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 IPR20 18-00 151
`Patent 8,138,229 B2
`
`DECLARATION OF CORY J . BERKLAND, Ph.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW
`
`Apotex v. Abraxis - IPR20 18-00 151, Ex. 1002, p.O I of 106
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION ......................................................................... .......... ....... 1
`
`BACKGROUND AND QUALIFICATIONS ................................................ .2
`
`II I.
`
`LEGAL STANDARDS USED IN MY ANALYSIS ...................................... 5
`
`A.
`
`B.
`
`C.
`
`D.
`
`Prior art .................................................................................................. 5
`
`Person of ordinary skill in the art ........................................ ....... .......... 6
`
`Anticipation ......................................................................... ....... .......... 7
`
`Obviousness ........................................................................ ... .. .. .... ...... 9
`
`IV. THE '229 PATENT ............................................................................... .... 11
`
`A.
`
`B.
`
`C.
`
`The alleged invention .......................................................... ....... ........ 1 I
`
`Challenged claims ..................................................................... ........ 16
`
`Claim constmction .............................................................. .......... ..... 18
`
`V.
`
`THE PRIOR ART .......................................................................... .... ... .... ..... 20
`
`A.
`
`B.
`
`C.
`
`D.
`
`Desai (EX I 006) .................................................................. .. ...... .... .. .. .20
`
`Kadima (EX I 004) .............................................................................. .28
`
`Liversidge (EX I 005) .......................................................................... .30
`
`Taxollabel (EXI008) ......................................................................... .32
`
`VI. ANTICIPATION .......................................................................... .. ... ... .... .. .. .32
`
`A.
`
`Claims 1- 19 and 21-48 of the '229 patent are anticipated ................ .32
`
`I .
`
`Claim I is anticipated by Desai ................................................ 32
`
`a.
`
`b.
`
`c.
`
`Albumin-paclitaxel combination .................................... 33
`
`Particle size of less than about 200 nm .......... ....... ........ 34
`
`Albumin-paclitaxel ratio of about 1: I to 9: I .. ....... ........ 35
`
`Apotex v. Abraxis - IPR20 18-00 151 , Ex. 1002, p.02 of 106
`
`

`

`d. Weight percentage of a lbumin ....................................... .35
`
`Claims 3 and 6 are anticipated by Desai .................................. .37
`
`Claims 15, 19, and 21 - 23 are anticipated by Desai ................. .38
`
`Claims 29, 34, and 38 are anticipated by Desai ............ ... ....... .40
`
`Claims 7 and 33 are anticipated by Desai ..................... ... ....... .42
`
`Claims 2, 8, I I, 12, 13, 14, 16, 24, 27, 28, 30, 35, and 39 are
`anticipated by Desai ...................................................... ... .. ...... .42
`
`Claims 4, 5, 9, 10, 17, 18, 25 , 26, 3 1, 32, 36,37,40, and 41 are
`anticipated by Desai ................................................................. .43
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`Claims 42-48 are anticipated by Desai .................................... .43
`
`B.
`
`The "starting" ratio of albumin to paciitaxel does not change .. .. .. ..... .44
`
`VII. OBViOUSNESS ................................................................................ ... ....... .47
`
`A.
`
`Claim I of the '229 patent would have been obvious ....... .
`
`. .. .... .47
`
`I.
`
`Obviousness over Desai alone ................................. .............. .47
`
`a.
`
`b.
`
`c.
`
`d.
`
`The albumin-paclitaxel ratio of about 9: I falls within a
`range disclosed by Desai ........................ ... .... ..... .. .... ...... 51
`
`A ski lled artisan would have been motivated to lower
`CapxoI's 13.3: I albumin-paclitaxel ratio ...... .. ... ....... .... . 53
`
`A skilled artisan would have reasonably expected an
`albumin-paclitaxel ratio of9: I to retain stability . ......... .55
`
`The claimed weight percentage of albumin, when the
`albumin-paclitaxel formulation is reconstituted in saline,
`falls within a range disclosed by Desai .............. ... .. ...... .58
`
`2.
`
`Obviousncss ovcr Desai, Kadima, and Livcrsidge ....... ... .. ...... .59
`
`a.
`
`Kadirna and Liversidge also disclose ranges of albumin-
`paclitaxel ratios, including about 9: I ............................. .59
`
`Apotex v. Abraxis - [PR20 18-00 15 [, Ex. 1002, p.03 of 106
`
`

