vocument Vescripuon. Frovisional VOover Oneet (Ob FO)
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`Title of Invention
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`ORAL AZACITIDINE AND EFFICACIOUS ESCALATED DOSAGE FORMS
`
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`298068-00042
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0001
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0001
`
`

`

`Liocument Vescnpuon: Mrovisional UOver ONeel (2b 10)
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`sown[A
`First Name
`Patrick
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`Higgins
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`39709
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0002
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0002
`
`

`

`A Phase 1, Open-label, Dose-escalation Study to Evaluate the Safety, Pharmacokinetics,
`and Pharmacodynamics of Oral Azacitidine in Subjects with Melodysplastic Syndromes
`(MDS)or Acute Myelogenous Leukemia (AML)
`
`B.S. Skikne’, MLR. Ward’, A. Nassar’, G. Garcia-Manero*
`
`University of Kansas Medical Center, Kansas City, KS‘, Celgene Corporation, Summit,
`NJ’, University of Texas MD Anderson Cancer Center, Houston, TX?
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0003
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0003
`
`

`

`May15, 2008 — US Provisional
`
`ORAL AZACITIDINE AND EFFICACIOUS ESCALATED DOSAGE FORMS
`
`Jeffrey B. Etter
`1318 Deer Trail Rd.
`Boulder, CO 80302
`
`The present invention is drawn toward azacitidine compositions and dosage forms thereof for
`
`oral administration which, for example, yield continuous low-dose drug release profiles upon
`
`oral administration and thereby result in improved efficacy, safety, pharmacokinetics, and
`
`pharmacodynamics. Oral dosages described herein are administered, for example, for the
`
`treatment of myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML)
`
`conditions. Etter, J.B., U.S. Application Ser. No.11/849,958 in incorporatedin its entirety by
`
`reference. See, for example, the primary examples, and formulation #1 described therein.
`
`15
`
`Oral azacitidine dosages (and methods of administration thereof and/or methodsoftreatment
`
`of at least one condition, including but not limited to MDS and AML)ofthe present
`invention may range, for example, between about 50 mg/m’/day and about 2,000mg/m7/day,
`between about 100 mg/m7/day and about 1,000mg/m?/day, between about 100 mg/m7/day and
`about 500mg/m?/day, between about 120 mg/m?/day and about 250mg/m’/day. Particular
`dosages, for example, are about 120 mg/m7/day, about 140 mg/m?/day, about 150 mg/m?/day,
`about 180 mg/m?/day, about 200 mg/m’/day, about 220 mg/m?/day, about 240 mg/m?/day,
`about 250 mg/m?/day, about 260 mg/m*/day, about 280 mg/m?/day, about 300 mg/m2/day,
`about 320 mg/m?/day, about 350 mg/m’/day, about 380 mg/m?/day, about 400 mg/m?/day,
`about 450 mg/m7/day, and about 500 mg/m7/day.
`
`20
`
`25
`
`A phase 1, open-label, dose-escalation study to evaluate the safety, pharmacokinetics, and
`
`pharmacodynamicsoforal azacitidine in subjects with myelodysplastic syndromes (MDS) or
`
`acute myelogenous leukemia (AML)is described herein. Azacitidine, a cytidine analog,
`
`through its effects on DNA metabolism, gene expression, and cell differentiation, has proven
`
`30
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`beneficial in treatment of MDS and AML. Most notably, prolonged azacitidine therapy
`
`recently has been shown to approximately double 2-year survival in higher-risk MDSsubjects
`
`compared to conventional care. Azacitidine is currently approved for intermittent
`
`subcutaneous (SC) and intravenous administration. Developmentof an oral formulation
`
`would provide more convenient dosing, eliminate injection-site reactions, and
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0004
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0004
`
`

