`415.561.6767
`415.840-0391 e-fax
`
`I nccrncr A rc h,ve
`300 Fumcon Avenue
`San Francisco, CA 94118
`
`AFFIDAVIT OF CHRISTOPHER BUTLER
`
`1. l am the Office Manager at the Internet Archive, located in an Francisco,
`California. I make this declaration of my own personal knowledge.
`2. The Internet Archive is a website that provides access to a digital library of
`Internet ites and other cultural artifact in digital form. Like a paper library, we provide
`free access to researchers, historians, scholars, and the general public. The I ntemet
`Archive has partnered with and receives support from various institutions, including the
`Library of Congress.
`3. The Internet Archive has created a service known as the Way back Mach ine. The
`tored in the
`Wayback Machine makes it possible to surf more than 450 bi llion page
`Internet Archive's web archi ve. Visitors to the Wayback Machine can earch archi e
`b URL (i .e. a website address). Tf archived record for a URL are available, the visitor
`will be pre ented with a Ii t of available dates. The visitor may select one of those
`dates, and then begin surfing on an archived version of the Web. The links on the
`archived files when served by the Wayback Machine point to other archived files
`(whether HTML pages or images). If a visitor clicks on a link on an archived page the
`Wayback Machine wi ll serve the archived file with the closest available date to the page
`upon which the link appeared and was clicked.
`4. The archived data made viewable and browseable by the Wayback Machine is
`compi led using software programs known as crawler , which urf the Web and
`automatically tore copie of web files, preserving these files as they exi tat the point of
`time of capture.
`5. The Internet Archive as ign a URL on its site to the archived file
`in the fo rmat
`http://web.archive.org/web/[Year in yyyy][Month in mm][Day in dd][Time code in
`rchive URL
`hh:mm:ss]/(Archived URL]. Thus the Internet
`http://web.archive.org/web/1 9970126045828/http://www.archive.org/ would be the
`URL for the record of the Internet Archive home page HTML file
`(http ://www .archive.org/) archi ved on January 26, 1997 at 4:58 a.rn. and 28 e onds
`( 1997/01 /26 at 04:58:28). A web browser may be set such that a printout from it wi ll
`display the URL of a web page in the printout 's footer. The date assigned by the Internet
`Archive applies to the HTML file but not to image files linked therein. Thus images that
`appear on a page may not have been archived on the same date as the HTML file.
`Likewise, if a we bsite is designed with "frames," the date assigned by the internet
`Archive applies to the frarneset as a whole and not the individual pages within each
`frame.
`6. Attached hereto as Exhibit A are true and accurate copies of printouts of the
`Internet Archive' records of the HTML files or PDF fi les for the RLs and the dates
`specified in the footer of the printout (HTML) or attached cover heet (PDF).
`7. I declare under penalty of perjury that the foregoing i true and correct.
`
`DATE: 10 j,o ~B
`
`Christopher Butler
`
`Regeneron Exhibit 1037.001
`
`
`
`CALIFORNIA JURA T
`
`ee Attached Document.
`
`State of California
`County of an Francisco
`
`A notary public or other officer completing this
`certificate verifies only the identity of the
`individual who signed the document to which thi
`certificate is attached and not th truthfulness,
`accuracy, or validity of that document.
`
`Subscribed and worn to (or affirm d) before me on
`thi
`
`l O day of
`_....,_Q,._C_;'f~0~0-£k""+---
`
`c-"
`' :tj (L
`
`, by
`
`Christopher Butler,
`
`proved to me on the basis of satisfactory evidence to e
`the person who appeared bef o,re me.
`
`Regeneron Exhibit 1037 .002
`
`
`
`Exhibit A
`Exhibit A
`
`Regeneron Exhibit 1037 .003
`
`Regeneron Exhibit 1037.003
`
`
`
`Drugs.com I Prescription Drugs - Information, Interactions & Side ...
`
`1 of 2
`
`Discover treatment
`options with the new
`Symptom Checker
`I, i
`I
`I
`I
`gu t· 11elps 1d nt
`the
`u11d ·rlym
`u of
`co1 mlOn syr pto111
`
`M@@d
`l'ublic,u 111 -
`
`H~r,·•rd
`H~tb
`
`Having trouble identifying
`your pills or medication?
`Try the Pill Identifier
`
`More Specialist Tools
`
`Custom search for
`Medical Transcriptionists
`
`Drug Interactions Checker
`
`Mednotes, free & secure
`personal medication records
`
`Veterinary Edition
`
`Welcome to Drugs.com
`Drugs.com is the most popular, comprehensive and up-to-date source of drug information online. Providing free, peer-reviewed,
`accurate and independent data on more than 24,000 prescription drugs, over-the-counter medicines & natural products.
