::opy for the designated Office (DO/EP)
`
`PATENT COOPERATION TREATY
`
`From the INTERNATIONAL BUREAU
`
`To:
`
`peT
`NOTIFICATION RELATING TO PRIORITY CLAIM
`
`(PCT Rules 26bis.1 and 26bis.2 and
`Administrative Instructions, Sections 402 and 409)
`
`Date of mailing (day/month/year)
`15 June 2001 (15.06.01)
`
`Applicant's or agent's file reference
`9596-330WO
`
`International application No.
`PCT/US01/01537
`
`Applicant
`
`COLBY, Gary, D.
`Akin, Gump, Strauss, Hauer & Feld,
`EPO - OS 1
`l.l.P.
`One Commerce Square
`22nd floor
`2005 Market Street
`Philadelphia, PA 19103-7986
`ETATS-UNIS D'AMERIQUE
`
`2~
`~j,
`
`L
`
`r0
`~t;:;,
`
`2C01
`
`(~I
`V
`
`IMPORTANT NOTIFICATION
`
`International filing date (day/month/year)
`12 January 2001 (12.01.01)
`
`THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA et al
`
`The applicant is hereby notified of the following in respect of the priority claim{s) made in the international application.
`1. [ZJ Correction of priority claim. In accordance with the applicant's notice received on: 08 March 2001 (08.03.01),
`the following priority claim has been corrected to read as follows:
`US 14 January 2000 (14.01.00) 60/176,086
`D even though the indication ofthe number of the earlier application is missing.
`D even though the following indication in the priority claim is not the same as the corresponding indication appearing
`in the priority document:
`
`2.0 Addition of priority claim. In accordance with the applicant's notice received on: ,
`the following priority claim has been added:
`D even though the indication of the number of the earlier application is missing.
`D even though the following indication in the priority claim is not the same as the corresponding indication appearing
`in the priority document:
`
`3. D As a result ofthe correction and/or addition of (a) priority claim(s) under items 1 and/or 2, the (earliest) priority date is:
`
`4.0 Priority claim considered not to have been made.
`D The applicant failed to respond to the Invitation under Rule 26bis.2(a) (Form PCTIIB/316) withi n the prescribed time limit.
`D The applicant's notice was received after the expiration of the prescribed time limit under Rule 26bis.l (a).
`D The applicant's notice failed to correct the priority claim so as to comply with the requirements of Rule 4.10.
`The applicant may, before the technical preparations for international publication have been completed and subject to the
`payment of a fee, request the International Bureau to publish, together with the international application, information
`concerning the priority claim. See Rule 26bis.2(c) and the PCT Applicant's Guide, Volume I, Annex 82(18).
`5. D In case where multiple priorities have been claimed, the above item(s) relate to the following priority claim(s):
`
`6. A copy of this notification has been sent to the receiving Office and
`[Zl to the International Searching Authority (where the international search report has not yet been issued).
`[Zl the designated Offices (which have already been notified of the receipt ofthe record copy).
`
`The International Bureau of WIPO
`34, chemin des Colombettes
`1211 Geneva 20, Switzerland
`
`Facsimile No. (41·22) 740.14.35
`
`Form PCT/IB/318 (July 1998)
`
`Authorized officer
`
`Sylvaine DESCLOUX
`
`Telephone No. (41-22) 338.83.38
`
`004092022
`
`NOVARTIS EXHIBIT 2019
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`Page 1 of 27
`
`

`

`J) ISJ
`
`"a"
`+49 89 2399-0
`523 656 epmu d
`TX
`FAX +49 89 2399-4465
`
`EPAIEPODEB
`0-80298 MOnchen
`
`Europaisches
`Patentamt
`
`European
`Patent Office
`
`Office europeen
`des brevets
`
`Generaldirektion 2
`
`Directorate General 2
`
`Direction Generale 2
`
`I
`
`Telephone numbers:
`
`Primary Examiner
`(substantive examination)
`
`+49 89 2399-8464
`
`Formalities Officer / Assistant
`(Formalities and other matters)
`
`+49 89 2399-0
`
`1111111111111111111111111111111111111111111111111111111
`
`.-J
`
`I
`
`Ref.
`E P25136-19A<j
`
`Date
`17.10.2006
`
`I
`
`GrOnecker, Kinkeldey,
`Stockmair & Schwanhausser
`Anwaltssozietat
`Maximilianstrasse 58
`80538 MOnchen
`ALLEMAGNE
`
`L
`
`Application No.
`01 903 095.6 - 2107
`
`Applicant
`THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
`
`Communication pursuant to Article 96(2) EPC
`
`The examination of the above-identified application has revealed that it does not meet the requirements
`of the European Patent Convention for the reasons enclosed herewith. If the deficiencies indicated are
`not rectified the application may be refused pursuant to Article 97(1) EPC.
`
`You are invited to file your observations and insofar as the deficiencies are such as to be rectifiable, to
`correct the indicated deficiencies within a period
`
`of
`
`4 months
`
`from the notification of this communication, this period being computed in accordance with Rules 78(2)
`and 83(2) and (4) EPC.
`
`One set of amendments to the description, claims and drawings is to be filed within the said period on
`separate sheets (Rule 36(1) EPC).
`
`Failure to comply with this invitation in due time will result in the application being deemed to be
`withdrawn (Article 96(3) EPC).
`
`Herrera, Suzanne
`Primary Examiner
`for the Examining Division
`
`Enclosure(s):
`
`2 pagels reasons (Form 2906)
`
`Registered Letter
`EPO Form 2001 07.02CSX
`
`NOVARTIS EXHIBIT 2019
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`
`

