UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Apotex Inc. and Apotex Corp. ,
`Petitioners
`
`v.
`
`ABRAXIS BIOSCIENCE, LLC,
`Patent Owner
`
`Case IPR2018-00 153
`Patent 7,923,536 B2
`
`DECLARATION OF CORY J. BERKLAND, Ph.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW
`
`Apotex v. Abraxis - IPR20 18-0015 3, Ex. 1002, p.OI 0[90
`
`

`

`TABLE OF CONTENTS
`
`INTRODUCTION ................................................................................. ...... 1
`
`I.
`
`II.
`
`BACKGROUND AND QUALIFICATIONS ............................. .
`
`III.
`
`LEGAL STANDARDS USED IN MY ANALYS IS .................. .
`
`. ......... 2
`
`. .. ....... 5
`
`A.
`
`B.
`
`C.
`
`D.
`
`Prior art .................................................................................................. 5
`
`Person of ordinary skill in the art .......................................................... 6
`
`Anticipation ........................................................................................... 7
`
`Obviousness ........................................................................ ... .. ...... ...... S
`
`IV. THE '536 PATENT .... ........................................................................... .... 11
`
`A.
`
`B.
`
`C.
`
`The alleged invention .......................................................................... 11
`
`Chal Ienged claims ............................................................................... 16
`
`Claim construction .............................................................................. 17
`
`V.
`
`THE PRIOR ART .................................................................................. .... IS
`
`A.
`
`B.
`
`C.
`
`Desai (EX I 006) .................................................................. ... .. ...... .... IS
`
`Kadima (EX I 004) .............................................................. ....... .... ..... 26
`
`Liversidge (EXI005) .............................................................. ............ .2S
`
`VI. ANTICIPATION ........................................................................... ....... .. ...... .29
`
`A.
`
`Claims 1- 16 of the ' 536 patent are anticipated ................... ....... ........ 30
`
`I.
`
`Claim I is anticipated by Desai. ..............................
`
`. ....... 30
`
`a.
`
`b.
`
`c.
`
`Treatment of cancer in humans ..................... ....... .... ... . 30
`
`Albumin-paclitaxel combination ................................... .32
`
`Palticle size of less than about 200 nm .......... ....... .. ....... 32
`
`Apotex v. Abraxis - IPR20 IS-00 153, Ex. 1002, p.02 of90
`
`

`

`d.
`
`Albumin-paclitaxel ratio of about I: I to 9: I ...... ............ 34
`
`B.
`
`C.
`
`Claims 2- 16 are anticipated by Desai ................................................. 34
`
`The "starting" ratio of albumin to paclitaxel does not change ............ 36
`
`VII . OBViOUSNESS ............................................................................................ 40
`
`A.
`
`Claim I of the '536 patent would have been obvious ........................ .40
`
`I.
`
`Obviousness over Desai alone .................................................. 40
`
`a.
`
`b.
`
`c.
`
`The albumin-paclitaxel ratio of about 9: I fall s within a
`range disclosed by Desai ............................................... .44
`
`A skilled artisan would have been motivated to lower
`Capxol's 13.3: I albumin-paclitaxel ratio ....................... 46
`
`A skilled artisan would have reasonably expected an
`albumin-paclitaxel ratio of9: I to retain stability .......... .48
`
`2.
`
`Obviousness over Desai , Kadima, and Liversidge ................... 51
`
`a.
`
`b.
`
`Kadima and Liversidge also di sclose ranges of
`albumin-paclitaxel ratios, including about 9: I ............... 51
`
`Kadima teaches additional reasons to lower a 13.3: 1 ratio
`of albumin to paclitaxel to about 9: I .............................. 53
`
`B.
`
`C.
`
`The other challenged claims would have been obvious ...................... 56
`
`There are no relevant secondary considerations indicating that the
`challenged claims would not have been obvious ....................... ........ . 58
`
`I.
`
`2.
`
`The allegedly "unexpected" cell-binding results lack a nexus to
`the '536 patent and would have been expected ............... ........ . 60
`
`The allegedly "unexpected" clinical data did not compare the
`closest prior art and would have been expected ....................... 63
`
`VIII. CONCLUS iON .............................................................................................. 67
`
`Apotex v. Abraxis - IPR201 8-0015 3, Ex. 1002, p.03 of90
`
`

