1
`
`3M COMPANY 2013
`Mylan Pharmaceuticals Inc. v. 3M Company
`IPR2015-02002
`
`

`

`European Patent No. 0 493 437
`
`Riker I.a‘t1tc:1fator'ies,
`
`Inc.
`
`and Opposition thereof by
`
`Iago Pharma AG
`
`Reply of Patentee
`
`1. Request
`
`Patentee requests that the Opposition be dismissed and the patent upheld in its granted
`form. In the event that the Opposition is not withdrawn or dismissed upon the basis
`of this reply, Patentee requests an Oral Hearing.
`
`II. General Remarks
`
`Q The grounds for opposition raised by the Opponent are those of Art. 100 a) EPC,
`in particular an alleged lack of novelty and inventive step (page 1 of the Opposition
`paper). Under Section 2 of the Opposition paper,
`the Opponent also criticizes the
`experimental
`investigations disclosed in the present patent, as they were carried out
`"only
`for the combination of the propellant 134a (1,1,1,2-tctrafluoroethanc) with
`Epikuron 2110, Span 85 and oleic acid."
`
`it would appear
`The relevance of this criticism for the present opposition is llnclear;
`to be an argument related to Art. 84 EPC, which is in any case unavailable in
`Opposition proceedings. Nevertheless it
`is to be noted that
`the experiments reported
`employ exemplary and relevant propellants (P134a and perfluoropmpane) as well as
`exemplary and several
`relevant surfactants. A series of experiments were performed
`and disclosed in the patent,
`involving the comparison of a multitude of diiferent
`aerosol compositions according to the invention, compositions prepared via the admixtu-
`re of propellant, surfactant and medicament according to conventional procedures and
`compositions prepared with no surfactant. These experiments and their results are more
`than sufficient
`to demonstrate the effectiveness of the compositions according to the
`invention and to support the claimed subject matter.
`
`that "claim 1
`_B_. The Opponent also claims under section 2 of the Opposition paper,
`comprises aerosol compositions with coated medicament particles irrespective of how
`the coating comes about
`..." and applies
`this line of argument
`throughout
`their
`opposition paper. The Opponent submits a number of prior art documents concerned
`with suspension aerosol
`formulations comprising of admixtures of CFC—propellants,
`propellant—soluble
`surfactants and medicament,
`in which in some documents it
`is
`disclosed that
`the soluble surfactants exert
`their activity by forming a film on the
`
`-1-
`
`._....,
`..
`....- ._..
`;1AA.H.
`'a'#:s9tz+escz; 69 612+ ”' ‘ ‘#6939’ its TLTO
`
`,--.._...
`:
`
`.
`
`_.-l—-
`
`-t-0:91
`
`:
`
`:
`
`._-._-
`so NaH3Nafi1iRl—vZI':iEE\’<)A'Ao2t
`
`2
`
`