`

`May 15, 2008 — US Provisional
`
`-2-
`
`allow evaluation of novel, continuous low-dose regimens that may sustain demethylation and
`
`improve efficacy. A proprietary formulation of oral azacitidine was shown to be absorbed in
`
`a pilot, single-dose study (ASCO 2007). See, e.g., U.S. Application Ser. No.11,849,958.
`
`Multicenter, open-label, Phase 1, sequential design, dose-escalation study of oral
`
`azacitidine. The study is designed to evaluate the maximum tolerated dose (MTD), dose
`
`limiting toxicities (DLTs), safety, pharmacokinetic (PK) and pharmacodynamic (PD)profiles
`
`of increasing doses of orally administered azacitidine in subjects with MDS or AML.
`
`Azacitidine was administered SC (75 mg/m2/day x 7 days) during cycle 1, then orally
`
`starting at 120 mg x 7 days/28 day cycle. Drug levels were measured in plasma andurine,
`
`and PD effects including global LINE methylation and gene-specific methylation were
`
`assayed.
`
`Results
`Currently, no toxicities have been observed in subjects who have completed both the SC and
`
`15
`
`oral phases ofthe study at 120 mg The study continues at the 180 mg dose level. Preliminary
`
`PK analysis indicates detectable plasma levels at the 120 mg oral dose. A comparison of
`
`plasma PK profiles and PD effects of azacitidine administered at increasing oral doses
`
`compared to those of azacitidine administered SC at the approved dose of 75 mg/m2/day for
`
`20
`
`all subjects evaluated to date.
`
`Conclusions
`Results of oral 5-azacitidine indicate that this formulation is orally bioavailable and safe in
`
`subjects with MDS, for example.
`
`25
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`*
`
`*
`
`*
`
`EXHIBIT I
`Attached hereto, is an Example (image Poster), entitled A Phase 1, Open-label, Dose-
`
`30
`
`escalation Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of
`
`Oral Azacitidine in Subjects with Melodysplastic Syndromes (MDS) or Acute
`
`Myelogenous Leukemia (AML), intended for presentation at ASCO 2008, on or about May
`
`16, 2008.
`
`35
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0005
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0005
`
`

`

`
`
`+ Azacitidine, an inhibitor of DNA methylation, has proven beneficial in treatment of MDS
`and AML.
`— Notably, prolonged azacitidine therapy recently has been shown to approximately double 2-
`year survival in highet-tisk MDS patients compared with conventional care.
`+ Azacitidine is currently approvedfor intermittent subcutaneous (SC) and intravenous
`administration. The availability of an oral azacitidine formulation for treatment of AML
`and MDSpatients would have numereus benefits:
`cone
`— Provide more convenient dosing
`— Eliminate injection-site reactions
`— Allow evaluation of a novel, continuous low-dosere
`and improve efficacy
`Eliminate the needfor hospitalvisits.
`- A proprietary formulation ofaral azacitidine was shown to be absorbedinapilot, single-
`dose study.
`
`gimen that may sustain demethylation
`
`! +
`
`To determine the maximumtolerated dose (MTD), dosefimiting toxicities (OLTs), safety,
`and pharmacokinetic (PK) prafiles of increasing dosesof orally administered azacitidine
`in patients with MDS or AML.
`* To determine the biologically active oral azacitidine dose based on safety and PK data.
`
`- Multicenter, cpentabel, Phase 1, sequential design, dose-escalation study (Figure 1).
`+ Patients >18 years of age with MDS or AML and ECOGstatus 0-2 wereeligible.
`- Azacitidine was administered SC (75 mg/day x 7 days) during cycle 1, then orally
`Starting at 120 mg x 7 days/28 daycycle.
`:
`~- Suggested 6-cycle minimum (cycle 7 on Study); patients continued treatment until disease
`progression,
`+ Patients enrolled in cohorts of 3 at each dose level, beginning at 120 mg, and DLT were
`evaluated as shown in Figure1.
`~ If MTD wasnotreach
`ed, doses were increasedin 60-mg increments to a maximum of.
`600 mg.
`~ 1f2 of more ofthe initial 3 patients at a dose level experience DLT, then the MTD was
`considered to have been exceeded and dose escatation stopped.
`+ PK was assessed at cycles 1,2, and 7.
`~ Azacitidine levels were measured in plasma andin urine using LC/MS/MS methods with
`fimit of quantitation (LOQ) values of 1 ng/ml and 10 ng/mL, respectively.
`+ Globalline methylation was assessed to determine PDeffects of oral azacitidine (these
`analyses not yet available).
`- Responseto treatment will be assessed(not yet available).
`* Safely was evaluated by adverse event (AE) teporting.
`
`'
`
`
`References
`:
`1, Fenaux et al. Blood 2007;110,817.
`2. Ward etal. J Clin Oncof 2007;25:18S_
`3. Marcucciet al. J Clin Pharmacol 2005;43:597-602
`
`Presented at the 44"AnnualMesting offreAmerican SovietyofClinical Oncology, May 30— June3, 2008, Chicago, i
`
`i
`
`4
`
`
`taeasthe
`ES
`RandBearewie
` q
`pottedoy
`
`i
`
`sagieatinticaabbhantetgore?
`
`
`
`&
`
`:
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0006
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0006
`
`

