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Table of Contents

Table of Content - alphabetical order

Sample monographs (full text):

RSV Mab, rDNA (Synagis from MedImmune)

EPO rDNA Amgen

FDA Approvals

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SAMPLE MONOGRAPH: EPO, rDNA/Amgen

Epoetin alfa - Epogen; Procrit; Erythropoietin, recombinant

Status: approved; marketed

Organizations involved:

Amgen, Inc. - Manuf.; R&D; Tech.; USA mark.

Ortho Biologics LLC - USA. mark.

Johnson & Johnson Co. (J&J) - Parent co.

Kirin Pharmaceuticals, Ltd. - R&D; Tech.

Transkaryotic Therapies, Inc. (TKT) - Patent dispute

Aventis Pharma AG - Patent dispute

University of Chicago - R&D; Tech.

Genetics Institute - Patent dispute; Former inv.

Wyeth - Parent co.

University of Washington - Patent dispute

Columbia University - Tech.; Patent dispute

Cross ref.: See the Erythropoietin (EPO) Products entry (#117) and the entry for the other EPO product (Eprex) (#119) manufactured by Ortho Biotech/J&J.

Description: Epoetin alfa, marketed as Epogen and Procrit, are aqueous formulations of recombinant human erythropoietin (EPO) glycoprotein expressed by Chinese Hamster Ovary (CHO) cell culture and having the same amino acid sequence as human EPO. Erythropoietin is a 165 amino acid, 30,400 Daltons (30.4 kDa) molecular weight glycoprotein (~62% protein, 38% carbohydrate). The carbohydrate moiety consists of three N-linked carbohydrate chains and one O-linked side chain. EPO has a calculated molecular formula of C809H1301N229OO240S5.

The recombinant EPO in both products, Epogen from Amgen and Procrit from Ortho/Johnson & Johson (Ortho/J&J) , is identical and manufactured by Amgen, and Amgen manufactures both finished products. Ortho/J&J also manufactures its own EPO, but only for marketing (as Eprex) outside of the U.S. (see entry below). Amgen supplied bulk EPO to Ortho/J&J for international marketing (as Eprex), until Ortho/J&J received approval for its own manufacturing facility in 1995. Epogen is marketed in the U.S. by Amgen for kidney dialysis (renal failure; end-stage renal disease) indications indications, while Ortho/J&J markets Procrit for all other indications, primarily cancer chemotherapy-associated anemia. See the Companies section below and the EPO Products entry above for further information about these companies' respective markets.

Epogen and Procrit are formulated as a sterile, colorless, isotonic sodium chloride/sodium citrate buffered solution for intravenous (IV) or subcutaneous (SC) administration in both preservative-free and preservative (benzyl alcohol)-containing single-dose and multidose vials. Preservative-free single-dose vials of Epogen and Procrit each contain 1 mL of solution containing either 2,000, 3,000, 4,000 or 10,000 Units of Epoetin alfa, along with 2.5 mg Albumin (Human) as stabilizer, 5.8 mg sodium citrate, 5.8 mg sodium chloride, and 0.06 mg citric acid in Water for Injection, USP (pH 6.9 ± 0.3). Also, a 40,000 Units single-dose, 1 mL, preservative-free vial contains Epoetin alfa at 40,000 Units/mL, alone with 2.5 mg Albumin (Human), 1.2 mg sodium phosphate monobasic monohydrate, 1.8 mg sodium phosphate dibasic anhydrate, 0.7 mg sodium citrate, 5.8 mg sodium chloride, and 6.8 mcg citric acid in Water for Injection, USP (pH 6.9 ± 0.3). The 2 mL multidose preserved vial contains 20,000 Units Epoetin alfa, with each 1 mL of solution containing 10,000 Units of Epoetin alfa, 2.5 mg Albumin (Human), 1.3 mg sodium citrate, 8.2 mg sodium chloride, 0.11 mg citric acid, and 1% benzyl alcohol as preservative in Water for Injection, USP (pH 6.1 ± 0.3). The 1 mL multidose preserved vial contains 20,000 Units Epoetin alfa, along with 2.5 mg Albumin (Human), 1.3 mg sodium citrate, 8.2 mg sodium chloride, 0.11 mg citric acid, and 1% benzyl alcohol as preservative in Water for Injection, USP (pH 6.1 ± 0.3). The dating period for these formulations is 24 months from the date of manufacture when stored at 2-8€C (refrigerated), with the date of manufacture defined as the date of the final sterile filtration of bulk product.

