WO 2007/084765
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`PCT/US2007/001649
`
`and/or fostering development of a more favorable environment in the host organism (Kotwal,
`GJ, Immunology Today, 21(5), 242-248, 2000). VCCPS areamong these proteins. Poxvirus
`complement control proteins are members of the complement control protein (CCP) superfamily
`and typically contain 4 SCR modules. These proteins possess features that make them
`
`particularly advantageous for treatment and prevention ofmacular degeneration related
`conditions and for treatment and prevention of choroidal neovascularization.
`[00180]
`Thus in certain embodiments of the invention one or both of the therapeutic agents is
`a poxvirus complement control protein (PVCCP). The PVCCP can comprise a sequence
`encoded by, e.g., vaccinia virus, variola major virus, variola minor virus, cowpox virus,
`monkeypox virus, ectromelia virus, rabbitpox virus, myxoma virus, Yaba—like disease virus, or
`swinepox virus. In other embodiments the VCCP is-a herpesvirus complement control protein
`(HVCCP). The HVCCP can comprise a sequence encoded by aMacacafiJs-cata rhadinovirus,
`cercopithecine herpesvirus 17, or human herpes virus 8. In other embodiments the HVCCP
`
`comprises a sequence encoded by herpes simplex virus saimiri ORF 4 or ORF 15 (Albrecht, JC.
`& Fleckenstein, B., J. Virol., 66, 3937-3940, 1992; Albrecht, J., et al., Virology, 190, 527—530,
`1 992).
`
`The VCCP may inhibit the classical complement pathway, the alternate complement
`[00181]
`pathway, the lectin pathway, or any combination of these. In certain embodiments of the
`
`invention the VCCP, e.g., a PVCCP, binds to C3b, C4b, or both. In certain embodiments of the
`invention the PVCCP comprises one or more putative heparin binding sites (K/R—X—K/R) and/or
`possesses an overall positive charge. Preferably the PVCCP comprises at least 3 SCR modules
`(e.g., modules 1-3), preferably 4 SCR modules. The PVCCP protein can be a precursor of a
`mature PVCCP (i-e., can include a signal sequence that is normally cleaved off when the protein
`is expressed in virus-infected cells) or. can be a mature form (i.e., lacking the signal sequence)-
`[00182] Vaccinia complement control protein (VCP) is a virus-encoded protein secreted from
`vaccinia infected cells. VCP is 244 amino acids in length, contains 4 SCRs, and is naturally
`produced by intracellular cleavage of a 263 amino acid precursor. VCP runs as an ~35 kD
`protein in a 12% SDS/polyacrylamide gel under reducing conditions and has a predicted
`molecular mass of about 28.6 kD. VCP is described in U.S. Patent Nos. 5,157,110 and
`6,140,472, and in Kotwal, GK, et al., Nature, 355, 176-178, 1988. Figures 3A and 3B show the
`sequence of the precursor and mature VCP proteins, respectively. VCP has been shown to
`inhibit the classical pathway of complement activation via its ability to bind to C3 and C4 and
`act as a cofactor for factor I mediated cleavage ofthese components as well as promoting decay
`of existing convertase (Kotwal, GK, et al., Science, 250, 827-830, 1990; McKenzie et al., .I
`
`50
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`Regeneron Exhibit 1002.0761
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`Infect. Dis, 1566, 1245-1250, 1992). It has also been shown to inhibit the alternative pathway
`
`by causing cleavage of C3b into iC3b and thereby preventing formation of the alternative
`
`pathway C3 convertase (Sahu, A, et al., J, Immunol, 160, 5596-5604, 1998). VCP thus blocks
`
`complement activation at multiple steps and reduces levels of the proinflammatory chemotactic
`factors C3a, C4a, and C5a.
`
`[00183]
`
`VCP also possesses the ability to strongly bind heparin in addition to heparan sulfate
`
`proteoglycans. VCP contains two putative heparin binding sites located in modules 1 and 4
`
`(Jha, P and Kotwal, GJ, and references therein). VCP is able to bind to the surface of
`
`endothelial cells, possibly via interaction with heparin and/or heparan sulfate at the cell surface,
`
`resulting in decreased antibody binding (Smith, SA, et al., J. Viral. , 74(12), 5659-5666, 2000).
