NOVARTIS EXHIBIT 2142
`Par v Novartis, IPR 2016-00084
`Page 1 of 59
`
`

`
`PATENT APPLICATION SERIAL NO. 1128.'19653
`
`U.S. DEPARTMENT OF COMMERCE
`PATENT AND TRADEMARK OFFICE
`.
`FEE RECORD SHEET
`
`DR1f8
`
`I
`
`Ii £I II zrofliQ -.-.,
`
`,,,inti. szw.
`
`DS20026 03/03/92 07839653
`
`01-1425 020 101
`
`762.00CH 9695-1N1
`
`P 30018 03/23/92 07839653
`
`01-1425 030. 101
`
`72.00CR
`
`PTO-lS56
`(5/87)
`
`NOVARTIS EXHIBIT 2142
`Par v Novartis, IPR 2016-00084
`Page 2 of 59
`
`

`
`SAR CODe 1.ABE1.
`
`IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII~ 11I1111111111
`
`u.s. PATENT APPLICATION
`
`SERIA1. NUMseR
`
`071839,653
`
`FILING DAn:
`
`02/20/92
`RULE 60
`
`C1.ASS
`
`546
`
`IiROUP ART uNIT
`
`1203
`
`PHI LIP F. HUGHES, HOPEWELL. NJ.
`-
`
`I-z
`~ ...
`~
`A.
`A. c
`
`**CONTINUING DATA*********************
`VERIFIED
`THIS APPLN IS A CON OF
`
`07/598.270 10/16/90
`
`**FOREIGN/PCT APPLICATIONS************
`VERIFIED
`
`FOREIGN FILING LICENSE GRANTED 03/25/92
`
`STATE OR
`COUNTRY
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`SHEETS
`DRAWING
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`TOTA1.
`CLAIMS
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`INDEPENDENT
`CLAIMS
`
`FI1.ING FEE
`RECEIVED
`
`ATTORNey DOCKET NO.
`
`NJ
`
`o
`
`8
`
`3
`
`$ 690.00
`
`9695-1-Nl
`
`RONALD W. ALI CE
`AMERICAN HOME PRODUCTS CORP.
`685 TH I RD AVE.
`NEW YORK, NY 10017
`
`~ ... I-
`
`RAPAMYCIN ALKOXYESTERS
`
`This is to certify that annexed hereto is a true copy from the records of the United States
`Patent and Trademark Office of the application as filed which is identified above.
`
`By authority of the
`COMMISSIONER OF PATENTS AND TRADEMARKS
`
`Date
`
`Certifying Officer
`
`NOVARTIS EXHIBIT 2142
`Par v Novartis, IPR 2016-00084
`Page 3 of 59
`
`

`
`Ul1839653
`AHP-9695:"1-N1
`PA1ENT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Patent Application of:
`
`Philip Floyd Hughes
`
`Attorney's Docket No.: AHP-9695-1-N1
`(Rule 60 Continuation of USSN 07/598,270)
`
`Examiner:. Chang
`
`Filed: . February 20, 1992 (By Express Mail)
`
`Group: 1203
`
`For: Rapamycin Alkoxyesters
`
`Honorable Commissioner of
`Patents and Trademarks
`Washington, D.C. 20231
`
`CERTIFICATE OF MAILING UNDER 37 CFR 1.10
`
`"Express Mail" mailing label number: LB 187217558
`
`Date of Deposit: February 20, 1992
`
`I hereby certify that:
`
`1. Rule 60 Application and Fee,
`
`2. Statement By Attorney of True Copy Under Rule 60, and
`
`3. Associate Authorization of Agent
`
`is being deposited with the United States Postal Service "Express Mail Post
`
`Office to Addressee" service under 37 CFR 1.10 on the date indicated above and is
`
`addressed to the Commissioner of Patents and Trademarks, Washington, D.C. 20231.
`
`, '
`I' if ,.
`! ~
`I;
`
`,
`, .
`
`Mazy Ellen Fiala
`Name of Person Mailing Paper or Fee
`
`~~~ -
`
`e of Person Mailing Paper or Fee
`
`Sl
`
`NOVARTIS EXHIBIT 2142
`Par v Novartis, IPR 2016-00084
`Page 4 of 59
`
`

`
`AHP-9695-1-Nl
`PATENT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Patent Application of:
`
`Phillip Floyd Hughes
`
`Attorney's Docket No.: AHP-9695-1-Nl
`(Rule 60 Continuation ofUSSN 07/598,270)
`
`Examiner: Chang
`
`. Filed: February 20, 1992 (By Express Mail)
`
`Group:
`
`1203
`
`iFor: Rapamycin Alkoxyesters
`
`Honorable Commissioner of
`Patents and Trademarks
`Washington, DC 20231
`
`STATEMENT BY ATTORNEY OF TRUE COPY UNDER RULE 60
`
`Sir:
`
`I, George Tarnowski, whose mailing address is c/oMr. RonaldW.Alice, American Home
`
`,Products Corporation, 685 Third Avenue, New York, New York, 10017, and whose Registration
`
`No. is 27,472, do hereby state:
`
`1)
`
`that I am the attorney of record in U.S. Patent Application Serial No. 07/598,270,
`
`filed October 16, 1990; and
`
`,
`
`;1,
`"
`
`I ! and confirm that said continuation application is a true copy of the original application and that no
`i 1 amendments referred to in the oath or declaration filed to complete the original application
`! i introduced new matter therein.
`
`2)
`
`that I have compared the accompanying continuation application with the original ,
`
`.
`
`,
`
`Respectfully submitted,
`
`~ci ~
`
`ieorg:rarnowski
`Attorney for Applicants
`Reg. No. 27,472
`
`/
`
`/
`
`, ; Dated: February 20, 1992
`: ~Telephone: (215) 341-2312
`
`NOVARTIS EXHIBIT 2142
`Par v Novartis, IPR 2016-00084
`Page 5 of 59
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`

