Harvard Journal of Law & Technology
`Volume 17, Number 2 Spring 2004
`
`RECENT DEVELOPMENTS
`
`
`Axel Patent Litigation, e.g., Genentech, Inc. v. Tr. of Columbia Univ.,
`N.D. Cal. 2003, No. 3:03-cv-01603...........................................583
`
`The Commercial Space Launch Amendments Act of 2004,
`H.R. 3752, 108th Cong. (2004).................................................619
`
`
`
`Columbia, Co-transformation, Commercialization & Controversy
`The Axel Patent Litigation
`
`
`
`TABLE OF CONTENTS
`
`I. Historical and Scientific Background...................................... 584
`A. The Axel Patent ............................................................... 588
`B. The Biotechnology Revolution: Protein-Based
`Pharmaceuticals and the Axel Patent................................ 591
`C. Columbia and the Axel Patent: Does Activ ism Signal
`Bad Faith or Defense of Intellectual Property?.................. 594
`II. Analysis of Patents-in-Suit ................................................... 600
`A. Comparison of the ’216, ’665, and ’017 Patents with the
`’275 Patent................................................................... 600
`B. Inequitable Prosecution Conduct ....................................... 602
`C. Statutory Bar and Obviousness .......................................... 604
`D. Specification Requirements............................................... 605
`E. Remedies ........................................................................ 606
`III. The University Transformed by the Profit Gene: Broader
`Policy Issues Raised by the Axel Patent Litigation ................... 608
`A. University Commercialization ........................................... 608
`B. Seeking Indiv idual Exemptions to Patent Law via
`Congress ...................................................................... 611
`C. Conclusion...................................................................... 612
`Appendix : Protein-Based Drugs Produced in Eukaryotic
`Vectors Based on Axel Patent Technology.............................. 614
`
`
`
`Merck Ex. 1041, pg 1168
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`“WHEN WE SPLICED THE PROFIT GENE INTO ACADEMIC CULTURE, WE
`CREATED A NEW ORGANISM — THE RECOMBINANT UNIVERSITY. WE
`REPROGRAMMED THE INCENTIVES THAT GUIDE SCIENCE. T HE RULE IN
`ACADEME USED TO BE ‘PUBLISH OR PERISH.’ NOW BIOSCIENTISTS
`HAVE AN ALTERNATIVE — ‘PATENT AND PROFIT.’” TOM ABATE1
`
`Eight biotechnology and pharmaceutical companies have recently
`sued Columbia University, alleging Columbia’s current patent on
`technology that enables production of many modern protein-based
`drugs is invalid and unenforceable. Though researchers at Columbia
`developed the ground-breaking technology in the late 1970s and early
`1980s, the patent-in-suit was actually issued in September 2002. This
`case has achieved some notoriety because it is the first example of a
`university mimicking a pharmaceutical company in aggressively
`attempting to prolong patent protection,2 and therefore has stirred
`controversy surrounding the doctrine of university commercialization.
`
`I. HISTORICAL AND SCIENTIFIC BACKGROUND
`
`In the 1960s and 1970s, the research of Professors Herbert W.
`Boyer, Stanley N. Cohen, and Paul Berg led to the seminal
`discoveries that would spawn the biotechnology revolution.3 Berg
`invented recombinant DNA technology, which is the process of
`constructing a DNA “molecule containing parts of DNA from
`different species.”4 This breakthrough allowed scientists
`to
`manipulate genes and spawned innumerable practical applications,5
`most notably through transformation, which modifies a host cell’s
`genome through introduction of exogenous DNA from a foreign cell.
`The
`transformation
`technique elicited significant academic
`interest, as it better allowed scientists to study the functional
`
`
`1. Tom Abate, Scientists’ ‘Publish or Perish’ Credo Now ‘Patent and Profit’;
`‘Recombinant U.’ Phenomenon Alters Academic Culture, S.F. CHRON., Aug. 13, 2001, at
`D1 (discussing interview with Paul Berg, recipient of the 1980 Nobel Prize in Chemistry).
`2. See Ownership at Too High a Price? , 21 NATURE BIOTECH. 953, 953 (2003).