`

`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`G.
`
`H.
`
`I.
`
`J.
`
`b.
`
`Kadima teaches additional reasons to lower a 13.3: I ratio
`of albumin to paclitaxel to about 9: I .............................. 61
`
`Claims 3 and 6 would have been obvious ............................ ............... 64
`
`Claims 15, \9, and 21 - 23 would have been obvious .......................... 65
`
`Claim 20 would have been obvious ..................................... ............... 67
`
`Claims 29, 34, and 38 would have been obvious ................................ 68
`
`Claims 7 and 33 would have been obvious ............................ .... .. .. ..... 69
`
`Claims 2, 8, II , 12, 13, 14, 16, 24, 27, 28, 30, 35, and 39 would have
`been obvious ........................................................................................ 70
`
`Claims 4, 5, 9, 10, 17, 18, 25, 26,31 , 32, 36,37,40, and 41 would
`have been obvious ............................................................................... 70
`
`Claims 42-48 would have been obvious ........................ ........ ..... ... ..... 7 1
`
`There are no relevant secondary considerations indicating that the
`challenged claims would not have been obvious ................................ 72
`
`I .
`
`2.
`
`The allegedly "unexpected" cell-binding results lack a nexus to
`the '229 patent and would have been expected ........................ 73
`
`The alleged ly "unexpected" clinical data did not compare the
`closest prior art and would have been expected ....................... 76
`
`VIII. CONCLUSiON .............................................................................................. 81
`
`Apotex v. Abraxis - [PR20 18-00 151 , Ex. 1002, p.04 of 106
`
`

`

`EX
`
`1001
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1017
`
`1018
`
`EXHIBITS CITED
`
`Description
`
`Desai et aI. , U.S. Patent No.8 , 138,229 B2, "Compositions and Meth-
`ods of Delivery of Pharmacological Agents" (issued Mar. 20, 2012)
`(the ''' 229 patent")
`Kadima et aI. , WO 00/06152 , "Pharmaceutically Acceptable Compo-
`sition Comprising an Aqueous Solution of Paclitaxel and Albumin"
`(published Feb. 10, 2000) ("Kadima")
`Liversidge et aI. , U.S. Patent No. 5,399,363, "Surface Modified An-
`ticancer Nanopmticles" (issued Mar. 21 , 1995) ("Liversidge")
`
`Desai et aI. , WO 1999/000113, "Novel Formulations of Phannaco-
`logical Agents, Methods for the Preparation thereof and Methods for
`the Use thereof' (published Jan. 7, 1999) ("Desai")
`Li et aI., "Fluorescein Binding to Normal Human Serum Proteins
`Demonstrated by Equi librium Dialysis," Arch Ophalmol. vol. 100,
`484-87 (March 1982)
`Physicians ' Desk Reference"' 309, 881 - 887 (54th ed. 2000) "Taxol"'
`(paclitaxel) Injection" (''Taxollabel'')
`
`FDA Guideline on Sterile Drug Products Produced by Aseptic Pro-
`cessing (June 1987, reprinted June 1991 and Feb. 1997)
`
`EMEA Guidance on Manufacture of the Finished Dosage Form
`(April 1996)
`
`Elan Pharma Int'l Ltd. v. Abraxis BioScience, Inc., Judgment and
`Verdict Form, No. 06-438-GMS, Ok!. 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 2001 Nov; 92( 10):2592- 2602 ("Damascelli")
`Ibrahim et aI. , "Phase I and pharmacokinetic snldy of ABI-007, a
`Cremophor-free, protein-stabilized, nanoparticle formulation of
`paclitaxel," Clin Cancer Res. 2002 May; 8: 1038-44 ("Ibrahim")
`
`Apotex v. Abraxis - IPR20 18-00 151 , Ex. 1002, p.05 of 106
`
`

