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`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`26 July 2007 (26.07.2007)
`
`PCT
`
`(51) International Patent Classification:
`A61P 27/02 (2006.01)
`A61K 39/395 (2006.01)
`A61F 2/14 (2006.01)
`A61K 38/17 (2006.01)
`A61K 47/06 (2006.01)
`A61K 31/00 (2006.01)
`
`(21) International Application Number:
`PCT/US2007/001649
`
`(22) International Filing Date: 19 January 2007 (19.01.2007)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/760,974
`11/544,389
`
`19 January 2006 (19.01.2006)
`6 October 2006 (06.10.2006)
`
`US
`US
`
`(71) Applicant (for all designated States except US): POTEN-
`TIA PHARMACEUTICALS, INC. [US/US]; 201 East
`Jefferson Street, Suite 3 11, Louisville, KY 40202 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): DESCHATELETS,
`Pascal [US/US]; 11031 Indian Legends, #202, Lexington,
`KY 40241 (US). OLSON, Paul [US/US]; 645 South 3rd
`Street, Apt. 227-E, Louisville, KY 40202 (US).
`
`(10) International Publication Number
`WO 2007/084765 A2
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
`GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS,
`JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS,
`LT, LU, LV,LY, MA, MD, MG, MK, MN, MW, MX, MY,
`MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS,
`RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN,
`TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT,
`RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`— without international search report and to be republished
`upon receipt of that report
`
`(74) Agent: JARRELL, Brenda, Herschbach; Choate, Hall & For two-letter codes and other abbreviations, refer to the "G uid
`Stewart, LLP, Two International Place, Boston, MA 021 10
`ance Notes on Codes and Abbreviations" appearing at the beg in
`(US).
`ning of each regular issue of the PCT Gazette.
`
`(54) Title: INJECTABLE COMBINATION THERAPY FOR EYE DISORDERS
`
`(57) Abstract: The present invention provides composition, methods, and articles of manufacture for treating an eye disorder,
`e.g., a disorder characterized by macular degeneration, choroidal neovascularization, or retinal neovascularization. One method
`of the invention comprises the step of: administering first and second therapeutic agents to the subject's eye in a single procedure,
`wherein the first therapeutic agent provides rapid improvement in the condition of the subject's eye and the second therapeutic agent is
`administered as a sustained release formulation of the second therapeutic agent. For example, the first and second therapeutic agents
`are administered by intravitreal injection. The first therapeutic agent may be dissolved in a liquid medium located in the syringe
`and the sustained formulation of the second therapeutic agent may comprise an ocular implant or plurality of particles located in the
`needle. The therapeutic agents may be selected from the group consisting of angiogenesis inhibors and complement inhibitors.
`
`Novartis Exhibit 2052.001
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`WO 2007/084765
`
`PCT/OS2007/001649
`
`A
`
`1
`
`INJECTABLE COMBINATION THERAPY FOR EYE DISORDERS
`
`Cross-Reference to Related Applications
`[0001]
`This application claims priority to, and the benefit of, U.S. Provisional Patent
`Application No. 60/760,974, filed Jan. 19, 2006, and U.S.S.N. 11/544,389, filed Oct. 6, 2006,
`both of which are incorporated herein by reference.
`
`Background of the Invention
`Macular degeneration is a term that refers to and describes a number of different
`[0002]
`diseases characterized by degenerative changes in the macula, all of which lead to a loss of
`central vision. The macula is a small area in the retina of the eye, approximately 3 to 5
`millimeters in size, adjacent to the optic nerve. It is the most sensitive area of the retina and
`contains the fovea, a depressed region that allows for high visual acuity and contains a dense
`concentration of cones, the photoreceptors that are responsible for color vision. Age-related
`macular degeneration (ARMD) is the most common cause of functional blindness in developed
`countries for those over 50 years of age. The disease is characterized by progressive
`degeneration of the retina, retinal pigment epithelium (RPE), and underlying choroid (the highly
`vascular tissue that lies beneath the RPE, between the retina and the sclera). Cells in the RPE
`recycle visual pigment (rhodopsin), phagocytose photoreceptor tips daily as part of rod and cone
`regeneration, and transport fluid across the membrane to the choroid. Central vision deteriorates
`when cells in the RPE cease to function properly. Despite extensive investigation, the
`pathogenesis of ARMD is not fully understood. Oxidative stress, inflammation, genetic
`background, and environmental or behavioral factors such as smoking and diet may contribute.
