`Filed on behalf of: Abraxis Biosciences, LLC
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________
`
`CIPLA LTD.
`Petitioner,
`
`v.
`
`ABRAXIS BIOSCIENCE, LLC
`Patent Owner.
`________________
`
`IPR2018-00162; IPR2018-00163; IPR2018-00164
`U.S. Patent Nos. 8,138,229; 7,820,788; and 7,923,536
`________________
`
`DECLARATION OF DAVID OUPICKY, Ph.D.
`
`
`
`
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`
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`Abraxis EX2066
`Cipla Ltd. v. Abraxis Bioscience, LLC
`IPR2018-00162; IPR2018-00163; IPR2018-00164
`Page 1 of 141
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`TABLE OF CONTENTS
`
`I. 
`INTRODUCTION .................................................................................................................. 1 
`II.  BACKGROUND & QUALIFICATIONS .............................................................................. 1 
`III. 
`BASIS OF OPINIONS ....................................................................................................... 4 
`IV. 
`LEGAL STANDARDS USED ........................................................................................... 6 
`A.  Anticipation......................................................................................................................... 6 
`B.  Obviousness ........................................................................................................................ 7 
`V.  THE ABRAXIS PATENTS .................................................................................................... 9 
`VI. 
`CLAIM CONSTRUCTION .............................................................................................. 13 
`VII. 
`STATEMENTS................................................................................................................. 14 
`A.  Summary of Opinions ....................................................................................................... 14 
`B.  The patents in suit are not anticipated by Desai (GROUND I) ........................................ 16 
`1.  Desai does not literally disclose a ratio of “about 9:1” or “9:1” ................................... 16 
`2.  Desai does not inherently disclose a ratio of 9:1 .......................................................... 18 
`(a)  Desai states that Example 1 produces a final product with a ratio of 13.3:1 .......... 19 
`(b)  Dr. Desai provided additional evidence showing a loss of paclitaxel during
`manufacturing ................................................................................................................... 27 
`(c)  A POSA would expect loss of paclitaxel in view of the references in the Peppas
`Decl. and in view of Kadima ............................................................................................ 29 
`C.  The Abraxis Patent claims would not have been obvious over the cited references ........ 30 
`1.  The claims would not have been obvious over Desai alone (GROUND II.A) ............. 30 
`(a)  Desai does not expressly or inherently disclose a final ratio of 9:1 or about 9:1 ... 31 
`(b)  A POSA would not have been motivated to adjust the ratios in Desai with a
`reasonable expectation of success ..................................................................................... 31 
`(c)  A POSA would not have been motivated to adjust the Capxol™ ratio with a
`reasonable expectation of success ..................................................................................... 34 
`(d)  The benefits of albumin teach away from reducing the albumin-to-paclitaxel ratio
`
`40 
`2.  The Abraxis Patent claims would not have been obvious over Desai in combination
`with Kadima and Liversidge (GROUND II.B) ..................................................................... 44 
`(a)  None of the references teach the “about 9:1” or “9:1” final ratios ......................... 45 
`(b)  Kadima teaches away from reducing the ratio from 13.3:1 to 9:1 .......................... 48 
`(c)  A POSA would not be motivated to reduce the ratio to 9:1 based on cost savings 50 
`(d)  A POSA Would Have No Reason To Combine Desai with Kadima With A
`Reasonable Expectation Of Success ................................................................................. 52 
`
`
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`i
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`Cipla Ltd. v. Abraxis Bioscience, LLC
`IPR2018-00162; IPR2018-00163; IPR2018-00164
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`Filed on behalf of: Abraxis Biosciences, LLC
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`(e)  A POSA Would Have No Reason To Combine Desai with Liversidge With A
`Reasonable Expectation Of Success ................................................................................. 52 
`3.  Claim 20 of the ’229 would not have been obvious (GROUNDS III.A AND III.B) ... 54 
`4.  Secondary considerations support nonobviousness ...................................................... 54 
`VIII.  DECLARATION .............................................................................................................. 58 
`
`
`
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`ii
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`Cipla Ltd. v. Abraxis Bioscience, LLC
`IPR2018-00162; IPR2018-00163; IPR2018-00164
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`Filed on behalf of: Abraxis Biosciences, LLC
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`I, David Oupicky, Ph.D., hereby declare and state as follows:
`
`I.