`
`--'
`
`.. -.I'October 1990
`3EDI :OCO.ASM:mef
`AHP-9695
`PATENf
`
`.
`
`50 I ________ --'
`
`-1-
`
`/--.--RaPAMYCIN ALKOXYESTERS
`
`-
`This invention relates to novel ethers of rapamycin and a method for using them
`in the treatment of transplantation reeon. host vs. graft disease, autoimmune
`diseases, diseases of inflammation, oBnd fungal infections.
`J\
`
`0
`
`"
`
`Rapamycin is a macrocyclic triene antibiotic produced by' ~treptomyces
`~Y&Ioscopicus. which was found to have antifungal activity, particularly against
`Candida albicans. both in.:riIm and in vivo [C. Vezina et al.. 1. Antibiol. 28. 721
`L
`\
`(1975); S.N. Seghnl et al.. J. Anlibiot. 28.727"'(1975); B.A. Baker et al.. J. Amibiot .
`.
`,J ~\
`IIII~ r
`31. 539 (1978); U.S(~atent/\3.929.992;.gnd U.S.(Paten~3.993,74?].
`Rapam~cin alone (U.S. £~t~nt 4,885,171) or in combinltion with picibanil
`__ -·C O r''''
`.
`'"
`(U.S.~c:fJ.tt,401.653) has been shown to have antitumor activity. R. Martel et al.
`[Can. J. Physiol. PharmacoL 55,48 (1977)] disclosed that rapamycin is effective in
`~ experimental allergic encephalomyelitis fuodel, a model for multiple sclerosis; in the
`adjuvant arthritis model, a model for rheumatoid arthritis; and effectively inhibited the
`formation of 19E-like antibodies.
`The immunosuppressive effects of rapamycin have been disclosed in FASEB 3,
`3411(1989). Cyclosporin A and FK-506, other macrocyclic molecules, also have
`been shown to be effective as immunosuppressive agents, therefore useful in
`preventing transplant rejection [FASEB 3, 3411 (1989); FASEB 3, 5256 (1989); and
`b-
`R. Y. Calne et al., Lancet 1183 (1978)1.
`Mono- and diacylated derivatites of rapamycin (esterified at the 28 and 43
`positions) have been shown to be useful as antifungal agents (U.S.~ii1;~,316,885)
`and used to make water soluble prodrugs of rapamycin (U.S.cP~ten(l.650.803).
`Recently. the numbering convention for rapamycin has been changed; therefore
`according to Chemical Abstracts nomenclature. the esters described above would be at
`the 31- and 42- positions.
`
`.-,
`':J,-
`
`, f
`I... I
`1 5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`NOVARTIS EXHIBIT 2142
`Par v Novartis, IPR 2016-00084
`Page 6 of 59
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`

`
`~O October 1990
`3ED1:OCO:ASM:mef
`AHP-9695
`PATENT
`
`-2-
`
`.
`0£
`~/C DESCRIPTION OF mE INVENTION
`f
`This invention provides deriva~s of rapamycin which are useful as
`immunosuppressive, anti-inflammatory,.ana antifungal agents having the structure
`A
`------ -------- --- --- "_._- ----
`
`~
`
`-
`
`(S5 wherein RI is
`
`.1\ • J'"
`10
`
`R2 is hydrogen, aI.k:y1 of 1-6 carbon atoms, cycloaI.k:yl of 3-8 carbon atoms which is
`optionally unsaturated, araI.k:yl of 7-10 carbon atoms, or phenyl which is
`optionally mono-, di-, or tri-substituted with a substituent selected from aI.k:y1
`of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro,
`carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or a carboxylic acid;_
`or a pharmaceutically acceptable salt thereof when R2 is hydrogen.
`~
`15
`P
`
`Of the compounds, preferred members are those in which R 2 is alkyl of 1-6
`carbon atoms.
`Thepharmaceutically acceptable salts may be formed from inorganic cations
`such as sodium, potassium, calcium, magnesium and the like or may be in the form of
`a quaternary ammonium salt.
`
`20
`
`NOVARTIS EXHIBIT 2142
`Par v Novartis, IPR 2016-00084
`Page 7 of 59
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`