`

`I Bescheid/Protokoll (Anlage)
`
`17.10.2006
`
`Datum
`Date
`Date
`
`Communication/Minutes (Annex)
`
`Notification/Proces-verbal (Annexe)
`
`Blatt
`Sheet
`Feuille
`
`1
`
`Anmelde-Nr.:
`Application No.: 01 903 095.6
`Demande nO:
`
`The examination is being carried out on the following application documents:
`
`Description, Pages
`
`1-32
`
`as published
`
`Claims, Numbers
`
`1-29
`
`received on
`
`14.08.2002 with letter of
`
`14.08.2002
`
`Drawings, Sheets
`
`1/8-8/8
`
`as published
`
`1.
`
`The following documents (D) are referred to in this communication; the numbering will
`be adhered to in the rest of the procedure:
`01: WO 94/09010 A (SANDOZ-ERFINDUNGEN VERWAL TUNGSGESELLSCHAFT
`M.B.H; SANDOZ-PATENT-GMBH;) 28 April 1994 (1994-04-28)
`02: BOEHLER T ET AL: "THE IN VIVO EFFECT OF RAPAMYCIN DERIVATIVE
`SDZ RAD ON LYMPHOCYTE PROLIFERATION" TRANSPLANTATION
`PROCEEDINGS, ORLANDO, FL, US, vol. 30, no. 5, 1998, pages 2195-2197,
`XP001065480 ISSN: 0041-1345
`03: SCHULER W ET AL: "SDZ RAD, A NEW RAPAMYCIN DERIVATIVE"
`TRANSPLANTATION, WILLIAMS AND WILKINS, BALTIMORE, MD, US, vol.
`64, no. 1, 15 July 1997 (1997-07-15), pages 36-42, XP0020480321SSN: 0041-
`1337
`04: SEDRANI R ET AL: "CHEMICAL MODIFICATION OF RAPAMYCIN: THE
`DISCOVERY OF SDZ RAD" TRANSPLANTATION PROCEEDINGS,
`
`EPO Form 2906 01.91CSX
`
`NOVARTIS EXHIBIT 2019
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`
`

`

`I Bescheid/Protokoll (Anlage)
`
`17.10.2006
`
`Datum
`Date
`Date
`
`Communication/Minutes (Annex)
`
`Notification/Proces-verbal (Annexe)
`
`Blatt
`Sheet
`Feuille
`
`2
`
`Anmelde-Nr.:
`Application No.: 01 903 095.6
`Demande nO:
`
`2.
`
`3.
`
`ORLANDO, FL, US, vol. 30, no. 5, August 1998 (1998-08), pages 2192-2194,
`XP000925138 ISSN: 0041-1345
`05: US-A-5 525 610
`
`An International Preliminary Report on Patentability / International Preliminary
`Examination Report has already been drawn up for the present application in
`accordance with the PCT. The deficiencies mentioned in that report give rise to
`objections under the corresponding provisions of the EPC.
`
`In addition to the objection raised in the IPER, documents 01 to 03 cited above
`discloses the activity of SDZ RAD on lymphocyte proliferation. Consequently also
`these documents are destroying the novelty and inventive step of the claimed
`subject-matter (ct. parts indicated in the search report). It is also pointed out that only
`SDZ RAD has been tested in the application.
`
`EPO Form 2906 01.91CSX
`
`NOVARTIS EXHIBIT 2019
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`
`