`
`Daily Medical News
`
`RSS
`FDA Weighs Pros, Cons of Home Genetic Testing
`TUESDAY, March 8 -- The U.S. Food and Drug Administration began a two-day hearing Tuesday to weigh the risks and benefits
`of those increasingly popular direct-to-consumer genetic tests. These tests, their manufacturers contend, can help predict a
`person's risk of disease or how someone might respond to a given medication. A panel of FDA advisers will look only at those
`genetic tests sold directly ...
`Genes May Affect Severity of Drug Addiction
`TUESDAY, March 8 -- Treatment for drug addiction is affected by a person's genetic makeup and the duration of substance
`abuse, U.S. scientists report. A research team at the Brookhaven National Laboratory found that drug addicts who have a
`certain genetic makeup have lower gray matter density -- and therefore fewer neurons -- in areas of the brain that are important
`for decision-making, ...
`Brain's Learning Ability Seems to Recharge During Light Slumber
`TUESDAY, March 8 -- Your brain's ability to learn may get recharged during the light, dreamless slumber that accounts for up to
`half of your night's sleep, according to a new study. Researchers at the University of California, Berkeley conducted tests on 44
`healthy young adults and found strong evidence that bursts of brain waves called sleep spindles may network between
`important regions of the ...
`More ...
`
`Latest Pharma Industry News
`
`RSS
`FDA Approves Dali resp to Treat Chronic Obstructive Pulmonary Disease
`SILVER SPRING, Md., March 1, 2011 /PRNewswire-USNewswire/ -- The U.S. Food and Drug Administration approved Dali resp
`(roflumilast), a pill taken daily to decrease the frequency of flare-ups (exacerbations) or worsening of symptoms from severe
`chronic obstructive pulmonary disease (COPD). COPD is a serious lung disease that makes breathing difficult. Symptoms can
`include breathlessness, ...
`Vanda Sleep Disorder Drug Getting EU Incentives
`From Associated Press (March 8, 2011) ROCKVILLE, Md. -- Vanda Pharmaceuticals Inc. said Tuesday that European Union
`regulators are giving special incentives to a drug Vanda is developing to treat a sleep disorder that affects blind people. Vanda
`said its drug candidate tasimelteon received orphan drug status, which comes with potential tax incentives, reduced application
`fees, and potential. ..
`Allergan Board of Directors Announces Departure of President F. Michael Ball; Chairman of the Board and Chief Executive
`Officer David E.I. Pyatt Resumes Role as President
`
`http://web.archive.org/web/20110308203650/http://www.drugs.com: 80/
`
`Regeneron Exhibit 1037.004
`
`
`
`Drugs.com I Prescription Drugs - Information, Interactions & Side ...
`
`2of2
`
`IRVINE, Calif.--(BUSINESS WIRE)--Mar 8, 2011 - Allergan, Inc. (NYSE: AGN) today announced that its Board of Directors has
`reappointed David E.I. Pyatt as President. Mr. Pyatt will also continue to serve Allergan in his current roles as Chairman of the
`Board and Chief Executive Officer. Mr. Pyott's role as President succeeds the duties performed by F. Michael Ball, who has
`accepted the position of ...
`More ...
`
`Latest Additions to Drugs.com
`
`Recently added consumer and prescribing information: Daliresp, Corifact, Gralise, Makena, DaTscan, Natroba, Viibryd, Abstral ,
`Fortesta, Safyral ... also see new filings.
`Medication Use While Breastfeeding - More Data Now Online
`Our developers and clinical staff have been working busily behind the scenes to add yet more detailed information in our
`continued effort to increase awareness of potential medication problems. This latest update includes comprehensive information
`relating to medicine use while breastfeeding (lactating). It includes drug levels and possible effects on the lactating mother and
`breastfed ...
`New Pill Identifier App for the iPad, iPhone and iPod Touch
`We are proud to announce the new Drugs.com Pill Identifier application for the iPad, iPhone and iPod Touch. The new iPhone
`Application adds an exciting new dimension by improving convenience and adding offline capabilities. The app features "search
`as you type" functionality with options for searching by imprint, drug name, shape, color and score. Access ...
`New Symptom Checker Released
`We are proud to announce the release of our new and comprehensive Symptom Checker. This powerful tool utilizes the
`prestigious and trusted Medical Decision Guides created by the Faculty of the Harvard Medical School. Covering a multitude of
`medical issues, patients and caregivers can use the step-by-step interactive wizard to help identify the underlying cause ...
`See more blog posts or follow us on twitter.