The EPO originally manufactured by Amgen and used in U.S. clinical trials differs slightly from the approved, commercial product. Modifications of the manufacturing process resulted in a slight difference in the distribution of EPO isoforms in the final product compared to that produced in the clinical research production facility (and used for various clinical trials). However, biochemical equivalence of the two products has been established using tryptic mapping, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), high pressure liquid chromatography (HPLC), Western blots, radioimmunoassay (RIA) and N-terminal protein sequencing. Clinical equivalence was demonstrated in a blinded, 74-patient, 6-week trial, with the same maintenance dosage of each showing comparable efficacy and safety.

This CHO-expressed recombinant EPO glycoprotein has a primary structural conformation duplicating that of native human erythropoietin and an average carbohydrate composition different from that of native human EPO. As described in a recent patent (5,955,422), purified human urinary EPO and recombinant CHO cell-produced EPO were subjected to carbohydrate analysis. Experimentally determined carbohydrate constitution values (expressed as molar ratios of carbohydrate in the product) for the urinary isolate were: hexoses, 1.73; N-acetylglucosamine, 1; N-acetylneuraminic acid, 0.93; fucose, 0; and N-acetyl-galactosamine, 0. Corresponding values for the recombinant product were: Hexoses, 15.09; N-acetylglucosamine, 1; N-acetylneuraminic acid, 0.998; Fucose, 0; and N-acetylgalactosamine, 0.

Nomenclature: EPO, rDNA/Amgen [BIO]; Epogen [TR reg. to Amgen]; Procrit [TR reg. to Ortho/J&J]; Epoetin alfa [FDA CAS USAN INN BAN]; 1-165-Erythropoietin (human clone lambda HEPOFL13 protein moiety) [CAS]; 1-165-Erythropoietin (human clone lambdaHEPOFL13 protein moiety), glycoform alpha [CAS]; 113427-24-0 [CAS RN]; EPO [SY]; erythropoietin, recombinant [SY]; Espo [TR Japan]; NDC 55513-126-10, NDC 55513-267-10, NDC 55513-148-10, NDC 55513-144-10, NDC 55513-823-10, NDC 55513-283-10, NDC 55513-478-10 [NDC for Epogen]; NDC 59676-302-01; NDC 59676-303-01; NDC 59676-304-01; NDC 59676-310-01; NDC 59676-340-01; NDC 59676-302-02; NDC 59676-303-02; NDC 59676-304-02; NDC 59676-310-02; NDC 59676-312-01; NDC 59676-320-01 [NDC for Procrit]

Companies: EPO (marketed as Epogen and Procrit) was initially developed by Amgen, Inc. in collaboration with Kirin Pharmaceuticals, Ltd., and is manufactured by Amgen, Inc., CBER/FDA est. no. 1080. Amgen supplies EPO to Ortho/J&J for marketing in the U.S. as Procrit (for its licensed/designated non-dialysis-related markets). Epoetin alpha (Epogen and Procrit) manufactured by Amgen has only been marketed in the U.S., since 1995 when Ortho/J&J received approval for manufacture of its own EPO.

