APPLICATION
`NUMBER
`61/770,421
`
`FILING or
`37l(c)DATE
`02/28/2013
`
`GRPART
`UNIT
`
`FIL FEE REC'D
`250
`
`32116
`WOOD, PHILLIPS, KATZ, CLARK & MORTIMER
`500 W. MADISON STREET
`SUITE 1130
`CHICAGO, IL 60661
`
`Ul\TfED STATES DEPA RTME'IT OF COMMERCE
`United States Patent and Trademark Office
`Adiliess. COMMISSIO'JER FOR PATENTS
`PO Box 1450
`Alexandria, Virgmia 22313-1450
`\VVi\V.USpto.gov
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`ATTY.DOCKET.NO
`COH10746P00031US
`
`TOT CLAIMS IND CLAIMS
`
`CONFIRMATION NO. 6868
`FILING RECEIPT
`
`11111111111111111 lllll ll]~!l]!~l!~l!~HUIH!i~ll lllll lllll lllll llll llll
`
`Date Mailed: 03/19/2013
`
`Receipt is acknowledged of this provisional patent application. It will not be examined for patentability and will
`become abandoned not later than twelve months after its filing date. Any correspondence concerning the application
`must include the following identification information: the U.S. APPLICATION NUMBER, FILING DATE, NAME OF
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`to the Notice, the USPTO will generate another Filing Receipt incorporating the requested corrections
`
`lnventor(s)
`
`Applicant( s)
`
`Mark Manning, Johnstown, CO;
`Robert W. Payne, Fort Collins, CO;
`
`Mark Manning, Johnstown, CO;
`Robert W. Payne, Fort Collins, CO;
`Power of Attorney:
`Steven Weinstock--30117
`
`If Required, Foreign Filing License Granted: 03/13/2013
`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is US 61 /770,421
`Projected Publication Date: None, application is not eligible for pre-grant publication
`Non-Publication Request: No
`Early Publication Request: No
`Title
`
`Stable Aqueous Formulations of Adalimumab
`
`Statement under 37 CFR 1.55 or 1.78 for AIA (First Inventor to File) Transition Applications:
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`PROTECTING YOUR INVENTION OUTSIDE THE UNITED STATES
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`Since the rights granted by a U.S. patent extend only throughout the territory of the United States and have no
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`page 1 of 3
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`1 of 53
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`Fresenius Kabi
`Exhibit 1009
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`

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`Almost every country has its own patent law, and a person desiring a patent in a particular country must make an
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`LICENSE FOR FOREIGN FILING UNDER
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`Title 35, United States Code, Section 184
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`Title 37, Code of Federal Regulations, 5.11 & 5.15
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`The grant of a license does not in any way lessen the responsibility of a licensee for the security of the subject matter
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`3 of 53
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`Exhibit 1009
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`

`

`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (11-08)
`Approved for use through 05/3112015. 0MB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid 0MB control number
`Provisional Application for Patent Cover Sheet
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53(c)
`
`lnventor(s)
`
`Inventor 1
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`Mark
`
`Inventor 2
`
`Manning
`
`Johnstown
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`Robert
`
`W.
`
`Payne
`
`Fort Collins
`
`State
`
`co
`
`State
`
`co
`
`Remove
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`generated within this form by selecting the Add button.
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`I
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`Add
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`I
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`Title of Invention
`
`Stable Aqueous Formulations of Adalimumab
`
`Attorney Docket Number (if applicable)
`
`COH10746P00031US
`
`Correspondence Address
`
`Direct all correspondence to (select one):
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`(!) The address corresponding to Customer Number
`
`0 Firm or Individual Name
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`Customer Number
`
`32116
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`The invention was made by an agency of the United States Government or under a contract with an agency of the United
`States Government.
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`(!) No.