`

`GRONECKER KINKELDEY STOCKMAIR & SCHWANH.A.USSER
`
`ANWALTSSOZIETAT
`
`EPO - Munich
`44
`2 1 Feb. 2007
`
`GKS & S MAXIMILIANSTRASSE S8 D-80S38 MONCHEN GERMANY
`
`RECHTSANWiiLTE
`LAWYERS
`
`PATENTANWiiLTE
`EUROPEAN PATENT ATIORNEYS
`
`PATENTANWiiLTE
`EUROPEAN PATENT ATIORNEYS
`
`Europaisches Patentamt
`Erhardtstrasse 27
`
`80298 MOnchen
`
`MONCHEN
`DR. HELMUT EICHMANN
`GERHARD BARTH
`DR. ULRICH BLUMENRODER, LL.M.
`CHRISTA NIKLAS-FALTER
`DR. MAXIMILIAN KINKELDEY, LL. M.
`DR. KARSTEN BRANDT
`ANJA FRANKE, LL. M.
`UTE STEPHANI
`DR. BERND ALLEKOTIE, LL. M.
`DR. ELVIRA BERTRAM, LL. M.
`KARIN LOCHNER
`BABETI ERTLE
`CHRISTINE NEUHIERL
`SABINE PROCKNER
`CORNELIA SCHMID
`BERNHARD MEHNERT, OIPl. ING
`PETRA LUBBE
`DR. SONJA BROTJE
`SONJA SCHiiFFLER
`DR. HOLGER GAUSS
`DR. NICOLAS SCHMITZ
`
`MONCHEN
`DR. HERMANN KINKELDEY
`PETER H. JAKOB
`HANS HILGERS
`ANNELIE EHNOLD
`THOMAS SCHUSTER
`DR. KLARA GOLDBACH
`MARTIN AUFENANGER
`GOTIFRIED KLlTZSCH
`DR. HElKE VOGELSANG-WENKE
`REINHARD KNAUER
`DIETMAR KUHL
`DR. FRANZ-JOSEF ZIMMER
`BETIINA K. REICHELT
`DR. ANTON K. PFAU
`DR. UDO WEIGELT
`RAINER BERTRAM
`JENS KOCH, M. S. (U of PAl M. S.
`BERND ROTHAEMEL
`THOMAS W. LAUBENTHAL
`DR. ANDREAS KAYSER
`DR. JENS HAMMER
`DR. THOMAS EICKELKAMP
`DR. CARLO TORTI'
`DR. PETER MILTENYI
`DR. MORITZ HOFFE
`
`• EUROPEAN PATENT ATIORNEY
`
`BERLIN
`PROF. DR. MANFRED BONING
`DR. PATRICK ERK, M.S. (MID
`
`KCLN
`DR. MARTIN DROPMANN
`
`CHEMNITZ
`DR. CARMEN STEINIGER'
`*PATENTANWALTIN
`
`ALiCANTE
`WOLFHARD MEISTER
`DR. ANDREAS TORKA'
`*RECHTSANWALT
`
`OF COUNSEL
`DR. HENNING MEYER-PLATH
`
`DR. WILFRIED STOCKMAIR
`(-1996)
`
`IHR ZEICHEN I YOUR REF.
`
`UNSER ZEICHEN lOUR REF.
`
`EP25136HV163
`
`DATUM I DATE
`
`February 26, 2007
`
`European Patent Application No. 01 903095.6-2112
`Applicant: The Trustees of the University of Pennsylvania
`
`In response to the Official Communication. dated October 17.2006
`
`Herewith new claims 1-26 are submitted, It is requested to continue examination on the
`basis of these new claims.
`
`1. Claim amendment and support
`
`New claims 1 to 26 are supported by previous claims 1-29 and the specification as follows
`(page and line numbering refer to the specification of W001/51 049):
`
`NEW CLAIM
`
`SUPPORTED BY
`
`1
`
`2
`
`3
`
`previous claim 1, * see below
`previous claim 2,
`specification page 6, line 28 to page 7, line 30
`previous claim 4
`
`GRUNECKER KINKELDEY
`STOCKMAIR & SCHWAN HAuSSER
`MAXIMILIANSTR. 58
`D-80538 MUNCHEN
`GERMANY
`
`TEl. +49 89 21 2350
`FAX +49 89 220287
`FAX +49 89 21 869293
`http://www.grunecker.de
`e-mail: info@grunecker.de
`
`DEUTSCHE BANK MUNCHEN
`No. 17 51734
`BLl 700 700 10
`SWIFT: DEUT DE MM
`
`NOVARTIS EXHIBIT 2019
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`Page 5 of 27
`
`

`

`2
`
`4
`
`5
`
`6-10
`
`11-18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`previous claim 5,
`specification ~age 8, lines 1-2
`previous claim 6
`claims 7-11 of W001/51 049,
`correction of copy/paste error during adaptation to use claims
`previous claims 12-19
`previous claim 20, amended claim dependency,
`specification page 10, lines 27-29
`previous claim 21
`
`previous claim 22, correction of typographical error
`
`previous claim 23, * see below
`
`previous claim 24
`
`previous claim 27, * see below
`
`25-26
`
`previous claims 28-29
`
`*: Previous claims 1, 23 and 27 (new claims 1, 22 and 24) were amended to exclude
`rapamycin by deleting one element, -H, of the Markush group of R1 and re-iterating the
`
`whole Markush group for R2. The separate recitation is supported by the original claims
`which recited "each of R1 and R2 is independently selected from".
`
`No new matter has been introduced by the amendments.
`
`2. Novelty (Article 54(2) EPC)
`
`2.1
`
`In the IPER it was stated that previous claims 1-29 lack novelty over 05. 05 discloses
`the use of 42-epi-rapamycin (or 40-epi-rapamycin, if the numbering convention used in
`the documents 01 to 04 and the present invention is applied). When discussing the
`
`background art, 05 (first and second column) refers to a number of therapeutic
`applications for rapamycin. 05 does not teach or suggest any O-alkylated derivates of
`
`rapamycin (such as SOZ-RAO).
`
`New claims 1-26 do no longer relate to rapamycin, rendering the objection with respect
`to 05 moot.
`
`NOVARTIS EXHIBIT 2019
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`
`