Kirin Pharmaceuticals, Ltd. assisted Amgen in development of EPO, and receives royalties from Amgen. In its deal originally negotiated in May, 1984 (prior to start of clinical trials), and renegotiated in Oct., 1989, with an investment of $44.5 million, Kirin receives 5% royalties from Amgen (according to Recombinant Capital). [Note, Epogen and several other Amgen products were actually developed through Kirin-Amgen, a joint venture company formed in 1984 and 50% owned by both Amgen and Kirin, with exclusive manufacturing, patent and marketing rights granted to Amgen in the U.S. (and other companies in certain other territories), Amgen (and other companies in other territories) paying Kirin-Amgen royalties on sales, and with Kirin-Amgen reimbursing Amgen for R&D expenses. However, most sources simply treat Epogen and other Kirin-Amgen products as though they originated solely from Amgen].

In 1985, Amgen licensed exclusive U.S. marketing rights for indications other than end-stage renal disease and all international (non-U.S.) marketing rights, including cancer chemotherapy-associated anemia, to Ortho Biotech LLC, a subsidiary of Johnson & Johnson Co. (J&J). Thus, EPO is marketed (as Epogen) in the U.S. by Amgen, Inc., but only for treatment of anemia associated with end stage renal disease. At the time, it was presumed that renal disease would constitute about one-third of the EPO market (i.e., Amgen negotiated away 2/3's or more of EPO's potential market). Amgen received $10 million upon signing the deal. Ortho/J&J markets EPO (from EPO supplied by Amgen) under the trade name Procrit in the U.S., and markets EPO it manufactures itself internationally (outside U.S.) under the trade name Eprex. Marketing and patent disputes have persisted between Amgen and Ortho/J&J since EPO was first introduced. See the Erythropoietin (EPO) Products entry (#113) and the Tech. transfer and Status sections of this entry and the EPO, rDNA/Ortho (Eprex) entry (#116). While some at the time accused Amgen of giving away too much in its deal with Ortho/J&J, in hindsight both parties have made considerable sums (now billions annually) from EPO (Amgen's first product), and EPO remains the single most important revenue source and factor responsible for the growth and success of Amgen. Amgen badly needed funds at the time just to survive and continue EPO and Neupogen development, and was involved in costly patent disputes with Genetics Institute over EPO that cast doubts on its likelihood of being able to market EPO.

On July 6, 2000, Amgen received FDA approval for manufacture of EPO at its new Longmont, CO, facilities. The plant has three times the EPO production capacity of Amgen's original plant in Thousand Oaks, CA.

Manufacture: Production begins with growth and expansion of CHO cells from the Master Working Cell Bank (MWCB). The MWCB has been shown to be genetically stable, homogenous and free from contaminating adventitious agents (microorganisms). CHO cell culture takes place in large numbers of roller bottles. The cells are cultured in conditions favoring accumulation of expressed EPO in the cell culture medium. The secreted product is isolated from medium using sequential column chromatography. A number of in-process tests are performed to assure purity. At time of original approval, Amgen committed to development of a culture process which would allow sterile sampling from prepurified bulk material for purposes of mycoplasma testing.

The purified bulk product is tested for identity using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), Western blot analysis, isoelectric focusing, and N-terminal protein sequence analysis. Potency is confirmed by radioimmunoassay (RIA) and in vivo bioassay. Purity is assessed by SDS-PAGE, high pressure liquid chromatography (HPLC), DNA analysis, and an immunoassay for potential contaminating proteins. Purified bulk product is also tested for mycoplasma. The formulated bulk product is tested for sterility, total protein, endotoxin, and potency (by RIA). The final vialed product is tested for appearance, potency (by RIA and in vivo bioassay), total protein, sterility, general safety, pyrogenicity, and endotoxin levels. The identity and quantity of all excipients are confirmed.

The product is manufactured through the formulated bulk phase by Amgen, and (as described in original approval-related FDA documents) then shipped under controlled conditions to Parke-Davis, subsidiary of Warner-Lambert Co., facilities in Rochester, MI . These facilities were later sold to Parkedale Pharmaceuticals, a subsidiary of King Pharmaceuticals (which may continue this task). Under supervision of Amgen personnel, the formulated bulk product is sterile-filtered, filled into final containers, labeled and packaged.

