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

MEMORANDUM AND ORDER

YOUNG, Chief Judge.

I. INTRODUCTION

This patent infringement action concerns patents held by Amgen, Inc. (“Am-gen”), relating to the manufacture of a recombinant (genetically engineered) DNA

1

product, known as epoietin alfa,

2

that is similar to natural erythropoietin (“EPO”), a hormone that stimulates production of red blood cells, and is useful in, among other things, treating patients who need blood transfusions and suffer from blood composition disorders such as hemophilia, anemia, and sickle cell disease. This product and this case are not new to the public or to this Court. The ease began brewing in 1997, when Amgen filed a declaratory judgment in the United States District Court for the District of Massachusetts against Defendants Hoechst Marion Roussel, Inc.

3

and Tran-skaryotic Therapies, Inc. (collectively “HMR/TKT”) claiming that three of its patents were infringed by HMR/TKT’s human EPO product, “HMR 4396,” produced from the R223 cell line grown in culture.

See Amgen, Inc. v. Hoechst Marion Rous-sel, Inc.,

3 F.Supp.2d 104, 106 (D.Mass.1998). In 1999, Amgen amended the complaint to include two other patents.

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

126 F.Supp.2d 69, 96-98 (D.Mass.2001)

(“Amgen I

”). A lengthy jury-waived trial ensued. It commenced in May 2000 and lasted twenty-three days over the course of four months. Id. at 78 . Not surprisingly, HMR/TKT appealed this Court’s decision, Amgen

I,

126 F.Supp.2d 69 . In

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

314 F.3d 1313 (Fed.Cir.2003)

(“Amgen II”),

the Federal Circuit affirmed a majority of this Court’s findings and rulings but vacated and remanded a few issues to this Court.

Id.

at 1358 . This memorandum and order addresses those issues on remand, some of which have already been decided by the Court and announced to the parties, thus requiring only a brief review.

II. BACKGROUND: PROCEDURAL AND SUBSTANTIVE HISTORY

A. The Patents, at Issue

There were originally five patents at issue in this case. Only four, however, remain on remand. The patents and claims now at issue are: Claim 1 of U.S. Patent No. 5,955,422 (issued Sept. 21, 1999) (“ ’422 patent”); Claims 2-4 of U.S. Patent No. 5,621,080 (issued Apr. 15, 1997) (“ ’080 patent”); Claims 4-9 of U.S. Patent No. 5,618,698 (issued Apr. 8, 1997) (“ ’698 patent”); and Claims 1, 3, 4, 6, and 7 of U.S. Patent No. 5,756,349 (issued May 26, 1998) (“ ’349 patent”).

Amgen I,

126 F.Supp.2d at 79 ;

Amgen II,

314 F.3d at 1320 .

4

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Although the patents vary, they all share a common disclosure and identical specifications.

Amgen I,

126 F.Supp.2d at 79 . For ease of reference, the Court cites to the specification found in the ’933 patent, which is identical to the specification of the patents in dispute on remand. ’933 Patent, Ex. I.

5

B. The Technology

As

Amgen I

set out the basics of the underlying technology in detail, only a brief summary is provided here. EPO is a naturally occurring hormone that controls erythropoiesis, the production of red blood cells in bone marrow. ’933 Patent, Ex. 1, col. 5: 39-67. Erythropoiesis occurs continuously to offset cell destruction.

Id.

It enables a sufficient (but not excessive) amount of red blood cells to be available in the blood to provide tissue oxygenation.

Id.

Hemoglobin is the protein in the red blood cells that actually transports the oxygen.

Amgen I,

126 F.Supp.2d at 98 . The amount of hemoglobin correlates to the amount of oxygen.

Id.

Hematocrit, which indicates the relative proportion of red blood cells to the total volume of blood, measures the ability of the blood to supply oxygen to the body.

Id.

Thus, generally an increase or decrease in hematocrit equates with an increase or decrease in the ability to supply oxygen to the body.

Id.

Under normal conditions, a person has a hematocrit of about forty-five to fifty, which means forty-five to fifty percent of the blood is made up of red blood cells.

Id.

EPO is produced in the kidney and liver. Therefore, patients with chronic renal failure lack normal levels of EPO and suffer from anemia.

Amgen II,

314 F.3d at 1321 . Introduction of additional EPO into the patient’s body can increase a patient’s he-matocrit level and sustain it at or near normal levels.

Id.

In other words, the blood is able to provide a steady supply of sufficient oxygen to the tissues.

Id.; Amgen I,

126 F.Supp.2d at 99 .

Early attempts to obtain EPO from plasma or urine proved unsuccessful 'because the body only produces human EPO in very small amounts, ’933 Patent, Ex. 1, col. 5: 54-58, and the techniques were very complicated and resulted in the collection of very small amounts of impure and unstable amounts of EPO,

id.

at col. 6: 60-65. Amgen is recognized as the pioneer in the production of a therapeutically effective amount of EPO via recombinant EPO (“rEPO”) techniques.

See, e.g., Molecular Biology and Biotechnology: A Comprehensive Desk Reference

108 (Robert A. Meyers ed., VCH Publishers 1995).

Dr. Fu-Kuen Lin (“Lin”), the named inventor of all the patents in issue, isolated and characterized DNA sequences encoding EPO from humans and monkeys. ’933 Patent, Ex. 1, col. 13: 50-53. Lin determined the DNA sequence of human EPO and its predicted amino acid sequence. ’933 Patent, Ex. 1, col. 10: 65-11: 2. Lin then produced large amounts of EPO by using recombinant DNA technology.

Id.

at col. 14: 23-29. In the patent specification, many methods of producing EPO are described. EPOGEN® is pro

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duced by the method described in Example 10, wherein human EPO is produced by introducing exogenous DNA into host Chinese hamster ovary (“CHO”) cells.

Id.

at col. 25: 30-29: 7.

6

The rEPO that is produced has the same or similar amino acid sequences or primary structural conformation as that of naturally-occurring EPO.

Id.

at col. 29: 1-7. As a result, it possesses one or more the biological properties of naturally-occurring EPO but differs from natural EPO in its “glycosylation,” that is, it has a different average carbohydrate composition.

Id.

at col. 10: 35-41.

HMR/TKT, in producing its human er-ythropoietin, HMR 4396 (also called Gene-Activated EPO “GA-EPO”), also uses recombinant technology. HMR/TKT, however, does not use a host cell from a nonhuman species but manipulates the ordinarily unexpressed human EPO gene where it naturally resides.

Amgen I,

126 F.Supp.2d at 102 . In that way, the human EPO DNA material is endogenous to the human cell.

Id.

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

Id.

C. The Federal Circuit’s Decision

A brief review of the key rulings and findings that were affirmed and remanded on appeal follows:

1. Claim Construction

a. Affirmed

The Federal Circuit upheld all of the Court’s claim constructions.

Amgen II,

314 F.3d at 1320 . Specifically, the Federal Circuit upheld this Court’s construction that Amgen’s claims do not limit the invention to using only exogenous DNA (as opposed to endogenous DNA).

Id.

at 1327 . It also upheld this Court’s determinations that (1) non-naturally occurring means “ ‘not occurring in nature” ’; (2) vertebrates are anything with “ ‘a segmented bony or cartilaginous spinal cord’ which obviously includes humans”; and (3) humans are a subset of mammals and mammals are a subset of vertebrates.

Id.

at 1327-28 (quoting

Amgen I,

126 F.Supp.2d at 85, 90-91 ). To that end, the Federal Circuit agreed that the specification indicates that the invention uses human DNA in human host cells in culture.

Id.

The Federal Circuit also upheld the Court’s determination that claim 1 of the ’422 patent, claims 2, 3, and 4 of the ’080 patent, and claims 1, 3, 4, and 6 of the ’349 patent are product claims (not process claims) and thus are not restricted or defined by any method of production or any particular source, other than what is specifically excluded.

Amgen II,

314 F.3d at 1329-30 .

b. Remanded

Although all the terms that this Court construed in

Amgen I

under the principles of

Markman v. Westview Instruments, Inc.,

517 U.S. 370 , 116 S.Ct. 1384 , 134 L.Ed.2d 577 (1996), were upheld, the Federal Circuit remanded to this Court the construction of the term “therapeutically effective.”

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Amgen II,

314 F.3d at 1354 .

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This phrase was not considered by the Court to be in dispute during the first trial. In its written analysis, however, this Court interpreted the term.

Amgen I,

126 F.Supp.2d at 112 ;

see also id.

at 99. While interpreting a term to provide context for the discussion is proper when the term is not in dispute, the Federal Circuit determined that the term “therapeutically effective” actually was in dispute “because it is central to whether Goldwasser is properly considered prior art.”

Amgen II,

314 F.3d at 1353 . Therefore, it remanded so this Court could construe “therapeutically effective” pursuant to

Markman. Id.

at 1358. Since claim construction is matter of law,

Markman,

517 U.S. at 386 , 116 S.Ct. 1384 ;

but see

Arthur R. Miller,

The Pretrial Rush to Judgment: Are the “Litigation Explosion,

”

“Liability Crisis,

”

and Efficiency Cliches Eroding Our Day in Court and Jury Trial Commitments?,

78 N.Y.U. L.Rev. 982, 1087 (2003). (criticizing the decision in

Markman),

the Federal Circuit could have proceeded to construe the phrase itself. Where a word or phrase has not been first construed in the district court, the Federal Circuit follows the courteous and prudential path of first seeking claim construction below. Hon. Pauline Newman, Remarks at the American Law Inst. — Am. Bar Assoc. Panel on the Trial of a Patent Case (Sept. 18, 2003).

2. Infringement

a. Affirmed

The Federal Circuit affirmed this Court’s ruling on summary judgment that claim 1 of the ’422 patent is literally infringed.

Amgen II,

314 F.3d at 1348 . It also affirmed this Court’s ruling that the ’080 patent is not literally infringed by HMR/TKT’s HMR 4396,

id.

at 1344-45 , but that claims 1, 3, 4, and 6 of the ’349 patent are literally infringed by it,

id.

at 1351-52 .

b. Remanded

(1) The ’080 Patent

After finding that HMR 4396 did not literally infringe claims 2, 3, and 4 of the ’080 patent because HMR 4396 comprised only 165 amino acids,

Amgen I,

126 F.Supp.2d at 99-101 , this Court held that HMR 4396 performed substantially the same function in substantially the same way to obtain substantially the same result as the EPO glycoprotein of claims 2 and 3 of the ’080 patent,

id.

at 133 . Therefore, it ruled that Amgen’s ’080 patent was infringed by HMR/TKT’s product under the doctrine of equivalents.

Id.

In response to HMR/TKT’s argument that Amgen should be estopped from arguing equivalent infringement, this Court ruled that prosecution history estoppel did not apply because Amgen did not add the “mature amino acid sequence of Figure 6” limitation “in an attempt to overcome a rejection [or] to avoid prior art,” but, instead, to “demonstrate that ‘same invention’ type double patenting did not apply,” — that is, to distinguish the ’080 patent from the ’933 patent.

Id.

at 134-35 .

The Federal Circuit agreed that the amendment was made for this purpose but made clear that under

Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki,

535 U.S. 722, 731 , 122 S.Ct. 1831 , 152 L.Ed.2d 944 (2002)

(“Festo II

”), “ ‘a narrowing amendment to satisfy

any

requirement of the Patent Act may give rise to an estoppel.’ ”

Amgen II,

314 F.3d at 1345 (quoting

Festo II,

535 U.S. at 736 ), 122 S.Ct. 1831 (emphasis added). Therefore, it held that the presumption of prosecution history estop-pel applied.

Id.

at 1345. The Federal Circuit then vacated this Court’s finding of equivalent infringement and remanded for an analysis based on the “narrow ways of

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rebutting the Supreme Court’s presumption of estoppel” outlined in

Festo II. Id.

at 1345.

(2) The ’698 Patent

On appeal, the Federal Circuit vacated and remanded this Court’s ruling regarding infringement of the ’698 patent because this Court had compared the accused device to the preferred or commercial embodiments of the patent instead of to the properly construed claims themselves.

Amgen II,

314 F.3d at 1347 . Therefore, it remanded to this Court the question whether claims 4-9 of the ’698 patent are infringed.

Id.

(3) The ’349 patent

Although this Court found that claims 1, 3, 4, and 6 of the ’349 patent are literally infringed by HMR/TKT’s 4396, it held that HMR/TKT did not literally or equivalently infringe claim 7, the process claim, of the ’349 patent.

Amgen I,

126 F.Supp.2d at 122 . The Court compared the accused process to the preferred embodiment in the claim and concluded that HMR/TKT’s “process for producing erythropoietin differs markedly from that disclosed by Am-gen’s specification.”

Id.

The Federal Circuit, as it did with the Court’s holding of infringement of the ’698 patent, vacated this ruling and remanded so that the Court could analyze infringement by comparing the accused process to the properly construed claims themselves.

Amgen II,

314 F.3d at 1350-51 .

3.Inequitable Conduct

The Court’s determination that HMR/ TKT had not proven by clear and convincing evidence that the ’933, ’080, ’349 and ’422 patents were unenforceable due to inequitable conduct was affirmed on appeal.

Amgen II,

314 F.3d at 1357-58 .

4. Written Description, Definiteness, and Enablement

a. Affirmed

The Federal Circuit affirmed this Court’s rulings that the ’422, ’080, and ’349 patents are adequately described and enabled.

Id.

at 1337 . In so ruling, the Federal Circuit explained that this Court “carefully considered these issues, finding in the end that HMR/TKT had not met its clear and convincing burden of proof.”

Id.

Because the Federal Circuit found “no clear error in these factual determinations,” and the parties did not allege any legal error, it reasoned that it would “not disturb [this Court’s] holding that the asserted patents are not invalid for failure to meet the enablement requirement of § 112 ¶ 1.”

Id.

As mentioned in an earlier footnote,

see

note 3,

supra,

this Court held and the Federal Circuit affirmed that the ’933 patent (specifically the claims requiring “gly-cosylation which differs”) was invalid for indefiniteness under section 112.

Amgen I,

126 F.Supp.2d at 156-57 . Therefore, the ’933 patent is not at issue on remand.

5. Anticipation and Obviousness

a. Affirmed

The Court’s ruling that the asserted claims of the ’080, ’349, and ’933 patents are not anticipated under 35 U.S.C. § 102 by the Sugimoto reference was affirmed by the Federal Circuit.