`clinical hallmark of ARMD is the appearance of drusen, localized deposits of
`[0003]
`lipoproteinaceous material that accumulate in the space between the RPE and Bruch's
`membrane. Drusen are typically the earliest clinical finding in ARMD, and the existence,
`location, and number of drusen are used in classifying the disease into stages and monitoring
`progression (Ambati, J.s et al.s Surv. Ophthalmol., 48(3): 257-293, 2003; "Preferred Practice
`Pattern: Age-Related Macular Degeneration", American Academy of Ophthalmology, 2003).
`[0004]
`ARMD has been classified into "dry" and "wet" (exudative, or neovascular) forms.
`Dry ARMD is much more common than wet, but the dry form can progress to the wet form, and
`the two occur simultaneously in a significant number of cases. Dry ARMD is typically
`characterized by progressive apoptosis of cells in the RPE, overlying photoreceptor cells, and
`frequently also the underlying cells in the choroidal capillary layer. Confluent areas (e.g., at
`
`Novartis Exhibit 2052.002
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`WO 2007/084765
`
`PCT/0S2007/001649
`
`2
`
`least 175 m m in minimum diameter) of RPE cell death accompanied by overlying photoreceptor
`atrophy are referred to as geographic atrophy. Patients with this form experience a slow and
`progressive deterioration in central vision. Wet ARMD is characterized by bleeding and/or
`leakage of fluid from abnormal vessels that have grown from the choroidal vessels
`(choriocapillaris) beneath the RPE and macula. This can be responsible for sudden and
`disabling vision loss. Much of the vision loss that patients experience is due to such choroidal
`neovascularization (CNV) and its complications. A subtype of neovascular ARMD in which
`angiomatous proliferation originates from the retina and extends posteriorly into the subretinal
`space, eventually communicating in some cases with choroidal new vessels has been identified
`(Yannuzzi, L.A., et al., Retina, 21(5):416-34, 2001). This form of neovascular ARMD, termed
`retinal angiomatous proliferation (RAP) can be particularly severe. The existence of macular
`drusen is a strong risk factor for development of both wet and dry forms of ARMD.
`The panels of Figure 1 show structures present in a normal eye and some of the
`[0005]
`processes that occur in ARMD. Figures IA and IB show structures present in the anterior and
`posterior segments of the eye. Figures 1C-1E depict the outer layers of a normal eye (1C), an
`eye suffering from dry ARMD (ID), and an eye suffering from wet ARMD (IE). The outer
`nuclear layer (ONL) contains nuclei of rod and cone photoreceptors. Each photoreceptor
`contains an inner segment (IS) and outer segment (OS), the latter of which contains the pigment
`rhodopsin, which initiates the phototransduction cascade following exposure to light. The RPE
`lies below the photoreceptors and above Bruch's membrane. As shown in Figures ID and IE,
`the normal structure of the retina is disrupted in a variety of ways as in patients with ARMD.
`Macular edema is associated with a variety of eye disorders including ARMD,
`[0006]
`diabetic retinopathy, inflammatory conditions such as anterior or posterior uveitis, etc. The
`macula becomes thickened as a result of the accumulation of fluid that leaks from weakened or
`otherwise abnormal blood vessels into nearby tissues. Leakage of blood or other fluids and the
`resulting increase in macular thickness can lead to acute alterations in visual acuity, color
`perception, etc. Thus macular edema can contribute to the visual disturbances and loss
`experienced by individuals suffering from ARMD and a variety of other eye disorders.
