Amgen, Inc. v. Hoechst Marion Roussel, Inc.

FINDINGS, RULINGS, AND ORDER

YOUNG, Chief Judge.

In this jury waived declaratory judgment action, Amgen, Inc. (“Amgen”) seeks a declaration that certain of the patents protecting its best selling drug EPOGEN ® are infringed by the conduct of the defendants, Hoechst Marion Roussel, Inc. and Transkaryotic Therapies, Inc. (collectively “TKT”). TKT denies infringement and, in turn, counterclaims that Amgen’s patents are invalid on a number of grounds.

Amgen, the first to discover and manufacture a recombinant DNA product similar to natural erythropoietin (“EPO”) and useful in various medical treatments, has reaped significant commercial rewards from its discoveries,

see

Patricia Van Arnum,

Active Pharmaceutical Ingredients: The Opportunities in the Branded Prescription Market,

Chemical Market Rep., Oct. 30, 2000, WL 10/30/00 CHEMMKT REP FR 14 (noting that Amgen’s Epogen had sales of $1.76 billion in 1999); Vicki Brower,

Amgen Comes Out on Top in Blood Drug Patent Tussle,

Biotechnology Newswatch, Jan. 4, 1999, WL 1/4/99 BIO-TECHNW 1 (noting that EPO was then the “biggest-selling biotechnology drug ever developed” and that Amgen’s EPO sales accounted for over fifty percent of its 1997 $2.4 billion revenue). As one would expect, Amgen has sought to preserve its commercial success through a cluster of related patents that it has defended with skill and perseverance.

1

In conjunction with Hoechst Marion Roussel, Inc., now known as Aventis Pharmaceuticals, Inc., TKT, a smaller company, seeks to capitalize upon apparent advances in genetic engineering by targeting the most lucrative commercial recombinant DNA products and designing around them.

See

Trial Tr. at 1772:21 to 1773:2,1786:5 to 1787:7. It, too, as one might expect, is no stranger to litigation.

2

The present litigation, in fact, has been brewing for some time,

see Amgen, Inc. v. Hoechst Marion Roussel, Inc.,

3 F.Supp.2d 104 (D.Mass.1998), and when it ultimately erupted in June of 1999, the parties were ready.

As an aside, it is only just to note that this case has been presented with high integrity, an unswerving fidelity to court rules and procedures, and a consummate excellence in trial practice that makes it a model not only for the intellectual property bar, but for lawyers everywhere. Any fail

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ings in understanding are mine, and mine alone.

The course of the litigation may be briefly sketched.

Early on, the parties agreed on a list of experts upon whom the Court might call for technical assistance. The Court chose Professor Chris Kaiser of the Massachusetts Institute of Technology from this list, and has met privately with him for background tutorial assistance.

3

Towards the close of discovery, Amgen moved for summary judgment on the issue of infringement.

4

This motion necessitated construction of the patent claims, and the Court held a

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hearing on March 27, March 28, and April 10, 2000. Thereafter, the Court granted summary judgment to Amgen on a particular claim in one of the five patents in issue. The motion for summary judgment was otherwise denied.

Trial commenced on May 15, 2000 and continued for twenty-three days spread over four months.

5

At the close of Am-

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gen’s case in chief, the Court held, pursuant to Fed.R.Civ.P. 52(c), that TKT had not infringed the process claims of Amgen’s U.S. Patent No. 5,618,698 (issued Apr. 8, 1997). Trial concluded on September 8, 2000, and the matter was taken under advisement.

I. THE PATENTS AT ISSUE

There are five patents at issue in this case: U.S. Patent No. 5,547,933 (issued Aug. 20, 1996) (“ ’933 patent”), Trial Ex. 2; U.S. Patent No. 5,618,698 (issued Apr. 8, 1997) (“’698 patent”), Trial Ex. 4; U.S. Patent No. 5,621,080 (issued Apr. 15, 1997) (“’080 patent”), Trial Ex. 3; U.S. Patent No. 5,756,349 (issued May 26, 1998) (“ ’349 patent”), Trial Ex. 5; and U.S. Patent No. 5,955,422 (issued Sept. 21, 1999) (“’422 patent”), Trial Ex. 6.

All of these patents share a common disclosure and identical specifications. Trial Exs. 2-6. Only the claims differ. Each of the patents claim priority from the following common applications: U.S. Patent Application Serial No. 675,298 (Nov. 30, 1984), which is a continuation-in-part of U.S. Patent Application Serial No. 655,841 (Sept. 28, 1984), which is a continuation-in-part of U.S. Patent Application Serial No. 582,185 (Feb. 21, 1984), which is a continuation-in-part of U.S. Patent Application Serial No. 561,024 (Dec. 13, 1983). Trial Exs. 2-6.

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Interactive Charting for Amgen, Inc.,

at

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Amgen's NASDAQ Quote,

at

http://www.quicken.com (last visited May 18, 2000).

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II. “THE NAME OF THE GAME IS THE CLAIM”:

6

CLAIM CONSTRUCTION

It is appropriate to pause for a moment to emphasize the particular procedural approach that this Court used in conducting the

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hearing. District courts have differed significantly in the timing and procedure for

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hearings— some engaging in claim construction prior to trial and others after hearing all of the evidence at trial.

See

William F. Lee & Anita K. Krug,

Still Adjusting to

Markman:

A Prescription for the Timing of Claim Construction Hearings,

13 Harv. J.L.

&

Tech. 55 , 73 (1999). I have consistently taken the procedural approach of conducting the

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hearing at the summary judgment stage of litigation or at the point when discovery has closed and trial is approaching.

See, e.g., MacNeill Eng’g Co. v. Trisport, Ltd.,

No. 98-12019, 2001 WL 46970 , slip op. at 7 (D.Mass. Jan. 10, 2001);

MediaCom,

4 F.Supp.2d at 22-23. I have taken care to note that the benefits of so doing range from constitutional concerns arising from conducting such a hearing too soon to efficiency concerns arising from conducting the hearing too late.

See MediaCom,

4 F.Supp.2d at 22; Lee & Krug,

supra

at 82-85.

Here, however, I want more specifically to emphasize that when the

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hearing is conducted at the summary judgment stage, it is also important to conduct the two hearings independently of each other — the

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hearing being held prior to and entirely independently of the summary judgment hearing. This is exactly the procedure that the Court followed in the case at hand, although other courts have chosen to address the issues raised with respect to claim construction in the context of the motion for summary judgment and hence conduct the

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hearing in conjunction with the hearings on summary judgment,

see, e.g., Biogen v. Berlex Labs., Inc.,

113 F.Supp.2d 77, 81 (D.Mass.2000) (conducting the

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hearing “in connection with” the summary judgment hearings).

This Court’s

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procedure turns on what this Court sees as the crucial distinction between construing patent claims in the

context

of considering motions for summary judgment as opposed to construing the patent claims

without regard

to the alleged infringement issue presented in the summary judgment motion. With this distinction in mind, this Court scrupulously kept the issues separate in order to avoid conflating the legal explication required by

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with the fact finding that the Seventh Amendment ultimately reserves for the American jury.

See Ciulla v. Rigny,

89 F.Supp.2d 97, 101 , 102 & n. 7 (D.Mass.2000) (discussing the constitutional and communitarian values strengthened by jury fact finding)

Although, under current law, both approaches are permitted in the wake of

Markman,

just as the Federal Circuit has spoken to the question of what evidence a court should consider in a

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hearing,

Vitronics Corp. v. Conceptronic, Inc.,

90 F.3d 1576, 1582-83 (Fed.Cir.1996), perhaps it ought similarly fashion flexible procedural boundaries within which to conduct such a hearing. Failure to do so not only deprives litigants of the benefit of consistent treatment among districts (or even among specific judges), but also risks descending a slippery slope toward the erosion of the role of the fact finder in patent litigation.

This latter fear is the central concern of this Court with the procedural approach to

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hearings that mixes issues of claim construction with that of infringement by simultaneously considering factual evidence of each. I concede that, analytically, such mixing ought not affect the outcome of claim construction. Nonetheless, I fear that such mixing cuts against the spirit of both

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itself and its recognition of the importance of the funda

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mental divide between fact and law (and consequently, fact finder and law definer) upon which our legal system is based because it openly invites the risk that issues of fact and law will be conflated.

7

Indeed, to limit proeedurally the consideration of factual issues at the

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hearing is analogous to the Federal Circuit’s own warning against the consideration of extrinsic evidence where intrinsic evidence alone will adequately allow for definition of the disputed claim term.

See Vitronics Corp.,

90 F.3d at 1583 .

Judges are expected to be objective and analytic in their role as law definer, and I daily seek to meet this standard. Moreover, I do not even mean to suggest that the outcome of this case would have somehow been different had this Court followed the approach that other courts apply and mixed the questions of claim construction into the hearing on summary judgment. But the risk that this procedure creates of conflating issues of fact and law is simply too high in my eyes. Let us not forget that the Seventh Amendment requires that infringement cases be tried to a jury.

Markman v. Westview Instruments, Inc.,

517 U.S. 370, 377 , 116 S.Ct. 1384 , 134 L.Ed.2d 577 (1996). The judiciary has recently mandated other procedural hurdles that seem to fly in the face of efficiency in the sole effort to preserve the role of the American jury.

See Apprendi v. New Jersey,

530 U.S. 466 , 120 S.Ct. 2348 , 147 L.Ed.2d 435 (2000). Believing in the benefits of such a simple prophylactic measure — considering claim construction without regard to infringement — I made careful efforts to follow this procedure consistently. The result is an honest effort to give meaning to the true spirit of

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and the due consideration that it gave to the role of the jury in patent litigation.

During the three-day

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hearing, the Court entertained oral argument from counsel for each party with respect to ten claim terms that were pre-selected due to their relationship to disputed issues arising in Amgen’s pending summary judgment motion. Counsel referred the Court to relevant portions of the specification as well as the prosecution history. Demonstrative exhibits were utilized, but evidence was neither offered nor admitted. After hearing each party’s presentation, the Court announced its constructions.

During the course of the

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hearing, the positions of each party remained generally consistent. On the one hand, Amgen consistently advocated what the Court referred to as the “ordinary meaning” of a particular claim term. On the other hand, TKT often sought to insert a limitation by arguing that without such limitation, the claim would be invalid for lack of adequate description or enablement. Their positions, of course, were not surprising. As the patent holder, Amgen had every incentive to persuade the Court to adopt the broadest possible interpretation in order to sweep within its patents’ span the greatest possible amount of its competitors’ activities. TKT meanwhile proffered limiting interpretations with an eye toward distinguishing its products and process from the scope of the patents’ language. This dance is well known.

8

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Both parties cite Federal Circuit case law that appears to support their conflicting views, thus creating the impression that the case law itself is contradictory. A close examination of this case law, however, reveals that TKT’s approach—though accepted in some limited circumstances—is inappropriate here.

In many instances, Amgen relied primarily on the familiar notion that “[f]irst, and most importantly, the language of the claim defines the scope of the protected invention.”

Bell Communications Research, Inc. v. Vitalink Communications Corp., 55

F.3d 615, 619 (Fed.Cir.1995);

see also Renishaw PLC v. Marposs Societa’ per Azioni,

158 F.3d 1243, 1248 (Fed.Cir.1998) (“[T]he claim construction inquiry, therefore, begins and ends in all cases with the actual words of the claim. [T]he resulting claim interpretation must, in the end, accord with the words chosen by the patentee to stake out the boundary of the claimed property.”);

Abtox, Inc. v. Exitron Corp.,

122 F.3d 1019, 1023 (Fed.Cir.1997) (“[T]he language of the claim frames and ultimately resolves all issues of claim interpretation”). Relatedly, absent a clear and specific statement in the patent specification giving a claim term a special definition, the Court must adopt the plain and ordinary meaning given by persons experienced in the field of the invention.

See Renishaw,

158 F.3d at 1249 ;

Hoechst Celanese Corp. v. BP Chems. Ltd.,

78 F.3d 1575, 1578 (Fed.Cir.1996);

see also Digital Biometrics, Inc. v. Identix, Inc.,

149 F.3d 1335, 1344 (Fed.Cir.1998) (patentee may be her own. lexicographer). Adhering to these cardinal principles of claim construction, this Court discharges its duty of claim construction by interpreting the claim terms pursuant to the plain and ordinary meaning ascribed to them by one skilled in the art.

Derived from these core principles is the additional canon of claim construction that a court may not read a limitation into a claim from the written description, but may look to the written description to define a term already in a claim limitation, for a claim must be read in light of the- specification.

Vitronics Corp.,

90 F.3d at 1582 . Thus, even when the Court looks at intrinsic evidence to assist it in identifying the meaning of a claim term, the words of the claim should still be given their preeminence. This canon creates a fine but important line for the Court to walk: “It is entirely proper to use the specification to interpret what the pat-entee meant by a word or a phrase in the claim. But this is not to be confused with adding an extraneous limitation appearing in the specification, which is improper.”

E.I. du Pont de Nemours & Co. v. Phillips Petroleum Co.,

849 F.2d 1430, 1433 (Fed.Cir.1988) (citation omitted);

see generally

David C. Radulescu,

The Federal Circuit’s Narrowing of the Literal Scope of Patent Claims by Focusing on Embodiments Disclosed in the Specification, 82 J.

Pat.

&

Trademark Off. Soc’y 59 (2000). To ensure that a litigant does not improperly cross this line, a party wishing to use statements in the written description to confine a patent’s scope must first point to a term in the claim with which to incorporate those statements.

Renishaw,

158 F.3d at 1248 . “Without any [such] claim term that is susceptible of clarification by the written description, there is no legitimate way to narrow the property right.”

Id.

Under such circumstances, use of the specifications to “define” the claim term would impermissibly cross over the line by

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using the specifications to add extraneous limits on the patent.

9

In contrast, TKT relies most heavily upon a number of Federal Circuit cases standing for the proposition that claims ought be construed so as to sustain their validity.

See, e.g., Wang Labs. v. Am. Online, Inc.,

197 F.3d 1377, 1383 (Fed.Cir. 1999). During the claim construction phase of the case, counsel for TKT implored the Court to reject Amgen’s proffered interpretations because such broad interpretations were not adequately disclosed in the patents’ specification. In short, TKT argued that while Amgen taught the production of EPO using a precise process and specific cells, Amgen went on to claim far beyond its teachings. Thus, if the Court adopted a claim construction commensurate with the plain and ordinary meaning of the overbroad claim terms, its construction would run counter to the Federal Circuit’s command that claims be construed so as to sustain their validity.

Indeed, incorporating validity concerns during claim construction may apply “where there are several common meanings for a claim term” and thus “the patent disclosure serves to point away from the improper meanings and toward the proper meaning.”

Renishaw,

158 F.3d at 1250 . In this sense, the canon that claim terms ought be construed to sustain their validity is simply an interpretation tool to aid courts in determining what a reasonably disputed claim term means in light of the specifications. The Federal Circuit has warned, however, that the canon that claims ought be interpreted to sustain their validity is not without limits:

The [Supreme] Court has consistently limited the axiom [that claims should be interpreted to preserve their validity] to cases where the construction is “practicable” and does not conflict with the explicit language of the claim. [The Federal Circuit also has] consistently employed the caveat, “if possible,” to our instruction that claims should be construed to sustain their validity. We have also admonished against judicial rewriting of claims to preserve validity

Rhine v. Casio, Inc.,

183 F.3d 1342, 1345 (Fed.Cir.1999) (citations omitted). With this limitation in mind, the claim term being construed must first be reasonably capable of the interpretation that is purportedly favored by the arguments for invalidity. Thus, in employing this doctrine, the Court is not permitted to construe a term that has a plain and ordinary meaning in a manner contrary to that meaning. This, of course, would constitute the type of “judicial rewriting” about which the Federal Circuit has warned.

See id.

Nor does it grant courts the authority to somehow jump to the conclusion that a claim term is reasonably susceptible of competing interpretations. Simply put, the doctrine does not grant courts the power to employ validity arguments to limit claim terms where such claim terms, even considering all alternative definitions, could not reasonably be construed to incorporate such limits. In such circumstances, validity concerns must lie in the province of the fact finder.

There is good reason, of course, to avoid conflating invalidity concerns with

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claim construction. First, the Court is mindful that determining whether a patent is invalid because it lacks a sufficient written description is an issue of fact.

See Union Oil Co. of Cal. v. Atl. Richfield Co.,

208 F.3d 989, 996 (Fed.Cir.2000). As a result, in a jury case, the members of the jury should determine whether the patent adequately describes each element of the claimed invention. If the Court were to conflate invalidity concerns involving the written description requirement with claim construction, then a function reserved for the jury would be usurped by the trial judge. At the same time, the Supreme Court has made clear that construing the claims of a patent is an issue of law and, as such, claim construction is within the province of the trial judge.

See Markman, 517

U.S. at 386, 116 S.Ct. 1384 . The conflict, then, becomes clear. If the Court were to select a construction that it believed was more consistent with the written description of the patent but contorted the language of the claim terms in order to do so, the jury, in effect, would be preempted from making the invalidity determination, which is within its province. This the Court cannot do.

Second, one must be cognizant that Congress has determined that “[a] patent shall be presumed valid.” 35 U.S.C. § 282 . This eongressionally-mandated presumption of validity not only places the burden of proving invalidity on the defendant, but also requires the defendant to prove the point by clear and convincing evidence.

SIBIA Neurosciences, Inc. v. Cadus Pharm. Corp.,

225 F.3d 1349, 1355 (Fed.Cir.2000). In order to give congressional will the deference it deserves, courts ought not permit defendants to shirk this responsibility by arguing that concerns regarding validity should be accounted for during claim construction. Instead, it strikes the Court that the proper way to proceed, where it is possible, is to interpret the claim terms consistent with their plain and ordinary meaning and hold the defendant to its burden to prove invalidity by clear and convincing evidence. Any other approach would neglect the congressional mandate.

In this case, the Court ruled during the

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hearing that TKT’s claim construction theory extends the canon that claims ought be construed in favor of their validity far beyond its intended reach. Instead, as explained below, because the terms to be construed simply are not reasonably capable of the interpretation proffered by TKT, it became apparent that TKT was actually attempting to add limitations to claim terms rather than merely attempting to define the disputed terms. At the end of the day, the canon that claims ought be construed so as to sustain their validity simply does not include under its umbrella TKT’s arguments as they apply in this matter.