`

`1023
`
`1027
`
`1028
`
`U.S. Application No. 11 /553,339, Declaration of Neil P. Desai Pur-
`suant to 37 C.F.R. § 1.132 (dated Apr. 14, 20 10)
`
`Remington's Phannaceutical Sciences (18th ed. 1990), Chapt. 85,
`"Intravenous Admixtures" (" Remington's")
`
`Camden, U.S. Patent No.6, 177,460 B I, "Method of Treatment for
`Cancer or Viral Infections" (issued Jan. 23 , 200 I)
`
`Apotex v. Abraxis - [PR20 18-00 15 [, Ex. 1002, p.06 of 106
`
`

`

`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 Pharmaceutical ChemistlY 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. 8, 138,229 ("the '229 patent").
`
`A copy of the '229 patent has been marked EXIOOI. I have reviewed and am
`
`familiar with the ' 229 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 1-48 of the '229 patent (the "challenged claims"). T his declaration in(cid:173)
`
`cludes a discussion of my background and qualifications, the legal standards used
`
`in my analysis, an ovelview of the '229 patent from the perspective ofa person of
`
`ordinary skill in the art at the time that the patent was fil ed (a "skilled artisan"),
`
`and my opinions regarding the patentability ofthe challenged claims.
`
`3.
`
`I am being compensated for my work in this proceeding at my stand-
`
`ard hourl y consulting rate of$500.00 per hour. My compensation is in no way
`
`Apotex v. Abraxis - IPR20 18-00 IS I, Ex. 1002, p.07 of 106
`
`

`

`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- 19 and
`
`21-48 of the '229 patent are anticipated by a previously published international pa(cid:173)
`
`tent application, WO 99/00113 to Desai et al. ("Desai") (EX I 006). Additionally, it
`
`is my opinion that claims 1- 19 and 21-48 would have been obvious to a skilled ar(cid:173)
`
`tisan in view of Desai, either alone or in combination with another previously pub(cid:173)
`
`lished international patent application, WO 00/06152 to Kadima et al. ("Kadima")
`
`(EXI004), and a previously issued patent, U.S . Patent No . 5,399,363 to Liversidge
`
`et al. (EX I 005). It is also my opinion that claim 20 would have been obvious to a
`
`skilled mtisan in view of Desai and the 2000 FDA-approved labeling for Taxol (the
`
`"Taxol label") (EX 1 008), and optionally in fulther view of Kadima and Liversidge.
`
`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 2001. I received a Ph.D. in Chemical and Biomolecular Engineer(cid:173)
`
`ing from the University ofIliinois 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 Pharmaceutical Chemistry at The University of Kansas. Since
`
`2009, I have been a Professor in these two departments with tenure.
`
`Apotex v. Abraxis - IPR20 18-00 15 I, Ex. 1002, p.08 of 106
`
`

`

`7.
`
`My areas of expeltise include drug formulation using palticulates and
`
`powde rs, microencapsulation of ph aIm ace utica Is, and controlled-release drug de(cid:173)
`
`livery. Through collaborations with industrial and academic partners, and close re(cid:173)
`
`lationships with other experts in controlled release, I have developed considerable
`
`expertise in the formulation 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. [
`
`have worked on particles and aspects of pharmaceutical formulation and delivery,
`
`including nanoparticle formulations, 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 dl1lgs.
`
`9. 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 ban'iers in the human body.
`
`Apotex v. Abraxis - [PR20 18-00 15 [, Ex. 1002, p.09 of 106
`
`