`
`VCP can be taken up by mast cells and possibly persist in tissue for lengthy periods of time,
`
`thereby potentially prolonging its activity (Kotwal, G], et al., In GP. Talwat, et al. (eds), 10th
`
`International Congress of Immunology, Monduzzi Editore, Bologna, Italy, 1998)- In addition,
`
`VCP can reduce chemotactic migration of leukocytes by blocking chemokine binding
`
`(Reynolds, D, et al., in S- Jameel and L. Villareal (ed., Advances in animal virology. Oxford and
`
`IBN Publishing, New Delhi, India, 1999).
`
`[00184] Variola virus major and minor encode proteins that are highly homologous to VCP
`
`and are referred to as smallpox inhibitor of complement enzymes (SPICE) (Rosengard, AM, et
`
`al., Proc. Natl. Acad. Sci, 99(13), 8803—8813. U.S. Pat. No. 6,551,595). SPICE from various
`variola strains sequenced to date differs from VCP by about 5% (e. g., about 11 amino acid
`
`differences). Similarly to VCP, SPICE binds to C3b and C4b and causes their degradation,
`
`acting as a cofactor for factor I. However, SPICE degrades C3b approximately 100 times as fast
`
`as VCP and degrades C4b approximately 6 times as fast as VCP. The amino acid sequence of
`SPICE is presented in Figure 6 and can be described as follows. Referring to Figure 6, a signal
`
`sequence extends from amino acid 1 to about amino acid 19. Four SCRs extend from about
`amino acid 20 to amino acid 263. Each SCR is characterized by four cysteine residues. The four
`
`cysteine residues form two disulfide bonds in the expressed protein. The boundaries of each
`
`SCR are best defined by the first and fourth cysteine residues in the sequence that forms the
`
`disulfide bonds of the SCR. An invariant tryptophan residue is present between cysteine 3 and
`
`cysteine 4 of each SCR. SCRI extends from amino acid 20 or 21 to amino acid 81. Both
`
`residues are cysteines that may be‘involved in disulfide bonding. SCR2 extends from amino acid
`
`86 to amino acid 143. SCR3 extends from amino acid 148 to amino acid 201. SCR4 extends
`from amino acid 206 to amino acid 261. The SCRs include the complement binding locations of
`SPICE. SPICE or any of the portions thereof that inhibit complement activation, e.g., SPICE and
`
`51
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`SPICE—related polypeptides containing four SCRs, such as those described in US. Pat. No.
`
`6,551,595, are of use in the present invention.
`
`[00185]
`
`Complement control proteins from cowpox virus (referred to as inflammation
`
`modulatory protein, IMP) and monkeypox virus (referred to herein as monkeypox virus
`complement control protein, MCP) have also been identified and sequenced (Miller, CG, et 31.,
`Virology, 229, 126-133, 1997 and Uvarova, EA and Shchelkunov, SN, Virus Res., 81(1-2), 39-
`45, 2001). MCP differs from the other PVCCPs described herein in that it contains a truncation
`
`of the C~terminal portion of the fourth SCR.
`
`It will be appreciated that the exact sequence of complement control proteins
`[00186]
`identified in different Virus isolates may differ slightly. Such proteins fall within the scope of
`the present invention Complement control proteins from any such isolate may be used,
`provided that the protein has not undergone a mutation that substantially abolishes its activity.
`Thus the sequence of a VCCP such as SPICE or VCP may difi'er from the exact sequences
`presented herein or under the accession numbers listed in Table 1. It will also be appreciated
`that a number of amino acid alterations, e.g., additions, deletions, or substitutions such as
`
`conservative amino acid substitutions, may be made in a typical polypeptide such as a VCCP
`without significantly affecting its activity, such that the resulting protein is considered
`equivalent to the original polypeptide. For example, up to about 10% of the amino acids, or up
`to about 20% of the amino acids may frequently be changed without significantly altering the
`activity. Also, of course, domains known to have similar functions can be substituted for one
`
`another. Such domains may be found Within a single polypeptide (e.g., repeated domains) or
`within different, homologous polypeptides. The effect of any particular amino acid alteration(s)
`or domain substitutions can readily be determined.