`It’s a story of greed, legal wrangling, and political intrigue . . . . For
`once, the story does not center on a secretive biotechnology
`corporation bent on world domination. It focuses instead on a center
`of learning, New York’s Columbia Universit y, which apparently is
`bent on dominating biotechnology research through patents issued in
`the early 1980s . . . .
`
`Id.
`3. See Lasker Found., Former Award Winners, Basic Medical Research 1980, available
`at http://www.laskerfoundation.org/awards/library/1980basic.shtml (last visited Mar. 29,
`2004); see also U.S. Patent No. 4,237,224 (issued Dec. 2, 1980); U.S. Patent No. 4,468,464
`(issued Aug. 28, 1984); U.S. Patent No. 4,740,470 (issued Apr. 26, 1988).
`4. The Royal Swedish Acad. of Sci., Press Release: The 1980 Nobel Prize in Chemistry
`(Oct. 14, 1980), available at http://www.nobel.se/chemistry/laureates/1980/press.html.
`5. See id.
`
`Merck Ex. 1041, pg 1169
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`molecular biology of DNA and genes.6 However, the true power of
`transformation was that it allowed scientists to convert normal cells
`into microscopic protein-producing “factories.” In the late 1970s,
`when molecular biology was relatively primitive, transformation
`technology was limited to using plasmids7 to deliver the foreign
`DNA; even after successful transformation, the plasmid would be lost
`over a few generations of bacterial replication.8 Most plasmid-based
`transformation was limited to transforming prokaryotes (cells without
`nuclei), despite the significant interest in producing proteins from
`eukaryotes (cells with nuclei, such as those in humans, mice, etc.)
`including insulin, antibodies, and growth hormones. Such eukaryotic
`proteins are, in general, extensively modified with various sugar
`linkages and packaged in certain subcellular components; prokaryotic
`cells lack the machinery to perform these functions. An additional
`obstacle is that even if a eukaryotic protein were produced in bacteria,
`it would be very difficult to totally purify it from the massive
`quantities of bacterial endotoxin, a highly antigenic lipoprotein. Thus,
`eukaryotic proteins must be produced in eukaryotes. However, few
`early transformation experiments were dedicated to eukaryotes, and
`all
`transformation procedures were plagued by a
`lack of
`reproducibility, low transformation efficiency (less than 0.01% chance
`of successful transformation), and the fact that the successful
`transformants could not be isolated from the non-transformants.9
`Between 1977 and 1981, Professor Ric hard Axel and his federally
`funded collaborators10 at Columbia University revolutionized the
`practice of
`transformation with
`their development of co-
`transformation, the simultaneous transformation of a eukaryotic cell’s
`
`
`6. See Angel Pellicer et al., Altering Genotype and Phenotype by DNA-Mediated Gene
`Transfer, 209 SCI. 1414, 1414–15 (1980) (noting that “transformation provides an in vivo
`assay for the functional role of DNA sequence organization about specific genes”).
`7. Plasmids are small circular extrachromosomal pieces of DNA th at replicate
`independently of the chromosome. See Giuseppe F. Miozzari, Strategies for Obtaining
`Expression Peptide Hormones in E. coli,
`in INSULINS, GROWTH HORMONE, AND
`RECOMBINANT DNA TECHNOLOGY 15 (John L. Gueriguian et al. eds., 1981).
`8. As extrachromosomal DNA, the plasmids would generally be lost after a few
`generations of bacterial replication, in part because there was no energetic or evolutionary
`advantage that would accrue to the bacteria if it used precious DNA precursors to synthesize
`and maintain new plasmids. Cf. Angel Pellicer et al., The Transfer and Stable Integration of
`the HSV Thymidine Kinase Gene into Mouse Cells, 14 CELL 133, 140 (1978) (noting
`requirements necessary for survival of independent extrachromosomal DNA).
`9. See Elizabeth H. Szybalska & Waclaw Szybalski, Genetics of Human Cell Lines, IV:
`DNA-Mediated Heritable Transformation of a Biochemical Trait, 48 PROC. NAT’L ACAD.
`SCI. 2026, 2026–27 (1962) (discussing the problems of transformation and reporting some
`solutions to those problems resulting from “the discovery of highly selective genetic
`markers”); see also Pellicer et al., supra note 8, at 140.