`

`EXH IBITS CITED
`
`Description
`
`Desai et aI., U.S. Patent No. 7,923,536 82, "Compositions and Meth-
`ods of Delivery of Pharmacological Agents" (issued Apr. 12, 20 II)
`I (the " '536 patent")
`Kadima et aI., WO 00106152, "Phalmaceutically Acceptable Compo-
`sition Comprising an Aqueous Solution of Pac lit axel and Albumin"
`I (published Feb. 10, 2000) ("Kadima")
`
`Liversidge et aI., U.S. Patent No. 5,399,363, "Surface Modified An-
`ticancer Nanoparticles" (issued Mar. 21 , 1995) ("Liversidge")
`
`Desai et aI., WO 19991000113, "Novel Formulations of Pharmaco-
`logical Agents, Methods for the Preparation thereof and Methods for
`the Use thereof' (published Jan. 7, 1999) ("Desai")
`Li et aI., "Fluorescein 8inding to Normal Human Serum Proteins
`Demonstrated by Equilibrium Dialysis," Arch Ophalmol. vol. 100,
`484---87 (March 1982)
`
`FDA Guideline on Sterile Drug Products Produced by Aseptic Pro-
`cessing (June 1987, reprinted June 1991 and Feb. 1997)
`
`EMEA Guidance on Manufacture ofthe Finished Dosage Form
`(April 1996)
`
`Elan Pharma In! 'I Ltd. v. Abraxis BioScience, Inc., Judgment and
`Verdict Form, No. 06-438-GMS, Dkt. 6 14 (D. Del. June 16, 2008)
`
`Damascelli, 8 et al. "Intraarterial chemotherapy with polyoxyethyl-
`ated castor oil free paclitaxe1, incorporated in albumin nanoparticles
`(ABI-007)," Cancer 200 I Nov; 92( I 0):2592- 2602 ("Damascelli")
`
`Ibrahim et aI., "Phase I and phalmacokinetic study of ABI-007, a
`Cremophor-free, protein-stabilized , nanoparticle formulation of
`paclitaxei," Clin Cancer Res. 2002 May; 8: I 038-44 ("Ibrahim")
`
`U.S. Application No. 11 /553,339, Declaration of Neil P. Desai Pur-
`suant to 37 C.F.R. § 1.1 32 (dated Apr. 14, 2010)
`
`EX
`
`1001
`
`1004
`
`1005
`
`1006
`
`1007
`
`1009
`
`1010
`
`1011
`
`1017
`
`1018
`
`1023
`
`Apotex v. Abraxis - IPR2018-00153 , Ex. 1002, p.04 of90
`
`

`

`[, Cory 1. Berkland, Ph.D., hereby declare as follows:
`
`I.
`
`INTRODUCTION
`
`I.
`
`[ am currently appointed as the Solon E. Summerfield Distinguished
`
`Professor in the Department of Pharmaceutical Chemistry and the Department of
`
`Chemical and Petroleum Engineering at the University of Kansas. [ have been re(cid:173)
`
`tained by Petitioners Apotex Inc. and Apotex Corp. ("Apotex") in connection with
`
`its request for inter partes review of U.S. Patent No. 7,923,536 ("the '536 patent"). A
`
`copy of the '536 patent has been marked EX[OO!. [have reviewed and am familiar
`
`with the '536 patent. Generally, it describes and claims methods of treating cancer
`
`by administering pharmaceutical compositions comprising the anticancer drug
`
`paclitaxe[ bound to the protein albumin and formulated as nanoparticles.
`
`2.
`
`I have been asked to provide my opinions regarding the patentability of
`
`claims [- [6 of the ' 536 patent (the "challenged claims"). This declaration includes a
`
`discuss ion of my background and qualifications, the legal standards used in my
`
`analysis, an overview of the '536 patent from the perspective of a person of ordinary
`
`skill in the art at the time that the patent was filed (a "skilled artisan"), and my
`
`opinions regarding the patentability of the challenged claims.
`
`3.
`
`I am being compensated for my work in this proceeding at my standard
`
`hourly consulting rate of $500.00 per hour. My compensation is in no way
`
`contingent on the substance of my opinions or the outcome of this proceeding.
`
`Apotex v. Abraxis - IPR2018-00153 , Ex. 1002, p.05 of90
`
`