`

`
`“Time from original diagnosis te informed consent, G
`
`
`
`ORLNORAPOTARESilnctagpiptmattaehPete
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0007
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0007
`
`

`

`~4 Day 7- 180 mg PO
`
`
`—e-Day 1-135 mg SC
`we- Day 7 - 135 mg SC
`~enDay 1-120 mg PO
`~e Day 7 - 120 mg PO
`~e-Day 1 - 180 mg PO
`
`
`
`
`
`}i
`
`t}i
`
`
`
`wwbation8acachataanedoctetten
`
`
`
`
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0008
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0008
`
`

`

`a4
`
`
`
`MASiSASRAintantiayShncoeateata
`
`
`
`iii
`
`4i
`i
`
`:
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0009
`
` Patients
`*6 patients enrolled to date.
`* Baseline demographic and disease characteristics shown in Table 1.
`Safety
`* No doseimiting toxicities have been observedin patients who have completed both the SC
`and orat phases ofthe Study with azacitidine 120 mg.
`* AEs with oral azacitidine are Consistentwith those observedwith SC azacitidine (Table2).
`PreliminaryPharmacokinetic Results (Figure 2and Table x)
`* Azacitidine plasma levels Werequantifiable following single and multiple oral doses at the
`'120 mg fevet,
`» Azacitidine plasma concentrations peakedat a Median of 1.0 to 1.5 hours followingoral
`doses and declined thereafter in a monophasic manner,
`' Accumulation ofazacitidine Was not observedafter multiple (7-day) SC doses of75 mgfm2,
`' Averageoral bioavailability relative to azacitidine SC 75 mg/m/day was observed to be 6%
`to 15%.
`’ Average half-tife after SC administration fangedfrom 1.6 to 1.8 hours and was shorterafter
`oral administration, which fangedfrom 0.4 and 0.5 hours.
`
`PK parameters, especially after oral administration, were confoundedby high variability. Conclusions
`
`.
`ela?
`* Initial results indicate 120 mg oral azacitidine iswel! Mellel
`ceeReaBice lg\e| AML.Safetydata elecae ee
`‘fecéived th
`ceererel
`al azacitidine ehtoeelgeect)
`
`i
`
`.
`
`Thisstudy was supported byCelgene Corporation Summé, NJ
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0009
`
`

`

`
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0010
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0010
`
`

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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0011
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0011
`
`

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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0012
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0012
`
`

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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0013
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0013
`
`

`

`
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`page 1 of 3
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0014
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0014
`
`

`

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`call the U.S. Governmenthotline at 1-866-999-HALT (1-866-999-4158).
`
`LICENSE FOR FOREIGN FILING UNDER
`
`Title 35, United States Code, Section 184
`
`Title 37, Code of Federal Regulations, 5.11 & 5.15
`
`GRANTED
`
`if the phrase "IF REQUIRED, FOREIGN FILING
`The applicant has been granted a license under 35 U.S.C. 184,
`LICENSE GRANTED"followed by a date appears on this form. Such licenses are issuedin all applications where
`the conditions for issuance of a license have been met, regardless of whether or not a license may be required as
`set forth in 37 CFR 5.15. The scope andlimitations of this license are set forth in 37 CFR 5.15(a) unless an earlier
`license has been issued under 37 CFR 5.15(b). The license is subject to revocation upon written notification. The
`date indicated is the effective date of the license, unless an earlier license of similar scope has been granted under
`37 CFR 5.13 or 5.14.
`
`This license is to be retained by the licensee and may be usedat any time onor after the effective date thereof unless
`itis revoked. This license is automatically transferred to any related applications(s)filed under 37 CFR 1.53(d). This
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`
`The grantof a license does not in any waylessen the responsibility of a licensee for the security of the subject matter
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`State (with respect to Arms, Munitions and Implements of War (22 CFR 121-128)); the Bureau of Industry and
`page 2 of 3
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0015
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0015
`
`

