European Patent No.1 725 234
`"Methods for treating disorders or diseases associated
`with hyperlipidemia and hypercholesterolemia
`while minimizing side-effects"
`In the name of The Trustees of The University of Pennsylvania
`
`Patentee's Observations in reply to the
`Notice of Opposition by Dr Evan Stein
`
`Introduction
`
`Dr Evan Stein (herein referred to as "Opponent") has filed certain documents
`1.
`with the EPO that are alleged to constitute an admissible opposition to European Patent
`No. 1 725 234 (herein referred to as "the Patent"). These are observations in reply by
`The Trustees of The University of Pennsylvania (herein referred to as "Patentee").
`
`Requests
`
`As its Main Request, Patentee requests the maintenance of the Patent on the
`2.
`basis of the amended set of claims that is filed herewith and a description to be revised
`as appropriate. A copy of the claims of the Patent as granted, showing the amendments
`in mark-up, is also filed herewith to assist the Opposition Division in reviewing the
`amendments that have been made.
`
`As a precaution, Patentee further requests the appointment of Oral Proceedings
`3.
`under Article 116 EPC in the event that the Opposition Division forms any intention to
`arrive at any other decision than to accept Patentee's Main Request.
`
`Patentee also hereby reserves the right to file further observations and/or one or
`4.
`more auxiliary requests during the course of these opposition proceedings to the extent
`that is necessary to address any outstanding objections.
`
`The Main Request
`
`The independent claims of the Main Request are identical to those of the Patent
`5.
`as granted, except in that they specify that the microsomal triglyceride transfer protein
`(MTP) inhibitor is a compound as defined in Claim 6 of the Patent as granted (see also
`Claims 24 and 30 of the Patent as granted). Basis for this amendment can be found e.g.
`in Claim 5 and paragraph [0024] of the application as filed. In addition, Claims 4-6, 24,
`28 and 30 have been deleted. The remaining claims have been revised and renumbered
`accordingly.
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`Non-Addition of Subject Matter (Articles lOO(c) and 123(2) EPC)
`
`Opponent has alleged that certain of the dependent claims of the Patent as
`6.
`granted, namely Claims 4, 5, 26 and 28 1
`, are directed to subject matter which extends
`beyond the content of the application for the Patent as filed, contrary to the
`requirements of Article 123(2) EPC.
`
`Without acceding to Opponent's objections, Patentee has deleted Claims 4, 5
`7.
`and 28 of the Patent as granted. Accordingly, the objections raised against those claims
`are moot and can be dismissed.
`
`With regard to Claim 26 of the Patent as granted (Claim 22 of the Main
`8.
`Request), Patentee submits that the application as filed provides adequate basis for the
`subject matter of this claim. For instance, paragraph [0037] of the application as filed
`teaches the skilled reader that a lipid modifying compound as recited in said claim may
`be employed in any of the methods described in the application as filed. This claim
`therefore does not introduce any subject matter which extends beyond the content of the
`application as filed. The requirements of Article 123(2) EPC are satisfied.
`
`In conclusion, Patentee submits that the subject matter that is defined by each
`9.
`and every claim of the Main Request is fully derivable from the content of the
`application as filed. The requirements of Article 123(2) EPC are therefore satisfied.
`Each of Opponent's objections can be dismissed.
`
`Sufficiency of Disclosure (Articles lOO(b) and 83 EPC)
`
`Opponent also alleges that the claims of the Patent embrace subject matter
`10.
`which is not disclosed in the Patent in a manner that is sufficiently clear and complete
`for it to be put into effect by a person skilled in the art. Referring to the Examples of
`the Patent, Opponent appears to acknowledge that the claimed subject matter is
`sufficiently disclosed to the extent that it relates to the use of the MTP inhibitor that is
`employed in the Examples. This compound, which is referred to in the Patent as "BMS-
`201038" and is also known as "lomitapide", has the chemical structure shown in e.g.
`Claim 6 of the Patent as granted. Opponent asserts, however, that the claims are unduly
`broad because the Patent allegedly does not provide the skilled person with sufficient
`information to put the claimed subject matter into effect using MTP inhibitors other
`than lomitapide.
`
`11. Without acceding to Opponent's objection, Patentee has amended the claims of
`the Patent to specify that the MTP inhibitor is lomitapide or a pharmaceutically
`acceptable salt thereof or the piperidine N-oxide thereof. Opponent's objection is
`therefore moot and can be dismissed. The requirements of Article 83 EPC are satisfied.
`
`Opponent refers in some instances to Claims ~. §, 26 and 28 of the Patent as granted. However, it would
`appear that reference to Claims :±. ~. 26 and 28 of the Patent was intended.