`0 Yes, the name of the U.S. Government agency and the Government contract number are:
`
`EFS - Web 1.0.1
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`4 of 53
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`

`

`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (11-08)
`Approved for use through 05/3112015. 0MB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid 0MB control number
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`Entity Status
`Applicant claims small entity status under 37 CFR 1.27
`0 Yes, applicant qualifies for small entity status under 37 CFR 1.27
`(!) No
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`Warning
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`numbers (other than a check or credit card authorization form PTO-2038 submitted for payment purposes) is never required
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`Signature
`
`Please see 37 CFR 1.4(d} for the form of the signature.
`
`Signature
`
`/Steven F. Weinstock/
`
`Date (YYYY-MM-DD}
`
`2013-02-28
`
`First Name
`
`Steven
`
`Last Name
`
`Weinstock
`
`Registration Number
`(If appropriate)
`
`30117
`
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`6 of 53
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`

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`Stable Aqueous Formulations of Adalimumab
`
`COH10746P00031US
`
`Field of the Invention
`
`The present
`
`invention relates
`
`to aqueous pharmaceutical compositions
`
`suitable for long-term storage of adalimumab, methods of manufacture of the
`
`5
`
`compositions, methods of their administration, and kits containing the same.
`
`Background of the Invention
`
`Tumor necrosis factor alpha (TNFa) is a naturally occurring mammalian
`
`cytokine produced by various cell types, including monocytes and macrophages in
`
`response to endotoxin or other stimuli. TNFa is a major mediator of inflammatory,
`
`10
`
`immunological, and pathophysiological reactions (Grell, M., et al. (1995) Cell, 83:
`
`793-802).
`
`Soluble TNFa is formed by the cleavage of a precursor transmembrane
`
`protein (Kriegler, et al. (1988) Cell 53: 45-53), and the secreted 17 kDa polypeptides
`assemble to soluble homotrimer complexes (Smith, et al. (1987), J. Biol. Chem. 262:
`6951-6954; for reviews of TNF, see Butler, et al. (1986), Nature 320:584; Old (1986),
`
`15
`
`Science 230: 630). These complexes then bind to receptors found on a variety of
`
`cells. Binding produces an array of pro-inflammatory effects, including (i) release of
`
`other pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, and IL-1, (ii) release
`
`of matrix metalloproteinases and (iii) up-regulation of the expression of endothelial
`
`20
`
`adhesion molecules, further amplifying the inflammatory and immune cascade by
`
`attracting leukocytes into extravascular tissues.
`
`There are many disorders associated with elevated levels of TNFa. For
`
`example, TNFa has been shown to be up-regulated in a number of human diseases,
`
`including chronic diseases such as rheumatoid arthritis (RA), inflammatory bowel
`
`25
`
`disorders, including Crohn's disease and ulcerative colitis, sepsis, congestive heart
`
`failure, asthma bronchiale and multiple sclerosis. TNFa is also referred to as a pro(cid:173)
`
`inflammatory cytokine.
`
`Physiologically, TNFa is also associated with protection from particular
`
`infections (Cerami. et al. (1988), lmmunol. Today 9:28). TNFa is released by
`
`30 macrophages that have been activated by lipopolysaccharides of Gram-negative
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`- 1 -
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`COH10746P00031US
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`bacteria. As such, TNFa appears to be an endogenous mediator of central
`
`importance involved in the development and pathogenesis of endotoxic shock
`
`associated with bacterial sepsis.
`
`Adalimumab (Humira®, Abbott Corporation) is a recombinant human lgG1
`
`5 monoclonal antibody specific for human TNF. This antibody is also known as D2E7.
`
`Adalimumab consists of 1330 amino acids and has a molecular weight of
`
`approximately 148 kilodaltons. Adalimumab has been described and claimed in U.S.