With these concerns in mind, the Court conducted the

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hearing and interpreted ten words and phrases central to the patents-in-suit and the dispute between the parties. Each term, the arguments relevant to it, and the Court’s construction are reproduced below seriatim.

10

A.

Vertebrate Cells

The term “vertebrate cells” is contained in Claims 4, 6, and dependent Claim 7 of the ’698 patent and Claims 1, 4, and dependent Claims 3, 6, and 7 of the ’349 patent. There is no contention by either party that the term should have a different meaning in the various claims. Aside from that agreement, however, the parties (not surprisingly) proffered quite different constructions. Amgen contended that “vertebrate cells” means “cells originating from an animal having a backbone,” Pl.’s

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Hr’g (Mar. 27, 2000) Demonstrative Ex. 12, whereas TKT argued that the term means “non-human cells that originate

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from an animal having a backbone,” Defs.’

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Hr’g Demonstrative Ex. 1. Thus, while Amgen proffered the broad, albeit ordinary meaning of the term, TKT sought to have the Court add a limitation to the claim by including the word “nonhuman.”

The reason for the particular distinction between the parties’ proffered constructions is, not surprisingly, fueled by the related infringement and validity analysis. In order to make EPO, TKT activates the native human EPO gene in a human cell. As a result, there is little wonder why TKT offered, and Amgen vehemently opposed, a construction of the term “vertebrate” that excluded human cells. Had the Court adopted TKT’s version, it would have been bound to issue, upon proper motion, summary judgment of non-infringement — at least as to literal infringement. That, of course, is no reason to reject TKT’s proffer, but merely explains the importance of construing the term appropriately.

While counsel for TKT admitted that its construction was contrary to the ordinary meaning of the term “vertebrate,” TKT argued that “the terms of a claim cannot be construed in a vacuum.” Tr. of

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Hr’g, Vol. I at 7:17-18.

11

Instead, implored TKT, the Court must interpret the claims in accordance with the specification and the prosecution history and, set in this context, “vertebrate cells” were not meant to encompass human cells even though humans are admittedly a subset of vertebrates.

Id.

at 7:22-25. For the reasons expressed above, however, TKT’s contention is untenable. Even if significant intrinsic evidence pointed toward a more limited definition of “vertebrate,” “the claim construction inquiry ... begins and ends in all cases with the actual words of the claim.... [T]he resulting claim interpretation must, in the end, accord with the words chosen by the patentee to stake out the boundary of the claimed property.”

Renishaw,

158 F.3d at 1248 (citations omitted). There simply is no hook in the claim term that allows for TKT’s alternate construction. The term “vertebrate” is a widely known and understood word which has a precise scientific meaning. A vertebrate is a member of the subphylum Vertebrata, which is a primary division of the phylum Chordata, which in turn is a division of the Animal Kingdom. A vertebrate is uniquely characterized by a segmented bony or cartilaginous spinal cord. Therefore, the plain and ordinary meaning of the term “vertebrate cells,” i.e., cells that originate from an animal having a backbone, accords with the words chosen by the pat-entee to identify the scope of the claimed invention. Because humans are vertebrates, TKT’s construction betrays the plain and ordinary meaning of the claim term. Thus, the Court construed the term “vertebrate cells” to mean “cells from an animal having a backbone.” Tr. of

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Hr’g, Vol. I at 67:8-9.

B.

Mammalian Cells

The term “mammalian cells” is contained in Claim 1 of the ’422 patent and dependent Claim 9 of the ’698 patent. Consistent with its approach to vertebrate cells, TKT proffered a construction of the term “mammalian cells” that excluded human cells. Specifically, TKT contended that “mammalian cells” are “[cjells from warm-blooded non-human vertebrate animals whose young are fed by milk secreted from the mammary glands.” Defs.’

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Hr’g Demonstrative Ex. 1. Again, with an eye toward literal infringement, Amgen opposed this construction and instead argued that “mammalian cells” are “cells from a warm-blooded animal that has a backbone and whose young are fed by milk secreted from mammary glands.” Pl.’s

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Hr’g (Mar. 27, 2000) Demonstrative Ex. 14. For the same reasons explained above, the Court could not re

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main faithful to the widely known and specific meaning of the word “mammalian” if it were to add the non-human limitation. Simply put, the claim term was not reasonably susceptible to TKT’s construction. As a result, the Court determined that “mammalian cells” are “cells from a warmblooded animal, whose young are fed by milk secreted from mammary glands.” Tr. of

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Hr’g, Vol. I at 67:9-11.

C.

Mature Erythropoietin Amino Acid Sequence of Fig. 6

This phrase is contained in Claims 4 and 6 of the ’698 patent and Claims 2 and 8 of the ’080 patent. Although the phrase sits in different contexts — and thus modifies different subjects- — the parties agree that the phrase should have the same meaning in both settings. Focusing on the ordinary meaning of the term “mature,” Amgen contended that the phrase means “the fully processed form of the protein secreted by a cell ... when it transcribes and translates the DNA in Figure 6.”

Id.

at 70:24 to 71:4. In contrast, relying on a portion of the specification that explains that “Fig. 6 thus serves to identify the primary structural conformation (amino acid sequence) of mature human EPO as including 166 specified amino acid residues,” Trial Ex. 1 at 21:3-6,

12

TKT contended that the phrase means “the 166 amino acid sequence of human EPO shown in Fig. 6,”

13

see

Tr. of

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Hr’g, Vol. I at 90:9 to 102:15. The dispute focused on the amino acid located in the 166th position, arginine. Unknown to Dr. Lin at the time of the invention, arginine is cleaved off at some point during protein synthesis prior to secretion from the cell. Thus, the protein that is actually secreted from the cell contains only 165 amino acids. Figure 6, however, depicts the arginine.

By proffering the language “fully processed,” Amgen hoped to obtain an interpretation encompassing the secreted version of the protein, regardless of the specific number of amino acids. Meanwhile, TKT, whose process produces secreted proteins containing only 165 amino acids, sought an interpretation of Figure 6 that specifically required 166 amino acids.

The Court agreed that the term “mature” implied the fully processed form of EPO secreted by the cell, but whether “mature” included the 165 amino acid sequence as well as the 166 amino acid sequence was ambiguous. The patent specification used “mature” to describe an EPO polypeptide that has been secreted by a cell:

the first residue designated for the amino acid sequence of the mature protein is indicative of the likelihood that EPO is initially expressed in the cytoplasm in a precursor form including a 27 amino acid “leader” region which is excised prior to entry of mature EPO into circulation.

Trial Ex. 1 at 19:86-41. By identifying the EPO that enters circulation as “mature,” Dr. Lin essentially defined the term “mature” to mean “the fully processed form of the protein that is secreted by the cell.” Consequently, on the one hand, the Court agreed with Amgen’s contention that “fully processed” or “fully realized” ought be incorporated into the Court’s construction of the phrase “mature erythropoietin amino acid sequence of Fig. 6.” On the other hand, the Court was not further persuaded by Amgen that reference to Figure 6 did

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not limit the meaning of the claim terms to the 166 amino acid sequence disclosed in that figure. Yet neither was TKT able to .persuade the Court at the

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hearing that the term was necessarily limited to a 166 amino acid construction. Consequently, the Court chose to abstain for the time being from deciding the “165-166 dispute” and concluded only that the phrase “the mature erythropoietin amino acid sequence of Figure 6” means “the fully realized form of amino acid sequence of Figure 6.” Tr. of

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Hr’g, Vol. II at 23:14-18.

D.

Non-human DNA Sequences That Control Transcription and Transcription Control DNA Sequences

As background, transcription is the process whereby RNA polymerase copies genetic information contained in a DNA nucleotide sequence into a complementary RNA sequence. As the patent explains, “the programming function of DNA is generally effected through a process wherein specific DNA nucleotide sequences (genes) are ‘transcribed’ into relatively unstable messenger RNA (mRNA) polymers.” Trial Ex. 1 at 1:52-55. Transcription is a critical step in the expression of proteins like erythropoietin and is itself controlled by its own DNA sequences. These “transcription control DNA sequences” “precede a selected gene (or series of genes) in a functional DNA polymer [and] cooperate to determine whether the transcription (and eventual expression) of a gene will occur.”

Id.

at 2:10-13. According to the patent, “transcription control sequences” is the collective term for DNA sequences that not only “provide a site for initiation of transcription into mRNA,” but also are capable of binding proteins that determine “the frequency (or rate) of transcriptional initiation.”

Id.

at 2:3-12. Claims referring to these transcription control sequences were the subject of the following disputes between the parties.

The phrase “non-human DNA sequences that control transcription” is contained in Claim 1 of the ’349 patent. Amgen contended that this phrase means “[n]on-human DNA sequences that are able to initiate or regulate RNA synthesis from EPO DNA.” Pl.’s

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Hr’g (Mar. 27, 2000) Demonstrative Ex. 69. In contrast, TKT argued that the phrase means “DNA sequences which did not originate in the human genome, which initiate and regulate RNA synthesis of adjacent DNA, and which replace the human EPO transcription control sequences.” Defs.’

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Hr’g (Mar. 27-28, 2000) Demonstrative Ex. 1. The dispute centered around a few crucial terms.

First, TKT contended that in order to “control” transcription, the DNA sequences must both initiate

and

regulate the transcription of a gene. Amgen objected to the use of “and,” preferring a construction that required DNA sequences either to initiate

or

regulate transcription.

Second, the parties disputed the importance of location. By including the term “adjacent DNA” in its construction, TKT sought to require the DNA sequences that control transcription to be located in a position adjacent to the gene segment intended to be expressed.

Third, the parties disagreed as to the meaning of “non-human.” Amgen argued that “non-human” means “not part of the human genome,” whereas TKT contended that it means “not originating in the human genome.” Because it is scientifically arguable that viral DNA originates in the human genome, the viral promoter DNA that TKT employs thus might not fall within the meaning of the claim.

The Court first determined that “nonhuman” DNA sequences are DNA sequences that are “not part of the human genome.” Tr. of

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Hr’g, Vol. II at 56:25 to 57:1. The Court rejected TKT’s construction, ruling that Amgen meant simply to exclude the human DNA sequences that control transcription from the reach of its claim, sequences which, of course, are part of the human genome. By construing the term “non-human” to

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mean “not part of the human genome,” then, the Court settled on a construction that best effectuated Amgen’s intent.

Second, the Court rejected TKT’s “adjacent” language because no claim term could reasonably be construed to be limiting the transcription control DNA sequences by their location. Consequently, the Court adopted a construction that was in no way limited by the location of the transcription control sequences relative to the gene to be expressed.

Third, the Court held that “DNA sequences that control transcription are DNA sequences that initiate and may regulate the processes of transcription.”

Id.

at 57:1-4. When it announced its construction of this phrase, the Court used the term “may,” which signifies that while the DNA sequence must initiate transcription, it need not regulate transcription.

The Court then considered the phrase “transcription control DNA sequences,” which is contained in Claim 4 of the ’349 patent. Borrowing extensively from the patent specification, the Court explained that “transcription control sequences” are “collectively promoter DNA sequences that provide a site that is capable of initiating transcription ... and regulator DNA sequences that are capable of binding proteins that determine the frequency or rate ... of transcription initiation.”

Id.

at 57:16-23. At the time, the Court did not recognize the inconsistency between these two constructions. Although “DNA sequences that control transcription” and “transcription control DNA sequences” should have the same meaning, the Court’s constructions permitted regulator functions in one instance and required them in the other instance. As will be explained in the infringement portion of the decision, however, the parties tried the case with the latter construction in mind and thus no harm to the parties resulted.

E.

Purified from Mammalian Cells Grown in Culture

The phrase “purified from mammalian cells grown in culture” is contained only in Claim 1 of the ’422 patent, for which the Court subsequently granted summary judgment on literal infringement grounds. The parties presented strikingly different constructions of this phrase during the

Markman

hearing. Amgen contended it means “[pjurified from the in vitro culture in which the mammalian cells have been grown,” Pl.’s

Markman

Hr’g (Apr. 10, 2000) Demonstrative Ex. Amgen’s ’422 Patent Claim 1, whereas TKT argued that it means “obtained in a substantially homogeneous state from the mammalian cells in which it was produced and not from the cell culture media,” Defs.’

Markman

Hr’g (Apr. 10, 2000) Demonstrative Ex. 50. TKT admitted that the specification taught three different methods of obtaining EPO: extraction (1) from the cell cytoplasm; (2) from the cell membrane; and (3) from the cell culture medium. TKT nonetheless contended that the plain and ordinary meaning of the phrase meant that the EPO had to be purified from the cells. Thus, argued TKT, Amgen only claimed one of the three methods it taught in the patent. Because TKT obtains its EPO from the cell culture media and not directly from its cells, the parties’ positions are not surprising.

The Court, however, disagreed with TKT’s interpretation of the claim with respect to both the plain and ordinary meaning of the terms and the consistency of its interpretation with the other claims. First, TKT’s construction would exclude the patent’s preferred embodiment: Example 10. Constructions that exclude the patent’s preferred embodiment should rarely be adopted.

Modine Mfg. Co. v. United States Int’l Trade Comm’n,

75 F.3d 1545 , 1550 (Fed.Cir.1996);

Media-Com,

4 F.Supp.2d at 28. Example 10 extensively describes techniques for obtaining substantially purified erythropoietin from cell culture media. Trial Ex. 1 at 27:15-50, 28:29-32. TKT’s claim construction would exclude the method taught in

*89

the patent’s preferred embodiment and hence is suspect.

Second, from the Court’s perspective, TKT’s construction ignored the language “grown in culture” and focused solely on the immediately preceding language, “purified from mammalian cells.” If the claim merely read “purified from mammalian cells,” then TKT’s argument that the human erythropoietin must be extracted from the cell itself would indeed have held more sway. Yet all of the terms of the claim must be given effect. Consequently, the Court read the phrase “mammalian cells grown in culture” as a whole and, therefore, as not specifying a particular method, but rather encompassing purification techniques from the cells or the cell culture medium. Thus, the Court held that “purified from mammalian cells grown in culture” means “obtained in substantially homogeneous form from the mammalian cells, using the word from in the sense that it originates in the mammalian cells, without limitation to it only taking it directly out of the interior of the cells, which have been grown in the in vitro culture.” Tr. of

Markman

Hr’g, Vol. III at 16:15-19.

F.

DNA Encoding Human Erythro-poietin

The phrase “DNA encoding human er-ythropoietin” is contained in Claim 1 and related to dependent Claims 3 and 7 of the ’349 patent. Amgen, on the one hand, contended that the claim terms are so straightforward that interpretation of any of the terms was unnecessary. TKT, on the other hand, argued that the phrase means “[h]uman EPO DNA that is exogenous to the cell in which the EPO is produced, i.e., the human EPO DNA did not originate in the genome of the cell into which it is inserted,” Defs.’

Markman

Hr’g (Apr. 10, 2000) Demonstrative Ex. 19— more succinctly, “exogenous DNA encoding human erythropoietin.” TKT argued that because the patent specification only taught using DNA that encoded for human erythropoietin that did not originate in the genome of the host cell (exogenous DNA), the claim term should not be interpreted to include both exogenous and endogenous human EPO DNA. Because TKT activates the human erythropoietin gene in the human host cell (the endogenous EPO gene), one can understand TKT’s motivation in proffering its construction.

Yet, as the Court pointed out, TKT’s construction is merely “a variant of the argument that’s already been made here.” Tr. of

Markman

Hr’g, Vol. III at 23:2-3. TKT was once again employing invalidity contentions in an attempt to add limitations into claim terms that by their plain meaning were not amenable to such limitations. The plain meaning of the claim terms simply do not call for any such limitation. This portion of the claim language claims any and all DNAs that encode human erythropoietin regardless of such DNA’s relationship to the host cell in which it is expressed. Thus, the Court held that “DNA encoding human erythro-poietin” means “DNA which encodes human erythropoietin, not including the word exogenous DNA which encodes human erythropoietin.”

Id.

at 35:1-3.

14

G.

Operatively Linked

“Operatively linked” is located in Claim 4 of the ’698 patent and related by dependency to Claims 5 and 9. In context, the phrase relates to the relationship between promoter DNA

15

and the DNA that is transcribed downstream from the promoter DNA. Amgen contended that the phrase

*90

means “[positioned such that it provides for initiation of transcription of a gene.” Pl.'s

Markman

Hr’g (Apr. 10, 2000) Demontrative Ex. Amgen’s ’698 Patent Claim 4. TKT argued that the term means “[positioned adjacent] to the DNA encoding EPO in a way that maintains the capability to initiate transcription of EPO DNA.” Defs.’

Markman

Hr’g (Apr 10, 2000) Demonstrative Ex. 69 (alteration in original). The parties disputed, once again, the issue of the location of the promoter relative to the gene to be expressed. Amgen argued that the words “operatively linked” imposed no locational restriction, whereas TKT contended that because the patent taught placing the promoter DNA immediately adjacent to the DNA encoding EPO, the term “operatively linked” ought be limited by location.

The term “linked” could, if unmodified by “operatively,” imply a spatial relationship in that a link could fix the maximum distance between the two linked objects. Yet modification by the term “operatively” implies a functional rather than physical link between the two objects — in this instance one entity’s exertion of influence on another entity. More specifically, in this case, the link between the promoter DNA and DNA encoding EPO consists of the influence possessed by the promoter DNA to initiate the transcription from the DNA encoding EPO. As a result, the term “op-eratively linked” is not defined by the physical location of the promoter DNA relative to the DNA encoding erythro-poietin, but rather by the functional effect the promoter DNA has on the EPO DNA. Thus, contrary to TKT’s contentions, the term “operatively linked” could not reasonably be construed to impose a locational restriction, because the link is limited only in the sense that the promoter DNA must initiate transcription of the EPO DNA. Consequently, the Court determined that “operatively linked” means “the promoter DNA is linked to the EPO DNA in a way that maintains the capability of the promoter DNA to initiate transcription of the EPO DNA.” Tr. of

Markman

Hr’g, Vol. III at 43:8-10.

