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 [PR20 18-00 152
`Patent 7,820,788 B2
`
`DECLARATION OF CORY J. BERKLAND, Ph.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW
`
`Apotex v. Abraxis· IPR2018-00152, Ex. 1002, p.OI 0[90
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION . . . . ................................................................ ..... .. .. ... I
`
`BACKGROUND AND QUALIFiCATIONS ................................................. 2
`
`III.
`
`LEGAL STANDARDS USED IN MY ANALYSIS ......................... ...... .... .. . 5
`
`A.
`
`B.
`
`C.
`
`D.
`
`Prior alt .................................................................................................. 5
`
`Person of ordinary skill in the art ............................................... ... ... .. ... 6
`
`Anticipation ........................................................................................... 7
`
`Obviousness .... .. ... .. .. .............................................................. ... ... .. ... .. ... 8
`
`IV. THE '788 PATENT ....................................................................................... 11
`
`A.
`
`B.
`
`C.
`
`The alleged invention ............................................................ ... .. ... .. ... . 11
`
`Challenged claims ............................................................................... 16
`
`Claim construction ........................................................................ .. ... . 17
`
`V.
`
`THE PRIOR ART ........................................... ..................................
`
`.. 18
`
`.. 18
`
`A.
`
`B.
`
`C.
`
`Desai (EX I 006) ......................................................................
`
`Kadima (EX I 004) ..................................................................... .... .. ... . 27
`
`Liversidge (EX I 005) .......................................................................... .28
`
`VI. ANTICIPATION ... ... .. ... .. ..................................................................... ... ... .. . 30
`
`A.
`
`Claims 1- 9 and 11 - 12 of the ' 788 patent are anticipated......
`
`I.
`
`Claim I is anticipated by Desai. ..................................
`
`..30
`
`..30
`
`a.
`
`b.
`
`c.
`
`Albumin· paciitaxel combination ........................... ... .... . 3 1
`
`Particle size of less than about 200 nm ............ ... ... .. .. .. . 3 1
`
`A1bumin-paciitaxel ratio of about I: I to 9: I ................. .32
`
`2.
`
`Claims 2- 9 and 11- 12 are anticipated by Desai. ...................... 33
`
`Apotex v. Abraxis - IPR2018-00152, Ex. 1002, p.02 of90
`
`

`

`B.
`
`The "stalting" ratio of albumin to paclitaxel does not change ............ 36
`
`VII . OBV IOUSNESS .... .................................................................................... .... 39
`
`A.
`
`Claim I of the '788 patent wou ld have been obvious .............. ..... .. ... . 39
`
`I.
`
`Obviousness over Desai alone ............................... .......... ..... .... 39
`
`a.
`
`b.
`
`c.
`
`The albumin-paclitaxel ratio of about 9: I falls within a
`range disclosed by Desai ............................................ ... .42
`
`A skilled artisan wou ld have been motivated to lower
`Capxol's 13 .3: I albumin-paclitaxel ratio ................... .. .44
`
`A skilled artisan would have reasonably expected an
`albumin-paclitaxel ratio of9: I to retain stability .. ..... ... .47
`
`2.
`
`Obviousness over Desai , Kadima, and Liversidge .......... ......... 50
`
`a.
`
`b.
`
`Kadima and Liversidge also di sclose ranges of albumin-
`paclitaxel ratios, including about 9: 1 ........................ .. ... . 50
`
`Kadima teaches additional reasons to lower a 13 .3: I ratio
`of albumin to paclitaxel to about 9: l. ....................... .. ... . 5 1
`
`B.
`
`C.
`
`The other challenged claims would have been obvious ................ .... . 55
`
`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 '788 patent and would have been expected ............... ..... .... 59
`
`The allegedly "unexpected" clinical data did not compare the
`closest prior art and would have been expected ....................... 62
`
`V III. CONCLUSiON .......................................................................................... .... 67
`
`Apotex v. Abraxis -IPR2018-00 152, Ex. 1002, p.03 of90
`
`

