Groningen Arnhem *
`Ame•sl'<lort Eindhoven • Munich * Re~<<,nsb•~r" * Leuven
`
`European Patent Office
`Directorate General 2
`Erhardstr. 27
`D-80298 Munich
`Germany
`
`Patents &: Trademarks
`
`Vereenigde Octrooibureaux NV
`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
`
`B.Hermann@vo.eu
`www.vo.eu
`
`Your ref. 05724887.4//1725234
`Our ref. BCH/023380EPOO
`
`21 August 2013
`
`Re:
`
`Opposition against European Patent No. 1725234
`in the name of The Trustees of The University of Pennsylvania
`Opponent: Evan Stein MD, PhD
`
`Herewith an
`
`OPPOSITION
`
`is filed against European Patent No. 1 725 234 B9
`
`5
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`in the name and on behalf of
`
`Evan Stein MD PhD
`
`25 E Superior St #4602
`
`10
`
`Chicago, Illinois USA 60611
`
`USA
`
`The subject matter of the opposed patent is based on former studies with microsomal
`
`triglyceride transfer protein (MTP) inhibitor implitapide, which is (2S)-2-cyclopentyl-2-
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`15
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`[ 4- [(2,4-dimethyl-9H-pyrido[2,3-b ]indol-9-yl)methyl]phenyl]-N- [(lS)-2-hydroxy-l-
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`phenylethyl]ethanamide, a phenylglycinolamide derivative such as the claimed subject
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`matter, particularly specified in claim 6, which is lomitapide (i.e., N-(2,2,2-
`
`Trifluoroethyl)-9- [ 4- [ 4- [[[ 4' -(trifluoromethyl) [1, 1 '-biphenyl] 2-yl]carbonyl]amino] -1-
`
`piperidinyl]butyl]9H-fluoren-9-carboxamde). One of the co-inventors, Dr. Daniel Rader,
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`5 was a consultant and clinical investigator in clinical research projects with implitapide.
`
`Prior art
`
`D1- Hussain et al., "Multiple functions of microsomal triglyceride transfer protein",
`
`10
`
`Nutrition & Metabolism, 2012
`
`(http://www.nutritionandmetabolism.com/content/pdf/17 43-7075-9-14.pdf)
`
`D2 - http://en.wikipedia.org/wiki/Microsomal_triglyceride_transfer_protein
`
`D3- lmplitapide presentation to financial analysts in New York on 5 February 2004
`
`D3a- News Releases of 15 January 2004 regarding announcement of PPD presenting
`
`15
`
`their business in New York on 5 February 2004
`
`D4- Chandler et al., ,CP-346086: an MTP inhibitor that lowers plasma cholesterol
`
`and triglycerides in experimental humans and animals", Journal of Lipid
`
`Research, 2003, Vol. 44, 1887-1901
`
`D5- Gruetzmann et al., ,lmplitapide (BAY 13-9952) inhibits secretion of apoB
`
`20
`
`associated lipoproteins by inhibition of the microsomal triglyceride transfer
`
`protein (MTP)", Eur Heart J 2000, 21(Suppl), Abst 3271
`
`D6- Bischoff et al., ,BAY 13-9952 (implitapide): Pharmacodynamic effects of a new
`
`microsomal triglyceride transfer protein (MTP) inhibitor on plasma lipids and
`
`adipose tissue in animals", Eur Heart J 2000, 21(Suppl), Abst P3501
`
`25 D7- Zaiss et al., "BAY 13-9952 (implitapide), an inhibitor of the microsomal
`
`triglyceride transfer protein (MTP), inhibits atherosclerosis and prolongs lifetime
`
`in apo-E knockout mice", Eur Heart J 2000, 21(Suppl), Abst 194
`
`D8- Excerpt of ClinicalTrials.gov., "lmplitapide in patients with homozygous familial
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`hypercholesterolemia (HoFH) on maximal concurrent lipid-lowering therapy"
`
`(ClinicalTrials.gov Identifier: NCT00079846); "Implitapide in patients with
`
`homozygous familial hypercholesterolemia (HoFH) on maximal concurrent lipid(cid:173)
`
`lowering therapy" (ClinicalTrials.gov Identifier: NCT00079859), and "Implitapide
`
`5
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`in patients with homozygous familial hypertriglyceridemia (HTG) on maximal,
`
`concurrent tiglyceride-lowering therapy" (ClinicalTrials.gov Identifier:
`
`NCT00080132)
`
`D9- Dam et al., "Efficacy and safety ofimplitapide (BAY 13-9952), a microsomal
`
`triglyceride transfer protein inhibitor, in patients with primary
`
`10
`
`hypercholesterolemia", Dissertation, 2001, 204.