Id.

at 1320, 1356 .

8

*218

In affirming, however, the Federal Circuit made clear that the Court’s determination that Sugimoto was not enabled was an error, though harmless, because the Court put the burden of proving enablement of Sugimoto on HMR/TKT when the burden of proving non-enablement should have been put on Amgen.

Id.

at 1356 .

9

b. Remanded

The Federal Circuit remanded, however, the Court’s findings that Sugimoto does not anticipate claim 1 of the ’422 patent stating that the “district court should consider whether claim 1 of the ’422 patent is novel over Sugimoto in light of the court’s new definition of ‘therapeutically effective’ ” and be “mindful of the principle that source limitations cannot impart novelty to old compositions.”

Id.

at 1356 .

10

Additionally, the Federal Circuit remanded this Court’s finding that the ’422, ’080, and ’349 patents were not obvious in light of Sugi-moto because this Court based its decision, in part, on the fact that it concluded that Sugimoto was not enabled.

Id.

at 1357 . The Federal Circuit explained that under section 103, a reference need not be enabled to qualify as prior art.

Id.

In

Amgen I ,

this Court found that the asserted claims of the ’080, ’422 and ’349 patents were not anticipated or rendered obvious by the Goldwasser reference.

Amgen I,

126 F.Supp.2d at 112-17 . The Federal Circuit remanded these findings for further proceedings given that “therapeutically effective” was not construed in accordance with

Markman. Amgen II,

314 F.3d at 1354 . As mentioned above, it directed the Court to construe the term and determine whether Goldwasser invalidates any of the asserted patents under 35 U.S.C. § 102 (a) or § 103. in light of the Court’s construction.

Id.

at 1354.

D. Procedural and Substantive History Since

Amgen II

The Federal Circuit’s decision issued on January 6, 2003. This Court received the action on remand on March 13, 2003 [Doc. No. 653], and it held a status conference on April 16, 2003 [Doc. No. 657]. On May 16, 2003, Amgen moved for: (1) judgment under Federal Rule of Civil Procedure 52(c) that claims 2-4 of the ’080 patent were infringed under the doctrine of equivalents [Doc. No. 659]; (2) summary judgment of infringement of claims 4-9 of the ’698 patent [Doc. No. 663]; (3) judgment pursuant to Rule 52(c) that claim 1 of the ’422 patent and claim 4 of the ’080 patent are valid [Doc. No. 670]; and (4) judgment pursuant to Rule 52(c) that claims 1, 3, 4, 6, and 7 of the ’349 patent are valid and that claim 7 of the ’349 patent is infringed [Doc. No. 674]. HMR/TKT simultaneously moved for: (1) judgment that Amgen is estopped from asserting infringement of the ’080 patent pursuant to the doctrine of equivalents [Doc. No. 678]; (2) judgment that claim 1 of the ’422 patent is invalid as

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anticipated [Doc. No. 682]; (3) judgment pursuant to Rule 52(c) that the asserted process claims of the ’698 patent and ’349 patents are not infringed [Doc. No. 686]; and (4) judgment that the ’422, ’080, and ’349 claims are invalid for obviousness [Doc. No. 690],

The memoranda in support of and in opposition to these motions raised additional issues that are reviewed in this opinion. They are described briefly below.

In its opposition to Amgen’s renewed motion for summary judgment of infringement of the ’698 patent,

11

HMR/TKT argued, among other things, that Amgen’s proposed construction of the words “DNA encoding” found in claims 4 and 6 of the ’698 patent is incorrect. HMR/TKT’s Mem. in Opp’n re ’698 [Doc. No. 700] at 7-8. Second, HMR/TKT argued that in claims 4 and 6 of the ’698 patent, Amgen set forth a step-plus-function claim in referring to the “steps of ... growing, under suitable nutrient conditions” and that an assessment of whether HMR/TKT infringed this aspect of the claim must focus on a comparison between HMR/TKT’s process for growing and the process for growing described by Amgen in the specification.

Id.

at 9. Finally, HMR/TKT argued that even if there is literal infringement here, it can justifiably invoke the defense of the reverse doctrine of equivalents.

Id.

at 13.

12

With regard to claim 7 of the ’349 patent, HMR/TKT made four “new” arguments, two of which are very similar to those made in conjunction with the ’698 patent. First, HMR/TKT contended that its process does not infringe claim 7 of the ’349 patent when considered in light of its proposed claim construction of “DNA encoding.” HMR/TKT’s Mem. in Support re ’698/’349 [Doc. No. 687] at 8-9. Second, HMR/TKT argued that its process does not infringe claim 7 of the ’349 patent because claim 7 is a step-plus-function limitation; and, as such, HMR/TKT’s process does not literally infringe the “step of culturing” found in claim 7 because it does not involve the culturing procedures set forth in Amgen’s specification.

Id.

at 12-15. Third, HMR/TKT claimed that its process does not infringe the process claim under the reverse doctrine of equivalents.

Id.

at 15-18. Fourth and lastly, HMR/ TKT argued that if the Court construes the term “DNA encoding” as Amgen urges, then the validity of the asserted claim of the ’349 patent is called into question.

Id.

at 12.

Amgen, in response, did not dispute that “DNA encoding” needs to be construed by the Court.

See, e.g.,

Amgen’s Reply re ’698 [Doc. No. 731] at 6-10. It did, however, assert that HMR/TKT should not be allowed to make its “new” arguments relating to step-plus-function and the reverse doctrine of equivalents given the procedural posture of the case.

13

See, e.g., id.

at 10-15.

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On July 29, 2003, this Court held a

Markman

hearing regarding those terms in dispute and in need of construction and considered other pending motions, including motions for summary judgment. At the end of the

Markman

portion of the hearing, the Court tentatively construed the terms “DNA encoding” and “therapeutically effective,” providing two constructions for the latter, one being an alternate. 7/29/03 Hr’g Tr. at 55: 1-56: 23. It then continued to hear argument. At the end of the day, the Court noted that it would determine whether the asserted claims of the ’698 and ’349 patents were step-plus-function claims at a later date.

Id.

at 176: 1-10. It then continued the motion hearing to July 31, 2003.

Id.

at 176: 11-15.

During a hearing two days later, the Court retracted the alternative construction and reiterated its primary “working construction,” retaining its right to revise it after a more careful review of the claims, specification, and prosecution history. 7/31/03 Hr’g Tr. at 87: 5-88: 7. Additionally, it ruled that claims 4 and 6 of the ’698 patent and claim 7 of the ’349 patent were not step-plus-function claims pursuant to 35 U.S.C. § 112 .

Id.

at 88: 8-89: 9. It then denied Amgen’s motion for summary judgment of infringement of the ’698 patent, citing Arthur Miller’s recent article,

The Pretrial Rush to Judgment. Id.

at 89: 23-90: 25;

see

Miller,

supra.

The Court took everything else under advisement and set the final pretrial conference for September 18, 2003.

Id.

at 91: 25-92: 2.

On August 5, 2003, the Court entered an order regarding the pending motions. [Doc. No. 740], It denied HMR/TKT’s motions for summary judgment with respect to the validity of the asserted claims of the ’422, ’080 and ’349 patents. Order of 8/5/03 at 1. It denied in part and allowed in part Amgen’s motions, under Rule 52(c), for judgment that claim 1 of the ’422 patent and claim 4 of the ’080 patent are valid and that claims 1, 3, 4, 6, and 7 of the ’349 patent are valid.

Id.

Because HMR/TKT did not dispute that the ’080 and ’349 patents are not anticipated by Goldwasser and that the ’349 patent is not rendered obvious by Goldwasser, the Court allowed Amgen’s motions with respect to these matters.

Id.

at 1-2. Specifically, the Court held that claim 4 of the ’080 patent is not anticipated by Goldwasser and that claims 1, 3, 4, 6, and 7 of the ’349 patent are not anticipated or rendered obvious by Goldwasser.

Id.

at 2. Because Amgen did not have the opportunity to rebut HMR/ TKT’s remaining validity arguments concerning the ’422, ’080, and ’349 patents during trial in 2000, the Court stated that Amgen would have that opportunity at the October trial.

Id.

On September 18, 2003, the Court held a final pretrial conference. After explaining that this case will not “turn into a patent version of Penelope’s robe,” in other words, that the Court and the parties were “not going to unravel anything [that the Court has] woven thus far which has not been unraveled by a higher court,” the Court made the following findings and rulings. First, it ruled that it would hear and take evidence on the reverse doctrine of equivalents as it related to the ’698 patent and that HMR/TKT could address other patent defenses. 9/18/03 Final Pretrial Conf. Tr. at 6: 4-16. Second, it ruled that Amgen had met its burden (outlined in

Festo II)

of proving that the prosecution history does not estop it from arguing equivalent infringement with regard to the ’080 patent and it affirmed its earlier

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finding that HMR/TKT infringes claims 2-4 of the ’080 patent.

Id.

at 7: 17-8: 5. It explained that it would issue a full opinion at a later date but that it might have to revisit the

Festo

issue due to the rapidly-developing law in that area.

Id.

at 7: 19-25. The Court then turned to the ’349 patent and explained that it would allow Amgen to put on rebuttal evidence as to the matter of obviousness and Sugimoto only and it made clear that the Court would not accept other evidence from HMR/TKT regarding the ’349 patent.

Id.

at 8: 12-19, 16: 5-6 (“As far as evidence goes, ’349 is in the can and I’m done with it.”). The Court then issued a revised claim construction of “therapeutically effective” based on a more thorough analysis of the claims, specification, and prosecution history.

Id.

at 9: 3-10: 25. The Court mentioned, however, that this revision may have made the third sentence of the construction unnecessary and, therefore, reserved its right to further consider the proper construction.

Id.

at 10: 21-25. It directed the parties to try the case based on the construction it had just issued along with a construction that eliminated the third sentence.

Id.

at 11: 1-5. The pretrial conference was continued until September 24, 2003.

Id.

at 30: 22-23.

During the further pretrial conference, the Court reviewed the issues to be tried and outlined the procedure for trial and the parameters for the introduction of evidence and expert testimony.

See

9/24/03 Final Pretrial Conf. Tr. After the Court provided both parties with an opportunity to be heard on the subject, pursuant to Federal Rule of Civil Procedure 53(b)(1), the Court appointed Michele D. Beardslee as Special Master, beginning January 1, 2004, to assist the Court in research, analysis, and drafting of the forthcoming opinion. Order re Special Master [Doc. No. 801];

see also

11/07/03 Beardslee Aff. [Doc. No. 799].

14

The trial on remand was set to commence on October 7, 2003. 9/24/03 Final Pretrial Conf. Tr. at 40: 23.

On October 30, 2003, the Court issued an opinion supporting its ruling that Am-gen had successfully rebutted the presumption of prosecution history estoppel as outlined in

Festo II

and, therefore, was not estopped from asserting equivalent infringement of the ’080 patent.

Amgen, Inc. v. Hoechst Manon Roussel, Inc.,

287 F.Supp.2d 126 (D.Mass.2003)

(“Amgen III”).

15

The remanded trial lasted nine days over the course of four and a half weeks.

16

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All the remaining issues — those remanded to the Court from the Federal Circuit and those raised by the parties in the course of this remanded trial — are addressed herein.

17

III. CLAIM CONSTRUCTION

As expounded in great detail in

Amgen I ,

this Court strongly believes in the importance of construing patent claims without regard to the alleged infringement issues.

Amgen I,

126 F.Supp.2d at 80-81 ;

MediaCom Corp. v. Rates Tech., Inc.,

4 F.Supp.2d 17, 21-24 (D.Mass.1998);

see also

Anthony R. Zeuli & Rachel Clark Hughey,

Avoiding Patent Claim Construction Errors: Determining the Ordinary and Customary Meaning Before Reading the Written Description,

Fed. Law., June 2004, at 29. One way to avoid conflating issues of fact and law and to ensure division between the fact finding and law explaining roles in a patent case is to hold the

Markman

hearing prior to and separate from the summary judgment motion hearing. Although (as mentioned above) this Court held the

Markman

hearing for the trial on remand on the same day as the summary judgment motions hearing, it kept the hearings independent of one another by separating the hearing into two parts. The first part dealt with claim construction. Then the Court held a recess, issued its preliminary constructions, and moved on to the summary judgment motions hearing.

The Court followed its usual procedure in conducting the

Markman

hearing. The Court entertained oral argument from counsel for each party. Counsel referred the Court to the relevant portions of the patent, specification, and prosecution history. Demonstrative exhibits were presented and references were made to certain expert testimony, but extrinsic evidence was not admitted.

At the conclusion of the

Markman

portion of the hearing the Court interpreted “therapeutically effective” and “DNA encoding”' — cautioning that they were “working constructions” — and held off deciding whether the asserted claims of the ’349 and ’698 patent were step-plus-function claims. The Court then announced during the July 31, 2003 hearing that it did not construe the asserted claims of the ’349 and ’698 patents as step-plus-function claims. During the pretrial conference on September 18, 2003, after the Court had engaged in a more careful review of the patents, specification, and prosecution history, the Court issued a revised claim construction for “therapeutically effective.” The final claim constructions are reproduced and explained below.

18

A. “Therapeutically Effective”

1. Background

The term “therapeutically effective” is contained in claim 1 of the ’422 patent and claim 4 of the ’080 patent.

19

As

*223

mentioned above, although this phrase was not construed during the first trial, in determining whether prior art anticipated the ’422 and ’080 patents, the Court interpreted the term to mean an increase in hematocrit:

Such evidence [of e.g., increased eryth-roid marrow stimulation] 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. 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.

Amgen I,

126 F.Supp.2d at 112 ;

see also id.

at 99 (“The therapeutic effectiveness or benefit of an erythropoietin preparation is shown by demonstrating a correction in anemia by increasing and maintaining the hematocrit of a patient to normal or near normal levels.”).

The Federal Circuit, in addition to remanding so that the Court could construe the term pursuant to

Markman ,

provided some guidance. It agreed that the “endgame in the treatment of chronically anemic patients is to increase the hematocrit,” but pointed out that the term should be construed in light of the specification.

Amgen II,

314 F.3d at 1353 . It stated, however, that the “specification appears to teach that results in addition to simply an increase in hematocrit can provide effective therapy.”

Id.