`

`EX
`
`1001
`
`1004
`
`1005
`
`1006
`
`1007
`
`1009
`
`1010
`
`1011
`
`1017
`
`1018
`
`1023
`
`EXH IBITS CITED
`
`Description
`
`Desai et aI. , U.S. Patent No. 7,820,788 B2, "Compositions and Meth-
`ods of Delivery of Pharmaco logica l Agents" (issued Oct. 26,20 I 0)
`(the "'788 patent")
`Kadima et aI., WO 00/06152, "Pharmaceutically Acceptable Compo-
`sition Comprising an Aqueous Solution of Pac lit axel and Albumin"
`(published Feb. 10,2000) ("Kadima")
`Liversidge et aI. , U.S. Patent No. 5,399,363, "Surface Modified An-
`ticancer Nanoparticles" (issued Mar. 2 1, 1995) ("Liversidge")
`Desai et aI., WO 1999/0001 13, "Novel Formulations of Pharmaco-
`logical Agents, Methods for the Preparation thereof and Methods for
`the Use thereof' (published Jan. 7, 1999) ("Desa i")
`Li et aI., "Fluorescein Binding to Normal Human Semm Proteins
`Demonstrated by Equi librium Dia lysis," Arch Ophalmol. vol. 100,
`484-87 (March 1982)
`FDA Guideline on Sterile Dmg Products Produced by Aseptic Pro-
`cessing (June 1987, reprinted June 199 1 and Feb. 1997)
`EMEA Guidance on Manufacture of the Fin ished Dosage Form
`(April 1996)
`Elan Pharll1a Inl 'l Ltd. v. Abraxis BioScience, Inc. , Judgment and
`Verdict Form, No. 06-438-GMS, Dkt. 614 (D. Del. June 16, 2008)
`Damascelli, B et al. "Intraarterial chemotherapy with polyoxyethyl-
`ated castor oil free paclitaxel, incorporated in albumin nanoparticles
`(ABI-007)," Cancer 200 I Nov; 92(10):2592- 2602 ("Damascelli")
`Ibrahim et aI., "Phase I and pharmacokinetic study of AB I-007, a
`Cremophor-free , protein-stabilized, nanoparticle formulation of
`paclitaxel," 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. § 1.132 (dated Apr. 14,2010)
`
`Apotex v. Abraxis - IPR2018-00 152, Ex. 1002, p.04 of90
`
`

`

`I, COIY J. Berkland, Ph.D., hereby declare as follows:
`
`I.
`
`INTRODUCTION
`
`I.
`
`I am currently appointed as the Solon E. Summerfield Distinguished
`
`Professor in the Department of Phannaceutical Chemistry and the Department of
`
`Chemical and Petroleum Engineering at the University of Kansas. I 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. 7,820,788 ("the '788 patent").
`
`A copy of the '788 patent has been marked EX I 00 I. I have reviewed and am
`
`familiar with the '788 patent. Generally, it describes and claims pharmaceutical
`
`compositions comprising the anticancer drug paclitaxel bound to the protein
`
`albumin and formulated as nanoparticles, and methods of using such compositions
`
`to treat diseases including cancer.
`
`2.
`
`I have been asked to provide my opinions regarding the patentability
`
`of claims 1- 12 of the ' 788 patent (the "challenged claims"). This declaration in(cid:173)
`
`cludes a discussion of my background and qualifications, the legal standards used
`
`in my analysis, an overview of the '788 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 stand-
`
`ard hourly consulting rate of$SOO.OO per hour. My compensation is in no way
`
`Apotex v. Abraxis -IPR2018-00IS2, Ex. 1002, p.OS of90
`
`