`
`Browse by Drug Name Using this Complete A-2 List
`
`A-Ac Ac-Ac Ac-Ac Ac-Ac Ac-Ac Ac-Ad Ad-Ad Ad-Ak Ak-AI Al-Al Al-Al Al-Al Al-Al Al-Al Al-Am Am-Am Am-Am Am-Am Am-An An(cid:173)
`An An-An An-Ap Ap-Ar Ar-Ar Ar-As As-At At-At At-Av Av-Az Az-Az B-Ba Ba-Be Be-Be Be-Be Be-Be Be-Be Be-Bi Bi-Bl Bl-Bo Bp(cid:173)
`Br Br-Br Br-Bu Bu-By By-By C-Ca Ca-Ca Ca-Ca Ca-Ca Ca-Ca Ca-Ca Ca-Ce Ce-Ce Ce-Ce Ce-Ce Ce-Ch Ch-Ch Ch-Ch Ch-Ch
`Ch-Ci Ci-Ci Ci-Cl Cl-Cl Cl-Cl Cl-Cl Cl-Co Co-Co Co-Co Co-Co Co-Co Co-Co Co-Cr Cr-Cy Cy-Cy Cy-Cy D-Da Da-Da Da-De De(cid:173)
`De De-De De-De De-De De-De De-Di Di-Di Di-Di Di-Di Di-Di Di-Di Di-Do Do-Do Do-Dr Dr-Du Du-Du Du-Dy E-Ed Ed-El El-Em
`Em-En En-Eo Eo-Ep Ep-Er Er-Es Es-Es Es-Et Et-Eu Eu-Ex Ex-Ez Fa-Fe Fe-Fe Fe-Fe Fe-Fl Fl-Fl Fl-Fl Fl-Fl Fl-Fl FI-Fo Fo-Fo
`Fo-Fu Fu-Fu G-Ga Ga-Ge Ge-Ge Ge-GI GI-GI GI-Gr Gr-Gu Gu-Gy H-Ha Ha-He He-Hi Hi-Hu Hu-Hy Hy-Hy Hy-Hy Hy-Hy Hy-Hy
`1-1111-lm Im-In In-In In-In In-lo lo-Ir Ir-ls ls-Iv Iv-Ix J-Ju K-Ka Ka-Ke Ke-Ko Ko-Ky L-La La-La La-Le Le-Le Le-Le Le-Li Li-Li Li-Li
`Li-Lo Lo-Lo Lo-Lo Lu-Lu Lu-Ly M-Ma Ma-Ma Ma-Md Me-Me Me-Me Me-Me Me-Me Me-Me Me-Me Me-Me Me-Mi Mi-Mi Mi-Mi
`Mi-Mo Mo-Mo Mo-Mu Mu-Mu Mu-My My-Mz N-Na Na-Na Na-Na Na-Ne Ne-Ne Ne-Ne Ne-Ni Ni-Ni Ni-Ni Ni-No No-No No-Nu
`Nu-Ny Ny-Ny 0-0f Of-Om Om-Op Op-Or Or-Os Os-Ox Ox-Ox Ox-Oz P-Pa Pa-Pa Pa-Pa Pa-Pe Pe-Pe Pe-Pe Pe-Pe Pe-Ph Ph(cid:173)
`Ph Ph-Ph Ph-Pi Pi-Pm Pm-Po Po-Po Po-Pr Pr-Pr Pr-Pr Pr-Pr Pr-Pr Pr-Pr Pr-Pr Pr-Pr Pr-Pr Pr-Ps Ps-Py Py-Py Q-Qu Qu-Qv
`R-Ra Ra-Re Re-Re Re-Re Re-Re Re-Ri Ri-Ri Ri-Ro Ro-Ro Ro-Ro Ro-Ry S-Sa Sa-Sa Sa-Se Se-Se Se-Se Se-Si Si-SI SI-So
`So-So So-So So-St St-St St-Su Su-Su Su-Su Su-Sy Sy-Sy T-Ta Ta-Ta Tb-Te Te-Te Te-Te Te-Th Th-Th Th-Ti Ti-Ti Ti-To To-To To(cid:173)
`To To-Tr Tr-Tr Tr-Tr Tr-Tr Tr-Tr Tr-Tr Tr-Tw Tw-Ty Ty-Ty U-Un Un-Ur Ur-Uv V-Va Va-Va Va-Ve Ve-Vi Vi-Vi Vi-Vi Vi-Vi Vi-Vo Vo-Vy
`Wa-Wy X-Xy Xy-Xy Y-Ys Z-Ze Ze-Zi Zi-Zi Zi-Zo Zo-Zy Zy-Zy 10-14 2-2 3-3t 4-415-58-8 sup
`
`http://web.archive.org/web/20110308203650/http://www.drugs.com: 80/
`
`Regeneron Exhibit 1037.005
`
`
`
`Macugen Official FDA information, side effects and uses.
