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`T
`
`THE CONTROLLER OF PATENT
`THE PATENT OFFICE
`DELHI
`
`11th April 2014
`
`Kind Attn.: Dr. Nilanjana Mukherjee
`Controller of Patent and Design
`
`TUSHA MALHOTRA
`UDITA PATRO
`Vl8HAV MITHAL
`
`Ma'am,
`
`Re: Pre-grant representation under Section 25(1)
`in respect oflndian Patent Application No. 2899 /DELNP /2005
`Applicant: Abraxis BioScience, LLC
`Opponent: NATCO Pharma Ltd.
`
`This is with reference to the hearing before the Learned Controller on l•t April and 2nd April 2014.
`
`We are enclosing herewith the additional affidavit of Dr. Neil Desai which clearly provides that as to why
`the comparison of efficacy was done by the applicant between old formulation and new formulation with
`a ratio 19:1/20:1versus9:1.
`
`Additionally, the said affidavit also clarifies the nomenclature that has been used as being ABI-007 for
`nanoparticle albumin-bound paclitaxel products under different stages of development. There was no
`mention of these two issues in the pleadings of the opponent but in good faith in order to clarify any
`doubts the Learned Controller might have, we are filing the said affidavit.
`
`Kindly take the said documents on record.
`
`Encl: as stated above
`
`j
`
`\\3 0.0 16\Patent Data\Hemlata\Archana maam\2014\April\Email docx
`
`CEO : Rajtv Maheshwan, CFO : Sanjeev Sharma, CIO : Subroto K Pando, Admin Head : Kov1to Sobhorwal
`
`For enrolment numbers of Advocates see reverse
`
`Abraxis EX2069
`Apotex Inc. and Apotex Corp. v. Abraxis Bioscience, LLC
`IPR2018-00151; IPR2018-00152; IPR2018-00153
`Page 1 of 14
`
`

`

`AFFIDAVIT OF DR. NEIL P. DESAI, Clo ABRAXIS BIOSCIENCE LLC OF LOS
`
`ANGELES, CALIFORNIA, USA
`
`I, the above named Deponent do hereby solemnly affirm and declare as under:
`
`1. I am the Vice President at Celgene, Inc., the parent company of Abraxis
`
`BioScience, LLC ("Abraxis"),
`
`the applicant/ assignee of Indian Patent
`
`Application No. 2899/DELNP/2005 (hereinafter referred to as "patent
`
`application"). Before Abraxis was acquired by Celgene, I was the Senior Vice
`
`President of Global Research and Development at Abraxis. A copy of my
`
`biography is attached hereto as Exhibit 1.
`
`2. I have more than 20 years of experience in the research and development of
`
`drug delivery systems and biocompatible polymers.
`
`I was one of the
`
`individuals responsible for the development of Abraxis' nanoparticle-albumin
`
`bound (nab®) drug delivery platform and its product Abraxane®.
`
`3. I am one of the named inventors of the above referenced patent application
`
`and am familiar with the technical features of the invention, the amended
`
`claims, and the specification.
`
`4. In this declaration, I provide information about the nanoparticle albumin(cid:173)
`
`bound paclitaxel products we developed and disclosed in the above referenced
`
`patent application and in W000/71079.
`
`5. Example 1 of W000/71079 discloses a lab-scale preparation method of
`
`nanoparticle albumin bound paclitaxel composition by high pressure
`
`homogenization method. 30 mg paclitaxel was dissolved in 3 ml methylene
`
`chloride and added to 27 ml of 1 % (w/v) albumin. The weight ratio of albumin
`
`to paclitaxel in the starting components was 9:1. Due to its poor water
`
`pa-1638335
`
`Abraxis EX2069
`Apotex Inc. and Apotex Corp. v. Abraxis Bioscience, LLC
`IPR2018-00151; IPR2018-00152; IPR2018-00153
`Page 2 of 14
`
`

