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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`
`Amgen Inc.
`Petitioner
`
`v.
`
`AbbVie Biotechnology Ltd.
`Patent Owner
`
`_______________
`
`Case IPR: Unassigned
`Patent 8,916,158
`_______________
`
`DECLARATION OF DR. THEODORE W. RANDOLPH
`
`Ex. 1002 - Page 1 of 179
`
`AMGEN INC.
`Exhibit 1002
`
`

`

`
`
`TABLE OF CONTENTS
`
`I. MY QUALIFICATIONS ................................................................................ 1
`
`II.
`
`RELEVANT LAW .......................................................................................... 5
`
`A.
`
`B.
`
`Claim Interpretation .............................................................................. 5
`
`Anticipation Invalidity .......................................................................... 5
`
`C. Obviousness Invalidity .......................................................................... 5
`
`III. THE CLAIMED SUBJECT MATTER AND THE LEVEL OF
`ORDINARY SKILL ........................................................................................ 8
`
`A.
`
`B.
`
`The Subject Matter Claimed in the ’158 Patent ................................... 8
`
`Level of Ordinary Skill in the Art ....................................................... 12
`
`IV.
`
`INTERPRETATION OF THE ’158 PATENT CLAIMS ............................. 14
`
`A.
`
`B.
`
`The Claims of the ’158 Patent ............................................................. 14
`
`Construction of Claim Terms .............................................................. 15
`
`(1)
`
`(2)
`
`(3)
`
`(4)
`
`“stable” ......................................................................................16
`
`“IgG1 . . . antibody” ..................................................................17
`
`“antigen binding portion” .........................................................19
`
`“wherein the antibody comprises the light chain
`variable region and the heavy chain variable region
`of D2E7” ...................................................................................19
`
`V.
`
`STATE OF THE ART AS OF AUGUST 16, 2002 ...................................... 20
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`Protein Degradation ............................................................................. 21
`
`Formulation Considerations ................................................................ 25
`
`Buffer and Optimal pH ........................................................................ 31
`
`Tonicity Agent ..................................................................................... 36
`
`Surfactant ............................................................................................. 37
`
`General Guidance in the Art ................................................................ 43
`
`G. Guidance in the Art from Specific Protein and Antibody
`Formulations ........................................................................................ 45
`
`H.
`
`Formulations Containing D2E7 .......................................................... 55
`
`i
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`Ex. 1002 - Page 2 of 179
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`

`

`
`
`I.
`
`Converting Between Concentration Units .......................................... 56
`
`VI. CLAIMS 1-4, 9-18, AND 20-30 WOULD HAVE BEEN
`OBVIOUS OVER THE COMBINATION OF THE LAM
`PATENT AND THE BARRERA ARTICLE................................................ 59
`
`A.
`
`Claims 1 and 17 Would Have Been Obvious...................................... 59
`
`(1) Claim 1 Would Have Been Obvious Over the Lam
`Patent in View of the Barrera Article .......................................60
`
`(2) Claim 1 Would Have Been Obvious Over the
`Barrera Article in View of the Lam Patent ...............................64
`
`(3) Claim 17 Would Have Been Obvious Under Either
`Combination of the Lam Patent and the Barrera
`Article ........................................................................................69
`
`B.
`
`C.
`
`Claims 2-4, 9-18, and 20-30 Would Have Been Obvious .................. 70
`
`The Skilled Person Would Have Had a Reasonable
`Expectation of Success in Combining the Lam Patent and
`the Barrera Article to Arrive at the Claimed Formulation .................. 76
`
`VII. CLAIMS 1-4, 9-18, AND 20-30 ARE RENDERED OBVIOUS
`BY THE COMBINATION OF THE SALFELD AND
`HEAVNER PATENTS .................................................................................. 87
`
`A.
`
`Claims 1 and 17 Would Have Been Obvious...................................... 87
`
`(1) Claim 1 Would Have Been Obvious Over the
`Salfeld Patent in View of the Heavner Patent ..........................89
`
`(2) Claim 17 Would Have Been Obvious Over the
`Salfeld Patent in View of the Heavner Patent ..........................93
`
`B.