`
`-'(0 October 1990
`3EDl:OCO.ASM:mef
`AHP-9695
`PATENT
`
`-3-
`
`The compounds of this inven~on can be prepared by reacting rapamycin with
`the appropriately substituted ester of diazoacetic acid in the presence of a divalent cation
`salt, such as rhodium (ll) diacetate diiner or copper (ll) triflate, as shown below.
`
`,...
`
`M (II)
`
`10
`
`15
`
`This method of preparing alkoxyesters has· been described by B. Ganem et al.,
`J. Am. Chem. Soc. liM.. 6787 (1982). The starting materials utilized are either
`commercially available or can be prepared by methods disclosed in the literature.
`The compounds of this invention, rapamycin-42-ethers, provide stability
`against hydrolysis of the 42-side chain by virturc of the ether moiety connecting the
`side chain to rapamycin at the 42-posi~0n.
`~unosuppressive activity was evaluated in an in.ri.O:n. standard
`pharmacological test procedure to m~asure lymphocyte proliferation (LAP) and in two
`in ~ standard pharmacological test procedures. The first in~ procedure was a
`popliteal lymph node (PLN) test procedure which measured the effect of compounds of
`this invention on a mixed lymph~yte reaction and the second inldm procedure
`evalUated the survival time of a pinch skin graft.
`The comitogen-induced thymocyte proliferation procedure (LAP) was used as
`an in:riml measure of the immunosuppressive effects of representative compounds.
`Briefly, cells from the thymus of normal BALB/c mice are cultured for 72 hours with
`PHA and ll.-1 and pulsed with tritiated thymidine during the last six hours. Cells are
`cultured with and without various concentrations of rapamycin, cyclosporin At or test
`compound. Cells are harvested and incorporated; radioactivity is determined.
`25
`Inhibition of lymphoproliferation is assessed in percent change in counts per minute
`from non-drug treated controls. Thei-esults ~ expressed by the following ratio, or as
`<r a-the percent inhibition of lymphoproliferation of 1 J.LM.
`
`20
`
`3H-contro1 thymus cells - H3-rapamycin-treated thymuscells-
`'r~/jg
`3H-control thymus cells - H3-test compound-treated cells
`r
`~---------------------------~-----
`A mixed lymphocyte reaction (MLR) occurs when' lymphoid cells from
`genetically distinct animals are combined in tissue culture. Each stimulates the other to
`undergo blast transformation which results in increased DNA synthesis that can be
`
`NOVARTIS EXHIBIT 2142
`Par v Novartis, IPR 2016-00084
`Page 8 of 59
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`
`J October 1990
`3ED1:OCO:ASM:mef
`AHP-9695
`PATENT
`
`-4-
`
`5
`
`quantified by the incorporation of tritiated thymidine. Since stimulating a MLR is a
`function of disparity at Major Histocompatibility antigens, an in vivo popliteal lymph
`node (pLN) test procedure closely correlates to host vs. graft disease. Briefly,
`~ated spleen cells from BALB/c dono~ are injected into the right bind foot pad of
`recipient C3H mice. The drugis given daily, p.o. from Day 0 to Day 4. On Day 3 and
`Day 4, tritiated thymidine is given i.p., h.i.d. On Day 5, the bind popliteal lymph
`nodes are removed and dissolved, arid radioactivity counted. The corresponding left
`PLN serves as the control for the P~N from the injected hind foot. Percent
`suppression is calculated using the non-drug treated animals as allogenic control.
`10 Rapamycin at a dose of 6 mg/kg, p.o. gave 86% suppression, whereas cyclosporin A
`at the same dose gave 43% suppression. Results are expressed by the following ratio:
`
`-------
`
`3H-PLN cells control OR mouse - 3H-PLN celIs rapamycin-treated C3R mouse
`3H-PLN cells control C3H mouse - 3H-PLN cells test compound-treated C3H mouse
`
`The second in.Yim test procedure is designed to determine the survival time of
`pinch skin graft from male DBA/2 donors transplanted to male BALB/c recipients. The
`method is adapted from Billingham R.E. and Medawar P .B., 1. Exp. BioI. 28:385-
`402, (1951). Briefly, a pinch skin graft from the donor is grafted on the dorsum of the
`recipient as a homograft, and an autograft is used as control in the same region. The
`recipients are treated with either varying concentrations of cyclosporin A as test control
`or the test compound, intraperitoneally. Untreated recipients serve as rejection control.
`The graft is monitored daily and observations are recorded until the graft becomes dry
`and forms a blackened scab. This is considered as the rejection day. The mean graft
`survival time (number of days ± S.D.) of the drug treatment group is compared with
`.
`...,.~-
`the control group.
`.::It .)
`The following table summarizes the results of representative compounds of this
`invention in these three standard test procedures.
`
`20
`
`25
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`NOVARTIS EXHIBIT 2142
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`Page 9 of 59
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`