`Development of pharmacological therapies for ARMD and other ocular disorders
`[0007]
`associated with neovascularization in the eye is an area of active investigation. Much effort has
`focused on methods for destroying or sealing abnormal blood vessels and/or inhibiting their
`development. Photodynamic therapy involves systemic intravenous administration of a light-
`sensitive dye (verteporfin) which is activated in the eye by a laser, resulting in formation of toxic
`products within the abnormal blood vessels. Local administration of angiogenesis inhibitors to
`
`Novartis Exhibit 2052.003
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`WO 2007/084765
`
`PCT/0S2007 /001649
`
`3
`
`the eye shows considerable promise. Pegaptanib sodium (Macugen®; Pfϊzer/Eyetech) was
`approved by the U.S. Food and Drug Administration for treatment of wet age-related macular
`degeneration in late 2004. Macugen is an aptamer that binds to an isoform of vascular
`endothelial growth factor (VEGF), a protein that acts as a signal in triggering the abnormal
`blood vessel growth, increased permeability, and consequent leakage that characterize wet
`ARMD. Binding of Macugen to VEGF prevents it from binding to VEGF receptors, thereby
`inhibiting its activity. Other angiogenesis inhibitors for the treatment of exudative ARMD
`include monoclonal antibodies such as ranibizumab (Lucentis®; Genentech) that bind to VEGF
`and block its interaction with VEGF receptors.
`Angiogenesis inhibitors that interfere with signal transduction pathways that play a
`[0008]
`fundamental role in angiogenesis, such as the VEGF pathway, offer a powerful approach to
`controlling neovascularization. However, therapy with angiogenesis inhibitors alone has a
`number of disadvantages. Clinical trials of angiogenesis inhibitors that interfere with the VEGF
`pathway have involved their administration in solution by intravitreal injection at intervals of 4-
`6 weeks. Unfortunately this procedure is associated with a significant risk of complications such
`as traumatic lens injury, retinal detachment, and endophalmitis associated with either trauma or
`intraocular infection. With an overall risk of 1%, over the course of a year a dosing interval of 6
`weeks would result in an overall risk of about 9% per eye, while a dosing interval of 4 weeks
`would result in an overall risk of about 13% per eye. For these and other reasons, current
`approaches to the use of angiogenesis inhibitors remain a less than optimal solution to treating
`wet ARMD. There remains a need in the art for improved approaches to treating ARMD. There
`also remains a need for improved approaches to treating other conditions characterized by
`macular degeneration, choroidal neovascularization, retinal neovascularization, retinal
`angiomatous proliferation, and/or blood vessel leakage in the eye.
`
`Summary of the Invention
`
`The present invention provides compositions, methods, and articles of manufacture
`[0009]
`for the treatment of eye disorders, particularly those associated with macular degeneration,
`CNV, and/or retinal neovascularization (RNV). In one aspect, the invention provides a method
`of treating an eye disorder characterized by macular degeneration, CNV5 or RNV, the method
`comprising the step of: administering first and second therapeutic agents to the subject's eye in a
`single procedure, wherein the first therapeutic agent provides rapid improvement in the
`condition of the subject's eye and the second therapeutic agent is administered as a sustained
`
`Novartis Exhibit 2052.004
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`WO 2007/084765
`
`PCT/US2007/001649
`
`4
`
`release formulation of the second therapeutic agent.
`
`In certain embodiments of the invention the
`
`second therapeutic agent is a long-acting therapeutic agent.
`
`In certain embodiments of the
`
`invention at least a portion of the first therapeutic agent, optionally essentially the entire
`
`administered dose of the first therapeutic agent, is provided as a component of a sustained
`
`release formulation. The first and second therapeutic agents may be provided as components of
`
`a single sustained release formulation or as components of separate sustained release
`
`formulations.
`
`[OOIOJ
`
`In certain embodiments of the invention the procedure is an injection procedure, e.g.,
`
`an intravitreal
`
`injection.
`
`In certain embodiments the procedure is an injection procedure in
`
`which, prior to administration,
`
`the first therapeutic agent is contained in a syringe and the
`
`sustained release formulation comprising the second therapeutic agent is contained in a needle
`
`attached to the syringe. For example,
`
`the first therapeutic agent may be dissolved in a liquid
`
`medium located in the syringe and the sustained formulation of the second therapeutic agent
`
`may comprise an ocular implant
`
`located in the needle.
`
`[0011]
`
`In another aspect,
`
`the invention provides a method of treating an eye disorder
`
`characterized by macular degeneration, CNV, or RNV comprising the step of: administering
`
`first and second compositions
`
`to a subject's eye in a single procedure, wherein the first
`
`composition comprises a first therapeutic agent that provides rapid improvement
`
`in the condition
`
`of the subject's eye and the second composition comprises a second therapeutic agent that is
`
`administered as a sustained release formulation comprising the second therapeutic agent. Either
`
`or both of the compositions can contain a plurality of therapeutic agents, e.g., two or more
`
`angiogenesis inhibitors,
`
`two or more complement
`
`inhibitors, or an angiogenesis inhibitor and a
`
`complement
`
`inhibitor.