`
`C.
`
`Claims 2-4, 9-16, 18, and 20-30 Would Have Been
`Obvious................................................................................................ 93
`
`The Skilled Person Would Have Had a Reasonable
`Expectation of Success in Combining the Salfeld and
`Heavner Patents to Arrive at the Claimed Formulation .................... 105
`
`ii
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`Ex. 1002 - Page 3 of 179
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`VIII. THE ’158 PATENT CONTAINS NO EVIDENCE OF NON-
`OBVIOUSNESS .......................................................................................... 112
`
`IX. PROSECUTION HISTORY OF EUROPEAN
`COUNTERPART CONTAINS NO EVIDENCE OF
`UNEXPECTED RESULTS ......................................................................... 118
`
`A. AbbVie’s Arguments and Data Purportedly
`Distinguishing the Salfeld Patent Do Not Demonstrate
`Nonobviousness ................................................................................. 122
`
`B.
`
`AbbVie’s Arguments and Data Purportedly
`Distinguishing the Barrera Article Do Not Demonstrate
`Non-obviousness ............................................................................... 141
`
`X.
`
`CROSS EXAMINATION AND OATH ..................................................... 147
`
`
`
`
`
`iii
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`Ex. 1002 - Page 4 of 179
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`
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`DECLARATION OF DR. THEODORE W. RANDOLPH
`
`I, Theodore W. Randolph, Ph.D. declare that:
`
`1. My name is Theodore W. Randolph.
`
`2.
`
`I understand that I am submitting this declaration in support of a
`
`petition that Amgen Inc., is filing in the U.S. Patent and Trademark Office seeking
`
`inter partes review of U.S. Patent No. 8,916,158 B2 (the ’158 patent, Ex. 1001).
`
`I. MY QUALIFICATIONS
`
`3.
`
`I am the Gillespie Professor of Bioengineering in the Department of
`
`Chemical and Biological Engineering at the University of Colorado (“Colorado”)
`
`in Boulder, CO.
`
`4. My education experience is summarized as follows:
`
`(a)
`
`I received a B.S. degree in Chemical Engineering from the
`
`University of Colorado, Boulder in 1983.
`
`(b)
`
`I received a Ph.D. in Chemical Engineering from the University
`
`of California, Berkeley in 1987.
`
`5. My professional experience is summarized as follows:
`
`1
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`Ex. 1002 - Page 5 of 179
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`
`(a)
`
`From 1987-1989, I worked as a Chemical
`
`Engineer/Collaborateur Scientifique at the Swiss Federal Institute of
`
`Technology in Lausanne, Switzerland.
`
`(b) From 1989-1993, I was an Assistant Professor, and then an
`
`Associate Professor in the Department of Chemical Engineering at Yale
`
`University, in New Haven CT.
`
`(c)
`
`Since 1993, I have been continuously employed as an Associate
`
`Professor, and then a Full Professor at the University of Colorado, in
`
`Boulder, CO.
`
`(d)
`
`In 1997, I also was named a Co-Director of the University of
`
`Colorado Center for Pharmaceutical Biotechnology at the University of
`
`Colorado.
`
`(e)
`
`For the past 21 years, my research at the University of Colorado
`
`has involved the stabilization and formulation of therapeutic proteins. In
`
`particular, I study how protein formulation variables, such as protein type
`
`and concentration, excipient type and concentration, and ionic strength, as
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`well as process variables (e.g., agitation) interact to stabilize or destabilize
`
`proteins.
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`2
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`Ex. 1002 - Page 6 of 179
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`
`6.
`
`A copy of my latest curriculum vitae (CV) is attached as Appendix A,
`
`and it provides a comprehensive description of my academic and employment
`
`history.
`
`7.
`
`I have been an expert in the field of pharmaceutical formulations
`
`containing proteins, such as aqueous liquid protein formulations, since before
`
`August 16, 2002. By August 16, 2002, I had authored several review articles
`
`describing the effect of various ingredients on the stability of proteins in
`
`formulations, including the effect of various ingredients on protein formulations,
`
`and had prepared many stable formulations containing proteins. See, e.g.,
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`Carpenter et al., Pharmaceutical Research (1997) 14(8):969-975 (Ex. 1007).
