The Hague ~ Groningen ~ Arnhern ~ ’s-Hertogenbosch
`Arnersfoort ¯ Eindhoven ~ Munich ~ Regensburg ~ Leuven
`
`Patents ~ Trademarks o Designs
`
`European Patent Office
`D-80298 Mfinchen
`Germany
`
`IG DE
`
`Vereenigde Octrooibureaux N.V.
`Johan de Wittlaan 7
`P.O. Box 87930
`2508 DH The Hague
`The Netherlands
`
`Telephone +31 70 416 67 11
`Telefax +31 70 416 67 99
`
`patent@vereenigde.com
`trademark@vereenigde.com
`legal@vereenigde.com
`www.vereenigde.com
`
`Your ref. 03753571.3/2119
`Our ref. HK/P100557EP00
`
`The Hague,
`29 January 2013
`
`European patent application No. 03753571.3
`Janssen R&D Ireland
`
`This concerns the communication pursuant to Article 94(3) EPC issued September 20,
`
`2012. Therein, the Examining Division refers to the Third Party Observations received
`
`in this application, and has indicated to take these into account under Article 114(1)
`
`EPC.
`
`In response to the invitation to file observations, and in the light of the Third Party
`
`Observations, we care to proffer the following comments. Also, an Experimental Report
`
`is attached, including additional Examples 25 and 26, accompanied by additional Table
`
`27 and additional Figures 27 to 33.
`
`10
`
`As to Article 83 EPC, reference is made in the communication to the statement in said
`
`Third Party Observations that "not a single concrete example" could be found in the
`
`application documents for the preparation of"the respective Form B or any
`
`hydrates/polymorphs." It is further mentioned that in Example 2 only a mixture of
`
`15
`
`Forms D and B can be obtained.
`
`Lupin Ex. 1020 (Page 1 of 9)
`
`

`

`Page
`Your ref.
`0~ ref.
`Date
`
`2
`03753571.3/2119
`HK/P100557EP00
`29 January 2013
`
`Patents ¯ Trademarks ¯ Designs
`
`Additionally, in the communication it is reiterated that for form I and J no data at all
`
`would be available. In respect hereof, we kindly remark that this objection does not
`
`relate to the current claims. Form I is the tetrahydrofuranate and Form J is the
`
`isopropanolate. We refer to page 3, line 32. These forms are not within the scope of the
`
`pending claims. The independent product claims relate solely to Form A (ethanolate,
`
`see claim 1) and form B (hydrate, claim 11). To the extent that independent claims are
`
`present in other categories, these claims (7, 9, 10, 16,17,18) are all limited by their
`
`reference to the definition of the pseudopolymorphs of their preceding claims.
`
`10
`
`Further, we respectfully disagree with the analysis that Example 2 would not support
`
`the invention. In this Example, Form B is expressly obtained.
`
`Moreover, ~ve kindly draw the Examining Division’s attention to the fact that the
`
`application as filed contains another disclosure of a method to produce Form B.
`
`15
`
`Example 7 on page 27 of the present application discloses an adsorption-desorption
`
`method that is performed with Form A (ethanolate). Form A itself can be produced as
`
`indicated in the description, see Example 1. Example 7 shows a set of conditions (page
`
`27, lines 27-31) that result in the ethanolate form changing into the hydrate form
`
`2O
`
`(same page, lines 34-35). This embodies a clear teaching to a person skilled in the art
`
`how to produce Form B, viz. by obtaining Form A (as disclosed) and subjecting it to the
`
`set of conditions (as disclosed).
`
`On the basis of the foregoing, we advance that the application doubtlessly provides a
`
`25
`
`sufficient disclosure for pseudopolymorphie Form B.
`
`The communication further contains an invitation to the applicant to indicate how the
`
`skilled person could prepare all the ethanol solvates of claims 1-10 and all the hydrates
`
`of claims 11-18.
`
`Lupin Ex. 1020 (Page 2 of 9)
`
`