`

`Security, Department of Commerce (15 CFR parts 730-774); the Office of Foreign AssetsControl, Department of
`Treasury (31 CFR Parts 500+) and the Departmentof Energy.
`
`NOT GRANTED
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`No license under 35 U.S.C. 184 has been granted atthis time, if the phrase "IF REQUIRED, FOREIGN FILING
`LIGENSE GRANTED" DOES NOTappear on this form. Applicant maystill petition for a license under 37 CFR 5.12,
`if a license is desired before the expiration of 6 months from thefiling date of the application. If 6 months has lapsed
`from thefiling date of this application and the licensee has not received any indication of a secrecy order under 35
`U.S.C. 181, the licensee may foreign file the application pursuant to 37 CFR 5.15(b).
`
`page 3 of 3
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0016
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0016
`
`

`

`ELECTRONIC FILING
`
`IN THE UNITED STATES PATENT AND TRADEMARKOFFICE
`
`Application of:
`
`Jeffrey B. ETTER
`
`Confirmation No.:
`
`7244
`
`Application No.: 61/053,609
`
`Art Unit:
`
`To Be Determined
`
`Filed:
`
`For:
`
`May 15, 2008
`
`Examiner:
`
`To Be Determined
`
`ORAL AZACITIDINE AND
`EFFICACIOUS ESCALATED
`DOSAGE FORMS
`
`Atty Docket No.: 9516-808-888 (new)
`(298068-00042)
`
`CHANGE OF CORRESPONDENCE ADDRESS
`
`Commissioner for Patents
`P.O. Box
`1450
`Alexandri
`a, VA 22313-1450
`
`Sir:
`
`Please recognize, under 37 C.F.R. § 1.33, the following mailing addressas the
`
`correspondence address forall purposes, includingall notices, official letters, maintenance
`
`fees and any other communications relating to the above-captioned application:
`JONES DAY
`222 East 41st Street
`New York, New York 10017
`Telephone: (212) 326-3939
`Facsimile:
`(212) 755-7306
`Customer No. 20583
`
`Pursuant to 37 C.F.R. § 1.34(a), Jones Day representsthatit is authorized to
`
`Date:
`
`act in a representative capacity on behalf of the Applicant of the above-identified application.
`Respectfully submitted,
`
`
`
`
`(Reg. No.)
`For: Anthony M. Insogna=(Reg. No. 35,203)
`JONES DAY
`222 East 41st Street
`New York, New York 10017
`(212) 326-3939
`
`November 19, 2008
`
`NY1-4139691 vi
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0017
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0017
`
`

`

`Electronic Acknowledgement Receipt
`
`4318738
`
`Confirmation Number:
`
`Title of Invention:
`
`ORAL AZACITIDINE AND EFFICACIOUS ESCALATED DOSAGE FORMS
`
`
`
`
`
`First Named Inventor/Applicant Name:
`
`JEFFREY B. ETTER
`
`Customer Number:
`
`03705
`
`
`
`Filer Authorized By: AndrewV.Trask
`
`Attorney Docket Number:
`
`298068-00042
`
`Filing Date:
`
`15-MAY-2008
`
`16:26:27
`Time Stamp:
`
`
`
`
`Application Type: Provisional
`
`Paymentinformation:
`
`.
`
`Pages
`Multi
`File Size(Bytes)/
`DocumentDescription
`Document
`
`
`
`Number Message Digest|Part/.zip|P (if appl.)
`
`Change of Address
`
`9516-808-888_Change_of_Corr|
`espondence.pdf
`
`181d1722cdffee22at74bbas119dbaé9bc66]
`4cSa
`
`Information:
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0018
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0018
`
`