`
`8.
`
`Throughout the remainder of this declaration, I may refer to the field
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`of pharmaceutical formulations containing proteins (including liquid aqueous
`
`formulations of antibodies) as the relevant field or the relevant art. In formulating
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`my opinions, I have relied upon my training, knowledge, and experience in the
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`relevant art.
`
`9.
`
`I make this declaration in my personal capacity and not on behalf of
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`Amgen Inc.
`
`10.
`
`I have been retained by Amgen Inc. as an expert in the relevant field
`
`to provide my opinions regarding the subject matter claimed in the ’158 patent.
`
`3
`
`Ex. 1002 - Page 7 of 179
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`
`11.
`
`I am being compensated for my time at my normal, hourly consulting
`
`rate. My compensation is not dependent on, and in no way affects, the substance of
`
`my statements in this declaration.
`
`12.
`
`I own 364 shares of stock in Amgen (NASDAQ: AMGN), 116 shares
`
`of stock in AbbVie Inc. (NYSE: ABBV), and 112 shares of stock in Abbott
`
`(NYSE: ABT). My 364 shares of Amgen stock is valued at about $59,000. My 116
`
`shares of AbbVie stock is valued at about $8,100. My 112 shares of Abbott stock is
`
`valued at about $5,600.These stock ownership interests in no way affect the
`
`substance of my statements in this declaration.
`
`13. Neither Amgen nor Abbott nor AbbVie currently sponsors research in
`
`my laboratory. Amgen has previously sponsored research in my laboratory, which
`
`resulted in the publications, which are listed in my CV as numbers 31, 84, 88, 90,
`
`93, 95, 102, 105, 106, 116, 118, 120, 123, 124, 129, 130, 133, 134, 137, 138, 147,
`
`148, 150, 151, 155, 167, 179, 201. See Appendix A. Abbott also has previously
`
`sponsored research in my laboratory, which resulted in publications listed in my
`
`CV as numbers 188, 202, and 205. These past sponsorships in no way affect the
`
`substance of my statements in this declaration.
`
`14. The Exhibits referred to throughout this document are listed in
`
`Appendix B.
`
`4
`
`Ex. 1002 - Page 8 of 179
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`

`

`
`II. RELEVANT LAW
`
`15.
`
`I am not an attorney. For the purposes of this declaration, I have been
`
`informed about certain aspects of the law that are relevant to my opinions.
`
`A. Claim Interpretation
`
`16.
`
`I have been informed that, in an inter partes review, the claims of a
`
`patent should be read in light of the specification and teachings in the underlying
`
`patent. I understand this means that the words of the claims are analyzed from the
`
`perspective of a person having ordinary skill in the art and meaning that person
`
`would give them in the context of the underlying patent when the words are used
`
`as they ordinarily are used. I also understand, however, that the Patent Office could
`
`determine that the inventors specifically defined a particular claim term in the
`
`patent (which I understand is referred to as “lexicography”), in which case that
`
`definition could control.
`
`B. Anticipation Invalidity
`
`17.
`
`I have been informed and understand that a patent claim is anticipated
`
`(not novel) and, therefore, invalid if a prior art document (reference) discloses all
`
`the features of the claim, expressly or inherently.
`
`C. Obviousness Invalidity
`
`18.
`
`I have been informed and understand that if a patent claim is novel, it
`
`can be invalid if it is considered to have been obvious to a person of ordinary skill
`
`5
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`Ex. 1002 - Page 9 of 179
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`in the art at the time the application was filed. This means that, even if all of the
`
`requirements of a claim are not found in a single prior art document, the claim is
`
`not patentable if the differences between the subject matter in the prior art and the
`
`subject matter in the claim would have been obvious to a person of ordinary skill in
`
`the art at the time the application was filed.
`
`19.