`10. Axel’s work was funded by two grants from the NIH. See U.S. Patent No. 4,399,216
`(issued August 16, 1983); see also CRISP Database, NIH Grant Numbers CA-23767, CA-
`76346, at http://crisp.cit.nih.gov/ (last visited Mar. 10, 2004).
`
`Merck Ex. 1041, pg 1170
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`genotype with two different foreign DNA molecules.11 One DNA
`molecule (hereinafter “DNA I”) would be the gene coding for the
`desired proteinaceous material, and the other DNA molecule
`(hereinafter “DNA II”) would be a gene for a selectable marker. A
`selectable marker is a particular gene that provides a cell with a
`necessary biological tool to survive and overcome a biological
`hardship, such as deprivation of a nutrient or the presence of an
`antibiotic. Therefore, experimental conditions could be designed such
`that only co-transformed “protein factory” cells — i.e., those that
`could both produce the desired proteinaceous material and survive the
`biological hardship — would be isolated. Selectable markers are
`generally amplifiable, meaning that in response to increasingly
`strenuous conditions, the cells that produce the most foreign DNA
`would be most likely to survive.
`The presence of the selectable marker solved the problem of
`identification and isolation of successful transformants because non-
`transformed cells perished. Co-transformation also solved the problem
`of insufficient protein production by designing recombinant DNA I
`such that it would integrate into the chromosome of a host cell, and
`thus persist even after hundreds of generations. Moreover, the
`selectable marker would allow amplification of a piece of DNA
`I/DNA II, as the host cell sought to survive in the exper imentally-
`induced harsh conditions.12
`
`
`11. See, e.g. , M. Wigler et al., Transformation of Mammalian Cells with an Amplifiable
`Dominant-Acting Gene, 77 PROC. NAT’L. ACAD. SCI. 3567 (1980) (prokaryote DNA to
`eukaryote host); Pellicer et al., supra note 8, at 133, 139 (viral gene to eukaryote host); B.
`Wold et al., Introduction and Expression of a Rabbit ß-Globin Gene in Mouse Fibroblasts,
`76 PROC. NAT’L. ACAD. SCI. 5684, 5687–88 (1979) (eukaryote gene to eukaryote host). See
`generally Richard Axel, Axel Lab Publications, at http://cpmcnet.columbia.edu/
`dept/neurobeh/axel/research.html (last visited Mar. 10, 2004).
`12. See Diane M. Robins et al., Transforming DNA Integrates into the Host
`Chromosome, 23 CELL 29, 29, 36–37 (1981) (stating that the selectable marker and DNA I
`“are found covalently linked in the transformed cell,” become stably integrated, and allow
`“amplification of selectable markers with nonselectable cotransformed genes”); see also
`Pellicer et al., supra note 6, at 1421.
`
`Merck Ex. 1041, pg 1171
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`Figure 1: The Scheme of Co-Transformation
`(Developed by Professor Axel)
`
`
`
`DNA I Coding for Desired
`
`Proteinaceous Material +
`
`
`DNA II Coding for Selectable
`Proteinaceous Marker (SM+)
`
`Nucleus with Host
`Chromosomal DNA
`
`Eukaryotic Cell (SM–)
`
`Co-transform in Presence of
`Selective Criteria / Conditions
`
`DNA II
`DNA I
`
`Eukaryotic Cell (SM+)
`
`Culture in Presence of
`Selective Criteria
`
`Desired
`Material
`
`Recovery of Protein and
`Purification
`Desired Material
`(e.g., Insulin, Interferon, Erythropoietin, Hormone, etc.)
`Two DNA molecules, with DNA I coding for the desired proteinaceous material and DNA
`II coding for a selectable marker, are introduced into a eukaryotic cell. The cell initially
`contains no selectable marker (hence the SM – designation) but does contain the marker after
`co-transformation (SM+). The SM+ cells thrive in the selective media while other, non-
`transformed SM– cells die. Co-transformed cells use DNA I to synthesize the desired protein
`product, which can be recovered and purified.13
`
`13. Adapted from U.S. Patent No. 4,399,216 (issued Aug. 16, 1983). The depicted
`proteinaceous material is a representation of the yeast Cdc-13 DNA binding domain,
`adapated from Rachel M. Mitton-Fry et al., Conserved Structure for Single-Stranded
`Telomeric DNA Recognition, 296 SCI. 145, 145 (2002).