`

`solubility, paclitaxel is inherently lost during a preparation or manufacturing
`
`process which occurs in the aqueous state. In contrast, albumin, which is
`
`freely water soluble, remains in solution. Consequently more paclitaxel than
`
`albumin would be lost during the preparation process, which would alter the
`
`ratio of the components in the finished product. Taking into account loss of
`
`paclitaxel during the nanoparticle preparation process,
`
`the estimated
`
`albumin/paclitaxel ratio
`
`in
`
`the
`
`resulting nanoparticle albumin-bound
`
`paclitaxel composition was about 13.3:1. See Example 1 and page 36 of
`
`W099/00113Al.
`
`6. Because the experiment reported in Example 1 of W000/70179 was on a very
`
`small lab scale using 30 mg paclitaxel (30 ml total volume), there was not
`
`sufficient nanoparticle composition made in Example 1 that could be used for
`
`further clinical studies.
`
`7. The starting albumin/paclitaxel ratio was subsequently changed during the
`
`scaling-up process.
`
`Scaling-up of a
`
`pharmaceutical preparation
`
`manufacturing process from laboratory and bench scale to a manufacturing
`
`plant scale is usually done in a series of steps, each at a suitably larger scale
`
`than the previous scale,
`
`in order to determine the reproducibility of
`
`manufacturing and product quality in moving from the laboratory bench to
`
`the manufacturing plant. Changes in scale of equipment, processing time,
`
`process conditions, surface area of contact for the key components, and many
`
`other factors that change in going from small scale to larger scale, may affect
`
`the composition of the final product. Therefore, experimentation at different
`
`scales of manufacture were conducted and necessary adjustments were made
`
`during product development.
`
`8. Examples 6 and 7 of W000/71079 disclose a larger scale preparation method
`
`of
`
`albumin/paclitaxel
`
`nanoparticle
`
`composition
`
`by
`
`high
`
`pressure
`
`pa-1638335
`
`2
`
`Abraxis EX2069
`Apotex Inc. and Apotex Corp. v. Abraxis Bioscience, LLC
`IPR2018-00151; IPR2018-00152; IPR2018-00153
`Page 3 of 14
`
`

`

`homogenization usmg 225 mg paclitaxel (100 ml total volume). 225 mg
`
`paclitaxel was dissolved in 2. 7 ml chloroform and 0.3 ml ethanol and then
`
`added to 97 ml 3% (w/v) albumin. The starting ratio of albumin to paclitaxel
`
`was about 13:1.
`
`9. Example 16 of W099/00113 provides a "Summary of the Presently Preferred
`
`Manufacturing Process: Starting with 1 gram Paclitaxel as the BDS." 51. 7 ml
`
`of 25% albumin was added to 379.3 ml water to make a total of 431 ml of 3%
`
`albumin. The starting ratio of albumin to paclitaxel was about 13:1. While
`
`the scale in Example 16 of W099/00113 was still relatively small (444 ml total
`
`volume) compared to the manufacturing scale, the 13: 1 starting ratio was
`
`indeed what we had used when manufacturing the nanoparticle albumin
`
`bound paclitaxel formulation ("old formulation") before switching to a new
`
`formulation having a lower albumin/paclitaxel ratio ("new formulation").
`
`10.Exhibit 2 provides the Master Formula for a manufacture lot of the old
`
`formulation (Product No. 101150, Lot No. C199-005). As shown in Exhibit 2,
`
`the initial concentration of paclitaxel per mL of the total solution was 2.25
`
`mg. The initial concentration of albumin per mL of the total solution was 30
`
`mg (20% x 0.15 ml). This makes a starting albumin/paclitaxel ratio of about
`
`13:1. Exhibit 3 provides the Certificate of Analysis for the old formulation
`
`(Product No. 101150, Lot No. C199-005). As shown in Exhibit 3, the amount
`
`of paclitaxel in the finished product was 32. 7 mg/vial. The amount of albumin
`
`in the finished product was 644 mg/vial. This makes the albumin/paclitaxel
`
`ratio in the finished product to be about 19:1. This old formulation having a
`
`final albumin/paclitaxel ratio of about 19:1 was used in the clinical study
`
`discussed in the affidavits submitted by me and separately by Dr. Anindiya
`
`during the pre-grant opposition proceedings.
`
`pa-1638335
`
`3
`
`Abraxis EX2069
`Apotex Inc. and Apotex Corp. v. Abraxis Bioscience, LLC
`IPR2018-00151; IPR2018-00152; IPR2018-00153
`Page 4 of 14
`
`