`
`1 of 11
`
`DfUgs:COm
`
`Home > Drugs by Condition > M > Macular Degeneration > Macugen > Prescribing Information
`
`Macugen
`Generic Name: pegaptanib sodium
`Dosage Form: injection, solution
`Macugen®
`(pegaptanib sodium injection)
`
`DESCRIPTION
`
`Macugen® (pegaptanib sodium injection) is a sterile, aqueous solution containing pegaptanib sodium for
`intravitreous injection. Macugen is supplied in a single-dose, pre-filled syringe and is formulated as a
`3.47 mg/ml solution, measured as the free acid form of the oligonucleotide. The active ingredient is 0.3 mg of
`the free acid form of the oligonucleotide without polyethylene glycol, in a nominal volume of 90 µL. This dose
`is equivalent to 1.6 mg of pegaptanib sodium (pegylated oligonucleotide) or 0.32 mg when expressed as the
`sodium salt form of the oligonucleotide moiety. The product is a sterile, clear, preservative-free solution
`containing sodium chloride, monobasic sodium phosphate monohydrate, dibasic sodium phosphate
`heptahydrate, hydrochloric acid, and/or sodium hydroxide to adjust the pH and water for injection.
`
`Pegaptanib sodium is a covalent conjugate of an oligonucleotide of twenty-eight nucleotides in length that
`terminates in a pentylamino linker, to which two 20-kilodalton monomethoxy polyethylene glycol (PEG) units
`are covalently attached via the two amino groups on a lysine residue.
`
`Pegaptanib sodium is represented by the following structural formula:
`
`---"""!-~11
`
`ayvary)
`
`l-= Rib (top edgel
`
`( c. ual a· b b
`Where R is
`
`http://web.archive.org/web/20110307065238/http://www.drugs.com: 80/pro/macugen.html
`
`Regeneron Exhibit 1037.006
`
`
`
`Macugen Official FDA information, side effects and uses.
`
`2 of 11
`
`Dosing linea.nd topedgeofl" ri baligned
`
`and n is approximately 450.
`
`The chemical name for pegaptanib sodium is as follows: RNA, ((2' - deoxy - 2' - fluoro)C - Gm - Gm - A - A -
`(2' - deoxy - 2' - fluoro)U - (2' - deoxy - 2' - fluoro)C - Am - Gm - (2' - deoxy - 2' - fluoro)U - Gm - Am - Am - (2'
`- deoxy - 2' - fluoro)U - Gm - (2' - deoxy - 2' - fluoro)C - (2' - deoxy - 2' - fluoro)U - (2' - deoxy - 2' - fluoro)U -
`Am - (2' - deoxy - 2' - fluoro)U - Am - (2' - deoxy - 2' - fluoro)C - Am - (2' - deoxy - 2' - fluoro)U - (2' - deoxy - 2'
`-fluoro)C- (2' - deoxy-2' - fluoro)C- Gm- (3'-----c>3') - dT), 5'-esterwith a,a' - [4,12 - dioxo - 6- [[[5 -
`(phosphoonoxy)pentyl]amino]carbonyl] - 3, 13 - dioxa - 5, 11 - diaza - 1, 15 - pentadecanediyl]bis[w -
`methoxypoly(oxy - 1,2 - ethanediyl)], sodium salt.
`
`The molecular formula for pegaptanib sodium is C294H342F13N 107Na280188P28[C2H40]n (where n is
`approximately 900) and the molecular weight is approximately 50 kilodaltons.
`
`Macugen is formulated to have an osmolality of 280-360 mOsm/Kg, and a pH of 6-7.
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`
`Pegaptanib is a selective vascular endothelial growth factor (VEGF) antagonist. VEGF is a secreted protein
`that selectively binds and activates its receptors located primarily on the surface of vascular endothelial cells.
`VEGF induces angiogenesis, and increases vascular permeability and inflammation, all of which are thought
`to contribute to the progression of the neovascular (wet) form of age-related macular degeneration (AMO), a
`leading cause of blindness. VEGF has been implicated in blood retinal barrier breakdown and pathological
`ocular neovascularization.
`
`Pegaptanib is an aptamer, a pegylated modified oligonucleotide, which adopts a three-dimensional
`conformation that enables it to bind to extracellular VEGF. Under in vitro testing conditions, pegaptanib binds
`to the major pathological VEGF isoform, extracellular VEGF165, thereby inhibiting VEGF165 binding to its
`VEGF receptors. The inhibition of VEGF164, the rodent counterpart of human VEGF165, was effective at
`suppressing pathological neovascularization.