`

`4.
`
`As set forth more fully below, it is my opinion that all claims of the
`
`' 536 patent are anticipated by a previously published international patent application,
`
`WO 99/00 I 13 to Desai et al. ("Desai") (EX I 006). Additionally, it is my opinion that
`
`all claims would have been obvious to a skilled artisan in view of Desai, either alone
`
`or in combination with another previously published international patent application,
`
`WO 00/06152 to Kadima et al. ("Kadima") (EX 1004), and a previously issued
`
`patent, U.S. Patent No. 5,399,363 to Liversidge et al. (EXI005).
`
`5.
`
`The bases for my opinions are set forth in this declaration.
`
`II.
`
`BACKGROUND AND QUALIFICATIONS
`
`6.
`
`I received a B.S. in Chemical Engineering from Iowa State University in
`
`December 1998, and an M.S. in Chemical Engineering from the University of
`
`Illinois in May 200 I. I received a Ph.D. in Chemical and Biomolecular Engineering
`
`from the University of Illinois in May 2003. From 2004 to 2009, I was an Assistant
`
`Professor in the Department of Chemical and Petroleum Engineering and the
`
`Department of Pharmaceutical Chemistry at The University of Kansas. Since 2009, I
`
`have been a Professor in these two dep3ltments with tenure.
`
`7. My areas ofexpeltise include drug fomnulation using particulates and
`
`powders, microencapsulation ofphamnaceuticals, and controlled-release drug
`
`delivery. Through collaborations with industrial and academic partners, and close
`
`Apotex v. Abraxis - IPR2018-00153 , Ex. 1002, p.06 of90
`
`

`

`relationships with other experts in controlled release, I have developed considerable
`
`expertise in the fonnulation and characterization of particles and powders.
`
`8.
`
`The primary focus of my research has been the design and analysis of
`
`drug delivery approaches for improving the performance oftherapeutic agents. I
`
`have worked on particles and aspects of ph 31m ace utica I fonnulation and delivery,
`
`including nanoparticle fonnulations, since 1997. Among other areas, I have con(cid:173)
`
`ducted research aimed to elucidate impOltant parameters (e.g., particle size, mor(cid:173)
`
`phology, surface chemistry) for controlling the release or dissolution of drugs.
`
`9.
`
`My research group at the University of Kansas cUlTentiy works on for-
`
`mulation approaches designed to modify drug dissolution kinetics and to control
`
`drug release rates. My work has encompassed microencapsulation, nanoparticle
`
`fonnulations, and polymers for delivering small molecules, proteins, and DNA. I
`
`have expertise in analyzing the perfonnance of such formulation s and in applying
`
`mathematical models to elucidate the underlying phenomena controlling the disso(cid:173)
`
`lution or release of such drugs. I have also designed and taught classes on drug de(cid:173)
`
`livery that focus primarily on drug transport in phannaceutical formulations and
`
`through different biological barriers in the human body.
`
`10.
`
`I have been a member of various professional organizations, including
`
`the American Institute of Chemical Engineers, the American Chemical Society, the
`
`American Association of Pharmaceutical Scientists, and the Controlled Release
`
`Apotex v. Abraxis -IPR2018-00153 , Ex. 1002, p.07 of90
`
`

