By Electronic Submission Only
`
`European Patent Office
`Erhardtstrasse 27
`D-80469 Munich
`Germany
`
`Our Ref:
`
`LUl-P873EP
`
`Dear Sirs
`
`14 December 2012
`
`Re:
`
`European Patent Application Number 07716309.5
`in the name of Luitpold Pharmaceuticals, Inc.
`
`Thank you for your communication under Article 94(3) EPC dated 4 June 2012. The
`Applicant has now considered the Examiner's objections and we therefore submit
`amended claims. Our comments on the objections are set out below.
`
`Claim amendments
`
`Claim 1 has been amended to include the limitation that the single dosage unit is
`adapted for administration to a patient in 15 minutes or less. Basis for this claim can
`be found in previous claim 6 and also in the specification as filed at page 8, line 34.
`The claim has also been amended to remove the feature that the iron carbohydrate
`complex has substantially no cross reactivity with anti-dextran antibodies. We submit
`that no subject matter has been added by the deletion of this feature since the
`specification as filed in the passage bridging pages 11 and 12 makes it clear that this
`is an optional (though preferred) feature by the use of the wording:
`
`"Preferably iron carbohydrate complexes for use in the methods described
`herein are those which have one or more of the following characteristics: ...
`no cross reactivity with anti-dextran antibodies".
`
`Thus, we submit that amended claim 1 does not contain added subject matter
`contrary to Article 123(2) EPC.
`
`The feature that the iron carbohydrate complex has substantially no cross reactivity
`with anti-dextran antibodies has now been made the subject of new claim 19.
`
`Claim 2 has been amended in a similar way to claim 1.
`
`Claims 3 to 5 are unamended.
`
`Claim 6 has been restricted to the case where the single dosage unit is administered
`in about ten minutes or less.
`
`Pharmacosmos, Exh. 1021, p. 1
`
`

`

`Claims 7 to 16 are unamended.
`
`Claim 17 is new and specifies that the single unit dose of iron carbohydrate complex
`is formulated for administration as an intravenous bolus injection without dilution.
`Basis for this claim can be found in the specification at page 8, lines 9-10 of the
`application as filed.
`
`Claim 18 is also new and specifies that the single unit dose of iron carbohydrate
`complex is formulated for administration once per week. Basis for this claim can be
`found at page 9, line19-20 of the application as filed.
`
`Claim 19 is new and, as set out above relates to the feature that the iron
`carbohydrate complex has substantially no cross reactivity with anti-dextran
`antibodies.
`
`We submit that no subject matter has been added and that the amended claims
`comply with Article 123(2) EPC.
`
`Novelty
`
`In Section 1 of the communication, the Examiner asserts that several claims lack
`novelty over 03.
`In particular, the Examiner refers to the passage on page 8, lines
`26-28 of 03. However, claims 1 and 2 have now been amended and are limited to a
`dosage form which is adapted for administration to a patient in 15 minutes or less.
`
`In contrast to amended claims 1 and 2 of the present application, 03 specifies that
`the dose can be administered over the course of 1 hour (03, page 8, lines 27-28).
`Thus, the present invention is novel over 03 because the single dosage unit to which
`it relates is adapted for administration to a patient in a time of 15 minutes or less.
`
`Inventive Step
`
`In Section 2 of the communication, the Examiner asserts that all claims are obvious
`over 02 when combined with 03. With respect, however, we submit that the
`amended claims submitted herewith are inventive over the prior art.
`
`The Examiner has defined the problem to be solved by the present invention as the
`provision of a means for iron delivery in fewer sessions. However, we submit that
`following the amendment of the claims, the problem to be solved should now be the
`provision of a means for iron delivery in fewer sessions and in a reduced time.
`
`The Examiner has designated 02 as the most relevant prior art document and has
`commented that 02 discloses the administration of 100 mg iron (Ill) hydroxide
`polymaltose to anaemic patients. However, it should be noted that this 100 mg of
`iron (Ill) hydroxide polymaltose was infused over a period of 10 minutes (page 854).
`This corresponds to an infusion rate of 10 mg iron (Ill) hydroxide polymaltose per
`minute and means that if the dose of iron (Ill) hydroxide polymaltose in 02 were to be
`raised to 1 OOOmg as taught in 03, the time taken for the infusion would be 100
`minutes; and if raised to 0.6 g as in present claim 1, the time taken for infusion would
`be 1 hour.
`
`03 teaches that the dose of 500 to 1000 mg of an iron carboxymaltose can be
`administered over a period of 1 hour (03, page 8, lines 27-28).
`
`Pharmacosmos, Exh. 1021, p. 2
`
`