H.

Non-naturally Occurring

The phrase “non-naturally occurring” modifies the erythropoietin glycoprotein product claimed in the ’933 patent, Claims 1 and 2 and dependent Claim 9, as well as Claim 3 and dependent Claim 4 of the ’080 patent. TKT argued that the phrase was meant to incorporate the exogenous DNA limitation that it had sought (unconvincingly) with respect to many of the prior construed claim terms. Thus, it proffered the following definition: “produced from an EPO DNA coding sequence which was not part of the native genome of the host cell in which the EPO protein is produced .... ” Defs.’

Markman

Hr’g Demonstrative Ex. 36. Amgen, in contrast, contended that the term means “[ojbtained from a source that does not naturally produce or contain EPO.” Pl.’s

Markman

Hr’g (Apr. 10, 2000) Demonstrative Ex. Amgen’s ’933 Patent Claim 1 (emphasis omitted). The contentions conflicted in this manner because TKT activates an endogenous EPO gene in a human cell, as opposed to generating EPO from an exogenous gene transfected into a host cell.

Unlike the prior instances in which TKT attempted to impose the exogenous DNA limitation into the construction of a claim term, there is a reasonable argument that the term “non-naturally occurring” has the meaning that TKT attempted to ascribe to it because, to put it simply, there

is

something a bit “non-natural” about an erythro-poietin glycoprotein being produced by transfecting host cells with exogenous EPO DNA. Yet TKT’s interpretation is deficient for various reasons.

First, TKT’s ship runs aground on the claim construction axiom that a claim will not be construed as containing a limitation that is expressed in other claims.

See Karlin Tech. Inc. v. Surgical Dynamics, Inc.,

177 F.3d 968, 971-72 (Fed.Cir.1999). Similarly, “[a]U the limitations of a claim must be considered

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meaningful,”

Unique Concepts, Inc. v. Brown,

939 F.2d 1558, 1562 (Fed.Cir.1991) (citation omitted), and if two separate and distinct limitations are construed as synonymous, the claim recitation of both limitations is redundant and superfluous.

See Beachcombers, Int'l v. WildeWood Creative Prods. Inc.,

31 F.3d 1154, 1162 (Fed.Cir.1994);

Tex. Instruments, Inc. v. United States Int’l Trade Comm’n,

988 F.2d 1165 , 1171 (Fed.Cir.1993). Claim 3 of the ’933 patent, though not in suit, claims a “non-naturally occurring glycoprotein product of the expression in a mammalian host cell of an exogenous DNA sequence comprising a DNA sequence encoding human erythropoietin .... ” If the Court were to adopt TKT’s construction of “non-naturally occurring,” it would render the terms redundant in the context of the ’933 patent’s Claim 3. Thus, neither the paten-tee nor the examiner could have meant the term “non-naturally occurring” to refer to the use of exogenous EPO DNA.

Second, the patent specification also explains that the recombinant-produced and synthetic products are both similar to and different from natural EPO. For example, one passage compares the biological activity of the synthetic products to that of “EPO isolates from natural sources” or “natural EPO isolates.” Trial Ex. 1 at 33:14, 33:24;

see id.

at 33:40-44. Thus, the specification indicates that Dr. Lin contemplated his polypeptide products visa-vis the unpatentable EPO polypeptide from natural sources. Furthermore, the Supreme Court has used the term “nonna-turally occurring” to distinguish a “product of human ingenuity” from the “natural phenomenon” that the non-natural version mimics.

See Diamond v. Chakrabarty,

447 U.S. 303, 309-10 , 100 S.Ct. 2204 , 65 L.Ed.2d 144 (1980). In considering the terms “non-naturally occurring” here, the Court held that Dr. Lin intended a similar meaning. By including this limitation, Dr. Lin meant to stand clear of the unpatentable, naturally occurring products. He intended nothing more.

In light of these considerations, after taking the matter under advisement on April 10, 2000, the Court informed the parties at the final pretrial conference on April 18, 2000 that “non-naturally occurring” means “not occurring in nature.”

I.

Glycosylation Which Differs

The phrase “glycosylation which differs” is recited only in Claim 1 of the ’933 patent and relates to Claims 2 and 9 of the same patent by dependency. The parties essentially agreed that glycosylation refers to the carbohydrate side chains that are attached to a molecule, in this case erythro-poietin. Yet Amgen further contended that the phrase means that “[t]he attached carbohydrate groups differ when analyzed by standard prior art techniques known as of 1983-84.” Pl.’s

Markman

Hr’g (Apr. 10, 2000) Demonstrative Ex. Amgen’s ’933 Patent Claim 1 (emphasis omitted). TKT argued that it means “the carbohydrate groups attached to side chains of the er-ythropoietin polypeptide backbone differ by Western blot analysis and SDS/ PAGE

16

and carbohydrate composition analysis

17

from those of human urinary erythropoietin to at least the degree described in the patents-in-suit.” Defs.’

Markman

Hr’g (Apr. 10, 2000) Demonstrative Ex. 89 (footnotes added). The primary discrepancy concerned which, if any, techniques would be specifically identified as methods encompassed under the meaning of the term “glycosylation which dif

*92

fers.” TKT contended that the specification describes two tests by which to prove differences in glycosylation: SDS-PAGE/Western Blot and carbohydrate composition analysis. Thus, TKT’s construction would require proof with respect to both types of tests and no others, whereas Amgen’s construction would not limit the manner by which differences in glycosylation are proven.

Example 10 of the patent describes comparisons made between recombinant glyco-protein products and human urinary eryth-ropoietin using various techniques.

See

Trial Ex. 1 at 28:33-67. The specification not only reports data obtained from SDS-PAGE/Western blot analysis, but also by monosaccharide, or carbohydrate, analysis.

See id.

Yet the claim term “glycosylation which differs” is not further limited by the methods used to identify such differences in Example 10. A comparison of Claims 1 and 2 of the ’933 patent exposes the significance of the exclusion of such a limitation. Claim 2 of the ’933 patent requires the EPO glycoprotein product to have “a higher molecular weight than human urinary EPO as

measured by SDS-PAGE.” Id.

at 38:23-25 (emphasis added). Claim 1, however, merely states that the erythropoietin glycoprotein product must have “glycosylation which differs from that of human urinary erythropoietin.”

Id.

at 38:20-21. The inference is that the patentee knew how to limit claim terms regarding differences in glycosylation by specifying the method by which such differences are empirically tested. Taking this into account, the Court was loath to mandate that proof of glycosylation differences must be shown using the particular types of tests specifically identified in the patent. As a result, the Court avoided mandatory language, but nonetheless ruled that “glycosylation which differs” means: “Glycosylation as to which there is a detectable difference based upon what was known in 1983-1984 from that of human urinary erythropoietin, having in mind that the patent holder, Amgen, taught the use of this Western blot, SDS-PAGE and monosaccharide test.” Tr. of

Markman

Hr’g, Vol. III at 102:18-23.

J.

Human Urinary Erythropoietin

The ’933 patent employs the phrase “human urinary erythropoietin” in Claims 1 and 2 and dependent Claim 9. Trial Ex. 2 at 38:21, 38:23, 39:3. Amgen contended that the term means “[h]uman EPO isolated from pooled urine of aplastic anemia patients isolated using any method used in the prior art,” Pl.’s

Markman

Hr’g (Apr. 10, 2000) Demonstrative Ex. Amgen’s ’933 Patent: The Parties Constructions (emphasis omitted), whereas TKT argued that it means “[a]ll EPO preparations that can be isolated or purified from human urine by any method,” Defs.’

Markman

Hr’g (Apr. 10, 2000) Demonstrative Ex. 2. The dispute, then, is essentially one of scope: Does the claim term encompass all eryth-ropoietin preparations obtained from human urine or is it limited to only EPO obtained from the pooled urine of aplastic anemia patients?

In order to support its construction, Am-gen relied on the specification and prosecution history. The specification, for instance, identifies and briefly describes the “Miyake procedure”

18

for “purifying human erythropoietin from urine of patients with aplastic anemia.” Trial Ex. 1 at 7:10-17. The patent cites other prior art sources that describe the isolation of human urinary erythropoietin from the pooled urine of aplastic anemia patients.

Id.

at 8:13-16. The specification also reports the results relating to molecular weight comparisons of CHO-produced EPO, COS-produced EPO, and the “pooled source human urinary extract.”

19

Id.

at 28:33-41. Similarly, Amgen pointed to

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comparisons between its recombinant er-ythropoietin and human urinary erythro-poietin purified by the Miyake procedure as evidence of novelty. Trial Ex. 2 Tab 6 at 11.

Though Amgen’s construction may be supported by these aspects of the specification and prosecution history, Amgen’s narrow interpretation of this claim limitation is not faithful to the plain and ordinary meaning of the claim language. The claim terms themselves do not specify which type of human urinary erythropoiet-in is contemplated. Instead, the plain and ordinary meaning of the phrase “human urinary erythropoietin” broadly encompasses all urinary EPOs. As a result, “on this one, in all candor, the shoe is on the other foot .... ” Tr. of

Markman

Hr’g, Vol. III at 106:11-12. Thus, adhering to the plain meaning of the terms, the Court concluded that “human urinary erythro-poietin” means “erythropoietin derived from human urine.”

Id.

at 112:23-24.

III. SUMMARY JUDGMENT OF INFRINGEMENT ON CLAIM 1 OF THE ’422 PATENT

Following the

Markman

hearing, the Court turned promptly- — albeit in an entirely separate hearing,

see supra

Part II — to considering the then pending motion for summary judgment. On April 26, 2000, the Court heard oral argument regarding whether TKT’s activities literally infringe Claim 1 of the ’422 patent and Claims 1, 3, 4, and 6 of the ’349 patent. Amgen argued that there were no genuine issues of material fact regarding the technologies of each party and that a plain reading of the claims of Amgen’s patents entitled Amgen to judgment as matter of law.

Summary judgment is appropriate when there are no genuine issues of material fact and the movant is entitled to judgment as matter of law. Fed.R.Civ.P. 66. Nonetheless, the Court must view the evidence in the light most favorable to the non-movant and must draw all reasonable inferences and resolve all doubts regarding factual issues in favor of the party opposing summary judgment.

Pfaff v. Wells Elecs., Inc.,

5 F.3d 514, 517 (Fed.Cir.1993). In considering a motion for summary judgment, the Court relies upon any “ ‘pleadings, depositions, answers to interrogatories, and admissions on file, together with the affidavits’” which, in toto, comprise the relevant record.

Rotec Indus., Inc. v. Mitsubishi Corp.,

215 F.3d 1246, 1250 (Fed.Cir.2000) (quoting Fed.R.Civ.P. 56[c]). As is required under controlling law, the Court considers only the documents in the summary judgment record as of April 26, 2000.

As this Court has previously held, “if there are no genuine issues of material fact, summary judgment is appropriate in a patent infringement case as in any other.”

Amgen, Inc. v. Hoechst Marion Roussel, Inc.,

3 F.Supp.2d 104, 107 (D.Mass.1998). Infringement is a two-part inquiry requiring the construction of the claims, which is a question of law, and the application of the properly construed claims to the allegedly infringing article, which is a question of fact.

Markman v. Westview Instruments, Inc.,

517 U.S. 370, 391 , 116 S.Ct. 1384 , 134 L.Ed.2d 577 (1996);

Renishaw PLC v. Marposs Societa’ per Azioni,

158 F.3d 1243, 1247-48 (Fed.Cir.1998).

When the parties do not dispute relevant facts regarding infringement, but merely disagree over claim construction, “the question of literal infringement collapses to one of claim construction and is thus amenable to summary judgment.”

Athletic Alternatives, Inc. v. Prince Mfg., Inc.,

73 F.3d 1573, 1578 (Fed.Cir.1996);

see K-2 Corp. v. Salomon S.A.,

191 F.3d 1356 , 52 U.S.P.Q.2d (BNA) 1001, 1004 (Fed.Cir.1999). In contrast, when the Court construes the claims in favor of the plaintiff, and a genuine issue of material fact regarding infringement nonetheless exists, summary judgment is not appropriate.

See MacNeill Eng’g Co. v. Trisport,

*94

Ltd.,

126 F.Supp.2d 51, 58 (D.Mass.2001). With these considerations in mind, the Court addressed the legal issue whether, upon the summary judgment record, TKT’s product, HMR4396, and TKT’s R223 cells literally infringe Claim 1 of the ’422 patent.

Claim 1 of the ’422 patent claims 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.” Trial Ex. 6 at 38:36-40. As Federal Circuit precedent requires, the Court broke down Claim 1 into each of its limiting terms and compared those terms — and any meanings ascribed to them during the

Markman

hearing — with TKT’s HMR4396 and R223 cells.

A.

Pharmaceutical Composition

Amgen submitted ample and uncontra-dicted evidence on the summary judgment record that TKT’s HMR4396 injection is a pharmaceutical composition. As explained in Section 3.6 of TKT’s Investigational New Drug Application (“IND”) for HMR4396, which is submitted to the Food and Drug Administration (“FDA”) in order to initiate and facilitate the agency’s clinical investigation of the product, “HMR4396 Injection is a sterile, nonpyro-genic, colorless aqueous solution in Water for Injection at 4000 U/ml or 10,000 U/ml concentrations.” Galvin Decl. (Nov. 4, 1999) Ex. 10 at IND000019. Furthermore, the fact that the product has been submitted for investigation by the FDA is clear evidence that HMR4396 is a pharmaceutical composition. Another IND document describes diluting the HMR4396 purified bulk “to obtain the desired drug product dosage strengths .... ”

Id.

Ex. 18 at IND501303;

see id.

Ex. 1 at 242:9 to 243:25, 282:8-21 (explaining that HMR4396 is an aqueous solution that is further formulated into a pharmaceutical composition). In light of this uncontra-dicted evidence, HMR4396 is a pharmaceutical composition as that term is used in Claim 1 of the ’422 patent.

B.

Therapeutically Effective Amount of Human Erythropoietin

It cannot be disputed that HMR4396 is human erythropoietin. Section 3.3 of the IND for TKT’s “Gene-Activated Erythropoietin” directly states that “HMR4396 is human erythropoietin produced by TKT’s gene-activation technology.”

Id.

Ex. 10 at IND000019;

see id.

Ex. 14 at IND000335-37, 000385 (identifying HMR4396 as human erythropoietin). Furthermore, in response to the question whether HMR4396 is human erythropoiet-in, TKT’s Federal Rule of Civil Procedure 30(b)(6) designee, David S. Johnson, answered affirmatively.

Id.

Ex. 4 at 37:10-11. Another TKT Rule 30(b)(6) designee, Richard F. Selden, admitted that HMR4396 is human erythropoietin. Stretch Decl. (Apr. 20, 2000) Ex. 4 at 399:15-19;

see

Galvin Decl. (Nov. 4, 1999) Ex. 1 at 14:12 to 15:6.

In the face of these significant admissions, TKT opted to take two tacks, but neither steadied its rocking boat because both were unsuccessful attempts at changing the Court’s claim construction rather than efforts to raise an issue of disputed material fact. First, in its initial response to Amgen’s summary judgment motion and during subsequent argument, TKT contended that HMR4396 was not human er-ythropoietin because as that term is used in the patent “human erythropoietin” means recombinant EPO produced in nonhuman cells transfected with cloned, exogenous human EPO DNA. Because HMR4396 is produced by activating the endogenous EPO gene in a human cell, such a construction would exclude TKT’s product. This contorted claim construction, however, was rejected by the Court.

See supra

Section II.F, at 33-34.

Second, during oral argument following claim construction, TKT attempted to add a further limitation into the claim. Rely

*95

ing on language from the specification regarding Claim 1 of the ’422 patent that explained that the pharmaceutical composition was comprised of “effective amounts of polypeptide products of the invention,” Trial Ex. 6 at 12:6-7, TKT argued that “human erythropoietin”should be limited by this phrase. Thus, contended TKT, because the polypeptide products of the invention are defined in part by Figure 6,

see id.

11:42-54, which erroneously specifies a 166 amino acid chain,

see

Trial Ex. 1 Fig.6, and TKT only isolates a 165 amino acid product, HMR4396 could not be human erythropoietin. TKT thus seeks to read a 166 amino acid limitation into the claim term “human erythropoietin.” This the Court cannot do. As with the previous tack, this argument drifted far astray from the language of the claim and was therefore unpersuasive. Rather than attack the Court’s claim construction, to forestall summary judgment, TKT needed to point to

evidence

that would demonstrate a genuine issue of material fact regarding infringement

in the context of

the Court’s construction. Because it failed to do so, and Amgen’s evidence on the same point was substantial, the Court determined that HMR4896 is human erythropoietin.

Moreover, when asked by the Court whether HMR4396 contains a therapeutically effective amount of human erythro-poietin, counsel for TKT admitted that, “If it didn’t, believe me, we wouldn’t be standing here.” Tr. of

Markman

Hr’g, Vol. II at 130:19-20. As admissions on the record constitute evidence upon which reliance may be placed at the summary judgment stage,

see

Fed.R.Civ.P. 56(c), counsel’s direct answer is more than sufficient to warrant summary judgment of infringement with respect to this claim term. Counsel’s response also comports with the common sense context of this case. TKT’s product would simply pose no real threat to EPO-GEN ® if it did not contain a therapeutically effective amount of human erythropoiet-in. Patients would not seek, nor doctors prescribe, such an ineffective product. Viewed in this context, TKT’s admission made perfect sense. As a result, the Court determined on the summary judgment record that HMR4396 contained a therapeutically effective amount of human erythropoietin.

C.

Pharmaceutically Acceptable Diluent, Adjuvant, or Carrier

The evidence on the summary judgment record with respect to HMR4396 showed that it contains a phosphate buffer that acts as a diluent. In particular, as TKT’s Rule 30(b)(6) designee explained, once the bulk is generated from the culturing of the human cells, the product is then diluted to provide a product of desired strength. Galvin Decl. (Nov. 4,1999) Ex. 1 at 243:12-19. The diluent is a phosphate buffer that “affords the pH control in the formulation.”