`

`Page
`Yo~r ref.
`o~r ref.
`Date
`
`3
`03753571.3/2119
`HK/P100557EP00
`29 January 2013
`
`Patents ¯ Trademarks ¯ Designs
`
`In response hereto, we emphasize that the skilled person will be well capable, on the
`
`basis of the description, of making the various solvates and hydrates.
`
`5
`
`The description explains that the term pseudopolymorph is applied to crystalline forms
`
`that have solvent molecules incorporated in their lattice structures. The skilled person
`
`will immediately rifler from this statement that the solvates of the present invention
`
`are channel solvates. In such solvates, the solvent molecules are contained in lattice
`
`channels and lie next to other solvent molecules of adjoining unit cells along an axis of
`
`10
`
`the lattice, forming channels through the crystal. We refer to Kenneth R. Morris, "
`
`Structural Aspects of Hydrates and Solvates", which is Chapter 4 in "Polymorphism in
`
`Pharmaceutical Solids," (1999) Harry G. Brittain, Ed., page 125, last paragraph. For
`
`completeness’ sake, we add that, already merely from the title of the chapter, it will be
`
`clear that the author discusses the structural aspects of hydrates and solvates alike.
`
`15 Also
`
`from page 6, line 10 of the description, it will be understood that above reference to
`
`incorporated solvent molecules equally applies to hydrates (viz. if the solvent is water).
`
`The amount of solvent in the solvates according to the invention can be varied
`
`20
`
`depending on the conditions applied (page 7, line 16-17).
`
`This is further clarified, inter alia, in Example 4. See page 23, lines 27-30, where it is
`
`indicated that form A loses ethanol under specific temperature conditions, with an
`
`optimum of 120 °C. The amount of ethanol present in form A (1:1) is around 7.5%, see
`
`25
`
`Table 12, page 26. Example 4 unequivocally guides the skilled person to obtaining
`
`ethanolates with different ranges of solvation, without undue burden. Viz., by applying
`
`a range of high temperature conditions, and subsequently determining the amount of
`
`residual ethanol.
`
`Lupin Ex. 1020 (Page 3 of 9)
`
`

`

`Page
`
`Your ref.
`OL~r ref.
`Date
`
`4
`03753571.3/2119
`HK/P100557EP00
`29 January 2013
`
`Patents ¯ Trademarks ¯ Designs
`
`With regard to water as a solvent, additional guidance is provided in Example 12 (page
`
`31, lines 1-8) and the accompanying Figure 20. Example 12 employs different
`
`conditions of relative humidity so as to affect the adsorption and desorption of water of
`
`form B. First and foremost, it thus indicates that form B is capable of adsorbing and
`
`5
`
`desorbing water. The manner in which this occurs, ~vill be immediately apparent to the
`
`skilled person, when having regard to the curves shown in Figure 20. The shape of
`
`these curves indicates that the range of the number of water molecules associated with
`
`the compound of formula X, is a continuum, as opposed to a discrete variable. In the
`
`latter case, one would expect a curve showing discrete steps rather than the relatively
`
`10 straight lines of Figure 20.
`
`Finally, as to sufficiency of disclosure, ~ve kindly point out that the description actually
`
`enlightens the skilled reader about the fact that the compound of formula (X) can
`
`comprise up to 5 molecules of solvent (in casu: ethanol or water) per molecule of the
`
`15
`
`compound. This is taught on page 7, lines 17-19.
`
`The communication further raises an objection of lack of inventive step.
`
`Thereby the Examining Division reverts to our letter of December 18, 2007, and
`
`20
`
`considers that the comparative data should have been provided with reference to the
`
`closest prior art. To this end, the communication refers to "the racemate" as being the
`
`necessary comparison, and then criticizes the data provided as being in comparison
`
`with the amorphous form. We respectfnlly fail to understand this.
`
`25
`
`Present independent claim 1 recites an ethanolate pseudopolymorph of a compound of
`
`formula (X). Present independent claim 11 recites a hydrate pseudopolymorph of a
`
`compound of formula (X). These are both crystalline forms of said compound. It is
`
`unclear to the applicant what the examiner means with his referral to a racemate as
`
`Lupin Ex. 1020 (Page 4 of 9)
`
`