(citing ’933 Patent, col. 33: 19-31). It pointed out that Amgen was arguing that one skilled in the art would construe “therapeutically effective” as “increasing and maintaining the patient’s hematocrit to normal or near normal levels,” but that “the relevant question is not whether one of ordinary skill would so understand the term, but whether that term should be limited based upon the express disclosure in the specification.”

Id.

at 1353-54 (citing

CCS Fitness v. Brunswick Corp.,

288 F.3d 1359, 1367 (Fed.Cir.2002) (“[A] claim term will not carry its ordinary meaning if the intrinsic evidence shows that the patentee distinguished that term from prior art on the basis of a particular embodiment, expressly disclaimed subject matter, or described a particular embodiment as important to the invention.”)). The Federal Circuit stated that it appeared that the term “therapeutically effective” encompassed the list of effects described in the specification and noted that if the Court also held this to be true, then the Goldwasser study may indeed invalidate some of the claims at issue in this case under 35 U.S.C. § 102 (a) or § 103.

Id.

at 1354 (“If the claim term ‘therapeutically effective’ encompasses the patient responses described in the specification,

as it appears to us it does,

then the Goldwasser study may constitute invalidating prior art under § 102(a) or § 103 even if he did not achieve his intended result.”) (emphasis added). Therefore, it vacated this Court’s determination that Goldwasser did not constitute prior art

20

and ordered this Court to construe the term and thereafter determine whether Goldwasser invalidates any of the asserted patents.

Id.

2. The Claims at Issue

The actual words of the claims are as follows:

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’422 Claim 1:

A pharmaceutical composition comprising a

therapeutically effective

amount of human erythropoietin and a pharmaceutically acceptable diluent, adjuvant or carrier, where insaid erythropoietin is purified from mammalian cells grown in culture.

’422 Patent, Ex. 1, col. 88: 36-41 (emphasis added).

21

’080 Claim 4:

A pharmaceutical composition comprising a

therapeutically effective

amount of an erythropoietin gly-coprotein product according to Claim 1, 2, or 3.

’080 Patent, Ex. 1, col. 38: 51-53 (emphasis added).

3. Summary of the Parties’ Arguments

Amgen urges adoption of the ordinary meaning of “therapeutically effective” given by those skilled in the art. Amgen’s Mem. in Support re ’422/’080 [Doc. No. 671] at 7. Specifically, it argues that (1) expert testimony shows that the ordinary meaning of “therapeutically effective” is “sufficient to produce a sustained increase in hematocrit,” and that the term requires a therapeutic — not merely biological — effect; (2) the other effects listed in the specification, to which the Federal Circuit referred, are known biological effects of EPO, not the intended therapeutic effects; (3) the specification taken as a whole supports the plain meaning of “therapeutically effective,” and that no special meaning was given to the term; (4) the prosecution history shows that Amgen specifically noted that its invention shares the same in vivo biological activity as naturally occurring human EPO, but differentiated its invention from prior art by pointing out that human recombinant EPO (unlike naturally-occurring human EPO) is not a viable, effective human therapeutic product; and (5) the doctrine of claim differentiation requires that this term have a different meaning than the recitation of EPO’s biological activities.

Id.

at 8-17. In its reply memorandum, Amgen also argues that the dictionary definition of the term supports its asserted meaning. Amgen’s Reply re ’422/’080 [Doc. No. 730] at 5-6.

HMR/TKT, on the other hand, argues that the Federal Circuit made clear that it believed that the term “therapeutically effective” encompasses all of the effects set forth in the specification described. HMR/ TKT’s Mem. in Opp’n re ’422/’080 [Doc. No. 702] at 5. Thus, it argues, the term encompasses those effects observed in the Goldwasser study.

Id.

at 6. Moreover, it asserts that Amgen is trying to import limitations from the specification to make the claims require an increase in the he-matocrit levels when the claims contain no language indicating such a requirement and the specification language itself is actually inconsistent with such a requirement. HMR/TKT points to the same section of the specification as did the Federal Circuit did to make its point:

[T]o the extent that polypeptide products of the invention share the in vivo activity of natural EPO isolates

they are conspicuously suitable for use in erythropoietin therapy procedures

practiced on mammals, including humans,

to develop any or all of the effects herefore attributed in vivo to EPO,

e.g., stimulation of reticulocyte response, development of ferrokinetic effects ... erythrocyte mass changes, stimulation of hemoglobin C syntheses ... and, as in

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dicated in Example 10, increasing he-matocrit levels in mammals.

Id.

at 13 (quoting ’933 Patent, Ex. 1, col. 33: 19-31). This, HMR/TKT asserts, makes clear that “erythropoietin therapy procedures” include procedures that “develop any or all of the effects heretofore attributed in vivo to EPO,” and, therefore, “therapeutically effective amount” includes any or all of the effects listed in this portion of the specification — which, HMR/ TKT argues, are defined in terms of biological effects.

Id.

at 14. HMR/TKT further argues that Amgen is trying to rely on isolated references of the specification to restrict the term meaning when these restrictions are not apparent in the plain language, and when the intrinsic record, as a whole, supports a broader interpretation.

Id.

at 16.

4. Discussion

While the Federal Circuit indeed mentioned that the term “therapeutically effective” appeared to encompass the biological effects listed within lines 19-31 of column 33, the Court notes that the Federal Circuit did not, in

Amgen II,

actually construe the term “therapeutically effective.”

See Amgen II,

314 F.3d at 1324 (noting that the Federal Circuit considers claim construction “afresh” on appellate review);

Bayer AG. v. Biovail Corp.,

279 F.3d 1340, 1349 (Fed.Cir.2002) (noting that, notwithstanding its

de novo

review, “it would be premature for this court to engage in its own claim construction without ... evidence of the meaning of the terms to one of skill in the art at the time of the invention”). On the contrary, the Federal Circuit remanded that task to this Court. To perform it properly, however, the Court must consider the prosecution history in addition to the claims and the specification — something that the Federal Circuit did not do.

See Amgen II,

314 F.3d at 1324 (“To properly construe the claims, a court must examine the claims, the rest of the specification, and if in evidence, the prosecution history.”);

Vitronics Corp. v. Conceptronic, Inc.,

90 F.3d 1576, 1582 (Fed.Cir.1996) (“[I]t is well-settled that, in interpreting an asserted claim, the court should look first to the intrinsic evidence of record, i.e., the patent itself, including the claims, the specification and, if in evidence, the prosecution history.”);

SRI Int’l v. Matsushita Elec. Corp. of Am.,

775 F.2d 1107, 1118 (Fed.Cir.1985) (noting that a claim is construed in light of its language, the specification, and the prosecution history). Moreover, the Court must begin by determining what the plain and ordinary meaning of “therapeutically effective” is in order to determine whether Amgen has become its own lexicographer.

Intellectual Prop. Dev., Inc. v. UA-Columbia Cablevision of Westchester, Inc.,

336 F.3d 1308, 1315 (Fed.Cir.2003) (“Consulting the written description and prosecution history as a threshold step in the claim construction process, before any effort is made to discern the ordinary and customary meanings attributed to the words themselves, invites a violation of our precedent counseling against importing limitations into the claims.” (quoting

Texas Digital Systems, Inc. v. Telegenix, Inc.,

308 F.3d 1193, 1204 (Fed.Cir.2002)) (internal quotation marks omitted)).

a. The Plain and Ordinary Meaning

Generally, it is the plain and ordinary meaning of the words — as defined by one skilled in the relevant art — that governs.

Vitronics,

90 F.3d at 1582 ; Erik Paul Belt,

Federal Circuit Stresses Ordinary Meaning,

Nat’l L.J., Sept. 22, 2003, at SI. Amgen argues that the plain and ordinary meaning of the term “therapeutically effective” is “sufficient to produce a sustained increase in hematocrit.” HMR/ TKT argues, on the other hand, that the

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plain and ordinary meaning of “therapeutically effective” is not so restricted.

22

Interestingly, HMR/TKT never states what it believes the plain and ordinary meaning of the term to be — it only discusses the meaning of the term with reference to how it believes Amgen has so defined it in the specification and prosecution history.

Amgen, on the other hand, grounds its assertion of the plain and customary meaning of the disputed term upon expert testimony. This, however, is extrinsic evidence to which resort ought be had only

“if necessary.” Vitronics,

90 F.3d at 1583 (quoting

Hormone Research Foundation, Inc. v. Genentech, Inc.,

904 F.2d 1558, 1562 (Fed.Cir.1990)). Therefore, the Court does not begin by considering this evidence. Instead, it turns first to the dictionary and to technical treatises to decipher the plain and ordinary meaning of “therapeutically effective.”

See id.

at 1584 & n. 6 (noting that judges are free to consult technical treatises and dictionaries in order to gain a better understanding of the claims and to interpret them, “so long as the dictionary definition does not contradict any definition found in or ascertained by a reading of the patent documents.”).

23

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The dictionary definition of “therapeutic” is “[h]aving healing or curative powers,” or “[o]f or relating to the treatment of disease or disorders by remedial agents or methods.”

The American Heritage Dictionary

1260 (2d college ed.1985);

Webster’s Ninth New Collegiate Dictionary

1223 (1984), attached as Tab X to Supp.App. [Doc. No. 735] to Amgen’s Reply re ’422/’080;

see also Chamber’s Technical Dictionary

844 (3d ed.1961), attached as Tab W to Supp.App. to Amgen’s Reply re ’422/’080 (“Of, or pertaining to, the medical treatment of disease: remedial: curative”). The definition of therapeutics is “[t]he medical treatment of disease.”

The American Heritage Dictionary, supra,

at 1260. The dictionary definition of “effective” is “[h]aving an intended or expected effect” or “[pjroducing or designed to produce the desired impression or response.”

Id.

at 439.

Based on these definitions alone, one would surmise that a “therapeutically effective” amount is one that produces healing or curing as it relates to medical treatment of disease.

24

This is, in essence, consistent with the definition that Amgen proposes.

See

Amgen’s Mem. in Support re ’422/’080 [Doc. No. 671] at 14 (arguing that the ordinary meaning is an amount sufficient to “cure or relieve a disease state” and “require[s] a meaningful benefit to the health of patients”). Amgen, however, goes further, asserting that the plain and ordinary meaning of “therapeutically effective amount,” to one skilled in the art, taken in the context of this patent, is an amount that provides more than the biological effects of EPO and “produce[s] a

*229

sustained increase in hematocrit,” because only this result provides a meaningful benefit to the health of patients suffering from anemia.

25

Id.

at 7-8, 14. Neither the claims, the specification, nor the prosecution history, however, demonstrate clearly that the plain and ordinary meaning of the term to one skilled in the art involves an increase in hematocrit. Therefore, the Court begins with the assumption that the plain and ordinary meaning of “therapeutically effective amount” is one in line with that found in the dictionaries and treatises noted above — i.e., one that heals or cures as it relates to medical treatment of disease.

The next step is to look to the claims, specification, and prosecution history to see if Amgen redefined the term in the file wrapper. In addition, the Court will look to these sources to determine whether the file wrapper indicates clearly the types of patients for which this product is “therapeutically effective” and thus infuses the term with real meaning. Indeed, this is the elephant in the room. Without tackling this question, the term “therapeutically effective” or “therapeutically effective amount” is vague and meaningless. The public must know upon reading the patent what disease state is cured or healed by the product.

26

As the Federal Circuit pointed out, “indiscriminate reliance on definitions found in dictionaries can often produce absurd results.... One need not arbitrarily pick and choose from the various accepted definitions of a word to decide which meaning was intended .... The subject matter, the context, etc., will more often than not lead to the correct conclusion.”

Renishaw PLC v. Marposs Societa’ per Azioni,

158 F.3d 1243, 1250 (Fed.Cir.1998) (quoting

Liebscher v. Boothroyd,

258 F.2d 948 , 46 C.C.P.A. 701 (1958)) (first alteration in original). Thus, the Court, in addition to determining whether Amgen has expanded or confined the meaning of the disputed term, will look to the file wrapper to clarify this ambiguity.

b. The Claims

“The name of the game is the claim.”

Amgen I,

126 F.Supp.2d at 80 (quoting Giles S. Rich,

Extent of Protection and Interpretation of Claims

— Amer

ican Perspectives,

21 Int’l Rev. Indus. Prop. & Copyright L. 497, 499 (1990)) (internal quotation marks omitted). Thus, the first step in claim construction is to look to the plain and ordinary meaning of the words of the patent claim to determine the meaning of a term.

Vitronics,

90 F.3d at 1582 ;

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

55 F.3d 615, 619-20 (Fed.Cir.1995);

Renishaw,

158 F.3d at 1248 (“[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.”).

Do the claims redefine the plain and ordinary meaning of the terms used? Am-gen asserts that the claims do not support HMR/TKT’s argument that it has redefined the term to include the biological effects of EPO. Amgen asserts that be

*230

cause claim terms are construed to give each term meaning,

Lantech, Inc. v. Keip Mack Co.,

32 F.3d 542, 546 (Fed.Cir.1994), the patent claims themselves distinguish between biological and therapeutic effects. Amgen’s Reply re ’422/’080 at 10. To make its point, it refers to claims 4 and 2 of the ’080 patent.

’080 Claim, 4:

A pharmaceutical composition comprising a therapeutically effective amount of an erythropoietin gly-coprotein product according to claim 1, 2, or 3.

’080 Claim 2:

An isolated erythro-poietin 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 and is not isolated from human urine.

Amgen asserts that under the doctrine of claim differentiation, claim 4 of the ’080 patent must not include any or all of the effects listed in the specification because otherwise claim 4 would be identical to that of claim 2. Specifically, it points out that claim 4 of the ’080 patent requires “[a] pharmaceutical composition comprising a therapeutically effective amount” of EPO according to claim 1, 2, or 3. Amgen’s Mem. re ’422/’080 at 15-16. It then asserts that the claim 2 requires the “in vivo biological activity of causing bone marrow cells to increase production of reticulocytes and red blood cells.” Therefore, if “therapeutically effective” included the effects listed in the specification to which the Federal Circuit pointed, Amgen argues, it would include the in vivo biological activity cited by claims 1, 2, or 3 of the ’080 patent and render claim 4 of the ’080 patent superfluous.

Id.

at 16.

As HMR/TKT urges, however, this argument is flawed because claim 4 concerns a

pharmaceutical composition

comprising a “therapeutically effective amount” of an

EPO

that happens to have the qualities described in claim 2. HMR/TKT’s Opp’s re ’422/’080 at 22. HMR/TKT correctly points out that claim 2 recites an isolated EPO glycoprotein and therefore refers to biological effects whereas claim 4 recites a pharmaceutical composition and involves therapeutic effects.