`
`[0012]
`
`In another aspect the invention provides a method of administering first and second
`
`therapeutic agents to the eye of a subject comprising:
`
`injecting (i) a solution containing the first
`
`therapeutic agent and (ii) a solid ocular implant containing the second therapeutic agent into the
`
`subject's eye in a single injection procedure.
`
`[0013]
`
`In any embodiment of the invention, either or both therapeutic agents may be an
`
`angiogenesis inhibitor or a complement
`
`inhibitor.
`
`In any embodiment of the invention the
`
`sustained release formulation may comprise an ocular implant.
`
`In any embodiment of the
`
`invention the sustained release formulation may comprise a polymer and one or more
`
`therapeutic agents.
`
`the invention provides articles of manufacture. The invention
`In other aspects,
`[0014]
`provides an article of manufacture comprising (i) a first therapeutic agent effective for treating
`
`Novartis Exhibit 2052.005
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`0 2007/084765
`
`PCT/US2007/001649
`
`5
`
`W
`
`an eye disorder; and (ii) a needle containing a second therapeutic agent. The article of
`manufacture may further comprise a syringe. The syringe may contain a therapeutic agent.
`[0015]
`In anyembodiment of the present invention, the eye disorder can be a macular
`degeneration related condition, diabetic retinopathy, retinopathy of prematurity, or any condition
`featuring CNV, RNV, or RAP.
`[0016]
`In any embodiment of the invention that features a complement inhibitor, the
`complement inhibitor can be any complement inhibitor known in the art, e.g., a viral
`complement control protein (VCCP) or fragment or variant thereof, a peptide or peptide analog
`that binds to a complement component, an antagonist of a complement receptor. The VCCP can
`be a poxvirus VCCP (PVCCP) or a herpesvirus VCCP (HVCCP). The PVCCP can be from
`vaccinia virus, variola virus, etc. The peptide or peptide analog can be, e.g., compstatin or a
`derivative thereof.
`[0017]
`In any embodiment of the invention that features an angiogenesis inhibitor, the
`angiogenesis inhibitor may be any angiogenesis inhibitor known in the art. The angiogenesis
`inhibitor may be selected from the group consisting of: Macugen® (pegaptanib sodium) or
`another VEGF aptamer or nucleic acid ligand; Lucentis® (ranibizumab), Avastin®
`(bevacizumb) or another antibody or antibody fragment that specifically binds to VEGF;
`combretastatin or a derivative or prodrug thereof such as Combretastatin A4 Prodrug (CA4P);
`VEGF-Trap; EVIZON™ (squalamine lactate); AG-Ol3958 (Pfizer, Inc.); JSM6427 (Jerini AG),
`b 2-glycoprotein 1 (b 2-GPl), and a short interfering RNA (siRNA) or short hairpin RNA
`(shRNA) that inhibits expression of one or more VEGF ϊsoforms, inhibits expression of a VEGF
`receptor, or inhibits expression of any other molecule whose expression in the eye contributes to
`angiogenesis. In certain embodiments of the invention the therapeutic agent is not a steroid.
`[0018]
`Those of skill in the art will appreciate that certain compounds encompassed by the
`structures herein may exhibit tautomerism, conformational isomerism, geometric isomerism
`and/or stereoisomerism. It should be understood that the invention encompasses use of any
`tautomeric, conformational isomeric, enantiomeric and/or geometric isomeric forms of the
`compounds described herein. Any references herein employing nomenclature that corresponds
`to illustrated structural formulae that represent only one of several tautomeric forms (or
`resonance structures) are not intended to limit the scope of the compounds described herein.
`Those of skill in the art also will recognize that the compounds disclosed as of use in the
`invention may exist in many different protonation states, depending on, among other things, the
`pH of their environment. Where structural formulae provided herein depict the compounds in
`only one of several possible protonation states, it will be understood that these structures are
`
`Novartis Exhibit 2052.006
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`0 2007/084765
`
`PCT/US2007/001649
`
`6
`
`W
`
`illustrative only, and that the invention is not limited to any particular protonation state—any and
`all protonated forms are intended to fall within the scope of the invention. .