`

`3
`
`2.2 The Examining Division stated that 01 to 03 disclose the activity of SDZ RAD on
`lymphocyte proliferation and thus, would also anticipate the novelty of the claimed
`subject matter.
`
`The applicant respectfully disagrees with the assessment of the Examining Division
`concerning previous claims 1-24 and 27-29 (new claims 1-26). Specifically taken
`together, the conditions that are subject to a treatment with rapamycin or its derivatives
`that are discussed in 01 to 03 do not comprise Iymphoproliferative disorders (like
`lymphoma or post transplant Iymphoproliferative disorders) or the
`inhibition of
`metastasis of lymphatic tumors. The specific medical uses of new claims 1-26 are not
`recited in any of documents 01 to 03. Therefore, it is respectfully submitted that the
`subject-matter of said claims is novel over the disclosures of 01 to 03 and that the
`novelty objection should be withdrawn.
`
`3.
`
`Inventive step (Article 56 EPC)
`
`The Examining Division expressed their concerns with respect to the inventive step of
`the present invention over the teachings of 01 to 03. However, the Examining Division
`did not substantiate this objection further.
`
`3.1 01 does not show any therapeutic application of any of the disclosed rapamycin
`derivatives at all; rather, it speculates that these derivatives may exhibit similar
`beneficial effects as rapamycin does. The conditions mentioned in 01 comprise
`various different diseases, e.g. allograft rejection, graft vs. host disease, infection,
`inflammatory disorders, multi drug resistance, autoimmune disorders, tumors or
`hyperproliferative disorders.
`
`Furthermore, the "hyperproliferative disorders" specified in 01 are limited to tumors
`and hyperproliferative skin disorder (page 6, pOint e)). These disorders are significantly
`different from a Iymphoproliferative disorder since they affect only non-lymphocytic
`cells or tissues. It is worth noting that 01 does not give a single example proving the
`pharmaceutical efficiency of the rapamycin derivatives and does equally not suggest
`their use for the treatment of any Iymphoproliferative disorder (like PTLD). Finally, 01
`does not provide any in vitro or in vivo data that could be taken into account for an
`
`NOVARTIS EXHIBIT 2019
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`
`

`

`4
`
`assessment of the pharmaceutical efficiency or even the pharmaceutical compatibility;
`from the disclosure of 01, a skilled person could not even exclude that the novel
`
`compounds may exhibit toxic effects.
`
`3.2
`
`If 02 were considered as the closest prior art for previous claims 6-11 (new claims 5-
`
`10), the problem to be solved by the present invention is the application of the same
`
`reagents (an immunosuppressive agent like CysA in conjunction with a rapamycin
`
`derivative) for the treatment of different conditions. The therapeutic indications that are
`
`treated in 02 are limited to the immunosuppressive activity of SOZ RAO on T-cell
`
`proliferation, i.e. the downregulation of a normal immune reaction of renal allograft
`
`recipients. The use of SOZ RAO for the treatment of Iymphoproliferative disorders is
`
`neither discussed nor suggested. 02 rather focuses on possible synergistic effects for
`
`ameliorating the known effects of the applied substances and does not give any
`
`incentive to transfer the results to any medical condition different from those known in
`
`the art.
`
`3.3 03 likewise focuses on the immunosuppressive effects of SOZ RAO and its efficiency
`
`in the downregulation of normal immune reactions upon transplantation of tissues from
`
`kidney and heart. The arguments put forward for 02 also apply for 03.
`
`3.4
`
`In contrast to the above, the in vitro and in vivo experiments of the present application
`
`reveal the surprising effectiveness of SOZ RAO in the treatment of Iymphoproliferative
`
`disorders, including PTLO, lymphoma, EBV-virus infected hyperproliferative lymphoma
`
`cells or established B-cell tumors as well as the inhibition of the establishment of
`PTLO-like lymphoma (see examples, pages 20-30). These surprising results were also
`
`the basis of a high impact publication from the inventors (post-published in PNAS 97;
`
`11 April 2000, pp. 4285-90).
`
`Thus, it is emphasized that the subject-matter of the present invention involves an
`
`inventive step over the prior art.
`
`Requests
`
`In view of the above, it is respectfully requested that the patentability of the subject-matter of
`
`new claims 1 to 26, submitted with this letter, be acknowledged. Further, it is kindly
`
`requested that the necessary amendments to the description of the present application may
`
`NOVARTIS EXHIBIT 2019
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`
`

`

`5
`
`be deferred until an agreement with the Examiner on an allowable set of claims is achieved.
`Should the Examiner not be in the position to acknowledge said new claims to be allowable,
`
`an
`
`is respectfully requested.
`
`Furthermore,
`
`Informal interview
`
`Oral Proceedings
`
`according to Article 116 EPC are requested.
`
`It.
`
`6~~
`
`Heike~ ang-Wenke
`
`Encl.
`
`laims 1-26 (marked up version)
`laims 1-26 (clear copy)
`
`NOVARTIS EXHIBIT 2019
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`