`
`Lack of patentability
`
`The opposed patent comprises 30 claims, wherein claims 1, 2, 21, 22, 27 and 29 are
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`15
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`independent claims. The granted claims comprise added matter, lack enablement as
`
`well as novelty and inventive step as will be shown in the following.
`
`The subject matter of granted claim 1 refers to
`
`20
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`25
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`1)
`
`2)
`
`3)
`
`3a)
`
`3b)
`
`4)
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`Use of an MTP inhibitor
`
`in the manufacture of a medicament
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`for the treatment of a subject suffering from a disorder
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`associated with hyperlipidemia and/or
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`hypercholesteremia
`
`wherein said treatment comprises the administration of at least three step(cid:173)
`
`wise, increasing dosages of said MTP inhibitor to said subject.
`
`Hence, claim 1 represents a second medical use claim.
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`The subject matter of granted claim 2 is directed to
`
`1)
`
`2)
`
`2a)
`
`2b)
`
`3)
`
`An MTP inhibitor
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`for use in treating a subject suffering from a disorder
`
`associated with hyperlipidemia and/or
`
`hypercholesterolemia
`
`wherein said treatment comprises the administration of at least three step(cid:173)
`
`wise, increasing dosages of said MTP inhibitor to said subject.
`
`Thus, the subject matter of claim 2 is a purpose-limited-product-claim allowable under
`
`EPC 2007.
`
`1. Added matter, Art. 123(2) EPC
`
`5
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`10
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`The granted set of claims comprises added matter in claims 5, 6, 26, and 28.
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`15
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`The subject matter of claims 5 and 6 was originally filed as subject matter of claims 3
`
`and 4, wherein the percentage of reduction of Total Cholesterol, LDL, fasting
`
`triglycerides (TG) etc. was specified "compared to control levels". This is supported by
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`the specification as filed on p. 14, paragraph 0043, disclosing a comparison with control
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`blood levels.
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`20
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`25
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`In granted claims 4 and 5 the percentage is specified "as a result of said treatment,
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`compared to control levels" (emphasis added). However, neither the specification nor
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`the clams as originally filed describe the percentage of the reduction as a result of the
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`treatment and do not provide proof that the reduction solely is based on the treatment.
`
`The subject matter of granted claim 26 corresponds to the subject matter of claims 17,
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`20 and 23 as originally filed, but refers now back to claims 21 and 23 to 25. Thus, the
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`subject matter of granted claim 26 is not limited to an administration of the dose level
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`for 1 to 4 weeks.
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`Further, the subject matter of granted claim 28 has been amended to refer to a fifth set
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`of dosage units for a fifth interval in the amount of 75 mg/day. Taking the amounts of
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`the first to third dose levels of claim 27 into account, where claim 28 refers back, only
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`the fourth dose level is described in the amount of 75 mg/day according to the
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`5
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`specification as filed (see p. 17, paragraphs 0060 and 0061).
`
`Therefore, the subject matter of the granted set of claims does not fulfil the
`
`requirements under Art. 123(2) EPC.
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`10
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`2. Lack of enablement, Art. 83 EPC
`
`The microsomal triglyceride transfer protein (MTP) plays for example a role in the
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`lipoprotein assembly, and deficiency or malfunction of the MTP can cause very low
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`production of lipoproteins resulting in severe diseases such as hypolipidemia and/or
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`15
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`abetalipoproteinemia. However to treat diseases where there is impaired clearance of
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`cholesterol or triglyceride carrying lipoproteins which then accumulate in the blood
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`stream to cause blockage of arteries or inflammation of the pancreas, inhibitors of MTP
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`are developed to reduce or control lipoprotein production and numerous MTP
`
`inhibitors, for example JTT-130, SLx40-90 (see D1, p. 12, right col., 2nd paragraph),
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`20
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`lomitapide, dirlotapide, mitratapide (see D2) or implitapide (Bay13-9952; see D9, p.
