r ) f
`
`'~ .......... ., ..... /
`REGULA~ UTILIT't
`Ii
`
`Form PTO-436
`(Rev 8178)
`
`\
`\
`
`\
`
`SERIAL
`NUMBER
`(series
`of 1979
`
`PATENT DATE
`
`PATENT
`NUMBER
`
`5f
`10
`7 -3 2 - 0 J -5-3
`4650803
`\III\\\I\I'III\\\\\\\\\\\\I\\\\~\I\I\\\\\\\\\
`
`*4050803*
`
`SERIAL NUMBER
`06/8Jo,152
`
`FILING DATE CLASS
`12/06/85 ~ $ILj
`
`sueCLASS
`
`GROUP AR! UNIT
`
`"".. ... .-
`
`EXAMINER
`, .', \
`/,..)
`.J.--' c> ,',j - '
`
`~ VALENTINO J. STELLA, LAWRENCE, KS; PAUL E. KENNEDY,
`z
`..;
`()
`
`~
`Cl.
`Cl.
`..;
`
`**CON Tl NUl NG O~,J A ******************** *
`IIERIfIED
`/"
`fLo'J -e
`,/
`__ ~'Z8 __ _
`
`**FOREIGN/PCT A~LICATIONS************
`VERI fI £0/11";1"
`rt6'1t:,
`....
`_1 ~ 5_ _ _ _",t"'
`
`CERnFICATE
`
`SEP 8 1987
`
`OF CORRECTION
`
`TOTAL
`CLAIMS
`
`INDEP
`CLAIMS
`
`FILING FEE
`RECEIVED
`
`ATTORNEY'S
`DOCKET NO
`
`1
`
`5
`
`1
`
`STATE OR SHEETS
`COUNTRY DRWGS
`
`eyes
`~no
`Foreign priority claimed
`[] yes
`.Qno
`35 USC 119 conditions met
`Verified and Acknowledged 4V~
`Examiners initials
`JOHN II. ROJTrt
`AME~lCAN HO~E PROOUCTS CJRP.
`685 HURD A'IIENUE
`NEW YORK, NY 10017
`
`AS
`FILED
`
`• KS
`
`CIJ
`CIJ
`UJ
`a:
`o
`o
`..;
`
`UJ
`
`~
`I-
`
`.... ,
`
`I
`
`I
`I
`
`.t.RODRJ6S Of RAPAMYCIN
`
`U,S, DEPT of COMM,-Pat. & TM Office - PTO-436L (rev 10-78)
`
`,
`
`,
`to
`r
`
`/
`I
`I
`
`~' J
`
`PARTS OF APPLICATION FILED SEPARATELY
`
`PREPARED FOR IS~
`
`SHEETS
`DRWGS
`
`~l
`
`FIGURES
`DRWGS
`
`f
`
`AT ALLOWANCE
`
`CLAIMS
`
`CLASS
`
`SUBCLASS
`
`5
`
`~. It!
`
`3,,1/
`
`,c;:;- 1/
`
`RETENTION LABEL
`
`/ ,
`
`I I
`V
`
`'''=~-_''~_'~_. ~ ~4~
`
`(Assistant Examiner)
`
`(Dockel Clerk)
`
`R08!~~.N~ND PASSED FOR ISSUE
`PRIMARY EXAMiNER
`__ W~rr~_E~_~~Z ___
`
`(Primary Examiner)
`Estimate of printed pages
`SpeC(s)
`
`Drawlng(s)
`
`(Art Unit)
`Issue fee due (est)
`
`~666.()O
`Notice of allowance and issue fee due (est.)
`Date mailed
`
`Date paid
`
`jhy/«
`
`I
`
`/ (
`
`{
`
`I ~j &/tc,
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 1 of 48
`
`

`
`PATENT APPLICATION SERIAL NO. ____ ..--__
`
`80f3152
`
`u.s. DEPARTMENT OF COMMERCE
`PATENT AND TRADEMARK OFFICE
`FEE RECORD SHEET
`
`30022 12/13/85 806152
`
`01-1425 030 101
`
`340.00CH
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 2 of 48
`
`

