PATENT COOPERATION TREATY
`
`PCT
`
`INTERNATIONAL PRELIlVIINARY REPORT ON PATENTABILITY
`
`(Chapter I of the Patent Cooperation Treaty)
`
`(PCT Rule 44bis)
`
`Applicant’s or agent’s file reference
`N406716WO
`
`FOR FURTHER ACTION
`
`See item 4 below
`
`International filing date (day/month/year)
`International application No.
`09 January 2017 (09.01.2017)
`PCT/GB2017/050038
`International Patent Classification (8th edition unless older edition indicated)
`See relevant information in Form PCT/ISA/237
`
`Priority date (day/month/yeaE)
`08 January 2016 (08.01.2016)
`
`Applicant
`REPLIMUNE LIMITED
`
`This international preliminary report on patentability (Chapter I) is issued by the International Bureau on behalf of the
`International Searching Authority under Rule 44 bis.1(a).
`
`This REPORT consists of a total of 10 sheets, including this cover sheet.
`
`In the attached sheets, any reference to the written opinion of the International Searching Authority should be read as a
`reference to the international preliminary report on patentability (Chapter I) instead.
`
`This report contains indications relating to the following items:
`
`Box \o. I
`
`Basis of the report
`
`Box \o. II
`
`Box \o.
`
`
`
`Priority
`
`Non—establishment of opinion with regard to novelty, inventive step and industrial
`applicability
`
`Lack of unity of invention
`
`Reasoned statement under Article 35(2) with regard to novelty, inventive step or
`industrial applicability; citations and explanations supporting such statement
`
`Certain documents cited
`
`Certain defects in the international application
`
`Certain observations on the international application
`
`lhe International Bureau will communicate this report to designated Offices in accordance with Rules 44bis.3(c) and 93bis.1
`but not, except where the applicant makes an express request under Article 23(2), before the expiration of 30 months from
`the priority date (Rule 44bis .2).
`
`The International Bureau of WIPO
`34, chemin des Colombettes
`1211 Geneva 20, Switzerland
`Facsimile NO. +41 22 338 82 70
`Form PCT/IB/373 (January 2004)
`
`Date of issuance of this report
`10 July 2018 (10.07.2018)
`
`AuthOHZEd officer
`
`Athlna NICkItaS-Etlenne
`e—mafl; pct.[eam4@wip0.int
`
`
`
`
`
`Box \o.
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`Box \o.
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`Box \o.
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`Box \o.
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`Box \o.
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`E '
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`

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`PATENT COOPERATION TREATY
`
`From the
`INTERNATIONAL SEARCHING AUTHORITY
`
`see form PCT/ISA/220
`
`
`
`PCT
`
`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`(PCT Rule 43bis.1)
`
`
`Date of mailing
`(day/month4/ear)
`
`see form PCT/ISA/210 (second sheet)
`
`
`
`Applicant's or agent‘s file reference
`see form PCT/ISA/220
`
`FOR FURTHER ACTION
`See paragraph 2 below
`
`International application No.
`PCT/GB2017/050038
`
`International filing date (day/fnonth/year)
`09.01.2017
`
`Priority date (day/month4/ear)
`08.01.2016
`
`
`
`
`
`International Patent Classification (IPC) or both national classification and IPC
`INV. C12N7/00
`
`
`Applicant
`REPLIMUNE LIMITED
`
`1.
`
`This opinion contains indications relating to the following items:
`
`Box No. I
`
`Basis of the opinion
`
`Box No. II
`
`Priority
`
`EEHXEIE Box No. V
`KEN] Box No. VIII Certain observations on the international application
`
`Box No. III
`
`Non-establishment of opinion with regard to novelty, inventive step and industrial applicability
`
`Box No. IV
`
`Box No. VI
`
`Lack of unity of invention
`Reasoned statement under Rule 43bis.1(a)(i) with regard to novelty, inventive step and industrial
`applicability; citations and explanations supporting such statement
`Certain documents cited
`
`Box No. VII
`
`Certain defects in the international application
`
`2.
`
`FURTHER ACTION
`
`If a demand for international preliminary examination is made, this opinion will usually be considered to be a
`written opinion of the International Preliminary Examining Authority ("IPEA") except that this does not apply where
`the applicant chooses an Authority other than this one to be the IPEA and the chosen IPEA has notifed the
`International Bureau under Rule 66.1bis(b) that written opinions of this International Searching Authority
`will not be so considered.
`
`If this opinion is, as provided above, considered to be a written opinion of the IPEA, the applicant is invited to
`submit to the IPEA a written reply together, where appropriate, with amendments, before the expiration of 3 months
`from the date of mailing of Form PCT/ISA/220 or before the expiration of 22 months from the priority date,
`whichever expires later.
`
`For further options, see Form PCT/ISA/220.
`
` Name and mailing address of the ISA:
`
`
`
`
`Date of completion of
`this opinion
`see form
`PCT/ISA/210
`
`Authorized Officer
`
`Herrmann, Klaus
`Telephone No. +49 89 2399-0
`
`F
`we“ “BMW-ts
`f3 o 6%:
`>
`3
`94’
`3.
`ewommw
`'
`
`
`
`—
`a) European Patent Office
`. J
`— D-80298 Munich
`Tel- +49 89 2399 ' 0
`Fax: +49 89 2399 - 4465
`
`Form PCT/ISA/237 (Cover Sheet) (January 2015)
`
`