`
`Merck Ex. 1041, pg 1172
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`

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`
`[Vol. 17
`
`A. The Axel Patent
`
`An abstract of one of Axel’s important papers hinted at the
`awesome power thus unlocked: “The use of this [process] may allow
`the introduction and amplification of virtually any [genetic or protein]
`in various new cellular environments.”14 Columbia
`element
`University quickly seized on Axel’s work and on February 25, 1980
`filed a patent application resulting in U.S. Patent No. 4,399,216,
`issued August 16, 1983 (“’216 patent” or “Axel patent”). The ’216
`patent describes the invention as a process for inserting DNA into
`eukaryotes to yield transformed cells with foreign DNA integrated
`into chromosomal DNA which can sustainably generate functional
`proteins, and lists seventy-three claims, as summarized here:
`
` •
`
` A process for co-transforming a suitable eukaryotic
`host cell with one or multiple copies of DNA I and
`DNA II, which can be either linked or unlinked,
`where DNA I may be a proteinaceous material that
`incorporates into the host cell chromosome and DNA
`II is the selectable marker.15
`
`• The scope of the claim “suitable eukaryotic host
`cell” is tapered by dependent claims defining the
`term as a mammalian cell, which itself is further
`delimited to either an erythroblast (red blood cell
`precursor) or a
`fibroblast
`(connective
`tissue
`precursor).16
`
`• The scope of the claim “proteinaceous material” is
`tapered by dependent claims defining the term as
`interferon protein, insulin, growth hormone, clotting
`factor, viral antigen, antibody, or enzyme.17
`
`• The scope of the claim “DNA II” is tapered by
`dependent claims for the gene for thymidine kinase,
`the gene for adenine phosphoribosyltransferase, or a
`gene for drug resistance, which includes antibiotic
`
`
`14. Wigler et al., supra note 11, at 3567.
`15. See U.S. Patent No. 4,399,216 (issued Aug. 16, 1983) claims 1, 2, 22, 27, 28, 31, 48,
`54, 55, 71.
`16. See id . claims 12–14, 20, 21, 24, 42–44, 65–67.
`17. See id . claims 3–8, 23, 32–38, 52, 56–61.
`
`Merck Ex. 1041, pg 1173
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`resistance genes and a dependent claim
`dihydrofolate reductase.18
`
`for
`
`• A process for detecting and identifying eukaryotic
`cells successfully
`transformed based on
`their
`selectable phenotype, as well as recovering these
`cells.19
`
`• A process for culturing the transformed cell to yield
`a multiplicity of such cells. A process by which the
`culture is grown in increasing amounts of an agent
`that exerts selective pressures, such that DNA II will
`be amplified and transformants can be identified.20
`
`• A process for producing proteinaceous material and
`recovering this protein.21
`
`• A claim for the cell, eukaryotic or mammalian, into
`which DNA I has been incorporated into the host
`cell’s genome. Also, a claim for the cell, eukaryotic
`or mammalian, into which DNA I, in the case where
`DNA I and DNA II were
`linked, has been
`incorporated into the host cell’s genome.22
`
`The written description of the Axel patent is substantial, fully
`disclosing background prior art of recombinant DNA as well as the
`experimentation undertaken by Axel and colleagues, as necessary to
`define the scientific protocol to a person reasonably skilled in
`molecular biology
`in 1980. The written description expressly
`discloses the embodiments of co-transforming multiple copies of
`DNA I linked to an amplifiable DNA II, identifying and culturing
`transformed cells, and obtaining large quantities of proteinaceous
`material.23 The preferred embodiment is to use DNA I and DNA II
`attached to phage DNA, which is encapsulated in the viral particle
`before co-transformation.24
`
`
`18. See id . claims 16–19, 46, 47, 69, 70.
`19. See id . claims 25, 26.
`20. See id . claims 22, 54.