FDA class: Biologic PLA

CBER class: Blood And Blood Derivatives

CBER to CDER: Among the products transferred within FDA on June 30, 2003

Approvals: Date = 19890601, first approval, PLA ref. no. 87-0535, ELA ref. no. 87-0536; orphan designation (granted 04/10/1986; expired 6/1996); Indication = treatment of anemia associated with end stage renal disease (ESRD)

Date = 19901231; PLA supplement; Indication = acute lymphocytic leukemia in HIV-infected patients

Date = 19901231; PLA supplement; orphan designation (07/01/1991); Indication = treatment of anemia associated with HIV infection or HIV treatment

Date = 19930401; PLA supplement; Indication = anemia associated with cancer chemotherapy

Date = 19961223; PLA supplement; Indication = reduce need for blood transfusions in anemic patients undergoing elective, non-cardiac, non-vascular surgery

Date = 19990726; BLA supplement (license converted from PLA to BLA); Indication = revision of package insert/labeling to include pediatric use

Date = 20000606; BLA supplement; Indication = manufacture of EPO at new facilities in Longmont, Colorado

Indications: [full text of "INDICATIONS AND USAGE" section of Epogen product insert/labeling]:

Treatment of Anemia of Chronic Renal Failure Patients: EPOGEN is indicated for the treatment of anemia associated with CRF, including patients on dialysis (ESRD) and patients not on dialysis. EPOGEN is indicated to elevate or maintain the red blood cell level (as manifested by the hematocrit or hemoglobin determinations) and to decrease the need for transfusions in these patients. Non-dialysis patients with symptomatic anemia considered for therapy should have a hematocrit less than 30%.

EPOGEN is not intended for patients who require immediate correction of severe anemia. EPOGEN may obviate the need for maintenance transfusions but is not a substitute for emergency transfusion.

Prior to initiation of therapy, the patient's iron stores should be evaluated. Transferrin saturation should be at least 20% and ferritin at least 100 ng/mL. Blood pressure should be adequately controlled prior to initiation of EPOGEN therapy, and must be closely monitored and controlled during therapy.

EPOGEN should be administered under the guidance of a qualified physician (see DOSAGE AND ADMINISTRATION).

Treatment of Anemia in Zidovudine-treated HIV-infected Patients: EPOGEN is indicated for the treatment of anemia related to therapy with zidovudine in HIV-infected patients. EPOGEN is indicated to elevate or maintain the red blood cell level (as manifested by the hematocrit or hemoglobin determinations) and to decrease the need for transfusions in these patients. EPOGEN is not indicated for the treatment of anemia in HIV-infected patients due to other factors such as iron or folate deficiencies, hemolysis or gastrointestinal bleeding, which should be managed appropriately.

EPOGEN, at a dose of 100 Units/kg TIW, is effective in decreasing the transfusion requirement and increasing the red blood cell level of anemic, HIV-infected patients treated with zidovudine, when the endogenous serum erythropoietin level is < 500 mUnits/mL and when patients are receiving a dose of zidovudine < 4200 mg/week.

Treatment of Anemia in Cancer Patients on Chemotherapy: EPOGEN is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy. EPOGEN is indicated to decrease the need for transfusions in patients who will be receiving concomitant chemotherapy for a minimum of 2 months. EPOGEN is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis or gastrointestinal bleeding which should be managed appropriately.

Reduction of Allogeneic Blood Transfusion in Surgery Patients: EPOGEN is indicated for the treatment of anemic patients (hemoglobin > 10 to < 13 g/dL) scheduled to undergo elective, noncardiac, nonvascular surgery to reduce the need for allogeneic blood transfusions. EPOGEN is indicated for patients at high risk for perioperative transfusions with significant, anticipated blood loss. EPOGEN is not indicated for anemic patients who are willing to donate autologous blood. The safety of the perioperative use of EPOGEN has been studied only in patients who are receiving anticoagulant prophylaxis.