`1.
`
`INTRODUCTION
`I submit this declaration on behalf of Abraxis Bioscience, LLC (“Abraxis”
`
`or “Patent Owner”), Patent Owner of U.S. Pat. Nos. 7,820,788 (“the ’788
`
`patent”), 7,923,536 (“the ’536 patent”), and 8,138,229 (“the ’229 patent”)
`
`(collectively, “the Abraxis Patents”) to provide my opinions on certain
`
`matters in connection with the petitions for inter partes reviews filed by
`
`Cipla Ltd. (“Cipla” or “Petitioner”) in case nos. IPR2018-00162, IPR2018-
`
`00163, and IPR2018-00164 (collectively, the “Cipla IPR Petitions”).
`
`
`
`BACKGROUND & QUALIFICATIONS
`II.
`2. My areas of expertise include formulation development of macromolecular
`
`and particulate delivery systems of small molecule drugs and therapeutic
`
`nucleic acids using self-assembly, bioconjugation, and encapsulation
`
`methods. The main focus of my research is the design of novel polymer-
`
`based systems for improved delivery and therapeutic efficacy of
`
`combination treatments.
`
`3. My research laboratories at the University of Nebraska Medical Center and
`
`China Pharmaceutical University currently work on the development of
`
`
`
`1
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`Cipla Ltd. v. Abraxis Bioscience, LLC
`IPR2018-00162; IPR2018-00163; IPR2018-00164
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`injectable anti-metastatic self-assembled polymers and nanoparticles as well
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`as nanoparticles for improved drug delivery in the treatment of inflammatory
`
`bowel disease, pulmonary fibrosis, and kidney injury. My research centers
`
`on multiple aspects related to the chemical synthesis, pharmaceutical
`
`formulation and characterization, and in vitro and in vivo assessment of
`
`delivery and efficacy in relevant disease models.
`
`4.
`
`I received an M.S. in Polymer Engineering from the Institute of Chemical
`
`Technology in Prague, Czech Republic in December 1993 and a Ph.D. in
`
`Macromolecular Chemistry from the Institute of Macromolecular Chemistry
`
`of the Czech Academy of Sciences in May 1999. From 1999 to 2002, I was
`
`a postdoctoral fellow in gene delivery at the CRC Institute for Cancer
`
`Studies at the University of Birmingham, United Kingdom.
`
`5.
`
`I am currently appointed as the Parke-Davis Professor of Pharmaceutics and
`
`Co-Director of the Center for Drug Delivery and Nanomedicine in the
`
`Department of Pharmaceutical Sciences at the University of Nebraska
`
`Medical Center. I am also appointed as part-time Changjiang Scholar Chair
`
`Professor at China Pharmaceutical University in Nanjing, China.
`
`6.
`
`Previously, I was an Assistant Professor (2002-2007) and an Associate
`
`Professor (2007-2013) in the Department of Pharmaceutical Sciences at
`
`
`
`2
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`Cipla Ltd. v. Abraxis Bioscience, LLC
`IPR2018-00162; IPR2018-00163; IPR2018-00164
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`Filed on behalf of: Abraxis Biosciences, LLC
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`Wayne State University, Detroit.
`
`7.
`
`I am a co-founder and president of Bohemica Pharmaceuticals – a start-up
`
`company focused on the development of combination anticancer drug
`
`delivery systems.
`
`8.