`
`"
`
`Q r! ~:" .L.... ~::;
`, '''''' . ...,,; vC-
`u.s. fk A.Rn.~NT OF COMMERCE
`Patent and Trademark Office'
`
`Address Only: COMMISSIONER OF PATENTS
`AND TRADEMARKS
`Washington, D.C. 20231
`
`Case Docket No. AHP-8776
`CERTIFI~ATE OF MAILING BY "EXPRESS MAIL"
`
`"EXPRESS MAIL" MAILING LABEL NUMBER j5'7/J/oSJdZ
`Id../C./J-S-
`
`DATE OF DEPOSIT
`
`THE COMMISSIONER OF PATENTS AND TRADEMARKS
`Washington, D.C. 20231
`
`Sir:
`
`~I~~:.\T '~':13 p,:~~'1:R cr.. !::::2 IS BEING
`1 HEtEr>~ CEP,"FJPY
`",,:XC":t
`r'.;"i.:')
`i,:~' :")!
`~'rl'''\~:·':'~ T-':",
`:.,:,I'.(,-·l)
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`J () h ~_~~,--J!. O~. +~ ______ ~ __
`(T-i!'ED:~~:~/' -~'~'E;:;Z""L~"G)
`
`~'.,.':~~L
`
`(SIGN
`Transmitted herewith for filing is the patent application of
`
`F PE"SlJ;; HULTNC: PI,nil. Qj( fEE)
`
`Inventor: Valentino J. Stella and Paul E. Kennedy
`
`For:
`
`PRODRUGS OF RAPAMYCIN
`
`Enclosed are:
`
`__ 1 ___ sheets of drawing.
`
`An assignment of the invent10n to ____________________ _
`
`o
`o A certified copy of a __________ application.
`
`Associate power of attorney.
`
`(2)
`NUMBER FILED
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`CLAIMS AS FILED
`(3)
`NUMBER EXTRA
`
`5
`
`1
`
`- 20 =
`
`- 3 =
`
`0
`
`0
`
`(1)
`
`FOR
`
`TOTAL
`CLAIMS
`
`INDEPENDENT
`CLAIMS
`
`MULTIPLE
`DEPENDENT
`CLAIMS
`
`(4)
`RATE
`
`x $10.00
`
`x $30.00
`
`$100.00
`
`(5)
`BASIC FEE
`$300.00
`
`n
`
`n
`
`0
`
`TOTAL FlUNG
`FEE
`
`?>
`
`300.00
`
`Please charge my Deposit Account No. 01-1425 in the amount of
`$ 300. 00
`A dupUcate copy of this sheet is enclosed.
`
`The Commissioner is hereby authorized to charge any fees under 37 CFR 1.16 and
`1.17 which may be required during the entire pendency of the application to Deposit
`Account No. 01-1425. A duplicate copy of this sheet is enclosed.
`
`D A check in the amount of ________ to cover the filing fee js enclosed.
`
`M-Z769B (a/83)
`
`FORM PO- 1082 (11-691
`
`Attorney of Record
`hn W. Routh
`Reg.No. 17,632
`
`USCOMM-OC eO .. 24-Peg
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 3 of 48
`
`

`
`-1-
`
`J
`
`Background Of The Invention
`
`This invention relates to water soluble prodrugs of rapamycin and in
`particular to certain derivatives of rapamycin such as, for example,
`the
`glycinate prodrugs of rapamycin, the propionate prodrugs of rapamycin and the
`pyrrolidino butyrate prod rugs of rapamycin.
`
`Rapamycin is a known compound described and claimed inJJ!lited States
`. Letters Patent Nos. 3,929,992, issued December 30, 1975, and 3,993,749 issued
`November 23, 1976. Moreover, certain of its acyl derivatives are disclosed and
`claimed in United States Letters Patent No. 4,316,885, issued February 23, 1982.
`
`Rapamycin has been disclosed and claimed as useful in the treatment of
`tumors in Belgian Patent No. 877,700. Rapamycin is, however, only very slightly
`soluble in water, i.e. 20 micrograms per milliliter,
`and special injectable
`formulations have been developed for administration to patients, such as those
`described and claimed
`in European Patent Number EP 41,795.
`These
`formulations are not altogether satisfactory for a number of reasons including
`toxicity of the carrier. Accordingly, there is a need in the art for a rapamycin
`derivative or prodrug which is relatively soluble in water so as to form a safe
`injectable solution and which is as effective as rapamycin in the treatment of
`tumors.
`
`5
`
`10
`
`15
`
`i
`
`'-..L
`
`Summary Of The Invention
`
`20
`
`25
`
`It has now been found that water soluble prodrugs of rapamycin can be
`synthesized which decompose into products including rapamycin in the presence
`of human plasma and animal tissue homogenates. Such prodrugs of rapamycin
`provide a component of a valuable pharmaceutical injectable composition for the
`treatment of tumor in humans.
`
`The water soluble prod rugs of this invention comprise mono-substituted
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 4 of 48
`
`

`
`AHP-Q716
`
`es
`
`-2-
`
`derivatives at position 28 and disubstituted derivatives at positions 28 and 43 of
`the rapamycin structure. The assignments are based on a structural elucidation
`published by Findlay et al in Can. J. of Chern. 58, 579 (1980). This structure is
`reproduced in Figure 1 of the accompanying dra wing.
`
`5
`
`The mono-substituted derivatives include those having a substituent at
`position 28 of the rapamycin structure having the following configuration.
`
`wherein m is an integer from 1 to 3, wherein RI and R2 are each hydrogen or an
`alkyl radical having from one to three carbon atoms or wherein RI and R2
`together with the nitrogen atom to which they are attached forIll a saturated
`heterocyclic ring having four to five carbon atoms.
`
`10
`
`The di-substituted derivatives include those having sUbstituents at both
`positions 28 and 43 of the rapamycin structure having the same configuration as
`the substituent for the mono-substituted derivative.
`
`Detailed Description Of The Invention
`
`15
`
`The preparation of typical water soluble prod rugs of rapamycin of this
`the examples which were carried out using the
`invention is illustrated in
`following procedures.
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 5 of 48
`
`