`
`Figure 4 shows a sequence alignment of a variety of poxvirus complement control
`[00187]
`proteins from isolates of variola major and minor, vaccinia, cowpox virus, and monkeypox
`virus. Figure 5 shows a comparison of the SCR domain structure of a number of complement
`control proteins and fragments thereof, the number of K+R residues, %K+R residues, pI,
`number of putative heparin binding sites, and ability to inhibit homelysis (indicative of
`complement inhibiting activity) and/or bind to heparin.
`
`[00188] Without limitation, any of the viral polypeptides identified by accession number in
`Table 2 below is of use in various embodiments of the invention.
`
`52
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`Regeneron Exhibit 1002.0763
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`Table 2: Re resentative Viral Com lement Control Proteins
`[00189]
`
`
`
`AccessionW
`
`m_m—_mm_
`
`
`
`—W_—W
`m_—mmr_
`mum—W
`
`—_—mm_
`MIKE-W
`
`CAE00484W
`__Mmm_
`AASQQQBi Rhadinavirus_ (HerpesvirUS)
`Macaca fuscata rhadinovirus
`JM4
`
` Complement binding
`orotein ORF4
` Human herpes virus 8
`
`AABS2602 Herpesvirus
`Complement binding
`-rotein ORF4
`
`
`
`
`
`
`
`
`
`
`
`Cercopithecine herpesvirus 17
`
`NP_570746 Herpesvirus
`
`[00190]
`
`Compounds that Inhibit C5 Activation or Activity
`
`[00191]
`
`In certain embodiments the complement inhibitor inhibits activation of C5. For
`
`example, the complement inhibitor may bind to C5. Exemplary agents include antibodies,
`antibody fragments, polypeptides, small molecules, and aptamers. Exemplary antibodies are
`described in US. Pat. No. 6,534,058. Exemplary compounds that bind to and inhibit C5 are
`
`described in US. Pat. Pub. Nos. 20050090448 and 200601 15476. In certain embodiments the
`
`complement inhibitor is an antibody, small molecule, aptamer, or polypeptide that binds to
`substantially the same binding site on C5 as an antibody described in US. Pat. No. 6,534,058 or
`a peptide described in USSN 10/937,912. US. Pat. Pub. No. 20060105980 discloses aptamers
`that bind to and inhibit C5. Also of use are R'NAi agents that inhibit expression of C5 or CSR.
`[00192]
`In other embodiments the agent is an antagonist of a C5a receptor (CSaR).
`Exemplary C5a receptor antagonists include a variety of small cyclic peptides such as those
`described in US. Pat. No- 6,821,950; USSN 11/375,587; and/or PCT/USO6/0896O
`
`(W02006/099330).
`
`For example, the therapeutic agent may be a compound of general formula I below:
`
`'
`
`o
`
`N
`
`H
`
`N
`
`”i0
`
`53
`
`Regeneron Exhibit 1002.0764
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`

`

`WO 2007/084765
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`
`where A is H, alkyl, aryl, NHZ, NHalkyl, N(alkyl)2, NHaryl or NHacyl; B is an alkyl,
`[00193]
`aryl, phenyl, benzyl, naphthyl or indole group, or the side chain of a D— or L-amino acid selected
`from the group consisting ofphenylalanine, homophenylalanine, tryptophan, homotryptophan,
`tyrosine, and homotyrosine; C is the side chain of a D-, L- or homo—amino acid selected from the
`group consisting ofproline, alanine, leucine, valine, isoleucine, arginine, histidine, aspartate,
`glutamate, glutamine, asparagine, lysine, tyrosine, phenylalanine, cyclohexylalanine, norleucine,
`tryptophan, cysteine and methionine; D is the side chain of a D- or L-amino acid selected from
`the group consisting of cyclohexylalanine, homocyclohexylalanine, leucine, norleucine,
`homoleucine, homonorleucine and tryptophan; E is the side chain of a D- or L—amino acid
`selected from the group consisting of tryptophan and homotryptophan; F is the side chain of a
`D— or L-amino acid selected from the group consisting of arginine, homoarginine, lysine and
`homolysine or is one of the following side—chains
`
`—(CH2)nO—u
`
`NHze
`Jk
`
`NHR1
`
`
`_(CH2)n
`
`a
`
`NH2®
`Jk
`
`NHR1
`
`sea
`
`
`‘10th
`
`NJL
`
`- H
`
`NHR‘
`
`
`—(CH2),.