`
`Pharmacokinetics
`
`Absorption
`
`In animals, pegaptanib is slowly absorbed into the systemic circulation from the eye after intravitreous
`administration. The rate of absorption from the eye is the rate limiting step in the disposition of pegaptanib in
`animals and is likely to be the rate limiting step in humans.
`
`In humans, a mean maximum plasma concentration of about 80 ng/ml occurs within 1 to 4 days after a 3 mg
`monocular dose (10 times the recommended dose). The mean area under the plasma concentration-time
`curve (AUC) is about 25 µg•hr/ml at this dose.
`
`http://web.archive.org/web/20110307065238/http://www.drugs.com: 80/pro/macugen.html
`
`Regeneron Exhibit 1037.007
`
`
`
`Macugen Official FDA information, side effects and uses.
`
`3 of 11
`
`Distribution/Metabolism/Excretion
`
`Twenty-four hours after intravitreous administration of a radiolabeled dose of pegaptanib to both eyes of
`rabbits, radioactivity was mainly distributed in vitreous fluid, retina, and aqueous fluid. After intravitreous and
`intravenous administrations of radiolabeled pegaptanib to rabbits, the highest concentrations of radioactivity
`(excluding the eye for the intravitreous dose) were obtained in the kidney. In rabbits, the component
`nucleotide, 2'-fluorouridine is found in plasma and urine after single radiolabeled pegaptanib intravenous and
`intravitreous doses. In rabbits, pegaptanib is eliminated as parent drug and metabolites primarily in the urine.
`
`Based on preclinical data, pegaptanib is metabolized by endo- and exonucleases.
`
`In humans, after a 3 mg monocular dose (10 times the recommended dose), the average (± standard
`deviation) apparent plasma half-life of pegaptanib is 10 (±4) days.
`
`Special Populations
`
`Plasma concentrations do not appear to be affected by age or gender, but have not been studied in patients
`under the age of 50.
`
`Renal Insufficiency
`
`Dose adjustment for patients with renal impairment is not needed when administering the 0.3 mg dose.
`
`Following a single 3 mg dose (10 times the recommended dose), in patients with severe (N=7), moderate
`(N=18), and mild (N=10) renal impairment, the mean (CV%) pegaptanib AUC values were 37.8 (17%), 26.7
`(31 %), and 23.6 (21 %) µg•hr/ml, respectively. The corresponding Cmax values were 96.8 (23%), 81.6
`(29.2%), and 66.5 (47%) ng/ml, respectively.
`
`In patients with renal impairment, following administration of 3 mg pegaptanib doses every 6 weeks, the last
`detectable pegaptanib concentrations in plasma after the fourth dose were highly variable (ranging from
`8 ng/ml to 66 ng/ml) and the variability was more pronounced in patients with severe renal impairment.
`
`Hemodialysis
`
`Macugen has not been studied in patients requiring hemodialysis.
`
`Hepatic Impairment
`
`Macugen has not been studied in patients with hepatic impairment.
`
`Clinical Studies
`
`Macugen was studied in two controlled, double-masked, and identically designed randomized studies in
`patients with neovascular AMO. Patients were randomized to receive control (sham treatment) or 0.3 mg,
`1 mg or 3 mg Macugen administered as intravitreous injections every 6 weeks for 48 weeks. A total of
`approximately 1200 patients were enrolled with 892 patients receiving Macugen and 298 receiving a sham
`injection. The median age of the patients was 77 years. Patients received a mean 8.5 treatments out of a
`possible 9 total treatments across all treatment arms. Patients were re-randomized between treatment and no
`treatment during the second year. Patients who continued treatment in year 2 received a mean of
`16 treatments out of a possible total 17 overall.
`
`The two trials enrolled patients with neovascular AMO characteristics including classic, occult, and mixed
`lesions of up to 12 disc areas and baseline visual acuity in the study eye between 20/40 and 20/320. The
`primary efficacy endpoint was the proportion of patients losing less than 15 letters of visual acuity, from
`
`http://web.archive.org/web/20110307065238/http://www.drugs.com: 80/pro/macugen.html
`
`Regeneron Exhibit 1037.008
`
`
`
`Macugen Official FDA information, side effects and uses.
`
`4of 11
`
`baseline up to 54 week assessment. Verteporfin photodynamic therapy (PDT) usage was permitted at the
`discretion of the investigators in patients with predominantly classic lesions.
`
`The groups treated with Macugen 0.3 mg exhibited a statistically significant result in both trials for the primary
`efficacy endpoint at 1 year: Study EOP1003, Macugen 73% vs. Sham 60%; Study EOP1004, Macugen 67%
`vs. Sham 53%. Concomitant use of PDT overall was low. More sham treated patients (75/296) received PDT
`than Macugen 0.3 mg treated patients (58/294).