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`Novelty (Articles lOO(a) and 54 EPC)
`
`Opponent alleges that the subject matter that is defined by Claims 1-26 of the
`12.
`Patent as granted lacks novelty over the disclosure in document D3. According to
`Opponent, document D3 provides evidence of a presentation which was purportedly
`given to the public before the priority date of the Patent. Opponent alleges that
`document D3 describes various uses of an MTP inhibitor known as "implitapide" (also
`known as "BAY 13-9952") which fall within the scope of Claims 1-26 as granted.
`
`13. Without acceding to Opponent's objection, Patentee has amended the claims of
`the Patent to specify that the MTP inhibitor is lomitapide or a pharmaceutically
`acceptable salt thereof or the piperidine N -oxide thereof. As Opponent himself appears
`to concede, document D3 is specifically concerned with implitapide, not lomitapide.
`Thus, even if one assumes arguendo that the disclosure in document D3 were to form
`part of the state of the art under Article 54(2) EPC, the subject matter that is defined by
`the claims of the Main Request is nonetheless novel. The requirements of Article 54
`EPC are satisfied. Opponent's objection can be dismissed.
`
`Inventive Step (Articles lOO(a) and 56 EPC)
`
`Opponent also alleges that the subject matter that is defined by the claims of the
`14.
`Patent lacks an inventive step over the disclosures in the cited documents D3-D8. Once
`again, without acceding to Opponent's objections, Patentee has amended the claims of
`the Patent to specify that the MTP inhibitor is lomitapide or a pharmaceutically
`acceptable salt thereof or the piperidine N -oxide thereof. For at least the following
`reasons, Patentee submits that the subject matter that is defined by the claims of the
`Main Request involves an inventive step over the state of the art.
`
`The technical contribution of the claimed invention
`
`As explained in detail in the Background section of the Patent, hyperlipidemia
`15.
`and hypercholesterolemia are risk factors for atherosclerotic cardiovascular disease
`(ASCVD), which is the major cause of mortality in the Western world. Prior to the
`making of the present invention, there was a need in the art for treatments for
`hyperlipidemia, hypercholesterolemia and associated disorders. In particular, there was
`a need in
`the art for
`treatments for familial hypercholesterolemia.
`Familial
`hypercholesterolemia, the two forms of which are known as homozygous familial
`hypercholesterolemia (hoFH) and heterozygous familial hypercholesterolemia (heFH),
`is an inherited disorder involving a genetic mutation and was challenging to treat.
`
`Inhibition of microsomal triglyceride transfer protein (MTP) had been identified
`16.
`as a promising approach to reducing low-density lipoprotein cholesterol (LDL-C). As
`paragraph [0021] of the Patent mentions, various compounds have been developed as
`MTP inhibitors. One of these compounds is lomitapide (BMS-201038), which is the
`subject of the claims of Patentee's Main Request. However, as paragraph [0022] of the
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`Patent explains, the clinical development of lomitapide was discontinued due to
`significant and serious hepatoxicities, including gastrointestinal side-effects, elevation
`of serum transaminases and hepatic fat accumulation. Prior to the making of the
`claimed invention, there was a need in the art for treatments for hyperlipidemia,
`hypercholesterolemia and associated disorders which did not suffer from such side(cid:173)
`effects (see paragraph [0022]).
`
`As outlined in paragraph [0027] of the Patent, the present invention as claimed
`17.
`is based at least in part on a surprising discovery that the side-effects previously
`observed with lomitapide can be eliminated or significantly reduced by employing a
`treatment regime involving the administration of at least three step-wise, increasing
`dosages of the compound. Reference is made in this regard to the data presented in
`Example 8 of the Patent, which demonstrate that lomitapide, when administered under
`such a regime, could be used to treat patients suffering from hypercholesterolemia with
`a significant reduction in side-effects such as steatorrhea and hepatic fat. Thus, as a
`result of these findings, it is possible to use lomitapide to treat hyperlipidemia,
`hypercholesterolemia and disorders associated therewith, especially hoFH, heFH and
`hypertriglyceridemia.
`
`The work that is presented in the Patent has led to the recent grant of a European
`18.
`marketing authorisation for lomitapide in the form of a medicinal product known as
`Lojuxta®, which is indicated as an adjunct to a low-fat diet and other lipid-lowering
`medicinal products in adult patients with hoFH. Thus, the work that is presented in the
`Patent has led to lomitapide, whose clinical development was originally discontinued
`due to safety concerns, being approved for use as a medicinal product for which there
`was a tremendous unmet need. The claimed invention therefore makes an important
`contribution to the art and, as explained in more detail below, involves an inventive step
`over the teaching in the state of the art.
`
`The claimed invention involves an inventive step over documents D3-D8
`
`Opponent alleges that the claimed subject matter lacks an inventive step over
`19.