`
`Pat. No. 6,090,382, the disclosure of which is hereby incorporated by reference in its
`
`entirety. Adalimumab is usually produced by recombinant DNA technology in a
`
`10 mammalian cell expression system, such as, for example, Chinese Hamster Ovary
`
`cells. Adalimumab binds specifically to TNFa and neutralizes the biological function
`
`of TNF by blocking its interaction with the p55 and p75 cell surface TNF receptors.
`
`Various formulations of adalimumab are known in the art. See, for example,
`
`U.S. Patent 8,216,583 B2. However, there is still a need for additional stable liquid
`
`15
`
`formulations of adalimumab that allow its long term storage without substantial loss
`
`of effectiveness.
`
`Summary of the Invention
`
`The invention provides stable aqueous formulations comprising adalimumab
`
`that allow its long term storage.
`
`20
`
`In a first embodiment, the invention provides a stable aqueous pharmaceutical
`
`composition comprising adalimumab; a stabilizer comprising at least one member
`
`selected from the group consisting of a polyol and a surfactant; and a buffer selected
`
`from the group consisting of citrate, phosphate, succinate, histidine, tartrate and
`
`maleate, wherein said composition has a pH of about 4 to about 8 and preferably
`
`25
`
`about 5 to about 6, and wherein said buffer does not comprise a combination of
`
`citrate and phosphate.
`
`In this embodiment, the stabilizer preferably comprises both
`
`polyol and surfactant.
`
`In a second embodiment, utilizing a single buffer system, the invention
`
`provides a stable aqueous pharmaceutical composition comprising adalimumab, a
`
`30
`
`polyol, a surfactant, and a buffer system comprising a single buffering agent, said
`
`single buffering agent being selected from citrate, phosphate, succinate, histidine,
`
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`COH10746P00031US
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`tartrate or maleate, but not including combinations of the foregoing; wherein the
`
`formulation has a pH of about 4 to 8, and preferably about 5 to about 6. Histidine
`
`and succinate are particularly preferred for use as single buffering agents.
`
`In a
`
`third embodiment,
`
`the
`
`invention provides a stable aqueous
`
`5
`
`pharmaceutical composition comprising adalimumab, a stabilizer comprising at least
`
`one member selected from a polyol and a surfactant, wherein said composition has a
`
`pH of about 4 to about 8, and preferably about 5 to about 6, and wherein said
`
`composition is substantially free of a buffer.
`
`In a
`
`fourth embodiment,
`
`the
`
`invention provides a stable aqueous
`
`10
`
`pharmaceutical composition comprising adalimumab, a polyol, and a buffer selected
`
`from the group consisting of citrate, phosphate, succinate, histidine, tartrate and
`
`maleate, wherein said composition has a pH of about 4 to about 8 and preferably
`
`about 5 to about 6, and wherein said composition is free or substantially free of a
`
`surfactant. Preferably, the composition (i) does not contain the buffer combination of
`
`15
`
`citrate and phosphate; and (ii) the buffer is at least one member selected from the
`
`group consisting of histidine and succinate; and (iii) the polyol is selected from the
`
`group consisting of sorbitol and trehalose.
`
`In a fifth embodiment, the invention provides a stable aqueous pharmaceutical
`
`composition comprising adalimumab, a surfactant, and a buffer selected from the
`
`20
`
`group consisting of citrate, phosphate, succinate, histidine, tartrate and maleate,
`
`wherein said composition has a pH of about 4 to 8 and preferably about 5 to about 6,
`
`and wherein said composition is substantially free of polyol. Preferably, the
`
`composition (i) does not contain the buffer combination of citrate and phosphate; and
`
`(ii) the buffer is at least one member selected from the group consisting of histidine
`
`25
`
`and succinate.
`
`In each of the five embodiments discussed above, the composition may
`
`optionally further comprise a stabilizer selected from the group consisting of an
`
`amino acid, a salt, ethylenediaminetetraacetic acid (EDTA) and a metal ion. The
`
`amino acid stabilizer may be selected from the group consisting of glycine, alanine,
`
`30
`
`glutamate, arginine and methionine. The salt stabilizer may be selected from the
`
`group consisting of sodium chloride and sodium sulfate. The metal ion stabilizer
`
`may be selected from the group consisting of zinc, magnesium and calcium.