`Compounds of use in this invention may, in certain embodiments, bear multiple
`[0019]
`positive or negative charges and may have appropriate counter ions associated therewith. The
`identity of the associated counter ions are may be governed by the synthesis and/or isolation
`methods by which the compounds are obtained. Counter ions include, but are not limited to,
`chloride and other halides, acetate, trifluoroacetate, citrate, sulfate, phosphate, etc., and mixtures
`thereof.
`It will be understood that the identity of any associated counter ion is not a critical
`feature and that the invention encompasses the compounds in association with any type of
`counter ion. Moreover, as the compounds can exists in a variety of different forms, the invention
`is intended to encompass not only forms that are in association with counter ions (e.g., dry salts),
`but also forms that are not in association with counter ions (e.g., aqueous or organic solutions).
`Unless otherwise stated or otherwise clearly evident from the context, the invention
`[0020]
`makes use of standard methods of molecular biology, cell culture, animal maintenance,
`ophthalmologic examination, and administration of therapeutic agents to subjects, etc., and uses
`art-accepted meanings of terms. This application refers to various patents and publications. The
`contents of all articles, books, patents, patent applications, and other publications mentioned in
`this application are incorporated herein by reference. In addition, the following publications are
`incorporated herein by reference: Current Protocols in Molecular Biology, Current Protocols in
`Immunology, Current Protocols in Protein Science, and Current Protocols in Cell Biology, all
`John Wiley & Sons, N.Y., edition as of July 2002; Sambrook, Russell, and Sambrook,
`Molecular Cloning: A Laboratory Manual, 3rd ed., Cold Spring Harbor Laboratory Press, Cold
`Spring Harbor, 2001; Kuby Immunology, 4th ed., Goldsby, R.A., Kindt, TJ., and Osborne, B.
`(eds.), W.H. Freeman, 2000, Goodman andGilman 's The Pharmacological Basis of
`Therapeutics, 10th Ed. .McGraw Hill, 2001, Katzung, B. (ed.) Basic and Clinical Pharmacology,
`McGraw-Hill/Appleton & Lange; 9th edition (December 2003), Ophthalmic Surgery: Principles
`and Practice, 3rd ed., W.B. Saunders Company, 2002; Albert, DM and Lucarelli, MJ (eds.),
`Clinical Atlas of Procedures in Ophthalmic Surgery, American Medical Association, 2003. In
`the event of a conflict or inconsistency between any of the incorporated references and the
`instant specification, the specification shall control, it being understood that the determination of
`whether a conflict or inconsistency exists is within the discretion of the inventors and can be
`made at any time.
`
`Brief Description of the Drawing
`
`Novartis Exhibit 2052.007
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`WO 2007/084765
`
`PCT/US2007/001649
`
`7
`
`Figures 1A-1E show schematic representations of the anterior and posterior
`[0021]
`segments of the eye (IA and IB) and the outer layers of the eye (1C-1E). Figure 1C depicts a
`normal eye. Figure ID depicts an eye suffering from dry ARMD. Figure IE depicts an eye
`suffering from exudative ARMD. ONL = outer nuclear layer; IS = inner segment; OS = outer
`segment; RPE = retinal pigment epithelial layer; BM = Bruch's membrane; CG =
`choriocapillaris. From Tezel, T., et al., Trends in Molecular Medicine, 10(9), 417-420, 2004.
`Figure 2 shows a consensus sequence for a short consensus repeat (SCR), a module
`[0022]
`found in complement control proteins. From Smith, SA, et al., J. Virol. 74(12), 5659-5666,
`2000.
`Figures 3A and 3B show sequences of vaccinia virus complement control protein
`[0023]
`precursor (SEQ ID NO: 33) and the mature vaccinia virus complement control protein (SEQ ID
`NO: 34).
`Figure 4 shows a sequence comparison of mature complement control proteins from
`[0024]
`a variety of orthopoxvirus isolates (SEQ ID NO: 35 —42). The corresponding genetic loci are
`listed. Modified from Smith, SA et al., J. Virol. 74(12), 5659-5666, 2000.