`
`8
`
`
`—(CH2)n
`
`[Ni
`
`NH2®
`
`NHR1
`
`8
`JK
`
`NHR1
`
`54
`
`Regeneron Exhibit 1002.0765
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`

`

`WO 2007/084765
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`
` J‘L
`—(CH2)n
`fl
`
`NHR1
`
`—(CHz)n—-NH3GB
`
`[00194]
`
`or another mimetic of an arginine side chain, where X is NCN, NNOz, CHNO; or
`
`NSOZNHz; n is an integer from 1 to 4, and R1 is H or an alkyl, aryi, CN, NHZ, OH, -—co—-
`
`CH2CH3, -—CO——CH3, -—CO—-CH2CH2CH3, --CO—-CH2 Ph, or «CO-Pb; and X1 is --(CH2)nNH--
`or (CH2); --S——, --(CH2)2 O--, --(CH2); 0-—, —-(CH2)3 -—, ——(CH2)4 —-, or ——CH2 COCI-IRNH——,
`
`where R is the side chain of any common or uncommon amino acid, and
`
`where n is an integer of from 1 to 4, e.g., 1, 2, 3, or 4.
`
`[00195]
`
`In certain embodiments of the invention F is one of the following side-chains:
`
`—(CH2)nO—u
`
`
`—-(CH2)n
`
`El
`
`
`——(<:H2)n
`
`M
`
`
`“(CH2)n
`
`S
`
`NH2®
`/”\
`
`NHR1
`
`NH2©
`Jk
`
`NHR1
`
`369
`
`NHR1
`
`NHze
`
`NHR1
`
`
`—(CH2)n
`
`a
`
`8
`JK
`
`NHR1
`
`55
`
`Regeneron Exhibit 1002.0766
`
`

`

`W
`
`O 2007/084765
`
`PCT/US2007/001649
`
`
`“03th If}:
`
`X
`Jk
`‘ NHR1
`
`
`*(CHZM NHa©
`
`or another mimetic of an arginine side chain; where X is NCN, NNOg, CI-INOz or NSOZNHZ; n
`is an integer from 1 to 4, and R1 is H or an alkyl, aryl, CN, NHz, OH, -—CO—CH2CH3, «CO--
`CH3, ——CO--CH2CH2CH3, --CO——CH2 Ph, or —-CO-Ph; B is an indole, indole methyl, benzyl,
`phenyl, naphthyl, naphthyl methyl, cinnamyl group, or any other derivative of the aromatic
`group; and C is D- or L-cyclohexylalanine (Cha), leucine, valine, isoleucine, phenylalanine,
`nyptophan or methionine. In certain embodiments ofthe invention A is L-arginine.
`In certain
`embodiments ofthe invention F is an L-amino acid. In certain embodiments F is L-arginine. In
`certain embodiments n = l, 2, 3, or 4.
`[00196]
`In certain embodiments ofthe invention the compound is selected from the group
`consisting of SEQ ID N05: 11, 12,13, 14,15,16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27 and
`
`compounds described above will be referred to collectively herein as GPCRA.