`
`AHP-8116
`
`es
`
`-3-
`
`In the examples, chemical stability studies for rapamycin and the
`prod rugs were done at 20 P g/ml with an ionic strength of 0.5. Stabilities at pH
`3.3 (0.05 M acetate buffer) and pH 7.4 (0.05 M phosphate buffer) were studied at
`25 and 37.5° C. No antioxidants were added and
`the buffers were not
`deoxygena ted.
`
`5
`
`The plasma studies were conducted at 37.5°C for rat and human
`plasma. Rat plasma was obtained from Sprague-Dawley male albino rats and was
`used within several days. Human plasma was obtained from the Lawrence
`Memorial Hospital in Lawrence, Kansas. The plasma studies were done at three
`10 prodrug concentrations: 200, 100 and 50 )Jg/ml of prodrug. The experimental
`procedure was as follows: The compound to be tested was taken from a stock
`aqueous solution of 5 mg/m 1 and added to the plasma to give the desired prodrug
`concentration. Samples of 200 )JI were removed at predetermined times and
`.added to 200 ).11 of 10% metaphosphoric acid to quench the reaction. Before
`15 centrifugation 200 )JI of methanol was added to further precipitate the plasma
`proteins. The results are expressed in half-lives in hours.
`
`The chemical and plasma studies were followed by HPLC using a RP C-
`18 column (150 mm) and a precolumn (50 mm). The mobile phase was 87:13
`methanol:phosphate buffer (0.025 M, pH 3.4). The detector was set at 254 nm
`20 and the flow rate was 1 ml/min for rapamycin studies and 1.5 ml/min for the
`prod rug studies. Chart speed was 1 inch/IO minutes.
`
`The liver homogenate studies were done using livers freshly obtained
`from male albino Sprague-Dawley rats. A 20% liver homogenate was prepared in
`Sorensen's buffer at pH 7.4. Chemical stability studies of rapamycin and the two
`25 prodrugs of Examples 2 and 3 were carried out at concentrations of 20, 50 and 50
`)Jg/ml respectively, at 37.5 C.
`
`in buffers, plasma and
`Rapamycin hydrolysis data
`homogenate are shown in the following table:
`
`in rat liver
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 6 of 48
`
`

`
`-4-
`
`TABLE I
`
`t1/2 (hrs)
`
`35.8
`47.6
`
`t1/2 (hrs)
`9.9
`10.2
`
`Chemical Stability Study
`
`A.
`
`25°C
`
`pH
`
`5
`
`B.
`
`3.3
`7.4
`37.5°C pH
`
`3.3
`7.4
`
`Plasma Stability Study (37.5° C)
`
`A.
`
`B.
`
`C.
`
`Human plasma
`
`Rat plasma
`
`Liver homogenate
`
`conc (].lg/mI)
`
`50
`conc (].lg/mI)
`
`50
`conc (].lg/ml)
`
`50
`
`tl/2 (hrs)
`
`3
`
`tl/2 (hrs)
`
`2.83
`
`tl/2 (hrs)
`5.5
`
`In all the prodrug studies, the disappearance of the prod rug peak
`appeared to result in the formation of a peak with a retention time nearly equal
`to rapamycin. Analysis of the plasma and homogenate studies by thin layer
`chromatography (TLC) tended to suggest that rapamycin initially formed but
`then it further degraded to other decomposition products, as does rapamycin
`itself in these studies.
`
`10
`
`15
`
`20
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 7 of 48
`
`

`
`· ~J)-8776
`
`cs
`
`-5-
`
`EXAMPLE 1
`
`Synthesis of Mono-(2S)-N ,N-DimethYlglycinate Ester of Rapamycin
`
`In a dry 100 mL round bottom flask was placed 2.S0 g(3.07 X 10~3, moles)
`of rapamycin, 0.616 g (5.98 X 10-3 moles) of N,N-dimethyl glycine and 1.40 g (6.80
`x 10-3 moles) of dicyclohexylcarbodiimide. The flask was placed under a nitrogen
`atmosphere and 60 mL of anhydrous methylene chloride (dried over P205) was
`added followed by 60 mg of 4-dimethylaminopyridine. The reaction was stirred
`overnight at room temperature. A thin layer chromatogram (TLC) of the
`reaction (solvent system 1:1 acetone:methylene chloride) was taken and indicated
`the reaction to be complete. The Rf of the monoglycinate prodrug was 0.32.
`Some bisglycinate was also present at a Rf of 0.09. The reaction was worked-up
`by first filtering off the dicyclohexylurea (DCU). The solvent was removed on
`the rotovapor to give a white solid. The crude product was chromatographed on
`IS gm of silica gel using 300 mL of ethyl acetate to elute rapamycin plus residual
`DCU. The product was eluted with 1:1 methylene chloride:acetone to give 1.67 g
`of product, yield 55%. This material was found difficult to recrystallize. NMR
`(300 MHZ, solvent CDCl3)
`indicated
`the spectrum of the prodrug to be
`practically identical to that of rapamycin except for the two singlets arising
`from the glycinate group. The N ,N dimethyl protons appeared as a singlet at
`a 2.32. The methylene group of the glycinate was found at a 3.16 as a singlet.
`
`EXAMPLE 2
`
`Synthesis of Methanesulfonic Acid Salt of Mono-(2S)-N ,N Dimethylglycinate
`Ester of Rapamycin
`In a dry 100 mL round bottom flask was placed 3.00 g (3.10 X 10-3 moles)
`of mono N ,N-dimethylglycinate prod rug of rapamycin. This was dissolved in 15
`mL of anhydrous methylene chloride (distilled from P205). To this was added
`2.71 X 10-3 moles) of a stock solution of methanesulfonic acid dissolved in diethyl
`
`5
`
`10
`
`15
`
`20
`
`25
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 8 of 48
`
`