`

`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/GBZO17/050038
`
`Box No. I Basis of the opinion
`
`1. With regard to the language, this opinion has been established on the basis of:
`
`the international application in the language in which it was filed.
`
`a translation of the international application into , which is the language of a translation furnished for the
`purposes of international search (Rules 12.3(a) and 23.1 (b)).
`
`This opinion has been established taking into account the rectification of an obvious mistake authorized
`by or notified to this Authority under Rule 91 (Rule 43bis.1(a))
`
`With regard to any nucleotide and/or amino acid sequence disclosed in the international application, this
`opinion has been established on the basis of a sequence listing:
`
`E E
`
`l
`
`a. E forming part of the international application as filed:
`
`E in the form of an Annex C/ST.25 text file.
`
`[I on paper or in the form of an image file.
`
`b. El furnished together with the international application under PCT Rule 13ter.1(a) for the purposes of
`international search only in the form of an Annex C/ST.25 text file.
`
`c. E furnished subsequent to the international filing date for the purposes of international search only:
`
`CI
`
`in the form of an Annex C/ST.25 text file (Rule 13ter.1(a)).
`
`El on paper or in the form of an image file (Rule 13ter.1(b) and Administrative Instructions, Section
`713).
`
`4.I:I
`
`In addition, in the case that more than one version or copy of a sequence listing has been filed or furnished,
`the required statements that the information in the subsequent or additional copies is identical to that
`forming part of the application as filed or does not go beyond the application as filed, as appropriate, were
`furnished.
`
`5. Additional comments:
`
`see separate sheet
`
`Form PCT/ISA/237 (January 2015)
`
`