Id.

at 21-22. Hence, claim 2 would not be rendered superfluous if this Court construed “therapeutically effective” to include the biological effects listed in the specification.

Id.

at 22.

Another equally flawed argument is that claim 4, by encompassing claim 2 (in referring to a “therapeutically effective” amount of the product claimed in claim 2), indicates that a

“therapeutically effective

amount” is one that does more than cause the in vivo biological activities described in claim 2. After a careful review of the technology and its history, it is clear that this is not a correct reading of the claims. This review relied on extrinsic evidence, as is permissible under Federal Circuit precedent.

Vitronics,

90 F.3d at 1584 (noting that a court may resort to extrinsic evidence and expert testimony to help it understand the technology);

Altiris, Inc. v. Symantec Corp.,

318 F.3d 1363, 1371 (Fed.Cir.2003) (“In this regard, the expert testimony serves the permissible purposes of aiding our understanding of the technology and in helping us view the patent through the eyes of the skilled artisan.”).

27

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Before Amgen’s invention, human EPO was known to elicit certain biological effects, but it was impossible to extract an efficient amount of it for use in treatment of patients with anemias and other low red blood cell disorders. Amgen invented a product, recombinant EPO, that had the same in vivo biological effects as natural EPO but differed in its carbohydrate composition and was capable of manufacture in quantities large enough to provide effective treatment.

With this understanding of the technology, it is clear that claims 2 and 4 of the ’080 patent, by themselves, do not define “therapeutically effective” beyond its plain and ordinary meaning, nor do they indicate that a “therapeutically effective amount” of EPO is one that does more than elicit the biological effects noted in claim 2. Instead, claim 2 stakes out Am-gen’s novel recombinant EPO that has the same in vivo biological activities of natural EPO (causing bone marrow cells to increase production of reticulocytes and red blood cells). Claim 4 sets out a pharmaceutical composition that has a novel amount of the EPO — an amount that can actually treat or cure patients. Notably, these claims do not indicate whether biological effects are themselves sufficient to treat or cure patients.

Similarly, the claims of the ’422 patent do not define a “therapeutically effective amount” as one that does something above and beyond eliciting the biological effects of EPO listed in the specification.

The next question is whether the claims themselves indicate for what types of patients this product is “therapeutically effective.” Amgen contends that its EPO is specifically designed for those suffering from anemias and thus only an increase in hematocrit is “therapeutically effective.” Indeed, the record shows that Amgen’s product

can

be used to increase levels of hematocrit, in other words, it

can

be used to “cure” or “relieve” the diseased state brought on by anemia.

Amgen I,

126 F.Supp.2d at 99 (“The therapeutic effectiveness or benefit of an erythropoietin preparation is shown by demonstrating a correction in anemia by increasing and maintaining the hematocrit of a patient to normal or near normal levels.”).

28

Dr. Er-slev testified at the first trial that a sustained increase in hematocrit and hemoglobin is required to determine whether or not anemia has been corrected. Erslev Test., Trial Tr. at 1688: 14-1689: 4; Means Test., Trial Tr. at 1905: 17-20; 1910: 9-13. Dr. Erslev also testified that the other effects listed in the specification such as an increase in reticulocyte count or an increase in iron uptake cannot — each standing alone — correct anemia. Erslev Test., Trial Tr. at 1688: 14-1689: 4.

The problem with Amgen’s argument, however, is that the claims that contain the disputed term do not themselves include a limitation directed to the specific clinical benefit of correcting

anemia.

Therefore, the plain and ordinary meaning of “therapeutically effective” cannot be limited to curing

anemia,

i.e., producing an increase in hematocrit levels based on the claims

*232

alone. The claim language simply does not allow for such a specific interpretation. This conclusion is further supported by the fact that claim 6 of the ’080 patent (unlike claim 4) does indeed specify the type of treatment (kidney dialysis) for which the EPO should be used and calls out, in that context, that an effective amount is one that increases hematocrit:

’080 Claim 6:

A method for treating a kidney dialysis patient which comprises administering a pharmaceutical composition of claim 4 in an amount effective to increase the hematocrit level of said patient.

’080 Patent, Ex. 1, col. 38: 57-60. Had Amgen used similar claim language in claim 4 — that is, had it referred specifically to anemia — then its argument would have merit. Based on the non-specific language of claim 4, however, this argument fails.

In sum, the claim language supports only the plain and ordinary definition of “therapeutically effective” — an amount that produces a result that, in and of itself, helps to heal or cure. The language of the claims at issue does not delineate the type of disease for which the EPO is “therapeutically effective.” Therefore, the Court must now turn to the specification and the prosecution history to determine whether Amgen has limited or altered the plain meaning of the term either by defining the term or specifying the disease states for which the product is intended.

c. The Specification

The second step in claim construction is to review the specification to determine whether the patentee has used terms in a manner inconsistent with the ordinary meaning or has become his own lexicographer.

Vitronics,

90 F.3d at 1582 . In essence, “[t]he specification acts as a dictionary when it expressly defines terms used in the claims or when it defines terms by implication.”

Id.

(noting that the specification is “the single best guide to the meaning of a disputed term”). The Federal Circuit has stated that “a claim must be read in view of the specification of which it is part,” and therefore, a court can use the written description to define a term that is already in a claim limitation.

Renishaw,

158 F.3d at 1248 ;

SciMed Life Sys. v. Advanced Cardiovascular Sys.,

242 F.3d 1337, 1341 (Fed.Cir.2001) (noting that claims can be given a narrow construction in light of the written description and explaining that one reason to look to the specification is “to determine if the paten-tee has limited the scope of the claims” (quoting

Watts v. XL Systems, Inc.,

232 F.3d 877, 882 (Fed.Cir.2000))).

The part of the specification to which the Federal Circuit in

Amgen II

pointed is as follows:

Similarly,

to the extent

that polypeptide products of the invention share the in vivo activity of natural EPO isolates they are conspicuously suitable for use in erythropoietin therapy procedures practiced on mammals, including humans, to develop any or all of the effects

herefore

attributed in vivo to EPO, e.g., stimulation of reticulocyte response, development of ferrokinetie effects (such as plasma iron turnover effects and marrow transit time effects), erythrocyte mass changes, stimulation of hemoglobin C synthesis (see, Eschbach, et al., supra)

and,

as indicated in Example 10, increasing hematocrit levels in mammals.

’933 Patent, Ex. 1, col. 33: 19-31 (emphases added).

The Court begins by analyzing whether this section defines therapeutically effective to include the effects listed above. It is undisputed that this section declares that Amgen’s recombinant EPO is similar to natural EPO in that it shares some of the same in vivo activity.

Id.

at col. 33:

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19-22.

“[T]o the extent

” that it does so— to the extent that it is similar to natural EPO — Amgen’s EPO are “conspicuously suitable for use in erythropoeitin therapy procedures” to develop any or all of the effects that were “herefore” (before) attributed in vivo to EPO, such as the stimulation of reticulocyte response, development of ferrokinectic effects, erythrocyte mass changes, and stimulation of hemoglobin C synthesis. What is unclear and disputed, however, is whether the section that begins with “and, as indicated in Example 10, increasing hematocrit levels in mammals” is part of the laundry list of effects previously attributed in vivo to EPO or a separate suitable use for the product. In other words, this portion of the specification can be interpreted one of the following two ways:

1) Amgen’s EPO is “conspicuously suitable for use in erythropoietin therapy procedures practiced on mammals, including humans, to develop any or all of the effects herefore attributed in vivo to EPO, e.g., stimulation of reticulocyte response, ... and, as indicated in Example 10, increasing hematocrit levels in mammals.”

2) Amgen’s EPO is “conspicuously suitable for” (a) “use in erythropoietin therapy procedures practiced on mammals, including humans, to develop any or all of the effects herefore attributed in vivo to EPO, e.g., stimulation of reticulocyte response, ...”

and,

(b) “as indicated in Example 10, increasing hematocrit levels in mammals.”

The former interpretation — a direct quote of the specification — suggests that an increase in hematocrit level was an effect previously attributed to natural EPO and that it, along with the biological effects, are a type of effective therapy. In other words, it includes “increasing the hematocrit levels” as

one of the many effects

of EPO that were previously identified and that are now produced by this product and useful in “erythropoietin

therapy

procedures.” The problem with this reading is that the intrinsic evidence (the claims, the specification, and the prosecution history) and extrinsic evidence suggest that an increase in hematocrit levels was

not

previously attributed to natural EPO.

29

In remarks following an amendment made during prosecution of the ’080 patent, Amgen explained to the Patent, and Trademark Office (“PTO”) that Example 10 is novel in that it is the first therapeutic procedure ever practiced with EPO to demonstrate that EPO has the capacity to generate an increase in hematocrit in vivo. Amgen’s ’422/’080 App., Tab G (Ex. 2), at Tab 6, at 179. The extrinsic record also suggests that an increase in hematocrit was not previously attributed to natural EPO.

Vitronics,

90 F.3d at 1583 (“Included within an analysis of the file history may be an examination of the prior art cited therein.”). Therefore, the first reading implies a factually incorrect conclusion.

The latter interpretation — and the one that the Court adopts — suggests that an increase in hematocrit is independent or different from the in vivo effects previously attributed to natural EPO. In other words, in this section, Amgen calls out that its recombinant EPO can elicit “any or all” of the effects that natural EPO does — and more. Admittedly, the use of the words “therapy procedures” supports the interpretation that a “therapeutically effective amount” encompasses an amount that would result in the biological effects because it implies that the effects are a part

*234

of therapy. That being said, however, the way in which the increase in hematocrit is set off from the rest of the language suggests that this product elicits something in addition to what the prior art elicited, something more than the biological effects. Moreover, it makes clear that “any or all” only modifies those effects previously attributed to natural EPO — not the increase in hematocrit. Indeed, if the phrase “as indicated in Example 10, increasing hemat-ocrit levels in mammals” were merely an item in the list of “any or all of the effects herefore attributed in vivo to EPO,” then the words “in mammals” would be redundant. The list of items refers to “effects herefore attributed in vivo to EPO” for “use in erythropoietin therapy procedures practiced

on mammals

”,

so

“increasing hematocrit levels

in mammals

” must be a second end for which Amgen’s EPO is “conspicuously suitable.”

This interpretation comports with the Court’s understanding — developed over the course of two intensive trials — of what hematocrit actually measures. Hematocrit measures the ability of the blood to supply oxygen to the body. It indicates the relative proportion of red blood cells to the total volume of blood. By introducing additional EPO into the patient’s body, a patient’s hematocrit level can be increased to and sustained at or near normal levels. In other words, the blood is able to provide a steady supply of sufficient oxygen to the tissues. It is the Court’s understanding that, in

most

cases, an increase in hemato-crit is accompanied, if not preceded, by “any or all” of the biological effects listed in the specification.

30

In other words, this portion of the specification explains what happens when a “therapeutically effective amount” of EPO is used — that is, it produces an increase in hematocrit — along with any or all of the biological affects previously attributed to natural EPO. As will be discussed below, this reading is further supported by other parts of the specification and the prosecution history.

Therefore, while this Court agrees with the Federal Circuit that therapeutic effectiveness “encompasses the patient responses described in the specification,” this part of the specification does not indicate that these biological responses are sufficient or that Amgen “broadened” the plain meaning of the term “therapeutically effective” to encompass the elicitation of biological effects alone regardless of whether they heal or cure. Indeed, the term “therapeutically effective” is never even mentioned in this section of the specification. While guidance as to a claim term’s meaning or a claim’s scope need not be provided in explicit definitional format,

SciMed Life Systems,

242 F.3d at 1344 , to alter the plain and customary meaning of a term that is not ambiguous on its face, a patentee must do so clearly and deliberately.

Renishaw,

158 F.3d at 1249 (noting that when a patent applicant “has elected to be a lexicographer by providing an explicit definition in the specification for a claim term[,] ... the definition selected by the patent applicant controls” as long as the patentee’s lexicography is made “ ‘with reasonable clarity, deliberateness, and precision’ ” (quoting

In re Paulsen,

30 F.3d

*235

1475, 1480 (Fed.Cir.1994)));

Vitronics,

90 F.3d at 1582 ;

Altiris,

318 F.3d at 1370 .

31

Here, there is no “manifest exclusion or restriction, representing a clear disavowal of claim scope.”

Teleflex, Inc. v. Ficosa N. Am. Corp.,

299 F.3d 1313, 1325 (Fed.Cir.2002). Thus, this portion of the specification does not redefine the plain and ordinary meaning of the term to include the biological effects regardless of whether they heal or cure. Likewise, this portion of the specification does not limit the term to an increase in hematocrit. While it makes clear that its product is useful because it can increase hematocrit, it does not redefine the term in question to equate only with an increase in hematocrit (or relate only to curing anemia).

Amgen points to a few other portions of the specification in support of its argument that while it did not alter the meaning of “therapeutically effective” to include the biological effects, it did limit the claimed therapy to patients suffering from anemia and anemia-like disorders and likewise limited the claim to an increase in hemato-crit.

32

The first such passage is the one immediately following the portion of the specification cited by the Federal Circuit:

Included within

the class of humans treatable with products of the invention are patients generally requiring blood transfusion and including trauma victims, surgical patients, renal disease patients including dialysis patients, and patients with a variety of blood composition affecting disorders, such as hemophilia, sickle cell disease, physiologic anemias, and the like.

’933 Patent, Ex. 1, col. 83: 31-36 (emphasis added).

33

As HMR/TKT correctly points out, this list of patients is obviously incomplete as it begins with the words “included within,” which suggests that there are other types of patients for which the product is intended. HMR/TKT’s Posb-Hr’g Mem. [Doc. No. 747] at 4. While this is true, it still provides insight into the type of patients who may receive a therapeutic benefit from the pharmaceutical compositions of the invention. Therefore, while the specification does not actively limit the term to this class of patients, it provides guidance to the Court in defining the term.