`

`Society. I am a Fellow of the American Institute of Medical and Biological Engi(cid:173)
`
`neering, and have received honors and awards from various national and interna(cid:173)
`
`tional organi zations, including the Leading Light Award from the University of
`
`Kansas, the Nagai Foundation Di stinguished Lectureship, and the Controlled Re(cid:173)
`
`lease Society Young lnvestigator Award. Other awards and honors I have received
`
`are listed in my CV, which is attached as the Appendix to this declaration.
`
`II .
`
`I have sat on editotial and scientific advisoty boards of scientific jour-
`
`nals including Therapeutic DelivelY, the Journal of Pharmaceutical Sciences, and
`
`the Jowl1al of Pharmaceutical Innovation .
`
`12.
`
`I have published on such topics as drug delivery, nanopmticle fOlmu-
`
`lation, surface modification, controlled release, and biomaterials. I have published
`
`approximately 150 alticles in peer-reviewed journals, three book chapters, and have
`
`been named as a co-inventor on more than 50 U.S. patents or applications.
`
`13.
`
`I have served as a consultant in the area of drug formulation and de-
`
`livery for U.S. and international companies, and have testified as an expert witness in
`
`the area of drug fonnulation and delivery in severa l trials. My publications, including
`
`publications authored within the past ten years, are listed in my CV.
`
`14.
`
`I have been involved in the development of numerous phannaceutical
`
`products, both in my capacity at the University of Kansas and as a company founder.
`
`For instance, I am a co-founder of four companies: Orbis Biosciences, Inc., Savara
`
`Apotex v. Abraxis - IPR20 18-0015 3, Ex. 1002, p.08 of90
`
`

`

`Pharmaceuticals, lnc., Orion BioScience, lnc., and Bond Biosciences, lnc. I am the
`
`acting Chief Scienti fie Officer at Orbis Biosciences. Orbis develops
`
`controlled-release delivery systems, including parenteral, injectable formulations. I
`
`was also a Member of the Scientific Advisory Boau'd and the fonner Chief Tech(cid:173)
`
`nology Officer for Savara Phannaceuticals, lnc. in Austin, Texas. Savara specializes
`
`in the development of pulmonary drug products. I am also the Chairperson of the
`
`Board of Directors of Orion BioScience, Inc., which develops injectable im(cid:173)
`
`mune-specific therapies for autoimmune diseases.
`
`ID.
`
`LEGAL STANDARDS USED IN MY ANALYSIS
`
`15 .
`
`I am not a patent attorney, nor have I independently researched patent
`
`law. Counsel for Petitioners have explained certain legal standards to me that I have
`
`relied upon in forming my opinions set forth in this Declaration.
`
`A.
`
`Prior art
`
`16.
`
`I have been infonned that the law provides certain categories of in for(cid:173)
`
`mation, known as prior art, that may be used to render patent claims anticipated or
`
`obvious. The reference materials I discuss in this declaration are prior art at least
`
`because they would have been available to members of the public as of December
`
`9, 2002, and are relevant to the subject matter of the '536 patent The references I
`
`discuss herein are from the same field of endeavor as the claimed invention (even if
`
`they address a different problem), and/or are reasonably pertinent to the problem
`
`Apotex v. Abraxis -IPR2018-00153 , Ex. 1002, p.09 of90
`
`

`

`faced by the inventor (even ifthey are not in the same field of endeavor as the
`
`claimed invention).
`
`B.
`
`Person of ordinary skill in the art
`
`17.
`
`I understand that U.S. provisional application no. 60/432,317, to which
`
`the '536 patent claims priority, was filed on December 9, 2002, as stated on the front
`
`of the patent under the title "Related U.S. Application Data." For purposes of my
`
`analysis, and without offering any opinion as to whether the '536 patent's claim to
`
`priority is valid or appropriate, I have used the December 9, 2002 date as the relevant
`
`date for my analysis of the prior art.
`
`IS.
`
`I understand that the assessment of the patentability of the claims of
`
`the '536 patent must be undertaken from the perspective of a hypothetical person
`
`of ordinalY skill in the ali of the earliest priority date of the '536 patent, Le. , a
`
`ski lled artisan. The person of ordinmy ski ll in the art is a hypothetical person who
`
`is presumed to have known the relevant art as of the effective filing date. Factors
`
`that may be considered in detennining the level of ordinary skill in the art may in(cid:173)
`
`clude, (i) type of problems encountered in the art, (ii) prior alt solutions to those
`
`problems, (iii) rapidity with which innovations are made, (iv) sophistication of the
`
`technology, and (v) educational level of active workers in the field. I understand that
`
`in a given case, every factor may not be present, and one or more factors may
`
`predominate.
`
`Apotex v. Abraxis - IPR20IS-00153 , Ex. 1002, p.IO of90
`
`