`

`11. To make a nanoparticle albumin bound paclitaxel formulation having a
`
`desired albumin/paclitaxel
`
`ratio, one can use
`
`routine methods and
`
`experimentation to determine the starting ratio of albumin and paclitaxel
`
`needed for the process, by taking into account the percentage of paclitaxel loss
`
`during the manufacturing process.
`
`12.ABI007 is a code name we used at Abraxis to designate the nanoparticle
`
`albumin bound paclitaxel products under development. The code name
`
`ABI007
`
`is not
`
`tied
`
`to any specific
`
`formulation having a
`
`specific
`
`albumin/paclitaxel ratio. While we altered the albumin/paclitaxel ratio from
`
`19:1 (old formulation) to 9:1 (new formulation) during product development,
`
`we continued to refer to the product as ABI007. The way we distinguished
`
`the old formulation from the new formulation was by using a unique
`
`manufacturing product code. For example, Exhibit 4 (an excerpt from an
`
`amendment to the Technical Report for Abraxane®) provides a
`
`table
`
`summarizing various ABI-007 lots used in characterization studies. Product
`
`Code No. 101150 refers to the old formulation, while Product Code No. 103350
`
`refers to the new formulation.
`
`DEPONENT
`
`Neil P. Desai. Ph.D.
`
`pa-1638335
`
`4
`
`Abraxis EX2069
`Apotex Inc. and Apotex Corp. v. Abraxis Bioscience, LLC
`IPR2018-00151; IPR2018-00152; IPR2018-00153
`Page 5 of 14
`
`

`

`VERIFICATION
`
`Verified at Los Angeles on the 9th day of April, 2014 that the contents of paragraphs 1
`
`to 12 of my affidavit are true to the best of my knowledge and belief and nothing
`
`material or relevant has been concealed therefrom.
`
`DEPONENT
`
`Neil P. Desai, Ph.D.
`
`pa-1638335
`
`5
`
`Abraxis EX2069
`Apotex Inc. and Apotex Corp. v. Abraxis Bioscience, LLC
`IPR2018-00151; IPR2018-00152; IPR2018-00153
`Page 6 of 14
`
`

`

`Exhibit 1
`
`Abraxis EX2069
`Apotex Inc. and Apotex Corp. v. Abraxis Bioscience, LLC
`IPR2018-00151; IPR2018-00152; IPR2018-00153
`Page 7 of 14
`
`

`

`BIOGRAPHY
`NEIL P DESAI, PhD
`
`Vice President, Strategic Platforms
`Abraxis Bioscience, LLC
`A wholly o.wned subsidiary of Celgene Corp
`Los Angeles, CA
`
`Neil Desai is currently Vice President of Strategic Platforms at Celgene Corp. Prior to its
`acquisition by Celgene in Oct 2010, he was Sr. Vice President of Global Research and
`Development at Abraxis Bioscience, in Los Angeles, California, USA, where he was
`responsible for the company's growing product pipeline and the development of the
`company's intellectual property portfolio. Dr. Desai
`is an
`inventor of ABI's
`nanotechnology and nanoparticle-albumin bound (nab®) drug delivery platform, was
`primarily responsible for the development of its nanotechnology drug, Abraxane® and the
`discovery of the novel targeted biological pathway utilized by nab®-drugs. This platform
`has been clinically proven to enhance the efficacy and safety of cytotoxic drugs through a
`novel targeted biological pathway and is the first protein-based nanotechnology product to
`be approved globally for the treatment of cancer.
`
`Prior to his positions at Abraxis, Dr. Desai was Senior Director of Biopolymer Research at
`VivoRx, Inc and VivoRx Pharmaceuticals, Inc. (predecessor companies of Abraxis),
`where he worked on the early discovery and development of Abraxane, developed novel
`encapsulation systems for living cells and was part of the team that performed the world's
`first successful encapsulated islet cell transplant in a diabetic patient.
`
`Dr. Desai has more than 25 years of experience in the research and development of novel
`therapeutic delivery systems. He holds over I 00 issued patents and peer-reviewed
`publications. He has served as reviewer for several scientific journals in the area of cancer
`therapeutics and drug delivery. He is an active participant in FDA and EU
`Nanotechnology initiatives and a member of the Steering Committee for the NCI Alliance
`for Nanotechnology in Cancer. Dr. Desai holds an M.S and Ph.D. in Chemical
`Engineering from the University of Texas at Austin, USA, and a B.S. in Chemical
`Engineering from the University Institute of Chemical Technology in Mumbai, India.
`
`DESAI, Page 111
`
`Abraxis EX2069
`Apotex Inc. and Apotex Corp. v. Abraxis Bioscience, LLC
`IPR2018-00151; IPR2018-00152; IPR2018-00153
`Page 8 of 14
`
`