`..
`
`Application No.:
`Applicant:
`Our Ref.:
`Date:
`
`01 903095.6-2112
`The Trustees of the University of Pennsylvania
`EP25136HV163
`February 26, 2007
`
`CLAIMS (marked up version)
`
`1. Use of a rapamycin derivative having the chemical structure
`
`0--
`
`wherein
`
`X is (H, H) or 0;
`
`Y is (H, OH) or 0;
`
`eaGh--Gf--R 1 aoo--R2--is ifldepemieRtly--selected from the group consisting of--M, alkyl,
`
`thioalkyl, arylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylarylalkyl,
`
`dihydroxyalkylarylalkyl, alkoxyalkyl, acyloxyalkyl, aminoalkyl, alkylaminoalkyl,
`
`alkoxycarbonylaminoalkyl, acylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl,
`dioxolanylallyl, carbalkoxyalkyl, and (R3h Si;
`
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`
`

`

`2
`
`R2 is selected from the group consisting of -H, alkvl, thioalkyl. arvlalkyl. hydroxyalkyl,
`
`dihydroxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, acyloxyalkyl,
`
`aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, acylam inoalkyl, arylsulfonamidoalkyl,
`allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl, and (R3h Si;
`each R3 is independently selected from the group conSisting of -H, methyl, ethyl,
`
`isopropyl, tert-butyl, and phenyl; and
`
`either R4 is methyl or R4 and R1 together form a C2-5 alkylene moiety for the
`
`preparation of a medicament for alleviating a Iymphoproliferative disorder in a human
`
`patient.
`
`2. The use of claim 1, wherein the rapamycin derivative is selected from the group
`
`consisting of
`
`rapamyGi-n j O
`
`40-0-benzyl-rapamycin,
`
`40-0-( 4' -hydroxymethyl)benzyl-rapamycin,
`
`40-0-[4'-(1,2 dihydroxyethyl)]benzyl-rapamycin,
`
`40-0-Allyl-rapamycin,
`
`40-0-[3'-(2,2-dimethyl-1 ,3-dioxolan-4(S)-yl)-prop-2'-en-1 '-yl]-rapamycin,
`
`(2'E, 4'S)-40-0-(4',5'-dihydroxypent-2'-en-1 '-yl)-rapamycin,
`
`40-0-(2-hydroxy)ethoxycarbonylmethyl-rapamycin,
`
`40-0-(2-hydroxy)ethyl-rapamycin,
`
`40-0-(3-hydroxy)propyl-rapamycin,
`
`40-0-(6-hyd roxy) hexyl-rapamycin,
`
`40-0-[2-(2hydroxy)ethoxy]ethyl-rapamycin,
`
`40-0-[(3S)-2,2-dimethyldioxolan-3-yl]methyl-rapamycin,
`
`40-0-[(2S)-2 ,3-dihydroxyprop-1-yl]-rapamycin,
`
`40-0-(2-acetoxy)ethyl-rapamycin,
`
`40-0-(2 -n icoti noyloxy)ethyl-rapamycin,
`
`40-0-[2 -( N-morpholi no )acetoxy ]ethyl-rapamyci n I
`
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`
`