Id.

at 243:5-6. The uncontroverted admissions in the Hancock deposition testimony satisfactorily proved that HMR4396 contains a pharmaceutically acceptable diluent, adjuvant, or carrier.

D.

Purified from Mammalian Cells Grown in Culture

Claim 1 of the ’422 patent claims a pharmaceutical composition comprising human erythropoietin that has been purified from mammalian .cells grown in culture. Trial Ex. 6 at 38:40-41. In light of the Court’s constructions of “mammalian cells” and “purified from mammalian cells grown in culture,”

see supra

Section II.B, at 23-24, Section II.E, at 31-33, the Court considers the evidentiary record. The record makes clear that TKT’s R223 cell line, which is used to make HMR4396, is derived from an HT1080 cell, which is a human skin cancer cell. Thus, although the cell undergoes a variety of changes during TKT’s process, it is — and at all times remains — a human cell.

See

Galvin Decl. (Nov. 4, 1999) Ex. 4 at 74:14 to 75:12. TKT’s approach to this claim term depended entirely on persuading the Court that “mammalian” did not include “human.” As explained above, the Court rejected this proffered construction, leav

*96

ing TKT in the Herculean position of proving that humans were somehow not mammalian. Not surprisingly, they opted instead to concede on the summary judgment record that the R223 cells are mammalian cells under the Court’s construction. Tr. of

Markman

Hr’g, Vol. II at 130:21-25. Consequently, the Court determined that TKT employs mammalian cells.

Id.

at 136:1-2.

With respect to the purification process, the evidence on the summary judgment record shows that TKT purifies its EPO from the cell culture supernatant or media rather than directly from the interior of the cells. Stretch Decl. (Apr. 20, 2000) Ex. 3 at 20:18-25. Having failed to convince the Court to adopt its limiting construction of “purified in mammalian cells grown in culture”, TKT saw the writing on the wall and, rather than attempt to adduce evidence indicating that TKT did not literally infringe the claim term as it had been construed by the Court, elected to request that the Court reconsider its construction. The Court declined to do so, and as a result, and in reliance on additional summary judgment evidence, it determined that TKT’s purification process literally infringed the relevant claim language.

See

Galvin Decl. (Nov. 4,1999) Ex. 1 at 311:19-25 to 312:2-8;

id.

Ex. 5 at 693:1-16.

E.

Conclusion

Because HMR4396 is a pharmaceutical composition comprising a diluent and a therapeutically effective amount of human erythropoietin which is purified from mammalian cells grown in culture, the Court ruled on the summary judgment record that HMR4396 infringed Claim 1 of the ’422 patent. To this extent, the Court granted Amgen’s summary judgment motion [docket no. 211], As to all remaining claims under consideration, the Court denied summary judgment.

IV. FINDINGS OF FACT

A.

Parties, Patents, and Products

Amgen is a Delaware corporation with its principal place of business in Thousand Oaks, California. Joint Pretrial Mem. at 3, ¶ 1. Hoechst Marion Roussel, Inc. — now known as Aventis Pharmaceuticals, Inc.— is a Delaware corporation with its principal place of business in Bridgewater, New Jersey.

Id.

at 3, ¶ 2. TKT is a Delaware corporation with its principal place of business in Cambridge, Massachusetts.

Id.

at 3, ¶ 3. The Court has subject matter jurisdiction over the claims asserted in Amgen’s Amended Complaint pursuant to 28 U.S.C. §§ 1338 (a) and 2201-02. Venue is proper in accordance with 28 U.S.C. §§ 1391 and 1400(b).

The five patents-in-suit include the ’933 patent, the ’698 patent, the ’080 patent, the ’349 patent, and the ’422 patent.

Id.

at 3-4, ¶¶ 5-9 . Amgen seeks to enforce the following claims of each patent:

The ’933 patent:

1. A non-naturally occurring eryth-ropoietin glycoprotein product having the in vivo biological activity of causing bone marrow cells to increase production of reticulocytes and red blood cells and having glycosylation which differs from that of human urinary erythro-poietin.

2. The non-naturally occurring EPO glycoprotein product according to claim 1 wherein said product has a higher molecular weight than human urinary EPO as measured by SDS-PAGE.

9. A pharmaceutical composition comprising an effective amount a glyco-protein product effective for erythro-poietin therapy according to claim 1, 2, 3, 4, 5, or 6 and a pharmaceutically acceptable diluent, adjuvant or carrier.

Trial Ex. 2 at 38:17-25, 39:1-4.

The ’698 patent:

4. A process for the production of a glycosylated erythropoietin polypeptide having the in vivo biological property of

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causing bone marrow cells to increase production of reticulocytes and red blood cells comprising the steps of:

a) growing, under suitable nutrient conditions, vertebrate cells comprising promoter DNA, other than human er-ythropoietin promoter DNA, opera-tively linked to DNA encoding the mature erythropoietin amino acid sequence of FIG. 6; and

b) isolating said glycosylated erythro-poietin polypeptide expressed by said cells.

5. The process of claim 4 wherein said promoter DNA is viral promoter DNA.

6. A process for the production of a glycosylated erythropoietin polypeptide having the in vivo biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells comprising the steps of:

a) growing, under suitable nutrient conditions, vertebrate cells comprising amplified DNA encoding the mature erythropoietin amino acid sequence of FIG. 6; and

b) isolating said glycosylated erythro-poietin polypeptide expressed by said cells.

7. The process of claim 6 wherein said vertebrate cells further comprise amplified marker gene DNA.

8. The process of claim 7 wherein said amplified marker gene DNA is Dih-ydrofolate reductase (DHFR) gene DNA.

9. The process according to claims 2, 4 and 6 wherein said cells are mammalian cells.

Trial Ex. 4 at 38:39-64.

The ’080 patent:

2.An isolated erythropoietin glyco-protein having the in vivo biological activity of causing bone marrow cells to increase production of reticulocytes and red blood cells, wherein said erythro-poietin glycoprotein comprises the mature erythropoietin amino acid sequence of FIG. 6 and is not isolated from human urine.

3. A non-naturally occurring eryth-ropoietin glycoprotein having the in vivo biological activity of causing bone marrow cells to increase production of reti-culocytes and red blood cells, wherein said erythropoietin glycoprotein comprises the mature erythropoietin amino acid sequence of FIG. 6.

4. A pharmaceutical composition comprising a therapeutically effective amount an erythropoietin glycoprotein product according to claim 1, 2, or 3.

Trial Ex. 3 at 38:39-53.

The ’349 patent:

1. Vertebrate cells which can be propagated in vitro and which are capable upon growth in culture of producing erythropoietin in the medium of their growth in excess of 100 U of erythro-poietin per 10 6 cells in 48 hours as determined by radioimmunoassay, said cells comprising non-human DNA sequences that control transcription of DNA encoding human erythropoietin.

3. Vertebrate cells according to claim 1 capable of producing in excess of 1000 U erythropoietin per 106 cells in 48 hours.

4. Vertebrate cells which can be propagated in vitro which comprise transcription control DNA sequences, other than human erythropoietin transcription control sequences, for production of human erythropoietin, and which upon growth in culture are capable of producing in the medium of their growth in excess of 100 U of erythropoietin per 106 cells in 48 hours as determined by radioimmunoassay.

6. Vertebrate cells according to claim 4 capable of producing in excess of 1000 U erythropoietin per 106 cells in 48 hours.

*98

7. A process for producing erythro-poietin comprising the step of culturing, under suitable nutrient conditions, vertebrate cells according to claim 1, 2, 3, 4, 5, or 6.

Trial Ex. 5 at 38:8-14, 38:18-27, 38:31-36.

The ’422 patent:

1. A pharmaceutical composition comprising a therapeutically effective amount of human erythropoietin and a pharmaceutically acceptable diluent, ad-juvant or carrier, wherein said erythro-poietin is purified from mammalian cells grown in culture.

Trial Ex. 6 at 38:36-40.

In conjunction with his research team, Amgen scientist Dr. Fu-Kuen Lin was the inventor of the inventions claimed in this group of patents.

See

Trial Tr. at 957:21 to 958:18. Amgen owns all five patents by assignment. Trial Exs. 140-49. All five patents share a common disclosure and specification while the claims, of course, vary.

See

Joint Pretrial Mem. at 4, ¶ 10.

Amgen manufactures and sells a human erythropoietin pharmaceutical product known as epoietin alfa under the trademark EPOGEN ®. Trial Tr. at 957:8-11. Specifically, EPOGEN ® is the product of Example 10 of the patents-in-suit.

See id.

at 957:8-18, 1044:9-20 .

In collaboration with TKT, Hoechst is developing HMR4396.

See

Joint Pretrial Mem. at 4, ¶ 12. HMR4396 is human erythropoietin.

See supra

Section III.B, at 48-50. HMR4396 is produced from the R223 cell line grown in culture. Joint Pretrial Mem. at 4, ¶ 13. Lonza Biologies, Inc. manufactures HMR4396 in the United States under a contract between TKT and Lonza Biologies PLC (the parent company of Lonza Biologies, Inc.).

Id.

at 4, ¶ 14. Using HMR4396 produced in the United States, Gruppo Lepetit, S.p.A. in Anagni, Italy currently formulates HMR4396 Injection.

Id.

at 4, ¶ 16. Ben Venue Laboratories, Inc. previously formulated HMR4396 Injection in the United States pursuant to a contract between TKT and Ben Venue.

Id.

at 4, ¶ 15. TKT intends to file a Biologies License Application for HMR4396 with the FDA.

Id.

at 4, ¶ 17. In addition, it is seeking regulatory approval to make and sell HMR4396 produced from the R223 cell line in the United States.

Id.

at 4, ¶ 18. TKT is the sponsor of the Investigational New Drug application for HMR4396.

Id.

at 4, ¶ 19.

B.

The Biological Activity of Erythro-poietin

As explained in the patent specification:

Erythropoiesis, the production of red blood cells, occurs continuously throughout the human life span to offset cell destruction. Erythropoiesis is a very precisely controlled physiological mechanism enabling sufficient numbers of red blood cells to be available in the blood for proper tissue oxygenation, but not so many that the cells would impede circulation. The formation of red blood cells occurs in the bone marrow and is under the control of the hormone, erythro-poietin.

Trial Ex. 1 at 5:39-47. In more basic terms, hemoglobin is the protein in red blood cells that transports oxygen. Trial Tr. at 1674:8-10. The amount of hemoglobin in the body correlates to the amount of oxygen that can be supplied to the body’s tissues.

Id.

at 1674:11-14. Hematocrit is a measurement of the ability of the blood to supply oxygen to the body.

Id.

at 1674:15-17. Hematocrit level indicates the relative proportion of red blood cells to the total volume of blood.

Id.

at 1674:18-21. An increase or decrease in the hematocrit or hemoglobin results in an increase or decrease in the ability of the blood to supply oxygen to the body.

Id.

at 1674:22 to 1675:4. Under normal conditions, forty-five to fifty percent of the blood is made up of red blood cells, and in such circumstances, the hematocrit would be referred to as forty-five to fifty.

Id.

at 1570:24 to 1571:2.

*99

Anemia occurs when a person does not have a steady, sufficient supply of red blood cells to carry oxygen to all the tissues of the body.

Id.

at 1674:4-7. Thus, the primary cause of anemia incident to chronic renal failure is a decrease in the production of red blood cells in the patient’s blood.

Id.

at 1676:15 to 1677:5. The first medical condition for which erythro-poietin was shown to be therapeutically effective as a pharmaceutical composition was this type of anemia.

Id.

at 2769:18-21. The therapeutic goal for treating patients with chronic renal failure is to increase and maintain the production of red blood cells in the patient’s blood to normal or near normal levels.

Id.

at 1675:5-20. By increasing and maintaining the patient’s hematocrit to normal or near normal levels, the ability of the patient’s blood to provide a steady supply of sufficient oxygen to body tissues can be restored.

Id.

at 1681:11-15, 18-20. In order to correct the anemia incident to chronic renal failure, a sustained increase in hematocrit or hemoglobin to normal or at least near normal levels is required.

Id.

at 1681:18-20, 1688:25 to 1689:4. The therapeutic effectiveness or benefit of an erythropoiet-in preparation is shown by demonstrating a correction in anemia by increasing and maintaining the hematocrit of a patient to ■ normal or near normal levels.

Id.

at 2763:4-8, 2777:14 to 2778:8. Measurements of hematocrit and hemoglobin were included in the first clinical trials involving recombinant erythropoietin (“rEPO”) to allow physicians to determine if a treatment with erythropoietin had been effective.

Id.

at 1689:15-23. In those trials, rEPO was determined to be therapeutically effective because it was able to increase and maintain the patients’ hematocrit level to thirty-five to forty percent.

Id.

at 2770:20-24, 2773:13-22, 2774:5-7. Furthermore, in conjunction with TKT’s clinical trials of HMR4396 Injection, the FDA has rejected mere increases in hemoglobin as a meaningful therapeutic endpoint, and instead has insisted that TKT test for a sustained increase in hemoglobin over a minimum twelve-week period.

See

Trial Ex. 198; Trial Tr. 2254:8 to 2255:24.

C.

Judgment of Non-infringement of the ’080 and ’698 Patents

Trial commenced on May 15, 2000. Following opening statements and pursuant to the schedule agreed upon during the April 18, 2000 final pretrial conference,

see

Fed.R.Civ.P. 16(a), Amgen began its infringement case. When Amgen rested on the issue of infringement, TKT moved for judgment on partial findings, see Fed.R.Civ.P. 52(c), contending that (1) Amgen’s infringement evidence was fatally deficient with respect to certain claims; and (2) judgment of non-infringement on those claims ought be issued. Following oral argument on June 9, 2000, the Court granted judgment of literal non-infringement with respect to the claims in suit of the ’080 and ’698 patents and judgment of non-infringement under the doctrine of equivalents with respect to the ’698 patent. The factual findings

20

undergirding these conclusions are set forth below.

1.

’080 Patent

On June 9, 2000, the Court found as matter of fact that there was no literal infringement of Claims 2, 3, and 4 of the ’080 patent. In summary, the asserted claims of the ’080 patent claim not only an erythropoietin glycoprotein having the in vivo biological activity of causing bone marrow cells to increase production of reticulocytes and red blood cells, but also a pharmaceutical composition comprising a therapeutically effective amount of such

*100

glycoprotein.

21

In addition, the glycoprotein is further limited because in all the relevant claims it must comprise “the mature erythropoietin amino acid sequence of FIG. 6.” Trial Ex. 3 at 38:42-43, 49-50. The Court had construed this highly significant phrase to mean “the fully realized form of the amino acid sequence of Figure 6.” Tr, of

Markman

Hr’g, Vol. II at 23:14-18. At the time of the

Markman

hearing, the determination of what, in fact, comprised the Figure 6 limitation was left for another day.

Supra

Section II.C, at 24-27. That day arrived when the Court was required to apply the claim construction to the factual record.

The patent specification’s Figure 6 contains a significant amount of information on a number of levels that the parties do not dispute. Figure 6 displays the nucleotide series or DNA sequence of human erythropoietin including both exons (the portions of the sequence which code for the desired protein) and introns (the portions of the sequence that do not code for the protein and are spliced out during transcription into mRNA).

See

Trial Ex. 1 at 20:39 to 21:2. Figure 6 also sets apart a series of “codons,” which are sets of three adjacent nucleotides that determine which of the twenty amino acids are incorporated into a protein at a particular location. Each amino acid is identified by its three letter abbreviation representing a codon. Figure 6 thus depicts the deduced amino acid sequence, which is arrived at by reading the codons of the DNA encoding the protein. Figure 6 also numbers the amino acids from -27 to 166. The span begins with a negative number because the negative amino acids represent the signal or leader peptide which is cleaved off in the rough endoplasmic reticulum prior to the protein’s secretion from the cell. The numbers then continue from 1 to the final amino acid at position 166, which is labeled arginine. As will soon be apparent, it seems safe to say that never before has one arginine been so significant in a court of law.

Key language in the patent specification describes what is depicted by Figure 6: “FIG. 6 thus serves to identify the primary structural conformation (amino acid sequence) of mature human EPO as including 166 specified amino acid residues .... ”

Id.

at 21:3-5. This language equates the amino acid sequence of mature human EPO with the specifically enumerated 166 amino acid sequence that is disclosed in Figure 6.

Id.

In this light, it can scarcely be doubted that the “mature erythropoiet-in amino acid sequence” is the sequence depicted in Figure 6. Had Amgen claimed only “the mature erythropoietin amino acid sequence” without associating or linking that amino acid sequence to Figure 6 its argument that its claims cover whatever sequence (whether it contained 165 or 166 amino acids) is ultimately secreted by the cell might have more momentum. Yet because the asserted claims are limited explicitly by the meaning of Figure 6, the specific amino acid sequence displayed therein is significant. Amgen’s attempt to persuade the Court that the claims reciting the amino acid sequence of Figure 6 reach the mature (i.e., fully realized or secreted) form of the protein, but are not further restricted by the specified amino acid sequence depicted in Figure 6 fails. As a result, in order to infringe Claims 2 -and 3 of the ’080 patent (and Claim 4 by dependence) literally, HMR4396 must contain an erythropoietin glycoprotein comprising the fully realized erythropoietin amino acid sequence of Figure 6, which depicts 166 amino acids.

With this claim construction, the Court turns to the trial testimony. During the trial, Dr. Harvey Lodish, a research biologist from the Whitehead Institute and the Massachusetts Institute of Technology,

see

Trial Tr. at 40:11-16, testified forthrightly

*101

about Figure 6 and specifically about the number of amino acid residues that comprise the erythropoietin protein. First, there is no dispute that the amino acids labeled 1 through 165 in Figure 6 are the same 1 through 165 that are contained in HMR4396.

Id.

at 202:14-16;

id.

at 348:10-12; Trial Ex. 25 at IND002357. During cross examination, however, Dr. Lodish and TKT’s counsel had the following exchange:

Q: You agree that Figure 6 displays an amino acid sequence of 166 amino acids?

A: It does. And — yes, it does. It certainly does.