`

`contingent on the substance of my opinions or the outcome of this proceeding.
`
`4.
`
`As set forth more fully below, it is my opinion that claims 1- 9 and
`
`11 - 12 of the '788 patent arc anticipated by a previously published international pa(cid:173)
`
`tent application, WO 99/0011 3 to Desai et al. ("Desai") (EX I006). Additionally, it
`
`is my opinion that claims 1- 12 would have been obvious to a ski lled al1isan in
`
`view of Desai, either alone or in combination with another previously published in(cid:173)
`
`ternational patent application, WO 00106152 to Kadima et al. ("Kadima")
`
`(EX I 004), and a previously issued patent, U.S. Patent No. 5,399,363 to Liversidge
`
`et al. (EX I 005). The bases for my opinions are set forth in this declaration.
`
`It BACKGROUND AND QUALIFICATIONS
`
`5.
`
`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 Engineer(cid:173)
`
`ing from the University of Illinois in May 2003. From 2004 to 2009, I was an As(cid:173)
`
`sistant Professor in the Department of Chemical and Petroleum Engineering and
`
`the Department of Ph ann ace utica I Chemistry at The University of Kansas. Since
`
`2009, I have been a Professor in these two departments with tenure.
`
`6.
`
`My areas of expel1ise include drug formulation using particulates and
`
`powders, microencapsulation of phannaceuticals, and controlled-release drug de(cid:173)
`
`livery. Through collaborations with industrial and academic partners, and close re-
`
`Apotex v. Abraxis - IPR20 18-0015 2, Ex. 1002, p.06 of90
`
`

`

`lationships with other experts in controlled release, I have developed considerable
`
`expertise in the formulation and characterization of particles and powders.
`
`7.
`
`The primary focus of my rescarch has been the design and analysis of
`
`drug delivelY approaches for improving the performance of therapeutic agents. I
`
`have worked on particles and aspects of phalmaceutical formulation and delivery,
`
`including nanopalticle fonnulations, since 1997. Among other areas, I have con(cid:173)
`
`ducted research aimed to elucidate important parameters (e.g. , particle size, mor(cid:173)
`
`phology, surface chemistry) for controlling the release or dissolution of drugs.
`
`8. My research group at the University of Kansas currently works on for-
`
`mulation approaches designed to modify drug dissolution kinetics and to control
`
`drug release rates. My work has encompassed microencapsulation, nanoparticle
`
`formulations, and polymers for delivering small molecules, proteins, and DNA. I
`
`have expertise in analyzing the performance of such formulations 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 pharmaceutical formulations and
`
`through different biological barriers in the human body.
`
`9.
`
`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 -IPR201 8-00152, 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 organizations, including the Leading Light Award from the University of
`
`Kansas, the Nagai Foundation Distinguished Lectureship, and the Controlled Re(cid:173)
`
`lease Society Young Investigator Award. Other awards and honors I have received
`
`are listed in my CV, which is attached as the Appendix to this declaration.
`
`] O.
`
`I have sat on editorial and scientific advisOlY boards of scientific jour-
`
`nals including Therapeutic Delivery, the Journal of Phannaceutical Sciences, and
`
`the Journal of Pharmaceutical Innovation.
`
`II.
`
`I have published on such topics as drug delivery, nanopalticle formu-
`
`lation, surface modification, controlled release, and biomaterials. I have published
`
`approximately 150 articles in peer-reviewed journals, three book chapters, and
`
`have been named as a co-inventor on more than 50 U.S. patents or applications.
`
`12.
`
`I have served as a consultant in the area of drug fOlmu lation 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 several trials. My publications, in(cid:173)
`
`cluding publications authored within the past ten years, are listed in my Cv.
`
`13.
`
`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 offour companies: Orbis Biosciences,
`
`Apotex v. Abraxis -IPR2018-00 152, Ex. 1002, p.08 of90
`
`