`

`3
`
`40-0-(2-N-imidazolylacetoxy)ethyl-rapamycin,
`
`40-0-[2-(N-methyl-N'-piperazinyl)acetoxy]ethyl-rapamycin,
`
`39-0-desmethyl-39,40-0,0-ethylene-rapamycin,
`
`(26R)-26-dihydro-40-0-(2-hydroxy)ethyl-rapamycin,
`
`28-0-methyl-rapamycin,
`
`40-0-(2-aminoethyl)-rapamycin,
`
`40-0-(2-acetaminoethyl)-rapamycin,
`
`40-0-(2-nicotinamidoethyl)-rapamycin,
`
`40-0-(2 -( N -methyl-im idazo-2'-ylcarbethoxamido )ethyl)-rapamycin,
`
`40-0-(2-ethoxycarbonylaminoethyl)-rapamycin,
`
`40-0-(2 -tolylsulfonamidoethyl)-rapamycin, and
`
`40-0-[2-( 4'5'-dicarboethoxy-1',2' ,3'-triazol-I'-yl)-ethyl]-rapamycin.
`
`3:--T-He-tJs&·Gf·-Glafm.··h·-wHer-ein·tHe-fapamyGA-Ger+vative·~s·seleGted-fr-om··tHe·.gr-oufc)
`
`CGflsistmg.-Gf
`
`r-apamyGifl,
`
`40 0 (2 hydr-oxy)ethyl r-afc)amycin,
`
`40 0 (3 hyd r-oxy) fc)r-ofc)yl rapamycin,
`
`40 0 [2 (2 hydmxy)ethoxy]ethyl rafc)arriycin, and
`
`················-40-0-~2-acetamifloeth-y~)-r-afc)8my-ciF1-:
`
`4-:3. The use of claim 1, wherein the rapamycin derivative is selected from the group
`
`consisting of
`
`40-0-(2-hydroxy)ethyl-rapamycin,
`
`40-0-(3-hydroxy)propyl-rapamycin,
`
`40-0-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
`
`40-0-(2 -acetami noethyl)-rapamycin.
`
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`4
`
`51. The use of claim 1, wherein the rapamycin derivative is 40-0-(2-hydroxy)ethyl(cid:173)
`rapamycin.
`
`OQ. The use of claim 1, wherein the rapamycin derivative is co-administered with a second
`
`pharmacologically active agent.
`
`79.. The use of claim 1, wherein the rapamycin derivative is .9., .. w..tJ.~r~.tDJ.h§ .. §.§~9..o.gJ~g~!lU§
`an immunosuppressive agent.
`
`aI. The use of claim ·~·i .. whefeill.the .. r-apamyGifl·der-i.vaUve .. is6! wherein the second agent is
`
`selected from the group consisting of azathioprine, a mycophenolic acid, Rho(D) immune
`
`globulin, cyclosporin, tacrolimus, cisplatin, a cyclophosphamide, and leflunomide.
`
`9§. The use of claim .~.§, wherein the rapamycin derivative is··and the second agent are
`
`administered to the patient in a composition comprising both the rapamycin derivative and
`
`the second agent.
`
`W~. The use of claim -1-.9., wherein the rapamycin derivative is administered to the patient at
`
`least one hour before the second agent is administered to the patient.
`
`·~·1-1 O. The use of claim ·1§, wherein the rapamycin derivative is administered to the patient
`
`at least one hour after the second agent is administered to the patient.
`
`1-2-11. The use of claim 1, wherein the patient is afflicted with a post-transplant
`
`Iymphoproliferative disorder.
`
`·1-312. The use of claim 1, wherein the patient is afflicted with a lymphatic cancer.
`
`-1-4.1.~. The use of claim -1-3.1.~., wherein the lymphatic cancer is a lymphocytic leukemia.
`
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`5
`
`1514. The use of claim~·312, wherein the lymphatic cancer is a lymphoma.
`
`1615. The use of claim ·l514, wherein the lymphoma is selected from the group consisting
`
`of an AIDS-related lymphoma, a Hodgkin's lymphoma, a non-Hodgkin's lymphoma, a
`
`Burkitt's lymphoma, a diffuse large cell lymphoma, a T-cell lymphoma, and a cutaneous T(cid:173)
`
`cell lymphoma.
`
`-1--7·16_ The use of claim~-51. wherein the Iymphoproliferative disorder is a disorder
`
`characterized by proliferation of lymphocytes that have been infected with an Epstein-Barr
`
`virus.
`
`4-817. The use of claim -1-7-16, wherein the patient is undergoing immunosuppressive
`
`therapy and the Iymphoproliferative disorder is a lymphoma.
`
`1918. The use of claim 1, wherein the Iymphoproliferative disorder is a malignant
`
`Iymphoproliferative disorder.
`
`2Q.1.~. The use of claim -1-.1.1, wherein the Iymphoproliferative disorder is selected from the
`
`group consisting of a polyclonal atypical lymphoid hyperplasia and a monoclonal overtly
`
`malignant B-cell lymphoma.
`
`2-1-20. The use of claim 1, wherein the amount is from 10 micrograms per kilogram body
`
`weight to 5 milligrams per kilogram body weight.
`
`2-221. The use of claim 1, wherein the rapamycin derivative is administered parenterally to
`
`the patient.
`
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`2-322_ Use of a rapamycin derivative having the chemical structure
`
`6
`
`0--
`
`wherein
`
`X is (H, H) orO;
`
`Y is (H, OH) or 0;
`
`eact-l--of. __ Rl and-R2-·is independenUy--selected from the group consisting of.--H,(cid:173)
`
`alkyl, thioalkyl, arylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylarylalkyl,
`
`dihydroxyalkylarylalkyl, alkoxyalkyl, acyloxyalkyl, aminoalkyl, alkylaminoalkyl,
`
`alkoxycarbonylaminoalkyl, acylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl,
`dioxolanylallyl, carbalkoxyalkyl, and (R3h Si;