`
`149, 2nd paragraph), are known. These inhibitors show different chemical structures
`
`and are used for treating humans and animals.
`
`The subject matter of granted claim 1 and 2, respectively, of the opposed patent refers
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`25
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`to the use of an MTP inhibitor for treating a subject suffering from a disorder
`
`associated with hyperlipidemia and/or hypercholesterolemia, wherein the MTP
`
`inhibitor is administered in at least three stepwise, increasing dosages of said MTP
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`inhibitor to said subject. All the examples of the opposed patent refer to one specific
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`MTP inhibitor which is BMS-201038, which is specified in dependent claim 6.
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`Hence, the opposed patent does not teach the skilled person any other MTP inhibitor,
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`and in which three-stepwise dosages of such MTP inhibitor should be used for the
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`treatment of a human being or an animal. Therefore, it is impossible for the skilled
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`person to rework the present alleged invention over the broad scope of protection
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`5
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`claimed. In particular, not all of the known MTP inhibitors may have an improved
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`tolerability, safety or even effect if it is administered three-stepwise with increasing
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`dosage of the MTP inhibitor.
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`Consequently, the subject matter of the granted set of claims does not fulfil the
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`10
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`requirements under Art. 83 EPC.
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`3. Lack of novelty, Art. 54 EPC
`
`The subject matter of claims 1 and 2 lacks novelty in view of D3.
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`15
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`D3 is a public presentation to analysts for Pharmaceutical Product Development, Inc
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`(PPD), which took place in New York on 5 February 2004.
`
`In this presentation analysts were informed that MTPs provide a successful addition to
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`20
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`statins and/or other lipid lowering drugs in treating hyperlipidemia and/or
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`hypercholesterolemia (see slides 19 to 26). Slide 21 shows several MTP inhibitors,
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`which were investigated from different companies beginning in the 1990s, comprising
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`for example implitapide of Bayer (see for example D9).
`
`25 According to slides 23 and 24, the inhibitory effect of implitapide on aortic
`
`atherosclerosis improved with stepwise increasing doses such as 5, 15 and 45 ppm/day
`
`implitapide. This effect was confirmed in human being with dosages of 20, 40, and even
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`80 and 160 mg/day implitapide (see slide 29).
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`Hence, D3 discloses an MTP inhibitor for use in treating hyperlipidemia and/or
`
`hypercholesterolemia, and the use of an MTP inhibitor for the preparation of a
`
`medicament for treating hyperlipidemia and/or hypercholesterolemia, wherein
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`treatment comprises the administration of at least three stepwise increasing dosage of
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`5
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`said MTP inhibitor according to claims 1 and 2, respectively, of the opposed patent.
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`Consequently, the subject matter of claims 1 and 2 as well as of dependent claims 3 to
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`20 and 23 to 26 referring back to claims 1, 2 and 21, respectively, lacks novelty in view
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`ofD3.
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`10
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`In addition, also the subject matter of claim 22 is anticipated by D3, which refers to an
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`MTP inhibitor for use in treating a subject suffering from a disorder selected from the
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`group consisting of homozygous/heterozygous familial hyperlipidemia or
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`hypercholesterolemia. Slides 56 and 61 of D3 for example specify these diseases.
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`15
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`4. Lack of inventive step, Art. 56 EPC
`
`The subject matter of the granted claims of the opposed patent does not only lack
`
`novelty, but likewise inventive step.
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`20
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`4.1 Lack of inventive step in view of D3
`
`In case, the Opposition Division considers the subject matter of claims 1 to 26 novel
`
`over D3, the subject matter of these claims lacks inventive step in view of D3. Based on
`
`D3 is obvious for a person skilled in the art to use an MTP inhibitor for treating
`
`25
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`hyperlipidemia and/or hypercholesterolemia in stepwise increasing dosages.
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`In addition, D3 also renders the subject matter of clam 27 obvious which refers to a kit
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`for treating hyperlipidemia and/or hypercholesterolemia in different sets of
`
`pharmaceutical dosage units. Taking the information provided in D3 into account, it is
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`pure "skilled manual work" to reach specific dosages for an MTP inhibitor such as
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`lomitapide. Thus, the subject matter of claim 27 and dependent claim 28 lack likewise
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`inventive step as well as the subject matter of claims 29 and 30.