`

`tries to give the impres-
`dispersed particles in the aerosol suspension. The Opponent
`sion that such film formation is the same as the coating referred to in claim 1 of the
`present patent. This argument of the Opponent is however based on a misinterpretation
`of the Wording of claim 1.
`
`is
`it
`From the wording of the main claim and the description of the present patent,
`readily understandable that
`the solid medicament
`is coated with propellant—insolub1e
`nonperlluorinated surfactant prior to dispersion in the aerosol propellant. This under-
`standing is clearly supported by the patent specification, for example
`
`"It has been found that nomperfluorinated surhctants which are insoluble in a
`propellant may nevertheless be used with such a propellant
`to form stable
`dispersions of powdered medicament providg the powdered medicament is pre-
`coaled with the non-perfluorinated surfactant prior to dispersing the powdered
`medicament in the propellant..." (page 3,
`lines 1-7, see also page 3,
`lines 17-
`25, phasis added).
`
`Further,
`
`the patent specification discloses that
`
`that the same stable
`is particularly surprising in view of the fact
`"Tb.is. result
`dispersions cannot be achieved by simple admixture of the surfactant, propellant
`and medicament." (page 3,
`lines 25-28)
`
`the coating in aerosol suspension (previously noted for
`According to this observation,
`propellant, propellant-soluble surfactant and drug systems) does not take place in those
`systems where the non-perfluorinated surfactant is substantially insoluble in propellant.
`Thus
`the argument presented by the Opponent
`that claim 1
`refers
`to "...aeroso1
`compositions with coated medicament particles irrespective of how the coating comes
`about ...', especially coating in aerosol suspension,
`is inconect.
`
`Ill. Subject Matter of the Claims
`
`Claim 1 of the present patent claims
`1)
`a self-propelling, powder dispensing aerosol composition
`comprising:
`at
`least 0.00] wt % of finely-divided solid medicament
`coated with a non—perliuorinated surface—active dispersing agent
`which constitutes at
`least 0.001% wt of the coated solid material
`and suspended in an aerosol propellant in which non-perfluorinated surfactant is
`substantially insoluble,
`requiring more than 10,000 parts of propellant
`to dis-
`solve one part of the surfactant at room temperature.
`
`2)
`3)
`4)
`5)
`
`Claims 2 to 10 relate to further embodiments of the aerosol compositions of claim 1,
`which are further defined with respect
`to the preferred amount of dispersing agent,
`average particle size of the medicament, amount of the medicament in the composition,
`preferred ratio of medicamentzdispersing agent, preferred dispersing agents, medica-
`ments, propellant and adjuvants and the prefen-ed amount of propellant and adjuvant.
`
`.2.
`
`8 #:s9tztz66cz es 6'I7+
`
`‘r’-69:9 us ILIO
`
`: 90281
`
`2 L6-I
`
`-01:
`
`so NsIH3N3r'1f«1—v2i‘aE‘N'<>A‘A3a
`
`3
`
`

`

`Claim 11 discloses
`
`1)
`
`2)
`
`3)
`4)
`5)
`
`a method for preparing a self—propelling, powder dispensing aerosol composition
`comprising:
`a)
`coating a finely divided solid medicament with non-perfluorinated surface-
`active dispersing agent
`in a solvent
`in which the said medicament
`is
`substantially insoluble,
`separating the coated solid material from the solvent by filtration,
`drying the coated finely divided solid material
`high energy dispersing said material
`in an aerosol propellant (in which
`surface~active dispersing agent
`is substantially insoluble,
`requiring more
`than 10,000 parts of propellant to dissolve one part of the surfactant at
`room temperature) such that
`the aerosol composition comprises at
`least
`0.001 wt % of said medicament and at
`least 0.001 wt % of the said
`
`b)
`c)
`cl)
`
`material
`
`is the non-perfluorinated surfactant.
`
`Claim 12 is directed to a method of claim 11 for preparing a composition as defined
`in any one of claims 1 to 10.
`
`IV. Novelty
`
`the claimed subject
`Opponent argues under section 16 of the opposition paper that
`matter of the patent is anticipated by D17 and D18, which represent prior rights in
`respect of the present patent. The disclosures of D17 and D18 are discussed further
`in sections 13 and 14 of the opposition paper,
`respectively.
`
`The Opponent puts forth that D17 discloses suspension aerosol formula-
`tions comprising of a medicament (identical
`to patent at
`issue). with a concentration
`in the range 0.01 to 5 wt % of total formulation, a surfactant (substantially identical
`to patent at issue), weight ratio 1:100 to (>)l0:l surfactant: drug, P134a, 60-95 wt
`%, and an adjuvant, weight ratio 50:50 to 99:1 P134a 2 adjuvant.
`
`the surfactant is dissolved and found (as
`In the aerosol formulations according to D17,
`a dissoluted species) in the liquified propellant system. D17 does not disclose aerosol
`compositions comprising surfacta.nt—coated medicament particles (according to features
`2) and 3) of claim 1. see Section III, supra) and propellant.
`
`The invention according to the present patent teaches that nomperfluorinated surfactants
`which are insoluble in a propellant may be used to form a stable dispersion of
`powdered medicament provided the said medicament
`is coated with the said surfactant
`prior to dispersing the powdered medicament
`in the propellant
`(page 3,
`lines 1-7).
`Thus in the aerosol compositions of the present invention,
`the surfactant
`is concentrat-
`ed as a coating on the suspended medicament particles.
`
`D17 does not anticipate the teaching or the aerosol compositions of the present patent.
`The present patent is clearly new over D17.
`
`-.
`
`_.. _....-.r
`....-..
`r-Aa.'.‘.I.
`'+"#:99Hseez s8‘?c'«t+ ""1—'osa'.9 us ILIO
`
`---_._.
`: sozer
`
`...._- -..r _._.—
`;s—r -or:
`
`:
`
`eo‘N:'ri'r5Nzrr'1l‘~1—vZrfa:'i\r'r>A'A32r
`
`4
`
`