`Figure S shows a comparison of the SCR domain structure of a number of
`[0025]
`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 hemolysis and/or
`bind to heparin. Modified from Smith, SA, et al., J. Virol 74(12), 5659-5666, 2000. The
`domains are SCR modules. Thus, for example, rVCP SCR (2, 3, 4), is a recombinantly
`produced polypeptide containing SCRs 2, 3, and 4 from VCP.
`Figure 6 shows the amino acid sequence of SPICE (SEQ ID NO: 44).
`[0026]
`Figure 7 shows the structure of compstatin and the structure of a compstatin analog
`[0027]
`showing increased complement inhibiting activity relative to compstatin. The figure also shows
`the IC50 of compstatin and the compstatin analog for inhibition of human complement. Amino
`acids 4 and 9 in the peptide chain depicted in the upper portion of the figure are as shown on the
`lower left for compstatin and as shown on the lower right for the compstatin analog. Thus the
`boxes labeled "X4" and "X9" in the peptide chain represent the side chains of the amino acids
`X4 and X9 shown in the lower portion of the figure for compstatin (left) and the compstatin
`analog (right) respectively.
`Figure 8 shows an exemplary compound for use in the invention.
`[0028]
`Figure 9 shows a needle/syringe assembly loaded with first and second therapeutic
`[0029]
`agents.
`
`Novartis Exhibit 2052.008
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`WO 2007/084765
`
`PCT/0S2007/001649
`
`8
`
`Definitions
`
`"Activity period" refers to the time period over which a subject experiences an
`[0030]
`improvement in one or more symptoms and/or signs of a disorder following administration of a
`therapeutic agent, relative to a baseline condition or state existing prior to administration of the
`therapeutic agent. The activity period begins when the subject first experiences improvement
`and ends when the subject's condition or state returns to a baseline that existed prior to
`administration of the agent.
`"Angiogenesis" or "angiogenic" refer to formation, growth, and/or development of
`[0031]
`new blood vessels.
`The terms "angiogenesis inhibitor" and "antiangiogenic agent" are used
`[0032]
`interchangeably herein to refer to agents that are capable of inhibiting or reducing one or more
`processes associated with angiogenesis including, but not limited to, endothelial cell
`proliferation, endothelial cell survival, endothelial cell migration, differentiation of precursor
`cells into endothelial cells, and capillary tube formation.
`"Antibody", as used herein, refers to an immunoglobulin or portion thereof that
`[0033]
`binds to an antigen. An antibody may be natural or wholly or partially synthetically produced.
`An antibody may be derived from natural sources, e.g., purified from an animal such as a rodent,
`rabbit, or chicken, that has been immunized with an antigen or a construct that encodes the
`antigen. An antibody may be a member of any immunoglobulin class, including any of the
`human classes: IgG, IgM, IgA, IgD, and IgE. An antibody of use in this invention may be an
`antibody fragment such as an Fab', F(ab') 2, scFv (single-chain variable) or other fragment that
`retains an antigen binding site, or a recombinantly produced scFv fragment, including
`recombinantly produced fragments that comprise an immunoglobulin antigen binding domain.
`See, e.g., Allen, T., Nature Reviews Cancer, Vol.2, 750-765, 2002, and references therein.
`Antibody fragments which contain the idiotype of the antibody molecule can be generated by
`known techniques. For example, F(ab')2 fragments can be produced by pepsin digestion of the
`antibody molecule, Fab' fragments can be produced by reducing the disulfide bridges of the
`F(ab')2 fragment, or by treating the antibody molecule with papain and a reducing agent. An
`antibody can be an antibody multimer or a multimer of antibody fragments. Antibodies,
`antibody fragments, and/or protein domains comprising an antigen binding site may be
`generated and/or selected in vitro, e.g., using techniques such as phage display (Winter, G. et al.,
`Annu. Rev. Immunol. 12:433-455, 1994), ribosome display (Hanes, J., and Pluckthun, A. Proc.
`Natl. Acad. ScL USA. 94:4937-4942, 1997), etc.
`
`Novartis Exhibit 2052.009
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`WO 2007/084765
`
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`
`9
`
`[0034]
`An antibody may be polyclonal (e.g., an affinity-purified polyclonal antibody) or
`monoclonal. A "monoclonal antibody" as used herein refers to a population of substantially
`homogeneous antibodies or a member of such a population, i.e., the individual antibodies
`comprising the population are identical except for possible naturally occurring mutations that
`can be present in minor amounts.