`
`I have served on various federal review panels, including multiple study
`
`sections of the National Institutes of Health. I was a standing 4-year term
`
`member of the Gene and Drug Delivery study section (2009-2013) and
`
`currently serve a 4-year term (2017-2021) as a member of the
`
`Nanotechnology study section. I have served on multiple SBIR/STTR study
`
`sections focused on development of drug delivery methods. I have been a
`
`member of various professional organizations, including the Controlled
`
`Release Society, the American Chemical Society, the American Association
`
`of Pharmaceutical Scientists, and the American Society of Gene Therapy.
`
`9.
`
`I served as the representative to the United States Pharmacopeia for Wayne
`
`State University from 2005 until 2012.
`
`10.
`
`I have developed and taught classes to graduate students and professional
`
`pharmacy students in pharmaceutical sciences that focus on the dosage form
`
`design, pharmacokinetics, physical pharmacy, and drug delivery. These
`
`courses address nanoparticles and formulation issues relevant to the topics
`
`
`
`3
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`IPR2018-00162; IPR2018-00163; IPR2018-00164
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`discussed in my declaration.
`
`11.
`
`I have received multiple honors and awards, including the Changjiang
`
`Scholar Professorship from the Chinese Ministry of Education, American
`
`Foundation for Pharmaceutical Education Faculty New Investigator award,
`
`and the distinguished scientist award at UNMC.
`
`12.
`
`I have published more than 125 peer-reviewed papers, reviews, and book
`
`chapters on various topics of drug and nucleic acid delivery, polymer
`
`synthesis and characterization, particle formulation, and bioconjugation. I
`
`have been invited to present talks at various national and international
`
`conferences on drug delivery and pharmaceutical sciences as well as
`
`multiple academic seminars at multiple universities in the US, Europe, and
`
`China.
`
`13.
`
`I am being compensated for my time spent in connection with this matter at
`
`a rate of $375 per hour. My compensation does not depend on the outcome
`
`of the proceedings, or the conclusions in this declaration.
`
`14. A copy of my curriculum vitae, including a list of publications I authored is
`
`attached to this declaration as Appendix A.
`
`III. BASIS OF OPINIONS
`15.
`In forming my opinions, I have reviewed the Cipla IPR Petitions, Patent
`
`
`
`4
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`IPR2018-00162; IPR2018-00163; IPR2018-00164
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`Filed on behalf of: Abraxis Biosciences, LLC
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`Owner’s Preliminary Responses in the Actavis IPRs1, the Actavis IPR
`
`Institution Decisions, the Abraxis Patents, the references cited in the Cipla
`
`IPR Petitions, as well as the other documents identified below.
`
`16. The opinions expressed in this declaration are also based on my knowledge,
`
`skill, experience, training, and education, particularly with respect to what
`
`one of ordinary skill in the art at the relevant priority date would have
`
`understood from the prior art.
`
`17.
`
`I understand that Cipla contends in the Cipla IPR Petitions that a
`
`“hypothetical person of ordinary skill in the art” (“POSA”) would have an
`
`advanced degree in chemistry, chemical engineering, pharmaceutics,
`
`pharmacy, or a related discipline, and/or having experience formulating
`
`compounds for use in pharmaceutical compositions, including nanoparticle
`
`suspensions, for several years. I further understand that for the Cipla IPR
`
`Petitions Cipla uses December 9, 2002, as the relevant date for analyzing the
`
`level of skill and knowledge of a hypothetical POSA. For purposes of this
`
`declaration, I have been asked to use Cipla’s definition of a POSA and to use
`
`
`1 By “Actavis IPRs,” I refer to IPR2017-1101, IPR2017-1103 and IPR2017-
`
`1104.
`
`
`
`5
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`Cipla Ltd. v. Abraxis Bioscience, LLC
`IPR2018-00162; IPR2018-00163; IPR2018-00164
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`December 9, 2002 as the relevant date for analyzing the level of skill and
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`knowledge of a hypothetical POSA.
`
`18. Based on my training and experience, I believe I am at least a POSA now
`
`and I was a POSA well before December 9, 2002.
`
`IV.
`19.