`
`I have been informed that a person of ordinary skill in the art at the
`
`time the application was filed would be a hypothetical person, who is presumed to
`
`know the contents of all relevant art at the time, with working experience in the
`
`relevant field.
`
`20.
`
`I have been informed and understand that a determination of whether
`
`a claim would have been obvious at the time the application (for patent) was filed
`
`is based upon several factors, including: (a) the level of ordinary skill in the art at
`
`the time the application was filed; (b) the scope and content of the prior art; and (c)
`
`what differences, if any, existed between the claimed invention and the prior art.
`
`21.
`
`I have been informed and understand that the teachings of two or
`
`more references may be combined in the same way as recited in the claims, if such
`
`a combination would have been obvious to one having ordinary skill in the art. In
`
`determining whether a combination or modification based on either a single
`
`6
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`Ex. 1002 - Page 10 of 179
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`

`

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`reference or multiple references would have been obvious, it is appropriate to
`
`consider, among other factors:
`
`(a) whether the teachings of the prior art references disclose known
`
`concepts combined in familiar ways, and when combined, would yield
`
`predictable results;
`
`(b) whether a person of ordinary skill in the art could implement a
`
`predictable variation, and would see the benefit of doing so;
`
`(c) whether the claimed elements represent one of a limited number
`
`of known design choices;
`
`(d) whether a person of ordinary skill would have recognized a
`
`reason to combine known elements in the manner described in the claim;
`
`(e) whether there is some teaching or suggestion in the prior art to
`
`make the modification or combination of elements claimed in the patent; and
`
`(f) whether the claims are the result of applying a known technique
`
`that had been used to improve a similar device or method in a similar way.
`
`22.
`
`I understand that reasons to combine prior art references can come
`
`from a variety of sources, not just the prior art itself or the specific problem the
`
`patentee was trying to solve. I also understand that the prior art references
`
`7
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`Ex. 1002 - Page 11 of 179
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`

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`themselves need not provide a specific hint or suggestion of the alteration needed
`
`to arrive at the claimed invention; the analysis may include recourse to logic,
`
`judgment, and common sense available to a person having ordinary skill in the art,
`
`who has ordinary creativity and is not an automaton.
`
`23.
`
`I understand that objective indicators may support a conclusion that an
`
`invention is nonobvious, such as, failure of others, unexpectedly superior results,
`
`perception in the industry, commercial success, and long-felt but unmet need. I
`
`also understand that objective indicators of nonobviousness are only applicable if
`
`they have some nexus to the subject matter in the claim that was not known in the
`
`prior art. I understand that this nexus includes a factual connection between the
`
`subject matter of the claim and the objective indicators alleged.
`
`24.
`
`I understand that in considering obviousness, it is important not to
`
`determine obviousness using the benefit of hindsight derived from the patent being
`
`considered.
`
`III. THE CLAIMED SUBJECT MATTER AND THE LEVEL OF
`ORDINARY SKILL
`
`A. The Subject Matter Claimed in the ’158 Patent
`
`25.
`
`I understand that the ’158 patent issued from a patent application filed
`
`August 6, 2014, and that August 16, 2002 is the earliest possible priority date for
`
`the subject matter claimed. I have been informed that the time period just before
`
`8
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`Ex. 1002 - Page 12 of 179
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`August 16, 2002, is relevant for considering the state of the art, the knowledge in
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`the art, and whether the claimed invention would have been obvious to a person
`
`having ordinary skill in the art.
`
`26.
`
`I have reviewed the specification, claims, and file history (Ex. 1008)
`
`of the ’158 patent. I am familiar with the subject matter disclosed in the ’158
`
`patent.