`[00197]
`' In one embodiment, the complement inhibitor is a C5a receptor inhibitor, e.g., a C5a
`antagonist. For example, the complement inhibitor may be a peptide having the following
`sequence: HC-[ORN—PRO-dCHA-TRP—ARG] (SEQ ID NO: 45) where HC = hydrocinnamate,
`dCHA = d-cyclohexylalaine, ORN = l—ornithine, and [] denotates cyclization through an amide
`bound. In another embodimentthe complement inhibitor is a peptide having sequence Ac-PHE-
`[ORN-PRO-dCHA-TRP—ARG] (SEQ ID NO: 46), using the same abbreviations. In one
`embodiment, the therapeutic agent is the compound depicted in Figure 8. In certain
`embodiments ofthe invention the complement inhibitor is a C3a receptor inhibitor, e.g., a C3a
`antagonist.
`
`[00198] Methods for making the GPCRA, confirming their structure, and testing their activity
`as modulators ofa GPCR are disclosed in US. Pat. No. 6,821,950. Certain ofthese compounds
`
`56
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`Regeneron Exhibit 1002.0767
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`

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`are available from Promics (Brisbane, Australia). In one embodiment the complement inhibitor
`is PMXZOS.
`
`[00199]
`
`C. Long-acting Therapeutic Agents
`
`In certain embodiments of the invention at least one of the therapeutic agents is a
`[00200]
`long-acting agent. For example, certain complement inhibitors may intrinsically have a long
`duration of activity even if not provided as a component of a sustained release formulation. The
`
`long-acting therapeutic agent may, for example, have an activity period of at least 3 months, at
`least 6 months, at least 9 months, or at least 12 months when administered in solution in a liquid
`medium in medically acceptable quantities. The long-acting therapeutic agent may be
`administered in solution in a liquid medium or may be a component of a solid or semi-solid
`formulation which optionally contains one or more additional therapeutically active or inactive
`components.
`
`In other embodiments a therapeutic agent that is not a long—acting agent is modified
`[00201]
`such that it becomes long-acting. The modification may, for example, stabilize the agent against
`the activity of various endogenous molecules such as proteases. Suitable modifications are
`known in the art and include, for example, pegylation.
`
`In certain embodiments of the invention the long-acting therapeutic agent is
`[00202]
`administered as a component of a sustained release formulation, e.g., an ocular implant or any
`sustained release formulation described herein.
`
`III. Liquid Compositions Comprising a Therapeutic Agent
`[00203]
`In certain embodiments of the invention at least one of the therapeutic agents, e.g.,
`[00204]
`any of the therapeutic agents discussed above, is administered in solution in a liquid medium.
`Suitable preparations, e.g., substantially pure preparations of one or more therapeutic agents may
`be combined with pharmaceutically acceptable carriers, diluents, solvents, etc., to produce an
`appropriate pharmaceutical composition, i.e., one that is pharmaceutically acceptable for
`administration to the eye. The preparation may contain a pharmaceutically acceptable carrier,
`diluent, etc. Suitable carriers are known in the art and include, for example, sterile water for
`injection, saline, etc. Additional components may include, but are not limited to, buffers,
`preservatives, salts, etc.
`
`[00205]
`
`The therapeutic agents themselves may be provided as pharmaceutically acceptable salts, which
`include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
`Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate,
`benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate,
`
`57
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`Regeneron Exhibit 1002.0768
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`cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,
`glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate,
`hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
`malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate,
`pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate,
`'succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Salts derived from appropriate
`bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium),
`ammonimn and N+(C1-4 alkyl)4 salts. This invention also envisions thequaternization of any
`basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or
`dispersible products may be obtained by such quaternization.
`
`Solutions or suspensions can include components such as a sterile diluent such as
`[00206]
`water for injection, saline solution, or other solvent acceptable for administration to the eye,
`bufi'ers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as
`sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid
`or sodium hydroxide. The preparation can be enclosed in ampoules, disposable syringes or
`single or multiple dose vials made of glass or plastic and provided for commercial sale and/or
`use in any such manner. The term “suspension” includes a composition comprising particles in
`a liquid medium. In some embodiments, the particles consist essentially of a therapeutic agent.
`In other embodiments the particles comprise a drug-releasing component such as a polymer and,
`optionally, one or more additional components such as an excipient.