Indications: [full text of the ÏINDICATIONS AND USAGEÓ section of Procrit product insert/labeling]:

[Same as for Epogen (above), except "PROCRIT" substituted for "EPOGEN."

Status: Note, both Epogen from Amgen and Procrit from Ortho/J&J (containing the same EPO from Amgen, marketed in the U.S. only) are approved for the same indications, including for anemia associated with chronic renal failure (kidney dialysis, an indication solely held by Amgen in the U.S.) and cancer chemotherapy and other indications (held by Ortho/J&J in the U.S.). Thus, technically, both products hold approvals for indications not allowed under the Amgen-Ortho/J&J licensing agreement. The 1985 Amgen/Ortho licensing agreement provides Ortho/J&J with exclusive U.S. rights to the market for indications other than chronic renal failure and exclusive rights for all indications outside the U.S., while Amgen retained exclusive U.S. rights for end-stage renal disease (kidney dialysis)-associated indications. Since the very beginning, Ortho/J&J and Amgen have tested the limits and encroached on each other's markets, resulting in accusations of each other company encroaching in their market(s). For example, currently (6/2004), the Ortho/J&J Procrit Web site (www.procrit.com) includes pages informing kidney disease patients (who are not on dialysis) that Procrit can treat their anemia, without mentioning dialysis, chronic renal failure," or end-stage renal disease. The companies have been through binding arbitration of such marketing disputes multiple times. See the Erythropoietin (EPO) Products entry for further information.

Procrit, with its high cost, has been a target of counterfeiters. For example, an estimated 110,000 vials of Epogen (costing about $22 each) were relabelled and sold as high-strength Procrit at about $445/vial, with the counterfeiters taking in about $46 million before shut down by authorities in May 2002. Only less than 10% of the counterfeit product was ever recovered, meaning as many as 25,000 patients may have received counterfeit product.

In Nov. 2003, Ortho/J&J filed a BLA supplement for a once weekly 40,000 unit dose for Procrit (the current starting dose being 150 units/kg three times weekly).

Tech. transfer: Amgen filed its first patent (Lin patent) application in 1984 for the EPO gene sequence and recombinant EPO (composition-of-matter). U.S. patents assigned to Amgen (or Kirin-Amgen) having the title "Production of erythropoietin" and including Dr. Lin as inventor include: 5,547,933; 5,618,698; 5,621,080; 5,756,349; and 5,955,422. Other Amgen EPO patents include 5,547,933 and 5,441,868. The earliest U.S. "Lin" patent is 4,703,008, granted to Amgen on Oct. 27, 1987. This simplistically provides a U.S. patent expiration date in 2004, which is often reported as the U.S. patent expiration date for EPO. However, Amgen has obtained many patents, particularly in the U.S. on diverse aspects of EPO, e.g., composition-of-matter, medical use, process, and formulation patents, and can be expected to aggressively defend its EPO patent-based exclusivity for as long as it can. Thus, it appears to be an oversimplification that Amgen's EPO U.S. patent coverage expires in 2004, which is what some sources report. Amgen and J&J claim coverage into 2013, which is more likely accurate. Other sources have reported U.S. patent protection to June, 2005. European patent coverage for EPO as composition-of-matter is, similarly, often reported to expire in 2004. The patent situation in Europe is not as complex, the 2004 date may be accurate, and will likely be tested by biogeneric or follow-on produts.

Kirin Pharmaceuticals Ltd. licensed EPO-related technology, particularly highly purified human EPO (and associated patents), from the University of Chicago, where researchers had long studied the natural protein and had developed methods for manufacture of human urine-derived EPO by the mid-1970s.. As part of its collaboration with Amgen for EPO development, Kirin contributed this material as part of EPO's development. Amgen researchers, particularly Dr. Fu Kuen Lin, et al., used this high purity urine-derived human EPO to determine its amino acid sequence. With knowledge of the protein sequence, oligonucleotide probes were designed and used to retrieve human EPO gene, which was cloned in bacteria. Once the proper human gene for EPO was confirmed, the gene was further cloned in CHO cells.