Trial Tr. at 347:16-18. Dr. Lodish explained the discrepancy between Amgen’s Figure 6 and the 165 amino acid sequence of the secreted EPO:

What is missing is the arginine at position 166, and that is because, as I testified, that arginine is present on the initial protein made by the ribosomes in the cells and it is removed by the cell before the protein is secreted, and that is why I have 165.

Id.

at 348:3-9. In fact, his testimony further reveals that at the time the patent was written, it was not yet known that the arginine at the carboxyl terminus was cleaved off prior to secretion of the protein from the cell.

Id.

at 350:20 to 351:4. But of particular importance in light of the Court’s interpretation of Figure 6, during direct examination by Amgen’s counsel, Dr. Lodish explained that “HMR4396 is a glycoprotein containing 165 amino acids.”

Id.

at 200:21-22 (quoting Trial Ex. 18 at IND000019). Such a glycoprotein literally does not infringe a patent claim that specifies a 166 amino acid sequence. Consequently, at the close of Amgen’s infringement case, the Court found that HMR4396 does not literally infringe Claims 2 and 3 (as well as Claim 4 by dependence) of the ’080 patent.

22

Id.

at 1306:19-23.

2.

’698 patent

Also on June 9, 2000, the Court granted judgment of non-infringement with respect to the ’698 patent, both literally and under the doctrine of equivalents. The asserted claims of the ’698 patent address the process by which glycosylated erythropoietin polypeptides having certain characteristics are produced. Claims 4 and 6 are independent and Claims 5, 7, 8, and 9 are dependent. Because the Court was not persuaded by a preponderance of the evidence that TKT infringes Claims 4 and 6, judgment of non-infringement as to all of the asserted claims of the ’698 patent is hereby entered.

In considering the ’698 patent, the Court notes an important distinction between product patents on the one hand and process patents on the other. A product patent claims a structural entity that, though some process must be undertaken in order to create it, is in no way defined or limited by how it is made.

See Procter & Gamble Co. v. Berlin Mills Co.,

256 F.23, 29 (2d Cir.1918);

Amgen, Inc. v. Chugai Pharm. Co., Ltd.,

706 F.Supp. 94, 103 (D.Mass.1989). A process patent, however, claims not a structural entity, “but rather an operation or series of steps leading to a useful result.” 1

Chisum on Patents

§ 1.03, at 1-58 (2000). Thus, the very details regarding how such “useful result” has come about are at the heart of a process patent, whereas the process by which a patented product is obtained is ordinarily irrelevant to a product patent.

This distinction between product and process patents plays itself out in the context of the set of patents owned by Amgen and asserted in this litigation. The cells, glycoproteins, and pharmaceutical compositions protected by the ’349, ’933, ’080, and ’422 patents are all structural entities. They are therefore products and the patents that protect them are product patents. In contrast, the processes claimed in

*102

the ’698 patent are different beasts all together. The claims of the ’698 patent recite a series of steps that, if followed by one skilled in the art, will produce an identified useful result. Thus, unlike the product claims, for which it does not matter how one reached the patented result provided that the same (or substantially equivalent) result has been reached,

how one reaches the useful result

is the very substance of a process patent.

To put meat on these abstractions, compare the ’349 patent with the ’698 patent. Claim 1 of the ’349 patent describes a certain entity — a type of cell that has additional specific characteristics. In order to avoid infringing that product claim a competitor must not make that product regardless whether the process used to do so differs in some way from the process or processes described in the patent. If indeed the same product is ultimately obtained, it matters not that in order to do so the ■ competitor tweaked the process in some manner. Of course, if the rule were any different, then product claims would easily be thwarted by even the most minuscule methodological modifications. Such a doctrine would render patent protection meaningless.

In contrast,

by its very nature as a process patent,

the ’698 patent requires those skilled in the art to familiarize themselves with the details of the process for the production of recombinant glycosylated erythropoietin polypeptides. The process patent gives notice to competitors that the steps described therein are not to be repeated to achieve the same result. Thus, whereas in the product patent context, differences in process are meaningless, here, in the process patent context, these differences mean everything. Thus, in the ’698 patent the devil is in the methodological details.

Based on this understanding of process patents, the many differences between Amgen’s and TKT’s processes, that were often admitted by Amgen’s witnesses, rendered Amgen’s proof of infringement on the ’698 patent insufficient to survive TKT’s Rule 52(c) motion. In short, the Court was not persuaded by a preponderance of the evidence that TKT’s process for making GA-EPO (TKT’s EPO product) infringed, either literally or by substantial equivalent, independent Claims 4 and 6 of the ’698 patent. As a result, judgment of non-infringement will also be entered on dependent Claims 5, 7, 8, and 9. The Court now turns to these key methodological distinctions.

Among the variety of distinctions, two aspects of TKT’s process stand out from Amgen’s. First, and most fundamentally, TKT employs homologous rather than heterologous recombination. In order to make EPOGEN®, Amgen transfects Chinese hamster ovary (“CHO”) cells with a vector that contains both viral promoter DNA and the human EPO gene.

See

Trial Ex. 1 at 25:55-61; Trial Tr. at 375:4-9. Thus, relative to the hamster host cell, the human EPO DNA material is exogenous because it has been removed from the cell in which it originated, placed in a vector, and reintroduced into a host cell. Trial Tr. at 174:18-22, 1330:2-5. In fact, the only type of recombination shown in Am-gen’s examples in the patent is heterolo-gous. Trial Tr. at 375:19-25, 376:25 to 381:1. In order to make GA-EPO, however, TKT does not utilize a host cell from a non-human species.

See id.

at 165:19-21. Instead, TKT manipulates the human EPO gene where it naturally resides in an HT1080 human cell line.

Id.

at 165:21. In that sense then, the human EPO gene is endogenous to the human cell.

Id.

at 174:23 to 175:4. Thus, in TKT’s process, after introducing a

promoter

sequence, human EPO is expressed in a human rather than hamster cell.

The Amgen patent specification’s repeated references to exogenous DNA reveals that the Amgen process was directed toward heterologous rather than homologous recombination. The patent announces, for example, that “[t]hese polypeptides are also uniquely characterized

*103

by being the product of procaryotic or eucaryotic host expression (e.g., by bacterial, yeast and mammalian cells in culture) of exogenous DNA sequences obtained by genomic or cDNA [complementary DNA] cloning or by gene synthesis.” Trial Ex. 1 at 10:15-20. The Amgen patent specifications also explain in summarizing what is depicted in Example 10 that:

Example 10 is directed to a development of mammalian host expression systems for ... human species genomic DNA involving Chinese hamster ovary (“CHO”) cells and to the immunological and biological activities of products of these expression systems as well as characterization of such products.

Id.

at 15:4-9. Here, Amgen makes plain that DNA material from one species and the cells from another have been utilized in order to effectuate expression. Amgen also specifically identified the content of the transfected vector, which included the human EPO gene, and the type of cell hosting the transfection, the CHO dihydro-folate reductase (“DHFR”)

23

cells.

Id.

at 25:51-59. There can be no dispute that the process most heavily relied upon by Amgen in its patent is the transfection of exogenous DNA. This process, however, is not the one performed by TKT in making GA-EPO nor is it substantially similar to TKT’s process. Instead, TKT is able to express high levels of human EPO in human cells without having to rely upon host cells from alternative species, an important distinction in the eyes of the Court.

A second distinction that the Court finds material to whether TKT’s process infringes the two independent claims of the ’698 patent concerns where the promoter DNA is located relative to the gene to be expressed. In the patent specification, Amgen described the exact location where the human EPO genetic fragment was cleaved in the process of creating the plasmid vector to be introduced into the host cell.

Id.

at 24:19-22. As explained in Example 7 and illustrated in Figure 4, Amgen created the vector by cleaving, with BstEII restriction endonucleases, within the 5.‘6 Kb EPO gene “at a position which is 44 base pairs 5’ to the initiating ATG coding for the pre-peptide and approximately 680 base pairs 3’ to the Hindl-II restriction site.”

Id.

Dr. Lodish agreed that Amgen’s endonucleases cleaved off genetic material at a position forty-four base pairs from the first codon that expresses the leader peptide.

See

Trial Tr. at 372:14-19. Furthermore, the patent specification reports:

The genomic human EPO gene can be isolated therefrom as a 4900 base pair BamHI digestion fragment carrying the complete structural gene with a single ATG 44 base pairs 3’ to BamHI site adjacent the amino terminal coding region.

Trial Ex. 1 at 24:28-32. Thus, Amgen’s process makes a point of leaving but one ATG in the region to be expressed. An ATG is often the codon where the ribo-some attaches and where, therefore, protein synthesis initiates.

TKT, however, does something different. TKT inserts its CMV promoter and enhancer farther upstream than the position at which Amgen inserts its SV40 promoter. Thus TKT’s process has within the DNA sequence upstream of the codons that express the EPO polypeptide several ATG sites.

See

Trial Tr. at 537:18-20. Despite the concern that these additional ATG sites might interfere with proper protein synthesis, TKT attaches its CMV promoter so many bases upstream that a number of these ATGs are present between the promoter and leader peptide. The Court finds that such a process is sufficiently different from that encompassed by Am-gen’s invention that judgment of non-infringement should follow.

*104

In particular, the Court finds that the technique of placing the promoter in close proximity to the gene intended to be expressed was believed, by those of ordinary skill in the art in 1984, to be the technique most likely to result in the proper transcription of that gene. Amgen’s patent itself teaches as much in Example 7.

See

Trial Ex. 1 at 24:15-32. Dr. Lodish’s testimony does nothing to alter this conclusion. Dr. Lodish testified with respect to the promoter issue that “[w]hat is important is that if I put the SV40 promoter in this case, or perhaps other promoters, upstream of the EPO gene I will make EPO, and that’s the critical issue.” Trial Tr. at 549:10-13. Yet, he shied away from definitively rejecting the idea that the location of the promoter relative to the desired gene was important. Instead, referring to the distance between the promoter and the gene to be expressed, he testified cautiously that “how far away from it,

perhaps

is not critical.”

Id.

at 549:9-10 (emphasis added). Furthermore, Dr. Lodish seemed to be testifying, at least on this precise point, from his understanding of today’s technology. He made no statement implying that one of ordinary skill in the art in 1984 would dare to place a promoter sequence in such a position that multiple ATGs would exist between it and the gene to be expressed. Thus, the process that Amgen described in its patent specification was one characterized by the placement of the promoter DNA in a position

adjacent

to the EPO leader peptide. Because TKT’s process is more technologically advanced because it does not require the more immediate adjacency of the promoter, the Court finds that TKT’s process for expressing the EPO protein in abundance is substantially different from the process identified in Amgen’s ’698 patent. As a result, Amgen has failed to prove by a preponderance of the evidence that TKT’s process infringes the independent claims of the ’698 patent.

Thus, because of TKT’s use of both endogenous rather than exogenous DNA and a viral promoter located far upstream from the EPO

coding region,

as well as other less fundamental distinctions, TKT is entitled to judgment of non-infringement on the ’698 patent both literally and under the doctrine of equivalents.

D.

Anticipation and Obviousness (Pri- or AH)

After the Court rendered its findings and conclusions as to the partial judgment of non-infringement, TKT proceeded to present its case as to the remaining issues. At the conclusion of TKT’s rebuttal case, Amgen moved for judgment of infringement and judgment of validity in separate motions. The motions were heard together on July 21, 2000, and at the conclusion of the hearing, the Court made certain findings under Rule 52(c). While the Court declined to make any determinations on the remaining issues of infringement, Trial Tr. at 2532:7-8, the Court found that TKT had failed to carry its burden of proving its obviousness and anticipation defenses by clear and convincing evidence,

see id.

at 2534:7-10. The required subsidiary findings and rulings follow.

“Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.” 35 U.S.C. § 101 . It comes as a surprise to no one that inventions must be new. “The novelty requirement lies at the heart of the patent system.” 1

Chisum on Patents

§ 3.01, at 3-3. Section 102 helps to define this novelty requirement. It provides that:

A person shall be entitled to a patent unless — ■

(a) the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention by the applicant for patent, or

*105

(e) the invention was described in—

(2) a patent granted on an application for patent by another filed in the United States before the invention by the applicant for patent ..., or

(g) (2) before the applicant’s invention thereof the invention was made in this country by another who had not abandoned, suppressed, or concealed it ....

35 U.S.C. § 102 . Thus, in order to negate the patent holder’s claim of novelty by the use of prior art, one must show evidence of a prior patent or publication anywhere or prior use, knowledge, or invention in the United States. An invention is anticipated if it was known, used, patented, described, or made by another prior to the applicant’s invention thereof.

See

1

Chisum on Patents

§ 3.02, at 3-6.

1.

Anticipation

“[Invalidity by anticipation requires that the four corners of a single, prior art document describe every element of the claimed invention, either expressly or inherently, such that a person of ordinary skill in the art could practice the invention without undue experimentation.’’

Advanced Display Sys., Inc. v. Kent State Univ.,

212 F.3d 1272 , 1282 (Fed.Cir.2000) (citing

Atlas Powder Co. v. Ireco Inc.,

190 F.3d 1342, 1347 [Fed.Cir.1999]; and

In re Paulsen,

30 F.3d 1475, 1479 [Fed.Cir.1994]). The identical invention must be shown in a single prior art reference in as complete detail as contained in the patent.

Richardson v. Suzuki Motor Co., Ltd.,

868 F.2d 1226, 1236 (Fed.Cir.1989). Furthermore prior art reference must be enabling, thus placing the claimed invention in the possession of the public.

Akzo N.V. v. United States Int’l Trade Comm’n,

808 F.2d 1471, 1479 (Fed.Cir.1986). “Anticipation, put simply, requires that every element of the claimed invention was previously ‘described in a single reference.’ ”

Advanced Display,

212 F.3d at 1283 (quoting

Scripps Clinic & Research Found, v. Genentech, Inc.,

927 F.2d 1565 , 1576 [Fed.Cir.1991]). Moreover, if the Patent Office considered a particular prior art reference, then the challenger has the “added burden of overcoming the deference that is due to a qualified government agency presumed to have properly done its job.”

Am. Hoist & Derrick Co. v. Sowa & Sons, Inc.,

725 F.2d 1350, 1359 (Fed.Cir.1984);

see Ultra-Tex Surfaces, Inc. v. Hill Bros. Chem. Co.,

204 F.3d 1360, 1367 (Fed.Cir.2000).

Determining whether a prior art reference has anticipated a patented invention is matter of fact.

Advanced Display,

212 F.3d at 1283. TKT bears the burden of proving invalidity by anticipation by clear and convincing evidence.

Robotic Vision Sys. v. View Eng’g, Inc.,

189 F.3d 1370, 1377 (Fed.Cir.1999). Clear and convincing evidence is “evidence which produces in the mind of the trier of fact an abiding conviction that the truth of [the] factual contentions is ‘highly probable.’ ”

Buildex, Inc. v. Kason Indus., Inc.,

849 F.2d 1461, 1463 (Fed.Cir.1988).

a.

EPO-Producing Human Tumor Cells

TKT contended that the cells described in a series of references anticipate certain Amgen claims because the references describe human tumor cells that produce EPO.

24

Among these nine references are

*106

Kaname Sugimoto’s United States Patent No. 4,377,518 (the ’513 patent), which identifies a process for the production of human erythropoietin from lymphoblastoid cells,

25

and an article by Masamichi Hagiwara et al., which reports the isolation of erythropoietin from human renal carcinoma cells.

See

Trial Exs. 2374, 2428. Dr. Erslev, a witness proffered by TKT, agreed that the remaining seven references report cells that are essentially the same as those identified in Hagiwara’s report,

see

Trial Tr. at 1743:21 to 1744:18. After examining these references, the Court agreed with Dr. Erslev. In each case, the researchers surgically removed tumor tissues from cancer patients who had high levels of EPO production, and then cultured those cells in order to try to detect erythropoietic activity.

See

Trial Exs. 2249, 2423-27, 2432. Amgen’s patent specification specifically disclosed the Sugi-moto patent and identified another article by Hagiwara that reported the same results. Trial Ex. 1 at 7:24-42.

Amgen’s disclosure of two references that are representative of the work in this area gives rise to the notion that “the burden of proving invalidity is especially heavy” when the defendant relies on “art that has previously been considered by the patent office during prosecution of the patent application.”

Pall Corp. v. Micron Separations, Inc.,

792 F.Supp. 1298, 1314 (D.Mass.1992),

affd in part, rev’d in part,

66 F.3d 1211 (Fed.Cir.1995);

see Am. Hoist,

725 F.2d at 1359 . Although this burden is not insurmountable, TKT failed to overcome it.

First, the Court considered whether these references constituted “pri- or art.” Amgen submitted that two of these nine references failed to satisfy the touchstone element of the prior art defense: that the art was in fact prior. Am-gen argued that the “printed publication” of the references was subsequent

to

Am-gen’s date of invention.

See 35

U.S.C. § 102 (a). The 1986 Sherwood and Shouval reference concerning production of EPO in human renal carcinoma cells was published years after the time necessary to be considered a prior art publication. Trial Ex. 2424;

see

35 U.S.C. § 102 (b). Likewise, the Saito et al. reference regarding EPO activity in renal tumor cells grown in culture was published in 1985, Trial Ex. 2427, a year after the last of Amgen’s patent applications was submitted to the Patent Office. While the document does bear the words, “Received 18 August 1983; accepted 18 July 1984,”

id.,

TKT has failed to persuade the Court that either of these earlier dates should be considered the appropriate date of the “printed publication.” 35 U.S.C. § 102 (a). To qualify as a “printed publication” under section 102, a party must show accessability and availability to those skilled in the art.

Carella v. Starlight Archery & Pro Line Co.,

804 F.2d 135, 139 (Fed.Cir.1986). The fact that a reference was received by a publication does not evidence that it was either available or accessible. Consequently, neither of these articles constitute a prior art publication.

Yet as the statute makes clear, there is more than one way to skin the prior art cat. If the invention is made, used, or known in the United States prior to invention by the patent holder, then it has been anticipated. 35 U.S.C. § 102 (a), (g). Thus, the fact that the 1985 Saito et al. and 1986 Sherwood and Shouval references

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were published after the filing of Amgen’s patent applications does not alone render the work described in those references inadequate for anticipation purposes. Instead, the Court finds that the Sherwood and Shouval and Saito et al. references evidence that the work performed by the researchers was done in the United States prior to Amgen’s breakthroughs in late 1983 and 1984.