`

`19.
`
`I understand that the hypothetical person having ordinary skill in the alt
`
`to which the claimed subject matter pertains would, of necessity have the capability of
`
`understanding the scientific and engineering principles applicable to the pertinent
`
`art. I further understand that a person of ordinary skill in the art is also a person of
`
`ordinary creativity, not an automaton. In many cases a person of ordinmy skill will
`
`be able to fit the teachings of multiple patents or prior art references together like
`
`pieces of a puzzle.
`
`20. Based on these factors, my knowledge and expertise, and the prior art to
`
`the '536 patent (Le., publications before December 9,2002), it is my opinion that a
`
`ski lled artisan would include a person with an advanced degree in chemistry,
`
`chemical engineering, pharmaceutics, phanmacy, or a related discipline, andlor
`
`having experience fonnulating compounds for use in phannaceutical compositions,
`
`including nanoparticle suspensions, for several years. FUither, it is my opinion that
`
`the skilled artisan would know how to evaluate potential drug therapies for in vitro
`
`and in vivo activity, including with biological assays.
`
`C.
`
`Anticipation
`
`21.
`
`I have been infonned that a claim is not patentable if a single prior art
`
`reference describes every element ofthe claim, either expressly or inherently, to a
`
`skilled artisan. I understand that this principle is called "anticipation." I have also
`
`been informed that, to anticipate a patent claim, the prior art reference does not need
`
`Apotex v. Abraxis - IPR201 8-00 153, Ex. 1002, p.11 of90
`
`

`

`to use the same words as the claim. However, it must describe the requirements of
`
`the claim with sufficient clarity that a skilled artisan would have been able to make
`
`and use the claimed invention based on that single prior al1 reference.
`
`22.
`
`In addition, I have been infonned and understand that, in order to es(cid:173)
`
`tablish that an element of a claim is "inherent" in the disclosure of a prior art refer(cid:173)
`
`ence, it must be clear to one skilled in the art that the missing element is an inevitable
`
`pal1 of what is explicitly described in the prior art reference, and that it would
`
`have been recognized as necessarily present by a skilled artisan.
`
`D. Obviousness
`
`23.
`
`I have been informed that, even ifevelY element ofa claim is not found
`
`explicitly or implicitly in a single prior art reference, the claim may still be
`
`unpatentable if the differences between the claim and the prior art are such that the
`
`claim as a whole would have been obvious to a skilled artisan at the time the in(cid:173)
`
`vention was made. For purposes of obviousness, I understand that a skilled artisan
`
`may rely on a single prior art reference, or multiple references in combination.
`
`24.
`
`I have been infonned that the following four factors are considered
`
`when detennining whether a patent claim would have been obvious to a skilled ar(cid:173)
`
`tisan: (a) the level of ordinary skill in the art; (b) the scope and content of the prior art;
`
`(c) the differences between the prior al1 and the claim; and (d) any "secondary
`
`considerations" tending to prove nonobviousness. These secondary considerations,
`
`Apotex v. Abraxis - IPR2018-00153 , Ex. 1002, p.12 of90
`
`

`

`which I understand are also called "objective indicia" or "objective evidence," may
`
`include factors such as: (i) the invention's satisfaction ofa long-felt unmet need in the
`
`81t; (ii) unexpected results ofthe invention; (iii) skepticism of the invention by
`
`experts; (iv) teaching away from the invention in the prior art; (v) conunercial success
`
`of an embodiment of the invention; and (vi) praise by others for the invention. I have
`
`also been informed that there must be an adequate nexus or connection between the
`
`evidence that is the basis for an asselted secondary consideration and the scope of the
`
`invention claimed in the patent.
`
`25.
`
`I understand that when evelY limitation of a claim is disclosed in the
`
`cited prior art references, the question of obviousness turns on whether a hypothetical
`
`person of ordinary skill in the art would have been motivated to combine those
`
`teachings to derive the claimed subject matter with a reasonable expectation of
`
`success. FllIther, I understand that obviousness does not require absolute predicta(cid:173)
`
`bility. Only a reasonable expectation that the beneficial result will be achieved is
`
`necessary to show obviousness.
`
`26.
`
`I have been informed that a claimed invention can be rendered obvious
`
`by the combination of teachings in the prior art even if there is no explicit teaching to
`
`combine them. Instead, any problem known in the field at the time of the alleged
`
`invention can provide a sufficient rationale to combine the elements of the prior 81t in
`
`the manner claimed in the patent.
`
`Apotex v. Abraxis - IPR2018-00153 , Ex. 1002, p.13 of90
`
`