`
`ABP-8776
`
`cs
`
`-6-
`
`ether. The solvent was immediately removed to give a white solid, wt. 3.25 g,
`yield 99%. This compound was also found difficult to recrystallize. The salt
`form of this compound was found to be unstable to long stirring times. Even in
`the crystalline form long exposures to light resulted in a slow discoloration of
`the material.
`
`5
`
`Data with respect to mono-(28)-N,N-dimethylglycinate methanesulfonic
`acid salt-prodrug of rapamycin are shown in the following table:
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 9 of 48
`
`

`
`AHP-8776
`
`cs
`
`-7-
`
`TABLE 2
`
`5
`
`10
`
`Physical Properties
`
`MW
`MP
`Solubility in water
`
`1095
`93-99°C
`> 50 mg/mL
`
`HPLC Operating Conditions
`
`Column
`Precolumn
`Mobile phase
`
`Detector
`
`Flow rate
`Retention
`
`RP-18, 150 mm length, 4.6 mm id
`50 mm length, 4.6 mm id
`87 parts methanol:13 parts phosphate buffer
`(0.025 M, pH 3.4)
`
`Kratos 783
`UV 254 nm
`1.5 mL/min
`9.5 mL*
`
`15
`
`* With a new RP C-18 column two peaks were observed which are believed to be
`cis-trans isomers about the amide bond in the macrocyclic lactone ring.
`
`Chemical Stability, 25° C
`
`Conditions
`pH 3.3
`pH 7.4
`
`tl/2(hrs)
`73
`45
`
`2 0
`
`Plasma/Tissue Stability, 37.5° C
`Conditions
`
`tl/2 (hrs)
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 10 of 48
`
`

`
`AHP-8776
`
`cs
`
`-s-
`
`50 ug prodrug/mL human plasma
`50 ug prodrug/mL rat plasma
`50 ug prodrug/mL liver homogenate
`
`5
`1.S
`4.5
`
`Plasma/Tissue Stability Study (37.5 C)
`
`5
`
`A.
`
`Human plasma
`
`H.
`
`Rat plasma
`
`10
`
`C.
`
`Liver homogenate
`
`15
`
`Reconstitution Procedure
`
`conc (]J g/m 1)
`
`200
`100
`50
`conc ( ]Jg/m 1)
`
`200
`100
`50
`conc (]Jg/m1)
`
`50
`
`t1/2 (hrs)
`
`5.6
`4.S
`5.0
`
`t1/2 (hrs)
`2.5
`1.S
`1.75
`
`t1/2 (hrs)
`4.5
`
`The prodrug can be reconstituted with either water for injection or
`distilled water containing 5% by weight dextrose (D5W). The solutions should be
`freshly prepared and used immediately «1 hr if possible). The prodrug appears to
`discolor upon prolonged exposure to light. Precaution should be taken to prevent
`this.
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 11 of 48
`
`

`
`AHP-8176
`
`cs
`
`-9-
`
`EXAMPLE 3
`
`._ .. Synthesis of Mono-(28)-3-(N ,N-Diethylamino)propionate Hydrochloride Salt Ester
`of Rapamycin
`
`In a dry 100 mL round bottom flask was placed 1.00 g (l.09 X 10-3 moles)
`of rapamycin, 0.34 g (2.16 X 10-3 moles) N ,N-diethylaminopropionic acid
`hydrochloride salt and 0.50 g (2.43 X 10-3 moles) of dicyclohexylcarbodiimide.
`
`The vessel was placed under a nitrogen atmosphere and 25 mL of
`anhydrous methylene chloride (dried over P205) was added followed by 15 mg of
`4-dimethylaminopyridine.
`The
`reaction was stirred overnight at
`room
`temperature. The next day a TLC of the reaction (solvent system: ethyl acetate)
`on silanized silica gel plate was taken and indicated the reaction to be complete.
`The Rf of the monopropionate hydrochloride salt of rapamycin was 0.34 and 0.01
`for the bispropionate hydrochloride salt which was also formed in the reaction.
`The dicyclohexylurea was filtered from the reaction and the solvent removed on
`the rotovapor. The crude product was chromatographed on 12 g of silanized
`silica gel. The column was first developed with 200 mL of ethyl acetate to
`remove any rapamycin and also residual dicyclohexylurea. The product was
`eluted with ethyl acetate to give 0.61 g of product, yield 53%. This compound
`was found difficult to recrystallize and unstable to prolonged exposure to light.
`NMR (300 MHz, solvent CDCL3) indicated the spectrum of the prod rug to be
`practically identical with that of rapamycin. The propionate group did not give
`sharp eas,ily interpreted resonances as was the case with the glycinate prod rug.
`This is the result of the resonances being multiplets resulting from the ethyl
`groups which are not as easily seen among the other resonances from rapamycin.
`Broad peaks did appear around 1.2 and 1.5 which were not found in rapamycin.
`
`to mono-(28)-N,N-diethylaminopropionate
`respect
`Data with
`hydrochloride salt - prodrug of rapamycin are shown in the following table:
`
`5
`
`10
`
`15
`
`20
`
`25
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 12 of 48
`
`