`

`
`
`Total Files Size (in bytes) 33869
`
`This AcknowledgementReceipt evidences receipt on the noted date by the USPTOof the indicated documents,
`characterized by the applicant, and including page counts, where applicable. It serves as evidence of receipt similar to a
`Post Card, as described in MPEP 503.
`
`
`New Applications Under 35 U.S.C. 111
`If a new application is being filed and the application includes the necessary componentsfor a filing date (see 37 CFR
`1.53(b)-(d) and MPEP 506), a Filing Receipt (37 CFR 1.54) will be issued in due course and the date shownon this
`Acknowledgement Receiptwill establish thefiling date of the application.
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`National Stage of an International Application under 35 U.S.C. 371
`If a timely submission to enter the national stage of an international application is compliant with the conditions of 35
`U.S.C. 371 and other applicable requirements a Form PCT/DO/EO/903indicating acceptance of the application asa
`national stage submission under 35 U.S.C. 371 will be issued in addition to the Filing Receipt, in due course.
`
`New International Application Filed with the USPTO as a Receiving Office
`If a new international application is being filed and the international application includes the necessary componentsfor
`an international filing date (see PCT Article 11 and MPEP 1810), a Notification of the International Application Number
`and of the International Filing Date (Form PCT/RO/105)will be issued in due course, subject to prescriptions concerning
`national security, and the date shown on this Acknowledgement Receiptwill establish the international filing date of
`the application.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0019
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0019
`
`

`

`PTO/SB/96 (09-04)
`Approved for use through 07/31/2006. OMB 0651-0031
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unlessit displays a valid OMB control number.
`
`ELECTRONIC FILING
`
`Applicant/Patent Owner:
`
`Celgene Corporation
`
`STATEMENT UNDER 37 CFR 3.73(b)
`
`Application No./Patent No.:|61/053,609 Filed/issue Date:|May15, 2008
`
`Entitled:|ORAL AZACITIDINE AND EFFICACIOUS ESCALATED DOSAGE FORMS
`Celgene Corporation
`|al corporation
`(Nameof Assignee)
`
`states thatit is:
`
`
`
`
`
`An assignment from the inventor(s) of the patent application/patent identified above. The assignment was
`recordedin the United States Patent and Trademark Office at Reel 022683, Frame 0503, or for which a
`thereof is attached.
`
`
`
`A chain oftitle from the inventor(s), of the patent application/patent identified above, to the current
`assignee as shownbelow:
`From:
`To:
`The document was recordedin the United States Patent and Trademark Office at
`Reel
`, Frame
`, or for which a copy thereofis attached.
`
`From:
`To:
`The document was recordedin the United States Patent and Trademark Office at
`Reel
`, Frame
`or for which a copythereof is attached.
`
`From:
`To:
`The documentwasrecordedin the United States Patent and Trademark Office at
`
`, Frame
`, or for which a copy thereof is attached.
`
`
`
`[NOTE: A separate copy(/.e., the original assignment documentor a true copy of the
`original document) must be submitted to Assignment Division in accordance with 37 CFR
`Part 3, if the assignment is to be recorded in the records of the USPTO. See MPEP 02.08
`
`of
`Date
`
`212-326-3939
`
`
`
`
`Title: Agent Reg. No. 59,239
`This collection of information is required by 37 CFR 3.73(b). The information is required to obtain or retain a benefit by the public whichis to file (and by the
`USPTOto process) an application, Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.14. This collection is estimated to take 12 minutes to complete,
`inciuding gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any
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`U.S. Patent and Trademark Office, U.S. Department of Commerce, P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED
`FORMSTO THIS ADDRESS. SEND TO: Commissionerfor Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
`
`if you need assistance in completing the form, call 1-800-PTO-9199 and select option 2.
`
`NYI- 4183871v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0020
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1036-0020
`
`

`

`PTO/SB/80 (11-08)
`Approved for use through 11/30/2011. OMB 0651-0035
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection ofinformation unless it displays a valid OMB control number.
`
`POWEROF ATTORNEY TO PROSECUTE APPLICATIONS BEFORE THE USPTO
`
`37 CFR 3.