`21. See id . claim 51.
`22. See id . claims 49, 50, 72, 73.
`23. See id ., col. 3, ll. 42–68.
`24. See id ., col. 5, ll. 51–57. Phages are viruses capable of delivering DNA to target cells,
`commandeering those target cells, and using them to replicate viruses, which then attack
`new target cells. See BRUCE ALBERTS ET AL., MOLECULAR BIOLOGY OF THE CELL 275 (3d
`ed. 1994).
`
`Merck Ex. 1041, pg 1174
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`
`It was quite ambitious for Columbia in February 1980 to even
`claim a living cell in its patent application, since the Supreme Court
`did not decide whether genetically modified organisms were
`patentable subject matter until June 1980.25 In Diamond v.
`Chakrabarty, the Court held
`that a living organism that (a) was
`entirely a product of human ingenuity and (b) possessed new
`characteristics that could not be found in nature constituted either a
`properly patentable manufacture or composition of matter under 35
`U.S.C. § 101.26 Chakrabarty’s patent claimed both a strain of
`Pseudomonas bacteria that degraded octane and the process he used to
`create the Pseudomonas.27 The subject matter of Columbia’s patent
`was quite similar to the one at issue in Chakrabarty, as both claimed a
`genetically enhanced cell and the process to create the cell.
`Regardless of whether the Axel patent could even be successfully
`prosecuted, Columbia could not have been assured of ultimately
`obtaining title to the invention. In the 1960s and 1970s, there was
`substantial disagreement within the federal government over the
`propriety of transferring to private entities the title to inventions
`developed via public subsidy.28 The Bayh-Dole Act, enacted on
`December 12, 1980, was designed as a means to resolve this debate,
`encouraging commercialization of research by allowing universities to
`inventions produced with federal funding.29 As
`take
`title
`to
`Columbia’s patent predated Bayh-Dole by ten months, Columbia was
`required to enter into an agreement with the National Institutes of
`Health (“NIH”) to take title to the inventions described in the Axel
`patent. The agreement allowed Columbia to license the technology,
`provided
`that
`those
`licenses specifically “include[d] adequate
`safeguards against unreasonable royalties and repressive practices”
`and guaranteed that royalties “not in any event be in excess of normal
`trade practice.”30
`
`
`25. Diamond v. Chakrabarty, 447 U.S. 303 (1980).
`26. See id . at 310.
`27. See id . at 305–06.
`28. See Univ . of Cal. Office of Tech. Transfer, The Bayh-Dole Act: A Guide to the Law
`and
`Implementing
`Regulations
`(Sept.
`1999),
`available
`at
`http://www.ucop.edu/ott/bayh.html.
`29. See The Patent and Trademark Law Amendments (Bayh-Dole) Act, 35 U.S.C.
`§§ 200–12 (2000); see also Univ. of Cal. Office of Tech. Transfer, supra note 28; Jane
`Larson, Tech Transfer on Table, ARIZ. REPUBLIC, Jan. 12, 2003, at D1; Innovation’s Golden
`Goose, THE ECONOMIST, Dec. 14, 2002, at 3.
`30. Ted Agres, Columbia Patents Under Attack
`http://www.biomedcentral.com/news/20030725/03.
`
`(July 25, 2003), at
`
`Merck Ex. 1041, pg 1175
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`

`No. 2]
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`B. The Biotechnology Revolution: Protein-Based Pharmaceuticals
`and the Axel Patent
`
`Enterprising scientists in the 1970s and 1980s decided to exploit
`the emergent field of molecular biology as an alternative to the
`prevailing model of producing drugs by chemical synthesis.