`
`27. The ’158 patent describes pharmaceutical formulations containing a
`
`protein, such as an antibody, suitable for therapeutic use to inhibit or counteract
`
`detrimental effects of human tumor necrosis factor alpha (“hTNFα”):
`
`This
`
`invention pertains
`
`to a
`
`liquid aqueous pharmaceutical
`
`formulation with a pH of about 4 to about 8 which contains a high
`
`protein concentration, including an antibody concentration ranging
`
`from about 1 to about 150 mg/ml, and has enhanced stability. This
`
`invention also pertains to a liquid aqueous pharmaceutical formulation
`
`for
`
`therapeutic use
`
`in a subject suffering from a condition
`
`characterized by detrimental TNFα activity. The formulation of the
`
`invention comprises the following constituents: an antibody which
`
`binds to human TNFα with high affinity, a low off rate and high
`
`neutralizing capacity; a buffer, which includes citric acid, sodium
`
`citrate, disodium phosphate dihydrate, and sodium dihydrogen
`
`phosphate dihydrate; tonicity agents, which include mannitol and
`
`9
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`Ex. 1002 - Page 13 of 179
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`
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`sodium chloride; a detergent, including polysorbate 80; and sodium
`
`hydroxide, for pH adjustment.
`
`Ex. 1001 at 6:54 to 7:2.
`
`28. Columns 13 through 15 of the ’158 patent describe various
`
`embodiments of the formulations containing antibodies. Generally, the aqueous
`
`formulation of the antibody includes: (1) a solution buffered to a pH ranging from
`
`about 4 to about 8 (adjustable by adding a sodium hydroxide solution), (2) a polyol
`
`that acts as a tonicity agent that may stabilize the antibody, and (3) a detergent (or
`
`surfactant) in an amount that reduces aggregation of the formulated antibody
`
`and/or minimizes the formation of particulates, and/or reduces adsorption. Id. at
`
`12:66 to 15:67.
`
`29. D2E7 is given as one example of an antibody that can be formulated
`
`according to the ’158 patent. Ex. 1001 at 3:30-33, 40-43, 48-51. Table 1 of the
`
`’158 patent describes a 0.8 ml formulation containing D2E7, a buffer, a polyol that
`
`acts as a tonicity agent, a surfactant, and other ingredients:
`
`10
`
`Ex. 1002 - Page 14 of 179
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`

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`
`
`Ex. 1001 at 15:5-34.
`
`
`
`30. The subject matter of the ’158 patent relates to pharmaceutical
`
`formulations containing a protein, such as an antibody (e.g., a D2E7 antibody). The
`
`11
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`Ex. 1002 - Page 15 of 179
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`’158 patent thus, relates to the field (or art) of designing pharmaceutical
`
`formulations containing proteins, including antibodies, such as liquid antibody
`
`formulations.
`
`B.
`
`Level of Ordinary Skill in the Art
`
`31. Due to my 25 years of research in the area of therapeutic protein
`
`formulations, I am an expert in the mechanisms by which protein formulation
`
`variables (e.g., concentration and type of excipients, protein type and
`
`concentration, solution ionic strength, agitation, and other process variables)
`
`interact to stabilize or destabilize proteins. In particular, and as evidenced by the
`
`publication list appended to my CV (Appendix A), I have studied mechanisms by
`
`which proteins aggregate and unfold in solution, and the thermodynamic and
`
`kinetic mechanisms by which surfactants and other excipients modulate these
`
`processes. See, e.g., Appendix A (citing, for example, references 21, 23, 27, 29-31,
`
`and 37-48); Bam et al. (1998) J Pharm Sci. 87(12):1554-9 (Ex. 1009); and Ex.
`
`1007.
`
`32.
`
`In my role as a Professor, I was and am responsible for supervising
`
`graduate students and post-doctoral researchers. Based on those roles, I am familiar
`
`with the level of skill encompassed by persons having ordinary skill in this art.
`
`12
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`Ex. 1002 - Page 16 of 179
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`
`
`33.
`
`I understand that a person having ordinary skill in the art is a
`
`hypothetical person who is presumed to be aware of all pertinent art, thinks along
`
`conventional wisdom in the art, and is a person of ordinary creativity. This person
`
`may also work as part of a multi-disciplinary team and draw upon not only his or
`
`her own skills, but also take advantage of certain specialized skills of others in the
`
`team, to solve a given problem.