`
`AIJ1>-8776
`
`es
`
`-10-
`
`TABLE 3
`
`Physical Properties
`
`M.W.
`M.P.
`Solubility
`
`1077
`99-106°C
`>50 mg/mL in water
`
`HPLC Operating Conditions
`
`Column
`Precolumn
`Mobile phase
`
`Detector
`
`RP - 18, 150 mm length, 4.6 mm id
`50 mm length, 4.6 mm id
`87 parts methanol: 13 parts phosphate
`buffer (0.025 M, pH 3.4)
`Kratos 783
`UV 254 nm
`1.5 mL/min
`9.75 mL*
`*Two peaks were also observed for this prodrug when a new RP-18 column was
`used. This was also believed to be cis-trans isomers as mentioned above for the
`glycinate prod rug.
`
`Flow rate
`Retention volume
`
`5
`
`10
`
`15
`
`20
`
`Chemical Stability
`Conditions
`
`pH 3.3,25°C
`pH 7.4,25°C
`pH 3.3, 37.5°C
`pH 7.4, 37.5°C
`
`tl/2(hrs)
`
`33
`17
`7.9
`6.3
`
`Plasma/Tissue Stability, 37.5° C
`
`25
`
`Conditions
`
`50 ug prodrug/mL human plasma
`
`2.5
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 13 of 48
`
`

`
`-11-
`
`50 ug prodrug/mL rat plasma
`50 ug prodrug/mL liver homogenate
`
`1
`3.7
`
`Plasma/Tissue Stability Study (37.5° C)
`
`A.
`
`Human plasma
`
`conc (\lg/ml)
`
`tl/2 (hrs)
`
`200
`100
`50
`conc (\lg/ml)
`
`200
`100
`50
`conc ()Jg/mI)
`
`50
`
`3.25
`2.15
`2.50
`
`tl/2 (min)
`
`60
`58
`58
`
`tl/2 (hrs)
`
`3.7
`
`B.
`
`Rat plasma
`
`C.
`
`Liver homogenate
`
`Reconstitution Procedure
`
`The prod rug can be reconstituted with either water for injection or
`D5W. The solutions should be freshly prepared and used immediately «1 hr if
`··L \
`possible). The prodrug appears to discolor upon prolonged exposure to light.
`
`Precaution should be taken to prevent this.
`
`5
`
`10
`
`15
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 14 of 48
`
`

`
`AHP-8776
`
`cs
`
`-12-
`
`EXAMPLE 4
`
`5
`
`10
`
`15
`
`20
`
`Synthesis of Mono-(28)-4'-(N-pyrrolidino)-butyrate Hydrochloride Salt Ester of
`
`Rapamycin.
`
`In a dry 100 mL round bottom flask was placed 3.50 g (3.83 x 10-3 moles)
`(7.66 x 10-3 moles) of 4-pyrrolidino-butyric acid
`of rapamycin, 1.48 g
`hydrochloride salt and 50 mL of anhydrous methylene chloride (distilled from
`
`The reaction was placed under a nitrogen atmosphere and 2.50 g
`P205)'
`,(1.21 x 10 -2 moles) of dicyclohexylcarbodiimide and 15 mg of 4-N ,N-dimethyl(cid:173)
`
`aminopyridine. The reaction was stirred overnight at room temperature. The
`
`following day the dicyclohexylurea was filtered from the reaction and the
`filtrate adsorbed onto 5 g of silanized silica gel. This was loaded onto a 12 g
`column of silanized silica gel and was developed with 75:25 ethyl acetate: hexane
`to remove the starting material. The product was eluted with ethylacetate to
`give 3.24 g of a white solid, yield 78%.
`
`the mono-(28)-4'-(pyrrolidino)butyrate
`to
`respect
`Data with
`hydrochloride salt-prodrug of rapamycin are shown below:
`
`Physical Properties
`
`M.W.
`M.P.
`Solubility
`
`1088
`94-98° C
`!V15 mg/mL in water
`
`Reconstitution Procedure
`
`The prodrug can be reconstituted with either water for injection or
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 15 of 48
`
`