`
` LEGAL STANDARDS USED
`I am not a patent attorney nor have I independently researched the law on
`
`patent validity. Abraxis’s attorneys have explained certain legal principles
`
`to me that provide the context for my opinions set forth in this declaration.
`
`The paragraphs below express my understanding of how I must apply
`
`current principles related to patentability.
`
`A.
`
`Anticipation
`I understand that for a patent claim to be considered anticipated, each and
`
`20.
`
`every limitation of the claim must be present, either explicitly or inherently,
`
`within a single piece of prior art. I further understand that anticipation also
`
`occurs when the claimed invention inherently results from practice of what
`
`is disclosed in the written reference, even if the inherent disclosure was
`
`unrecognized or unappreciated by one of ordinary skill in the field of the
`
`invention. To rely on inherency, I have been informed by counsel and I
`
`understand that a patent challenger must show that the claim limitation at
`
`
`
`6
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`IPR2018-00162; IPR2018-00163; IPR2018-00164
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`issue must be necessarily present in the prior art disclosure, or that the claim
`
`limitation is the natural and inevitable result of the combination of elements
`
`explicitly disclosed by the prior art. I have been informed by counsel and I
`
`understand that a finding of inherency cannot be based on mere probabilities
`
`or possibilities.
`
`B. Obviousness
`It is my understanding that a claim is unpatentable under 35 U.S.C. § 103 if
`
`21.
`
`the claimed subject matter as a whole would have been obvious to a person
`
`of ordinary skill in the art at the time of the alleged invention. I also
`
`understand that an obviousness analysis takes into account the scope and
`
`content of the prior art, the differences between the claimed subject matter
`
`and the prior art, and the level of ordinary skill in the art at the time of the
`
`invention.
`
`22.
`
`I further understand that the challenger cannot rely on the hindsight of
`
`today’s knowledge, and that the party challenging the patent may not use the
`
`patent as a blueprint or template to pick and choose references within the
`
`prior art, or portions thereof, to rely on in an obviousness analysis.
`
`23.
`
`In determining the scope and content of the prior art, it is my understanding
`
`that a reference is considered appropriate prior art if it falls within the field
`
`
`
`7
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`of the inventor’s endeavor. In addition, a reference is prior art if it is
`
`reasonably pertinent to the particular problem with which the inventor was
`
`involved. A reference is reasonably pertinent if it logically would have
`
`commended itself to an inventor’s attention in considering his problem. If a
`
`reference relates to the same problem as the claimed invention, that supports
`
`use of the reference as prior art in an obviousness analysis.
`
`24. To assess the differences between prior art and the claimed subject matter, it
`
`is my understanding that 35 U.S.C. § 103 requires the claimed invention be
`
`considered as a whole. This “as a whole” assessment requires showing that
`
`one of ordinary skill in the art at the time of invention, confronted by the
`
`same problems as the inventor and with no knowledge of the claimed
`
`invention, would have selected the elements from the prior art and combined
`
`them in the claimed manner.
`
`25.
`
`It is my understanding that the challenger must show that a person of
`
`ordinary skill in the art would have had a reason to combine the teachings of
`
`the prior art references to obtain the claimed invention and would have had a
`
`reasonable expectation of success in achieving the claimed result. I further
`
`understand that the Supreme Court has recognized several rationales for
`
`combining references or modifying a reference to show obviousness of
`
`
`
`8
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`IPR2018-00162; IPR2018-00163; IPR2018-00164
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`claimed subject matter. Some of these rationales include: combining prior
`
`art elements according to known methods to yield predictable results; simple
`
`substitution of one known element for another to obtain predictable results; a
`
`predictable use of prior art elements according to their established functions;
`
`applying a known technique to a known device (method or product) ready
`
`for improvement to yield predictable results; choosing from a finite number
`
`of identified, predictable solutions, with a reasonable expectation of success;
`
`and some teaching, suggestion, or motivation in the prior art that would have
`
`led one of ordinary skill to modify the prior art reference or to combine prior
`
`art reference teachings to arrive at the claimed invention.