Amgen (Kirin-Amgen) was involved in patent disputes with Genetics Institute (now part of Wyeth), with both companies having developed methods for recombinant manufacture of EPO. The University of Washington joined the suit on behalf of Genetics Inst. Genetic Inst. had licensed its EPO technology to Boehringer Mannheim (now Hoffmann-La Roche), which markets epoetin beta (NeoRecormon) in international markets (see related entry). The disputes were resolved in favor of Kirin-Amgen. In July 2001, Roche settled its decade-long European patent dispute with Ortho/J&J, Amgen, and Genetics Inst (now Wyeth) concerning recombinant EPO. Terms were not disclosed, but all suits were dropped and European marketing of Eprex (Ortho/J&J) and (Neo)Recormon (Roche) continued unchanged (indicating the parties cross-licensed their patents).

U.S. 5,955,422, the most recent Amgen "Lin" patent, has only two claims: "1. A pharmaceutical composition comprising a therapeutically effective amount of human erythropoietin and a pharmaceutically acceptable diluent, adjuvant or carrier, wherein said erythropoietin is purified from mammalian cells grown in culture. 2. A pharmaceutically-acceptable preparation containing a therapeutically effective amount of erythropoietin wherein human serum albumin is mixed with said erythropoietin. " This patent includes Descriptions of EPO manufacture by various recombinant methods, including detailed Descriptions of CHO expression, presumably relevant to the product's actual manufacture.

Amgen was involved in an interference dispute (to determin first--to-invent) concerning a U.S. patent application assigned to Chugai Pharmaceuticals claiming aspects of recombinant purified EPO. The case was decided by the patent office in favor of Amgen in 1991.

Amgen filed suit in U.S. District Court in 1999/2000 alleging that Transkaryotic Technologies (TKT) and its collaborator, Aventis Pharma, were infringing five of AmgenÌs U.S. patents covering recombinant EPO. TKT and Aventis were collaboratively developing gene-activated EPO (see the GA-EPO or Dynepo entry below) involving selective induction of human cells to express EPO. TKT also challenged the five Amgen patents claiming recombinant EPO. GA-EPO would cost must less to manufacture in large quantities than EPO. TKT claims that because its EPO is made by selective activation of human genes in culture, rather than more traditional recombinant methods (using transformed Chinese hamster ovary cells in the case of Epogen/Procrit and Eprex), it is not covered by Amgen's patents concerning recombinant EPO. A decision against TKT (and Aventis Pharma) was announced in Jan. 2001, ruling that claims 2 through 4 of Amgen's U.S. 5,621,080, while not literally infringed, were valid and infringed under the doctrine of equivalents; four of the five claims (claims 1,3,4, and 6) of Amgen's 5,756,349 were valid and literally infringed; and claim 1 of Amgen's U.S. 5,955,422 was valid and literally infringed. The court ruled in favor of TKT/Aventis on some issues, finding that Amgen's U.S. 5,547,933 was not infringed, and that it would be invalid if it were infringed; Amgen's U.S. 5,618,698 was not infringed; claim 7 of Amgen's 5,756,349 was not infringed; and Amgen's U.S. 5,621,080 was not literally infringed. The court essentially ruled that the EPO resulting from TKT's in vivo expression system was basically equivalent to Amgen's recombinant EPO molecule obtained from cell culture. The rulings of infringement of Amgen's patents were sufficient to allow Amgen to bar commercial marketing of Dynepo in the U.S.