`

`the disclosure for fentanyl citrate
`is of the opinion that
`5_9¢£i£I1_léL; The Opponent
`formulations common to D18, W0-A-90/07333 filed 4.1.1990. and D19,
`the priority
`application GB 8900267.9 filed 6.1.1989, represents a prior art which is prejudicial as
`to novelty for the patent at issue.
`
`the Opponent argues that D19 (anrl D18) teaches solution or suspension
`In particular,
`formulations comprising fentanyl citrate 0.1-1.0 wt %, surfactant, amounts to 01.-1.0
`wt % for Span 85 or in the case of lecithin 1:1 to 1:16 ratio effective substance:lecit-
`hin, solvent 5-25 wt % and P1342 as propellant, referring to D18 page 2,
`line 28 to
`page 3,
`line 4 and to D19 page 2,
`lines 8-11 and page 3,
`lines 7-11.
`
`the priority application does not disclose the use of P134a alone as the
`However,
`this was only introduced in D18 at
`the International filing date. Rather,
`propellant;
`D19 discloses on page 4, 3rd paragraph "[o]tber preferred propellant systems
`comprise 1,1,1.2,-tetrafluoroethane, a surface active agent and at
`least one compound
`having a higher polarity than 1.1.1.2-tettafluoroethane." Hence the "propellant" dis-
`closed in D19 is in fact a ternary propellant system including P1343. In such ternary
`P134-a-based propellant systems,
`the non-pcrfiuorinated surfactant
`is soluble. Thus,
`the
`common disclosure for D18/D19 does not teach the application of substantially propel-
`lant-insoluble non-perfluorinated surfactants according to feature 5) of claim 1.
`
`Furthermore the D18/D19 common disclosure for fentanyl citrate formulations does not
`disclose the application of surfactantcoated medicament particles according to features
`2)-3) of claim 1 and features 2)4) of claim 11 of the present patent for the prepara-
`tion of aerosol formulations.
`
`is novel over D19. and novel over the disclosure of D18 as
`the present patent
`Thus,
`far as it is prior an in respect of the present patent.
`
`V. Inventive Step - Problem-Solution Approach
`
`In the Opposition paper the Opponent oifers a number of combinations to substantiate
`the alleged lack of inventive step of the independent claims 1 and 11. Basically the
`combinations can be ordered in two groups: D1 alone or with D3-D8 (and maybe D9)
`(see sections 4-5 and 9) and D11 with each D1, D3-D10 (see section 11). Apparently
`the Opponent was unable to decide between D1 or D11 as the closest prior art. Also,
`the Opponent obviously did not consider
`inventive step in view of
`the technical
`problem actually solved by the subject matter claimed. D1 and D11 as closest prior
`art will be discussed,
`individually, below.
`
`A.
`
`[)1 as Closest prior art
`
`D1 filed on April 4, 1963 discloses compositions for inhalation therapy in which solid
`drugs, specifically epinephrine or isoproterenol, are dispersed in a non-toxic propellant
`employing a.
`fatty alcohol as a dispersing agent,
`in particular oleyl alcohol or
`in
`
`.4.
`
`‘<§‘#':‘§s§fizsccz'cri 617+
`
`costs’ ILS ILIO
`
`: 90:81
`
`:
`
`‘[671 ‘-61:
`
`c0'l§IéFI5Nar'1I7u—v?r:=15’z‘\;'(),\-,\33
`
`5
`
`