`

`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
`
`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 intema(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.
`
`I I.
`
`I have sat on editorial and scientific advisOlY boards of scientific jour-
`
`nals including Therapeutic Delivery, the Journal of Phannaceutical Sciences, and
`
`the Joumal of Phannaceutical Innovation.
`
`12.
`
`I have published on such topics as drug de livelY, nanoparticle 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 .
`
`13.
`
`I have served as a consultant in the area of drug fonnulation and de-
`
`livelY 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.
`
`Apotex v. Abraxis - IPR20 18-00 151 , Ex. 1002, p.1 0 of 106
`
`

`

`14.
`
`I have been involved in the development of numerous pharmaceutical
`
`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,
`
`Inc., Savara Pharmaceuticals, Inc ., Orion BioScience, Inc. , and Bond Biosciences,
`
`Inc. I am the acting Chief Scientific Officer at Orbis Biosciences. Orbis develops
`
`controlled-release delivery systems, including parenteral, injectable formulation s.
`
`I was also a Member of the Scientific Advisory Board and the former Chief Tech(cid:173)
`
`nology Officer for Savara Phannaceuticals, Inc. in Austin, Texas. Savara special(cid:173)
`
`izes 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.
`
`Ill. 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 f0l1h in this Declaration.
`
`A.
`
`Prior art
`
`16.
`
`I have been informed that the law provides certain categories of in for-
`
`mati on, 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
`
`Apotex v. Abraxis - IPR20 18-00 151, Ex. 1002, p.11 of 106
`
`

`

`9,2002, and are relevant to the subject matter of the '229 patent. The references I
`
`discuss herein are from the same field of endeavor as the claimed invention (even
`
`if they address a different problem), andlor are reasonably pertinent to the problem
`
`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
`
`17.
`
`I understand that U.S. provisional application no. 60/432,317, to
`
`which the '229 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 '229 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 al1.
`
`18.
`
`I understand that the assessment of the patentability of the claims of
`
`the '229 patent must be undel1aken from the perspective of a hypothetical person
`
`of ordinalY skill in the al1 as ofthe earliest priority date of the '229 patent, i.e. , a
`
`skilled artisan. The person of ordinalY skill in the art is a hypothetical person who
`
`is presumed to have known the relevant alt as of the effective filing date. Factors
`
`that may be considered in detennining the level of ordinalY skill in the art may in(cid:173)
`
`clude, (i) type of problems encountered in the al1, (ii) prior art solutions to those
`
`problems, (iii) rapidity with which innovations are made, (iv) sophistication of the
`
`Apotex v. Abraxis - IPR20 18-00 151 , Ex. 1002, p.12 of 106
`
`

`

`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.
`
`19.
`
`I understand that the hypothetical person having ordinary skill in the
`
`art 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 art. I further understand that a person of ordinary skill in the alt is also a
`
`person of ordinary 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 art references
`
`together like pieces of a puzzle.
`
`20. Based on these factors, my knowledge and expel1ise, and the prior art
`
`to the '229 patent (i.e. , publications before December 9, 2002), it is my opinion
`
`that a skilled artisan would include a person with an advanced degree in chemistry,
`
`chemical engineering, phannaceutics, phalmacy, or a related discipline, and/or
`
`having experience formulating compounds for use in pharmaceutical compositions,
`
`including nanoparticle suspensions, for several years. Further, 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
`
`2 1.
`
`I have been infonned that a claim is not patentable if a single prior art
`
`Apotex v. Abraxis - IPR20 18-00 151, Ex. 1002, p.1 3 of 106
`
`