`
`On average, Macugen 0.3 mg treated patients and sham treated patients continued to experience vision loss.
`However, the rate of vision decline in the Macugen treated group was slower than the rate in the patients who
`received sham treatment. See Figure 1.
`
`Figure 1
`
`P~~
`oxi'
`
`At the end of the first year (week 54), approximately 1050 of the original 1200 patients were re-randomized to
`either continue the same treatment or to discontinue treatment through week 102. See Figure 2.
`
`Macugen was less effective during the second year than during the first year. The percentage of patients
`losing less than 15 letters from baseline to week 102 was: Study EOP1003, Macugen 38/67 (57%); Sham
`30/54 (56%); Study EOP1004, Macugen 40/66 (61 %); Sham 18/53 (34%).
`
`Figure 2
`
`H
`
`,CJ'f.~N~
`
`0
`
`~
`
`OyN-1
`n O
`,ci'-);,o
`
`Dose levels above 0.3 mg did not demonstrate any additional benefit.
`
`The safety or efficacy of Macugen beyond 2 years has not been demonstrated.
`
`http://web.archive.org/web/20110307065238/http://www.drugs.com: 80/pro/macugen.html
`
`Regeneron Exhibit 1037.009
`
`
`
`Macugen Official FDA information, side effects and uses.
`
`5 of 11
`
`INDICATIONS AND USAGE
`
`Macugen is indicated for the treatment of neovascular (wet) age-related macular degeneration.
`
`CONTRAINDICATIONS
`
`Macugen is contraindicated in patients with ocular or periocular infections.
`
`Macugen is contraindicated in patients with known hypersensitivity to pegaptanib sodium or any other
`excipient in this product.
`
`WARNINGS
`
`lntravitreous injections including those with Macugen have been associated with endophthalmitis. Proper
`aseptic injection technique should always be utilized when administering Macugen. In addition, patients
`should be monitored during the week following the injection to permit early treatment, should an infection
`occur (see DOSAGE AND ADMINISTRATION ).
`
`Increases in intraocular pressure have been seen within 30 minutes of injection with Macugen. Therefore,
`intra ocular pressure as well as the perfusion of the optic nerve head should be monitored and managed
`appropriately.
`
`PRECAUTIONS
`
`General
`
`FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY.
`
`Rare cases of anaphylaxis/anaphylactoid reactions, including angioedema, have been reported in the post(cid:173)
`marketing experience following the Macugen intravitreal administration procedure (see ADVERSE EVENTS
`and DOSAGE AND ADMINISTRATION ).
`
`Information for Patients
`
`In the days following Macugen administration, patients are at risk for the development of endophthalmitis. If
`the eye becomes red, sensitive to light, painful or develops a change in vision, the patient should seek the
`immediate care with their ophthalmologist.
`
`Drug Interactions
`
`Drug interaction studies have not been conducted with Macugen. Pegaptanib is metabolized by nucleases
`and is generally not affected by the cytochrome P450 system.
`
`Two early clinical studies conducted in patients who received Macugen alone and in combination with PDT
`revealed no apparent difference in the plasma pharmacokinetics of pegaptanib.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Carcinogenicity studies with pegaptanib have not been conducted.
`
`Pegaptanib and its monomer component nucleotides (2'-MA, 2'-MG, 2'-FU, 2'-FC) were evaluated for
`genotoxicity in a battery of in vitro and in vivo assay systems. Pegaptanib, 2'-0-methyladenosine (2'-MA), and
`2'-0-methylguanosine (2'-MG) were negative in all assay systems evaluated. 2'-fluorouridine (2'-FU) and 2'-
`
`http://web.archive.org/web/20110307065238/http://www.drugs.com: 80/pro/macugen.html
`
`Regeneron Exhibit 1037.010
`
`
`
`Macugen Official FDA information, side effects and uses.
`
`6 of 11
`
`fluorocytidine (2'-FC) were nonclastogenic and were negative in all S. typhimurium tester strains, but
`produced a non-dose related increase in revertant frequency in a single E. coli tester strain. Pegaptanib, 2'(cid:173)
`FU, and 2'-FC tested negative in cell transformation assays.
`
`No data are available to evaluate male or female mating or fertility indices.
`
`Pregnancy
`
`Teratogenic Effects: Pregnancy Category B.
`
`Pegaptanib produced no maternal toxicity and no evidence of teratogenicity or fetal mortality in mice at
`intravenous doses of up to 40 mg/kg/day (about 7,000 times the recommended human monocular ophthalmic
`dose of 0.3 mg/eye). Pegaptanib crosses the placenta in mice.
`
`There are no studies in pregnant women. The potential risk to humans is unknown. Macugen should be used
`during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
`
`Nursing Mothers
`
`It is not known whether pegaptanib is excreted in human milk. Because many drugs are excreted in human
`milk, caution should be exercised when Macugen is administered to a nursing woman.