`

`lines 30-37).
`admixture with other saturated and unsaturated fatty alcohols (column 3,
`The dispersing agent
`is present as a coating on the finely divided drug particles
`(column 2,
`lines 79-80).
`
`The dispersing agents applied according to D1 are exclusively non-pcrfluorinated and
`soluble in the propellants or propellant blends disclosed in D1.
`(See our communica-
`tion with the EPD from September 3, 1991).
`
`As suitable non—toxic volatile liquid propellants are disclosed those known in the art
`and those discussed in D2,
`i.e. US Patent 2,868,691 (column 4,
`lines 83-85). At the
`time of the filing and issue of the patent D1,
`the non-toxic propellants known in the
`an included CFCS, e.g. P12, P11, P114, and C313; but not propellants in which the
`applied surfactants would be, as determined more than 20 years later,
`substantially
`insoluble,
`like I-IFCs, for example Pl34a. For the skilled person formulating medicinal
`aerosols,
`such I-IFC—p1-opellants were not
`state of
`the art propellants. Either
`the
`propellant as such or its toxicological properties were, at
`that
`time, not known and
`therefore their application for medicinal
`inhalation compositions was not known in the
`art and could not be considered as a suitable non-toxic propellant according to D1.
`
`incorporated by reference in D1, discusses in general non-toxic propellants for
`D2,
`medicinal purposes in which preferred compounds may be represented with the general
`"formula C,,,H,,Cl,F, wherein in is an integer less than 3, n is an integer or zero, y is
`an integer or zero and z is an integer such that n+y+z = 2m+2; and more spe-
`cifically Pll, P12 and P114. Although I~[FCs propellants,
`like P134a, would fall under
`the general formula of D2, at the priority date the skilled person's understanding of
`D2 would not have extended to H1=Cs because the toxicological properties of such
`propellants and,
`in some cases,
`their existence were at
`that
`time unknown. More
`importantly the problem that
`the commonly used non-perfluorinated surfactants could
`not be simply used with HFC propellants due to insuflicient solubility was not known.
`
`B. The Technical Problem in view of D;
`
`the technical problem underlying the invention
`In view of the above analysis of D1,
`as claimed in claim 1
`is to provide effective suspension aerosol compositions with
`non-perfluorinated surfactants which are substantially insoluble in the propellant applied.
`
`is to provide a
`The technical problem underlying the subject matter of claim 11
`method to prepare effective suspension aerosol compositions with non-pcrfluorinated
`surfactants which are substantially insoluble in the propellant applied.
`
`C. Comparative ggsgggt
`
`1. Section 3 - D1: Under section 3 of the opposition paper, Opponent argues that
`C1311-n
`1 of the present patent conesporlds merely to a consistent application of the
`
`-5-
`
`9 u:c917e6oec 643‘ 617+ ""€—'0sz9
`
`I/.9 11.10
`
`: 90:81
`
`: L8-l
`
`-01:
`
`eo'i§l;51t'i5N3r'1i\l—vZi'E~i£i\I?)A'Ao2i
`
`6
`
`

`

`teaching of D1 to the propellants included in the present patent,
`active agents are now poorly soluble.
`
`in which surface-
`
`in which it was recog-
`The teaching of D1 is consistent within the state of the art,
`nized that
`in order
`to obtain eficctive suspension formulations
`the application of
`propellant-soluble surfactant is necessary (please see the discussion below of D3, D4
`and D8; D3 is prior art for D1).
`
`D1 discloses that although oleyl alcohol alone is an extremely satisfactory suspending
`agent,
`if used in large amounts,
`the drug may settle in the pre-mixed drug-alcohol
`compositions, and in such a case a solid alcohol (the solid alcohols according to D1
`are soluble in the propellants of D1) may be added to oleyl alcohol
`to increase its
`viscosity (cf. column 5,
`lines 39-49).
`
`in any way the application of substantially
`The disclosure of D1 does not suggest
`propellant-insoluble surfactants or how to effective apply such surfactants.
`In fact D1
`did not
`recognize potential problems associated with surfactant and its solubility in
`non-CFC propellants or propellant blends used in the present patent. Thus the disclo-
`sure of D1 does not and could not suggest
`the inventive aerosol formulations accord-
`ing to the present patent.
`
`Thus, claim 1 of the present patent shows an inventive step over the teaching of D1.
`
`the Opponent argues that claim 11 of the present patent dilfers from
`Under section 3.
`the method disclosed in D1 only in that
`the coating of the medicament particles is
`achieved in a solution of the surfactant
`instead of with the surfactant
`itself, and the
`solvent has to be subsequently separated. The Opponent argues that this modification
`appears to be already obvious to the skilled worker on the basis of D1 in particular
`with the use of solid surfactants. Dl however, does not suggest coating the medica-
`ment with a propellant-insoluble surfactant prior to dispersing it
`in a propellant.
`
`the preparation of
`for
`is a process
`the present patent
`Furthermore, claim 11 of
`compositions according to claim 1. Since the compositions are new and inventive, and
`thus patentable. The same holds true for the process according to claim 11; sec e.g.
`Decision of the Technical Board of Appeal 3.3.1 T119/82.
`
`2. Section 4 - D3 & D3; Here the Opponent submits two patent specifications US-A-3
`014 844 (D3) and DE—PS 1 178 975 (D4) (in which D3 is a priority document for
`the German patent) and indicates that through these specifications, aerosol compositions
`in which medicament particles are coated with a non-pet-fluorinated surfactant were
`known.
`
`formulations comprising in
`D3 and D4 disclose and/or claim (medicinal) aerosol
`in liquefied (for medicinal
`essence finely-divided (medicament) powder
`suspended,
`purposes non-toxic) propellant having surfactant being soluble in said liquefied propel-
`lant (see claims 1 and 20 of D3).
`
`L azgowsssrz 68 617+
`
`'<—'69z’9 ILS [L10
`
`sofiétitémafiiit-v2té;£‘Nb,\gtga
`
`7
`
`