Vitronics,

90 F.3d at 1582 ;

Teleflex, Inc.,

299 F.3d at 1325 (“The specification may assist in resolving ambiguity where the ordinary and customary meaning of the words used in the claims lack sufficient clarity to permit the scope of the claim to be ascertained from the words alone.”). By listing the types of patients responding to treatment by the product, the specification implies that the term “therapeutically effective” amount was written with respect

*236

to these types or classes of patients. “The specification acts as a dictionary when it expressly defines terms used in the claims or when it defines terms by

implication.” Vitronics,

90 F.3d at 1582 (emphasis added).

34

It does not, however, indicate that this invention is only for the treatment of anemia but instead for all the ailments listed. While this may not be an exhaustive list and patients with similar or like disorders might also benefit from the product, this list begins to infuse “therapeutically effective amount” with real meaning.

Other portions of the specification support interpreting the claims with reference to the class of patients listed in the specification. For example, the specification states: “The minimization of the need for transfusion therapy through use of EPO therapy can be expected to result in reduced transmission of infectious agents.” ’933 Patent, Ex. 1., col. 33: 37-39. While this is only one example of how the product is useful or advantageous, it falls within the class of patients listed in the specification.

35

Other pertinent sections are as follows:

It has recently been estimated that the availability of erythropoietin in quantity would allow for treatment each year of anemias of 1,600,000 persons in the United States alone.

Id.

at col. 6: 35-39.

... clinical testing and potential wide-ranging

therapeutic use

of [Lin’s recombinant EPO] in treatment of e.g., chronic kidney disease wherein diseased tissues fail to sustain production of er-ythropoietin.

Id.

at col. 9: 6-9 (emphasis added).

Also

comprehended by the invention are pharmaceutical compositions comprising effective amounts of polypeptide products of the invention together with suitable diluents, adjuvants and/or carriers which allow for provision of erythro-poietin therapy,

especially in

the treatment of anemic disease states and most especially such anemic states as attend chronic renal failure.

Id.

at col. 12: 1-7 (emphasis added).

Because erythropoietin is essential in the process of red blood cell formation, the hormone has potential useful application in both the diagnosis and the

treatment

of blood disorders characterized by low or defective red blood cell production.

*237

Id.

at col. 6: 20-24 (emphasis added).

36

Amgen also points to column 6, lines 28-33 of the ’933 patent, which cites a study-done by Eschbaeh:

See, generally, ... Eschbaeh, et al[.] ... describing a therapeutic regimen for uremic sheep based on in vivo response to erythropoietin-rich plasma infusions and proposing a dosage of 10 U EPO/kg per day for 15-40 days as corrective of anemia of the type associated with chronic renal failure.

That Amgen intended its invention to treat anemic patients is clear from these sections (along with the prosecution history, as will be discussed below) and is pertinent to the analysis.

Renishaw,

158 F.3d at 1250 (noting that what the “inventors actually invented and intended to envelop with the claim” is relevant in claim construction);

CVI/Beta Ventures v. Tura LP,

112 F.3d 1146 , 1160 (Fed.Cir.1997) (“In construing claims, the problem the inventor was attempting to solve, as discerned from the specification and the prosecution history, is a relevant consideration.”). None of these sections, however, shows that Amgen intentionally re-defined the plain meaning of the term “therapeutically effective” to refer exclusively to anemia or to an increase in hematocrit.

While these sections do not suggest that the product is solely intended for anemic patients and to increase hematocrit, they do imply, in combination, that it is designed for the class of patients listed in column 33 and noted above.

37

That being said, it seems to stretch the doctrine of claim construction too far to incorporate into the plain and ordinary meaning a reference to a class of patients that at best is only implied in the specification.

Northern Telecom Ltd. v. Samsung Elees. Co.,

215 F.3d 1281, 1294 (Fed.Cir.2000);

EX Indus., L.P. & Koslow Technologies Corp.,

18 Fed. Appx. 871, 876 (Fed.Cir. Aug.10, 2001) (unpublished opinion)

38

(“[W]hat is determinative is whether the patentee has defined a claim term as excluding a broader interpretation with reasonable clarity and deliberateness.”). On the other hand, it seems foolish to construe a term such as “therapeutically effective,” without reference to a class of patients for which the product is intended to be “therapeutically effective.” This quandary, however, is put to rest by the prosecution history. When the specification is considered along with the prosecution history, it becomes apparent that a class-of-patients limitation is appropriate.

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d. The Prosecution History

The third step in claim construction is to consider the prosecution history to determine whether the applicant has made any express representations regarding the claim’s scope.

Vitronics,

90 F.3d at 1582-83 ;

Standard Oil Co. v. American Cyanamid Co.,

774 F.2d 448, 452 (Fed.Cir.1985) (“[A]ll express representations made by or on behalf of the applicant to the examiner to induce a patent grant ... [can] limit[ ] the interpretation of claims.”);

Alpex Computer Corp. v. Nintendo Co. Ltd.,

102 F.3d 1214, 1220 (Fed.Cir.1996) (noting that prosecution history is “relevant ... for construing the meaning and scope of the claims”).

The amendments made early on in pursuance of the patents support HMR/TKT’s contention that Amgen defined a “therapeutically effective amount” of EPO to encompass an amount sufficient to elicit any or all of the biological effects that were attributed to natural EPO.

On December 5, 1988, in response to a rejection under 35 U.S.C. §§ 112 , 102(b) and 103 of what eventually became the ’080 patent, Amgen submitted independent claim 41 and dependent claims 55-57 and 61-66. The pertinent amendments are claim 41 (which relates to claim 2 of the ’080 patent), claim 55 (which relates to claim 4 of the ’080 patent), claim 57 (which relates to claim 6 of the ’080 patent), and claim 56 (because it is referenced in claim 57).

Claim 41: A

glycoprotein product having a primary structural conformation and glycosylation sufficiently duplicative of that of a naturally occurring human erythropoietin to allow possession of the in vivo biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells and having an average carbohydrate composition which differs from that of naturally occurring human erythropoiet-in.

Claim 55:

A pharmaceutical composition comprising an effective amount of a glycoprotein product according to claim 41 and a pharmaceutically acceptable diluent, adjuvant or carrier.

Claim 56:

A method for providing er-ythropoietin therapy to a mammal comprising administering an effective amount of a glycoprotein product according to claim 41.

Claim 57:

A method according to claim 56 wherein the therapy comprises enhancing hematocrit levels.

Amgen’s ’422/’080 App., Tab G (Ex. 2), at Tab 6, at 174-75.

These claims make clear that Amgen’s product purposefully duplicates natural EPO in that it elicits the in vivo biological activity of causing bone marrow cells to increase production of reticulocytes and red blood cells, but that it differs from natural EPO in its carbohydrate composition. These claims also make clear that claim 55 (similar to claim 4 in the ’080 patent) is not limited to increasing hemato-crit because that is precisely what claim 57 does (and what claim 6 in the ’080 patent how does). In the remarks accompanying the amendment, Amgen twice explained that its product produces the same in vivo biological activity as that of natural EPO:

Applicant’s novel glycoprotein preparations ... hav[e] the glycosylation-requir-ing

in vivo

biological activity (promoting reticulocyte and red blood cell production) characteristics of naturally occurring human erythropoietin.

Amgen’s ’422/’080 App., Tab G (Ex. 2), at Tab 6, at 175.

[T]he glycoprotein products herein claimed ... possess the essential

in vivo

biological activity of naturally occurring erythropoietin.

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Amgen’s ’422/’080 App., Tab G (Ex. 2), at Tab 6, at 181. It then explained, with reference to claim 56, that Amgen “first developed knowledge of the full amino acid sequence of erythropoietin and first generated the presently claimed glycoprotien products which allowed for full scale clinical application to provide

therapeutic effects

consistent with the

in vivo

activity of naturally occurring erythropoietin.”

Id.

at 177 (first emphasis added). With reference to claim 41, it stated that Amgen “was the first to provide a glycoprotein which is

both

different from previously isolated urinary erythropoietin in its glycoys-lation and yet sufficiently like the natural product ... in terms of its glycosylation to allow it to fill the long-felt need (unsatisfiable by urinary isolates) for life-sustaining human therapeutic agents for, e.g., the anemia associated with dialysis in renal failure patients.”

Id.

at 178 . It then explained that the product is “sufficiently like” natural EPO in glycosylation because it “allow[s] for

in vivo

biological activity.”

Id.

at 179 . Later, it explained that Example 10 is novel in that it is the first therapeutic procedure ever practiced with EPO to demonstrate that EPO has the capacity to generate in vivo an increase in hemato-crit.

Id.

Taken in combination, the amendments and these remarks support the interpretation that Amgen intended “therapeutically effective amounts” of EPO to encompass an amount that elicited in patients any or all of the biological effects previously attributed to natural EPO and that it did not limit the term to an increase in hemato-crit.

39

Such an effect is separately claimed in claim 6 (here claim 57).

Were this the entire prosecution history, the Court would agree with HMR/TKT and the Federal Circuit that Amgen broadened the term to mean one that elicits any or all of the in vivo effects before attributed to natural EPO regardless of whether they actually heal or cure the patient. In the course of overcoming two additional rejections later on in the process, however, Amgen differentiated its product from natural EPO (i.e., it overcame rejection) by asserting that natural EPO — which elicits the biological effects— was not therapeutically viable, whereas its product was clinically effective and designed specifically for a class of patients for which the product was intended. In doing so, Amgen avowed that its invention produced enough quantity of EPO to elicit responses that actually healed or cured the patient.

Renishaw,

158 F.3d at 1249 n. 3 (“[A]ny interpretation that is provided or disavowed in the prosecution history also shapes the claim scope.”);

Standard Oil Co.,

774 F.2d at 452 (“[T]he prosecution history (or file wrapper) limits the interpretation of claims so as to exclude any interpretation that may have been disclaimed or disavowed during prosecution in order to obtain claim allowance.”).

For example, in a June 5, 1989 amendment, in response to a PTO rejection under 35 U.S.C. § 103 for obviousness, Am-gen distinguished its recombinant EPO product from natural EPO by claiming natural EPO was “not a viable therapeutic product” whereas its recombinant EPO was “clinically effective” and the “first

*240

therapeutic product” successfully to treat anemia and other disorders involving low red blood cell counts:

All of the references cited by the Examiner in this rejection relate to naturally occurring erythropoietin. The claims of the subject invention relate to erythro-poeitin which is produced through recombinant DNA techniques. Recombinant erythropoietin is different from naturally occurring erythropoietin... Moreover, naturally occurring human erythropoietin is not a viable human therapeutic product; human recombinant erythropoietin, on the other hand, has been proven to be clinically effective,

and

is the first therapeutic product which can be used to effectively treat the hundreds of thousands of patients who suffer from anemia and other disorders involving low red blood cell counts.

Amgen’s ’422/’080 App., Tab G (Ex. 2), at Tab 11, at 227 (emphasis omitted). Amgen further explained that “[i]n contrast to recombinant erythropoietin, naturally occurring human erythropoietin is not used to treat patients. In the past, efforts were made to obtain purified erythropoietin from natural sources .... The results of these efforts however yielded only a small amount of material which was far too little for clinical research.”

Id.

at 229 . As the FDA stated in its approval of recombinant EPO “there is not enough naturally occurring enthropoetin produced to collect it from healthy persons for use in treatment,” but “gene splicing techniques have permitted its production.”

Id.

Thus, in response to this rejection, Amgen differentiated its EPO from natural EPO in two respects. First, Amgen claimed its invention allowed for a sufficient amount of EPO actually to treat patients — as opposed to natural EPO which was not available in large enough quantities. Second, it claimed its EPO, as opposed to prior art, effectively treated patients suffering from anemia or other disorders involving low red blood cell count.

40

This was a clear and definitive statement about what the invention “envelopes.”

Renishaw,

158 F.3d at 1250 (noting that a term can only be properly interpreted “with a full understanding of what the inventors actually invented and intended to envelop with the claim” and that the correct construction is that which “stays true to the claim language and most naturally aligns with the patent’s description of the invention”). Here, the prosecution history makes clear that Amgen intended its invention to be clinically effective at least for the class of patients suffering from anemia and low red blood cell disorders.

See Standard Oil Co.,

774 F.2d at 452 (“[A]ll express representations made by or on behalf of the applicant to the examiner to induce a patent grant or ... to reissue a patent ... [can] limit[ ] the interpretation of claims.”);

Spectrum Int’l Inc. v. Sterilite Corp.,

164 F.3d 1372, 1378 (Fed.Cir.1998) (“[Explicit statements made by a patent applicant during prosecution to distinguish a claimed invention over prior art may serve to narrow the scope of the claim.”). Amgen was trying to cure anemia and other diseases associated with low red blood cell count— not simply to duplicate the effects of natural EPO regardless of whether those effects cured or healed.

CVI/Beta Ventures,

112 F.3d at 1160 (“In construing claims, the problem the inventor was attempting to solve, as discerned from the specification and the prosecution history, is a relevant consideration.”).

*241

That Amgen intended its invention to provide a meaningful health benefit to the list of patients expressly mentioned in the specification is supported by another portion of the prosecution history. On November 6, 1990, Amgen claimed the following in an application that eventually resulted in the ’422 patent:

Claim 61: An erythropoietin-containing, pharmaceutically-acceptable composition wherein human serum albumin is mixed with erythropoietin.

Claim 62: A composition according to claim 61 containing a therapeutically effective amount of erythropoietin.

Claim 63: A composition according to claim 61 containing a therapeutically effective amount of recombinant erythro-poietin.

41

HMR/TKT’s App. to Opp’n [Doc. No. 705], Tab 2 (Ex.2003, 11/6/90 Preliminary Amendment) at 9. The examiner rejected claims 62 and 63 as “being indefinite for failing to particularly point out and distinctly claim the subject matter which [the] applicant regard[ed] as the invention.”

Id.

(Ex.2003, 6/1/94 Examiner’s Action) at 2. Claim 62 was rejected for being “vague and indefinite because it is unclear what the claimed composition is required to be ‘effective’ for,” and claim 63 was rejected as “vague and indefinite because it is unclear as to how the recitation that the claimed erythropoietin is ‘recombinant’ modifies the physical erythropoietin composition[;] ... while the claimed erythro-poietin may be prepared using recombinant techniques, the product would not necessarily distinguish over that found in nature.”

Id.

In essence, then, the examiner rejected Amgen’s patent because it did not specify for what type of patients the product was intended to be “therapeutieally effective”

and

it did not distinguish how the recombinant EPO was different than natural EPO besides its preparation. In other words, it did not differentiate what recombinant EPO provided to patients that natural EPO did not.