`

`27.
`
`I have been informed that examples of sufficient rationales for
`
`establishing obviousness include the following:
`
`• combining prior art elements according to known methods to yield
`
`predictable results;
`
`• substituting known elements for other known elements to obtain
`
`predictable results;
`
`• using a known technique to improve similar devices, methods, or
`
`products in the same way;
`
`• choosing from a finite number of identi fied, predictable solutions that
`
`would be obvious to try; and
`
`• providing some teaching, suggestion, or motivation to modifY the prior
`
`art reference or to combine teachings in prior art references to arrive at
`
`the claimed invention.
`
`28.
`
`I understand that where there is a range disclosed in the prior art, and
`
`the claimed invention falls within that range, the burden of production falls upon
`
`the patentee to come forward with evidence that (l) the prior art taught away from
`
`the claimed invention; (2) there were new and unexpected results relative to the
`
`prior art; or (3) there are other pertinent secondary considerations. For purposes of
`
`this analysis, I understand that a prior art reference does not "teach away" from a
`
`Apotex v. Abraxis - IPR2018-00153 , Ex. 1002, p. 14 of90
`
`

`

`claimed invention unless it criticizes, discredits, or otherwise discourages
`
`investigation into the invention claimed.
`
`[v.
`
`THE '536 PATENT
`
`A.
`
`The alleged invention
`
`29. The '536 patent is entitled "Compositions and Methods of Delivery of
`
`Pharmacological Agents," and generally relates to pharmaceutical compositions
`
`compri sing paclitaxel and a pharmaceutically acceptable can-ier, such as human se(cid:173)
`
`rum albumin, and methods of treating diseases, including cancer, by administering
`
`such compositions. EXIOOl , cover, abst.
`
`30. As background, the '536 patent explains that "many drugs for
`
`parenteral use, especially those administered intravenously, cause undesirable side
`
`effects" that are "administration related." [d. at I :29- 33. "Many ofthese drugs," the
`
`patent explains, "are insoluble in water, and are thus formulated with solubilizing
`
`agents, surfactants, solvents, andlor emulsifiers that are irritating, allergenic, or toxic
`
`when administered to patients" /d. at I :33- 36. The patent goes on to state that
`
`known "drugs that exhibit administration-associated side effects include, for
`
`example, Taxol (paclitaxel)." [d. at 1 :54-56.
`
`31.
`
`Paclitaxel, which as the '536 patent acknowledges is sold under the
`
`brand name Taxol, was known to be "active against carcinomas of the ovary, breast,
`
`lung, esophagus and head and neck. " [d. at 4:33- 35. "Taxol, however, has been
`
`Apotex v. Abraxis - IPR2018-00153 , Ex. 1002, p.15 of90
`
`