`

`Both D3 and D4 teach that the employed surfactant must be soluble in the propellant
`in order to obtain effective suspensions aerosols. For example, D3 disclosed in column
`5,
`lines 5-10 and 37-39:
`
`"After an extensive investigation employing many surface-active agents, we have
`discovered that particular agents or combinations of them are required to give
`desirable results. During this investigation it was
`found unexpectedly that a
`number of surface-active agents provided poor suspensions and failed to prevent
`gglomeration.
`Those surface—active agents which are soluble or dispensible
`in the propellant are eifective. The more propel1ant—soluble surface-active agents
`are the most eflisctive."
`
`The said investigations were performed using CFC-propellant blends consisting of P11,
`P12 and P114 (D4 column 6, lines 24-32 and D3 column 5,
`lines 68-73). D3 and D4
`make clear that soluble surfactants are required to obtain effective suspension aerosol
`formulations, and thus,
`they teach away from the invention according to the present
`patent.
`
`formula given for
`the general
`fall under
`like Pl34a,
`Although HFC propellants,
`propellants, only the conventional propellants known at
`that
`time were explicitly
`disclosed and once again P134a (as well as other HFC propellants) itself as well as
`its chemical properties were at that time not known.
`
`line 5) indicates
`line 72 to column 5,
`lines 17-24 (of. D3 column 4,
`D4 in column '7,
`that the results may be due to the surfactant forming a mono-molecular film on the
`finely-divided powder which prevents the particles
`from agglomerating either while
`dispersed in the propellant or when in the valve of the container: This disclosure is
`related to the formulations according to D4 in which the surfactant is dissolved in the
`liquid propellant and the powder is dispensed in this surfactant-propellant solution. This
`disclosure is not applicable to systems comprising a p1'ope1lanI—insolI.lble surfactant-
`coaied powder dispersed in propellant. This disclosure as well as the disclosure of D4
`in its entirety alone or in combination with the teaching of D1 do not suggest
`the
`formulations according to present invention or indicate that such formulations would be
`effective.
`
`in which
`Claim 1 of D4 claims the production process of such aerosol compositions,
`the components are mixed in any order under the exclusion of water. However,
`this
`process does not in any way suggest the process according to claim ll of the present
`patent. Neither D3 nor D4 teach coating of the powdered medicament with surfactant,
`then suspending the coated medicament in the non-toxic propellant.
`
`the subject matter of claims 1 and 11 of the present patent
`Accordingly,
`in light of D3 or D4 alone or in combination with D1.
`
`is unobvious
`
`3. gection 5 — D5: The Opponent submits D5 which discloses aerosol formulations in
`which a solid or salve—form non-iouogenic surfaceactive substance is used as emulsifier
`(column 1.
`lines 40-62). The Opponent presents the argument that "although it is not
`
`-7-
`
`'§‘4£?<_‘iét7re68'z':'Es‘é"ét+
`
`150339 [LS um
`
`: LO:8I
`
`: L6-I
`
`-01:
`
`co't\‘{2‘ifi5Nzir'1ft-vIi‘EI':N'oA"Asa
`
`8
`
`