Amgen requested reconsideration, stating that the terms “effective” and “recombinant” are, “in view of the extensive disclosure of the specification,” well-defined and understood by a person of skilled in the art.

Id.

(Ex.2003, 12/1/94 Request for Reconsideration) at 1. Amgen argued that “the specification indicates

several potential therapeutic uses

for the claimed invention.”

Id.

at 2 (emphasis added). It then quoted the exact portion of the specification to which the Federal Circuit had pointed, where the in vivo effects along with the effect of an increase in hematocrit levels are mentioned.

Id.

Importantly, however, Amgen also quoted the following sections regarding the class of humans treatable with products:

Similarly, to the extent that polypeptide products of the invention share the in vivo activity of natural EPO isolates they are conspicuously suitable for use in erythropoietin therapy procedures practiced on mammals, including humans, to develop any or all of the effects heretofore attributed in vivo to EPO e.g., stimulation of reticulocyte response, development of ferrokinetie effects (such as plasma iron turnover effects and marrow transit time effects), erythrocyte mass changes, stimulation of hemoglobin C synthesis (see, Eschbach, et al[.], supra) and[,] as indicated in Example 10, increasing hematocrit levels in mammals. Included within the class of humans treatable with products of the invention are patients generally requiring

*242

blood transfusions and including trauma victims, surgical patients, renal disease patients including dialysis patients, and patients with a variety of blood composition affecting disorders, such as hemophilia, sickle cell disease, physiologic anemias[,] and the like.

Id.

(Ex.2003, 12/1/94 Request for Reconsideration) at 2 (emphasis omitted) (quoting ’933 Patent, Ex. 1, col. 33: 19-36). According to Amgen,

these sentences from the specification and others provide a clear and definite description of the

uses for which the claimed erythropoietin compositions would be therapeutically effective.

A person of skill in the art would understand that the amount of erythropoeitin necessary to achieve these defined therapeutic results would vary for each use. However,

clinicians can readily determine the “therapeutically effective” amounts for each condition, and indeed for each patient.

Id.

(emphasis added).

The question then is what are the “uses” to which Amgen refers. At first blush, it may appear that the “therapeutic uses” are the effects listed in the specification. A close reading of the remarks, however, makes clear that the words “uses” and “use” refer to treatment of the conditions listed in the specification — not to eliciting the effects. If this were not the case, the following sentence would not make sense: “A person of skill in the art would understand that the amount of erythropoeitin necessary to achieve these defined therapeutic results would vary for each

use.” Id.

(emphasis added). Amgen overcame a rejection of indefiniteness, in part by claiming that its product was specifically designed to treat patients suffering from the types of disease listed in the specification. Such a clear avowal — when considered alone or along with the other parts of the prosecution history and specification— would estop Amgen now were it to try to claim that its product was “therapeutically effective” in treating patients with

high

red blood cell counts.

Alpex Computer Corp.,

102 F.3d at 1221 (“Just as prosecution history estoppel may act to estop an equivalence argument under the doctrine of equivalents, positions taken before the PTO may bar an inconsistent position on claim construction.”);

Ekchian v. Home Depot, Inc.,

104 F.3d 1299, 1304 (Fed.Cir.1997) (“[B]y distinguishing the claimed invention over the prior art, an applicant is indicating what the claims do not cover, [and] he is by implication surrendering such protection.”). Here we have prosecution history estoppel in reverse — that is, Amgen wants this Court to constrain the meaning of the term to this class of patients. This does not change the effect the Court must give Amgen’s clear and definite statements. Thus, the Court holds that Amgen limited the term in dispute to refer to the class of patients listed in the specification and quoted to the examiner.

Teleflex,

299 F.3d at 1327 (noting that a term can be limited or extended by the specification or prosecution history as long as the patentee

clearly

intended to do so);

Altiris,

318 F.3d at 1370 (same).

42

The trickier question, however, is whether these remarks define the disputed term to include the in vivo effects of EPO

regardless

of whether they heal or cure this

*243

class of patients.

43

While it is a close call, the Court does not so read these remarks. Admittedly, all of the effects — the in vivo effects and an increase in hematocrit — are labeled together as “therapeutic results.” What is not made clear, however, is whether “therapeutic results” equates with “therapeutically effective.” While there is support for reading the terms as coextensive, there is also support for viewing them differently. Amgen specifically differentiates between an amount that achieves therapeutic

results

and a “therapeutically effective amount:”

A person of skill in the art would understand that the

amount

of erythropoeitin necessary to achieve these defined therapeutic results would vary for each use. However, clinicians can readily determine the

“therapeutically effective”

amounts for each condition, and indeed for each patient.

HMR/TKT’s App. to Opp’n, Tab 2 (Ex. 2003, 12/1/94 Request for Reconsideration), at 2 (emphasis added). These two sentences indicate that a different amount of EPO is used to achieve each of the effects listed in the specification — including the in vivo effects — depending on the condition and needs of the patient,

but

that a clinician can determine the amount that would be “therapeutically effective.” Thus, when read together, these sentences indicate that (1) the biological effects listed in the specification are part- of the “therapy” but not necessarily “therapeutically effective,” i.e., they do not necessarily heal or cure the patient, and (2) the amount necessary for therapeutic effectiveness — an amount that heals or cures — depends on the types of patients to which the recombinant EPO is being administered.

Because these remarks do not clearly disavow the ordinary and customary meaning of the disputed term and can actually be interpreted to support the ordinary and customary meaning of the disputed term,

44

the Court does not construe “therapeutically effective” to encompass any or all of the biological effects regardless of whether they work to heal or cure.

Amgen II,

314 F.3d at 1327 (“We indulge a heavy presumption that a claim term carries its ordinary and customary meaning ... [Prosecution history may not be used to infer the intentional narrowing of a claim absent the applicant’s clear disavowal of claim coverage.”);

see KX Industries, L.P. & Koslow Technologies Corp.,

18 Fed. Appx. 871, 876 (Fed.Cir.2001) (unpublished opinion);

see also Northern Telecom Ltd. v. Samsung Elec. Co., Ltd.,

215 F.3d 1281, 1294-95 (Fed.Cir.2000) (analyzing whether the pat-entee in the prosecution history “with reasonable clarity and deliberateness” excluded a broader interpretation of the claims).

45

In further support of this con-

*244

elusion is the fact that the examiner allowed the claims to stand. As the Federal Circuit pointed out in a slightly different context in

Amgen II,

“[w]e must presume the examiner did his job, and if he truly thought that” Amgen’s EPO was the same as natural EPO in that it merely elicited the biological effects, “the asserted claims would not have issued.” 314 F.3d at 1327 .

46

5. Conclusion and Claim Construction of “Therapeutically Effective”

The Federal Circuit has stated that “any interpretation [of a patent claim term] that is provided or disavowed in the prosecution history shapes the claim scope.”

Renishaw,

158 F.3d at 1243 n. 3;

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

149 F.3d 1335, 1347 (Fed.Cir.1998) (“The public has a right to rely on such definitive statements made during prosecution.”);

Ekchian,

104 F.3d at 1303-04 (noting that the courts and the public may rely on an information disclosure statement to interpret a claim). Here, to overcome a patent rejection for indefiniteness, Amgen avowed that its invention was “therapeutically effective” for the class of patients listed in column 33 of the specification. Therefore, the Court rules that “therapeutically effective” must be read with reference to this class of patients despite the fact that the specification uses the words “included within.” Amgen did not, however, go so far as to limit the list of patients to those suffering from anemia only or refine the term to mean an increase in hematocrit.

47

Nor did Amgen

*245

clearly redefine the term “therapeutically effective amount” to mean an amount that induces the effects heretofore attributed to natural EPO regardless of whether they work to heal or cure the patient. To the contrary, Amgen repeatedly states in the prosecution history and in the specification that recombinant EPO’s novelty is that it can actually effectively treat, that is heal or cure, patients. While “the inventor’s subjective intent as to claim scope,

when unexpressed in the patent documents,

[should not] have any effect,”

Vitronics,

90 F.3d at 1584 (emphasis added), the correct construction is that which “stays true to the claim language and most naturally aligns with the patent’s description of the invention,”

Renishaw,

158 F.3d at 1243 . Throughout the prosecution history, Am-gen repeatedly describes the invention as one that

heals

patients suffering from low red blood cell counts — something that could not be done before. While the prosecution history and specification indicate a clear intent to define “therapeutically effective amount” as one that elicits “one or more” of the in vivo effects of natural EPO, they do not define the in vivo effects as

necessarily

being “therapeutically effective.” In other words, they do not define these effects as being “therapeutically effective” regardless of whether they heal or cure. Instead, the plain and ordinary meaning of the term “therapeutically effective amount” was refined to (1)

reqidre

(in addition to healing or curing) an elicitation of one or more of the in vivo effects that was attributed to natural EPO and (2) be read in the context of a certain class of patients. Thus, the Court’s claim construction is as follows:

A therapeutically effective amount is a quantity that produces a result that in and of itself helps to heal or cure. A therapeutically effective amount is one that elicits in vivo biological activity of natural EPO such as those listed in the specification, column 33, lines 24 through 28: stimulation of reticulocyte response, development of ferrokinetic effects (such as plasma iron turnover effects and marrow transit time effects), erythrocyte mass changes, stimulation of hemoglobin C synthesis (see, Eschbach, et al., supra) and, as indicated in Example 10, increasing hematocrit levels in mammals.

Therapeutically effective is to be interpreted as being therapeutically effective with respect to the class of patients listed in the specification, column 33 lines 31 through 36: patients generally requiring blood transfusions and including trauma victims, surgical patients, renal disease patients including dialysis patients, and patients with a variety of

*246

blood composition affecting disorders, such as hemophilia, sickle cell disease, physiologic anemias, and the like.

See

9/18/03 Pretrial Conference Tr. at 9-11.

As will be discussed further below, in deciding whether the Goldwasser reference anticipates Amgen’s patents, this construction leaves the Court with a very fact-intensive task: determining which, if any, of the effects listed in the specification actually heal or cure the class of patients referred to therein.

B. “DNA Encoding”

1. Background

At the close of Amgen’s case-in-chief during the first trial, this Court granted HMR/TKT’s Fed.R.Civ.P. 52(c) motions for judgment of non-infringement of claims 4-9 of Amgen’s ’698 process patent.

Amgen I,

126 F.Supp.2d at 99-101 . On appeal, the Federal Circuit vacated and remanded this Court’s rulings regarding infringement of the ’698 patent because the Court had compared the accused device to the preferred or commercial embodiments of the patent instead of to the properly construed claims themselves.

Amgen II,

314 F.3d at 1347 .

In the memoranda in support and in opposition to each party’s motions regarding infringement of the ’698 patent, the parties argued different interpretations of the term “DNA encoding” found in claims 4 and 6 of the ’698 patent. Thus, the Court concluded that the term is in dispute and needed to be construed in order properly to determine the issue of literal infringement.

48

2. The Claims at Issue

Claim 4 of the ’698 Patent:

A process for the production of a glyco-sylated 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 promoter DNA, other than human erythropoietin promoter DNA, operatively linked to

DNA encoding

the mature erythropoiet-in amino acid sequence of FIG. 6; and (b) isolating said glycosylated erythro-poietin polypeptide expressed by said cells.

’698 Patent, Ex. 1, col. 38: 37-47 (emphasis added) (paragraph structure altered).

Claim 6 of the ’698 Patent:

A process for the production of a glyco-sylated 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 erythropoiet-in amino acid sequence of FIG. 6; and (b) isolating said glycoslated erythro-poietin polypeptide expressed by said cells.

Id.

at col. 38: 50-59 (emphasis added) (paragraph structure altered).

3.Summary of the Parties’ Arguments

HMR/TKT’s proposed claim construction rests on the argument that the word “encoding” means “producing.” HMR/ TKT’s Mem. in Opp’n re ’698 [Doc. No. 700] at 8. HMR/TKT argues that the phrase at issue in Amgen’s ’698 patent means that the DNA actually produces a

*247

glycosylated erythropoietin polypeptide having a 166 amino acid sequence.

Id.

In other words, HMR/TKT argues that section (a) of claims 4 and 6 of the ’698 patent should be construed to require the production of an EPO protein with 166 amino acids.

Id.

at 1; HMR/TKT’s Reply re ’698 [Doc. No. 725] at 3.

Amgen agrees that the term “mature erythropoietin amino acid sequence of FIG 6” refers to a fully processed EPO glyco-protein having a 166 amino acid sequence. Amgen argues, however, that section (a) of the disputed claims refers to the

DNA

that encodes the fully processed EPO glycopro-tein — not to the EPO glycoprotein itself. In other words, Amgen argues that the disputed claims refer to the type of DNA that is involved and describe that DNA as one that has a certain sequence, the genetic code, for the amino acid sequence spanning +1 through +166 of Figure 6. Am-gen’s Reply re ’698 [Doc. No. 731] at 6. Amgen asserts that the proper construction of the claim language is “a DNA sequence that contains the genetic code for the amino acid sequence spanning from position +1 through position +166 of Figure 6.” Amgen’s Reply re ’698 at 6. Amgen contends that a process can contain DNA that encodes the full 166 amino acids but result in an end-product that does not have the full 166 amino acid sequence. Thus, according to Amgen, this portion of the disputed claims refers to a

type

of DNA and to what that DNA

encodes

— not the end-protein that is ultimately

produced.

4. Discussion

It is true that the Court construed the “mature erythropoietin amino acid sequence of FIG. 6,” as stated in both the ’080 and ’698 patent, to mean a mature (fully realized) erythropoietin having 166 amino acids.

Amgen I,

126 F.Supp.2d at 100 . HMR/TKT’s argument that “DNA encoding ... [the] amino acid sequence of FIG. 6” means that the DNA actually must produce an EPO with a 166 amino acid sequence, however, stretches this construction too far.

The Court notes that HMR/TKT supports its definition of “encoding” primarily with extrinsic evidence — evidence to which resort ought be had only “if necessary.”

Vitronics,

90 F.3d at 1583 . As will be discussed below, use of extrinsic evidence here is not appropriate in construing these terms because “the patent documents, taken as a whole,” are sufficient “to enable the court to construe [the] disputed claim terms.”

Id.