`

`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 informed that, to anticipate a patent claim, the prior art reference does not
`
`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 sk illed artisan would have been
`
`able to make and use the claimed invention based on that single prior art 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 inevita(cid:173)
`
`ble palt of what is explicitly described in the prior art reference, and that it would
`
`have been recognized as necessarily present by a skilled artisan.
`
`23.
`
`I understand that when a patent claims a range, that range is antici(cid:173)
`
`pated by a prior art reference if the reference discloses a point within the range. If
`
`the prior al1 discloses its own range, rather than a specific point, then the prior art
`
`is anticipatory ifit describes the claimed range with sufficient specificity such that
`
`a skilled al1isan wo uld conclude that there is no difference in how the invention
`
`operates over the ranges. Further, I understand that a patentee must establish the
`
`"criticality" of a claimed range to the claimed invention in order to avoid anticipa(cid:173)
`
`tion by a prior art reference disclosing a broader, overlapping range.
`
`Apotex v. Abraxis -IPR201 8-001 5 1, Ex. 1002, p.14 of 106
`
`

`

`D. Obviousness
`
`24.
`
`I have been informed 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 altisan 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.
`
`25.
`
`I have been informed 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 alt and the claim; and (d) any "secondary
`
`considerations" tending to prove nonobviousness. These secondalY considerations,
`
`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 the invention; (iii) skepticism of the invention by
`
`expelts; (iv) teaching away from the invention in the prior alt; (v) commercial suc(cid:173)
`
`cess of an embodiment of the invention; and (vi) praise by others for the invention.
`
`I have also been infonned that there must be an adequate nexus or connection be(cid:173)
`
`tween the evidence that is the basis for an asselted secondary consideration and the
`
`scope of the invention claimed in the patent.
`
`Apotex v. Abraxis - IPR20 18-00 15 I, Ex. 1002, p.lS of 106
`
`