`R:'!§J?~j§.9.t~.g .. tr9..mJ!:t~Lg[Q~Q .. 9..Qo§i§.~i.o.g .. Qf..:.t:L..~!~.y.L .. !bi.Q~J.~.yJ.,.J~.!Y.l§J.~.y.L.
`.b.y'g[Q?'s'y'g.l~.Y.l .. g.!b'y.gJQ?'s'y'g.l!SY.l .. b.y.g[QKY.9'!!s.Y.jg.!y.!gJ.~.y.L .. g.!b'y.g.r.Q?Sy.~J.~.Y.l~[YJ.~!'~.Y.J. •.. ~J.~.Q?SY.~J.~.Y.l~
`acyloxyalkyL aminoalkyL alkylaminoalkyl. alkoxycarbonylaminoalkyl, acylaminoalkyL
`arylsulfonamidoalkyl, allyl. dihydroxyalkylallyL dioxolanylallyl. carbalkoxyalkyL and (R3b Si;
`
`each R3 is independently selected from the group consisting of -H, methyl,
`
`ethyl, isopropyl, tert-butyl, and phenyl; and
`
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`either R4 is methyl or R4 and R1 together form a C2-5 alkylene moiety for the
`
`preparation of a medicament for inhibiting a Iymphoproliferative disorder in a human patient
`
`at risk for developing the disorder.
`
`24~.~. The use of claim ~.?~., wherein the rapamycin derivative is 40-0-(2-hydroxy)ethyl(cid:173)
`
`rapamycin.
`
`2-5-:---tJ-se-of-·an·fmmUAosuppr-essive·agemt-·aru:;t·-a·f-apamyQA-·de.rfvative·h-aving .. the·chemiBaI
`
`stf-uct.ur-e
`
`0--
`
`wt-1er-ein
`
`X is (H, H) or 0;
`
`Y is (H, OH) or 0;
`each of R1
`. and R2 is independently selected from the group consisting of H,
`alkyl·j .. thioalkyl·j--ar-ylalkyl-j·nydroxy-alkyl·j .. dihydroxy-alkyl-; .. hydfoxy-alkyffir-ylalkyl-j
`
`dmydroxyalkylar-y·la~kylj··alkoxyalkyl·j·-acyloxy-alkyh--ammoalkyl·j·-alkylamiROa1-kY~i
`
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`
`alkoxycarbonylaminoalkyl-,--acylam+noalkyl-,---arylsulfoAamidoalk-ylj--allyl-,--dih-ydroxyalkylallyl-j
`d+oxOlaAylal~y-l,caf-GaIkGxyalky-l,and-tR3}3--Si-;­
`eaGR--R3.-~s--independeRtIy--seffict-ed--f-rom--tAe-grOUP--COAs+stfnQ--of--Hi--meth-y-l,
`
`etlwh--isopropy-l,ter-t-butYh--aAd-pt-lenyli-ami
`eitt-ler R4 is methyl or R4 and R~ -together form a C2-5 alkylene mOiety for the
`
`preparation of a medicament for inhibitinQ Qraft rejection in a human patient.
`
`26,----The--use-of--claim--2J-,--wher-eill-the-i-mmuAosuppr-essive-aQent--is--selected--from-the-grotip
`
`consist+ng-of--azath-iopr+nej--a--my-copheAOlic-acidi---Rho~[)}-immune--QlolJuliA-,--cydospDrillj
`
`tacrolimusj--cisplatillj--a-cyclophosphamidsj--aoo--leflUflomkfe--aoo-wher-ein-the-rapamycin
`
`derivative-fs-40-0-(2-hydroxy)ethyl-rapamycin;·
`
`2-7-24_ Use of a rapamycin derivative having the chemical structure
`
`o
`
`0--
`
`wherein
`
`X is (H, H) or 0;
`
`Y is (H, OH) or 0;
`
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`9
`
`eaGh·of.·-R 1 and·-R2·is independenUy··selected from the group consisting of -H'i
`
`alkyl, thioalkyl, arylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylarylalkyl,
`
`dihydroxyalkylarylalkyl, alkoxyalkyl, acyloxyalkyl, aminoalkyl, alkylaminoalkyl,
`
`alkoxycarbonylaminoalkyl, acylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl,
`dioxolanylallyl, carbalkoxyalkyl, and (R3h Si;
`R=..i§'J?~!.~.9.t~.g..ff..Q.m.Jbg .. gr.Q1JQ .. g.9.!J§.J.§Ji.o.g .. Qf. .. :.t:LJ~J.~.Y.L..!bJ.9.§!.~.Y.L .. §.r.yJ§!'~.Y.l..
`b.y.Q[Q}s.Y.§.l!$yJ .... Qi.tJ.y.Q[Q?S.Y.§.l!$yL...tJ.y9 rq2s.Y..~.!.Is.Y.J.~.r.Y.!§.l!$YL...g.ib'yg.r.Q?SY§.LIsY!§'r.Y..I.§!.ts.YJ....§J.~.925y'§!!$y.!..
`acyloxyalkyl. aminoalkyl. alkylaminoalkyl, alkoxycarbonylaminoalkyl, acylaminoalkyl.
`arylsulfonamidoalkyl. allyl. dihydroxyalkylallyl. dioxolanylallyl, carbalkoxyalkyl. and (R3h Si;
`
`each R3 is independently selected from the group consisting of -H, methyl,
`
`ethyl, isopropyl, tert-butyl, and phenyl; and
`either R4 is methyl or R4 and R 1 together form a C2-5 alkylene moiety for the
`
`preparation of a medicament for inhibiting metastasis of a lymphatic tumor in a human
`
`patient afflicted with a lymphatic cancer.
`
`2-825. The use of claim 2-724, wherein the rapamycin derivative is 40-0-(2-hydroxy)ethyl(cid:173)
`
`rapamycin.
`
`29.;?§. A method of assessing whether an agent is useful for alleviating or inhibiting a
`
`Iymphoproliferative disorder in a human patient, the method comprising
`
`exposing a B lymphocyte to an Epstein-Barr virus, whereby the B lymphocyte
`
`exhibits a transformed phenotype,
`
`injecting the transformed B lymphocyte into a mouse having a severe
`
`combined immunodeficiency,
`
`administering the agent to the mouse, and
`
`monitoring tumor growth in the mouse for at least about 21 days,
`
`whereby observation in the mouse of one or more of tumor regression,
`
`tumor eradication, and absence of a second tumor in the mouse is an indication that the
`
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`10
`
`agent is useful for alleviating or inhibiting a post-transplant Iymphoproliferative disorder in a
`
`mammal.
`
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`

