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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 are-among these proteins. Poxvirus
`complement control proteins are members ofthe complementcontrol protein (CCP) superfamily
`and typically contain 4 SCR modules. These proteins possess features that make them
`particularly advantageousfor treatment and prevention ofmacular degeneration related
`conditions and for treatment and prevention of choroidal neovascularization.
`[00180]
`Thusin certain embodimentsofthe invention one or both ofthe therapeutic agents is
`a poxvirus complement control protein (PVCCP). The PVCCP can comprise a sequence
`encodedby,e.g., vaccinia virus, variola major virus, variola minorvirus, COWpoOx virus,
`monkeypox virus, ectromelia virus, rabbitpox virus, myxoma virus, Yaba-like disease virus, or
`swinepox virus. In other embodiments the VCCPisa herpesvirus complementcontrol protein
`(HVCCP). The HVCCP can comprise a sequence encoded by aMacacafuscata rhadinovirus,
`cercopithecine herpesvirus 17, or human herpesvirus 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,
`1992).
`The VCCP mayinhibit the classical complement pathway, the alternate complement
`[00181]
`pathway,the lectin pathway, or any combination of these. In certain embodiments ofthe
`invention the VCCP,e.g., a PVCCP,bindsto C3b, C4b, or both. In certain embodiments ofthe
`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 sequencethat is normally cleaved offwhen the protein
`is expressed in virus-infected cells) orcan be a mature form (i.e., lacking the signal sequence).
`[80182] Vaccinia complement control protein (VCP)is a virus-encoded protein secreted from
`vaccinia infected cells. VCP is 244 aminoacids in length, contains 4 SCRs, andis 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. VCPis 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 VCPproteins, respectively. VCP has been shown to
`inhibit the classical pathway ofcomplementactivation 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; McKenzieetal., J.
`
`50
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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
`complementactivation at multiple steps and reduces levels of the proinflammatory chemotactic
`factors C3a, C4a, and CSa.
`[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. Virol., 74(12), 5659-5666, 2000).
`VCP can be taken up by mast cells and possibly persist in tissue for lengthy periods oftime,
`thereby potentially prolongingits activity (Kotwal, GJ, et al., In GP. Talwat,et al. (eds); 10
`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 encodeproteins that are highly homologous to VCP
`and are referred to as smallpox inhibitor of complement enzymes (SPICE) (Rosengard, AM,et
`al., Proc. Nati. Acad. Sci., 99(13), 8803-8813. U.S. Pat. No. 6,55 1,595). SPICE from various
`variola strains sequencedto date differs from VCP by about 5% (e.g., about 11 amino acid
`differences). Similarly to VCP, SPICE binds to C3b and C4b andcausestheir degradation,
`acting as a cofactor for factor I. However, SPICE degrades C3b approximately 100 timesas fast
`as VCP and degrades C4b approximately 6 times as fast as VCP. The amino acid sequence of
`SPICEis 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 SCRis 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 residueis present between cysteine 3 and
`cysteine 4 of each SCR. SCR1 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 complementbinding locations of
`SPICE. SPICEor any ofthe portions thereofthat inhibit complementactivation, e.g., SPICE and
`
`51
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`SPICE-related polypeptides containing four SCRs, such as those described in U.S. Pat. No,
`6,551,595, are of use in the present invention.
`[00185]
`Complementcontrol proteins from cowpox virus (referred to as inflammation
`modulatory protein, IMP) and monkeypoxvirus(referred to herein as monkeypox virus
`complement control protein, MCP) have also been identified and sequenced (Miller, CG,etal.,
`Virology, 229, 126-133, 1997 and Uvarova, EA and Shchelkunov, SN, Virus Res., 81€1-2), 39-
`45,2001). MCPdiffers from the other PVCCPs described herein in thatit contains a truncation
`of the C-terminal portion of the fourth SCR.
`[00186]=It will be appreciated that the exact sequence ofcomplement control proteins
`identified in different virus isolates may differslightly. Such proteins fall within the scope of
`the present invention. Complementcontrol proteins from any such isolate may be used,|
`provided that the protein has not undergone a mutation that substantially abolishesits activity.
`Thus the sequence of a VCCP such as SPICE or VCP may differ from the exact sequences
`presented herein or under the accession numberslisted in Table 1. It will also be appreciated
`that a number of amino acidalterations,e.g., additions, deletions, or substitutions such as
`conservative amino acid substitutions, may be madein a typical polypeptide such as a VCCP
`withoutsignificantly affecting its activity, such that the resulting protein is considered
`equivalent to the original polypeptide. For example, up to about 10% of the aminoacids, or up
`to about 20% ofthe amino acids may frequently be changed withoutsignificantly 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.