`
`In some embodiments of the invention the liquid composition comprises an agent
`[00207]
`that enhances uptake of the therapeutic agent by cells, enhances bioavailability of the agent at its
`site ofaction, or otherwise enhances activity ofthe therapeutic agent. For example, a variety of
`delivery vehicles that enhance uptake and/or activity ofRNAi agents such as siRNAs are known '
`in the art and may be included in the liquid composition.
`[00208]
`Preferred pharmaceutical formulations are stable under the conditions of manufacture
`and storage and may be preserved against the contaminating action of microorganisms such as
`bacteria and fungi.
`
`[00209]
`
`IV: Sustained Release Formulations
`
`A sustained release formulation of use in the present invention provides a therapeutic
`[00210]
`concentration of a drug within the eye or a portion or region thereof for a prolonged period of
`time. The period of time during which a therapeutic level of the drug is present can be, e.g., at
`least I, 2, 4, or 6 weeks, at least I, 2, 3, 4, 6, 8, 10, 12, 15, 18, 24 months, or longer. Release
`
`58
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`Regeneron Exhibit 1002.0769
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`may begin immediately or shortly (e.g_, within 24 hours) after administration of the sustained
`
`delivery formulation. Alte'rnatcly, release may be delayed, e.g., it may commence at atime
`I point at least 24 hours following administration. Without limitation, release may occur steadily
`or may occur intermittently (e.g., in bursts during which a substantial amount of the agent is
`released) or periods of steady release may alternate with bursts. In certain embodiments the
`
`therapeutic agent is released at controlled orpredetermined rates when the sustained release
`formulation18 placed'in the eye. Such rates may range, for example, fiom about 0.003
`micrograms/day to about 5000 micrograms/day, or between about .01 micrograms/day to about
`
`5 micrograms/day, or between about .05 micrograms to about 1 microgram/day. In some
`
`embodiments the rate of release is between 1 pig and 5 pig/day.
`
`[00211] A sustained release formulation of use in the present invention typically comprises a
`therapeutic agent and an additional component, element, or structure that contributes to the
`
`sustained release properties ofthe formulation. The additional component, element, or structure
`
`that is effective to provide sustained release is referred to herein as a “drug delivery regulating
`
`componen ”. Optionally the drug delivery regulating element is designed to provide control
`
`over the kinetics of release. It will be appreciated that the physical nature of the formulation,
`e.g., the shape and total surface area of any solid or semi-solid constituents, may contribute to its
`sustained release properties. As another example, tight compression ofparticles containing an
`active agent may result in release that takes place over a longer time period than if the particles
`
`were not compressed. In some embodiments the structure is provided at least in part by the
`therapeutic agent itself and, optionally, one or more substances present at the site of
`
`administration such as an ion, protein, etc. In some embodiments no additional drug delivery
`regulating component need be present in the administered composition. For example, a
`composition comprising a therapeutic agent in a liquid medium may form a structure having
`properties of a gel following its administration. The therapeutic agent may be released over time,
`optionally as the structure degrades. The drug delivery regulating component may comprise or
`consist of a polymer matrix that is physically associated with the therapeutic agent. For
`example, the therapeutic agent may be entrapped, embedded, or encapsulated by the polymer
`
`matrix. A sustained release formulation can be in the form of anlindividual ocular implant, a
`plurality of nanoparticles, microparticles, or liposomes, a semi-solid or viscous material such as
`
`a gel, etc. The therapeutic agent may preferably be from about 1% to 90% by weight of the
`
`Sustained release formulation. More preferably, the therapeutic agent is from about 20% to
`about 80% by weight of the of the sustained release formulation. In certain embodiments, the
`
`59
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`therapeutic agent comprises about 40% by weight of the sustained release formulation (e.g.,
`30%..5 0%).
`
`A number of polymeric delivery vehicles for providing sustained release have been
`[00212]
`used in an ocular context and can be used to administer the compositions ofthe invention.