`
`34. As of August 16, 2002, the education and experience level of a person
`
`having ordinary skill in the art who would be asked to design a pharmaceutical
`
`formulation, such as a formulation containing an antibody, was a person having a
`
`Pharm.D., or Ph.D. in biology, biochemistry, or chemistry. The person also would
`
`have had at least two years of experience preparing a stable formulation of proteins
`
`suitable for therapeutic use.
`
`35. As a skilled practitioner in the relevant field since before August 16,
`
`2002, I am qualified to provide an opinion as to what a person having ordinary
`
`skill in this art would have understood, known, or concluded as of August 16,
`
`2002.
`
`36.
`
`I have considered certain issues from the perspective of a person of
`
`ordinary skill in the art as of August 16, 2002. In my opinion, a person of ordinary
`
`skill in the art for the ’158 patent would have found the subject matter claimed
`
`13
`
`Ex. 1002 - Page 17 of 179
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`therein to be obvious, in view of the state of the art and disclosures in the prior art
`
`as of August 16, 2002. In formulating this opinion and my other opinions
`
`expressed herein, I reviewed the documents cited in Appendix B to this
`
`declaration, which are discussed below.
`
`IV.
`
`INTERPRETATION OF THE ’158 PATENT CLAIMS
`
`A. The Claims of the ’158 Patent
`
`37. The ’158 patent issued with one independent claim—claims 1:
`
`Claim 1. A stable liquid aqueous pharmaceutical
`
`formulation comprising
`
`(a) a human IgG1 anti-human Tumor Necrosis
`
`Factor alpha (TNFα) antibody, or an antigen-
`
`binding portion thereof, at a concentration of 20 to
`
`150 mg/ml,
`
`(b) a polyol,
`
`(c) a surfactant, and
`
`(d) a buffer system having a pH of 4 to 8,
`
`wherein the antibody comprises the light chain variable
`
`region and the heavy chain variable region of D2E7.
`
`14
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`Ex. 1002 - Page 18 of 179
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`

`

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`Ex. 1001 at 39:11-20. Claims 2-30 depend from claim 1. Human Tumor Necrosis
`
`Factor alpha (TNFα) is sometimes referred to by a shorthand abbreviation,
`
`“hTNFα.”
`
`38. Generally, dependent claims 2, 3, and 26 specify concentrations of the
`
`antibody or antigen binding portion thereof, and dependent claim 17 specifies the
`
`antibody is D2E7. Dependent claims 27-30 specify the buffer system of the
`
`formulation; dependent claims 4 and 18 specify the polyol is a sugar alcohol;
`
`dependent claims 14, 15, 23 and 24 specify the pH. Dependent claims 9-13 and 20-
`
`22 specify features of the surfactant, and dependent claims 16 and 25 specify the
`
`formulation is suitable for subcutaneous injection.
`
`B. Construction of Claim Terms
`
`39. The claims of the ’158 patent recite a number of terms that, while not
`
`expressly defined in the patent, have a well-known meaning to the skilled person in
`
`the relevant field (e.g., “concentration” or “subcutaneous injection”). Such terms
`
`may be defined with a commonly-referenced dictionary.
`
`40. The claims recite a number of terms that the specification of the ’158
`
`patent expressly defines such as, for example, “pharmaceutical formulation,”
`
`“polyol,” “nonreducing sugar,” and “buffer.” Ex. 1001 at 7:4 to 8:39. Other claim
`
`terms should be understood and construed as set forth below.
`
`15
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`Ex. 1002 - Page 19 of 179
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`

`

`
`
`(1)
`
`“stable”
`
`41. The preamble of each independent claim recites the term “stable” in
`
`the context of a “stable liquid aqueous pharmaceutical formulation.” A “stable”
`
`formulation is expressly defined as one “in which the antibody therein essentially
`
`retains its physical stability and/or chemical stability and/or biological activity
`
`upon storage.” Ex. 1001 at 7:23-25. Various exemplary storage conditions (time
`
`and temperature) are disclosed. See id. at 7:30-67. For example, the specification
`
`states that the formulation preferably is “stable at room temperature (about 30° C.)