`

`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/GBZO17/050038
`
`Box No. Ill Non-establishment of opinion with regard to novelty, inventive step and industrial
`applicability
`
`The questions whether the claimed invention appears to be novel, to involve an inventive step (to be non
`obvious), or to be industrially applicable have not been examined in respect of
`
`El
`
`the entire international application
`
`E claims Nos. 19, 23(completely); 20-22, 24-48(partially)
`
`because:
`
`El
`
`El
`
`El
`
`the said international application, or the said claims Nos.
`not require an international search (specify):
`
`relate to the following subject matter which does
`
`the description, claims or drawings (indicate particular elements below) or said claims Nos.
`that no meaningful opinion could be formed (specify):
`
`are so unclear
`
`the claims, or said claims Nos. are so inadequately supported by the description that no meaningful opinion
`could be formed (specify):
`
`E no international search report has been established for the whole application or for said claims Nos. E,
`
`23(completely): 20—22, 24—48(partially)
`
`El
`
`a meaningful opinion could not be formed without the sequence listing; the applicant did not, within the
`prescribed time limit:
`
`El furnish a sequence listing in the form of an Annex C/ST.25 text file, and such listing was not available
`to the International Searching Authority in the form and manner acceptable to it; or the sequence listing
`furnished did not comply with the standard provided for in Annex C of the Administrative Instructions.
`
`El furnish a sequence listing on paper or in the form of an image file complying with the standard provided
`for in Annex C of the Administrative Instructions, and such listing was not available to the International
`Searching Authority in the form and manner acceptable to it; or the sequence listing furnished did not
`comply with the standard provided for in Annex C of the Administrative Instructions.
`
`El pay the required late furnishing fee for the furnishing of a sequence listing in response to an
`invitation under Rule 13ter.1(a) or (b).
`
`E See Supplemental Box for further details
`
`Form PCT/ISA/237 (January 2015)
`
`

`

`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/GBZO17/050038
`
`Box No. IV Lack of unity of invention
`
`1. E In response to the invitation (Form PCT/ISA/206) to pay additional fees, the applicant has, within the
`applicable time limit:
`
`III
`
`El
`
`El
`
`paid additional fees
`
`paid additional fees under protest and, where applicable, the protest fee
`
`paid additional fees under protest but the applicable protest fee was not paid
`
`E not paid additional fees
`
`2. El
`
`This Authority found that the requirement of unity of invention is not complied with and chose not to invite
`the applicant to pay additional fees.
`
`3. This Authority considers that the requirement of unity of invention in accordance with Rule 13.1, 13.2 and 13.3 is
`
`III complied with
`
`E not complied with for the following reasons:
`
`see separate sheet
`
`4. Consequently, this report has been established in respect of the following parts of the international application:
`
`III all parts.
`
`E the parts relating to claims Nos. 1-18(completely); 20-22, 24-48(partially)
`
`Box No. V Reasoned statement under Rule 43bis.1(a)(i) with regard to novelty, inventive step or
`industrial applicability; citations and explanations supporting such statement
`
`Yes: Claims
`No:
`Claims
`
`Yes: Claims
`No:
`Claims
`
`Yes: Claims
`No:
`Claims
`
`1-18(completely); 20-22I 24-48(partially)
`
`1-18(completely); 20-22, 24-48(partially)
`
`1-18(completely); 20-22, 24-48(partially)
`
`1. Statement
`
`Novelty (N)
`
`Inventive step (IS)
`
`Industrial applicability (IA)
`
`2. Citations and explanations
`
`see separate sheet
`
`Form PCT/ISA/237 (January 2015)
`
`

`

`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/GBZO17/050038
`
`Box No. VIII Certain observations on the international application
`
`The following observations on the clarity of the claims, description, and drawings or on the question whether the
`claims are fully supported by the description, are made:
`
`see separate sheet
`
`Form PCT/ISA/237 (January 2015)
`
`