`
`-f0 October 1990
`3ED1:OCO.ASM:mef
`AHP-9695
`PATENf
`
`-
`
`-5-
`
`TABLE 1
`
`5
`
`10
`
`Compound
`
`Examplel
`Example 2
`Rapamycin
`
`LAF*
`(ratiQ)
`
`PLN*
`(ratio)_
`
`Skin Graft
`(days +SD)
`
`0.46
`0.27
`1.0
`
`,0.74**
`+
`1.0
`
`7.5± 1.2
`+
`12.0 ± 1.7
`
`* Calculation of ratios was described smm.
`,** A result of -0.14 also was obtained for Example l.
`+ Not evaluated
`
`armacological test proCedures demonstrate
`~ I
`immunosuppressive activity both, ~ and in. vivo for the compounds of this
`
`• venlion. posiliathe .•. and PLN test procedures indicate suppression of
`
`lanted pinch skin grafts are typically rejected within 6-7
`T cell proliferatio As a
`unosuppressive agent, the increased survival time of the
`days without the
`an .
`skin graft when treated
`the compounds of this invention further demonstrates their
`.
`utility as immunosupp ssive agents.,
`Antifungal activity of the compounds of this invention was measured against 5
`strains of Eandida albicans using a plate test procedure for measurement of inhibition.
`The following represents the typi~~ procedure used. Compound to be tested was
`placed on sterile dried 1/4" plate ~kst and an,?wed to dry. Agar plates were seeded
`with fungi and allowed to solidify. ':}'he impregnated disks were placed on the seeded
`Agar surface and incubated for the time required for the particular culture. Results are
`expressed in lvfiC ( J.l.g/ml) to inhibit growth. The results of this test procedure showed
`that the compounds of this invention have antifungal activity.
`
`11)
`
`. 30
`
`- {1/~ Example 1
`
`Compound ATCC 10231
`0.5
`0.05
`0.003
`
`Example 2
`35 Rapamycin
`
`Table 2*
`Strain of Candida albicans
`ATCC 38246 A fCc 38247
`.. -
`. 0.1
`0.2
`0.2
`0.05
`0.025
`0.003
`
`ATCC38248
`0.1
`0.1
`0.006
`
`~
`0.05.
`0.2
`0.025
`
`* expressed as lvfiC (J.Lg/ml)
`
`1
`
`NOVARTIS EXHIBIT 2142
`Par v Novartis, IPR 2016-00084
`Page 10 of 59
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`