`Genentech was co-founded in 1976 by Professor Herbert Boyer and
`immediately undertook the task of producing sufficient quantities of
`human proteins for use as pharmaceutical agents; its early projects
`included
`insulin, growth hormone, a clotting factor, and an
`interferon.31 Amgen was founded in 1980 and sought to develop its
`products based on recent “advances in recombinant DNA and
`molecular bio logy.”32 The successful efforts of Amgen, Genentech,
`and others in the burgeoning biotechnology industry revolutionized
`the entire notion of pharmaceuticals and expanded the paradigm of
`drug development from the classic small molecule model to include
`protein-based drugs like insulin, antibodies, and enzymes:
`
`
`to making
`approach
`Biotechnology’s unique
`pharmaceuticals has been to use human proteins as
`drugs rather
`than
`the chemicals of
`traditional
`pharmaceuticals . . . . The first step in the manu-
`facturing of [a desired proteinaceous product] is to
`genetically engineer a cell so that it produces the
`[desired proteinaceous product]. This
`requires
`introducing the genetic information, or DNA, that
`provides the cell with the instructions it needs to
`produce [the proteinaceous product]. Once a cell has
`been engineered to express the product, it is used to
`establish a cell line [and then used to grow a large
`quantity of the protein].33
`
`The Axel patent was instrumental in facilitating the development
`of a number of modern protein-based drugs expressed in eukaryotic
`vectors.34 Columbia
`lic ensed
`the Axel patent
`to over
`thirty
`
`31. See Genentech, Corporate Chronology, available at http://www.gene.com/gene/
`about/corporate/history/timeline/index.jsp (last visited Jan. 31, 2004).
`32. Amgen, Inc., Amgen Backgrounder, available at http://www.amgen.com/corporate/
`AboutAmgen/backgrounder.html (last visited Feb. 14, 2004).
`33. Genentech, Manufacturing Xolair (Omalizumab) for Subcutaneous Use, at
`http://www.gene.com/gene/products/information/immunological/xolair/development.jsp
`(last visited Mar. 24, 2004).
`34. See, e.g., Ken Howard, Biotechs Sue Columbia over Fourth Axel Patent, 21 NATURE
`BIOTECH. 955, 955 (2003); Ownership at Too High a Price?, supra note 2, at 953. Note that
`due to other aspects of genetic engineering, protein structure, and protein purification
`technology, some protein drugs can be produced in bacterial vectors, especially in the
`bacterium Escherichia coli. Drugs produced in E. coli include Amgen’s Neupogen, Leukine,
`
`Merck Ex. 1041, pg 1176
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`companies,35 including Genentech, Amgen, Immunex,36 Genzyme,
`Abbott, Biogen, 37 Wyeth,38 Baxter, and Serono, thus directly
`contributing to the successful development of at least twenty-nine
`drugs by these companies39 as shown in Appendix A, infra. Several
`observations regarding this sub-group of protein-based drugs are
`noteworthy:
`(1) Twenty-three of the twenty-nine drugs are in categories
`claimed by the Axel Patent:40 nine drugs are antibodies or antibody
`
`
`and Kineret; Genentech’s Nutropin (all variants), Actimmune, and Protropin; Wyeth’s
`Neumega; Lilly’s Humatrope and Humalog; Chiron’s Proleukin and Betaseron; Schering-
`Plough’s Intron A, PEG-Intron, and Rebetron; Johnson & Johnson’s Retavase and Natrecor;
`and Aventis’ Lantus. See generally Gary Walsh, Biopharmaceutical Benchmarks — 2003,
`21 NATURE BIOTECH. 865 (2003); Centocor, Inc., Retavase (reteplase) U.S. Prescribing
`Information (Nov. 2000), available at http://www.centocor.com/pi/retavasePI_11-00A.pdf;
`Scios, Inc., Natrecor (nesiritide) U.S. Prescribing Information (Oct. 2003), available at
`http://www.sciosinc.com/pdf/natrecorpi_final.pdf. Additionally, Wyeth’s Mylotarg
`is
`produced in the bacterium Micromonospora echinospora ssp. calichensis. See Wyeth Labs.,
`Mylotarg
`(gemtuzumab ozogamicin) U.S. Prescribing Information, available at
`http://www.wyeth.com/content/ShowLabeling.asp?id=119 (last visited Mar. 10, 2004).