`

`Therefore neither 02 nor 03 teaches or suggests a single dosage unit of an iron
`carbohydrate complex which is adapted for administration over a period of 15
`minutes or less as specified in amended claims 1 and 2 of the present application.
`
`Surprisingly, however, the present inventors have found that, in spite of the teaching
`of the prior art, it is possible to administer high doses of iron over a relatively short
`period of time without causing adverse side effects in the patient. Example 5
`describes studies A to J in which VIT-45 was administered to patients. In studies A,
`B, C, 0, I and J a 500-1000mg dose of VIT-45 was administered over 15 minutes.
`The results showed that the high dose administered over a short period of time did
`not lead to adverse side effects.
`
`it
`time has considerable advantages as
`The reduced administration
`less
`is
`unpleasant for the patient and less time consuming for the medical staff supervising
`the treatment. In view of this we submit that the amended claims are inventive over
`02 when combined with 03.
`
`We note that in paragraph 2.3 the Examiner comments that the technical problem
`In response to this
`does not appear to be solved over the whole range claimed.
`objection, we submit a copy of Jahn et al, European Journal of Pharmaceutics and
`Biopharmaceutics, 78 (2011 ), 480-491. This document describes a study of the
`physicochemical properties of iron
`isomaltoside and other iron carbohydrate
`complexes.
`
`An iron isomaltoside (e.g., Monofer@) is an iron carbohydrate complex where
`the carbohydrate component is a pure linear chemical structure of repeating
`a-(1-6)-linked glucose units; i.e. repeating isomaltose units. Thus, an iron
`isomaltoside is an example of an iron polyisomaltose complex.
`
`Table 4 on page 490 of Jahn et al compares several iron carbohydrate
`complexes, some of which fall within the scope of amended claim 1 and some
`of which do not.
`
`Thus, Cosmofer® and Venofer® are respectively iron dextran and an iron
`sucrose complexes and are therefore not encompassed by claim 1.
`Ferrlecit® is an iron gluconate complex, Ferinject® is an iron carboxymaltose
`complex and both of these fall within the scope of claim 1. Monofer ®is an
`iron isomaltoside, which as discussed above is an iron polyisomaltose
`complex and so falls within the scope of claim 1.
`
`Feraheme® (ferumoxytol) is described by Jahn et al as an iron
`carboxymethyl dextran. As discussed on page 16, lines 2-10 of the present
`application, ferumoxytol (i.e. polyglucose sorbitol carboxymethyl ether-coated
`non-stoichiometric magnetite) is a preferred complex for use in the present
`invention. It falls within the scope of claim 1 as it is an iron sorbitol complex.
`
`Table 4 of Jahn et al shows that large doses (1000 mg) of Ferinject® and
`Monofer ® can be administered over less than 1 hour without adverse side effects
`(page 490, Table 4 and column 1 ). The document concludes that Monofer ® can be
`administered as a rapid high dose infusion in doses over 1 OOOmg (page 490,
`conclusion). Table 4 of Jahn et al also shows that a 510 mg dose of Feraheme® can
`also be administered over less than 1 hour. Although this dose is slightly lower than
`
`Pharmacosmos, Exh. 1021, p. 3
`
`

`

`the 0.6g dosage specified in claim 1, we submit that it is still evidence that larger
`doses of Feraheme® can be rapidly administered to a patient without adverse side
`effects.
`
`In contrast, neither Cosmofer® nor Venofer® can be administered over less than 1
`hour. These complexes both fall outside the scope of claim 1. No results were
`obtained for the iron gluconate complex Ferrlecit®.
`
`It is clear from Jahn et al that other iron carbohydrate complexes encompassed by
`the claims can be administered in a similar way to the iron carboxymaltose complex
`is used
`in
`the examples and
`that they therefore have similar
`VIT-45 which
`In view of this, we submit that the
`inventive step has been
`advantages.
`demonstrated over the scope of the claims.
`
`Further to paragraphs 3.3 and 3.4 of the communication, we request that the
`amendment of the description should be deferred until an acceptable set of claims
`has been agreed with the Examiner.
`
`We submit that the claims are now in an allowable form but if the Examiner has
`further objections, we request that we be notified either in writing or by telephone. In
`the event that the Examiner intends to refuse the application, we request oral
`proceedings.
`
`Yours faithfully
`
`/ANDREW TEUTEN/
`
`Andrew Teuten
`European Patent Attorney
`Authorised Representative
`
`Enc
`
`Pharmacosmos, Exh. 1021, p. 4
`
`