`

`the emulsifier forms a coating on the effective sub
`in D5 that
`expressly pointed out
`stance particles,
`this is obvious in view of D1, D3, D4 ...." and thus the subject
`matter of Claim 1 is already suggested by D5.
`
`D5 discloses that the suspension formulations taught by D4. whereby a soluble liquid
`surfactant
`is dissolved in the propellant and in this
`solution the active substance
`particles are suspended, are in some cases not sufliciently stabile and deposit sediment
`relatively quickly (colunm 1,
`lines 40-52).
`
`It is clear that the patentee of D5, a skilled person in the art. did not understand the
`teaching of D4 (and thus D3) to be the coating of the particles with a (propellant-
`insoluhle) surfactant and then suspending these in the propellant. This further supports
`our assertions above that D4 and D3 do not suggest precoating the active substance
`particles with a surfactant, especially a propellant—inso1uble surfactant.
`
`D5 teaches an improvement of the suspension formulations disclosed in D4 in which
`solid or salve-form surfactants are used as emulsifiers and through this teaching stable
`suspensions are obtained in which the particle remain evenly distributed (no sedimenta-
`tion Occurs)
`(cf. column 1,
`lines 57-69 and column 3,
`lines 4-9).
`
`It is evident to those skilled in the art that the application solid or salve—forrn emulsi-
`fiers according to D5 acts to increase the viscosity of the suspension. The application
`of such solid and salve-form materials to increase the viscosity and thus prevent
`sedimentation was at
`that
`time generally well-known. For
`instance regarding settling
`problems D1 (state of the art for D5)
`teaches "in such a case,
`the other alcohols,
`which are solids at room temperature, may be added to oleyl alcohol
`to increase its
`Viscosity" (page 3,
`left column,
`lines 43-49).
`
`teach or in any way suggest, either alone or in combination
`D5 does not disclose,
`the coating of the particles to be suspended with a surfactant
`with D1, D3 and D4,
`according to the invention of the present patent,
`i.e. claim 1.
`
`The Opponents also argues that D5 suggests the subject matter of claim 11 of the
`present patent. D5 teaches the homogenization of the active substance in a solution of
`surfactant in a liquid suitable for grinding (cf. column 2,
`lines 53-63). Homogenimtion
`is well known to the skilled worker to mean,
`to reduce and uniform particle size and
`to distribute the particles evenly throughout an emulsion. The method disclosed and
`claimed in D5 is not comparable to that of the present patent. The method described
`in D5 does not suggest
`to the skilled worker to coat the particles with the surfactant
`or to dry the particles before dispersing them in the propellant. Moreover there is no
`suggestion in D5 to the skilled person faced with the the problem of formulating
`inhalation aerosol with substantially propellant-insoluble non-perfluorinated surfactants
`(cf.
`technical problem under Section V. B., stpm) that precoating would result
`in a
`stable suspension. Thus D5 alone or in combination with D1, D3 or D4 does not
`suggest the process according to claim 11 of the present patent.
`
`6 #:99Hz66£:a so 617+
`
`+0939 [LS ILIO
`
`: _I_():g[
`
`: 13-1 -61;
`
`g0‘,Q;‘;fi5N3f,;t_V;,§,,;\,;,‘,\-A3,,
`
`9
`
`