`

`shown to induce toxicities associated with administration. " Id. at 4:35- 36. "Because
`
`paclitaxel is poorly soluble in water, cremophor [I.e. , polyethoxylated castor oil]
`
`typically is used as a solvent, requiring large infusion volumes and special tubing and
`
`filters." Id. at 4:39-41. "Cremophor is associated with side effects that can be severe,
`
`including anaphylaxis and other hypersensitivity reactions that can require
`
`pretreatment" with various drugs. Id. at 4:41-44.
`
`32.
`
`The '536 patent discloses compositions and methods that supposedly
`
`reduce or eliminate the cremophor -related side effects that had been associated with
`
`the administration of pac lit axel. Id. at 2:36- 38. Specifically, the patent discloses
`
`compositions comprising paclitaxel together with a pharmaceutical carrier, which is
`
`preferably human serum albumin. /d. at 2:56-60. "Preferably, the formulation is
`
`essentially free of cremophor," thus avoiding its "side effects that can be severe." Id.
`
`at 11 :67- 12:6.
`
`33. Human serum albumin is a highly soluble protein, and is the most
`
`abundant protein in human blood plasma. Id. at 5: 17- 20. The ' 536 patent
`
`acknowledges that the intravenous use of human serum albumin solution was known
`
`in the alt. Id. at 5:23- 24. Human serum albumin has "multiple hydrophobic binding
`
`sites," allowing it to bind to hydrophobic, water-insoluble drugs like paclitaxel.ld.
`
`at 5:31-48. The '536 patent theorizes that "the inclusion of proteins such as albumin
`
`in the inventive pharmaceutical compositions results in a reduction in side effects
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`Apotex v. Abraxis - IPR20 18-0015 3, Ex. 1002, p.16 of90
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`associated with administration of the phannaceutical composition that is due, at least
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`in part, to the binding of human serum albumin to any free drug that is present in the
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`composition." Id. at 5:55- 60.
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`34.
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`The '536 patent states generally that "[tJhe amount of albumin included
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`in the phannaceutical composition of the present invention will vary depending on
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`the pharmaceutical active agent, other excipients, and the route and site of intended
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`administration," so long as "the amount of albumin included in the composition is an
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`amount effective to reduce one or more side effects the active phannaceutical agent
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`due to the [1 administration of the inventive phannaceutical composition to a
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`human." Id. at 5:61 - 6: I. In general, "compositions with lower amounts of albumin
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`are preferred as this can greatly reduce cost," among other alleged reasons. !d. at
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`34:54-56.
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`35. The '536 patent discloses a wide range of albumin-pac lit axel ratios for
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`its compositions: "Exemplary ranges for protein-drug preparations are protein to
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`drug ratios (w/w) of 0.01: I to about 100: 1. More preferably, the ratios are in the
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`range of 0.02: I to about 40: I ." Id. at II :58- 61 . As the patent explains, "the ratio of
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`protein to pharmaceutical agent will have to be optimized for different protein and
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`pharmaceutical agent combinations." Id. at 11:61-63. The patent then discloses
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`celtain "prefelTed" ranges, and concludes by stating: "Most preferably, the ratio is
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`about I: I to about 9: I." Id. at II :66-67.
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`Apotex v. Abraxis - IPR2018-00153 , Ex. 1002, p.17 of90
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`36.
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`The patent includes examples of various pharmaceutical compositions.
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`None of these examples discloses a formulation with an albumin-paclitaxel ratio of
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`about 9: I . The only examples that mention the ratio of albumin to paclitaxel disclose
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`ratios of27: 1, 4.5: l , and 10: I, and each of these examples makes clear that the ratio
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`is calculated based on the ingredients used to make the composition, and/or that the
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`ratio of the final composition remains the same as the ratio of the starting ingredients.
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`See id. at 34:63-66 (Example 47), 35:27- 30 (Example 4S), 35:59- 36: II (Example
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`49).
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`37.
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`For instance, Example 47 states: "30 mg of pac lit axel was dissolved in
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`3.0 ml methylene chloride. The solution was added to 27.0 ml of human serum al(cid:173)
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`bumin solution (3% w/v) (corresponding to a ratio of albumin to paclitaxel of27)" Id.
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`at 34:63- 66. Likewise, Example 4S states: "300 mg of paclitaxel was dissolved in
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`3.0 ml methylene chloride. The solution was added to 27 ml of human serum
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`albumin solution (5% w/v) (corresponding to a ratio of albumin to paclitaxel of 4.5)."
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`Id. at 35:27- 30. [n both of these examples, the recited ratio is based on the starting
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`materials used to make the composition.
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`3S.
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`Similarly, Example 49 states: " 135 mg ofpaclitaxel was dissolved in
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`3.0 ml methylene chloride. The solution was added to 27 ml of human serum albumin
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`solution (5% w/v)." Id. at 35:59- 61. [n other words, 135 mg of paclitaxel was