`
`-;(0 October 1990
`3ED1:OCO:ASM:mef
`AHP-9695
`PATENT
`
`-6-
`
`Based on the results of these standaTd pharmacological test procedures. the
`compounds are useful in the treatment o~ transplantation rejection such as, hean.
`kidney, liver, bone marrow. and skin transp!~ts; autoimmune diseases such as. lUpus.
`rheumatoid arthritis. diabetes mellitUs. myasthenia gravis, and multiple sclerosis; and
`diseases of inflammation such as, psoriasis. dermatitis, eczema, seborrhea,
`~., .
`~ammatory bowel disease;~ fungal infeciions.
`The compounds may be a~stered neat or with a pharmaceutical carrier to a
`mammal, in need thereof. The phat'lIlliceutical canicr may be solid or liquid.
`A solid carrier can include 'one ~r ~ore substances which may also act as
`flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants,
`compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating
`material. In powders, the carrier is ~finely divided solid which is in admixture with the
`finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier
`having the necessary compression properties in suitable proportions and compacted in
`the shape and size desired. The powders and ?blets preferably contain up to 99% of
`the active ingredient. Suitable solid eamers iDciude, for example, calcium phosphate,
`. magnesium stearate, talc, sugars, lactose, deXtrin, starch, gelatin. cellulose, methyl
`cellulose, sodium carboxymethyl cellulose, polyvinylpynolidine, low melting waxes
`and ion exchange resins.
`Liquid carriers are used in preparing solutions, suspensions, emulsions,
`syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or
`suspended in a pharmaceutically acceptable liquid carrier such as water, an organic
`solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier
`can contain other suitable pharmaceutical additives such as solubilizers. emulsifiers,
`buffers. preservatives, sweeteners. flavoring agents, suspending agents. thickening
`agents, colors, viscosity regulators, stabilizers or os me-regulators. Suitable examples
`of liquid carriers for oral and parenteral administration include water (partially
`containing additives as above, e.g. cellulose derivatives. preferably sodium
`,.'
`carboxymethyl cellulose solution); alcohols (including monohydric alcohols and
`polyhydric alcohols. e.g. glycols) and their derivatives, and oils (e.g. fractionated
`coconut oil and arachis oil). For parenteral administration, the carrier can also be an
`oily ester such as ethyl oleate and isopropyl myristate. _ Sterile liquid carriers are useful
`-in sterile liquid form compOSitionS for pare~teraI administration, The liquid carrier for
`pressurized compositions can be halogenated hydrocarbon or other pharmaceutically
`acceptable propellent.
`
`5
`
`10
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`15
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`20
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`25
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`30
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`
`. ,
`
`--10 October 1990
`3EDl:OCO:ASM:mef
`AHP-9695
`PATENT
`
`-7-
`
`;
`
`Liquid pharmaceutical compositions which are sterile solutions or suspensions
`can be utilized by, for example, .inttimuscular, intraperitoneal or subcutaneous
`injection. Sterile solutions can also be ~tered intravenously. The compound can
`. ....
`.
`also be administered orally either in liquid or solid composition form.
`Preferably, the pharmaceutical' co~position is in unit dosage form. e.g. as
`In such fon:xl, the composition is sub-divided in unit dose
`tablets or capsules.
`containing appropriate quantities of the aCtive ingredient; the unit dosage forms can be
`packaged compositions, for example, p~keted powders, vials, ampoules, preiilled
`syringes or sachets containing liqui~. The unit dosage form can be, for example, a
`capsule or tablet itself, or it can be th~ appropriate number of any such compositions in
`.
`.
`package form. The dosage to be used in the treatment must be subjectively determined
`by the attending physician.
`In addition, the compounds ~f this ~vention may be employed as a solution.
`cream, or lotion by formulation with pharmaceuticallY acceptable vehicles containing
`0.1-0.5 percent, preferably 2%, of active c~inPound which may be administered to a
`fungally affected area.
`
`The following examples illustrate the preparation of representative compounds .
`of this invention.
`
`S
`
`10
`
`15
`
`20
`
`Example 1.
`
`42-Deoxv-42-(2-ethoxy-2-oxoethoxy)nmarnvcin
`
`. ' .
`. ' A solution of rapamycin (Z.O, g, 2.187 mmol) and rhodium (II) diacetate
`(37 mg, 0.08 mmol) in benzene (SO mL) was heated to reflux and ethyl diazoacetate
`(750 mg, 690 #!:. 6.56 mmol) in be~ene ~10 mL) was added over 10 min. The
`mixture was concentrated and puri~ed by chromatography (silica gel, ethyl acetate(cid:173)
`hexane,I:I) to give 700 mg ofprodtict (32%) as a glass. The product was stirred
`
`30
`
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`Page 12 of 59
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`
`'10 October 1990
`3EDl:OCO:ASM:mef
`AHP-9695
`PATENT
`
`-8-
`
`5
`
`with hexane with the addition of small amounts of ethyl acetate, ether and methylene
`chloride for 3 d to yield a white powder which was filtered to give 42-deoxy-42-(2.-"
`ethoxy-2-oxoethoxy)rapamycin (496 mg,23%). The product was isolated as the
`IR (KBr) 1680, 1730.2920,3430 cm.-1; lR-NMR (CDCL3) S 1.28
`hemihydrate.
`(3R, t, J = 7.14 Hz), 1.65 ( 3H, s). 1.74 (3H, s). 3!J~ (3R. s) 3.34 (3R, ~? 3.41
`(3H, s), 4.20 (2H, q. J = 7.14 Hz), 4.30 (2H, dd); Mass Spect (neg. ion FAB) m/z
`999 (94%),590 (15%),407 (16%), 379 (4%),253 (6%). 167 (100%).
`-
`D
`.
`-------.
`f Analysis Calcd for CSS Hss N 01~O~ R20: __ ~_.",,~_65.45; _ H, ._8_~~i!l~_1.3?_~-·)
`C, 65.29; H, 8.64; N, 1.60 t',
`C Found: ,
`'---
`
`10 f
`
`The following representative Compounds can be prepared from rapamycin and
`the appzopriately substituted ester of ciiazoacetic acid by employing the method used to
`prepare the tide compound in Example 1.
`42-Deoxy-42-(2-phenoxy-2-oxoethoxy)rapamycin
`42-Deoxy-42-[2-(4-chlorophenoxy)-2-oxoethoxy]rapamycin
`42-Deoxy-42-(2-phenylmethoxy)-2-oxoethoxy)rapamycin
`. 42-Deoxy-42-(2-cyclobutoxy)-2-oxoethoxy)rapamycin
`42-Deoxy-42-[2-(cyclohex-2-enyloxy)-2-oxoethoxy]rapamycin
`
`15
`
`t.L7jo
`
`Example 2.
`
`42-Deoxv-42-f2-Cl, l-dimethylethoxv)-2-oxoethoxyJrapamvcin
`l'
`~
`To solution of rapamycin (2.0 g. 2.187 mmol) and rhodium (IT) diacetate (20 mg.
`0.04 mmol) in methylene chloride (50 mL) was added with t-butyl diazoacetate
`(750 mg, 690 J.1L. 6.56 mmol) in methylene .chloride (20 mL) over 1.5 h and the
`reaction mixture was allowed to stir overnight The mixture was concentrated and
`purified by chromatography (silica gel, ethyl acetate-hexane, 4:6) to give the product as
`a glass. The product was dissolved with methylene chloride and concentrated to give
`the product as a white solid (588 mg, 26%). The product was then dried in vacuo
`at 68°C overnight and isolated as the hemihydrate. IR (KBr) 1650, 1725, 1750,2940,
`3440 cm.-l; lR-NMR (CDCL3) 0 1.47 (9H, s), 1.65 ( 3H, s). 1.74 (3H, s), 3,14
`(3R, s) 3.34 (3H, s), 3.43 (3H, s), 4.20 (2H, dd); Mass Spect (neg. ion FAB) m/z
`1027 (32%),590 (13%),435 (9%), 167 (100%).
`Analysis Calcd for CS7 Hs9 N OlSiP,? H20:
`~Found:
`.
`
`C, 66.00; H. 8.74; N, 1.35=>
`C. 65.83; H,--S:60; N, 1.29 (f:'
`
`30
`
`NOVARTIS EXHIBIT 2142
`Par v Novartis, IPR 2016-00084
`Page 13 of 59
`
`