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`5
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`4.2 Lack of inventive step in view of D8 in combination with D3
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`D8 refers to clinical studies, which were performed with implitapide regarding its use
`
`in the treatment of homozygous as well as heterozygous familial hyperlipidemia and
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`hypercholesterolemia. The studies were performed between September 2003 and April
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`10
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`2005 as disclosed in D8, and were designed, conducted and guided by Dr. Stein, who
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`included Dr. Rader, inventor of the opposed patent, as a consultant and one of the
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`clinical investigators for these studies.
`
`The ClinicalTrials.gov identifier, indicated in D8 for each study, provides access to
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`15 more detailed information about the studies such as inclusion and exclusion criteria in
`
`the clinical studies. The clinical studies using implitapide for treating hyperlipidemia
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`and hypercholesterolemia started in 2003.
`
`Starting from D8 and combining the information with D3, which specifies four
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`20
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`different concentrations having increasing effect in the use for treating hyperlipidemia
`
`and hypercholesterolemia, teaches the skilled person the use of an MTP inhibitor, in
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`particular implitapide, wherein said treatment comprises the administration of at least
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`three step-wise, increasing dosage of said MTP inhibitor. Hence, the subject matter of
`
`claims 1 to 21 and 23 to 26 lacks inventive step in view of the combination of D8 and
`
`25 D3.
`
`As D8 specifies homozygous/heterozygous familial hyperlipidemia or
`
`hypercholesterolemia, the combination of D8 and D3 also render the subject matter of
`
`claim 22 obvious as well as the subject matter of claims 27 to 30, which refer to a kit
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`comprising the MTP inhibitor. The dose finding of the MTP inhibitor is based on trial
`
`and error, if the skilled person is provided with all the other information of D8 and D3.
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`4.3 Lack of inventive step in view of D4 as well as in view of D4 in
`
`5
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`combination with D3
`
`D4 refers to the MTP inhibitor CP-346086 that lowers plasma cholesterol and
`
`triglycerides in humans and animals dependent on the dosage and incubation time (see
`
`D4, Abstract). Thus, D4 teaches an MTP inhibitor, which is thus suitable to treat
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`10
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`hyperlipidemia and/or hypercholesterolemia. Reading D4, it is obvious for a person
`
`skilled in the art to administer an MTP inhibitor in different dosages.
`
`As discussed above, D3 teaches the use of an MTP inhibitor in treating hyperlipidemia
`
`and/or hypercholesterolemia in at least three stepwise increasing dosages of the MTP
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`15
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`inhibitor.
`
`Beside the MTP inhibitor CP-346086, D4 suggests further MTP inhibitors such as
`
`implitapide (corresponding to BAY 13-9952; see D4, p. 1898, re. Sp., 2. Abs.). Thus, a
`
`skilled person is motivated to combine D4 and D3, and this combination renders the
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`20
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`subject matter of the granted set of claims obvious.
`
`Therefore, the subject matter of claims 1 to 30 lacks inventive step in view of D4 alone
`
`as well as in view of a combination of D4 and D3.
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`25
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`4.4 Lack of inventive step in view of D5, D6 or D7 in combination with D3
`
`D5 relates to the identification of implitapide in HepG2 cells, where it blocked the
`
`secretion of apoB associated particles; other secretory processes were not affected.
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`Hence, D5 describes implitapide as a highly active and diastereoselective MTP
`
`inhibitor for use in the treatment of treating hyperlipidemia and hypercholesterolemia.
`
`D6 refers to in vivo studies of the effect of implitapide on genetically
`
`5
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`hypertriglyceridemic fa, fa-Zucker rats and dogs, and on obese Zucker rats. lmplitapide
`
`reduced the triglyceride and cholesterol concentration in this animal, and the studies
`
`confirmed that implitapide is successful in the treatment of hyperlipidemia and
`
`hypercholesterolemia.
`
`10 D7 is directed to further in vivo studies of implitapide. In D7 the effect of implitapide
`
`on apoE knockout mice, which is an artherosclerosis model, is tested. The animals
`
`received a Western-type diet containing 0, 5, 15 and 45 ppm implitapide for 14 days,
`
`and implitapide resulted in all dosages in significant reduction of lipid concentrations
`
`and atherosclerosis lesions. Thus, D7 shows a dose-dependent effect, which increased
`
`15 with increasing dosage of implitapide.