See

Trial Exs. 2424, 2427. The Sherwood and Shouval reference reports that their human renal carcinoma cell line had maintained its EPO-producing function continuously since 1981. Trial Ex. 2424 at 165. Though it is not explicitly mentioned in the article, the Court infers from Dr. Sherwood’s Bronx, New York business address that her work was performed in the United States.

Id.

Similarly, the work reported in the 1985 Saito et al. reference appears to have been performed at the University of Tennessee College of Medicine in Knoxville sometime prior to August of 1983. Trial Ex. 2427 at 23.

Beyond the fact that the work appears to have been performed somewhere in the United States prior to Amgen’s work, the knowledge or use of the work must also be accessible to the public.

See Carella,

804 F.2d at 139 . “A prior use is sufficient to anticipate a patent if it involves work done openly and in the ordinary course of business activities without any deliberate attempt at concealment or effort to exclude the public, even though no deliberate act was taken to bring the work to the attention of the public at large .... ”

State Indus., Inc. v. Rheem Mfg. Co.,

No. 3-83-0362, 1984 WL 1243 , at *18 (M.D.Tenn. June 5, 1984),

aff'd in part, rev’d in part,

769 F.2d 762 (Fed.Cir.1985) (reversing on inequitable conduct and award of attorneys fees). Rather than requiring widespread public use or knowledge, section 102(a) only requires courts to examine whether prior inventors made deliberate efforts to conceal (or otherwise exclude the public from) their inventive work.

See W.L. Gore & Assocs., Inc. v. Garlock, Inc.,

721 F.2d 1540, 1550 (Fed.Cir.1983). If they did not, and instead performed their work openly and in the ordinary course of business, then their use (and by implication, knowledge) should be considered accessible to the public.

See Elec. Storage Battery Co. v. Shimadzu,

307 U.S. 5, 20 , 59 S.Ct. 675 , 83 L.Ed. 1071 (1939);

Baxter Int’l, Inc. v. Cobe Lab., Inc.,

88 F.3d 1054, 1058 (Fed.Cir.1996). Because the record contains no evidence to suggest that Saito or Sherwood and their colleagues took any actions to shield their work from others, the Court finds that the knowledge and use of the work that was subsequently described in the two references meets the requirements of section 102(a). As a result, the EPO-producing tumor cell work described by the Sherwood and Shouval and Saito et al. references qualifies as prior art, though it remains to be seen whether this art anticipates any of Amgen’s claims.

The second step in an anticipation analysis involves a comparison of the construed claim to the prior art. A prior art reference must disclose “each and every limitation of the claimed invention ... must be enabling!,] and [must] describe ... [the] claimed invention sufficiently to have placed it in possession of a person of ordinary skill in the field of the invention.”

In re Paulsen,

30 F.3d at 1478-79 .

After comparing the construed claim with the 1983 Saito et al. reference, the 1983 Sherwood et al. reference, and the never-issued patent application of Tajima, Trial Exs. 2426, 2432, 2423, the Court was unpersuaded that the references described or enabled “the claimed invention sufficiently to have placed it in possession of a person of ordinary skill in the field of the invention.”

Helifix Ltd. v. Blok-Lok, Ltd.,

208 F.3d 1339, 1346 (Fed.Cir.2000);

see Advanced Display Sys., Inc. v. Kent State University,

212 F.3d 1272 , 1282 (Fed.Cir.2000). Further, TKT failed to elicit persuasive testimony from its witnesses that showed that one of ordinary skill in the art could produce Amgen’s cells after examining any of these references. Moreover,

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although not dispositive, these references were never scrutinized by the scientific community. Both the 1983 Sherwood et al. and 1983 Saito et al. references were simply abstracts and were not peer reviewed prior to publication. Absent the close and careful scrutiny afforded by such review, the abstracts lack significant persuasive punch. Similarly, the unexamined, never-issued Tajima patent constitutes nothing more than unchallenged scientific claims. In contrast, an issued patent stands on far more solid footing because it has been scrutinized and challenged by an examiner trained in the field in which the patent teaches:

To further support its anticipation defense, TKT relies most heavily on Sugimoto’s ’513 patent.

See

Trial Ex. 2374. Recall that the ’513 patent, as well as Sugimoto’s related work, was disclosed in Amgen’s patent specification.

See

Trial Ex. 1 at 7:24-35. In light of the subsequent issuance of Amgen’s patents, the Patent Office clearly concluded that this reference was not anticipating. Nonetheless, it was open to TKT to persuade the Court that the examiner erred. Ultimately, however, TKT could not carry its burden of proof by clear and convincing evidence.

The ’513 patent describes a process for the production of human EPO from human lymphoblastoid cells. Trial Ex. 2374 at 1:21-26. More precisely, Sugimoto teaches that if a human cell line that produces EPO is fused with a human lymphoblastoid cell line, the resulting fused cells produce significant amounts of EPO. Trial Tr. at 1226:21 to 1227:7, 1797:10-19. Sugimoto also advises that (1) conventional techniques can be utilized to achieve purification; and (2) the human EPO produced thereby can be used in pharmaceutical compositions for the treatment of anemia. Trial Ex. 2374 at 3:51 to 4:2. During the

Mcurkman

hearing, counsel for Amgen admitted that its patent covered subject matter that included Sugimoto’s work, but counsel also explained that Amgen distinguished Sugimoto during prosecution on the basis that Sugimoto “didn’t succeed in actually making a cell that was capable of producing EPO.” Tr. of

Markman

Hr’g, Vol. Ill at 50:1-7. Not surprisingly then, Amgen countered TKT’s contention that Sugimoto anticipated Amgen’s invention by arguing that Sugimoto was not enabled.

Amgen’s contention was supported by trial testimony. On cross examination, Dr. Erslev agreed that the Sugimoto process was “very complex” and that he was “flabbergasted” when he first read Sugimoto’s procedure. Trial Tr. at 1754:24 to 1755:9. According to Dr. Erslev, no one had attempted to use Sugimoto’s process to produce erythropoietin prior to 1984 despite significant financial incentives to do so.

See id.

at 1755:10-12. Furthermore, according to Dr. Erslev, no one reported using Sugimoto’s process to make a pharmaceutical composition of human EPO, nor has any patient ever been treated by any EPO produced by the Sugimoto procedure.

Id.

at 1755:17 to 1756:3. In light of the intense competition that grew out of the race to make human EPO suitable for treatment of chronic anemia, one would imagine that if Sugimoto’s invention were truly enabling, then he would have won that lucrative race.

To counter, TKT proffered its Vice President of Molecular Biology, Dr. Michael Heartlein, who testified regarding experiments he performed in which he fused a lymphoblastoid cell with a human cell producing EPO and studied the results of these fused, or hybrid cells.

Id.

at 1791:12-20, 1795:13-17. In addition to using TKT’s EPO-producing HT1080 cells, Dr. Heartlein selected two types of liver carcinoma cells as his EPO producing cells, HepG2 and Hep3B cells.

Id.

at 1798:12-21. In the presence of polyethylene glycol (“PEG”), which causes the dest-ablilization of the cell membranes, the contents of the two cells were mixed together. Once PEG is removed, the membranes resealed, forming the fused or hybrid cells.

Id.

at 1799:17-22. After fusing the cells,

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Dr. Heartlein cloned out individual cell lines from the pool of fused cells,

see id.

at 1800:11-13, and then quantified the EPO in each of these clones using a commercially available EPO immunoassay,

see id.

at 1801:14-18. He found approximately a six-fold increase in EPO production rates in the cloned cells compared to that of the parental EPO producing cells.

Id.

at 1802:6-7, 1803:15-17. Thus, Dr. Heartlein concluded that he was “able to isolate hybrid cells between a lymphoblastoid cell and a human cell producing EPO, and ... found that the majority of the clones that were isolated were producing more EPO than the original ... human cell producing EPO.”

Id.

at 1796:12-16. His testimony was intended to show that Sugimoto’s process could be performed with routine experimentation and would produce results similar to those reported by Sugimoto. Yet Dr. Heartlein’s procedures suffer from a series of deficiencies.

First, Dr. Heartlein could not identify any clones producing EPO in fusions involving the HepG2 cells.

Id.

at 1803:18 to 1804:3, 1829:19-21. Because Sugimoto’s patent is not limited to certain types of EPO-producing cells, Trial Ex. 2374 at 6:64-65 (describing “human cells capable of producing human erythropoietin”), the failure to produce EPO from a lymphob-lastoid/HepG2 hybrid cell alone indicates that Sugimoto’s patent is not enabled.

Genentech, Inc. v. Novo Nordisk, A/S,

108 F.3d 1361, 1366 (Fed.Cir.1997). In fact, the only fused cells that were successful in producing EPO were those that were produced with HT1080 cells that had been altered by the addition of a nonhuman promoter. Trial Tr. at 1830:1-4. These cells, however, were not available in 1983.

Id.

at 1831:9-11.

Second, Dr. Heartlein’s process diverged in a number of ways from that taught by Sugimoto. Whereas Sugimoto’s patent only addresses growing up his lymphoblas-toid cells in vivo, Dr. Heartlein used only in vitro processes.

Id.

at 1809:14 to 1810:5. Additionally, unlike the EPO-producing cells utilized by Dr. Heartlein, Sugimoto actually used and disclosed minced human kidney tumor cells.

Id.

at 1812:10 to 1813:3. Though he searched, Dr. Heartlein was unable to obtain such cells.

Id.

at 1813:4-13. Dr. Heartlein was also unable to obtain any of the lymphoblastoid cells that are identified in the patent.

Id.

at 1816:2-14. Because he could not obtain the same starting materials as Sugimoto, Dr. Heartlein could not directly repeat any of Sugimoto’s examples.

Id.

at 1819:18-23. Thus, TKT provided no evidence adequate to overcome the presumption that the Patent Office correctly rejected the contention that Sugimoto was an anticipating reference. TKT’s evidence merely confirms that rejection. Consequently, TKT has failed to show by clear and convincing evidence that Sugimoto’s ’513 patent anticipated the Amgen patent.

Furthermore, none of the cited references disclose each and every limitation of any of Amgen’s individual claims.

Helifix,

208 F.3d at 1346 . As to Claim 1 of the ’422 patent, none of the cited references describe a therapeutically effective amount of EPO or the purification of human EPO from mammalian cells grown in culture. Additionally, all but two of the sources (Sugimoto’s patent and Tajima’s patent application) fail to mention the potential use of EPO generated from hybrid cells in a pharmaceutical composition. Because these references do not describe each claim limitation of Claim 1 of the ’422 patent, they do not anticipate that claim.

Similarly, none of the references anticipate the ’349 patent. Independent Claims 1 and 4 of the ’349 patent are not anticipated by any of these references because none of them disclose the use of nonhuman DNA sequences that control transcription. Furthermore, other than Sugi-moto’s patent, none of the references describe the cells as capable of producing in the medium of their growth in excess of 100 units of EPO per 106 cells. In addition, neither the Toyama et al. nor Sugi-moto references discuss in vitro propa

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gation of their hybrid cells. Because these references fail to disclose essential elements of the relevant claims, they do not anticipate the ’349 claims.

Likewise, none of the references anticipate the ’933 patent. Because these references fail to address glyeosylation of the EPO glycoproteins produced from their hybrid cells, they simply do not describe (1) any differences in glyeosylation between their proteins and urinary EPO proteins, as required by Claim 1 of the ’933 patent; or (2) any molecular weight comparisons with human urinary EPO as required by Claim 2 of the same patent. In addition, all of the references fail to examine the in vivo biological activity of causing bone marrow cells to increase production of reticulocytes and red blood cells. Thus, because the references do not disclose each and every limitation of the ’933 claims, they do not anticipate the ’933 patent.

The same conclusion arises with respect to the ’080 patent. Each asserted claim makes reference to the mature erythro-poietin amino acid sequence of Figure 6 which, of course, is unique to the Amgen patent. In fact, as Dr. Lodish explained, the sequence disclosed in Figure 6 is at the heart of Amgen’s invention. None of the cited references discuss in any way the amino acid sequence of human erythro-poietin. Moreover, as previously mentioned with respect to the ’933 claims, all of the references fail to examine the in vivo biological activity of causing bone marrow cells to increase production of reti-culocytes and red blood cells, which is a limitation contained in all three asserted claims of the ’080 patent. Thus, because none of these references disclose each element of any specific asserted claim in this litigation, these references do not anticipate any of Amgen’s claims.

b.

Prior Administration of Raw Plasma

TKT also failed to show by clear and convincing evidence that Dr. U. Essers’ raw plasma preparation references meet each and every limitation of Amgen’s claims.

26

See

Trial Exs. 2415-17. The three references report experiments performed by Dr. Essers whereby a small group of both anemic and healthy patients received infusions of erythropoietin-rich plasma.

See id.

Dr. Essers had to use raw human plasma because, at the time she performed her work, there was no erythropoietin available in the quantity and purity required for therapeutic use. Trial Tr. at 1709:4-10. Dr. Essers reported that many of the patients showed an increase in their reticulocyte counts.

See

Trial Exs. 2415-17; Trial Tr. at 1555:20 to 1556:7. Yet despite this increase in the reticulocytes, Dr. Essers saw no improvement in the more meaningful measurement of hematocrit or hemoglobin levels of her patients.

See

Trial Ex. 2415; Trial Tr. at 1710:21-25, 1712:7 to 1713:13. In the “Open Discussion” portion of the document published after the European Dialysis and Transplant Association Proceedings, Dr. Essers participated in the following exchange:

LEBER You have demonstrated that after erythropoietin infusion reticulo-cytes increased in uraemic patients. Was this accompanied or followed by an increased haemoglobin haematocrit value, and erythrocyte count as well. Or was it only an increase in the reticulo-cyte count?

ESSERS There was only an increase in the absolute reticulocyte count. I think

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this was due to the fact that we did not have enough erythropoietin to give the patient to stimulate an increase in hae-moglobin.

Trial Ex. 2417 at 401-02. Dr. Essers never proved that anemia could be corrected using her raw plasma preparation. Trial Tr. at 1714:21-23. Thus, while Dr. Essers may have been successful in elevating the reticulocyte counts of some of her patients, the failure to initiate and sustain an increase in the hematocrit or hemoglobin levels reveals that the Essers’ work did not meet Amgen’s therapeutic effectiveness standard.

See

Trial Ex. 2 at 39:1-4, Trial Ex. 3 at 38:51-53, Trial Ex. 6 at 38:36-41 (pharmaceutical composition claims of ’933, ’080, and ’422 patents, respectively). As a result, Dr. Essers’ references do not anticipate the pharmaceutical composition claims.

The references fail to meet other limitations of Amgen’s various claims as well. Because the raw plasma was drawn from human blood, Trial Exs. 2415-17, Dr. Essers’ EPO product could not be said to be non-naturally occurring, as is required by Claim 1 of the ’933 patent, Trial Ex. 2 at 36:17, and Claim 3 of the ’080 patent, Trial Ex. 3 at 38:45. In addition, because the EPO glycoprotein is not isolated from the plasma preparation, the Essers’ preparation does not satisfy the first limitation of Claim 2 of the ’080 patent.

See id.

Trial Ex. 3 at 38:39^14. Moreover, like the tumor cell references, Dr. Essers’ articles do not address glycosylation or molecular weight differences and, therefore, do not anticipate either Claim 1 or Claim 2 of the ’933 patent.

See

Trial Ex. 2 at 38:17-24. With respect to the ’422 patent, in addition to its failure to provide a therapeutically effective amount of human er-ythropoietin, Dr. Essers’ plasma preparation is not purified from mammalian cells grown in culture, as it is drawn from human blood. Trial Ex. 6 at 38:37-41. Thus, the references regarding Dr. Essers’ plasma preparation work fail to anticipate any of the claims asserted by Amgen.

c.

Prior Administration of Urinary EPO

In support of its anticipation defense, TKT also relies upon a clinical study performed under the direction of Dr. Eugene Goldwasser. As an initial matter, Amgen again challenges whether this study constitutes prior art under 35 U.S.C. § 102 . For the same reasons that the Court rejected Amgen’s attack on the 1985 Saito et al. and 1986 Sherwood and Shouval experiments, the Court rebuffs this attack as well. Because the documents submitted as exhibits in this case reveal that Dr. Gold-wasser began this clinical study in 1979-1980 at the University of Chicago in Illinois,

see

Trial Ex.2055, it could fairly be said that it predates Amgen’s patent application.

See

35 U.S.C. § 102 (a), (g). That it appears to be prior art is only part of the analysis, for the only prior art that renders Amgen’s claims invalid is that which anticipates Amgen’s claims. In order to make that determination, one must understand what it is Dr. Goldwasser accomplished.

Dr. Goldwasser obtained a preparation of highly purified erythropoietin derived from human urine. Trial Ex.2055. Then, in the clinical study, approximately 10,000 units (in dosages of 500 and 1000 units) of human urinary EPO was administered to three anemic patients. Trial Ex.2057 at 19;

see also

Trial Tr. at 1579:5-9. Dr. Goldwasser observed a number of biologic effects in the patients. He reported an increase in reticulocyte count in all three patients, an increase in erythroid cells in the marrow and an increased plasma iron clearance rate in two patients, and an increase in red cell mass in one patient.

See

Trial Ex.2057 at 19. Testifying about Dr. Goldwasser’s work, Dr. Erslev explained that these “results ... indicate very strongly that the patients did respond by having an increase in the rate of red cell production.” Trial Tr. at 1578:4-6. According to Dr. Erslev, the increase in (1) the reticulocytes; (2) the plasma iron

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clearance rate; and (3) the red blood cell mass are all “strong evidence for an increase in the rate of red cell production.”

Id.

at 1578:10-12 ; see

id.

at 1578:7 to 1579:2. Dr. Erslev also conceded that an increase in reticulocytes alone does not correct a patient’s anemia.

Id.

at 1688:14 to 1689:4.