`
`10 October 1990
`3ED1:OCO:ASM:mef
`AHP-9695
`PATENT
`
`What is claimed is:
`1.
`A COmpound of the structure
`
`-------
`
`-9-
`
`.---
`(~ArMr
`
`- - - -
`OR!
`
`42
`
`I
`
`. 0
`
`N
`
`00
`
`OMe
`
`.
`
`I
`I
`
`-----------------------------------------
`
`wherein R 1 is
`
`." , ,
`
`PD R2 is hydrogen, alkyl of 1-6 ~ ~1 of 3-8 carbon atoms which is
`optionally unsaturate aralkyl of 7-10 carbon atoms, or phenyl which is
`10
`A
`.
`optionally mono-, di-, or tri-substituted with a substituent selected from alkyl
`of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro,
`carbalkoxy of 2-7 carbon atoIm, tritlu0:foI?ethyl, amino, or a carboxylic acid;
`f3 or a phannaceutically acceptable salt thereof when R2 is hydrogen.
`15
`
`A compound of cJai:n 1 where R2 is alkyl of 1-6 carbon atoms.
`2.
`A compound of claim 1 which is 42-deoxy-42-(2-ethoxy_ 2-oxoetlloxylrapamycin.
`3.
`A Compound of claim 1 which is 42-deoxy-42-[2-( l,l-dimethyle!hoxy)-2-oxoethoxy 16
`4.
`'('
`y
`rapamycin.
`-
`-
`
`~
`
`20
`
`--/~ t
`.1.tj~jI _______ _
`
`Ii
`
`NOVARTIS EXHIBIT 2142
`Par v Novartis, IPR 2016-00084
`Page 14 of 59
`
`

`
`'10 October 1990
`3ED1:OCO.ASM:mef
`AHP-9695
`PATENT
`
`-10-
`
`A method of treating transplantation rejection, hos . vs. ~aft disease,
`5.
`autoimmune diseases, and diseases of infl~tion in a
`by admjnistering an
`effective amount of a compound having the structure
`
`ORt
`
`42
`
`o
`
`o
`
`OMe
`• •
`
`5 wherein R 1 is
`
`n atoms, cycloalkyl of 3-8 carbon atoms which is
`R2 is hydrogen, alkyl of 1-6 c
`optionally unsaturate. aralkyl of 7-10 carbon atoms, or phenyl which is
`. optionally mono-, di • or ni-substituted with a substituent selected from alkyl
`of 1-6 carbon ato
`, alkoxy of 1-6 carbon atoms, hydroxy, cyano. halo, nitro,
`carbalkoxy of 2-7
`n atoms, trlfluoromethyl, amino, or a carboxylic acid;-
`/ ptable salt thereof when R2 is hydrogen.
`or a phannaceutically
`
`10
`
`15
`
`NOVARTIS EXHIBIT 2142
`Par v Novartis, IPR 2016-00084
`Page 15 of 59
`
`

`
`.loOctober 1990
`3ED1:OCO.ASM-mef
`AHP-9695
`PATENI'
`
`-11-
`
`A method of treating fungal infections by ~WWl
`6.
`of a compound having the structure
`
`."
`
`wherein R 1 is
`
`5
`
`10
`
`R2 is hydrogen, alkyl of 1- cartx:>~lo~l of 3-8 carbon atoms which is
`optionally unsa ted,,,~Of7-1~6o~atoms, or phenyl which is
`optionally mono- di-, or tri-substituted with a substituent selected from alkyl
`of 1-6 carbon a
`,alkoxy of 1-6 carbon atoms, hydroxy. cyano, halo, nitro,
`: carbalkoxy of 2- carbon atoms, trlfluoromethyl, amino, or a carboxylic acid;
`or a pharmaceutically ceptable salt therecf when R 2 is hydrogen.
`
`15
`
`7.
`
`omposition comprising a compound of claim 1 or a
`'laOJ,li:O&lJt thereof.
`
`8.
`
`A compositio as claimed in claim 7 in unit dosage form.
`
`NOVARTIS EXHIBIT 2142
`Par v Novartis, IPR 2016-00084
`Page 16 of 59
`
`

`
`,
`
`-12-
`
`ABSTRAcr
`
`10 October 1990
`3ED1:OCO.ASM:mef
`AHP-969S
`PATENf
`
`A compound of the structure
`
`wherein R 1 is
`
`-
`
`p ;J..
`
`~ .
`
`po R2 is hydrogen. alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms which is
`10
`optionally unsaturated. aralkyl of 7-10 carbon atoms, or phenyl which is
`optionally mono-. di-. or tri-substituted with a substituent selected from alkyl
`of 1-6 carbon atoms. alkoxy of 1-6 carbon atoms. hydroxy, cyano. halo. nitro.
`. carbalkoxy of 2-7 carbon atoms, trlfluoromethyl, amino. or a carbOxylic acid;
`is ~r ~ pharmaceutically. acCep~~le .salt th~n:of whe~ R2 is hydrog~n. w~~ vAe of.
`IS tIts unmuno- suppresSIve ac;!V1 useful m treatIng ttansplantanon reJ~--host vs.
`s, and diseases of inflammation. and by vinue of its
`~ graft disease, autoimmune di
`t1 (, antifungal activity is useful .
`ating fungal infections.
`Ii;!-
`
`.
`
`NOVARTIS EXHIBIT 2142
`Par v Novartis, IPR 2016-00084
`Page 17 of 59
`
`