`
`Pediatric Use
`
`Safety and effectiveness of Macugen in pediatric patients have not been studied.
`
`Geriatric Use
`
`Approximately 94% (834/892) of the patients treated with Macugen were~ 65 years of age and
`approximately 62% (553/892) were~ 75 years of age. No difference in treatment effect or systemic exposure
`was seen with increasing age.
`
`ADVERSE EVENTS
`
`Serious adverse events related to the injection procedure occurring in < 1 % of intravitreous injections
`included endophthalmitis (see WARNINGS), retinal detachment, and iatrogenic traumatic cataract.
`
`The most frequently reported adverse events in patients treated with Macugen 0.3 mg for up to two years
`were anterior chamber inflammation, blurred vision, cataract, conjunctiva! hemorrhage, corneal edema, eye
`discharge, eye irritation, eye pain, hypertension, increased intraocular pressure (IOP), ocular discomfort,
`punctate keratitis, reduced visual acuity, visual disturbance, vitreous floaters, and vitreous opacities. These
`events occurred in approximately 10-40% of patients.
`
`The following events were reported in 6-10% of patients receiving Macugen 0.3 mg therapy:
`
`Ocular: blepharitis, conjunctivitis, photopsia, vitreous disorder.
`
`Non-Ocular: bronchitis, diarrhea, dizziness, headache, nausea, urinary tract infection.
`
`The following events were reported in 1-5% of patients receiving Macugen 0.3 mg therapy:
`
`Ocular: allergic conjunctivitis, conjunctiva! edema, corneal abrasion, corneal deposits, corneal epithelium
`disorder, endophthalmitis, eye inflammation, eye swelling, eyelid irritation, meibomianitis, mydriasis,
`periorbital hematoma, retinal edema, vitreous hemorrhage.
`
`http://web.archive.org/web/20110307065238/http://www.drugs.com: 80/pro/macugen.html
`
`Regeneron Exhibit 1037.011
`
`
`
`Macugen Official FDA information, side effects and uses.
`
`7 of 11
`
`Non-Ocular: arthritis, bone spur, carotid artery occlusion, cerebrovascular accident, chest pain, contact
`dermatitis, contusion, diabetes mellitus, dyspepsia, hearing loss, pleural effusion, transient ischemic attack,
`urinary retention, vertigo, vomiting.
`
`Post-Marketing Experience: Anaphylaxis/anaphylactoid reactions, including angioedema, have been
`identified during postapproval use of Macugen. Because these reactions are reported voluntarily from a
`population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal
`relationship to drug exposure (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
`
`OVERDOSAGE
`
`Doses of Macugen up to 10 times the recommended dosage of 0.3 mg have been studied. No additional
`adverse events have been noted but there is decreased efficacy with doses above 1 mg.
`
`DOSAGE AND ADMINISTRATION
`
`Macugen 0.3 mg should be administered once every six weeks by intravitreous injection into the eye to be
`treated.
`
`Macugen should be inspected visually for particulate matter and discoloration prior to administration.
`
`Administration of the syringe contents involves assembly of the syringe with the administration needle. The
`injection procedure should be carried out under controlled aseptic conditions, which includes the use of sterile
`gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). When ready to assemble syringe and
`administer injection, carefully peel open pouches, remove contents, and place on sterile field. If upon opening
`the pouch, the plastic clip is missing or not attached to the syringe, the syringe should not be used.
`
`To avoid compromising the sterility of the product, do not pull back on the plunger.
`
`• Remove the syringe from the plastic clip.
`• Twist off cap.
`• Attach the sterile BD® 30G 1/2" Precision Glide® administration needle (included) to the syringe by
`screwing it into the syringe tip.
`-- Another sterile administration needle may be used in lieu of the one included. Remove the plastic
`needle shield from the needle.
`• Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles,
`gently tap the syringe with your finger until the bubbles rise to the top of the syringe. SLOWLY
`depress the plunger to eliminate all the bubbles and to expel the excess drug so that the top edge
`of the 3rd rib on the plunger stopper aligns with the pre-printed black dosing line (See Fig 2, below).
`• Inject the entire contents of the syringe.
`
`PRIOR to Injection
`Fig 1. Before expelling air bubble and excess drug
`
`http://web.archive.org/web/20110307065238/http://www.drugs.com: 80/pro/macugen.html
`
`Regeneron Exhibit 1037.012
`
`
`
`Macugen Official FDA information, side effects and uses.
`
`8 of 11
`
`Figure 1
`
`..
