
`the oxo-substituent projects towards the viewer while the OR 1 substituent
`projects away from the viewer, and vice versa, i.e., where the Cahn-lngold(cid:173)
`Prelog stereochemical designation of phosphorous is either R or S.
`Therefore, the structures below include all possible stereochemical
`configurations possible for phosphorus."
`
`19.4
`
`This is then followed by the formula 11
`
`11
`
`19.5
`
`In the case of IX-25-2 each of R2-R9 have been specified and should be read
`in combination with formula IX on page 246. The Patentee considered that
`the passage on page 99 referring to the first orientation of R3a and R3b is a
`preferred variation as is further shown e.g. by example 82, on pages 693-697,
`where all of the tested compounds have this configuration. There is also no
`
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`
`19.6
`
`19. 7
`
`selection from lists involved because all substituents in formula II are set out
`in a single line. This should be combined with the statement of all possible
`stereochemical configurations possible for phosphorus and IX-25-2 which is
`considered to be directly related to it, thereby directly individualising the
`enantiomers of claims 2 and 3.
`
`The Patentee also referred back to page 20, which reads "It is contemplated
`that compounds of the formula I are racemic because the chirality at
`phosphorous. Applicants contemplate use of the racemate and/or the
`resolved enantiomers".
`
`Example 81 on pages 692-693, is said to make it clear that enantiomers of
`the patent have been separated and isolated. Claim 2 gives example 25 and
`its stereoisomer and this only gives the possibility of the two enantiomers.
`There is a direct disclosure of a single compound which includes the 2
`stereoisomers thereof, the skilled person knows that these are at the P atom
`and knows how to extract them. The Patentee referred to T658/91, points 2.1
`and 2.4, which was taken to show that documents not only disclose explicitly
`defined enantiomers, but also enantiomers when these are listed as being
`part of the invention. This is the same as the current case. With reference to
`T1046/97 this is said to only apply for the case where an optically active form
`can be a mixture, but not to the current case which has individualised
`enantiomers and is therefore less relevant. The Patentee considers that D13
`makes specific reference to enantiomers and that these have effectively been
`individualised. When reading the table (i.e. for IX.25-2) both configurations for
`the phosphorous centre have to be read into the table, thereby providing a
`simple and direct disclosure. As there are only two possibilities, Rand S, the
`compounds of claims 2 and 3 are also not just covered but also disclosed.
`
`19.8
`
`The following points were raised by the Opponents. 01 argued that the
`compounds of claims 2 and 3 show different configurations at the phosphorus
`atom. However, these structures are neither depicted nor described as such
`in D13. 01 considered the disclosure on p.20, 1.8 to be only a general
`statement. Example 81 relates to the separation of a fast and a slow moving
`isomer. This example not only leaves undetermined the nature of the
`separated diastereoisomers, but also none of the separated examples in
`Example 81 relates to the compounds of claims 2 and 3. The claimed
`
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`
`compounds are seen as a selection from several lists, which require: a
`selection from the list of structures; the selection of one configuration as R
`and S; the selection of the configuration at the phosphorous atom, and the
`selection of a set of substituents within the Tables. 01 did not consider the
`claimed matter to be unambiguously and directly derivable from the
`application as originally filed. 02 considered that page 99 only says that P is
`a chiral atom, but does not individualise its isomers. 04 referred to the very
`large scope of D13 therefore necessitating that both a single compound and
`its individual isomers be disclosed. It was stressed that P chirality is not
`disclosed in example 25 and that while pages 99-100 specify some chiralities
`other chiralities are also given. With reference to the Case Law Book, 8th
`Edition, page 127 reference was made to T1048/92 which is taken to mean
`that a racemate does not disclose the enantiomers. Example 81 is irrelevant
`since it does not refer to example 25 and that this is in any case an Art. 83
`EPC issue. 02 stressed that formula II does not specify the chirality of the
`carbon atom and that IX-25-2 is only the scope of the racemate of claim 1.
`
`19.9
`
`It is undisputed that the structures of claims 2 and 3 are not drawn in the
`application as originally filed, nor are the chemical names mentioned
`expressis verbis.
`
`19.10 The OD notes that the decisions T1046/97 and T658/91 cited by the parties
`do not come to the same conclusions as to whether or not specific
`enantiomers are disclosed when compounds have been disclosed and there
`has only been a general reference to their enantiomers. The OD considers
`that the approach in T1046/97 is more relevant for the current situation. The
`OD notes that while p99-100 specify possible chiralities, phrases such as "not
`meant to be limiting" or "vice versa" mean that the disclosure is not limited
`thereto. Page 20 does not indicate a preferred chirality. Formula II and
`therefore IX-25-2 have two possible points of chirality leading to 4 possible
`enantiomers. Even when pages 20 and 99-100 are taken into account the
`enantiomers have not been individualised for IX-25-2.
`
`19.11
`
`In the case of example 25 on page 683 the chirality at the carbon atom has
`been defined so that there are two possibilities at the P atom. There is no
`indication on pages 682-683 that enantiomers are exemplified or comprised.
`
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`Datum
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`31.10.2016
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`16
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`Anmelde-Nr:
`Application No: 0 8 7 32 818. 3
`Demande n°:
`
`Pages 99-100 are taken to refer to IX-25-2, but it is not unambiguously clear
`that they apply to example 25 since page 99 refers to the "following tables",
`which would only be taken as a reference to tables which have been labelled
`as such i.e. Tables II-XXX-I1. Example 25 is, however, only listed in the
`examples section. Even if p99-100 are combined with example 25 the OD
`notes that while p99-100 specify possible chiralities, phrases such as "not
`meant to be limiting" or "vice versa" mean that the disclosure is not limited
`thereto. It is not apparent that pages 99-100 should be read as a limitation to
`a fixed, simultaneous chirality at the P and C atoms.
`
`19.12 The reference in claim 2 of the original application to stereochemistry reads
`"A compound its stereoisomer ... "
`
`19.13 Thereafter follows a list of individualised compounds including the compound
`of example 25. This means that claim 2 does not claim only example 25, but
`instead also claims a stereoisomer of example 25.
`
`19.14
`
`It is noted, that the passage of claim 2 mentioned above refers to the
`stereoisomer in singular form. In claim 2 this compound is in the (S)
`configuration i.e. where chirality has been defined at the carbon atom and not
`at the P atom. In the case of the compound of example 25 this means that a
`chirality has been defined for the carbon atom, but not for the phosphorus
`atom.
`
`19.15 The OD considered that the stereoisomer of claim 2 mentioned in singular
`form can only relate to the corresponding (R) isomer, and not extend to more,
`other stereoisomers e.g. the specific enantiomers due to the two possibilities
`on the P atom.
`
`19.16 Claim 2 of the original application does not therefore individualise the
`compounds of current claims 2 and 3.
`
`19.17 The OD considers that the enantiomers of claims 2 and 3 as well as
`composition claims 5 and 6 containing them were not disclosed in D13 and
`that the main request fails to meet the requirements of Art 123