`
`Reading D5, D6, or D7 and combining this information with D3, which teaches the
`
`stepwise increasing dosages of implitapide in humans and animals, leads the skilled
`
`person to an MTP inhibitor for use in treating hyperlipidemia and/or
`
`20
`
`hypercholesterolemia, and the use of an MTP inhibitor for the preparation of a
`
`medicament for treating hyperlipidemia and/or hypercholesterolemia, wherein
`
`treatment comprises the administration of at least three stepwise increasing dosage of
`
`said MTP inhibitor.
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`25
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`Consequently, the subject matter of claims 1 and 2 as well as of claims 3 to 21 and 23
`to 26 is not inventive in view of D5, D6, or D7 in combination with D3. As D3 also
`
`specifies homozygous/heterozygous familial hyperlipidemia or hypercholesterolemia
`
`(see slide 56), also the subject matter of claim 22 is not inventive in view of these
`
`combinations. Based on all this information it is obvious for a skilled person to set up a
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`kit comprising specific dosages of an MTP inhibitor, and therefore, the subject matter
`
`of claims 27 and 28 is likewise not inventive as well as the subject matter of claims 29
`
`and 30.
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`5
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`5. Summary
`
`It is shown that the opposed patent comprises added matter, is not enabled, and lacks
`
`novelty as well as inventive step. Therefore, it is requested to reject the opposed
`
`patent. If the Opposition Division will not follow the present request, oral proceedings
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`10
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`are herewith requested.
`
`The professional representative,
`
`15 Dr. Bettina C. Hermann
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`20
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`25
`
`Enclosures:
`D1- Hussain et al., "Multiple functions of microsomal triglyceride transfer protein",
`Nutrition & Metabolism, 2012
`(http://www.nutritionandmetabolism.com/content/pdf/17 43-7075-9-14.pdf)
`D2 - http://en.wikipedia.org/wiki/Microsomal_triglyceride_transfer_protein
`D3- lmplitapide presentation to financial analysts in New York on 5 February 2004
`byPPD
`D3a- News Releases of 15 January 2004 regarding announcement of PPD presenting
`their business in New York on 5 February 2004
`D4- Chandler et al., ,CP-346086: an MTP inhibitor that lowers plasma cholesterol
`and triglycerides in experimental humans and animals", Journal of Lipid
`Research, 2003, Vol. 44, 1887-1901
`D5- Gruetzmann et al., ,lmplitapide (BAY 13-9952) inhibits secretion of apoB
`associated lipoproteins by inhibition of the microsomal triglyceride transfer
`protein (MTP)", Eur Heart J 2000, 21(Suppl), Abst 3271
`D6- Bischoff et al., ,BAY 13-9952 (implitapide): Pharmacodynamic effects of a new
`microsomal triglyceride transfer protein (MTP) inhibitor on plasma lipids and
`adipose tissue in animals", Eur Heart J 2000, 21(Suppl), Abst P3501
`35 D7- Zaiss et al., "BAY 13-9952 (implitapide), an inhibitor of the microsomal
`triglyceride transfer protein (MTP), inhibits atherosclerosis and prolongs lifetime
`in apo-E knockout mice", Eur Heart J 2000, 21(Suppl), Abst 194
`
`30
`
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`Patents l!i: Trademarks
`
`D8- Excerpt of ClinicalTrials.gov., "Implitapide in patients with homozygous familial
`hypercholesterolemia (HoFH) on maximal concurrent lipid-lowering therapy"
`(ClinicalTrials.gov Identifier: NCT00079846); "Implitapide in patients with
`homozygous familial hypercholesterolemia (HoFH) on maximal concurrent lipid-
`lowering therapy" (ClinicalTrials.gov Identifier: NCT00079859), and "Implitapide
`in patients with homozygous familial hypertriglyceridemia (HTG) on maximal,
`concurrent triglyceride-lowering therapy" (ClinicalTrials.gov Identifier:
`NCT00080132), 2003
`D9- Dam et al., "Efficacy and safety ofimplitapide (BAY 13-9952), a microsomal
`triglyceride transfer protein inhibitor, in patients with primary
`hypercholesterolemia", Dissertation, 2001, 204
`
`5
`
`10
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`CFAD Ex. 1020 (12 of 12)