Both Amgen and TKT appealed this ruling before the U.S. Court of Appeals for the Federal Circuit (CAFC). In Jan. 2003, the CAFC agreed in part with the District Court's ruling, including that TKT/Aventis infringes two of Amgen's patents (5,756,349 and 5,955,422), disagreed in part, and remanded to the District Court various issues related to the appeal by TKT/Aventis. The lower court was to reconsider the validity of AmgenÌs patents 5,756,349, 5,955,422, and 5,621,080; reconsider whether TKT infringes 5,621,080; and reconsider its finding that TKT does not infringe EPO process claims in AmgenÌs patents 5,618,698 and 5,756,349.

With the CAFC affirming TKT's infringement of at least two Amgen patents, Amgen believes that it will be able to keep GA-EPO out of the U.S. market (through the life of its patents found to be valid). However, with billions of dollars at stake (Dynepo potentially providing competition for Epogen, Procrit, Eprex, and Aranesp), TKT/Aventis appealed, and further appeals may be expected.

In July 2001, a U.K. appeals court ruled against Amgen Inc. and Kirin-Amgen, Inc., in favor of TKT, that TKTÌs GA-EPO technology did not infringe AmgenÌs U.K. EPO patents. The court stated, Ïthird parties could reasonably expect that if they did not use a DNA sequence for insertion into a host cell, there would be no infringement.Ó Amgen has appealed the case to the House of Lords, which decides final appeals in the U.K. and upholding of the appeals court's ruling would enable TKT to market its product in the U.K.

In June 1999, TKT and Aventis sought a declaration of non-infringement and revocation of European Patent No. 0 148 605 B2 from Amgen and Kirin-Amgen, which responded by asserting that TKT and Aventis infringed the four claims of the patent. In April 2001, the High Court of Justice in London found that one of the four claims asserted against TKT and Aventis would not be infringed on a literal basis, but would be infringed when the claim is construed on a purposive basis (similar to the U.S. doctrine of equivalents), i.e. the court ruled in favor of Amgen. The court also found that three claims of Amgen's European patent were invalid and, even if valid, were incapable of infringement.

It is commonly reported that U.S. (and European) patent (and patent extension) protection for Epogen (and Eprex and Procrit) expires in 2004, based on expiration of the "Lin" patents. However, this apparently does not take into account the patents Amgen has received covering aspects of EPO other than its composition-of-matter (gene/protein sequences), including its manufacture, recombinant constructs, processes, formulations, and uses. In the U.K., patent and SPC (patent extension) protection for Eprex [and also for epoetin beta (NeoRecormon)] has been reported by the National Health Service (NHS) to expire on Dec. 11, 2004. Similarly, European Patent expiration is expected in 2004.

Amgen was a licensee of Columbia UniversityÌs patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. The original patents and license expired in 2000, but Columbia received another patent in 2002 and is again seeking royalties, which Amgen and other companies are challenging in court. See the ÏTech. transferÓ section of the Recombinant DNA Products entry (#100) for further information.

Medical: See the Erythropoietin (EPO) Products entry above. Patients with end-stage renal disease (ESRD) generally receiving dialysis on a regular basis, and usually receive Epogen intravenously while undergoing dialysis. These patient generally receive an EPO product for the rest of his life (unlike most non-ESRD indications where EPO is used on an as-needed basis). For adult chronic renal failure patients, the starting dose is 50 to 100 Units/kg TIW, with dosage reduced as the hematocrit approaches 36% or increases by more than 4 points in any 2-week period. The dosage must be individualized to maintain the hematocrit within the suggested target range. Epogen/Procrit may be given either as an intravenous (IV) or subcutaneous (SC) injection. Patients on hemodialysis usually receive an IV bolus TIW. Dosage is titrated to maintain hematocrit in the 30%-36% range. For cancer patients on chemotherapy, the starting dose is 150 Units/kg SC TIW, with dosage adjusted up to 300 Units/kg TIW, if needed (in terms of reducing transfusion requirements or increasing hematocrit), after 8 weeks of therapy. Patient not responding to 300 Unit/kg are unlikely to respond to higher doses. If the initial dose of includes a very rapid hematocrit response (e.g., an increase of more than 4% in any 2-week period), the dose should be reduced. EPO is also less frequently used to boost red blood cells for those expecting to undergo elective orthopedic surgery and autologous blood donation, and HIV-infected patients experiencing anemia as a side effect of AZT (zidovudine) drug treatment.