`[00187]
`Figure 4 shows a sequence alignment of a variety ofpoxvirus complementcontrol
`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 ofcomplement
`control proteins and fragments thereof, the number of K+R residues, %K-+Rresidues,pl,
`numberofputative heparin binding sites, and ability to inhibit hemolysis (indicative of
`complement inhibiting activity) and/or bind to heparin.
`[00188]=Withoutlimitation, any of the viral polypeptides identified by accession numberin
`Table 2 below is of use in various embodiments of the invention.
`
`52
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`Table 2: Representative Viral Complement Control Proteins
`[00189]
`
`
`
`Protein
`=
`Accession
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Monkeypox
`
`
`Ectromelia virus
`
`
`
`
`p
`Rabbitpox
`
`
`Macaca fuscata rhadinovirus AAS99981|RhadinavirusJM4
`
`
`
`
`
`(Herpesvirus)
`
`Cercopithecine herpesvirus 17[Complementbinding NP-870748)Herpesvirus
`protein (ORF4
`
`
`
`Human herpes virus 8
`
`Compiementbinding AABG62602|Herpesvirus
`
`
`Complement control protein
`
`5
`CAE00484
`
`[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 CS. Exemplary agents include antibodies,
`antibody fragments, polypeptides, small molecules, and aptamers. Exemplary antibodies are
`described in U-S. Pat. No. 6,534,058. Exemplary compoundsthat bind to and inhibit C5 are
`described in U.S. Pat. Pub. Nos. 20050090448 and 20060115476. In certain embodiments the
`complementinhibitor is an antibody, small molecule, aptamer, or polypeptidethat binds to
`substantially the same bindingsite on C5 as an antibody described in U.S. Pat. No. 6,534,058 or
`a peptide described in USSN 10/937,912. U.S. Pat. Pub. No. 20060105980 discloses aptamers
`that bind to and inhibit C5. Also of use are RNAi agents that inhibit expression of C5 or C5R.
`[00192]
`In other embodiments the agent is an antagonist of a C5a receptor (C5aR).
`Exemplary C5a receptor antagonists include a variety of small cyclic peptides such as those
`described in U.S. Pat. No. 6,821,950; USSN 11/375,587; and/or PCT/US06/08960
`(W02006/099330).
`For example, the therapeutic agent may be a compoundof general formula I below:
`
`Regeneron Exhibit 1002.0764
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`where A is H,alkyl, aryl, NH2, 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 ofa D-, L- or homo-aminoacid 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 ofa D- or L-aminoacid selected from
`the group consisting of cyclohexylalanine, homocyclohexylalanine, leucine, norleucine,
`homoleucine, homonorleucine and tryptophan;E is the side chain of a D- or L-aminoacid
`selected from the group consisting oftryptophan and homotryptophan;F is the side chain of a
`D- or L-amino acid selected from the group consisting ofarginine, homoarginine, lysine and
`homolysine oris one of the following side-chains
`
`~~(CH2)nO—N
`
`NH,?
`Au
`
`NHR?
`
`
`
`—(CHa)a
`
`NH,©
`NHR"
`
`N
`
`
`——(CHa)A
`
`s$@®
`
`_ NHR!
`
`@
`
`Z x=
`
`2
`
`
`—-(CH2)g—S
`
`NHR’
`
`\na
`—(CHo2)F
`N
`
`NHR?
`
`54
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`Regeneron Exhibit 1002.0765
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`

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`WO 2007/084765
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`
`
`—(CHo)a
`
`N
`
`NHR"
`
`
`
`—(CH2)7 —NH3”
`
`or another mimetic of an arginine side chain, where X is NCN, NNO2, CHNO>or
`{00194]
`NSO.NHp; n is an integer from 1 to 4, and R! is H or an alkyl, aryl, CN, NH2, OH, --CO--
`CH2CHs, --CO--CHs, --CO--CH2CH2CHs3, --CO--CH) Ph, or --CO-Ph; and X’is --(CH2),NH--
`or (CH)a --S--, --(CH2)2 O--, --(CH2)3 O--, --(CH2)3 --, --(CH2)a4 --, or --CH, COCHRNH--,
`where R is the side chain of any common or uncommon aminoacid, 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),O-N
`
`®
`
`z H2
`NHR!
`
`Zz =
`
`®
`2.
`
`
`
`—(CH2)z
`
`N
`
`NHR'
`
`
`
`—(CHa)a
`
`N
`
`NHR‘
`
`= xNn
`
`
`—(CH2)a—S7
`
`~NHR'
`
`
`
`—(CH2)a—N
`
`NHR?
`
`55
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`Regeneron Exhibit 1002.0766
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`

`

`Ww
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`
`
`—(CHa)a
`
`N
`
`“NHR?
