PATENT COOPERATION TREATY
`
`PCT
`
`INTERNATIONAL PRELIMINARY REPORT ON PATENTABILITY
`
`(Chapter I of the Patent Cooperation Treaty)
`
`(PCT Rule 44bis)
`
`Applicant’s or agent’s file reference
`6656A-97-POA
`
`FOR FURTHER ACTION
`
`See item 4 below
`
`International filing date (day/month/yeGE)
`International application No.
`21 October 2015 (21.10.2015)
`PCT/U82015/056686
`International Patent Classification (8th edition unless older edition indicated)
`See relevant information in Form PCT/ISA/237
`
`Priority date (day/month/yeCIE)
`21 October 2014 (21.10.2014)
`
`Applicant
`ABBVI E INC.
`
`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 7 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 \0. I
`
`Basis of the report
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`Box \0. II
`
`Box \0.
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`
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`Priority
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`Non—establishment of opinion with regard to novelty, inventive step and industrial
`applicability
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`Lack of unity of invention
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`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
`25 April 2017 (25.04.2017)
`
`AthHZEd officer
`
`Athma NICkItaS-Etlenne
`e—mail; pct.[eam4@wip0.int
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`Box \0.
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`Box \0.
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`Box \0.
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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/US2015/056686
`
`International filing date (day/fnonth/year)
`21.10.2015
`
`Priority date (day/month4/ear)
`21.10.2014
`
`
`
`
`
`International Patent Classification (IPC) or both national classification and IPC
`INV. A61K31/661 A61K31B615 A61 P25/16
`
`
`Applicant
`ABBVIE INC.
`
`1.
`
`This opinion contains indications relating to the following items:
`
`Box No. I
`
`Basis of the opinion
`
`Box No. II
`
`Priority
`
`ROOKIE 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
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`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/22O 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
`
`Trifilieff-Riolo, S
`Telephone No. +49 89 2399-0
`
`F
`we“ “BMW-ts
`f3 o 6%:
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`3’
`94’
`3.
`ewmmw
`-
`
`
`
`—
`a) European Patent Office
`)
`— 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/U82015/056686
`
`Box No. I Basis of the opinion
`
`1. With regard to the language, this opinion has been established on the basis of:
`
`IZI
`
`El
`
`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:
`
`a. El
`
`forming part of the international application as filed:
`
`CI
`
`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. D 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:
`
`Form PCT/ISA/237 (January 2015)
`
`

`

`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING AUTHORITY
`
`International application No.
`PCT/U82015/056686
`
`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
`
`1. Statement
`
`Novelty (N)
`
`Yes: Claims
`No:
`Claims
`
`1-44, 46-63, 65-70
`
`45 64
`
`Inventive step (IS)
`
`Yes: Claims
`No:
`Claims
`
`1-44, 46-63, 65-70
`
`45 64
`
`Industrial applicability (IA)
`
`Yes: Claims
`No:
`Claims
`
`1-70
`
`2. Citations and explanations
`
`see separate sheet
`
`Box No. VII Certain defects in the international application
`
`The following defects in the form or contents of the international application have been noted:
`
`see separate sheet
`
`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
`
`AUTHORITY (SEPARATE SHEET)
`
`International application No.
`
`PCT/U82015/056686
`
`Item V:
`
`Reference is made to the following documents:
`
`D1
`
`D2
`
`EP 0 393 781 A2 (SIMES [IT]) 24 October 1990 (1990-10-24)
`
`US 2012/288446 A1 (GARIGAPATI VENKAT R [US] ET AL) 15 November
`
`2012 (2012—11—15)
`
`D3
`
`PAWELEK ET AL.: "INCREASE IN MELANIN FORMATION AND
`
`PROMOTION OF CYTOTOXICITY IN CULTURED MELANOMA CELLS
`
`CAUSED BY PHOSPHORYLATED ISOMERS OF L-DOPA",
`
`CANCER RESEARCH,
`
`vol. 46, no. 2, February 1996 (1996-02), pages 493-497,
`
`1.1.
`
`Subject-matter of claims 1-17: "combination" comprising a compound (I) and
`
`compound (II) in separate compositions or in the same composition (see item VIII)
`
`Subject-matter of claims 18-33: method to treat Parkinson with the compositions
`
`Subject-matter of claims 34-44: compound per se formula (I)
`
`Subject-matter of claims 45-48: compound per se formula (II)
`
`Subject—matter of claims 49—52: composition comprising compound of formula (I)
`
`Subject-matter of claims 53-61: composition comprising compound of formula (I) and
`
`compound of formula (II)
`
`Subject-matter of claims 62,63: kit comprising composition or combination above
`
`Subject-matter of claims 64: compounds per se : synthetic intermediates
`
`Subject-matter of claims 65-70: crystalline polymorphs of different compounds I and II
`as above
`
`1.2. Claims 18—33 relate to subject—matter considered by this Authority to be covered
`
`by the provisions of Rule 39.1 (iv) / 67.1 (iv) PCT.
`
`Patentability, in particular novelty and inventive step, of these claims has been
`
`assessed on the basis of a purpose-limited product claim taking into account the
`
`alleged effects of the compound/composition.
`
`The patentability can be dependent upon the formulation of the claims. The EPO, for
`
`example, does not recognise as patentable claims to the use of a compound in
`
`medical treatment, but may allow Claims to a product, in particular substances or
`
`compositions for use in a first or further medical treatment.
`
`Form PCT/ISA/237 (Separate Sheet) (Sheet 1) (EPO-April 2005)
`
`