`
`AHP-8776
`
`es
`
`-13-
`
`D5 W. The solutions should be freshly prepared and used immediately «1 hr if
`. ,
`,:. I
`possible). The prodrug appears to discolor upon prolonged exposure to light.
`Precaution should be taken to prevent this.
`
`EXAMPLE 5
`
`Synthesis of Bis N ,N-Dimethylglycinate Ester of Rapamycin
`
`The bis-glycinate prodrug of rapamycin substituted at positions 28 and
`43 of the rapamycin structure was synthesized by the addition of 1 eq. of
`rapamycin, 3 eq. of N ,N-dimethylglycine, 3.3 eq. of dicyclohexylcarbodiimide
`and 0.16 eq. of 4-N ,N-dimethylaminopyridine. After purification on silica gel,
`64% of bis-glycinate was obtained. NMR confirmed the product with two 6
`proton singlets for the methyl groups of the two glycinate groups.
`
`The formation of the methane sulfonic acid salt of the bis-glycinate
`was accomplished by the addition of 1.95 eq. of methane sulfonic acid. The use
`of two equivalents caused the decomposition of the prodrug. This gave 92% yield
`of the bis-glycinate prodrug of rapamycin.
`
`The studies carried out using fresh human plasma and fresh rat plasma
`indicate that the half life of the prodrug of Example 3 was the shortest, i.e. that
`half of the prodrug decomposed into products including mainly rapamycin within
`two and one-half hours with rapamycin being the only observed product of
`hydrolysis.
`
`Similarly as in Example 1, other water soluble derivatives of rapamycin
`can be prepared using as a reagent instead of N ,N-dimethyl glycine, glycine,
`N ,N-diethylglycine, N ,N-diisopropylglycine, N-propylglycine, 3-aminopropionic
`acid, N-ethyl-3-aminopropionic acid, 4-aminobutyric acid, N-ethyl-4-amino
`butyric acid, N ,N-dipropyl-4-aminobutyric acid, 2-(N-pyrrolidino) acetic acid,
`and 3-(N-piperidino) propionic acid and using appropriate protecting groups
`where necessary.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 16 of 48
`
`

`
`AHP-8776
`
`cs
`
`-14-
`
`.... ~ ,
`
`!,
`
`\
`
`Claims
`
`/~ Water soluble derivatives 0
`r~erivatives at position 28 and disubstit ted derivatives at positions 28 and 43 of
`
`/
`
`rapamycin which are mono-substituted
`
`\
`
`rapamycin with the sUbstituents havin
`
`the configuration.
`
`l
`
`t
`
`~ i
`1 ~ t
`1 1 ~ 't wherein m is an integer from I 0 3,
`f wherein RI and R2 is each h~ rogen or an alkyl radical having from one to three
`t carbon atoms or wherein RI nd R2 together with the nitrogen to which they are
`" f' attached form a saturated eterocyclic ring having four to five carbon atoms and
`1 i the pharmaceutically acc ptable salts of such derivatives.
`l-----"','
`
`2. The mono-substituted derivative of claim I wherein the substituent
`
`10
`
`is
`
`3.
`SUbstituent is
`
`The mono-substituted prodrug derivative claim I wherein the
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 17 of 48
`
`

`
`AHP-8116
`
`es
`
`-15-
`
`4. The mono-substituted derivative of claim 1 wherein the sUbstituent
`
`is
`
`'v·'"
`
`.
`
`'\ '-../'
`<'1\,\)"
`'iU ,; ".1/'
`c
`I
`
`/
`
`/~-!
`An
`5.
`j
`J
`/ ~ . ,
`j{
`. harmaceutically ac
`",J
`~
`/ as defined in cl
`~j\ ' L-.,~, ..
`
`I
`
`'.
`
`a
`comprising
`composition
`pharmaceutical
`ble carrier and a water soluble derivative of rapamycin
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 18 of 48
`
`

`
`AHP-8776
`
`cs
`
`-16-
`
`ABSTRACT OF DISCLOSURE
`
`Water soluble prodrugs of rapamycin are disclosed which are useful as
`components in injectable pharmaceutical formulations for the treatment of
`tumors in mammals.
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 19 of 48
`
`

`
`,
`
`AHP- 8776
`Sole or Joint
`
`Declaration And Power Of Attorney
`
`As a below named inventor, I hereby declare that:
`
`My residence, post office address and citizenship are as stated 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 subject matter
`which
`is
`claimed
`and
`for which
`a patent
`is
`sought on
`the
`invention
`PRODRUGS OF RAPAMYCIN
`entitled
`----------------------------------------------------------------------1
`the specification of which
`
`(check one)
`
`is attached hereto.
`
`as
`was filed on
`Application Serial No. __________________ _
`~~~----------------------
`and was amended on
`----~h~·f~a-p-p=li-ca~b~l~e)~-----
`
`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, SI.S6 (a).
`
`I hereby claim foreign priority benefits under Title 35, United States Code, SU9 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 Application(s)
`
`(Number)
`
`(Country)
`
`(Number)
`
`(Country)
`
`Priority Claimed
`
`DO
`DO
`
`(Day/Month/Year Filed) Yes No
`
`(Day/Month/Year Filed) Yes No
`
`(Number)
`
`(Country)
`
`. (Day/Month/Year Filed) Yes No
`
`DO
`
`I hereby claim the benefit under Title 35, United States Code, Sl20 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, SU2, I acknowledge the duty to
`disclose material information as defined in Title 37, Code of Federal Regulations,
`SI.S6 (a) which occurred between the filing date of the prior application and the national
`or PCT international filing date of this application:
`
`Application Serial N2..:
`
`Filing Date
`
`Status
`(patented, pending, abandoned)
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 20 of 48
`
`