`Various polymers, e.g., biocompatible polymers, which may be biodegradable, can be used. The
`polymers may be homopolymers, copolymers (including block copolymers), straight, branched-
`chain, or cross-linked. Useful polymers include, but are not limited to, poly-lactic acid (PLA),
`poly-glycolic acid (PGA), poly-lactide-co-glycolide (PLGA), poly(phosphazine), poly
`(phosphate ester), polycaprolactones, polyanhydrides, ethylene vinyl acetate, polyorthoesters,
`polyethers, and poly (beta amino esters). Peptides, proteins such as collagen or albumin,
`_
`polysaccharides such as chitosan, alginate, hyaluronic acid (or derivatives of any of these) and
`dendrimers (e.g., PAMAM dendrimers) are also of use. Methods for preparation of such
`formulations will be apparent to those skilled in the art. Certain of the materials can also be
`obtained commercially, e.g., from Alza Corporation Any ofthese polymers, or combinations
`thereof, can be used in various embodiments of the invention.
`
`[00213] Additional exemplary polymers include cellulose derivatives such as
`carboxymethylcellulose, polycarbamates or polyureas, cross-linked poly(vinyl acetate) and the
`like, ethylene—vinyl ester copolymers having an ester content of 4 to 80% such as ethylene-vinyl
`acetate (EVA) copolymer, ethylene-vinyl hexanoate copolymer, ethylene—vinyl propionate
`copolymer, ethylene-vinyl butyrate copolymer, ethylene—vinyl pentantoate copolymer, ethylene- '
`vinyl trimethyl acetate copolymer, ethylene-vinyl diethyl acetate copolymer, ethylene-Vinyl 3-
`methyl butanoate copolymer, ethylene-vinyl 3-3 -dimethyl butanoate copolymer, and ethylene-
`vinyl benzoate copolymer, or mixtures thereof.
`
`[002.14] . Poly(ortho esters) 5have been introduced into the eye and demonstrated favorable
`properties for sustained release ocular drug delivery (Einmahl, 8., Invest. Ophthalmol. Vis. Sci. ,
`43(5), 2002). Polylactide particles have been used to target an agent to the retina and RPE
`following intravitreous injection of a suspension of such particles (Bourges, J-L, et al, Invest.
`Ophthalmol. Vis. Sci, 44(8), 2003).
`[00215]
`Sustained release formulations including various ocular implants and other ocular
`drug delivery systems that are of use in various embodiments ofthe invention are described, for
`example, in US. Patent Nos. 6,692,759; 6,331,313; 5,869,079; 5,824,072; and U.S.S.N.
`10/918,597 (Pub. No. 20050048099); 10/837,357 (Pub. No. 20050244469); 11/092,122 (Pub.
`No. 20050244472) and 11/1 16,698 (Pub. No. 20050281861) as well as a number of other
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`patents and publications referenced in the foregoing, all of which are incorporated herein by
`reference.
`
`A method of making a sustained release formulation involves combining or mixing
`[00216]
`the therapeutic agent with a polymeric component to form a mixture. The mixture may then be
`extruded, compressed, molded, etc., to form a single composition. Optionally, heat and/or
`pressure can be used. The single composition may then be processed to form individual
`implants or particles suitable for placement in an eye of a patient. Additional methods for
`
`incorporating therapeutically active agents into polymeric matrices are known in the art. The
`
`polymeric matrix can be formed into various shapes such as rods, disks, wafers, etc., which may
`have a range of different dimensions (e.g., length, width, etc.) and volumes. Exemplary shapes
`include spherical, cylindrical, helical, coil-shaped or helical, screw-shaped, cubical, conical,
`ellipsoidical, biconvex, hemispherical or near-hemispherical etc.