`In contrast to polyclonal antibody preparations that typically
`include different antibodies directed against different determinants (epitopes), each monoclonal
`antibody is directed against a single determinant on the antigen and is therefore highly specific.
`The modifier "monoclonal" indicates the character of the antibody as being obtained from a
`substantially homogeneous population of antibodies, and is not to be construed as requiring
`production of the antibody by any particular method. For example, monoclonal antibodies to be
`used in accordance with the present invention can be made by the hybridoma method first
`described by Kohler & Milstein, Nature 256: 495, 1975, or alternatively can be made by
`recombinant DNA methods (see e.g., U.S. Pat. No. 4,816,567).
`[0035]
`An antibody may be a "chimeric" antibody in which for example, a variable domain
`of rodent origin is fused to a constant domain of human origin, thus retaining the specificity of
`the rodent antibody. The domain of human origin need not originate directly from a human in
`the sense that it is first synthesized in a human being. Instead, "human" domains may be
`generated in rodents whose genome incorporates human immunoglobulin genes. Such an
`antibody is considered at least partially "humanized". The degree to which an antibody is
`"humanized" can vary. Thus part or most of the variable domain of a rodent antibody may be
`replaced by human sequences, e.g., by site-directed mutagenesis of a polynucleotide that
`encodes the antibody or a portion thereof. According to one approach rodent, e.g., murine,
`complementarity-determining regions (CDRs) are grafted onto the variable light (VL) and
`variable heavy (VH) frameworks of human immunoglobulin molecules, while retaining only
`those rodent framework residues deemed essential for the integrity of the antigen-binding site.
`See Gonzales NR, Tumour Biol. Jan-Feb;26(l):3 1-43, 2005 for a review of various methods of
`minimizing antigenicity of a monoclonal antibody. Such human or humanized chimeric
`antibodies are often preferred for use in therapy of human diseases or disorders, since the human
`or humanized antibodies are less likely than to induce an immune response.
`[0036]
`A variety of methods are known for determining whether or not an antibody reacts
`with, or specifically binds to, an antigen such and for determining the affinity of such binding if
`desired. Examples include enzyme-linked immunosorbent assays (ELISA), radioimmunoassays
`(RIA) and the like. Binding of an antibody to a target molecule such as a protein may inhibit or
`interfere with the activity of the target molecule. For example, binding of an antibody to ligand
`
`Novartis Exhibit 2052.010
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`WO 2007/084765
`
`PCT/0S2007/001649
`
`such as a growth factor may interfere with the binding of the ligand to its receptor(s); binding of
`an antibody to a receptor may interfere with the binding of the receptor to its ligand(s).
`The terms "approximately" or "about" in reference to a number include numbers that
`[0037]
`fall within a range of 5% in either direction (greater than or less than) of the number unless
`otherwise stated or otherwise "evident from the context (except where such number would exceed
`100% of a possible value).
`"Biocompatible" refers to a material that is substantially nontoxic to a recipient's
`[0038]
`cells in the quantities and at the location used, and does not elicit or cause a significant
`deleterious or untoward effect on the recipient's body at the location used, e.g., an unacceptable
`immunological or inflammatory reaction, unacceptable scar tissue formation, etc. A material
`that is biocompatible with the eye does not substantially interfere with the physiology or
`function of the eye.
`"Biodegradable" means that a material is capable of being broken down physically
`[0039]
`and/or chemically within cells or within the body of a subject, e.g., by hydrolysis under
`physiological conditions and/or by natural biological processes such as the action of enzymes
`present within cells or within the body, and/or by processes such as dissolution, dispersion, etc.,
`to form smaller chemical species which can typically be metabolized and, optionally, used by
`the body, and/or excreted or otherwise disposed of. Preferably a biodegradable compound is
`biocompatible. A polymer whose molecular weight decreases over time in vivo due to a
`reduction in the number of monomers is considered biodegradable.
`A "biological macromolecule" is a large molecule composed of smaller subunits of a
`[0040]
`type that are found in biological systems. Examples include polypeptides, nucleic acids, and
`polysaccharides. Typically a biological macromolecule contains at least 3 subunits (e.g., amino
`acids, nucleosides, monosaccharides, etc.). The biological macromolecule may be a naturally
`occurring polypeptide, nucleic acid, or polysa