`

` J-_l3Q The Opponent submits as D6 Us Patent 3,897,779 in which a
`suspension aerosol
`is disclosed consisting of an admixture of medicament (specifically
`micronized triamcinolone acetonide), CFC-propellant (specifically P11) and surfactant,
`sorbitan trioleate. The Opponent claims "...
`the effective substance is obviously coated
`here with the nompetfluorinated surfice—active agent“ as shown by the provision of a
`stabilized formulation.
`
`"in a chlorofluoroalkane
`D6 is concerned only with the preparation of suspensions
`propellant of finely divided triamcinolone acetonide ..." (cf. claim 1). The Examples
`I-Ill
`teach the preparation of such suspensions via admixture of the drug, P11 and
`sorbitan trioleate (which is
`soluble in P11) or ethanol. The drug particle are not
`coated with surfactant prior to dispersion and there is also no hint
`in the disclosure
`that
`the drug particles are coated within the suspension. There is also no teaching
`conoeming the application of propel1ant—insoluble perliuorinated surfactants or how to
`obtain stable aerosol suspensions when using propellants in which non—perfluorinated
`surfactants are insoluble. The disclosure of D6 alone or in combination with D1 does
`
`not suggest the solution to the problem as claimed.
`
`suspension aerosol consisting of
`- D7: D7 discloses a commercial
`§ect._ign 7
`§.
`epinephrine bitartrate, sorbitan trioleate and fluorocatbons and the Opponent concludes
`from this that "...coated efiective substance particles are also present here".
`
`the publication year of D7, commercial aerosols contained only CFC propel-
`In 1986,
`lant and at that time the term "fluorocarbon" was generally used for CFCS and it is
`obvious to the skilled reader that the formulation of D7 is based on CFC-propellants.
`Once again the surfactant, sorbitan trioleate,
`is soluble in CFC propellant,
`thus the
`disclosure does not provide any teaching concerning formulations with propellant-
`insoluble nonperfluorinated surfactant. The disclosure also does not provide any hint
`about coating the drug with surfactant prior to dispersion in propellant. D7 alone or
`in combination with D1 does not suggest the teaching of the present patent.
`
`6. Section 8 — Q3: As put forth by the Opponent D8 states on page 155:
`
`the effective substances must in most cases be rnicroni-
`"In suspension aerosols,
`sed before they are processed. The guaranteeing of unchanged particle sizes by
`eliminating agglomeration has a particular importance here.
`
`For the production of very homogeneous suspensions, grindings of the microbi-
`sed effective substances with materials such as isopropyl myristate and neutral
`oil, , are recommended." (emphasis addcd)
`
`in the propellant are to be
`D8 clearly teaches that substances which dissolve well
`used, and thus clearly teaches away from the application of substantially prope1lant—
`insoluble non-perfiuorinated surfactants in aerosol suspension formulations. Again there
`is no indication to the technical problem underlying the present
`invention or how to
`solve such a probl.
`
`-9- t
`
`‘o't‘#':‘§97t7iz66ez 68 612+ "“'¥—T)9z9 [LS ILIO
`
`:
`
`./.0:8T
`
`2 L6-I
`
`-01:
`
`so Nangnann-vzfaémbmtgg
`
`10
`
`

`

`Thus D8 alone or in combination with the disclosure of D1 does not suggest
`invention according to the present patent.
`
`the
`
`the Opponent submits
`Under section 9 of the opposition paper,
`sections from two handbooks D9 and D13. The provided pages of Chapter 21 (pages
`427-433) of D9 provide very general information about inhalation aerosols; there is no
`teaching concerning formulations of any type of inhalation aerosol,
`let alone fonnula-
`tions employing a propellant—insoluble surfactant.
`
`in particular those suspensions which are
`Chapter 18 is concerned with suspensions,
`used internally by the spoon; for treatment of the skin;
`lotions; ointments, supposito-
`ries,
`injection and eye preparations with suspended medicaments; suspension filled in
`capsules; dry suspension to which water
`is added shortly before use (see first
`two
`paragraphs of Chapter 18). Suspension inhalation aerosols are not explicitly addressed
`in Chapter 18.
`
`through the
`that
`forth by the Opponent,
`In general, Chapter 18 discloses, as put
`addition of amphiphilic compounds to a hydrophilic suspension medium, a reduction of
`the surface tension takes place between the dispersed solid and the liquid phase and
`the surfactant molecules form a film around the particles — coating in aerosol suspen-
`sion. Once again the disclosure teaches the addition of a (now) suspension-medium-
`soluble surfactant to the suspension-medium with a dispersed solid (page 362 next to
`last paragraph),
`to form an adnnjxture. D9 does not teach how to apply a substantially
`propellant-insoluble non-perfluorinated surfactant to provide an efi’ective aerosol formula-
`tion. D9 provides no hint about pre-coating the particles with any type of surfactant
`before dispersion in the suspension-medium.
`
`inhalation
`this time in direct relation to oral
`D13 provides a similar disclosure as D9,
`aerosols. In the examples disclosed in D13 on page 603, each of which are consisting
`of admixtures of drug, CFC-propellant blends and surfactant,
`the surfactant applied is
`soluble in the given CFC—propellant blend. Once again the disclosure of D13 does not
`suggest how to prepare an effective suspension aerosol employing a
`substantially
`prope1lant—insoluble non-perfluorinated surfactant and there is no hint about pre-coating
`the drug particles with any type of surfactant prior to dispersion in the propellant
`blend.
`
`The teaching of the present patent is not obvious in light of the disclosures of D9 or
`D13. Furthermore the combination of the disclosure of D9 (or D13) with D1 also
`does not suggest the invention according to the present patent.
`
`§, sgtjgn 10 - D10: The Opponent submits as D10 an article in which "[a]ggregation
`of five surfiictants, sorbitan mono and tri—o1eates (Span 80 and 85), dioleiu (D0), oleic
`acid
`(QA)
`and purified phosphatidylcholiue
`(PC), was monitored
`in a model
`chlorofluorocarbon, nichlorotrifluoroethane (P113) by an iodine solubilization method
`
`Tia Fééfisscz es‘ E§>t»+
`
`«-0939 IL9 Trio’
`
`: 90:31
`
`: L6-I —'ot:
`
`2:o'r§i:'iFi5NEtf1it—vTi‘a£N'o,\-A33,
`
`11
`
`