`
`or at 40° C. for at least 1 month and/or stable at about 2-8° C. for at least 1 year for
`
`[sic, or] at least 2 years” Id. at 7:30-37. But, the skilled person would not
`
`understand the term “stable,” as used in the ’158 patent, to be limited to such a
`
`preference or to any period of time or any particular temperature. Thus, the skilled
`
`person would have read the phrase “stable formulation” as meaning a formulation
`
`“that retains its physical stability and/or chemical stability and/or biological
`
`stability upon storage” for any period of time, no matter how short. Id. at 7:23-25.
`
`For example, the skilled person would have read the phrase as meaning a
`
`formulation that retains its biological activity upon storage for a period of time
`
`sufficient for its intended use (e.g., immediate assaying, storage for an intermediate
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`process hold step, Phase I clinical trials, or commercial formulations), no matter
`
`how short.
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`16
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`Ex. 1002 - Page 20 of 179
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`(2)
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`“IgG1 . . . antibody”
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`42. The term “IgG1 . . . antibody” is recited in independent claim 1.
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`Generally, an antibody is a type of protein that is generated by the immune system
`
`and able to recognize and bind to an antigen with specificity. The term “antibody”
`
`is defined in the ’158 patent as referring to “immunoglobulin molecules comprised
`
`of four polypeptide chains, two heavy (H) chains and two light (L) chains
`
`interconnected by disulfide bonds.” Ex. 1001 at 9:37-40. This definition could
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`encompass any number of variations within the variable regions and/or constant
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`regions of each of the heavy chains and light chains.
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`(a) Generally, an IgG antibody molecule contains two identical
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`heavy chains and two identical light chains, in a complex that is held
`
`together by disulfide bonds. A generalized structure of an IgG antibody is
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`illustrated below:
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`17
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`Ex. 1002 - Page 21 of 179
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`
`.
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`(b) Each heavy chain is composed of a variable region (VH
`
`domain), shown in light blue color in the image above, and a longer constant
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`region, shown in dark blue color in the image above. Likewise, each light
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`chain is composed of a variable region (VL domain), shown in light green
`
`color in the image above, and a very short constant region, shown in dark
`
`green color in the image above. Each of the heavy and light chain variable
`
`regions contain antigen-binding sites at their distal end that are composed of
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`three hypervariable complementarity-determining regions (CDRs). The term
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`“IgG1 . . . antibody” encompasses any number of variations within the
`
`variable regions and/or constant regions. The heavy chain constant regions
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`are different among IgG isotypes, and would determine whether the antibody
`
`was an IgG1 isotype, for example.
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`18
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`Ex. 1002 - Page 22 of 179
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`
`(3)
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`“antigen binding portion”
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`43. The ’158 patent defines “antigen binding portion” of an antibody as
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`“one or more fragments of an antibody that retain the ability to specifically bind to
`
`an antigen (e.g., hTNFα).” Ex. 1001 at 9:58-61. The ’158 patent further identifies
`
`examples of such fragments, such as an isolated CDR. Id. at 9:61-10:7. Thus, the
`
`term “an antigen-binding portion” encompasses an antibody fragment that can be
`
`as small as one CDR. CDRs range in size from 5 amino acids to 17 amino acids.
`
`Johnson et al. Nucleic Acids Research (2000) 28(1):214-218 (Ex. 1010).
`
`(4)
`
`“wherein the antibody comprises the light chain variable
`region and the heavy chain variable region of D2E7”
`
`44.
`
`Instead of specifying sequences by SEQ ID NOs, the ’158 patent uses
`
`the broad phrase “the light chain variable region and the heavy chain variable
`
`region of D2E7.” This phrase is recited in independent claims 1 and 24. D2E7 is
`
`not expressly defined in the ’158 patent, but it is described in U.S. Patent No.