`35. See Paying Twice?, 2 NATURE DRUG DISCOVERY 690 (2003); Complaint at ¶ 21,
`Genentech, Inc. v. Tr. of Columbia Univ. (N.D. Cal. 2003) (No. 3:03-cv-01603) [hereinafter
`“Genentech Complaint”]; Complaint, Immunex, Inc. and Amgen, Inc. v. Tr. of Columbia
`Univ. (C.D. Cal. 2003) (No. 2:03-cv-04349) [hereinafter “Amgen Complaint”]; Complaint
`at ¶¶ 3, 5, 7, 9, 24, Biogen, Inc., Genzyme Corp., and Abbott Bioresearch Ctr., Inc. v. Tr. of
`Columbia Univ. (D. Mass. 2003) (No. 03-cv-11329-MLW) [hereinafter “Biogen
`Complaint”]; Complaint at ¶ 2, Wyeth, et al., v. Tr. of Columbia Univ. (D. Mass. 2003) (No.
`03-cv-11570-MLW) [hereinafter “Wyeth Complaint”]; Complaint at ¶ 6, Baxter Healthcare
`Corp. v. Tr. of Columbia Univ. (D. Mass. 2003) (No. 03-cv-12221-MLW) [hereinafter
`“Baxter Complaint”]; Complaint at ¶ 7, Serono, Inc. v. Tr. of Columbia Univ. (D. Mass.
`2003) (No. 03-cv-12401-MLW) [hereinafter “Serono Complaint”]; see also Herbert Pardes,
`Molecular Genetics at Columbia , 1 BIOMEDICAL FRONTIERS (Winter 1994), available at
`http://cpmcnet.columbia.edu/news/frontiers/archives/biomed_v1n2_0002.html.
`36. Immunex Corporation had licensed the Axel patent, but was acquired by Amgen in
`July 2002. See Amgen, Inc., supra note 32. Immunex was named as a joint plaintiff on the
`Amgen Complaint.
`37. Biogen merged with Idec Pharmaceuticals in November 2003 to form Biogen Idec.
`See Biogen Idec, Company, available at http://www.biogen.com/site/013.html (last visited
`Feb. 14, 2004).
`38. Columbia originally licensed the Axe l patent to The Genetics Institute, Inc., and this
`license was extended to Wyeth when the successor to The Genetics Institute, Inc., became a
`wholly-owned subsidiary of Wyeth. See Wyeth Complaint, supra note 35, ¶¶ 2, 5.
`39. Approximately ninety recombinant protein pharmaceuticals are approved for use in
`the U.S. See generally Walsh, supra note 34. Virtually every major pharmaceutical
`company markets at least one recombinant protein product in the United States, including
`Pfizer (Rebif, Somavert), Merck (recombinant vaccines Recombivax HB and Comvax), and
`GlaxoSmithKline (recombinant vaccines Engerix -B, Pediarix, and Twinrix ). See, e.g.,
`Pfizer, Inc., Medicines & Product s, available at http://www.pfizer.com/do/medicines
`/mn_uspi.html (last visited Mar. 31, 2004); Merck & Co., Inc., Vaccine and Disease
`Information, available at http://www.merckvaccines.com/vaccineInfo_frmst.html (last
`visited Mar. 31, 2004); GlaxoSmithKlin e PLC, Vaccines, available at http://www.gsk.com/
`products/vaccines.htm (last visited Mar. 31, 2004).
`40. See supra text accompanying note 17.
`
`Merck Ex. 1041, pg 1177
`
`

`

`593
`
`Columbia
`
`No. 2]
`
`derivatives, seven are enzymes, four are clotting factors, two are
`interferons, and one is a growth hormone.41
`(2) A number of
`the drugs
`in Appendix A are recent
`developments: Avastin, for example, was approved by the Food and
`Drug Administration
`(“FDA”)
`in February 2004. Advate,
`Aldurazyme, Amevive, Fabrazyme, Raptiva, and Xolair were
`approved in 2003, and others including Humira, Rebif, and Zevalin
`received approval in 2002. A number of additional novel protein
`drugs are in late stages of development or are pending approval as of
`the publication of this Note.42
`(3) Of the twenty-nine drugs, twenty-eight have been confirmed
`to have used the Chinese hamster ovary (“CHO”) cell43 as a
`mammalian expression system that reliably produces large quantities
`of the relevant glycoproteins.