`
`26.
`
`I have been informed by counsel and I understand that other evidence,
`
`referred to generally as “objective indicia,” may indicate the nonobviousness
`
`of an invention, such as unexpected results, and commercial success where
`
`there is a causal relationship or “nexus” between the claimed invention and
`
`its commercial embodiment.
`
`V.
`27.
`
`THE ABRAXIS PATENTS
`I have reviewed the Abraxis Patents (IPR2018-00151, EX1001; IPR2018-
`
`00152, EX1001; IPR2018-00153, EX1001) and I am familiar with the
`
`patented subject matter, which is within the scope of my field of expertise.
`
`
`
`9
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`IPR2018-00162; IPR2018-00163; IPR2018-00164
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`28. The Abraxis Patents provide a description of and methods for making
`
`Abraxane®, a breakthrough injectable nanoparticle formulation of
`
`paclitaxel. (EX2011, 1.) The nanoparticles consist of a solid core of non-
`
`crystalline, amorphous paclitaxel surrounded by a shell of human serum
`
`albumin. (Id.) The mean size of the nanoparticles is approximately 130
`
`nanometers. (EX2011, 15.) Abraxane® is presented lyophilized, and each
`
`vial contains 900 mg albumin per 100 mg paclitaxel (i.e., a 9:1 weight ratio
`
`of albumin to paclitaxel) prior to reconstitution with 0.9% saline. (Id.)
`
`29. The Abraxis Patents cover the final ratios of Abraxane® and are listed in the
`
`Orange Book as covering Abraxane®. The inventors unexpectedly found
`
`that reducing the albumin to paclitaxel weight ratio in the finished
`
`formulation to 9:1 or below showed both higher therapeutic efficacy and
`
`reduced toxicity compared to older albumin/paclitaxel nanoparticle
`
`formulations containing higher ratios. (EX1023 ¶¶ 4–6.2) The inventors
`
`have noted that the biological significance of the albumin-to-paclitaxel
`
`
`2 EX1023, (“Inventor Declaration”) refers to Inventor Neil Desai’s April 14,
`
`2010 Declaration submitted in response to the December 31, 2009 Office Action
`
`issued by the PTO during prosecution of the ’788 patent.
`
`
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`10
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`IPR2018-00162; IPR2018-00163; IPR2018-00164
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`weight ratio could not have been predicted based on the prior art. (EX1023
`
`¶¶ 16–22.)
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`30. The ’788 patent, which issued on October 26, 2010, to Desai et al. is
`
`directed to novel paclitaxel-albumin nanoparticle compositions and methods
`
`of treating cancer therewith. Independent claim 1, which is representative of
`
`the composition claims, recites an injectable liquid pharmaceutical
`
`composition comprising paclitaxel and albumin nanoparticles having a size
`
`of less than about 200 nm, wherein the weight ratio of albumin to paclitaxel
`
`in the composition is about 1:1 to about 9:1 (i.e., Abraxane®’s 9:1 ratio).
`
`Independent claim 4, which is representative of the method claims, recites a
`
`method of treating a disease with the pharmaceutical composition of claim 1.
`
`The ’788 patent and its patent family were the first to disclose nanoparticle
`
`compositions with an albumin-to-paclitaxel weight ratio of 9:1. Claims 1-9
`
`and 11 include the claim limitation “about 9:1”, while claim 11 includes the
`
`narrower claim limitation of “9:1” without using the word “about”.
`
`
`
`31. The ’229 patent, which issued on March 20, 2012 from U.S. Appl. No.