`
`Mean Visual Acuity: Year 1
`
`EOP 1003
`
`PllhntTrn1mont cvnr o
`IJ).I mg)
`•
`o (lh•m )
`
`..
`
`..
`
`EOP1004
`
`Pahnt Troatn ontc vnr o
`• (D.B mg )
`o (lh •m)
`
`'IIHH
`
`WH H
`
`,., -+----..---.--~----.--..----..----r-~--.
`
`READY for Injection
`Fig 2. After expelling air bubble and excess drug
`
`Figure 2
`
`SD
`
`'"
`~ 'D
`c"'
`i
`:s 40
`
`s,
`
`30
`64
`
`Mean Visual Acuity: Year 2
`
`EOP 1003
`
`Pat entTrnbnuit(Vnr , J-+(VHr2)
`.. co.3 mg)-+ caicontm»)
`+ (0.3 mg) -+ (O.S mg)
`o.(S1111m) -+ SllBm crdl1conlnlll)
`
`~---
`
`ID
`
`II
`
`1'2
`
`71
`;MU
`
`B4
`
`ID
`
`Pl
`
`102
`
`ID
`
`"
`~ ,D
`c"'
`i
`:s 40
`
`s,
`
`ID ,4
`
`EOP1004
`
`Pahntltntnenl(VHr, )-+(l'Hr 2J
`... (O. S mg)-+ (0.3 mg )
`(O.S mg) -+ (Cllconllrue)
`•
`.o.cs11am J -+ s1111m ore11ce<1tl\Je
`
`SD
`
`H
`
`n
`
`n
`··MU
`
`w
`
`n
`
`"
`
`w
`
`The patient's medical history for hypersensitivity reactions should be evaluated prior to performing the
`intravitreal procedure (see PRECAUTIONS and ADVERSE EVENTS). Adequate anesthesia and a broad(cid:173)
`spectrum microbicide should be given prior to the injection.
`
`Following the injection, patients should be monitored for elevation in intraocular pressure and for
`endophthalmitis. Monitoring may consist of a check for perfusion of the optic nerve head immediately after
`the injection, tonometry within 30 minutes following the injection, and biomicroscopy between two and seven
`days following the injection. Patients should be instructed to report any symptoms suggestive of
`endophthalmitis without delay.
`
`No special dosage modification is required for any of the populations that have been studied (i.e. gender,
`elderly).
`
`The safety and efficacy of Macugen therapy administered to both eyes concurrently have not been studied.
`
`HOW SUPPLIED
`
`Macugen (pegaptanib sodium injection) is supplied in a sterile foil pouch as a single-use glass syringe pre-
`
`http://web.archive.org/web/20110307065238/http://www.drugs.com: 80/pro/macugen.html
`
`Regeneron Exhibit 1037.013
`
`
`
`Macugen Official FDA information, side effects and uses.
`
`9 of 11
`
`filled with 0.3 mg of Macugen® in a nominal 90 µL deliverable volume pack. A sterile packaged BD® single
`use 30G x 1/2" Precision Glide® Luer Lok® needle is supplied in a separate pouch. The foil pouch and
`needle are packaged together in a carton.
`
`Storage
`
`Store in the refrigerator at 2° to 8°C (36° to 46°F). Do not freeze or shake vigorously.
`
`Rx only.
`
`BD and Precision Glide Luer Lok® are registered trademarks of Becton Dickinson & CO, Franklin Lakes, New
`Jersey 07417
`
`NOC 68782-001-02
`
`Manufactured by:
`Gilead Sciences, Inc
`650 Cliffside Drive
`San Dimas, CA 91773
`
`For:
`Eyetech Inc.
`140 East Hanover Avenue
`Cedar Knolls, NJ 07927
`
`Revised 08/2008
`
`PRINCIPAL DISPLAY PANEL
`
`NOC 68782-001-02
`Rx only
`Macugen®
`(pegaptanib sodium injection)
`For lntravitreous Injection
`0.3 mg I 90 µL*
`
`······-·····-·i~~,;:,a-fu-1 w~,;~;-q,uei-d~~~~-i-
`
`·····-- ~ Ii
`··--····---·········-····----····--······-~~~.~.~-~~~ ·-····-·····~~'.:'?:'.~~~~~.~ .... l.~~t -- o -
`
`:Stare rtlrilllualed, Z - l"'C 13& • U'f). a. 101111m1 or :s:h'a: , iaorimlr.
`
`CIOSAGEAMU US£
`Fo,inlravill'ti)!JS r'l~ion.
`SN actompanying pmaibu\f fnformili'oo and t!il't:tti:orl:s: lo1 nSl!lllMJ.
`
`"bell t ml syringe delivers a unit ®Seor D.3 mm peiµ~:Jntb sodium In 90 µl. when :iidmini.stmd