`

`Inc., Savara Phannaceuticals, Inc. , Orion BioScience, Inc. , and Bond Biosciences,
`
`Inc. I am the acting Chief Scientific Officer at Orbis Biosciences. Orbis develops
`
`controllcd-rcleasc delivcry systcms, including parentcral, injectable fonnulations.
`
`I was a lso a Member of the Scientific Advisory Board and the former Chief Tech(cid:173)
`
`nology Officer for Savara Pharmaceuticals, Inc. in Austin, Texas. Savara special(cid:173)
`
`izes in the development of pulmonary dlUg 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.
`
`III. LEGAL STANDARDS USED IN MY ANALYSIS
`
`14.
`
`J 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
`
`IS.
`
`J have been informed that the law provides certain categories of infor-
`
`mation, known as prior art, that may be used to render patent claims anticipated or
`
`obvious. The reference materials I di scuss in this declaration are prior ali 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 '788 patent. The references I
`
`discuss herein are fro m 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 - IPR201 8-00152, Ex. 1002, p.09 of90
`
`

`

`faced by the inventor (even if they are not in the same field of endeavor as the
`
`claimed invention).
`
`B.
`
`Person of ordinary skill in the art
`
`16.
`
`I understand that U.S. provisional application no. 60/432,317, to
`
`which the '788 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 pur(cid:173)
`
`poses of my analysis, and without offering any opinion as to whether the '788 pa(cid:173)
`
`tent'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.
`
`17.
`
`I understand that the assessment oflhe patentability of the claims of
`
`the '788 patent must be undertaken from the perspective of a hypothetical person
`
`of ordinary skill in the art of the earliest priority date ofthe '788 patent, Le., a
`
`skilled artisan. The person of ordinary skill 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 determining the level of ordinary ski ll in the art may in(cid:173)
`
`clude, (i) type of problems encountered in the art , (ii) prior al1 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 - IPR2018-00152, Ex. 1002, p.IO of90
`
`

`

`18.
`
`I understand that the hypothetical person having ordinary skill in the
`
`alt to which the claimed subject matter pertains would, of necessity have the capa(cid:173)
`
`bility of understanding the scientific and engineering principles applicable to the
`
`pertinent alt. I further understand that a person of ordinary skill in the a1t is also a
`
`person of ordinalY creativity, not an automaton. In many cases a person of ordi(cid:173)
`
`nary skill will be able to fit the teachings of multiple patents or prior alt references
`
`together like pieces of a puzzle.
`
`19. Based on these factors, my knowledge and expeltise, and the prior art
`
`to the '788 patent (Le., publications before December 9, 2002), it is my opinion
`
`that a skilled altisan would include a person with an advanced degree in chemistry,
`
`chemical engineering, phannaceutics, phannacy, or a related discipline, and/or
`
`having experience fOlmulating compounds for use in phalmaceutical compositions,
`
`including nanoparticle suspensions, for several years. Further, it is my opinion that
`
`the skilled altisan would know how to evaluate potential drug therapies for in vitro
`
`and in vivo activity, including with biological assays.
`
`C.
`
`Anticipation
`
`20.
`
`I have been infonned that a claim is not patentable if a single prior art
`
`reference describes every element of the claim, either expressly or inherently, to a
`
`skilled artisan. I understand that this principle is called "anticipation." I have also
`
`been infonned that, to anticipate a patent claim, the prior a1t reference does not
`
`Apotex v. Abraxis -IPR2018-00152, Ex. 1002, p.11 of90
`
`