`
`-'
`
`AHP-9695
`PATENT
`
`DECLARATIDN AND POWER OF AITORNEY
`.
`As a below-named inven:tor, I hereby declare that:
`
`My residence, post office address and citizenship are as sta~ below next to my name:
`
`I believe I am the original, first and sole inventor (if only one name is listed below) or an original, fIrst and
`joint inventor (if plural names are listed below) of the siibject matter which is claimed and for which a
`, the
`patent is sought on the invention entitled
`RAPAMYCIN ALKOXYESTERS
`specification of which
`
`(check one) _.-LIX~_ is attached hereto.
`____ was filed on ___________ as
`
`Application Serial No. _ _ __ _ _ _
`
`and was amended on_~_~~~ _ _ .
`. (if applicable)
`
`I hereby state that I have reviewed and understand the contents of the above-identifIed specifIcation,
`including the claims, as amended by any amendment referred to above.
`
`I acknowledge the duty to disclose information which is material to the examination of this application in
`accordance with TItle 37, Code of Federal Regulations, Section 1.56 (a).
`
`I hereby claim foreign priority benefIts under Tide 35, United States Code, Section 119 of any foreign
`application(s) for patent or inventor's certifIcate listed below and have also identifIed below any foreign
`application for patent or inventor's certifIcate having a filing date before that of the application on which
`priority is claimed:
`.
`
`Prior Foreign Applicationfs)
`
`Priority Claimed
`N2
`
`Yes
`
`NONE
`(Number)
`
`(Number)
`
`(Country)
`
`(Country)
`
`(Day/Month/Year Filed)
`
`(Day/Month/Y ear Filed)
`
`I hereby claim the benefIt under Title 35, United. SqLt~s Code, Section 120 of any United States
`Application(s) listed below and, insofar as the subject matter of each of the claims of this application is not
`disclosed in the prior United States application in the manner provided by the fIrst paragraph of TItle 35,
`United States Code, Section 112, I acknowledge the duty to disclose material information as defined in TItle
`37, Code of Federal Regulations, Section 1.56(a) which occurred between the filing date of-the prior
`application and the national or 'per international filing date of this application:
`
`NONE
`(Application Serial No.)
`
`(Filing Date)
`
`(Status - Patented, pending, abandoned)
`
`(Application Serial No.)
`
`(Filing Date)
`
`(Status - Patented, pending, abandoned)
`
`NOVARTIS EXHIBIT 2142
`Par v Novartis, IPR 2016-00084
`Page 18 of 59
`
`

`
`-
`
`AHP-9695
`PATENT
`
`I hereby declare that all statements made herein of. my own knowledge are true and that all
`statements made on information and belief are believed to be true; and further that these statements
`were made with the knowledge that willful false statements and the like so made are punishable by
`tme or imprisonment. or both. under Section 1001 of Title 18 of the United States Code and that
`such willful false statements may jeopardize the validity of the application or any patent issued
`thereon.
`
`I hereby appoint the following anomeys to prosecute this application and to tranSact all business in
`the Patent and Trademark Office connected therewith:
`
`Egon E. Berg. Reg. No. 21,117; Ronald W. Alice. Reg. No. 27.609; both of 685 Third Avenue. New
`York. New York, 10017; and Richard K. Jackson, Reg. No. 24,348; Arthur G. Seifert, Reg. No.
`28,040; George Tarnowski, Reg. No. 27,472; Roben Wiser, Reg. No. 24,457; all of P.O. Box 8299,
`Philadelphia, Pennsylvania, 19101; and Walter Patton, Reg. No. 26,973, of CN-80OD, Princeton,
`New Jersey, 08543.
`
`Address all telephone calls to Richard K. Jackson at telephone number (215)341-2310.
`
`Address all correspondence to Ronald W. Alice, American Home Products Corporation, 685 Third
`Avenue, New York, New York 10017.
`
`~o/t/i)
`Full name of sole or ~ in~entor_...:Jl~hl.Aoli~~iP-~1:il;or.:.V.!:!.d.J..Hil"l;U!¥g.u;heir:.iis~ _____ ......:. ______ _
`Inventor's signature 7!i..M,j ~ JLk
`OCfobpc /2, 117'0
`ry
`} .. -(' Date
`'
`4 Eaton Place. HooeW/;11. Mercer County, New Jersev !JL''--L
`a~hlp ____ ~U~niwt~~S~ta~te~s~m~Allm~e~ri~ca~ __________________________ ___
`
`Residence
`
`Post Office Address
`
`Same as Residence
`
`Full name of second joint inventor, if any __________________ _
`
`Inventor's signature _______________ _
`Date
`Regdence _________________________________________ __
`
`Ci~nshlp _______________________________________________________ __
`
`Po~OfficeAd~ess __________________________ ~----------------
`
`Full name of third joint inve~tor, if any ______________________ _
`
`Inventor's signature ____________________ _
`Date
`Regdence _______________________________________________ ~ __ __
`
`a~nshlp _________________________________________________________ __
`
`Po~OfficeAdme~ __________________________________________________ ____
`
`NOVARTIS EXHIBIT 2142
`Par v Novartis, IPR 2016-00084
`Page 19 of 59
`
`