`
`12/910,693 as a continuation of U.S. Appl. No. 11/553,339, now the ’788
`
`patent to Desai et al. is directed to novel paclitaxel-albumin nanoparticle
`
`
`
`11
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`compositions and methods of treating cancer therewith. Independent claim 1,
`
`which is representative of the composition claims, recites an injectable liquid
`
`pharmaceutical composition comprising paclitaxel and albumin
`
`nanoparticles having a size of less than about 200 nm, wherein the weight
`
`ratio of albumin to paclitaxel in the composition is about 1:1 to about 9:1
`
`(i.e., Abraxane®’s 9:1 ratio) and the albumin comprises about 0.5% to about
`
`5% by weight of the composition. Independent claim 29, which is
`
`representative of the method claims, recites a method of treating cancer with
`
`the pharmaceutical composition of claim 1. Claims 1-3, 5-8, 10-16, 18-24,
`
`26-31, 32-36, 37-39, and 41-48 include the claim limitation “about 9:1”,
`
`while claims 4, 9, 17, 25, 31, 36, and 40 include the narrower claim
`
`limitation “9:1” without using the word “about”.
`
`
`
`32. The ’536 patent, which issued on April 12, 2011, to Desai et al. from U.S.
`
`Appl. No. 12/758,413, which is also a continuation of U.S. Appl. No.
`
`11/553,339, is directed to methods of treating cancer with novel paclitaxel-
`
`albumin nanoparticle compositions. Independent claim 1, which is
`
`representative of the method claims, recites a method of treating cancer by
`
`injecting a pharmaceutical composition comprising paclitaxel and albumin
`
`
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`12
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`nanoparticles having a size of less than about 200 nm, wherein the weight
`
`ratio of albumin to paclitaxel in the composition is about 1:1 to about 9:1
`
`(i.e., Abraxane®’s 9:1 ratio). Claims 1-5, 6-9 and 10-16 include the claim
`
`limitation “about 9:1”, while claims 5 and 9 include the narrower claim
`
`limitation “9:1” without using the word “about”.
`
`
`
`VI. CLAIM CONSTRUCTION
`33. Based on the plain language of the claim, the Board adopted Patent Owner’s
`
`construction in the Actavis IPRs, concluding that “the 9:1 ratio of ‘the
`
`composition’ in claim 1 of the Abraxis Patents must be the ratio of albumin
`
`to paclitaxel in the final product injected into the patient.” IPR2017-01101
`
`(paper 7 at 6); IPR2017-01103 (paper 7 at 6); IPR2017-01104 (paper 7 at 6.)
`
`I agree with this construction and have applied it throughout in my
`
`declaration.
`
`34. Claims 1-9 and 11 of the ’788 patent, claims 1-5, 6-9 and 10-16 of the ’536
`
`patent, and claims 1-3, 5-8, 10-16, 18-24, 26-31, 32-36, 37-39, and 41-48 of
`
`the ’229 patent include the claim limitation “about 9:1”, while claim 11 of
`
`the ’788 patent, claims 5 and 9 of the ’536 patent, and claims 4, 9, 17, 25,
`
`31, 36, and 40 of the ’229 patent include the narrower claim limitation “9:1”.
`
`
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`13
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`35.
`
`I understand that in the Actavis IPRs, the Board took the position that the
`
`term “about” includes a variation of up to 10%, and that Dr. Berkland agrees
`
`with such a position. (IPR2017-01101 (paper 7 at 19); IPR2017-01103
`
`(paper 7 at 18-19); IPR2017-01104 (paper 7 at 19); EX2070, 120:1-8) In
`
`my opinion, the claims that do not contain the word “about” with respect to
`
`the final ratio do not include such variation and have a narrower scope.
`
`
`
`VII. STATEMENTS
`Summary of Opinions
`I have been asked to consider whether the cited prior art references from the
`
`36.
`
`A.
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`Cipla IPR petitions render the challenged claims invalid as anticipated or
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`obvious.
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`37.