`

`Page
`Your ref.
`Our ref.
`Date
`
`5
`03153511.3/2119
`HK/P100557EP00
`29 ~January 2013
`
`Patents ¯ Trademarks - Designs
`
`closest prior art. The applicant is of the opinion that a racemate has no apparent
`
`relation to a specific form of a compound, e.g. an amorphous or crystalline form.
`
`D5 (WO 95/06030) discloses hydroxyethylamino sulfonamides as retroviral protease
`
`5 inhibitors. Table 16K on page 204 of D5 discloses the structure of the compound of
`
`formula (X). D5 further discloses at page 158 that the compounds of this table 16K can
`
`be prepared following the procedures of examples 1-21. When looking at procedures 1-
`
`21 of D5, the skilled person ~vill note that, among the examples given, example 18B
`
`represents the closest structural analogue of the compound of formula (X). After
`
`10
`
`detailing a synthetic method for the preparation of the disclosed compound, Example
`
`18B further discloses at page 135, line 6-8 that silica gel chromatography of the crude
`
`product of this structural analogue resulted in a white foam. A white foam indicates
`
`that the product is not in a crystalline form, but in an amorphous state.
`
`15
`
`Therefore, we advance that the teaching of the closest prior art is an amorphous (non-
`
`crystalline) form of the compound of formula (X) obtainable by an analogous method
`
`according to example 18B of D5. We emphasize that the comparison as made, is thus
`
`fully appropriate. In fact, the prior art does not disclose any form of the compound of
`
`formula X closer to the present invention, than the very form with which the
`
`20 comparison ~vas made, viz. the compound of formula X in an amorphous state.
`
`The invention as claimed differs from the aforementioned prior art. The difference is
`
`that the compound of formula (X) is provided in a crystalline form, and specifically the
`
`ethanolate or the hydrate crystalline form.
`
`25
`
`First of all, we emphasize that it was not known from the prior art at all, nor even
`
`remotely suggested, that the present compound could be provided in a crystalline form,
`
`let alone in a specific ethanolate or hydrate form as provided by the invention.
`
`Lupin Ex. 1020 (Page 5 of 9)
`
`

`

`Page
`Your ref.
`0~ ref.
`Date
`
`6
`03753571.3/2119
`HK/P100557EP00
`29 January 2013
`
`Patents ¯ Trademarks ¯ Designs
`
`As outlined previously, the crystalline forms of the invention provide unexpected
`
`benefits as compared to the amorphous form. In addition to the results reflected in the
`
`application, we now provide further evidence, see the attached experimental report,
`
`containing additional Examples 25 and 26.
`
`In Example 25, the thermal characteristics (by DSC - differential scanning
`
`calorimetry) and powder dissolution are determined for the compound of formula (X) in
`
`the hydrate crystalline form and in the amorphous form, with reference to storage
`
`under defined conditions (viz. up to 1 month of storage under 93% Relative Humidity
`
`10
`
`at 25°C and 40°C).
`
`From the DSC melting peak onset temperatures measured, it can be concluded that the
`
`thermal characteristics of the hydrate form of the compound of formula (X) do not
`
`change as a result of storage under the conditions indicated. In summary, this can be
`
`15
`
`indicated with reference to a A°C of the DSC melting peak onset temperature after one
`
`month of storage of only - 0.89 (at 25°C) and only - 2.61 (at 40°C).
`
`The amorphous form, however, is not stable. The change in Tg is at least -19.42°C
`
`after a month of storage at 25°C/93% RH and -31.49°C after a month of storage at
`
`20
`
`40°C/93% RH. From these values it is concluded that the thermal characteristics of the
`
`compound change significantly as a result of storage.
`
`As to the ethanolate form of the compound of formula (X), we refer to the long term
`
`stability tests reported in the application, see Examples 8 and 9. In Tables 13 and 14 it
`
`25
`
`is shown that the DSC melting peak onset temperature does not change, neither as a
`
`result of long-term storage at 25°C/60% RH, nor after an accelerated stability study at
`
`40°C/75% RH. After six months, the A°C of the DSC melting peak onset temperature is
`
`only 1.2°C (at 25°C/60% RH) and only 0.6°C (at 40°C/75% RH).
`
`Lupin Ex. 1020 (Page 6 of 9)
`
`