Moreover, even if it were necessary, and thus appropriate, for this Court to consider extrinsic evidence as to the meaning of the word “encoding,” HMR/TKT’s arguments would still fail. HMR/TKT misinterprets the extrinsic evidence to which it points from the first trial. Dr. Kingston did indeed state that “the protein that is encoded is the protein that is actually produced,” Kingston Test., Trial Tr. at 1390-91, but this does not define “DNA encoding” as referring directly and exclusively to the specific product that is actually produced. Instead, what this language requires is DNA that is

capable

of encoding the final product — not DNA that produces the final product. HMR/TKT’s interpretation of Dr. Lodish’s testimony is also faulty. In the trial transcript pages to which HMR/ TKT referred, Dr. Lodish never states that “encoding” means “producing,” nor does Dr. Lodish define the fragment in question. He does indeed explain the end of the process as one that produces the same EPO glycoprotein. Lodish Test., Trial Tr. at 156-60. But this is the same point. Amgen’s argument, and it is a sound one, is that this part of the claim is not describing the last step of the process, but an interim step — -one that requires a

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DNA with a certain type of sequence or encoding capability.

Furthermore, the extrinsic evidence adduced during the second trial shows that “DNA encoding” in these claims does not mean that the end product must be produced. Dr. Lodish testified that those of skill in the art at the time would understand the plain meaning of the disputed term to mean “a DNA which when copied into RNA, and if necessary spliced, specifies the order of amino acids that are the mature erythropoietin amino-acid sequence depicted in Figure 6 of the patent.”

49

Lodish Test., R. Trial Tr. at 1054: 17-22, 1058: 10, 1059: 1-3 (explaining that genes have two parts, one of which involves the “coding sequence, the piece of DNA that actually specifies the amino acids in the encoded product” and stating that it is this part that is the subject of the claim, “that is, it is an issue of DNA encoding specifying an amino-acid sequence as determined by the genetic code”);

id.

at 1059: 16-21 (stating that “DNA encoding the mature erythropoietin amino acid sequence of FIG. 6” refers to “the DNA sequences that encode all of the amino acids from +1 to +166 of the EPO sequence”);

id.

at 1063: 17-19 (explaining that “DNA encoding” refers to DNA in the cell, not to “the polypeptide that is ultimately secreted by the cell. It’s a statement of the coding capacity of the DNA in the cell”);

id.

at 1055: 13-18 (“It simply refers to a sequence of DNA which has the capability of encoding, which encodes, a particular protein. It is not a statement about a protein that the cell actually makes or secretes.”). Indeed, even Dr. Kingston, HMR/TKT’s expert, admitted that one way the word “encoding” “could be used very precisely is to describe a very, very precise small bit of the gene, and that is the codons.” Kingston Test., R. Trial Tr. at 163: 2-16.

50

Further, consistent with Dr. Lodish’s testimony, Dr. Kingston stated that the phrase “DNA encoding the mature erythropoietin amino acid sequence of FIG. 6” means “DNA that provides the instruction to make th[e] protein which would be the sequences” found in Figure 6 and depicted as the codons encoding amino acids +1 through +166. Kingston Test., R. Trial Tr. at 135: 2-142: 7 (circling the entire sequence of Figure 6); Lodish Test., R. Trial Tr. at 1059: 22-1060: 25 (same).

Again, however, none of this evidence is necessary to the Court’s construction because an examination of the plain and ordinary meaning of the words, the claims themselves, and the specification demonstrates that HMR/TKT’s asserted construction is off base.

Vitronics,

90 F.3d at 1582 ;

SRI Int’l,

775 F.2d at 1118 ;

Autogiro,

384 F.2d at 397.

51

a. The Plain and Ordinary Meaning

The plain and ordinary meaning of “encode” is to “convert from one system of communication to another” and “to convert (a message) into code.”

Webster’s Ninth New Collegiate Dictionary

1990. This implies that “DNA encoding” is DNA that converts one type of message or text into

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another type of message and that it provides information to the cell.

b. The Claims

The claim language supports the plain and ordinary meaning of the term. The claim language establishes that “DNA encoding” refers to DNA that contains a certain sequence in the cells. Both claims 4 and 6 describe processes for producing a glycosylated erythropoietin polypeptide. The sentences in section (a) of the disputed claims do not, as HMR/TKT argues, require the production of the end-product of the claimed processes — an EPO polypeptide with 166 amino acids. To the contrary, the claims clearly distinguish between the cells grown in step (a) (which comprise “DNA encoding the mature er-ythropoietin amino acid sequence of Figure 6”) and the EPO glycoprotein itself that is isolated in step (b). Here, the “mature erythropoietin amino acid sequence of FIG. 6” modifies “DNA encoding” in the cells grown in step (a) — not the “glycosylated erythropoietin polypeptide” isolated in step (b). Therefore, based on the claim language and the ordinary meaning of the words, it appears that the sentences containing the disputed phrase mean, in conjunction, that the DNA must provide or contain the code or instructions for the “mature erythropoietin amino acid sequence of FIG. 6.”

The claims do not, however, imply that a protein with the “mature erythropoietin amino acid sequence of FIG. 6” must at the end of the process be produced. This point becomes clear when comparing these claims to that of the ’080 patent. The ’698 claims recite a “DNA

encoding

the mature erythropoietin amino acid sequence of FIG. 6.” as opposed to the claims of the ’080 patent that specifically recite an

EPO glycoprotein

that “comprises the mature erythropoietin amino acid sequence of FIG. 6.” ’080 Patent, Ex. 1, col. 38: 42-43.

In a nutshell, HMR/TKT’s construction conflates the concept of DNA that encodes for a protein with requiring the production of a specific protein and in so doing ignores how proteins are actually produced. The DNA encodes the protein. It provides the instruction set used by the

cell

to synthesize a polypeptide that is later processed to its final form. DNA encoding a specific amino acid sequence, however, does not necessarily determine the final length of the polypeptide produced by the cell. The testimony adduced at trial regarding the 166th arginine makes this clear. Dr. Lodish explained that “as long as that DNA encodes the mature erythro-poietin — mature EPO sequence, it matters not at all how many other amino acids might be there. Whatever it is, as long as it encodes that sequence, it’s fine.” Lodish Test., Trial Tr. at 248: 23-249: 1.

HMR/TKT counterargues that it is the protein that is produced by the cell that determines what instructions were actually present in the cell

and used

in the process, that is, that erroneous instructions are not really instructions at all.

See, e.g.,

7/28/03 Hr’g Tr. at 52: 1-9 (explaining that “there’s no proof one way or another as to what the intermediary is,” and “the only proof that there is in this case is as to the end product”).

52

The Court, however, is not persuaded. The evidence adduced at the first trial overwhelmingly suggested that although

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the DNA encodes for a 166 amino acid sequence, ultimately, the

cell

cleaves off the last amino acid residue prior to secretion of the final protein, EPO that has a 165 amino acid sequence.

Amgen I,

126 F.Supp.2d at 86, 101 ; Lodish Test., Trial Tr. at 347: 16-18, 348: 3-9; 7/28/03 Hr’g Tr. at 52: 1-9. As Amgen’s counsel explained at the

Markman

hearing, “DNA encoding the mature erythropoietin amino acid sequence of FIG. 6” is DNA containing codons for amino acids 1-166 of FIG. 6. These instructions will be used by the cell to produce a 165 amino acid erythropoiet-in. 7/28/03 Hr’g Tr. at 44: 11-47: ll.

53

Thus, DNA can encode or provide the genetic instructions for a protein that when ultimately secreted has a structure different from the one that the instructions dictate. That some of these instructions are not in the end “used” does not erase the fact that the DNA contained the information in the first place.

Moreover, as Amgen argues, HMR/ TKT’s construction makes the claims illogical. With HMR/TKT’s construction, the claimed processes would require the use of a cell containing “a promoter DNA opera-tively linked to an EPO protein” or “an amplified EPO protein.” Amgen’s Mem. In Opp’n re ’698 [Doc. No. 717] at 6-7. As asserted by Amgen and undisputed by HMR/TKT, this does not make sense.

In sum, any argument based on the claims that the words “producing” or “that produces” should be inserted in lieu of “encoding” fails along with HMR/TKT’s argument that “encoding” refers to the EPO protein itself.

54

c. The Specification

Like the claims, the specification supports the.plain and ordinary meaning of the word “DNA encoding.” It demonstrates that one skilled in the art at the time would have defined “encoding” as providing genetic instructions, that is, the sequence.

At the

Markman

hearing, HMR/TKT pointed to columns 11 and 13 in the specification to support its argument that DNA encoding means producing or that the protein is actually produced. 7/28/03 Hr’g Tr. at 51: 6-11. Those sections state that:

The isolation of the desired cDNA clones containing EPO encoding DNA was accomplished through the use of DNA/DNA colony hybridization.

’933 Patent, Ex. 1, col. 13: 64-66.

Specifically comprehended in part (b) are genomic DNA sequences encoding allelic variant forms of monkey and human erythropoietin and/or encoding other mammalian species of erythropoietin. Specifically comprehended by part (c)

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are manufactured DNA sequences encoding EPO, EPO fragments and EPO analogs which DNA sequences may incorporate codons facilitating translation of messenger RNA in non-vertebrate hosts.

’933 Patent, Ex. 1, col. 11: 54-61.

As this Court pointed out during the hearing, however, neither of these sections equates “encoding” with producing. 7/28/03 Hr’g Tr. at 51: 12-15. Likewise, neither shows a clear and deliberate attempt by the patentee to become its own lexicographer.

See Renishaw,

158 F.3d at 1249 ;

Vitronics,

90 F.3d at 1582 ;

Altiris,

318 F.3d at 1370 ;

Teleflex,

299 F.3d at 1326 . Each can be read consistently with the ordinary and customary meaning as understood by one skilled in the art, that is, inserting “providing the genetic instructions for” in lieu of “encoding.” In fact, the section to which HMR/TKT points in column 11 works against its argument that “DNA encoding” means DNA producing the actual protein because it refers to DNA sequences encoding EPO and EPO fragments. Under HMR/TKT’s construction, this section would require EPO fragments actually to be produced instead of requiring that the DNA have the genetic instructions for, that is, provide the codons or genetic sequence for, EPO fragments.

5. Conclusion and Claim Construction of “DNA Encoding”

Accordingly, the Court construed “DNA encoding” to mean “the genetic instructions for.” 7/28/03 Hr’g Tr. at 56: 18-23.

55

TKT/HMR, however, did not give up. As a last-ditch effort to win on literal infringement — which is what claim construction is really all about — HMR/TKT argued at the second trial via Dr. Kingston’s testimony that “genetic instructions for,” the Court’s construction of DNA encoding, could mean either the codons for the amino acids plus 1 to 166 of Figure 6 of the patent, or alternatively, all the instructions to make the mature protein including the regulatory sequences. Kingston, R. Trial Tr. at 161-163. Dr. Kingston explained that a scientist could use the term differently depending on the context.

Id.

To be clear, in this context, the Court interprets the claim to be referring to the coding sequence, the piece of DNA that actually specifies the amino acid sequence — not the regulatory sequences that determine when and under what conditions the cells copy the gene into RNA.

56

This interpretation is supported by the claims themselves, which refer to DNA that encodes — provides the genetic instructions for — “the mature er-ythropoietin amino acid sequence of FIG. 6.” Figure 6 indeed depicts, among other things, the deduced amino acid sequence that is arrived at by reading the codons of the DNA encoding the protein. Importantly, HMR/TKT points to no support in the prosecution history for its argument on this point. Thus, the Court interprets the claims to require the use of cells contain

*252

ing DNA that provides the genetic instructions, the codons, for a 166 amino acid sequence.

C. Are Claims 4 and 6 of the ’698 Patent Step-Plus-Function Claims?

1. Background

57

and Summary of The Parties’ Arguments

Whether Amgen, in referring to the “step[ ] of ... growing under suitable nutrient conditions” in claims 4 and 6 of the ’698 patent, was making step-plus-function claims is an issue raised for the first time by HMR/TKT in its Memorandum in Opposition to Amgen’s Renewed Motion for Summary Judgment of infringement of claims 4-9 of the ’698 patent. HMR/TKT’s Mem. In Opp’n re ’698 [Doc. No. 700] at 9. Paragraph 6 of 35 U.S.C. § 112 , which sets forth the notion of step-plus-function and means-plus-function, “obligates this court to interpret each functional element in a combination claim by reference to the corresponding structure, material, or acts described in the

specification and their equivalents.” Seal-Flex, Inc. v. Athletic Trade and Court Const.,

172 F.3d 836, 843 (Fed.Cir.1999) (emphasis added);

O.I. Corp. v. Tekmar Co., Inc.,

115 F.3d 1576, 1583 (Fed. Cir.1997).

58

In other words, if this section applies, the Court must limit its infringement analysis to a comparison of the type of “growing” claimed in the

specification

to the type of growing utilized by HMR/ TKT.

Ironically, this is exactly what the Court

did

— in error— in the first go-round. In

Amgen I ,

the Court based its holding of non-infringement of the ’698 patent on a comparison of HMR/TKT’s process to the processes outlined in the patent specification.

59

This was error because the Court had never ruled that the relevant claims qualified as a step-plus-function claims.

60

HMR/TKT now presses the Court to address the issue and so to rule.

The wrinkle here is whether the Court now can address this issue — that is, whether the Court can or should permit HMR/ TKT to raise the argument at this stage. After all, in 2000, the Court issued a sanction order against HMR/TKT limiting it to

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the contentions specifically described in its responses to interrogatories. Amgen’s Mem. in Opp’n re ’698

&

’349 [Doc. No. 717] at 4; Amgen’s App. to Mem. in Opp’n re ’698

&

’349 [Doc. No. 719], Ex. A (1/28/00 Order Granting Sanction). HMR/ TKT never identified its step-plus-function theory in its responses to Amgen’s contention interrogatories as a basis for non-infringement of the ’698 patent. Amgen’s App. to Mem. in Opp’n re ’698 & ’349, Tab C (12/7/99 HMR/TKT’s Supplemental Answers and Objections to Amgen’s Interrog. Nos. 2, 3, and 9) at 5-7, 17. Moreover, HMR/TKT never stated that this aspect of the ’698 patent (i.e., whether it included a step-plus-function claim) needed to be resolved through a

Markman

hearing. Am-gen asserts that the Court should therefore not allow this argument, and, at a minimum, the Court should afford Amgen the opportunity to present evidence directed to this new step-plus-function argument.