`the disclosures in the cited documents D3-D8. More specifically, Opponent alleges that
`the claimed subject matter lacks an inventive step over: (i) the disclosure in document
`D3 alone; (ii) the disclosure in document D4, taken alone or in combination with the
`teaching in document D3; or (iii) the disclosure in any of documents D5-D8 in
`combination with the teaching in document D3. Patentee submits, however, that
`Opponent's objections are clearly devoid of merit.
`
`In connection with document D3, it will be recalled that this document is
`20.
`specifically concerned with the compound implitapide. Given this, it is difficult to see
`why a person of ordinary skill in the art, starting from document D3, would have chosen
`to devise a treatment regime that utilised a different MTP inhibitor, much less
`lomitapide. Opponent has failed to provide any explanation or rationale as to why a
`person of ordinary skill in the art, starting from a document relating to implitapide and
`knowing that the clinical development of lomitapide had been halted due to safety
`concerns, would have chosen to devise a treatment regime involving lomitapide.
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`21. With regard to Opponent's allegation that document D3 describes a treatment
`regime in which implitapide was administered in step-wise, increasing dosages, it is
`clear that the passages referred to by Opponent merely describe a dose-finding study to
`establish a single effective dose of implitapide. There is, moreover, nothing in
`document D3 to suggest that the side-effects of any MTP inhibitor, much less
`lomitapide, could be reduced by following a treatment regime which involves
`administering at least three step-wise, increasing dosages of the inhibitor. Furthermore,
`Opponent himself appears to question the extent to which any findings regarding
`implitapide that may be presented in document D3 can be extrapolated to lomitapide or
`other MTP inhibitors, commenting that "not all of the known MTP inhibitors may have
`an improved tolerability, safety or even effect if it is administered three-stepwise with
`increasing dosage of the MTP inhibitor" (see page 6, lines 5-7 of the Notice of
`Opposition). In this regard, it should be noted that the chemical structures of lomitapide
`and implitapide are markedly different?
`
`Thus, even if one assumes arguendo that document D3 were to form part of the
`22.
`state of the art, Patentee submits that a person of ordinary skill in the art would not have
`found it obvious to arrive at the subject matter defined by the claims of the Main
`Request based on the disclosure in this document. The claimed subject matter involves
`an inventive step.
`
`23. With regard to document D4, the Opposition Division will note that this
`document is specifically concerned with yet another MTP inhibitor, namely a
`compound known as "CP-346086" (see e.g. the title and the abstract of document D4).
`Since document D4 is specifically concerned with CP-346086, and the document also
`acknowledges that the clinical development of lomitapide was halted due to safety
`concerns (see the discussion regarding BMS-201038 in the penultimate paragraph of
`page 1899), a person of ordinary skill in the art evidently would not have found it
`obvious to arrive at the claimed subject matter based on this document. There is
`nothing in the document that would have led the skilled person to devise a treatment
`regime which involves the use of lomitapide. Moreover, the document does not suggest
`that the side-effects of any MTP inhibitor, let alone lomitapide, could be reduced by
`administering the inhibitor in the form of at least three step-wise, increasing dosages.
`The claimed subject matter involves an inventive step over the disclosure in document
`D4, taken alone or in combination with document D3.
`
`2
`
`The structures of lomitapide and implitapide are as follows:
`
`Lomitapide
`
`Implitapide
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`With regard to documents D5-D8, the Opposition Division will note that these
`24.
`documents merely describe the results of clinical or pre-clinical studies involving the
`use of implitapide. These documents do not even mention lomitapide, let alone suggest
`that the side-effects of lomitapide could be reduced by administering the compound in
`the form of at least three step-wise, increasing dosages. The subject matter that is
`defined by the claims of the Main Request therefore also involves an inventive step over
`the disclosure in any of documents D5-D8, taken alone or in combination with the
`teaching in document D3.
`
`In sum, Patentee submits that Opponent's allegations of lack of inventive step
`25.
`are wholly without foundation and should be dismissed. The subject matter that is
`defined by the claims of the Main Request involves an inventive step over the state of
`the art. The requirements of Article 56 EPC are satisfied.
`
`Conclusion
`
`In conclusion, Patentee submits that none of Opponent's objections against the
`26.
`Patent prejudices maintenance of the Patent on the basis of the claims of the Main
`Request. Each of Opponent's objections should be dismissed.
`
`The claims of Patentee's Main Request satisfy all of the provisions of the EPC.
`27.
`The Patent should be maintained on the basis of the Main Request.
`
`Respectfully,
`
`SIMPSON, Tobias Rutger
`For and on behalf of
`MATHYS & SQUIRE LLP
`Association No. 171
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