`
`
`—(CHoa)a
`
`NH3”
`
`or another mimetic ofan arginine side chain; where X is NCN, NNO2, CHNO; or NSO2NHb; n
`is an integer from 1 to 4, and R! is H or an alkyl, aryl, CN, NH>2, OH, --CO—CH>CHs,--CO--
`CHs, --CO--CH2CH2CH3, --CO--CHb>Ph, or --CO-Ph;B is an indole, indole methyl, benzyl,
`phenyl, naphthyl, naphthyl methyl, cinnamyl group, or any other derivative ofthe aromatic
`group; and C is D- or L-cyclohexylalanine (Cha), leucine, valine, isoleucine, phenylalanine,
`tryptophan 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 = 1, 2, 3, or 4.
`{00196]
`In certain embodiments ofthe invention the compoundis selected from the group
`consisting of SEQ ID NOs: 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and
`28, as described in U.S. Pat. No. 6,821,950. Other embodiments disclosed therein may also be
`used. For example, A, B, C, D, E, F, and R? may be any ofthe groups mentioned in U.S, Pat.
`No. 6,821,950.
`It is noted that the letters A, B, C, D, E, and F in the formulas presented herein
`are to be given the meanings described herein and in U.S. Pat. No. 6,821,950 and do not stand
`for chemical elements or isotopes such as boron, carbon, deuterium, or fluorine. The
`compounds described above will be referred to collectively herein as GPCRA.
`[00197]
`- Inone embodiment, the complementinhibitor is a CS5a receptorinhibitor, 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 = 1-ornithine, and [ ] denotates cyclization through an amide
`bound. In another embodimentthe complementinhibitoris 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 complementinhibitor is a C3a receptor inhibitor, e.g., a C3a
`
`antagonist.
`
`[00198] Methodsfor making the GPCRA,confirmingtheir Structure, and testing their activity
`as modulators ofa GPCRare disclosed in U.S. Pat. No. 6,821,950. Certain ofthese compounds
`
`56
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`Regeneron Exhibit 1002.0767
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`are available from Promics (Brisbane, Australia). In one embodimentthe complement inhibitor
`is PMX205.
`
`C. Long-acting Therapeutic Agents
`[00199]
`In certain embodiments ofthe inventionat least one ofthe 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 ofa solid or semi-solid
`formulation which optionally contains one or more additional therapeutically active or inactive
`components.
`[00201]
`In other embodiments a therapeutic agent that is not a long-acting agent is modified
`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 inthe art and include, for example, pegylation.
`[00202]
`Incertain embodimentsofthe invention the long-acting therapeutic agentis
`administered as a componentof a sustained release formulation, e.g., an ocular implant or any
`sustained release formulation described herein.
`[00203]
`If. Liquid Compositions Comprising a Therapeutic Agent
`[00204]
`Incertain embodiments of the invention at least one ofthe therapeutic agents,e.g.,
`any ofthe therapeutic agents discussed above, is administered in solution ina liquid medium.
`Suitable preparations, ¢.g., substantially pure preparations of one or more therapeutic agents may
`be combined with pharmaceutically acceptablecarriers, diluents, solvents, etc., to produce an
`appropriate pharmaceutical composition,i.e., one thatis 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.
`Examplesof 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
`basesinclude alkali metal (e.g., sodium and potassium),alkaline earth metal (e.g., magnesium),
`ammonium and N+(C1-4 alkyl)4 salts. This invention also envisions the.quaternization of any
`basic nitrogen-containing groupsofthe compoundsdisclosed herein. Wateror oil-soluble or
`dispersible products may be obtained by such quaternization.
`[00206]
`Solutions or suspensions can include components such as a sterile diluent such as
`water for injection, saline solution, or other solvent acceptable for administration to the eye,
`buffers such as acetates, citrates or phosphates and agents for the adjustment oftonicity such as
`sodium chloride or dextrose. pH can be adjusted with acidsor 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 embodimentsofthe invention the liquid composition comprises an agent
`[90207]
`that enhances uptake ofthe therapeutic agent by cells, enhances bioavailability ofthe agent atits
`site ofaction, or otherwise enhances activity ofthe therapeutic agent. For example, a variety of
`delivery vehicles that enhance uptake and/oractivity ofRNAi agents such as siRNAsare known _
`in the art and maybe included in the liquid composition.
`[00208]
`Preferred pharmaceutical formulations are stable under the conditions ofmanufacture
`and storage and may be preserved against the contaminating action ofmicroorganisms such as
`bacteria and fungi.