`{
`
`Application No.:
`Applicant:
`Our Ref.:
`Date:
`
`CLAIMS
`
`01 903095.6-2112
`The Trustees of the University of Pennsylvania
`EP25136HV163
`February 26, 2007
`
`1. Use of a rapamycin derivative having the chemical structure
`
`1 R -0/;"
`
`0--
`
`wherein
`
`X is (H, H) or 0;
`
`Y is (H, OH) or 0;
`
`Rl is selected from the group consisting of alkyl, thioalkyl, arylalkyl, hydroxyalkyl,
`
`dihydroxyalkyl, hydroxya Ikylarylalkyl, dih ydroxyalkylarylalkyl, alkoxyalkyl, acyloxyalkyl,
`
`aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, acylaminoalkyl, arylsulfonamidoalkyl,
`allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl, and (R 3h Si;
`R2 is selected from the group consisting of -H, alkyl, thioalkyl, arylalkyl, hydroxyalkyl,
`
`dihydroxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, acyloxyalkyl,
`
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`2
`
`aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, acylaminoalkyl, arylsulfonamidoalkyl,
`allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl, and (R 3h Si;
`each R3 is independently selected from the group consisting of -H, methyl, ethyl,
`
`isopropyl, tert-butyl, and phenyl; and
`either R4 is methyl or R4 and R 1 together form a C2-5 alkylene moiety for the
`
`preparation of a medicament for alleviating a Iymphoproliferative disorder in a human
`
`patient.
`
`2. The use of claim 1, wherein the rapamycin derivative is selected from the group
`
`conSisting of
`
`40-0-benzyl-rapamycin,
`
`40-0-( 4'-hydroxymethyl)benzyl-ra pamycin,
`
`40-0-[4'-(1,2 dihydroxyethyl)]benzyl-rapamycin,
`
`40-0-allyl-rapamycin,
`
`40-0-[3'-(2,2-dimethyl-1 ,3-dioxolan-4(S)-yl)-prop-2'-en-1'-yl]-rapamycin,
`
`(2' E, 4'S)-40-0-( 4' ,5'-dihydroxypent-2' -en-1'-yl)-rapamycin,
`
`40-0-(2-hydroxy)ethoxycarbonylmethyl-rapamycin,
`
`40-0-(2-hydroxy)ethyl-rapamycin,
`
`40-0-(3-hydroxy)propyl-rapamycin,
`
`40-0-(6-hydroxy )hexyl-rapamycin,
`
`40-0-[2-(2hydroxy)ethoxy]ethyl-rapamycin,
`
`40-0-[ (3S )-2 ,2 -dimethyldioxola n-3-yl]meth yl-rapamycin,
`
`40-0-[(2S)-2,3-dihydroxyprop-1-yl]-rapamycin,
`
`40-0-(2 -acetoxy )ethyl-rapamyci n,
`
`40-0-(2-nicotinoyloxy)ethyl-rapamycin,
`
`40-0-[2 -(N -morpholino )acetoxy ]ethyl-rapamycin,
`
`40-0-(2-N-imidazolylacetoxy)ethyl-rapamycin,
`
`40-0-[2-(N-methyl-N'-piperazinyl)acetoxy]ethyl-rapamycin,
`
`39-0-desmethyl-39,40-0,0-ethylene-rapamycin,
`
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`3
`
`(26 R )-26-dihyd ro-40-0-(2 -hydroxy )ethyl-rapamycin,
`
`28-0-methyl-rapamycin,
`
`40-0-(2-aminoethyl)-rapamycin,
`
`40-0-(2-acetaminoethyl)-rapamycin,
`
`40-0-(2-nicotinamidoethyl)-rapamycin,
`
`40-0-(2-(N-methyl-imidazo-2'-ylcarbethoxamido)ethyl)-rapamycin,
`
`40-0-(2-ethoxycarbonylaminoethyl)-rapamycin,
`
`40-0-(2-tolylsulfonamidoethyl)-rapamycin, and
`
`40-0-[2-( 4'5'-dicarboethoxy-1',2',3'-triazol-I'-yl)-ethyl]-rapamycin.
`
`3. The use of claim 1, wherein the rapamycin derivative is selected from the group
`
`consisting of
`
`40-0-(2 -hydroxy)ethyl-rapamycin,
`
`40-0-(3-hydroxy)propyl-rapamycin,
`
`40-0-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
`
`40-0-(2-acetaminoethyl)-rapamycin.
`
`4. The use of claim 1, wherein the rapamycin derivative is 40-0-(2-hydroxy)ethyl-rapamycin.
`
`5. The use of claim 1, wherein the rapamycin derivative is co-administered with a second
`
`pharmacologically active agent.
`
`6. The use of claim 5, wherein the second agent is an immunosuppressive agent.
`
`7. The use of claim 6, wherein the second agent is