`

`WRITTEN OPINION OF THE
`
`INTERNATIONAL SEARCHING
`
`International application No.
`
`AUTHORITY (SEPARATE SHEET)
`
`PCT/GBZOI 7/050038
`
`Citations
`
`The documents mentioned in this Written Opinion are numbered as in the
`
`International Search Report (ISR), i.e. D1 and D8 correspond to the first and the last
`
`document of the search report, respectively.
`
`Re ITEM I
`
`The application as filed contains a sequence listing consisting of 45 sequences.
`
`Re ITEM III
`
`
`No search report was established for the subject-matter of claims 19 23 and partially
`
`claims 20-22 24-48 (see ITEM IV). Consequently, preliminary examination has been
`
`restricted to the subject-matter of invention 1 (Rule 66.1 (e) PCT).
`
`Re ITEM IV
`
`1
`
`In response to an invitation, the Applicant did not pay additional search fees.
`
`Consequently, international search and examination have been restricted to the
`
`subject-matter of claims 1-18 and partially claims 20-22 24-48 (invention 1). The
`
`present application lacks unity as required by Art. 3(4)(iii) and Rule 13 PCT because it
`
`contains 2 separate inventions:
`
`
`Invention 1: claims 1—1 8 and partially claims 20—22 24—48
`
`An oncolytic virus comprising: (i) a GM-CSF-encoding gene; and (ii) an immune co-
`
`stimulatory pathway activating molecule or an immune co-stimulatory pathway
`
`activating molecule-encoding gene, and subject-matter relating thereto.
`
`Invention 2: claims 19, 23 and partially claims 20-22, 24-48
`
`A virus which expresses three heterologous genes.
`
`2 According to Art. 3(4)(iii) and Rule 13 PCT an application shall relate to one
`
`invention only or to a group of inventions so linked as to form a single general
`
`inventive concept. Where a group of inventions is claimed, the requirement of unity of
`
`invention referred to in Rule 13.1 PCT shall be fulfilled only when there is a technical
`
`relationship among those inventions involving one or more of the same or
`
`corresponding special technical features.
`
`Form PCT/ISA/237 (Separate Sheet) (Sheet 1) (EPO-April 2005)
`
`

`

`WRITTEN OPINION OF THE
`
`INTERNATIONAL SEARCHING
`
`International application No.
`
`AUTHORITY (SEPARATE SHEET)
`
`PCT/GBZO17/050038
`
`The technical feature which distinguishes invention 1 from invention 2 is presence of
`
`(i) a GM-CSF-encoding gene and (ii) an immune co-stimulatory pathway activating
`
`molecule or an immune co-stimulatory pathway activating molecule-encoding gene in
`
`an oncolytic.
`
`Invention 2 is not directed to oncolytic viruses, let alone oncolytic viruses comprising a
`
`GM—CSF—encoding gene.
`
`3 Since invention 2 does not share said technical feature of invention 1, each of the
`
`above mentioned groups of claims represents an independent invention.
`
`4
`
`In view of the above the "single general concept" (Rule 13.1 PCT) linking the
`
`above mentioned inventions cannot even be formulated as oncolytic viruses
`
`comprising a GM-CSF-encoding gene, let alone oncolytic viruses comprising a GM-
`
`CSF-encoding gene for use in the treatment of cancer.
`
`Even if one formulated the single general concept in such a way then such concept
`
`could not be regarded as novel with regard to the prior art:
`
`For instance, D1 (Liu et al.), D2 (Senzer et al.), D3 (Simpson et al., 2006) and D4
`
`(Piasecki et al.) disclose an oncolytic herpes simplex virus type 1 (HSV1) for use in
`
`the treatment of cancer. Such viruses comprise inter alia an agonist of an immune co-
`
`stimulatory pathway (GM-CSF). Said documents also disclose combination therapies.
`
`D4 (Piasecki et al.), for instance, discloses the use of a combination of the vector
`
`disclosed in D3 with an immune checkpoint inhibiting antibody for the treatment of
`cancer.
`
`5
`
`Said prior art documents also address and solve the problem underlying parts of
`
`present application, namely the provision of means for an improved oncolytic therapy
`
`or oncolytic immunotherapy, respectively (p. 3, l. 3-5).
`
`6 Because said single general concept is evidently not novel it cannot be inventive
`
`as required by Rule 13.1 PCT.
`
`7
`
`Furthermore, this authority is of the opinion that the effort necessary for searching
`
`the individual inventions justifies an additional search fee for each invention
`
`mentioned above because, as explained above, the separate inventions are directed
`
`to different subject-matter for which a separate search has to be performed in the
`available databases.
`
`N.B.: The use of the term "invention" here in no way implies recognition of an
`
`inventive step for the subject—matter of any group of claims.
`
`Re ITEM V
`
`Form PCT/ISA/237 (Separate Sheet) (Sheet 2) (EPO-April 2005)
`
`