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`I understand that Petitioner challenges the claims of the Abraxis Patents on
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`several grounds. In Ground I, Petitioners argue that claims 1-19 and 21-48
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`of the ’229 patent, claims 1-16 of the ’536 patent and claims 1-9 and 11-12
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`of the ’788 patent are anticipated under § 102 by WO 99/00113 (“Desai”)
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`(EX1006.) In Ground II.A, Petitioner challenges claims 1-19 and 21-48 of
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`the ’229 patent, claims 1-16 of the ’536 patent and claims 1-12 of the ’788
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`patent as obvious under § 103 over Desai alone, and in Ground II.B over
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`14
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`Abraxis EX2066
`Cipla Ltd. v. Abraxis Bioscience, LLC
`IPR2018-00162; IPR2018-00163; IPR2018-00164
`Page 17 of 141
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`Filed on behalf of: Abraxis Biosciences, LLC
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`Desai in view of Kadima (EX1004) and Liversidge (EX1005.) In Ground
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`III.A, Petitioner challenges claim 20 of the ’229 patent as obvious over
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`Desai in view of the Taxol® label, and in III.B, as obvious over Desai in
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`view of the Taxol® label, Kadima, and Liversidge. The Board instituted the
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`IPRs under each of these grounds in the Actavis IPRs.
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`38. As described below, I disagree with Petitioner’s conclusions and the Boards’
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`preliminary findings regarding anticipation and obviousness. Specifically, it
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`is my opinion that the challenged claims of the Abraxis Patents are not
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`anticipated by or obvious over the cited prior art references.
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`39.
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`It is my opinion that the challenged claims are not anticipated by Desai
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`because it does not disclose, either expressly or inherently, the “about 9:1”
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`or “9:1” ratio of albumin to paclitaxel in the final product that is present as a
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`claim limitation in all the claims of the Abraxis Patents.
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`40.
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`It is further my opinion that the challenged claims are not rendered obvious
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`by any combination of prior art presented by Petitioner, at least, because:
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` The cited references do not disclose the “about 9:1” or “9:1” ratio of
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`albumin to paclitaxel in the final product that is present in all the
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`challenged claims of the Abraxis Patents;
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` The claimed albumin to paclitaxel ratio of the final pharmaceutical
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`15
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`Abraxis EX2066
`Cipla Ltd. v. Abraxis Bioscience, LLC
`IPR2018-00162; IPR2018-00163; IPR2018-00164
`Page 18 of 141
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`Filed on behalf of: Abraxis Biosciences, LLC
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`product is not inherent in the cited references; and
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` A POSA would not have combined the cited references in such a way
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`as to arrive at the challenged claims of the Abraxis Patents.
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`1.
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`B.
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`The patents in suit are not anticipated by Desai (GROUND I)
`Desai does not literally disclose a ratio of “about 9:1” or
`“9:1”
` I understand that the Board relied upon Desai in instituting the IPRs for
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`41.
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`claims 1-9 and 11-12 of the ’788 patent, claims 1-12 of the ’536 patent, and
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`1-19 and 21-48 of the ’229 patent. I have reviewed Petitioner’s Ground I
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`challenge and the materials it relies on, including Desai. I have also
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`reviewed the Board’s Institution Decisions in the Actavis IPRs. I do not
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`agree with the Board’s preliminary findings or the Petitioner’s assertions
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`that Desai anticipates any claims of the Abraxis Patents.
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`42. Petitioner relied solely on Desai’s Example 1 in its attempt to demonstrate
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`that Desai disclosed the albumin-paclitaxel weight ratio. (’229 Pet. 26; ’788
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`Pet. 26; ’536 Pet. 27)3. In Example 1, “30 mg paclitaxel is dissolved in 3.0
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`3 ’229 Pet. refers to Cipla’s Petition for Inter Partes Review in IPR2018-
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`00164. ’788 Pet. refers to Cipla’s Petition for Inter Partes Review in IPR2018-
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`16
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`Abraxis EX2066
`Cipla Ltd. v. Abraxis Bioscience, LLC
`IPR2018-00162; IPR2018-00163; IPR2018-00164
`Page 19 of 141
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`Filed on behalf of: Abraxis Biosciences, LLC
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`ml methylene chloride,” which “was added to 27.0 ml of human serum
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`albumin solution (1% w/v).” (EX1006, 62; ’229 Pet. 26; ’788 Pet. 26; ’536
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`Pet. 27.) This Example provides a starting albumin/paclitaxel ratio of 9:1.