Importantly, however, Dr. Goldwasser admits that “[t]here was no significant change in hematocrit in any patient,” Trial Ex.2057 at 19, and Dr. Erslev agreed that the accepted standard by which physicians measure a therapeutic response to EPO is an increase in hematocrit,

see

Trial Tr. at 1675:12-23. Due to this lack of effect upon hematocrit levels, the patients did not appear to receive any health benefits from the reported biologic effects.

See id.

at 1719:7-21, 1720:11-13, 1919:4-12 . Furthermore, Dr. Goldwasser himself has testified that his abortive, three-patient trial was a failure.

See

Goldwasser Dep. at 317:14 to 321:2. Consequently, the Gold-wasser study could not anticipate any of Amgen’s claims requiring a therapeutically effective amount of EPO. As the Federal Circuit explained in

Fromson v. Advance Offset Plate, Inc.,

755 F.2d 1549 (Fed.Cir. 1985), “another’s experiment, imperfect and never perfected will not serve either as an anticipation or as part of the prior art, for it has not served to enrich it.”

Id.

at 1558 (quoting

Picard v. United Aircraft Corp.,

128 F.2d 632, 635 [2d Cir.1942]). Such is the case here.

In order to refute Dr. Goldwasser’s downplaying of his own work, TKT points to statements made by him and Dr. Baron, the researcher working on the project under Dr. Goldwasser’s direction, which were made shortly after the experiments. Dr. Baron reported to the FDA that “[definite evidence of erythroid marrow stimulation was detected.” Trial Ex.2058 at 2. Dr. Goldwasser also explained in his National Institute of Health grant application that EPO “can have a physiological effect in this type of anemia.” Trial Ex.2057 at 19. First, these statements do not contradict the conclusion that the clinical study was limited, in the sense that only three patients participated, and abortive, in the sense that sufficient amounts of urinary EPO material was not readily accessible to continue it. Second, while urinary EPO may have had some “physiological effects” including “erythroid marrow stimulation,” such effects serve as only evidence of the stimulation of red blood cell production. Such evidence should be outweighed by the fact that the

actual

production of mature red blood cells was not achieved and, as a result, hematocrit levels were unchanged.

27

Because an increase in hematocrit and hemoglobin levels is the true mark of therapeutic effectiveness, Dr. Goldwasser’s study, which revealed only inchoate indicators of red blood cell production, falls far short of anticipating claims requiring a therapeutic amount of human EPO. Thus, the study does not anticipate the pharmaceutical composition claims of the ’933, ’080, and ’422 patents. Likewise, because Goldwasser’s work failed to stimulate production of red blood cells as well as reticulocytes, the study does not anticipate Claim 1 of the ’933 patent and Claims 2 and 3 of the ’080 patent.

Furthermore, the Goldwasser study fails to address many of the additional aspects of Amgen’s claims. For example, Amgen specifically excluded urinary EPO preparations from the scope of the claims by including the claim limitation “non-naturally

*113

occurring” and “not isolated from human urine.” Trial Ex. 2 at 38:17; Trial Ex. 3 at 38:44. The purification of EPO from patients with anemia, whose urine often has a high volume of EPO, constitutes an example of naturally-occurring EPO. Thus, Claims 1 and 2 of the ’933 patent and Claims 2 and 3 of the ’080 patent simply do not encompass Dr. Goldwasser’s urinary EPO treatment.

See

Trial Ex. 2 at 3:17-25; Trial Ex. 3 at 38:39-50. Likewise, because Dr. Goldwasser’s work does not pertain to cells that have been altered by recombinant means in order to express high levels of EPO, it does not implicate any of the claims of the ’349 patent. Trial Ex. 5 at 38:7-14, 18-27, 31-37. Because Dr. Goldwasser’s work cannot satisfy these claim limitations, it cannot anticipate Am-gen’s claims.

2.

Obviousness

A patent is invalid if the differences between the patented subject matter and the prior art are such that the patented subject matter as a whole would have been obvious at the time of the invention to a person having ordinary skill in the art. 35 U.S.C. § 103 (a). Whether an invention is obvious is a legal conclusion based upon underlying factual inquiries.

See Graham v. John Deere Co.,

383 U.S. 1, 17-18 , 86 S.Ct. 684 , 15 L.Ed.2d 545 (1966). As in all other invalidity analyses, the party asserting an obviousness defense must prove the disputed facts by clear and convincing evidence.

See Ga.-Pac. Corp. v. United States Gypsum Co.,

195 F.3d 1322, 1330 (Fed.Cir.1999).

“Obviousness rests on several critical factual underpinnings: (1) the scope and content of the prior art; (2) the differences between the prior art and the claimed invention; (3) the level of skill in the art; and (4) the objective indicia of nonobviousness.”

Yamanouchi Pharm. Co., Ltd. v. Danbury Pharm., Inc.,

231 F.3d 1339, 1342 (Fed.Cir.2000);

see also Graham,

383 U.S. at 17-18 , 86 S.Ct. 684 . Among the relevant objective, secondary considerations are: (1) copying; (2) long-felt, but unresolved need; (3) the failure of others; (4) commercial success; (5) unexpected results created by the claimed inventions; (6) unexpected properties of the claimed inventions; (7) licenses revealing industry respect for the invention; and (8) skepticism of skilled artisans before the invention.

See In re Rouffet,

149 F.3d 1350, 1355 (Fed.Cir.1998). Although secondary considerations must be weighed, they do not control the determination of obviousness.

See Richardson-Vicks, Inc. v. Upjohn Co.,

122 F.3d 1476, 1483 (Fed.Cir.1997) (“Evidence of secondary considerations [is] but a part of the ‘totality of the evidence’ that is used to reach the ultimate conclusion of obviousness.”).

Unlike the defense of anticipation, which requires a

single

prior art reference to contain each and every limitation of the claimed invention, the defense of obviousness may be made out where it would be obvious to one of ordinary skill in the art to

combine

the teachings of more than one prior art source in order to accomplish the claimed invention. The Federal Circuit, however, has made clear that the elements of this “combination theory” require “a showing of a suggestion, teaching, or motivation to combine the prior art references is an ‘essential evidentiary component of an obviousness holding.’ ”

28

*114

Brown & Williamson Tobacco Corp. v. Philip Morris Inc.,

229 F.3d 1120, 1125 (Fed.Cir.2000) (quoting

C.R. Bard, Inc. v. M3 Sys. Inc.,

157 F.3d 1340, 1352 [Fed.Cir.1998]). Such “evidence may flow from the prior art references themselves, the knowledge of one of ordinary skill in the art, or, in some cases, from the nature of the problem to be solved.”

Id.

(citing

Pro-Mold & Tool Co. v. Great Lakes Plastics, Inc.,

75 F.3d 1568, 1573 [Fed.Cir.1996]). The Federal Circuit has made clear that the showing must be by clear and convincing evidence. Specifically, the showing must be clear and particular, and broad conclusory statements about the teaching of multiple references, standing alone, are insufficient.

In re Dembiczak,

175 F.3d 994, 999 (Fed.Cir.1999),

abrogated on other grounds by In re Gartside,

203 F.3d 1305 (Fed.Cir.2000). Furthermore, the alleged infringer must show that one of ordinary skill in the art would reasonably expect that combining the teachings of myriad sources would achieve success.

Yamanouchi,

231 F.3d at 1341 (citing

In re Longi,

759 F.2d 887, 896 [Fed.Cir.

1985]); Ortho Pharm. Corp. v. Smith,

959 F.2d 936 , 942 (Fed.Cir.1992).

TKT first argued that the Sug-imoto patent rendered a number of Am-gen’s claims invalid due to obviousness. A prior art reference must be enabling, however, which thereby places the claimed invention in the possession of the public.

See Akzo N.V. v. United States Int’l Trade Comm’n,

808 F.2d 1471, 1479 (Fed.Cir. 1986). In addressing the defense of anticipation, the Court found that the Sugimoto patent was not enabled and, therefore, that it had no effect upon the validity of Amgen’s patents.

Supra

Section IV.D.1.a, at 84-89. Because TKT failed to prove that Sugimoto was enabled,

29

Sugimoto is not prior art, and therefore it cannot support TKT’s obviousness defense.

Second, TKT relied upon Dr. Goldwasser’s urinary EPO preparation as a potential base from which to launch an obviousness sortie. Because Dr. Goldwasser’s study was a failure,

see

Goldwasser Dep. at 317:14 to 321:2, the Court already concluded that Dr. Goldwasser’s work did not constitute prior art,

supra

Section IV. D.l.c, at 94-98. In addition, particularly where the lead scientist implicitly revealed his disappointment by aborting the work, it seems clear that a person of ordinary skill in the art would not reasonably have expected that Dr. Goldwasser’s work would eventually bear fruit. Instead, the more reasonable conclusion would be that a urinary EPO preparation would remain unsuccessful in treating anemia despite its stimulation of some preliminary biologic effects.

As against the claims of the ’349 patent, TKT points to the various EPO-producing human tumor cell references identified above,

see supra

note 24. Yet all of these references fail to render obvious any of the ’349 claims because of one important distinction. The two independent claims of the ’349 patent describe cells comprising

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(1) “non-human DNA sequences that control transcription of DNA encoding human erythropoietin”; or (2) “transcription control DNA sequences, other than human erythropoietin transcription control sequences.” Trial Ex. 5 at 38:13-14, 22-23. The references do not describe cells comprising these DNA elements, nor could one of ordinary skill in the art make the cells claimed in the ’349 patent with the knowledge provided by the tumor cell references. The key knowledge that the art lacked prior to Amgen’s disclosure was EPO’s genetic sequence. Without identifying the sequence of the DNA encoding human erythropoietin, one of ordinary skill in the art would be unable to hook up transcription control sequences in a way that caused transcription of the EPO gene. The cells claimed in the ’349 patent are distinct not only because of the high volume of EPO they are capable of producing, but also because of the cells’ unique genetic makeup. The tumor cell references do not speak to these genetic characteristics nor would any knowledge possessed by those of ordinary skill in the art in 1983-1984 fill this gap. Moreover, there is no clear evidence that these prior art tumor cells produced EPO in the medium of their growth in excess of 100 or 1000 U of erythropoietin per 106 cells in forty-eight hours. While producing EPO in such abundance was indeed one of the primary goals of researchers at that time, that goal continued to escape their grasp. Even with knowledge of these prior art cells, those of ordinary skill at that time simply did not have the ability to induce greater EPO production from these cells or from other sources of EPO for that matter. Thus, having cells that showed some EPO production was a far cry from having cells that produced EPO to the degree claimed in the ’349 patent. Consequently, the Court finds that TKT has failed to show by clear and convincing evidence that the tumor cell references render the ’349 claims obvious.

Third, TKT contended that the human tumor cell references could be combined with the work of Drs. Essers or Goldwas-ser as well as the purification work of Yanagawa or Chiba to defeat the validity of Amgen’s pharmaceutical composition claims.

See

Trial Exs.2055-56, 2058, 2231, 2252, 2415-17. A number of the tumor cell references and the Yanagawa reference were explicitly disclosed by Amgen during the patent prosecution. Trial Ex. 1 at 7:63 to 8:15. The Court infers that the Patent Office, therefore, contemplated this question and decided in favor of nonobvi-ousness. Importantly, TKT failed to prove the existence of any suggestion in the prior art to combine these references so as to produce the pharmaceutical compositions claimed in the ’933, ’080, and ’422 patents. Furthermore, the Court is not persuaded that one of ordinary skill in the art could have used the Yanagawa or Chiba purification methods to purify to substantial homogeneity the EPO produced in the tumor cell cultures. Likewise, the evidence was insufficient to warrant the conclusion that plasma EPO could be purified to homogeneity. The fact that no one has ever— then or now — attempted to determine if a pharmaceutical composition comprising human EPO could be made from these cultured prior art cells also informs the Court’s decision. Trial Tr. at 1750:23 to 1751:14, 1753:17-25; 1755:10 to 1756:3. In light of all these facts, the contention that these various references could be combined to produce a pharmaceutical composition meeting the limitations of Claim 9 of the ’933 patent, Claim 4 of the ’080 patent, and Claim 1 of the ’422 patent is simply unsubstantiated conjecture.

Finally, the secondary considerations in this case are telling.

See Pall Corp. v. Micron Separations, Inc.,

792 F.Supp. 1298, 1316 (D.Mass.1992) (“Objective evidence of non-obviousness may well be the most pertinent probative and revealing evidence available to aid in reaching a conclusion with respect to [the] issue [of obviousness.]”) (citations omitted),

affd in part, rev’d in part,

66 F.3d 1211 (Fed.Cir.1995);

see also Richardson,

122 F.3d at

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1483. Dr. Erslev testified at length about the repeated failures of researchers around the world who were attempting to create an EPO product effective in treating patients with anemia.

See, e.g.,

Trial Tr. at 1650:8 to 1651:12, 1657:4-13, 1657:19 to 1658:3, 1658:12 to 1659:1, 1709:4-10, 1710:15-20, 1712:7 to 1714:20, 1715:15 to 1716:25. Throughout the 1970s, researchers sought to conduct clinical studies with EPO to determine its therapeutic effectiveness, but such trials were hampered by a lack of supply of EPO from natural sources.

Id.

at 1651:22 to 1652:18. Thus, Dr. Erslev explained that the need for the mass production of EPO had existed for “many, many, many years.”

Id.

at 1673:14-21. Additionally, in light of the complications associated with the then existing forms of treatment for the anemia of chronic renal failure, there was a need for an alternative therapy.

Id.

at 1669:6 to 1670:13. Indeed, until the advent of Am-gen’s recombinant EPO product, the anemia associated with chronic renal failure remained uncorrected.

See id.

at 1659:2 to 1666:25, 1667:15 to 1668:10, 1669:1-5, 1720:14-17. The results of the first clinical trials with recombinant human EPO were “dramatic beyond anyone’s dreams.”

Id.

at 1665:10 to 1667:4. Before the advent of Amgen’s product, whether EPO could actually produce a sustainable increase in a patient’s hematocrit was not known.

Id.

at 1579:22 to 1580:19, 1656:11-18, 1669:1-9, 1720:11-17. Furthermore, Amgen’s EPO product, which was the first EPO-containing pharmaceutical composition to obtain FDA approval, has greatly improved the quality of life of chronic renal failure patients throughout the world.

Id.

at 1671:16 to 1673:3. As a result, Dr. Lin received widespread public acclaim for his work. Trial Exs. 156-58; Trial Tr. at 981:17 to 982:6, 984:8 to 985:10.

From these uncontested factual conclusions, it is but a short hop to infer that, prior to Amgen’s pathbreaking invention, there was a long-felt need for a human EPO preparation that was therapeutically effective in treating the anemia of chronic renal failure. Despite researchers all across the globe seeking to fulfill that need (and commercial entities desperately hoping to capitalize on it), Amgen was the first to succeed. Amgen’s invention opened the floodgates for EPO production and ultimately led to a therapeutically effective pharmaceutical composition containing human EPO. One cannot help but wonder if achieving such an outcome by combining certain known prior art techniques were truly obvious to those of ordinary skill in the art, why didn’t one of the myriad competitors do it? Consequently, the Court finds that the secondary considerations strongly counsel the Court against a finding of obviousness.

Thus, having considered the scope and content of various prior art references, the differences between such references and the claimed inventions, how one skilled in the art might combine such references in order to make what was claimed by Am-gen, and the objective, secondary considerations, the Court concluded that TKT failed to persuade the Court by clear and convincing evidence that Amgen’s inventions were obvious in light of prior art. As a result, pursuant to Rule 52(c), the Court granted judgment of validity with respect to the defense of obviousness.

30

See

Trial Tr. at 2534:7-10. The Court declined to make any further rulings regarding TKT’s validity defenses.

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Following the Court’s Rule 52(c) prior art determinations, the Court undertook to receive Amgen’s rebuttal evidence regarding TKT’s validity defenses and also received testimony, offered by TKT, from attorneys involved in the prosecution of Amgen’s patents. When all the evidence had been received, the Court entertained closing arguments and took the remaining issues under advisement. Beginning with the question of infringement, the latter portion of this memorandum resolves these issues.

E.

Infringement

Proof of infringement may be made out pursuant to either of two theories: literal infringement or the doctrine of equivalents. In determining whether an accused product literally infringes a patent claim, the Court applies a two-step analysis.

CAE Screenplates, Inc. v. Heinrich Fiedler GmbH & Co. KG,

224 F.3d 1308, 1316 (Fed.Cir.2000). First, the claims must be construed to determine the scope of the claims.

Id.; see also Kahn v. Gen. Motors Corp.,

135 F.3d 1472, 1476 (Fed.Cir.1998). Second, the claims must be compared to the accused product.

CAE Screenplates,

224 F.3d at 1316 ;

Kahn,

135 F.3d at 1476 . If the accused product meets each of the limitations contained in a claim, then the product literally infringes that claim. If, however, even one limitation is not met, then the product does not literally infringe. A plaintiff in the latter circumstance is not without a remedy and, therefore, the defendant is not yet out of the woods. “A device which does not infringe a patent claim literally may still infringe the claim under the doctrine of equivalents if each and every limitation of the claim is literally or equivalently present.”

CAE Screenplates,

224 F.3d at 1318 -19 (citing

Pennwalt Corp. v. Durand-Wayland, Inc.,

833 F.2d 931, 934-35 [Fed.Cir.1987]). A claim limitation is equivalently present in an accused product if there are only “insubstantial differences” between the limitation and the corresponding aspects of the product.

Hilton Davis Chem. Co. v. Warner-Jenkinson Co.,

62 F.3d 1512, 1517-18 (Fed.Cir.1995),

rev’d on other grounds,

520 U.S. 17 , 117 S.Ct. 1040 , 137 L.Ed.2d 146 (1997). “The usual test of the substantiality of the differences is whether the element in the accused composition performs substantially the same function in substantially the same way to obtain substantially the same result as the claimed element.”

Upjohn Co. v. Mova Pharm. Corp.,

225 F.3d 1306, 1309 (Fed.Cir.2000);

see also Graver Tank & Mfg. Co. v. Linde Air Prods. Co.,

339 U.S. 605, 608 , 70 S.Ct. 854 , 94 L.Ed. 1097 (1950). “The application of infringement by equivalents, however, is limited by the doctrine of prosecution history estoppel.”