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`COH10746P00031US
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`Preferably, adalimumab formulations containing the stabilizers mentioned above also
`
`do not contain buffer systems in which phosphate buffer and citrate buffer are
`
`present in combination. Most preferably (i) the optional additional stabilizer present
`
`in this embodiment is not sodium chloride, and comprises at least one of arginine
`
`5
`
`and glycine; (ii) the buffer, when present, contains no citrate and phosphate
`
`combination but is instead at least one of histidine and succinate; and (iii) the
`
`stabilizer when it includes a polyol is preferably not mannitol, but is instead selected
`
`from trehalose and sorbitol.
`
`In the foregoing embodiments, where the above referenced stabilizers may be
`
`10
`
`included in the formulations, it is further discovered that satisfactory stabilization can
`
`be attained when such stabilizers are used in place of both polyol and surfactant and
`
`hence stabilized formulations of the present invention can be free or substantially
`
`free of both polyol and surfactant. Accordingly, in a sixth embodiment, the invention
`
`provides a stable aqueous pharmaceutical composition comprising adalimumab,
`
`15
`
`optionally a buffer, a stabilizer selected from the group consisting of an amino acid, a
`
`salt, EDTA, and a metal ion, and wherein said composition has a pH of about 4 to
`
`about 8, and preferably 5 to about 6, and wherein said composition is either
`
`substantially free of both polyol and surfactant. When buffer is present in this
`
`embodiment, it is especially preferred that (i) the buffer not include the combination
`
`20
`
`of citrate and phosphate; (ii) the buffer is selected from the group consisting of
`
`histidine and succinate; and (iii) the stabilizer does not comprise sodium chloride, but
`
`instead is at least one member selected from the group consisting of arginine and
`
`glycine.
`
`Important aspects of the present invention in certain embodiments include (i)
`
`25
`
`that sorbitol and trehalose are discovered to be significantly better stabilizers of
`
`adalimumab formulations than mannitol; (ii) arginine and glycine are discovered to
`
`be significantly better stabilizers of adalimumab formulations than sodium chloride;
`
`and; (iii) when buffers are used in
`
`the formulation,
`
`it is discovered that the
`
`combination of citrate and phosphate is surprisingly significantly poorer in stabilizing
`
`30
`
`adalimumab than other buffers such as succinate, histidine, phosphate and tartrate.
`
`The relatively poor performance of the buffer combination of citrate and phosphate is
`
`surprising considering
`
`the apparent
`
`importance attributed
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`to
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`the use of a
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`citrate/phosphate combined buffer in U.S Patent 8,216,583. To the contrary, we
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`have now found that a phosphate/citrate buffer combination is not an optimal choice
`
`for obtaining a stabilized adalimumab formulation.
`
`Preferably, a polyol is a sugar alcohol; and even more preferably, the sugar
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`alcohol is selected from the group consisting of mannitol, sorbitol and trehalose.
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`5
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`However, as between mannitol and sorbitol, the invention has discovered, as noted
`
`above, a distinct stabilization advantage in using sorbitol or trehalose instead of
`
`mannitol. Mannitol has been found to be a poorer stabilizer than sorbitol or trehalose
`
`in an adalimumab formulation.
`
`Preferably, a surfactant is a polysorbate or poloxamer; and even more
`
`10
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`preferably polysorbate 80 or Pluronic F-68.
`
`These and other aspects will become apparent from the following description
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`of the various embodiments, although variations and modifications therein may be
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`affected without departing from the spirit and scope of the novel concepts of the
`
`disclosure.
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`15
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`It is to be understood that both the foregoing general description and the
`
`following detailed description are exemplary and explanatory only and are not
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`restrictive of the invention, as claimed.