`

`need to use the same words as the claim. However, it must describe the require(cid:173)
`
`ments of the claim with sufficient clarity that a skilled artisan would have been
`
`able to make and usc the claimed invention based on that sing le prior ali reference.
`
`21.
`
`In addition, I have been infonned and understand that, in order to es-
`
`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 mi ssing element is an inevita(cid:173)
`
`ble part of what is explicitly described in the prior ali reference, and that it would
`
`have been recognized as necessarily present by a skilled artisan.
`
`D. Obviousness
`
`22.
`
`I have been infonned that, even if every element of a 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, [ understand that a skilled artisan
`
`may rel y on a single prior art reference, or multiple references in combination.
`
`23.
`
`I have been infonned that the following four factors are considered
`
`when determining 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 art and the claim; and (d) any "secondary
`
`considerations" tending to prove nonobviousness. These secondalY considerations,
`
`Apotex v. Abraxis - IPR201 8-00152, 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 art; (ii) unexpected results of thc invcntion ; (iii) skcpticism of thc invention by
`
`expelts; (iv) teaching away from the invention in the prior mt; (v) commercial suc(cid:173)
`
`cess 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 be(cid:173)
`
`tween the evidence that is the basis for an asserted secondary consideration and the
`
`scope of the invention claimed in the patent.
`
`24.
`
`I understand that when every limitation of a claim is di sclosed in the
`
`cited prior art references, the question of obviousness turns on whether a hypothet(cid:173)
`
`ical 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. FUlther, 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.
`
`25.
`
`I have been informed that a claimed invention can be rendered obvi-
`
`ous 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 art in the manner claimed in the patent.
`
`Apotex v. Abraxis - IPR201 8-00152, Ex. 1002, p.13 of90
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`

`

`26.
`
`I have been infonned that examples of sufficient rationales for estab-
`
`lishing 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;
`
`•
`
`lIsing a known technique to improve similar devices, methods, or
`
`products in the same way;
`
`• choosing from a finite number of identified, predictable solutions that
`
`would be obvious to try; and
`
`• providing some teaching, suggestion, or moti vation to modify the prior
`
`alt reference or to combine teachings in prior 31t references to arrive at
`
`the claimed invention.
`
`27.
`
`I understand that where there is a range disclosed in the prior alt, and
`
`the claimed invention fall s within that range, the burden of production fall s upon
`
`the patentee to come forward with evidence that (I) the prior alt 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
`
`claimed invention unless it criticizes, discredits, or otherwise discourages investi-
`
`Apotex v. Abraxis -IPR2018-00 152, Ex. 1002, p. 14 of90
`
`

`

`gation into the invention claimed.
`
`IV. THE '788 PATENT
`
`A.
`
`The alleged invention
`
`28. The '788 patent is entitled "Compositions and Methods of Delivery of
`
`Pharmacological Agents," and generally relates to phannaceutical compositions
`
`comprising paclitaxel and a phannaceutically acceptable calTier, such as human se(cid:173)
`
`rum albumin, and methods of treating diseases, including cancer, by administering
`
`such compositions. EX I 00 I, cover, abst.
`
`29. As background, the ' 788 patent explains that "many drugs for paren(cid:173)
`
`teral use, especially those administered intravenously, cause undesirable side ef(cid:173)
`
`fects" that are "admini stration related. " Id. at I :27- 31. "Many of these drugs," the
`
`patent explains, "are insoluble in water, and are thus fonnulated with solubilizing
`
`agents, surfactants, solvents, andIor emulsifiers that are irritating, allergenic, or
`
`toxic when administered to patients" !d. at I :31 - 34. The patent goes on to state
`
`that known "drugs that exhibit administration-associated side effects include, for
`
`example, Taxol (paclitaxel)." Id. at 1:52- 54.
`
`30.
`
`Paclitaxel, which as the '788 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. " Id. at 4:31 - 33. "Taxol , however, has
`
`been shown to induce toxicities associated with administration ." Id. at 4:33- 34.
`
`Apotex v. Abraxis - IPR201 8-00152, Ex. 1002, p.15 of90
`
`