`

`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING
`
`AUTHORITY (SEPARATE SHEET)
`
`International application No.
`
`PCT/U82015/056686
`
`2.1.
`
`D1 in ex. 5 describes compounds of formula (II) as follows:
`
`3-hydroxy-4-phosphonyloxy-L-phenylalanine ethyl ester
`
`4-hydroxy-3-phosphonyloxy-L-phenylalanine ethyl ester
`
`3-hydroxy-4-phosphonyloxy-L-phenylalanine n-butyl ester
`
`3—hydroxy—4—phosphonyloxy—L—phenylalanine isopropyl ester
`
`Thus the subject-matter of claim 45 is not novel (A. 33.2).
`
`It also describes (p. 8, l. 25) the compound (a) of claim 64 which thus also lacks
`
`novehy.
`
`2.2. D2 (p. 6 §30) describes L-DOPA 3- and 4-monophosphate and L-DOPA
`
`diphosphate which emphasizes the lack of novelty of claim 45 (A. 33.2).
`
`2.3. D3 describes 3-phospho,-4-hydroxyphenylalanine and 3-hydroxyl,-4-
`
`phosphophenylalanine.
`
`Although it is stated that the isomers are not separated by HPLC in this experiment, at
`
`the date of publication of this document the skilled person was capable to separate
`
`them by means of known chromatographic techniques.
`
`D3 thus emphasizes the lack of novelty of claim 45 (A. 33.2).
`
`3. The present invention is concerned with Parkinson's disease and tries to solve the
`
`problem of providing continuous and consistent dopamine level in the brain.
`
`The use of combinations of L-DOPA and Carbidopa to this end is known in the art (as
`
`stated in the present description p. 1, |. 27-28). However alternative solutions are
`
`always needed.
`
`The solution proposed by the present application is to use a combination of
`
`phosphorylated derivatives of DOPA and phosphorylated derivatives of Carbidopa.
`
`Ex. 20 of the application shows that in mini-pigs a combination of L-Dopa 4-
`
`monophosphate and carbidopa-4-monophosphate allows a steady plasma
`
`concentration of Dopa during at least 13 hours. Until any proof of the contrary it is
`
`assumed that this effect exists with the other Dopa and Carbidopa phosphorylated
`derivatives claimed.
`
`The closest prior art document seems to be D1.
`
`It is concerned with the same problem
`
`of providing continuous and consistent dopamine level in the brain by means of
`
`modified Dopa derivatives. Its solution is to use monophosphorylated Dopa
`derivatives.
`
`Form PCT/ISA/237 (Separate Sheet) (Sheet 2) (EPO-April 2005)
`
`

`

`WRITTEN OPINION OF THE
`INTERNATIONAL SEARCHING
`
`AUTHORITY {SEPARATE SHEET)
`
`International application No.
`
`PCT/U82015/056686
`
`The difference with the present invention lies in the use of a combination of
`
`phosphorylated derivatives of DOPA and phosphorylated derivatives of Carbidopa.
`
`No technical effect linked to it is shown, thus the problem is to provide an alternative
`solution to that of D1.
`
`It is known to combine Dopa and Carbidopa to treat Parkinson and it is known that
`
`phosphorylated Dopa derivatives are advantageous too.
`
`Nothing however suggested that these teachings could be combined to arrive at the
`
`present invention, particularly nothing suggested that Carbidopa could also be
`
`phosphorylated.
`
`It thus appears that the subject-matter of the present invention, as far as it is novel,
`
`would meet the requirements of inventive step (A. 33.3).
`
`Item Vll:
`
`Contrary to the requirements of Rule 5.1 (a)(ii) PCT, the relevant background art
`
`disclosed in D1, D2 and D3 is not mentioned in the description, nor is this document
`identified therein.
`
`Item VIII:
`
`The application does not meet the requirements of Article 6 PCT, because claims 1 to
`
`6 and those depending on them are not clear.
`
`It is not understood how " a pharmaceutical combination" comprising 2 compounds
`
`can be different from a "pharmaceutical composition" comprising the same 2
`
`compounds.
`
`Form PCT/ISA/237 (Separate Sheet) (Sheet 3) (EPO-April 2005)
`
`