`[00209]
`IV. Sustained Release Formulations
`[00210]
`A sustained release formulation of use in the present invention provides a therapeutic
`concentration of a drug within the eye or a portion or region thereof for a prolonged period of
`time. Theperiod oftime during which a therapeutic level ofthe drug is present can be, e.g., at
`least 1, 2, 4, or 6 weeks,at least 1, 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 (¢.g., within 24 hours) after administration ofthe sustained
`delivery formulation. Alternately, release may be delayed,e.g., it may commenceat a.time
`. point at least 24 hours following administration. Without limitation, release may occur steadily
`or may occurintermittently (e.g., in bursts during which a substantial amountofthe agent is
`released), or periods of steady release may alternate with bursts. In certain embodiments the
`therapeutic agentis released at controlled or predetermined rates when the sustained release
`formulationis placed in the eye. Suchrates may range, for example, from 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 microgramsto about 1 microgram/day. In some
`embodimentsthe rate ofrelease is between 1 ug and 5 pg/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
`component”. Optionally the drug delivery regulating clement is designed to provide control
`over the kinetics of release. It will be appreciated that the physical nature of the formulation,
`e.2., the shape and total surface area of any solid or semi-solid constituents, may contributeto 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 ifthe particles
`were not compressed. In some embodimentsthe structure is provided at least in part by the
`therapeutic agentitself 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 mayformastructure having
`properties of a gel following its administration. The therapeutic agent may be released overtime,
`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 an individual 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 ofthe
`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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`Regeneron Exhibit 1002.0770
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`therapeutic agent comprises about 40% by weight ofthe sustained release formulation (e.g.,
`30%-50%).
`[00212]
`A numberofpolymeric delivery vehicles for providing sustained release have been
`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 notlimited 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 ofthese) and
`dendrimers (e.g., PAMAM dendrimers) are also of use. Methods for preparation of such
`formulations will be apparentto 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 of4 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-dimethy] butanoate copolymer, and ethylene-
`vinyl benzoate copolymer, or mixtures thereof.
`{00214 _ Poly(ortho esters)‘have been introducedinto the eye and demonstrated favorable
`properties for sustained release ocular drug delivery (Einmahl, S., Invest. Ophthalmol. Vis. Sci. 5
`43(5), 2002). Polylactide particles have been used to target an agent to the retina and RPE
`following intravitreous injection ofa suspension of such particles (Bourges, J-L, et al, Jnvest.
`Ophthalmol. Vis. Sci., 44(8), 2003).
`[00215]
`Sustained release formulations including various ocular implants and other ocular
`drug delivery systemsthat are of use in various embodiments ofthe invention are described, for
`example, in U.S. Patent Nos. 6,692,759: 6,33 1,313; 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 11/116,698 (Pub. No. 2005028186 1) as well as a numberof 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 bé processed to form individual
`implants or particles suitable for placementin 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 formedinto 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 embodimentsofthe invention an ocular implant is so dimensioned and
`shapedthatit 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
`dimensionsfor 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
`havea 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 dimensionis greater than 1 mm,or greater than 2 mm, such as 3 mm or
`up to 10 mm. The vitreous chamber in humansis able to accommodate relatively large implants
`of varying geometries, having lengths of, for example, 1 to 10 mm.
`[00218]
`In certain embodiments ofthe invention the implants may also be at least somewhat
`flexible, which may facilitate both insertion ofthe implant in the eye, e.g., in the vitreous, and/or
`may facilitate accommodation ofthe 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 microgramsor 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 ofa therapeutic agent are provided in the implant, as used.
`[00219]
`In one embodimentthe sustained release formulation is a biocompatible ocular
`implant comprising a substantially impermeable polymeric outer layer covering a core which
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`Regeneron Exhibit 1002.0772
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`WO 2007/084765
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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 openingsin the outer layer through which, whenthe 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 embodimentsthe 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 layerthat is
`permeable to the therapeutic agent, allowing its slow diffusion out of the implant. The
`composition, structure, and/ or thickness of the coating layer may be selected to provide a
`
`particular permeability and diffusionrate.
`
`[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. Ocularimplants, may be havetheactive agent or agents homogenously distributed
`through the polymeric matrix, e.g., they may be monolithic. In other embodimentsthe 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-
`homogenouspattern in the matrix. For example, an implant may include a portion that has a
`greater concentration of the therapeutic agent relative to a secondportion of the implant.
`Multilayered structures, with the layers having different compositions and may have different
`physical characteristics such as density or porosity are anotherpossibility. 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.
`
`The biodegradable polymeric materials which are included to form the matrix may be
`[90221]
`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 ofstability 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 about5 to
`about 500 kD, e.g., from about 10 to 100 kD, or from about 15 to 56 kD.
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`Regeneron Exhibit 1002.077