`(4) Nine drugs (Activase, Avastin, Cathflo Activase, Herceptin,
`Pulmozyme, Raptiva, Rituxan, TNKase, and Xolair) expressly
`document the use of an antibiotic in the culture medium for growth of
`transformed cells, as described in the Axel patent, while six (Enbrel,
`Epogen, Procrit,44 Rebif, Ovidrel, and Gonal-f45) are otherwise known
`to be directly based on the Axel patent. However, it is almost certain
`that all use some selective agents in culturing their transformed cells
`in accordance with the Axel patent.46
`
`
`41. Note that of the other six products, three are erythropoietins, one is thyroid
`stimulating hormone, one is human chorionic gonadotropin, and one is follicle stimulating
`hormone.
`42. See Walsh, supra note 34, at 868 (estimating 500 candidate biopharmaceuticals are in
`development); PHARM. RESEARCH AND MFRS. OF AM., NEW MEDICINES IN DEVELOPMENT:
`BIOTECHNOLOGY
`(Sept.
`27,
`2002),
`available
`at
`http://www.phrma.org/
`newmedicines/resources/2002-10-21.93.pdf (listing 371 biotechnology medicines
`in
`development).
`43. CHO cells are used in mo lecular biology laboratories for study and expression of
`proteins. See Am. Type Culture Collection, CHO-K1 Cell Line Catalog Detail, at
`http://www.atcc.org/SearchCatalogs/longview.cfm?view=ce,419766,CCL-61&text=cho
`(last visited Mar. 31, 2004). See generally Theodore T. Puck et al., Genetics of Somatic
`Mammalian Cells. III. Long-term Cultivation of Euploid Cells from Human and Animal
`Subjects, 108 J. EXPERIMENTAL MED. 945, 947, 949–50 (1958) (noting that CHO cell
`cultures are “particularly hardy and reliable” and grow in “continuous cultivation for more
`than 10 months with no diminution in growth rat e or change in . . . morphology,” and that
`the CHO-K1 cell line arose from this experiment in 1958).
`44. See Pardes, supra note 35.
`45. See Serono Complaint, supra note 35, ¶¶ 6, 40.
`46. See generally Genentech Complaint, supra note 35; Amgen Complaint, supra note
`35; Biogen Complaint, supra note 35; Wyeth Complaint, supra note 35; Baxter Co mplaint,
`supra note 35. The fact that the drug companies are suing Columbia for patent invalidity
`suggests that their drugs did utilize Axel patent technology, even though the companies may
`not have fully disclosed their production processes. Note that all of the nine drugs that did
`explicitly disclose their reliance on the Axel patent in their prescribing information are
`Genentech drugs. The disclosure of the antibiotic is probably a result of Genentech’s
`individual practice in drafting package inserts, as the other companies most likely also use
`selectable media in their co-transformation and production processes.
`
`Merck Ex. 1041, pg 1178
`
`

`

`Harvard Journal of Law & Technology
`
`594
`
`C. Columbia and the Axel Patent: Does Activism Signal Bad Faith or
`Defense of Intellectual Property?
`
`[Vol. 17
`
`Columbia’s licensing of the Axel patent has become legendary,
`such that it is cited as the University’s “single most successful
`innovation.”47 Columbia has collected license fees of $70 million
`from Genentech, $35 million from Biogen, $27 million from Wyeth,
`$25 million from Genzyme, $6 million from Serono, and $5 million
`from Baxter.48 Between 1983 and 2002, it is estimated that the Axel
`patent generated some $400 million in aggregate revenue for
`Columbia. 49 The pace of licensing increased over time, and its
`licenses were generating approximately $100 million per year 50 in
`2000 (the year it was set to expire) out of the $139 million in total
`technology transfer royalties generated by Columbia University as a
`whole.51 These figures show Columbia was the most successful
`university in technology transfer in the years before expiration of the
`Axel patent52; the 2001 Association of University Technology
`Managers Licensing Survey found that North American universities,
`hospitals, and research institutions in aggregate collected $1.071
`billion in licensing royalties and fees on 13,000 patents, and Columbia
`captured almost ten percent of that total based on one patent.53
`
`47. Technology Office Renamed as License Income Rises, COLUM. UNIV. REC., Oct. 14,
`1994,
`available
`at
`http://www.columbia.edu/cu/recor