`
`[00217]
`In certain embodiments of the invention an ocular implant is so dimensioned and
`shaped that it fits within the hollow shaft of an injection needle, e.g., a 22, 25, 27, 30, 33, or 35
`
`gauge needle (or needle of any gauge ranging between 22 and 35). Exemplary and nonlimiting
`dimensions for a cylindrical implant may be about 0.5 to 8 millimeters in length and about 0.1 to
`2 millimeters in diameter, e.g., about 0.75 mm to about 1.5 mm in diameter. Implants having
`other shapes, e.g., other rodlike structures with cross-sections that are rectangular or square in
`cross-section may have a cross-section in which the two points most distant from each other are
`
`separated by at most 0.1 mm to 1 mm. In particular embodiments the intraocular implant may
`have a length or other longest dimension of between about 5 microns and about 2 mm, or
`between about 10 microns and about 1 mm for administration with a needle. Alternately, the
`length or other longest dimension is greater than 1 mm, or greater than 2 mm, such as 3 mm or
`up to 10 mm. The vitreous chamber in humans is able to accommodate relatively large implants
`of varying geometries, having lengths of, for example, 1 to 10 mm.
`
`In certain embodiments of the invention the implants may also be at least somewhat
`[00218]
`flexible, which may facilitate both insertion of the implant in the eye, e.g., in the vitreous, and/or
`may facilitate accommodation of the implant. The total weight of the implant may be about
`250-5000 micrograms, e.g., about 500-1000 micrograms. For example, an implant may be about
`500 micrograms or about 1000 micrograms. Larger implants may also be formed and further
`processed before administration to an eye. In addition, larger implants may be desirable where
`relatively greater amounts of a therapeutic agent are provided in the implant, as used.
`[00219]
`In one embodiment the sustained release formulation is a biocompatible ocular
`implant comprising a substantially impermeable polymeric outer layer covering a core which
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`comprises the drug to be delivered, wherein said outer layer has one or more orifices, by which
`
`is meant one or more openings in the outer layer through which, when the device is in use, body
`
`fluids can enter the device and the drug contained in the device (e. g., dissolved, encapsulated, or
`
`entrapped within the device) can migrate out of the device. In certain embodiments the orifices
`
`in total have a surface area of less than 10 percent ofthe total surface area of the device. In
`
`certain embodiments of the invention the ocular implant comprises an outer coating layer that is
`
`permeable to the therapeutic agent, allowing its slow diffiJsion out of the implant. The
`
`composition, structure, and/ or thickness of the coating layer may be selected to provide a
`
`particular permeability and diffusion rate.
`
`[00220]
`A drug can be contained in an ocular implant as a dry powder, particles, granules, or
`as a compressed solid. The drug may also be' present as a solution or be dispersed in a‘polymer
`matrix. Ocular implants, may be have the active agent or agents homogenously distributed
`
`through the polymeric matrix, e.g., they may be monolithic. In other embodiments the active
`
`agent(s) are heterogeneously distributed in the polymeric matrix. For example, discrete regions
`
`of the implant may contain solid particles of an active agent, or a reservoir of active agent may
`
`be encapsulated by the polymeric matrix. The therapeutic agent(s) may be distributed in a non—
`
`homogenous pattern in the matrix. For example, an implant may include a portion that has a
`
`greater concentration of the therapeutic agent relative to a second- portion of the implant.
`Multilayered structures, with the layers having different compositions and may have different
`
`physical characteristics such as density or porosity are another possibility. For example, the
`
`layers may contain different therapeutic agents or combinations thereof. In another
`
`embodiment, layers that are relatively resistant to degradation are interspersed with layers that
`
`degrade more rapidly.
`
`[00221]
`
`The biodegradable polymeric materials which are included to form the matrix may be
`
`subject to enzymatic or hydrolytic instability. Water soluble polymers may be cross-linked with
`
`hydrolytic or biodegradable unstable cross-links to provide useful water insoluble polymers.
`
`The degree of stability can vary widely, depending, for example, upon the choice of monomer,
`
`whether a homopolymer or copolymer or mixture, is employed, and whether the polymer
`
`includes terminal acid groups. The biodegradation of the polymer and hence the extended
`
`release profile of the sustained release formulation may also influenced by the relative average
`
`molecular weight of the polymeric materials employed. Different molecular weights of the same
`
`or different polymeric materials may be included in the formulations to modulate the release
`
`profile. For example, the average molecular weight of the polymer may range from about 5 to
`
`about 500 kD, e.g., from about 10 to 100 kD, or from about 15 to 50 kD,
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`[00222] Nanoparticles or microparticles can be made using any method known