`
`2
`
`AHP..;.8776
`
`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 fine 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 attorney(s) to prosecute this application and to transact all
`business in the Patent and Trademark Office connected therewith:
`
`J olm W. Routh, Reg. m;! h.§ 32 -::r~% ;0 Victor Bellino, Reg. No. 20. 51'\7
`
`Arthur E. Wilfond, Reg. No. ~J • Adley F. Mandel, Reg_ 26,94;S
`and Walter Patton, Reg. No. ~~ each of 685 Third Avenue,
`New York, New York
`10017
`
`Address all telephone calls to __ J_o_hn __ W_-_R_o_u_t_h _________ .at
`
`telephone no.
`
`( 212) 878-6227
`
`•
`
`AQ,qr~ss all corres~O,p,~nce t~ (FJohn W. ROUth~ 4tmerican
`Corporatioif685 Third Avenue~1!few York, New York 10017.
`,If 1~1/
`Full name of sole or first inventor ~n:t.!D-sL/··,,S,:tel.la,, ..
`Inventor's signature __ __ \~/~(~~~·~.::..o:rL.....:...;:: S;QQ:::'-' ~~~~ __ --:==-J/+:-/7-.::;..7"-1/":'· 8>':!-S-~_
`Residence 777 Sunset Drive , ~,a.1?r~!1g,~.,Kanr~~_ 66044
`Citizenship U. S.
`I '\ :~
`Post Office-A-:-d-id~r~e~ss!.--~S;:;-a-m-e--------~-.:...-:::.:::..----------
`
`Date '
`
`Home Products
`
`Second Inventor's signature
`
`LfPJ/ I)
`.
`Full name of second joint inventor, if any __ ----'.1::1!::.-... ~.;;;:u:::l~~;..:. ......... IL=e=~==:J!:::. .. _____ _
`I
`/7 ! ·
`i 1121 I K<;;
`\U'w.. .... -'l
`1 ct"-..CL
`J
`Date
`516 Fireside Drive, Apt. 1, Lawrence Kan:-s 66044
`Residence
`J1. S
`U. S -
`Citizenship
`Post Office Address Same
`--~==--------------------------------------
`
`Full name of third joint inventor, if any __________________ _
`
`Third Inventor's signature ________________ --=:-:-_____ _
`Date
`
`Residence
`Citizenship~-----------------------------
`Post Office Address __________________________ _
`
`Full name of fourth joint inventor, if any -----------------------
`Fourth Inven tor's signa. tUi e -----.
`Date
`Residence
`Citizenshi::"p----------------------------
`
`Post Office Address ----------------------------------------------
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 21 of 48
`
`

`
`?rint Of Drawin~
`As Original
`filed
`
`i
`~..
`U
`
`0
`
`...,.
`
`' - • •
`
`'.,_.
`..J
`~,.,.I t"OJ ... ~' L
`
`' , ' " "
`
`I
`i
`
`I , .
`
`Rapamycin
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 22 of 48
`
`

`
`~ ---------------------------~
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`AHP-8776 jr Ifo
`
`~/
`
`In re Application of
`
`Valentino J. Stella et a1.
`
`Serial No.
`
`Filed
`
`For
`
`· ·
`
`:
`
`· ·
`
`806,152
`
`December 6, 1985
`
`PRODRUGS OF RAPAMYCIN
`
`J2j
`Art Unit :~
`
`R E:~ (-: :~=! -. -, ',:":'\
`FEB 24 1986
`( 'Rr"'r I r
`1 . i " 1:-' "'.''',
`• ..... ~~.It
`l.:~)
`
`Information Disclosure Statement 37 CRF 1.97
`
`Hon. Commissioner of
`Patents & Trademarks
`Washington, D. C. 20231
`
`Sir:
`
`Applic~nts wish to bring the following references to the Examiner's attention:
`
`u.S. Patent 4,316,885
`European Patent EP 41795
`Belgian Patent 877,700
`
`These patents are discussed on page 1 of the specification and copies of the
`
`patents are enclosed.
`
`ResPf~'/JIlY submitted,
`
`i
`
`rCJ<\j~V -~
`:!-' /~L)
`!J'o'\l W. Rou'th
`. , tOrney for Applicants
`\
`\
`ego No. 17,632
`Te1e. No. (212) 878-6227
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 23 of 48
`
`