Market: The 2004 Average Wholesale Price (AWP) for Epogen is $26.92/1 mL, 2,000 u/mL vial, and $269.20 for a package of 10; $40.38/1 mL, 3,000 u/mL vial, and $403.80 for 10; $53.83/1 mL, 4,000 u/ml vial, and $538.80 for 10; $134.59/1 mL, 10,000 u/mL vial, $1,345.90 for 10; $269.18/2 mL, 10,000 u/mL vial, $2,691.80 for 10; $289.45/1 ml, 20,000 u/mL vial, $2,894.80 for 10; and $568.00/1 mL, 40,000 u/mL vial, $5,680.00 for 10 (Red Book, 2004).

The 2004 Average Wholesale Price (AWP) for Procrit is $160.27 for six 1 mL, 2,000 u/mL vials; $667.80 for 25 1-mL, 2,000 u/mL vials; $240.42 for six 1 mL, 3,000 u/mL vials; $1,001.70 for 25 1-mL, 3,000 u/mL via; $320.54 for six 1 mL, 4,000 u/mL vials; $1,335.60 for 25 1-mL, 4,000 u/mL vials; $801.36 for six 1-mL, 10,000 u/mL vials; $3,339.00 for 25 1-mL, 10,000 u/mL vials; $1,602 for six 1 mL, 20,000 u/mL vials; and $2,136.96 for 4 1-mL, 40,000 u/mL vials (Red Book, 2004).

Total Epogen sales (U.S.) by Amgen were $2.4 billion in 2003; $2.3 billion in 2002; $1.96 billion in 2000, $1.76 billion in 1999, $1.38 billion in 1998, $1.107 billion in 1997, $1.071 billion in 1996, $883 million in 1995, $721 million in 1994, and $586 million in 1993. Total EPO product sales (U.S.) by Amgen (i.e., Epogen sales for end-stage renal disease/kidney dialysis indications, plus Aranesp sales for chemotherapy and renal disease indications) were ~$4 billion in 2003, ~$2.7 billion in 2002 (48% of total Amgen sales), and nearly $2.2 billion in 2001.

Analysts with Friedman Billings Ramsey (FBR) project Epogen sales will be $2.521 billion in 2004, $2.558 billion in 2005, and $2.621 billion in 2006.

About 300,000 dialysis patients in the U.S. regularly receive Epogen, according to Amgen's 2002 annual report.

Since signing their original licensing agreement in 1985, Amgen and Ortho/J&J have long been involved in various marketing disputes, with each charging the other with encroaching on their exclusive marketing rights.

In May 2004, a report from the Office of Inspector General, Department of Health and Human Services (DHHS), surveyed the four largest dialysis centers (those likely to get the most discounted price), and found their average profit spread on EPO (Epogen) was 12%, versus the 22% average spread for all Medicare-reimbursed dialysis drugs. These findings are counter to what had been presumed (i.e., that dialysis centers were making considerable/excessive profit from EPO), and suggest that CMS may not significantly lower reimbursement rates for Epogen.

In July 2004, Centers for Medicare & Medicaid Services (CMS) announced it would decrease its in-hospital Medicare reimbursement rate for Epogen for ESRD by 11%. CMS also increased the reimbursable hematocrit level for EPO therapy to 39% from 37.5%, so more patients qualify. These actions are not expected to significantly affect overall sales of Epogen (and with the reimbursement rate for Aranesp reduced by 15%, Epogen has gained a slight advantage, relative to Aranesp).