`

`26.
`
`I understand that when every limitation of a claim is disclosed 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. Further, 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.
`
`27.
`
`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.
`
`2S.
`
`I have been informed 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
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`predictable results;
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`• using a known technique to improve similar devices, methods, or
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`products in the same way;
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`Apotex v. Abraxis - [PR20 IS-OO 15 [, Ex. 1002, p.16 of 106
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`• choosing from a finite number of identified, predictable solutions
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`that would be obvious to try; and
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`• providing some teaching, suggestion, or motivation to modify the
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`prior art reference or to combine teachings in prior art references
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`to alTive at tile claimed invention.
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`29.
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`I understand that where there is a range disclosed in the prior art, and
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`the claimed invention falls within that range, the burden of production falls upon
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`the patentee to come forward with evidence that (I) the prior art taught away from
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`the claimed invention; (2) there were new and unexpected results relative to the
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`prior art; or (3) there are other pertinent secondary considerations. For purposes of
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`this analysis, I understand that a prior art reference does not "teach away" from a
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`claimed invention unless it criticizes, discredits, or otherwise discourages investi(cid:173)
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`gation into the invention claimed.
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`IV. THE ' 229 PATENT
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`A.
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`The alleged invention
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`30. The '229 patent is entitled "Compositions and Methods of Delivery of
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`Phannacological Agents," and generally relates to pharmaceutical compositions
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`comprising pac1itaxel and a pharmaceutically acceptable calTier, such as human se(cid:173)
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`rum albumin, and methods of treating diseases, including cancer, by administering
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`such compositions. EXIOO I, cover, abst.
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`Apotex v. Abraxis - IPR20 18-00 151, Ex. 1002, p.17 of 106
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`31. As background, the '229 patent explains that "many drugs for paren(cid:173)
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`teral use, especially those administered intravenously, cause undesirable side ef(cid:173)
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`fects" that are "administration related" !d. at I :2S- 32. "Many of these drugs," the
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`patent explains, "are insoluble in water, and are thus formulated with solubilizing
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`agents, surfactants, solvents, and/or emulsifiers that are irritating, allergenic, or
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`toxic when administered to patients." Id. at I :32- 35. The patent goes on to state
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`that known "drugs that exhibit administration-associated side effects include, for
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`example, Taxol (paclitaxel)." Id. at 1:53- 55.
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`32.
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`Paclitaxel, which as the '229 patent acknowledges is sold under the
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`brand name Taxol, was known to be "active against carcinomas of the ovary,
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`breast, lung, esophagus and head and neck." Id. at 4:32- 34. "Taxal, however, has
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`been shown to induce toxicities associated with administration." Jd. at 4:34- 35.
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`"Because paclitaxel is poorly soluble in water, cremophor [i. e., polyethoxylated
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`castor oil] typically is used as a solvent, requiring large infusion volumes and spe(cid:173)
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`cial tubing and filters." Id. at 4 :3S-40. "Cremophor is associated with side effects
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`that can be severe, including anaphylaxis and other hypersensitivity reactions that
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`can require pretreatment" with various drugs. Id. at 4:40-43.
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`33. The '229 patent discloses compositions and methods that supposedly
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`reduce or eliminate the cremophor-related side effects that had been associated
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`with the administration ofpaclitaxel. Jd. at 2:35-46. Specifically, the patent dis-
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`Apotex v. Abraxis - IPR20 IS-OO 151, Ex. 1002, p.IS of 106
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`closes compositions comprising paclitaxel together with a phannaceutical carrier,
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`which is preferably human serum albumin. [d. at 2:55- 59. "Preferably, the formu(cid:173)
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`lation is essentially free of cremophor," thus avoiding its "side effects that can be
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`severe." [d. at 12:3- 9.
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`34. Human serum albumin is a highly soluble protein, and is the most
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`abundant protein in human blood plasma. !d. at 5: 15- 18. The '229 patent
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`acknowledges that the intravenous use of human serum albumin solution was
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`known in the art. [d. at 5:22- 23 . 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. [d. at 5:30-47. The ' 229 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(cid:173)
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`tion that is due, at least in part, to the binding of human serum albumin to any free
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`drug that is present in the composition." ld. at 5:54-59.
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`35. The '229 patent states generally that "[t]he amou.nt 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 of albumin included in the
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`composition is an amount effective to reduce one or more side effects the active
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`pharmaceutical agent due to the [ ] administration of the inventive pharmaceutical
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`Apotex v. Abraxis - [PR20 18-00 15 [, Ex. 1002, p.19 of 106
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`composition to a human ." [d. at 5:60-67. 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 34:53- 55.
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`36. The '229 patent discloses a wide range of albumin-paclitaxel ratios for
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`its compositions: " ExemplalY ranges for protein-drug preparations are protein to
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`drug ratios (w/w) of 0.01 :1 to about 100:1. More preferably, the ratios are in the
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`range of 0.02:1 to about 40:1." Id. at 11:61 -64. 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 pharmaceutical agent combinations." !d. at II :64-66. 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." Id. at 12:2- 3.
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`37. The patent includes examples of various phannaceutical composi(cid:173)
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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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`paclitaxel 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 ingred ients 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 34:62-65 (Example 47), 35:26--29 (Ex(cid:173)
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`ample 48), 35:58- 36:10 (Example 49).
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`38.
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`For instance, Example 47 states: "30 mg ofpaciitaxel was dissolved in
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`Apotex v. Abraxis - [PR20 18-00 15 [, Ex. 1002, p.20 of 106
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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 34:62-65. Likewise, Example 48 states: "300 mg ofpaciitaxel was dis(cid:173)
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`solved in 3.0 ml methylene chloride. The solution was added to 27 ml of human
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`serum albumin solution (5% w/v) (corresponding to a ratio of albumin to paclitaxel
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`of 4.5)." Id. at 35:26-29. In both of these examples, the recited ratio is based on
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`the starting materials used to make the composition.
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`39. Similarly, Example 49 states: " 135 mg ofpaclitaxei 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 35:58-60. In other words, 135 mg ofpaclitaxel
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`was combined with 1,350 mg of albumin (27 ml of 5% w/v solution), correspond(cid:173)
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`ing to a 10: I ratio. After reciting several process steps, Example 49 states: "The
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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." Id. at 36:9- 10. Apparently, therefore, the albumin-paclitaxel ra(cid:173)
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`tio of Example 49 was either "calculated" based on the starting materials, or meas(cid:173)
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`ured after the process