`
`--_ ..
`
`','
`
`" ~,
`
`FOAM PTO-1449
`(R~v. 2-32)
`
`U.S. DEP,~.RTMENT OF COMMEnCE
`PATENT AND TRADEMARK OFFICE
`
`1
`
`ATTY. DOCKET NO.
`
`SheeLl.- 01._1--
`-----
`
`SERIAL NO.
`
`AHP-8776
`
`806,152
`
`,
`
`.
`
`.~
`
`INFORMA TlON 'DISCLOS'i\JRE BY APPLlCMIT
`(Use sever' I sheels'recessary)
`-If
`;,l'
`
`APPL.lCANT
`
`~ .. --.
`FILING DATE
`
`December 6 2
`U.S. PATENT DOCUMENTS
`
`._---
`Valentino J. Stella et al. __
`I GROIJP
`1285
`
`125
`
`--
`- -
`
`• EXAMINER
`INITIAL
`
`I{dE>
`
`I( r-7 13
`
`!I V<,;?M
`I
`
`f,,,
`
`DOCUMENT NUMBER
`
`DATE
`
`NAME
`
`CLASS
`
`SUBCLASS
`
`4 3 1 6 EIR
`-
`
`r::; n') 1'-'-;'; ~.-, S. Rakhit:
`, -J
`)
`
`I
`
`-
`=< 'i I
`Sf1-
`~ ~ - -
`
`FILING DATE
`IF APPROPRIATE
`
`R€C Si2L:!
`FEB 24 1QOl
`...
`GROliE-fl')l'\
`·c..u
`
`-.---
`
`----
`
`f - - - - - - -
`
`T--------
`t:~
`
`FOREIGN PATENT DOCUMENTS
`
`-
`
`I
`
`I
`
`J
`I
`
`I
`
`DOCUMENT NUMBER
`
`E P 4 1 " 9
`r: 0
`
`7 7
`
`8
`
`.I
`!DATE
`:
`,.1.fD £.c,.
`17~ I
`ILf JA Ai,
`j 4~ ti
`
`0
`
`COUNTRY
`
`European Patent
`
`Belgian Patent
`
`Cl.ASS
`
`o I Of
`
`~ 't I
`
`~''f ~ q /
`
`SUBCLASS TRANSL'\l~
`1 - ._ - -
`I NO·
`YES
`----r----
`- -
`»(
`
`-
`
`-
`Ol'HER DOCUMENTS (Including Author, Title, Dale, Pertinent Pages, Etc_)
`
`I
`
`-
`
`DATE CONSIDERED
`
`~
`-I
`PMINER
`r-
`,I?~ C7 .z3~)
`dO
`J'C1N[ 11181,
`EXAMINER: Initial if citation considered, whether or not citation is in conformance with MPEP
`L
`609; Draw line through citation if not in conformance and not considered. Include copy of
`________ ~th~i~s~f~o~rm~w~ith~n~e~x~t~c~o~m~m~u~n~i~c~at~io~n~to~a~p~p~li~ca~n~t~. ____________________________________ ___
`
`----f---
`1 - -f---l
`-I
`I
`
`..
`
`.
`
`.. _---
`
`.. 3
`~
`'3
`I J
`
`Telephone No. 212-878-6227
`
`NOVARTIS EXHIBIT 2218
`Par v. Novartis, IPR 2016-00084
`Page 24 of 48
`
`

`
`SERIAL NUMBER
`
`I FILING DATE I
`..j. ~
`
`I ' . " \_
`." ..... J
`',; '".'.
`
`,
`
`L., .. ,,,-:
`
`•• J.,
`
`"Ii'"! :
`••••• ,~ • .' \..
`
`•
`
`J
`
`l
`
`I'; j
`
`,;. '~
`
`. .L,
`
`UNITED STATES DEPARTMENT OF COMMERCE
`Patent and Trademark Office
`
`Address
`
`COMMISSIONER OF PATENTS AND TRADEMARKS
`Washington, 0 C 20231
`I ATTORNEY DOCKET NO.
`
`FIRST NAMED APPLICANT
`
`• 1..+ r '
`[ '~r : I
`
`,;.;, ..
`
`EXAMINER
`
`,,"1:-.• )"
`:
`I ,\ . .' I "\~ ;
`
`,,,
`
`ART UNIT
`
`.1 ..... ,)
`
`I PAPER NUMBER
`
`DATE MAILED:
`
`',,', .. J:
`
`This 15 a communIcation from the examiner in charge of your application,
`
`COMMISSIONER OF PATENTS AND TRADEMARKS
`
`~ This application has been examined
`
`D ResponsIvE to communication filed on _______ _ o This action IS made final.
`A shortened statutory period for response to this action is set to expire~month(S), ____ ~ from the date of this letter.
`Failure to respond within the period for response Will cause the application to become abandoned.
`35 U.S.C. 133
`
`Part I
`
`THE FOLLOWING ATTACHMENT(S) ARE PART OF THIS ACTION:
`2. ~ Notice re Patent Drawing, PTO-948.
`4. 0 Notice of informal Patent Application, Form PTO-152
`6. []
`
`L [ ] Notice of References Cited by Examiner, PTO-892.
`3. g Notice of Art Cited by Applicant, PTO-1449
`5. [~Information on How to Effect DraWing Changes, PTO-1474
`
`Part II
`
`SUMMARY OF ACTION
`
`1. ~ Claims
`
`1-'-5
`
`Of the above, cia ims
`
`2.
`
`3.
`
`[=:J Claims
`
`[=:J Claims
`
`4. ~ Claims
`
`5. f~ Claims
`
`6. [J Claims
`
`/ a..hJ 5
`;t I ;3 "- I\-'~ If
`
`are pending in the application.
`
`are withdrawn from consideration.
`
`have been cancelled.
`
`are allowed.
`
`are rejected.
`
`are objected to.
`
`are subject to