`

`"Because paclitaxel is poorly soluble in water, cremophor [i. e., polyethoxylated
`
`castor oil] typically is used as a solvent, requiring large infusion volumes and spe(cid:173)
`
`cial tubing and filters." Id. at 4:37- 39. "Crcmophor is associated with side effects
`
`that can be severe, including anaphylaxis and other hypersensitivity reactions that
`
`can require pretreatment" with various drugs. Jd. at 4:39-43.
`
`31. The '788 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. Jd. at 2:34-45. Specifically, the patent dis(cid:173)
`
`closes compositions comprising paclitaxel together with a pharmaceutical carrier,
`
`which is preferably human serum albumin. Id. at 2:54- 58. "Preferably, the formu(cid:173)
`
`lation is essentially free of cremophor," thus avoiding its "side effects that can be
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`severe." Id. at II :67- 12:6.
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`32. Human serum albumin is a highly soluble protein, and is the most
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`abundant protein in human blood plasma. Jd. at 5: 15- 18. The '788 patent
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`acknowledges that the intravenous use of human serum albumin solution was
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`known in the art. Jd. at 5:21 - 22. Human serum albumin has "multiple hydropho(cid:173)
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`bic binding sites," allowing it to bind to hydrophobic, water-insoluble drugs like
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`paclitaxel. Id. at 5:29-46. The '788 patent theorizes that "the inclusion of proteins
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`such as albumin in the inventive pharmaceutical compositions results in a reduc(cid:173)
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`tion in side effects associated with administration of the pharmaceutical composi-
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`Apotex v. Abraxis - IPR20 18-0015 2, Ex. 1002, p.16 of90
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`tion that is due, at least in part, to the binding of llUman serum albumin to any free
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`drug that is present in the composition." Id. at 5:52- 58.
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`33. The '788 patent states generally that "[t)he amount of albumin in(cid:173)
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`cluded in the pharmaceutical composition of the present invention will vary de(cid:173)
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`pending on the pharmaceutical active agent, other excipients, and the route and site
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`of intended administration," so long as "the amount ofalbumin included in the
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`compo sition is an amount effective to reduce one or more side effects the active
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`phannaceutical agent due to the [) administration of the inventive phannaceutical
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`composition to a human." Id. at 5:59-66. In general, "compositions with lower
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`amounts of albumin are preferred as this can greatly reduce cost," among other al(cid:173)
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`leged reasons. Id. at 35:34-36.
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`34. The '788 patent di scloses a wide range of albumin-paclitaxel 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: I. More preferably, the ratios are in the
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`range of 0.02: I to about 40: I." Id. at II :58-6 1. As the patent explains, "the ratio
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`of protein to pharmaceutical agent will have to be optimized for different protein
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`and phalmaceutical agent combinations." Id. at 11:61 -63. The patent then dis(cid:173)
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`closes certain "preferred" ranges, and concludes by stating: "Most preferably, the
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`ratio is about I: I to about 9: I." !d. at 11:66-67.
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`35 . The patent includes examples of various pharmaceutical composi-
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`Apotex v. Abraxis - IPR2018-00152, Ex. 1002, p.17 of90
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`tions. None of these examples discloses a formulation with an albumin-paclitaxel
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`ratio of about 9: I. The only examples that mention the ratio of albumin to
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`paclitaxcl disclose ratios of27: 1, 4.5 : I, and 10: I, and each of these examples
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`makes clear that the ratio is calculated based on the ingredients used to make the
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`composition, and/or that the ratio of the final composition remains the same as the
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`ratio of the starting ingredients. See id. at 35:44-47 (Example 47); 36:10- 13 (Ex(cid:173)
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`ampl e 48); 36:42- 61 (Example 49).
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`36.
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`For instance, Example 47 states: "30 mg of pac lit axel was di ssolved 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)."
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`Id. at 35:44-47. Likewise, Example 48 states: "3 00 mg ofpaclitaxel was dissolved
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`in 3.0 ml methylene chloride. The solution was added to 27 ml of human serum
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`albumin so lution (5% w/v) (corresponding to a ratio of albumin to paclitaxel of
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`4.5)."!d. at 36: 10- \3. [n both of these examples, the recited ratio is based on the
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`starting materials used to make the composition.
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`37.
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`Similarly, Example 49 states: " 135 mg ofpachtaxel was dissolved in