`

`The results showed that for Span 80, 85, DO and PC above a certain concentration,
`the surfactant molecules in the P113-solution organize into cyclic aggregates. Such
`aggregation was not observed for DA, and D10 discloses
`that OA would probably
`associate at much higher concentrations than those studied.
`
`The results of D10 are concerned with a pa.rn'cular model system P113. D10 clearly
`indicates that "alteration of the macroscopic polarity of solvent systems has in some
`instances been shown to afiect the association of surfactant systems." Thus the beha-
`vior of surfactants in other solvent systems according to Dl0 is not generally predicta-
`ble, and this is especially true in the case where the surfactant
`is substantially insolu-
`ble in the solvent. D10 does not provide any information to the skilled worker about
`the application of substantially solvent-insoluble non-perfluorinated surfactants
`in a
`solvent in a pure state or present as a coating on a dispersed particle.
`
`Concerning aerosol formulations D10 indicates that optically transparent solutions with
`surfactant micellar structures "... may offer mtengj in solubilt§'gag’ a range of hydro-
`philic drugs particularly ij the size and polarity of the micelle can be optimised by
`the (e-g. polyethylene slycols; PEG’s)" and
`therapeutic concentrations of a model bronchodilator, salbutamol, have been solubilized
`in such systems" (emphasis added). Thus,
`the teaching of D10 is directed towards the
`solubilization of drugs,
`i.e. present in solution as monomers, not towards the stabiliza-
`tion of drug particles from 2 pm to 100 run in suspension (which is
`the subject
`matter of the present invention).
`
`The teaching of D10 in combination with D1 clearly does not suggest
`of the present patent.
`
`the invention
`
`D. Conclgion
`
`The subject matter of claims 1 and ll of the present patent are not suggested in any
`manner by the disclosure of D1 alone or in combination with any one of D3-D10.
`The subject matter of the present patent is inventive.
`
`AA. D11 as Closest prim art
`
`D11 is US Patent 4,352,789, which was already examined by the EPO during the
`prosecution of the present patent. D11 discloses an aerosol composition comprising
`approximately 0.001 to 20 % by weight of a finely-divided solid substance which is
`coated with a dry coating of a perfluorinated surfactant which represents approximately
`0.1 to 20 % by weight of the solid coated substance and is suspended in a halogenat-
`ed propellant,
`in which the
`solid - substance and the perfluorinated surface-active
`dispersing are substantially insoluble.
`
`pg. The Technical Problem in view of D11
`
`-11-
`
`“" '--~'5
`
`----v--—
`
`-.- —-.-..
`
`-..-.....
`
`zt#:99w66ea 69 617+ '“'1—?)9’z'9 IL9 TLIO
`
`: 80:61
`
`:
`
`'
`
`;
`
`'
`
`'
`
`go'gQjfi5Ngfi;3i—v:;§;;’1\1bA-A-ng
`
`12
`
`

`

`The subject matter of the present patent differs from that of D11 in that a non-
`perfluorinated surfactant is being employed.
`
`the technical problem underlying the invention as claimed in claim 1 in
`Accordingly,
`view of D11 again is to provide efiective suspension aerosol