`

`Exhibit 2
`
`Abraxis EX2069
`Apotex Inc. and Apotex Corp. v. Abraxis Bioscience, LLC
`IPR2018-00151; IPR2018-00152; IPR2018-00153
`Page 9 of 14
`
`

`

`AMERICAN
`PHARMACf:UT!CAL
`PARTNERS. INC.
`
`(Page I of2)
`
`PaOl>UC'f CODS1~ _ __.lu0~1·1~5~0--~---~
`APP Lot ~·---'c .. 1.,1 ... 2 .... -... 0 .. o'"'s _____ _
`Date Qf Xauufacture1
`lQ/2/tt
`
`2020 RUIY SlllfU
`MEIROSE PAlll:.. llllNOIS 60160
`
`!CL (7011) 34~·61/ll
`l[lfFAX f7011) 4!.0·7St.~
`WWW "MPHARMAPAlllNfRS.CCIM
`
`Abraxis EX2069
`Apotex Inc. and Apotex Corp. v. Abraxis Bioscience, LLC
`IPR2018-00151; IPR2018-00152; IPR2018-00153
`Page 10 of 14
`
`

`

`Exhibit 3
`
`Abraxis EX2069
`Apotex Inc. and Apotex Corp. v. Abraxis Bioscience, LLC
`IPR2018-00151; IPR2018-00152; IPR2018-00153
`Page 11 of 14
`
`

`

`..
`
`..
`
`,
`.AMERICAN PHARMAClmTICAL PAR1'NBRS, INC.
`MASTE1l P'ORMOLA
`.
`MBLR.OSB PARX
`
`(APP)
`
`M-1
`PAGE _!__ OF _3_
`
`FORKtJLATION
`NDC No. 63323-111-50
`TBA
`TBA
`Exp. Date
`By
`~ months frOlll date of manufacture
`Site Approved On _ _,TBA="-------
`NDA # --'TBA="--- Supplement #
`TBA
`~TBA = To Be Announced
`Cl99005
`
`101150
`PRODUCT NO.
`
`Time Compounding Started:
`
`q: o-rpn1c €3)/p.m.
`
`PermL
`
`Ingredient
`
`Part
`
`Abraxis EX2069
`Apotex Inc. and Apotex Corp. v. Abraxis Bioscience, LLC
`IPR2018-00151; IPR2018-00152; IPR2018-00153
`Page 12 of 14
`
`

`

`Exhibit 4
`
`Abraxis EX2069
`Apotex Inc. and Apotex Corp. v. Abraxis Bioscience, LLC
`IPR2018-00151; IPR2018-00152; IPR2018-00153
`Page 13 of 14
`
`

`

`TABLE II
`ABI-007 Lots Used in Characterization Study
`
`PD03-NP/F-027 - Amendment I
`
`Page 6 of83
`
`Abraxis EX2069
`Apotex Inc. and Apotex Corp. v. Abraxis Bioscience, LLC
`IPR2018-00151; IPR2018-00152; IPR2018-00153
`Page 14 of 14
`
`