`

`Page
`Yo~r ref.
`o~r ref.
`Date
`
`7
`03753571.3/2119
`HK/P100557EP00
`29 January 2013
`
`Patents ¯ Trademarks ¯ Designs
`
`Further, reference is made to the dissolution tests conducted. As the skilled person
`
`knows, dissolution is related to solubility, but is a more precise reflection of the
`
`conditions in the stomach, resulting in an orally ingested compound becoming bio-
`
`available.
`
`In Example 25, the dissolution profiles are presented in four figures. These are paired
`
`on two pages, so to enable a directly visible comparison between the hydrate and
`
`amorphous forms, for either of the two storage conditions referred to.
`
`10
`
`Figure 27 shows that the hydrate crystalline form, after one day of storage at
`
`25°C/93%RH, exhibits a dissolution of near 100% in 120 minutes. After prolonged
`
`storage the dissolution rate is decreased to some extent. Nevertheless, the sample
`
`stored for one month still exhibits a dissolution of more than 80% after 120 minutes.
`
`15
`
`Figure 28 shows the dissolution rates for the samples of amorphous compound after
`
`storage at 25°C/93%RH. It is immediately evident that all profiles, in terms of
`
`percentage dissolution achieved after a defined time period, are well below those
`
`obtained for the hydrate. A similar comparison is apparent for the hydrate and
`
`amorphous samples after storage at 40°C/93% RH.
`
`2O
`
`Figure 29 shows that all dissolution percentages for the hydrate crystalline form, after
`
`storage at 40°C/93%RH, are within the 80%-100% range in 120 minutes.
`
`Figure 29 shows the dissolution rates for the samples of amorphous compound after
`
`25
`
`storage at 40°C/93%RH have fallen below 50%.
`
`A direct comparison of dissolution profiles for the ethanolate crystalline form and the
`
`amorphous form is obtained from Example 26. The results are depicted in Figures 30 to
`
`33, which relate to different storage times (zero, one month, three months) at 25°C.
`
`Lupin Ex. 1020 (Page 7 of 9)
`
`

`

`Page
`
`Your ref.
`oL~r ref.
`Date
`
`8
`03753571.3/2119
`HK/P100557EP00
`29 January 2013
`
`Patents ¯ Trademarks ¯ Designs
`
`From these figures it is apparent that the dissolution characteristics of the amorphous
`
`form are not stable upon storage. This can be seen from the relatively large variation in
`
`the mean dissolution percentage after one month of storage (81.07%) and after three
`
`months of storage (87.92%). These values represent, respectively, 107.87% and116.99%
`
`5
`
`compared to the value found after zero storage time (75.16%). For the ethanolate
`
`crystalline form, the dissolution percentage found after one month of storage is 97.28%,
`
`and after three months of storage 102.67%. These values represent, respectively,
`
`97.29% and 102.69% compared to the value found after zero storage time (99.98%).
`
`This indicates that the storage does not substantially affect the stability of the
`
`10 dissolution characteristics for the ethanolate crystalline form.
`
`As explained above, it is beyond doubt that the amorphous form of the compound of
`
`formula (X) represents the closest prior art. The invention differs therefrom in
`
`providing the compound in a crystalline ethanolate or hydrate form. The effect of this
`
`15
`
`difference is an improvement in dissolution behavior and in crystallographic stability
`
`behavior. The objective technical problem can therefore be defined as the provision of a
`
`form of a compound of formula (X) that provides an improved dissolution behavior as
`
`well as crystallographic stability. This problem is solved by the crystalline
`
`pseudopolymorphic forms of the present invention. It has nowhere been suggested in
`
`20
`
`the art that the compound (X) can exist as a crystalline form, let alone as a specific
`
`ethanolate or hydrate crystalline form. Moreover, it has nowhere been suggested in the
`
`art that these crystalline forms provide an improvement in dissolution and stability.
`
`Hence, it is not obvious to the skilled person that the crystalline forms as claimed
`
`present a solution to the aforementioned problem. It can therefore be unequivocally
`
`25
`
`concluded that the crystalline forms as claimed satisfy the requirement of Inventive
`
`Step.
`
`In view of the foregoing, we maintain that the invention as claimed satisfies the
`
`requirements of the European Patent Convention.
`
`Lupin Ex. 1020 (Page 8 of 9)
`
`

`

`Page
`Your ref.
`O~r ref.
`Date
`
`9
`03753571.3/2119
`HK/P100557EP00
`29 January 2013
`
`Patents ¯ Trademarks ¯ Designs
`
`We trust that the above explanation, as well as the further evidence provided, serves to
`
`remove the objections raised, and that a communication pursuant to Rule 71(3) EPC
`
`can be swiftly issued. Should, nevertheless, any concerns remain, the Examiner is
`
`kindly requested to contact the undersigned representative by phone at +31 73 548
`
`5 2070.
`
`The professional representative,
`
`H. Kraak
`
`Encl s.:
`Experimental Report
`Structural Aspects of Hydrates and Solvates, Kenneth R. Morris
`
`Lupin Ex. 1020 (Page 9 of 9)
`
`