CAE Screenplates,

224 F.3d at 1319 ;

see also Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., Ltd.,

234 F.3d 558, 566 (Fed.Cir.2000). Prosecution history estoppel “provides that a patent owner can be estopped from relying upon the doctrine of equivalents when the patent applicant relinquishes coverage of subject matter during the prosecution of the patent, either by amendment or argument.”

CAE Screenplates,

224 F.3d at 1319 ;

Pharmacia & Upjohn Co. v. Mylan Pharms., Inc.,

170 F.3d 1373, 1376-77 (Fed.Cir.1999). With this legal framework in mind and having already construed a number of key terms, the Court turns its face “to the stormy seas [of infringement] and bids the land farewell.” Tommy Makem,

Ballad of the Lady Jane, on

Lonesome Waters (Shanachie Records Co.1993).

1.

The ’319 Patent

As matter of fact, the Court finds that TKT’s R223 cells meet each of the limitations of Claims 1, 3, 4, and 6 of the ’349 patent. A number of subsidiary factual findings relevant to this patent have already been made on the summary judgment record. First, the Court ruled on March 28, 2000 that R223 cells are vertebrate cells. Tr. of

Markman

Hr’g, Vol. II at 136:3-4. The admission by TKT’s counsel during the

Markman

hear

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ing that R228 cells are vertebrate cells under the Court’s construction, i.e. cells from an animal having a backbone, is sufficient to warrant a factual finding in that regard.

Id.

at 131:5-6. Second, TKT’s Rule 30(b)(6) designee, David S. Johnson, testified at his deposition that R223 cells are vertebrate cells. Galvin Decl. (Nov. 4, 1999) Ex. 4 at 76:12-14. In short, the R223 cell line is derived from the HT1080 cell line which is, in turn, derived from a cancerous human cell. Thus, the cell is from an animal having a backbone — a human. Trial testimony by Dr. Kingston during Amgen’s cross examination— though unnecessary in light of the summary judgment determination — bolsters this finding. Trial Tr. at 1380:25 to 1381:16. Third, the Court ruled that R223 cells are capable upon growth in culture of producing erythropoietin in the medium of their growth in excess of 100 units of erythropoietin per 106 cells in forty-eight hours as determined by radioimmunoassay (“RIA”).

31

Dr. Ronald W. McLawhon’s second declaration was very influential in this determination. In particular, after performing RIAs with TKT’s R223 cells, which yielded erythropoietin in amounts far in excess of 100 units per 106 cells in forty-eight hours, Dr. McLawhon concluded that R223 cells were capable of producing more than 1000 units of human eryth-ropoietin per 106 cells in forty-eight hours.

See

McLawhon Dec! (Mar. 3, 2000) at 8, ¶ 23. TKT produced no evidence refuting the implications of Dr. McLawhon’s RIA tests. Again, though such evidence is unnecessary in light of the Court’s summary judgment determination, substantial evidence introduced at trial supports this ruling.

See

Trial Ex. 14 at HMR 336545; Trial Ex. 19 at IND000568; Trial Tr. at 277:7 to 279:5, 1473:12-25. Fourth, the Court ruled on the summary judgment record that the R223 cell line contains nonhuman DNA sequences that control transcription. The R223 cells contain the cyto-megalovirus (“CMV”) promoter, a viral (and therefore, non-human) DNA sequence that initiates transcription. Galvin Decl. (Nov. 4, 1999) Ex. 4 at 98:11-14, 129:23 to 130:13, 134:3-25. The CMV promoter is not derived from the human genome.

Id.

Ex. 3 at 37:21-22. This CMV promoter is present in R223 cells and initiates the transcription of sequences that encode human erythropoietin.

Id.

Ex. 5 at 438:19 to 439:2, 480:3-13. Finally, the IND displays a schematic diagram of the vector used by TKT, known as the targeting construct pREP022, which depicts the CMV promoter “used for

initiation of the

GA-EPO mRNA transcript .... ”

Id.

Ex. 12 at IND000788. In light of the evidence presented by Amgen and not refuted by TKT, the Court ruled on summary judgment that the R223 cell line contains non-human DNA sequences that control transcription. Upon further reflection, however, the Court modifies its summary judgment determination. The evidence on the summary judgment record was sufficient to show that the CMV promoter

initiates

transcription, but upon reflection was insufficient to prove that the CMV sequence also

regulates

transcription. Under the Court’s construction, both actions are necessary in order to “control” transcription. Neither party has been prejudiced by this modification for, as is seen below, this issue was the subject of much testimony during trial.

As to the remaining limitations in Claim 1 of the ’349 patent, the Court ruled that a trial was necessary in order to determine whether the R223 cells literally infringe. After hearing evidence on these matters, the Court now finds as matter of fact that the R223 cells meet the remaining limitations in Claim 1. First, the R223 cells can be propagated in vitro. Joint Pretrial Mem. at 5, ¶ 23. Second, R223 cells contain a DNA sequence that not only initiates transcription, but also regu

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lates transcription of DNA encoding human erythropoietin. In particular, the R223 cells contain CMV enhancer sequences that regulate transcription of DNA encoding human erythropoietin by determining the rate at which RNA polymerase binds and makes an RNA copy of the DNA encoding human EPO.

See

Trial Ex. 19 at IND000559; Trial Ex. 20 at IND000829-30. As Dr. Harvey Lodish explained, a regulatory DNA sequence called an enhancer not only binds proteins that interact physically with RNA polymerase, but also increase the ability of RNA polymerase to bind to the promoter sequence. Trial Tr. at 106:11 to 107:2. Thus, “a strong enhancer would be one which would initiate or cause RNA polymerase to initiate transcription at a very high rate.”

Id.

at 107:3-5. Dr. Lodish subsequently testified that TKT’s CMV sequence contains several strong enhancers that are capable of binding proteins that determine the frequency or rate of transcription initiation of DNA encoding human EPO.

Id.

at 271:11-17. Dr. Lodish firmly based his opinion not only on his review of the relevant literature, but also on TKT’s own IND submissions.

Id.

at 271:11 to 276:10. Similarly, Dr. Robert E. Kingston admitted on cross-examination that the R223 cells contain CMV enhancer sequences.

Id.

at 1384:2-3. He agreed that the CMV enhancer sequences are capable of attracting or binding certain proteins that can affect the rate or frequency of transcription initiation.

Id.

at 1393:16-22. Dr. Kingston also agreed that the CMV enhancer sequences are positioned in the R223 cells at a location so as to affect the rate or frequency at which RNA transcripts that include the EPO DNA are formed.

See id.

at 1393:23 to 1394:9. As a result, the Court now finds that the CMV enhancer DNA sequences regulate transcription of DNA encoding human EPO. Thus, in conjunction with its summary judgment ruling that the CMV promoter initiates transcription of EPO DNA, the Court finds that the R223 cells contain non-human DNA sequences that control transcription of DNA encoding human er-ythropoietin.

Thus, the Court finds as matter of fact that TKT’s R223 cells (1) are vertebrate cells that can be propagated in vitro; (2) are capable, upon growth in culture, of producing erythropoietin in the medium of their growth in excess of 100 units of erythropoietin per 106 cells in forty-eight hours as determined by RIA; and (3) contain non-human DNA sequences that control transcription of DNA encoding human erythropoietin. Consequently, the defendants’ R223 cells literally infringe Claim 1 of the ’349 patent.

Dependent Claim 3 of the ’349 patent differs from Claim 1 only in that it specifies that the vertebrate cells be capable of producing in excess of 1000 units of EPO per 106 cells in forty-eight hours as opposed to the 100 units specified in Claim 1. Trial Ex. 5 at 38:18-20. The trial evidence on this point is somewhat circuitous, for Amgen relies on data obtained from an enzyme-linked immunosorbent assay (“ELISA”)

32

as opposed to a RIA. The terms of Claim 3, however, fail to specify the test by which the amount of EPO must be measured. Furthermore, the Court sees no reason why it should incorporate the RIA limitation of Claim 1 into dependent Claim 3. Claim 3’s dependence upon Claim 1 requires certain elements of Claim 1 to be satisfied in order to infringe Claim 3. Yet Claim 3 introduces a heightened standard for EPO production that is not limited by the method of measurement. Thus, Claim 3 can be literally infringed upon evidence that the infringing cells produce the required amount of EPO as measured by tests other than RIAs. Nevertheless, even if the. Court were to hold that radioimmunoassays were required under

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Claim 3, Amgen’s evidence regarding the comparability of ELISA and RIA measurements would more than support the Court’s finding of infringement under the doctrine of equivalents. A summary of the relevant evidence follows. First, TKT’s IND discloses that the R223 cells are capable of producing 2118 units of EPO per 106 cells per day when grown in culture as measured by an ELISA assay.

See

Trial Ex. 19 at IND000568, 000842. Furthermore, the ELISA and RIA assays provide comparable measures of EPO activity because, in each test, the results are normalized to a known amount of EPO. Trial Ex. 14 at HMR 336545; Trial Tr. at 278:17 to 279:5, 1473:12-25. As a result, the R223 cells are capable of producing in excess of 1000 units of EPO per 106 cells in forty-eight hours when grown in culture.

See

Trial Ex. 14 at HMR 336545; Trial Ex. 19 at IND000568; Trial Tr. 277:7 to 279:5, 281:12-19, 1473:12-25. Thus, either literally or under the doctrine of equivalents, the Court finds that the R223 cells infringe Claim 3 of the ’349 patent.

Claim 4 of the ’349 patent differs from Claim 1 in the phraseology describing the transcription control DNA sequences. Whereas Claim 1 specifies vertebrate cells “comprising non-human DNA sequences that control transcription of DNA encoding human erythropoietin,” Trial Ex. 5 at 38:12-14, Claim 4 claims vertebrate cells “which comprise transcription control DNA sequences, other than human eryth-ropoietin transcription control sequences, for production of human erythropoietin.”

Id.

at 38:22-24. Claim 4 actually describes a larger subset of claimed transcription control sequences than Claim 1 because it sweeps within its reach not only all nonhuman DNA sequences, but also all human DNA sequences other than human EPO transcription control sequences. Despite this distinction in the claim language, the same factual finding results. The CMV DNA sequences in R223 cells are not human erythropoietin control sequences. A CMV is a virus whose DNA material is not naturally found on the human genome.

See

David Johnson Designated Dep. at 98:8-14. The CMV DNA sequences, therefore, are not human. Because the CMV DNA sequences are not human, they cannot possibly be human erythropoietin transcription control sequences.

See

Trial Ex. 18 at IND000017; Trial Ex. 20 at IND000790. The trial testimony of Dr. Lodish and Dr. Kingston, in addition to the exhibits and testimony referred to regarding Claim 1,

see

Trial Tr. at 282:12 to 283:6, 296:20 to 298:14, 299:21 to 300:5, 1409:4-25, and designated deposition testimony amply supports this finding,

see

David Johnson Designated Dep. at 96:8 to 98:14, 129:5 to 130:7; Treco Designated Dep. at 446:24 to 447:2, 478:9 to 479:14 (explaining that the CMV immediate early gene has transcription control sequences that control transcription of the DNA sequences that encode gene activated eryth-ropoietin). In light of such admissions and the other evidence presented during the course of trial, the Court is persuaded that R223 cells contain transcription control DNA sequences, other than human eryth-ropoietin transcription control sequences, for production of human erythropoietin. Consequently, the Court finds as matter of fact that TKT’s R223 cells literally infringe Claim 4 of the ’349 patent.

Claim 6 of the ’349 patent depends upon Claim 4, but differs, just as Claim 3 differs from Claim 1, in the amount of units of EPO that the cell is capable of producing. Trial Ex. 5 at 38:31-33. Having already determined both that the R223 cells are capable of producing in excess of 1000 units of EPO per 106 cells in forty-eight hours when grown in culture and that the R223 cells meet the other limitations of Claim 4, nothing more need be said. Thus, based on the evidence discussed above underlying the factual findings regarding Claims 3 and 4 of the ’349 patent, the Court finds as matter of fact that the R223 cells infringe Claim 6 of the ’349 patent.

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In determining that the R223 cells infringe Claims 1, 3, 4 and 6 of the ’349 patent, the Court necessarily rejected all of TKT’s infringement defenses. The most plausible, but ultimately unavailing contentions, are considered here. TKT primarily attempts to distinguish its cells on the basis of the origin of the human EPO DNA contained therein. Indeed, it is true that Amgen inserts the EPO DNA by transfection into the non-human host cell, whereas TKT’s human cell already contains the human EPO DNA. Yet this factual distinction is immaterial because the claim language is not limited by the origin of the EPO DNA. In short, Amgen only had to show and actually showed that the DNA that the non-human transcription control DNA sequences controlled was the DNA encoding human EPO.

See, e.g.,

Trial Tr. 270:4 to 271:6, 276:15 to 277:1, 1393:5 to 1394:9. This is all it needs to show on this point. Whether the DNA encoding human EPO originated within or outside of the host cell simply does not matter.

Even if TKT’s distinctions were sufficient to defend against literal infringement, it could not have defended against the doctrine of equivalents given Amgen’s proffered evidence. Dr. Lodish explained that because the two distinct cells have the same sequence within the coding region, the origin of the DNA is immaterial, and precisely the same glycoprotein is produced in terms of structure and biological activity.

33

Trial Tr. at 174:18 to 175:18;

see also id.

at 175:1-18, 303:3-15, 1376:15 to 1378:8, 1448:2 to 1451:9 (explaining that the fact that TKT’s R223 cells produce EPO from DNA that is endogenous rather than exogenous to the host cell does not alter the structure or the glycosylation of the EPO protein that is ultimately secreted by the R223 cell). Furthermore, TKT admitted to the FDA that its clinical trials show that HMR4396 produced from vertebrate cells containing endogenous human EPO DNA and EPOGEN ® produced from vertebrate cells containing exogenous human EPO DNA are equivalent in their therapeutic properties. Trial Ex. 122 at HMR 801225, 801231, 801281; Trial Ex. 123 at HMR 801510; Trial Tr. at 492:8 to 493:1. A subsequent pharmaceutical manufacturer may argue to the FDA that its product is as safe or as effective as another product already on the market, but it ought not be permitted to run from its earlier representations once the matter of patent infringement comes its way.

The Court also finds that the chromosomal location of the DNA encoding EPO as well as the genomic environment surrounding the EPO DNA is irrelevant to the infringement analysis of the ’349 claims, and therefore, TKT’s attempts to distinguish its cells on these bases is simply misguided. TKT’s evidence in this regard seems to be offered for the purpose of showing that its cells are somehow less engineered (and more natural) than Am-gen’s. Yet without making any determination regarding whether these distinctions even exist, the Court concludes that nothing in the claim language of the ’349 claims calls for these distinctions. As a result, the Court deems both TKT’s evidence supporting these contentions and Amgen’s rebuttal evidence on these issues (including Dr. Tlsty’s flourescent in situ hybridization [“FISH”] analysis data with respect to the R223 cells) immaterial.

Finally, and importantly, the fact that the R223 cells contain the endogenous human EPO promoter and regulatory elements does not matter. The term of art “comprise” or “comprising” as used in Claims 1 and 4 is not meant to indicate that an exhaustive list is following. In

*122

stead, it merely means that the object of the phrase—in this case, the cells—contains at least (though not exclusively) the item or items listed thereafter. While the specified elements following “comprise” and “comprising” are essential, additional elements may be added to the specified elements and still form a construct within the scope of the claim.

Genentech, Inc. v. Chiron Corp.,

112 F.3d 495, 501 (Fed.Cir.1997). Thus, it matters not that the endogenous EPO promoter and enhancer sequences are present, as long as the cells contain the non-human (Claim 1) or other than human (Claim 4) EPO promoter sequences. Because the R223 cells do, they infringe Claims 1, 3, 4, and 6 of the ’349 patent.

Amgen also contends that TKT infringes Claim 7 of the ’349 patent. Unlike the other claims of the ’349 patent, Claim 7 is directed to a process for producing erythropoietin comprising the step of culturing, under suitable nutrient conditions, the claimed vertebrate cells. While the methods employed by TKT to reach the result protected by Amgen’s cell product claims are immaterial to the infringement analysis of those cell product claims, such methods are crucial with respect to Claim 7.

See supra

Section IV.C.2, at 66-74 (regarding the judgment of non-infringement of the ’698 patent).

In light of this, the Court concludes that Amgen has failed to prove by a preponderance of the evidence that TKT’s process for the production of erythropoietin infringes Claim 7. As described in more detail with respect to the ruling of non-infringement of the ’698 patent,

see supra

Section IV.C.2, at 68-74, TKT’s process for producing erythropoietin differs markedly from that disclosed by Amgen’s specification. Of particular significance, TKT (1) utilizes the endogenous rather than exogenous EPO gene; and (2) places its promoter upstream from rather than adjacent to the EPO gene.

See

Trial Ex. 1 at 24:19-22, 24:28-32, 25:55-61; Trial Tr. at 165:19-21, 174:18 to 175:4, 372:14-19, 375:19-25, 376:20 to 381:1, 537:18-20,1330:2-5. Thus, relying on the same reasoning that gave rise to the non-infringement ruling with respect to the ’698 patent, the Court here finds that TKT does not infringe literally or under the document of equivalents Claim 7 of the ’349 patent. Nevertheless, judgment of infringement will enter with respect to Claims 1, 3, 4, and 6 of the ’349 patent.

2.

The ’933 Patent

Claim 1 of the ’933 patent is directed to non-naturally occurring EPO gly-coprotein products having both the in vivo biological activity of causing bone marrow cells to increase production of reticulocytes and red blood cells and glycosylation which differs from that of human urinary EPO. Trial Ex. 2 at 38:17-21. Each claim limitation and the evidence relating thereto is considered seriatim.

First, the Court finds that HMR4396 is “non-naturally occurring,” which the Court interpreted as meaning “not occurring in nature” or “would not occur but for human intervention,”

see supra

Section II.H, at 36-39. One technique contemplated by this claim limitation is recombinant DNA techn

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