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`43.
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`I understand that to anticipate the claims, each claim limitation must be
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`present in the cited reference. I disagree with the anticipation position taken
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`by Petitioner and do not agree with the Board’s preliminary findings in its
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`Actavis IPR Institution Decisions. Desai does not disclose a pharmaceutical
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`composition for injection comprising albumin-paclitaxel nanoparticles
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`wherein the weight ratio of albumin to paclitaxel in the composition is
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`“about 9:1” as reflected in claims 1-9 and 12 of the ’788 patent, claims 1-5,
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`6-9 and 10-16 of the ’536 patent, and claims 1-3, 5-8, 10-16, 18-24, 26-31,
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`32-36, 37-39, and 41-48 of the ’229 patent and furthermore, Desai does not
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`disclose a ratio of “1:1 to 9:1” as reflected in claim 11 of the ’788 patent,
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`claims 5 and 9 of the ’536 patent, and claims 4, 9, 13, 17, 25, 27, 31, 36, 40
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`and 44 of the ’229 patent.
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`
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`44. As noted above, Petitioner relied upon Example 1 of Desai as producing a
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`00162. ’536 Pet. refers to Cipla’s Petition for Inter Partes Review in IPR2018-
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`00163.
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`17
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`Abraxis EX2066
`Cipla Ltd. v. Abraxis Bioscience, LLC
`IPR2018-00162; IPR2018-00163; IPR2018-00164
`Page 20 of 141
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`Filed on behalf of: Abraxis Biosciences, LLC
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`pharmaceutical composition for injection comprising albumin-paclitaxel
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`particles wherein the weight ratio of albumin to paclitaxel in the composition
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`is “about 1:1 to 9:1”. Example 1 of Desai provides the starting ratios of the
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`albumin and paclitaxel and does not provide the final ratio of the formulated
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`drug product. As such, Example 1 of Desai does not literally provide a
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`pharmaceutical composition having a final ratio of “about 1:1 to 9:1” or “1:1
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`to 9:1”. Since these claim limitations are absent from Example 1 of Desai,
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`Desai does not expressly anticipate the claims of the Abraxis Patents.
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`2.
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`Desai does not inherently disclose a ratio of 9:1
` I understand that a prior art reference does not anticipate a patent claim by
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`45.
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`inherency if the prior art does not necessarily meet every claim limitation.
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`46.
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`In my opinion, following the steps of Example 1 would not necessarily result
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`in the same recovery of both paclitaxel and albumin, which is required for
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`the starting ratio of the components to be the same as the final ratio. A
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`POSA would not expect the starting ratio of albumin-to-paclitaxel to be the
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`same as the final ratio. Paclitaxel is a relatively hydrophobic substance with
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`poor water solubility that would be preferentially lost during the steps of
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`18
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`Abraxis EX2066
`Cipla Ltd. v. Abraxis Bioscience, LLC
`IPR2018-00162; IPR2018-00163; IPR2018-00164
`Page 21 of 141
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`Filed on behalf of: Abraxis Biosciences, LLC
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`Example 14 in comparison to albumin, which is water soluble and is less
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`likely to be lost. Loss of paclitaxel can occur by a variety of phenomena,
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`processes, or mechanisms during manufacture, including epimerization or
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`other degradation or transformations, binding to processing vessels and other
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`equipment, and precipitation. (EX2001 ¶ 28; see, e.g., EX2028, 1224,
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`1231–35; EX2029, 3106–08; EX2030, 1295–97.)
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`47.
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`In view of the statements from sections (a)-(d) below, it is my opinion that
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`following the steps of Example 1 of Desai would not necessarily result in a
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`product having a final ratio of “about 1:1 to 9:1” or “1:1 to 9:1”. Since a
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`POSA would not expect the process of Example 1 t