`
`6,090,382 (the “Salfeld patent,” Ex. 1005), which the ’158 patent incorporates by
`
`reference for its disclosure of antibodies and antigen-binding portions. Ex. 1001 at
`
`9:54-57 and 10:25-28. The Salfeld patent states that D2E7 has a light chain CDR3
`
`domain that includes the amino acid sequence of SEQ ID NO:3, and a heavy chain
`
`CDR3 domain that includes the amino acid sequence of SEQ ID NO:4. Ex. 1005 at
`
`2:59-63. The other amino acid residues in the variable regions are not defined in
`
`19
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`Ex. 1002 - Page 23 of 179
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`the Salfeld patent. Thus, a light (or heavy) chain “variable region of D2E7”
`
`encompasses a variable region with any number of mutations so long as the
`
`variable region retains the light (or heavy) chain CDR3.
`
`V.
`
`STATE OF THE ART AS OF AUGUST 16, 2002
`
`45. The science of designing parenteral protein formulations was well-
`
`established by August 16, 2002. By August 16, 2002, the skilled person would
`
`have understood that protein formulations should be stable and also should be
`
`isotonic when administered to patients. The skilled person would have known that
`
`the important excipients for achieving a stable and isotonic protein formulation
`
`included a buffer, a tonicity agent (e.g., a polyol), and often a surfactant. The
`
`skilled person would have understood how to select each of these excipients, and
`
`would have known to perform routine experiments to determine an appropriate
`
`concentration of the excipients that would result in a stable formulation. When
`
`developing a new protein (e.g., antibody) formulation, the skilled person would
`
`have merely selected from the standard, limited set of buffers, tonicity agents, and
`
`surfactants that were known to be safe and effective in similar pharmaceutical
`
`formulations, and determined an appropriate combination (including
`
`concentrations) through routine experimentation. When developing a new anti-
`
`TNFα antibody formulation, for example, the skilled person would have looked to
`
`known anti-TNFα antibody formulations or IgG formulations.
`
`20
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`Ex. 1002 - Page 24 of 179
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`
`A.
`
`Protein Degradation
`
`46. As of August 16, 2002, it was well known that protein molecules were
`
`prone to physical and chemical degradation in solution (e.g., denaturation,
`
`aggregation, fragmentation, isomerization, deamidation, oxidation, disulfide
`
`scrambling, oligomerization, and cross-linking). For example, Table 6 on page 13
`
`of Rational Design of Stable Protein Formulations: Theory and Practice (Carpenter
`
`and Manning, ed., April 30, 2002) (Ex. 1011), lists potential stability problems in
`
`protein formulations, potential causes, and possible solutions.
`
`Ex. 1011 at 13 (Table 6). See also, e.g., Manning et al., Pharm. Res. (1989)
`
`6(11):903-918 (Ex. 1012) (providing a summary of both physical and chemical
`
`
`
`21
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`Ex. 1002 - Page 25 of 179
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`decomposition pathways of proteins); Cleland et al., Crit. Rev. Ther. Drug Carrier
`
`Syst. (1993) 10(4):307-377 (Ex. 1013).
`
`47. Thus as of August 16, 2002, the skilled person would have understood
`
`that stabilization of protein pharmaceuticals was critical for the development of
`
`successful therapeutic products, and that the end use of a protein formulation
`
`dictated its stability requirements. For example, the skilled person would have
`
`understood that formulations intended as commercial products needed to be robust
`
`enough to withstand shipping stress and long term storage. However, formulations
`
`intended for more immediate use (e.g., immediate assaying or Phase I clinical
`
`trials) had less stringent stability requirements. Therefore, a first goal when
`
`developing a parenteral protein formulation was to ensure that the formulation was
`
`stable, the degree to which depended on whether the formulation was intended to
`
`be used immediately, shipped, or stored long term.
`
`48. As of August 16, 2002, the skilled person also would have understood
`
`that a parenteral pharmaceutical formulation should exhibit essentially the same
`
`osmotic pressure as human blood (i.e., 250 to 350 mOsm) when administered to a
`
`patient to minimize or prevent tissue damage at the injection site and, therefore,
`
`minimize pain at the injection site. See, e.g., U.S. Patent No. 6, 171,586 (the “Lam
`
`patent,” Ex. 1003) at 6:32-37; Pharmaceut