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`DETAILED DESCRIPTION OF THE INVENTION
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`Various embodiments of the invention are now described in detail. As used in
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`20
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`the description and throughout the claims, the meaning of "a", "an", and "the"
`
`includes plural reference unless the context clearly dictates otherwise. Also, as used
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`in the description and throughout the claims, the meaning of "in" includes "in" and
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`"on" unless the context clearly dictates otherwise. Additionally, some terms used in
`
`this specification are more specifically defined below.
`
`25 DEFINITIONS
`
`The terms used in this specification generally have their ordinary meanings in
`
`the art, within the context of the invention, and in the specific context where each
`
`term is used. Certain terms that are used to describe the invention are discussed
`
`below, or elsewhere in the specification, to provide additional guidance to the
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`30
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`practitioner regarding the description of the invention. Synonyms for certain terms
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`are provided. A recital of one or more synonyms does not exclude the use of other
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`synonyms. The use of examples anywhere in this specification including examples
`
`of any terms discussed herein is illustrative only, and in no way limits the scope and
`
`meaning of the invention or of any exemplified term. The invention is not limited to
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`5
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`the various embodiments given in this specification.
`
`Unless otherwise defined, all technical and scientific terms used herein have
`
`the same meaning as commonly understood by one of ordinary skill in the art to
`
`which this invention pertains. In the case of conflict, the present document, including
`
`definitions will control.
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`10
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`"Around," "about" or "approximately" shall generally mean within 20 percent,
`
`within 10 percent, within 5, 4, 3, 2 or 1 percent of a given value or range. Numerical
`
`quantities given are approximate, meaning that the term "around," "about" or
`
`"approximately" can be inferred if not expressly stated.
`
`The term "adalimumab"
`
`is synonymous with
`
`the active pharmaceutical
`
`15
`
`ingredient in Humira® as well as biosimilar or bio-better variants thereof.
`
`It is a
`
`recombinant human lgG1 monoclonal antibody specific for human TNF. Adalimumab
`
`is also known as D2E7. Adalimumab has two light chains, each with a molecular
`
`weight of approximately 24 kilodaltons (kDa) and two lgG1 heavy chains each with a
`
`molecular weight of approximately 49 kDa. Each light chain consists of 214 amino
`
`20
`
`acid residues and each heavy chain consists of 451 amino acid residues. Thus,
`
`adalimumab consists of 1330 amino acids and has a total molecular weight of
`
`approximately 148 kDa. The term adalimumab is also intended to encompass so(cid:173)
`
`called bio-similar or bio-better variants of the adalimumab protein used
`
`in
`
`commercially available Humira. For example, a variant of commercial Humira® may
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`25
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`be acceptable to the FDA when it has essentially the same pharmacological effects
`
`as commercially available Humira, even though it may exhibit certain physical
`
`properties, such as glycosylation profile, that may be similar if not identical to
`
`Humira®.
`
`For the purposes of the present application, the term "adalimumab" also
`
`30
`
`encompasses adalimumab with minor modifications in the amino acid structure
`
`(including deletions, additions, and/or substitutions of amino acids) or in
`
`the
`
`glycosylation properties, which do not significantly affect the function of the
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`polypeptide. The term "adalimumab" encompasses all forms and formulations of
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`Humira®, including but not limited to concentrated formulations, injectable ready-to(cid:173)
`
`use formulations;
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`formulations reconstituted with water, alcohol, and/or other
`
`ingredients, and others.
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`5
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`The term "human TNFa" (which may be abbreviated as hTNFa, or simply
`
`hTNF), as used herein, is intended to refer to a human cytokine that exists as a 17
`
`kD secreted form and a 26 kD membrane associated form, the biologically active
`
`form of which is composed of a trimer of noncovalently bound 17 kD molecules. The
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`structure of hTNFa is described further in, for example, Pennica, D., et al. (1984)
`
`1