`
`Q17839~~p 9695-1-N1 fJ-
`-I.
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE ;I/. ~~,e
`41=-%
`
`GROUP
`
`1203
`
`EXAMINER __ Ch_a_ng'---__
`
`MMISSIONER OF PATENTS AND TRADEMARKS
`TH
`SHINGTON, D.C. 20231
`
`SIR: THIS IS A REQUEST FOR FILING A
`~ CONTINl,!ATION
`o DIVISIONAL
`
`APPLICATION UNDER RULE 60
`
`OF PENDING APPLICATIONALSERIAL NO. 07/598,270
`Philip Floyd Hughes
`
`FILED ON October 16, 1990
`
`RAPAt1YCIN ALKOXYESTERS
`
`AFFIDAVIT OR DECLARATION VERIFYING IT AS TRUE COPY.
`
`1. ill ENCLOSEPIS A COpy OF THE PRIOR APPLICATION AS ORIGINALLY FILED AND AN
`2.0 PREPARE A COpy OF THE PRIOR APPLICATION .
`. ill THE FILING FEE IS CALCULATED BELOW:
`
`LAIMS FILED. LESS CLAIMS CANCELLED BY AMENDMENT
`FOR
`NO. FILED
`NO. EXTRA
`Total Claims ....•....•..•..... 8 - 20 =
`0
`Independent Claims ..•.....•.••.. 4 -
`1
`3 =
`..•••••. 0
`0
`Multiple Dependent Claims
`Total Filing Fee •.•••..•••....•• $762.00
`.
`
`RATE
`x $ 20.00 =
`x $ 72.00 =
`x $ 220.00 =
`
`BASIC FEE $690.00
`0.00
`72.00
`0.00
`
`4./25J THE COMMISSIONER IS HEREBY AUTHORIZED TO CHARGE ANY FEES WHICH MAY BE
`REQUIRED.
`INCLUDING ANY ADDITIONAL CHARGES, OR TO CREDIT ANY OVER PAY(cid:173)
`MENT TO ACCOUNT NO. 01-1425. A DUPLICATE COpy OF THIS SHEET IS ENCLOSED.
`
`5.0 CANCEL CLAIMS ________ --.-______________ _
`X
`
`A COpy OF THE POWER FOR ANY SUBSEQUENTLY APPOINTED ATTORNEY IS
`ENCLOSED •
`
`IN - - - - - - - - - - - - - - -
`
`FILED
`
`,J
`. 0 PRIORITY OF APPLICATION SERIAL NO.
`tJ {
`~NCLAIMED UNDER 35 U.S.C. 119.
`o THE CERTIFIED COpy HAS BEEN FILED IN PRIOR APPLICATION
`
`SERIAL NO.
`
`FILED ___________ _
`
`Tf:J~ POWER OF ATTORNEY APPEARS IN THE ORIGINAL PAPERS OF THE PRIOR APPLICATION.
`ADDRESS ALL FUTUR~ COMMUN ICATION T~" 'RONALD W. ALICE
`cRo:l-AMERICAN HOME PRODUCTS CORPORATION
`-?tJ I 685 THIRD AVENUE
`7"2,NEW YORK, NEW YORK 10017
`
`tPJ-'-r:
`.27,472
`REGISTRATION NO.
`AREA CODE 215 -37.41;---.,:2~31:-::2:---------
`
`NOVARTIS EXHIBIT 2142
`Par v Novartis, IPR 2016-00084
`Page 20 of 59
`
`

`
`u.s. DEP-ARTMENT OF COMMERCE
`
`ATTY. DOCKET NO.
`
`-.---- -,-~- --, -,-"-"",--~.-,,,-.---.----- -~.-------
`
`S"Ht 1
`~SERIA1. NO.
`07 /!g3q~,.,.3
`
`of
`
`3
`
`'-~!R" PL~:'9'
`J41EV''''990
`PATENT AND TR .. DE .... "'K OFFICE AHP- 9695
`~. :~~
`~ ,
`<:s
`. fI ~ •• ,;~.~ PRIOR ART CITED BY APPLICANT
`(Use several sheets if necessary)
`
`APP1.ICANT
`
`P. F. Hughes.
`
`I G~OUP
`
`\'2.o.!>
`
`FI1.ING DATE
`
`Oct. 16, 1990
`u.s. PATENT DOCUMENTS
`
`EXAMINER
`INITIAL
`
`DOCUMENT HUMBER
`
`D"TE!
`
`NAME
`
`C1. "55
`
`5UBC1."SS
`
`FILING D .. TE
`IF "PPROPRI"TE
`
`Lt '}A..f
`
`/} 2.-
`
`/) .!..-
`
`II). )_
`
`90
`
`I
`
`I
`
`All.
`
`AB
`
`AC
`
`t:.{, I AD
`
`(.f....
`
`(L-
`
`t{..
`
`et.-
`le-
`
`AE
`
`AF
`
`AG
`
`I
`
`I
`
`I
`
`I
`I
`
`!
`
`!
`
`AM
`
`11.0
`
`I AP
`
`FOREIGN PATENT DOCUMENTS
`
`COUNTRY
`
`I CLASS
`I
`
`I
`
`I
`
`SUS= .... ss