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`combined with 1,350 mg of albumin (27 ml of 5% w/v solution), corresponding to a
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`Apotex v. Abraxis - [PR20 IS-00 153, Ex. 1002, p.IS of90
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`10: I ratio. After reciting several process steps, Example 49 states: "The calculated
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`ratio (w/w) of albumin to paclitaxel in this invention composition is approximately
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`10." Id. at 36: I 0-11. Apparently, therefore, the albumin-paclitaxel ratio of Example
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`49 was either "calculated" based on the starting materials, or measured after the
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`process steps were completed, at which point the ratio remained the same as the ratio
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`of starting materials.
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`39.
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`There is no suggestion in the '536 patent that the ratio of albumin to
`
`paclitaxel materially changes during the manufacturing process. Nor is there any
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`disclosed assay or discussion of how to measure or predict the ratio of albumin to
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`paclitaxel in the final pharmaceutical composition.
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`40.
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`The '536 patent provides that the claimed compositions can be pre(cid:173)
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`pared as nanoparticles. Id. at 9:33- 35. Several examples in the patent describe
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`nanoparticle formulations. In each one, the example provides that "the typical aver(cid:173)
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`age diameter" of the particles ranges from "50- 220 nm (Z-average, Malvern
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`Zetasizer)." See id. at 14:61- 63 (Example I); 15:23- 26 (Example 2); 15:67- 16:2
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`(Example 4); 16:24- 26 (Example 5); 16:51 - 53 (Example 6); 17: 12- 14 (Example 7);
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`17:45-47 (Example 8); 18: 11- 13 (Example 9); 18:42-44 (Example 10); 19:2-4
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`(Example II); 19:27- 28; (Example 12); 19:47-48 (Example 13); 20:4-6 (Example
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`14); 35:8- 10 (Example 47); 35:40-42 (Example 48); 36:4-6 (Example 49). The
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`Apotex v. Abraxis - IPR2018-00153 , Ex. 1002, p.19 of90
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`"Z-average" is one possible measurement of par1icle diameter, and a "Malvern
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`Zetasizer" is a particular device that is capable of determining that measurement.
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`B.
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`Challenged claims
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`41. Claim I of the '536 patent is directed to a method of treating cancer in
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`humans by injecting an effective amount of a phamlaceutical composition com(cid:173)
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`prising paclitaxel and albumin, formulated as particles having a par1icle size ofless
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`than about 200 run, "wherein the weight ratio of albumin to paclitaxel in the com(cid:173)
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`position is about I: I to about 9: I ."
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`42. Claim 2 depends from claim I (L e., it incorporates all the limitations of
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`claim I) and further requires that the albumin is human serum albumin.
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`43. Claims 3, 7, II , 13 , 14, and 16 depend from claims 1, 2, 4, 12, 8, and 15,
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`respectively, and further require that the cancer being treated is breast cancer.
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`44. Claims 4,8, 12, and 15 depend from claims 1, 2, 6, and 10, respectively,
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`and further require that the pharmaceutical composition is injected intravenously.
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`45. Claims 5 and 9 depend from claims 1 and 2, respectively, and further
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`require that "the ratio (w/w) of the albumin to the paclitaxel in the pharmaceutical
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`composition is I: 1 to 9: \."
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`46. Claims 6 and 1 0 depend from claims I and 2, respectively, and further
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`require that "the ratio (w/w) of the albumin to the paclitaxel in the pharmaceutical
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`composition is about 9: I."
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`Apotex v. Abraxis - IPR201 8-00153 , Ex. 1002, p.20 of90
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`C. Claim construction
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`47. Counsel for Petitioners has informed me that in proceedings before the
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`Patent Office, the claims of a patent must be construed to have their broadest rea(cid:173)
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`sonable interpretation in light of the specification and prosecution history of the
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`patent. Furthermore, I understand that, in general, the broadest reasonable inter(cid:173)
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`pretation of the claims of a patent corresponds to their plain and ordinary meaning
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`from the perspective of a skilled artisan.
`
`48.
`
`In my opinion, a skilled artisan would have understood that the broadest
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`reasonable interpretation of the terms "weight ratio of albumin to paclitaxel in
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`the composition" and "ratio (w/w) of albumin to the paclitaxel in the pharmaceutical
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`composition" in the challenged claims includes the ratio of albumin to
`
`paclitaxel in the starting ingredients used to make the composition. A skilled artisan
`
`reading the '536 patent would have understood that the