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`3.0 ml methylene chloride. The solution was added to 27 ml of human serum albu(cid:173)
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`min solution (5% w/v)." Id. at 36:42-44. [n other words, 135 mg ofpachtaxel was
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`combined with 1,350 mg of albumin (27 ml of 5% w/v solution), corresponding to
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`a 10: I ratio. After reciting several process steps, Example 49 states: "The
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`Apotex v. Abraxis - IPR20 18-0015 2, Ex. 1002, p.18 of90
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`calculated ratio (w/w) of albumin to paclitaxel in this invention composition is ap(cid:173)
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`proximately 10." Jd. at 36:42- 61. Apparently, therefore, the albumin-paclitaxel
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`ratio of Example 49 was cithcr "calculatcd" bascd on the statting materials, or
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`measured after the process steps were completed, at which point the ratio remained
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`the same as the ratio of statting materials.
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`38. There is no suggestion in the ' 788 patent that the ratio of albumin to
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`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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`39. The '788 patent provides that the claimed compositions can be
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`prepared as nanop3lticles.ld. 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 14:62- 63 (Example I); 15:23- 25 (Example 2); 16: 1- 3 (Ex(cid:173)
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`ample 4); 16:28- 31 (Example 5); 16:58-61 (Example 6); 17:22- 24 (Example 7);
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`17:58- 60 (Example 8); 18:26-28 (Example 9); 18:58- 61 (Example 10); 19: 19- 21
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`(Example II); 19:44-45; (Example 12); 19:63- 65 (Example 13); 20:21 - 23 (Exam(cid:173)
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`ple 14); 35:57- 59 (Example 47); 36:23- 25 (Example 48); 36:54- 56 (Example 49).
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`The "Z-average" is one possible measurement of particle diameter, and a " Malvern
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`Zetasizer" is a particular device that is capable of determining that measurement.
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`Apotex v. Abraxis - IPR2018-00152, Ex. 1002, p.19 of90
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`B.
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`Challenged claims
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`40. Claim I of the '788 patent is directed to a pharmaceutical composition
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`for injection comprising paclitaxel and albumin, formulated as particles having a
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`particle size of less than about 200 nm, "wherein the weight ratio of albumin to
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`paclitaxel in the composition is about I: I to about 9: I."
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`41 . Claim 2 depends from claim I (i.e. , it incorporates all the limitations
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`of claim I) and fUlther requires that the albumin is human semm albumin.
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`42. Claim 3 depends from claim I and further requires that the composi(cid:173)
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`tion is free of Cremophor.
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`43 . Claim 4 is directed to a method of treating cancer, arthritis, or resteno(cid:173)
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`sis by administering the composition of claim I.
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`44. Claim 5 depends from claim 4 and requires that the disease treated is
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`cancer.
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`45. Claim 6 depends from claim 4 and requires that the disease treated is
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`arthritis.
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`46. Claim 7 depends from claim 4 and requires that the disease treated is
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`restenosis.
`
`47. Claim 8 depends from claim 4 and further requires that the composi(cid:173)
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`tion is administered "intravenously, intraarterially, intrapulmonarily, orally, by in(cid:173)
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`halation, intravesiculariy, intramuscularly, intratracheally, subcutaneously, intraoc-
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`Apotex v. Abraxis - IPR20 18-0015 2, Ex. 1002, p.20 of90
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`ularly, intrathecally, or transdennally."
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`48. Claim 9 depends from claim 8 and specifies that the method of admin -
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`istration is intravenous.
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`49. Claim 10 depends from claim I and specifies that "the ratio (w/w) of
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`albumin to the paclitaxel in the pharmaceutical composition is about I: I to about
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`5: 1 ."
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`50. Claim II depends from claim I and specifies that "the ratio (w/w) of
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`albumin to the paclitaxel in the pharmaceutical composition is I: I to 9: I."
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`51. Claim 12 depends from claim I and specifies that "the ratio (w/w) of
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`albumin to the paclitaxel in the pharmaceutical composition is about 9: I."
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`C. Claim construction
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`52. Counsel for Petitioners has infonned me that in proceedings before
`
`th