`

`WRITTEN OPINION OF THE
`
`INTERNATIONAL SEARCHING
`
`International application No.
`
`AUTHORITY (SEPARATE SHEET)
`
`PCT/G82017/050038
`
`1
`
`Novelty and inventive step (Art. 33(2) and (3) PCT)
`
`1.1
`
`
`The subject-matter of claims 1-18 20-22 and 24-48 does not meet the
`
`requirements of Art. 33(2) and 33(3) PCT.
`
`1.2 The definitions "oncolytic virus comprising an immune co-stimulatory pathway
`
`activating molecule" and "oncolytic virus comprising an immune co-stimulatory
`
`
`pathway activating molecule-encoding gene" render the scope of independent claim 1
`
`so broad that practically any prior art virus falls under such definition. Practically any
`
`prior art virus comprises molecules or genes having such property.
`
`Prior art oncolytic viruses further comprising a GM-CSF-encoding gene are well
`1.3
`known in the art.
`
`D1 (Liu et al.), for instance, discloses a "second generation" oncolytic herpes simplex
`
`virus type 1 (HSV1) ("OncoVEXGM'CSF"), wherein the virus:
`
`(a) does not express functional |CP34.5;
`
`(b) does not express functional |CP47; and/or
`
`(c) expresses the US11 gene as an immed iate early gene; and
`
`(d) one or more immune stimulatory molecules or one or more immune stimulatory
`
`molecule encoding genes, wherein the immune stimulatory molecule is GM-CSF (cf.
`
`p. 299, left col. of D1).
`
`1.4
`
`Similar results are disclosed in D2 (Senzer et al.) (p. 5763, right col.).
`
`1.5
`
`Furthermore, a "third generation" oncolytic HSV1 ("OncoVEXGALV/CD" = T-VEC)
`
`based on the "second generation" is disclosed in D3 (Simpson et al., 2006). Said
`
`"third generation oncolytic HSV1 further comprises:
`
`(e) a highly potent pro—drug activating gene (yeast cytosine deaminase (CD)/uraci|
`
`phospho-ribosyltransferase (UPRP) fusion (Fcy::Fur)) and
`
`(f) the fusogenic glycoprotein from gibbon ape leukemia virus (GALV) (e.g. D3, p.
`
`4835, right co|., bottom). A method of treating cancer by applying such vector in
`
`combination with 5—fluorocytosine (5—FC) is also disclosed in D3 (abstract, p. 4835,
`
`right co|., bottom).
`
`1.6 A method of treating cancer with the vector of D3 in combination with an
`
`immune checkpoint inhibiting antibody is also known in the art (see e.g. D4 (Piasecki
`
`et al.): T-VEC + anti CTLA-4 mab ipilimumab or T-VEC + anti-PD1 mab
`
`pembrolizumab).
`
`
`1.7 The subject-matter of independent claim 1 can thus not be regarded as novel.
`
`Form PCT/|SA/237 (Separate Sheet) (Sheet 3) (EPO-April 2005)
`
`

`

`WRITTEN OPINION OF THE
`
`INTERNATIONAL SEARCHING
`
`International application No.
`
`AUTHORITY (SEPARATE SHEET)
`
`PCT/GBZO17/050038
`
`1.8 A positive international preliminary report on patentability can only be
`
`established if claims 2-18 20-22 and 24-48 refer to a claim which can be regarded as
`novel and inventive.
`
`NB: No unified criteria exists among the PCT member states for the examination of
`
`claims directed to methods for treatment of the human or animal body surgery or
`
`therapy (claims 39—46).
`
`2
`
`Industrial application (Art. 33(4) PCT)
`
`
`Claims 1-18 20-22 and 24-48 meet the criteria as set forth by Art. 33(4) PCT.
`
`ITEM VIII
`
`Clarity (Art. 6 PCT)
`
`1 What is a "modified version" of e.g. GM—CSF (e.g. claims 2 and 3)?
`
`2 No "SEQ ID" No is defined in claim 19.
`
`Form PCT/ISA/237 (Separate Sheet) (Sheet 4) (EPO-April 2005)
`
`