Id.

at 4-5. Moreover, Amgen argues that even if the Court allows such an argument, it lacks merit because “growing” is an “act,” not a “function.”

2. Discussion

61

a. Should the Court Allow HMR/ TKT to Make Its Step-Plus-Function Argument?

Whether the language of a claim is in step-plus-function format is a question of claim construction.

See, e.g., Kemco Sales, Inc. v. Control Papers Co., Inc.,

208 F.3d 1352, 1360 (Fed.Cir.2000) (“Whether the language of a claim is to be interpreted according to 35 U.S.C. § 112 , ¶ 6, i.e., whether a claim limitation is in means-plus-function [or step-plus function] format, is a matter of claim construction and is thus a question of law, reviewed de novo.”);

Personalized Media Communications, LLC v. Int’l Trade Comm’n,

161 F.3d 696 , 702 (Fed.Cir.1998) (“An infringement analysis entails two steps.... The first step, claim construction, is a question of law which we review de novo.... The second step is factual.... Whether certain claim language invokes 35 U.S.C. § 112 , f 6 is an exercise in claim construction and is therefore a question of law.” (citations and internal quotation marks omitted)). Generally, on appeal, a party cannot proffer a new claim construction that changes its scope, but it can present additional arguments in support of a previously proposed construction.

See, e.g., CCS Fitness, Inc. v. Brunswick Corp.,

288 F.3d 1359, 1371 (Fed.Cir.2002). The rationale is that the parties deserve notice and an opportunity to develop the record and, at the same time, the appellate court needs to have a properly reviewable record on an issue raised on appeal.

Interactive Gift Exp., Inc. v. CompuServe, Inc.,

256 F.3d 1323 , 1346-46 (Fed.Cir.2001);

cf. Finnigan Corp. v. Int’l Trade Comm’n,

180 F.3d 1354 , 1363 (Fed.Cir.1999). Thus, a relevant inquiry in determining whether a new claim construction can be pressed is “whether the trial court and the party claiming waiver had fair notice and an opportunity to address the issue concerning the scope of a claim limitation.”

CCS Fitness,

288 F.3d at 1371 .

The situation here is unusual. First, this is not a new claim construction argument raised on appeal but instead a new claim construction argument raised on remand to the trial court. Second, counsel for Amgen—the party now seeking to have the issue deemed waived—acknowledged the possible applicability of the step-plus-function doctrine to the Court. On June 9,

*254

2000, after the Court made its finding of non-infringement of the ’698 patent, Am-gen queried whether the Court was construing the ’698 process claims as “means plus function” claims. Trial Tr. at 1308-1309. The Court replied as follows:

I don’t mean to be elliptical. That is my analogy. That’s right.... Now I think you’ve missed on the ’698 patent. I think that because I do think you have to spell out a means-plus-function. And I have read this patent with great care and I’ve reflected on it throughout the testimony of all the witnesses. I don’t see either by equivalent or by literal infringement.

Trial Tr. at 1309-1310. Thus, the Court referred to the means-plus-function doctrine in relation to the ’698 patent

62

but, as noted earlier, did not definitively rule that the asserted claims were in means or step-plus-function format nor even mention step-plus-function in the opinion despite applying the infringement analysis required when a claim is in step-plus-function format.

Although the situation is not straightforward, it is clear that Amgen was on notice of the issue but did not get an opportunity to argue it. Given the procedural posture of the case with respect to the ’698 patent specifically, Amgen was fully afforded the opportunity during the remand trial to address the issue, which substantially reduces any prejudice to it.

Indeed, the Federal Circuit has suggested that it is appropriate to consider whether a claim is in means-plus-function or step-plus-function format even when one party has essentially waived the issue.

Rodime PLC v. Seagate Technology, Inc.,

174 F.3d 1294 (Fed.Cir.1999). In that case, the parties contested at trial whether the plaintiffs claim was in means-plus-function format, with the plaintiff arguing that it was not.

Id.

at 1302 . The district court ruled that the claim

was

in means-plus-function format.

Id.

The plaintiff appealed, but did not press that particular issue and thus apparently conceded that the claim was in means-plus function format.

Id.

The Federal Circuit nonetheless assessed

de novo

whether the claim was indeed in means-plus-function format, explaining that:

[The plaintiffs] concession ... does not relieve this court of its responsibility to interpret the claims as a matter of law. To interpret the claims, this court must decide the subsidiary question of whether the claim element disputed by the parties invokes § 112, ¶ 6 in the first instance.... Only by undertaking this inquiry can this court ensure consistency in statutory application. Moreover, this court’s claim interpretation affects entities beyond the parties to this case. Therefore, this court examines the district court’s decision that this claim falls under § 112, ¶ 6.

Id.

(internal citations omitted). The Federal Circuit subsequently concluded that the district court had erred and that the claim was not in means-plus-function format.

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Similarly, in this case, whether this portion of the ’698 patent is in step-plus-function format determines the entire analytic framework for analyzing whether HMR/TKT’s process infringes this part of the patent. To make this assessment, therefore, this Court needs to determine which analytic framework is implicated. The Court can either make this decision on the merits or can simply decide that the regular infringement framework must be used because HMR/TKT waived its argument that the step-plus-function framework should be used. The problem with the latter approach is that, if the step-plus function framework is truly the applicable one, and the Court nonetheless declines to use it on grounds of waiver, the Court will essentially be applying the wrong law to this aspect of the claim. This, in turn, undermines consistency in statutory application.

For these prudential reasons, this Court analyses whether claims 4 and 6 of the patent are step-plus-function claims. It does so in the course of construing the claims because, as noted above, whether the language of a claim is in step-plus-function format is a question of claim construction.

See, e.g., Kemco Sales, Inc.,

208 F.3d at 1360 ;

Personalized Media Communications, LLC,

161 F.3d at 702.

b. Are Claims 4 and 6 of the ’698 Patent Step-Plus-Function Claims?

This is a close question, but, on balance, claims 4 and 6 of the ’698 patent do not qualify as step-plus-function claims.

63

Five reasons support this conclusion.

First — although this is not dispositive— the words “steps of’ are used in the claim. Such a grammatical structure indicates that this is not a step-plus-function claim, because the phrase “steps of’ colloquially signals the introduction of specific acts, rather than functions.

See Seal-Flex,

172 F.3d at 850 (“[T]he ... phrase ‘steps of tend[s] to show that § 112, ¶ 6 does not govern that limitation. Accordingly, this court has similarly denied step-plus-function treatment to method claims which use the conventional ‘steps of language.”);

see also 0.1. Corp.,

115 F.3d at 1582-83 ;

Serrano v. Telular Corp.,

111 F.3d 1578, 1583 (Fed.Cir.1997). Similarly,

Amgen

did

not

use the phrase that typically signals the introduction of a step-plus-function limitation: “step for.”

See Seal-Flex,

172 F.3d at 849 (Rader, J., concurring);

Masco Corp. v. United States,

303 F.3d 1316, 1326-27 (Fed.Cir.2002). Accordingly, there is a presumption that section 112, paragraph 6 does not apply, that is, that this is not a step-plus-function claim.

Generation II Orthotics Inc. v. Med. Tech. Inc.,

263 F.3d 1356, 1368 (Fed.Cir.2001).

Second, upon examination, the claim element “growing” appears to recite a specific act for performing an ultimate function, that is, it appears to explain how the function is accomplished, rather than reciting the ultimate function itself. This is a key distinction. As Judge Rader explained in his concurrence in

Seal-Flex,

“the ‘underlying function’ of a method claim element corresponds to

what

that element ultimately accomplishes in relationship to what the other elements of the claim and the claim as a whole accomplish. ‘Acts,’ on the other hand, correspond to

how

the function is accomplished.”

Sealr-Flex,

172 F.3d at 849-50 . Here the “what” that is ultimately accomplished is the production of glyco-sylated erythropoietin, and the “how” is “growing [vertebrate cells] under suitable

*256

conditions.”

64

The dictionary definition of “growing” supports the interpretation that this is an act.

Masco,

303 F.3d at 1327 (looking to a mechanical engineering dictionary and a regular unabridged dictionary to determine whether “transmitting” is an act);

Vitronics,

90 F.3d at 1584 (noting that judges are free to consult technical treatises and dictionaries “so long as the dictionary definition does not contradict any definition found in or ascertained by a reading of the patent documents”). Here, the dictionary definitions of growing are “to increase in size by a natural process” or “to develop and reach maturity.”

The American Heritage Dictionary, supra,

at 579. These definitions support that growing is an act. Moreover, they do not contradict the meaning of “growing” that may be inferred from the prosecution history, and HMR/TKT does not argue that Amgen defined the term to have anything other than its plain and customary meaning.

Third, HMR/TKT does not even attempt to explain, much less show, how Amgen’s language — “growing under suitable nutrient conditions”' — -fails to describe an act. “[W]here a method claim does not contain the term ‘step[s] for,’ a limitation of that claim cannot be construed as a step-plus-function limitation

without

a showing that the limitation contains no act.”

Masco,

303 F.3d at 1327 (emphasis added). To the contrary, HMR/TKT makes only a half-hearted assertion- — in a footnote in a memorandum in opposition — that these claims are in step-plus-function format. Indeed, the footnote merely states that the argument HMR/TKT made with reference to claim 7 of the ’349 patent can be applied to claims 4 and 6 of the ’698 patent. HMR/TKT’s Mem. In Opp’n re ’698 at 9 n.* *.

65

HMR/TKT does not dispute Am-gen’s evidence, but simply claims that “growing” is not an act. HMR/TKT contradicts itself, however, as it implicitly refers to “growing” as an act in the Corrected Joint Pretrial Memorandum when it admits that HMR 4396 is produced by “growing, under suitable nutrient conditions R223 cells.” Amgen’s App. to Mot. for Judgment re ’349 [Doc. No. 676], Tab M (4/26/00 Corrected Joint Pretrial Mem.)

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¶ 25. This implies that “growing ...” is not in step-plus-function format. If “growing” was a function and needed further explanation, arguably HMR/TKT would not have admitted to such a statement in the Joint Pretrial Memorandum — at least not without further explanation. HMR/ TKT cannot merely assert that there is “no act” contained in this part of the claim without producing some evidence that there is not, i.e., that growing is not an act.

Celotex Corp. v. Catrett,

477 U.S. 317, 324 , 106 S.Ct. 2548 , 91 L.Ed.2d 265 (1986) (quoting Fed.R.Civ.P. 56(e)) (stating that the non-moving party must “go beyond the pleadings, and by [its] own affidavits, or by the ‘depositions, answers to interrogatories, and admissions on file,’ designate ‘specific facts showing there is a material issue for trial” ’);

Seal-Flex,

172 F.3d at 849-50 (noting that step-plus-function applies only when the “limitation contains nothing that can be construed as an act”).

Fourth, the Federal Circuit has made clear that “claiming a step by itself, or even a series of steps, does not implicate section 112, ¶ 6,” and that courts must be

careful not to extend the language of this provision to situations not contemplated by Congress. If we were to construe every process claim containing steps described by an “ing” verb, such as passing, heating, reacting, transferring, etc. into a step-plus-function limitation, we would be limiting process claims in a manner never intended by Congress.

O.I. Corp.,

115 F.3d at 1583 . If the Court were to construe this process claim that begins with “growing” — an “ing” verb very much like heating, reacting, or transferring, — as a step-plus-function limitation, it would be doing just that, that is, limiting the process claims in a manner never intended by Congress. Moreover, the Court would be “rendering] the scope of coverage of these method claims uncertain and disrupting] the patentees’ settled expectations regarding the scope of their claims.”

Masco,

303 F.3d at 1327 (noting that “method claims are commonly drafted ... by reciting the phrase ‘steps of followed by a list of actions comprising the method claimed”).

As a final matter, the Federal Circuit’s silence as to whether these claims are step-plus-function claims may be indicative. True, the Federal Circuit probably may not even have considered the possibility.

66

Alternatively, however, the Federal Circuit may have considered the step-plus-function possibility but rejected it as without merit. This latter interpretation of the Federal Court’s silence is supported by the Federal Circuit’s statement that this Court’s analysis (comparing HMR/TKT’s process to the specification) was “legally unsupportable.”

Amgen II,

314 F.3d at 1350-51 . If the analysis was “legally supportable” by, for example, a finding that the claim was in step-plus-function format, the Federal Circuit certainly could have reached in and decided the issue itself,

see Rodime,

174 F.3d at 1294 . While it is true that in

Rodime,

the issue had been squarely before the district court and thus apparent to the Federal Circuit, here the issue was flagged by the way this Court erroneously conducted its infringement analysis. To anyone familiar with patent law, step-plus-function would have come to mind upon reading the Court’s infringement analysis which limited Amgen’s processes to those outlined in the specification. That the Federal Circuit failed to address the issue may, therefore, be significant.

Ethicon Endo-Surgery, Inc. v. U.S. Surgical Corp.,

93 F.3d 1572 , 1582 (Fed.Cir.1996)

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(“We must affirm the decision of the district court if it is supported by any ground properly preserved on appeal.”);

Datascope Corp. v. SMEC Inc.,

879 F.2d 820 , 822 n. 1 (Fed.Cir.1989) (“Appellees always have the right to assert alternative grounds for affirming the judgment that are supported by the record.”).

3. Conclusion and Claim Construction

Though it is a close question, this Court rules that claims 4 and 6 of the ’698 patent, in referring to the “steps of: (a)

growing under suitable nutrient conditions

...,” are not step-plus-function claims and that the regular infringement framework should therefore apply.

D. Is Claim 7 of the ’349 Patent a Step-Plus-Function Claim?

1.Background

Amgen’s ’349 patent contains six product claims (claims 1-6) and one process claim (claim 7). ’349 Patent, Ex. 1. This Court held, and the Federal Circuit affirmed, that HMR/TKT’s HMR 4396 literally infringes the product claims of the ’349 patent.

Amgen II,

314 F.3d at 1352, 1358 . Based on a comparison between the accused product and the preferred embodiment, this Court held that HMR/TKT did not literally or equivalently infringe the process claim, claim 7.

Amgen I,

126 F.Supp.2d at 122 . The Federal Circuit, as it did with the Court’s holding of infringement of the ’698 patent, vacated this ruling and remanded it so that the Court could analyze infringement by comparing the accused process to the properly construed claims themselves.

Amgen II,

314 F.3d at 1351, 1347, 1313 . Therefore, the remaining issue regarding this patent is whether HMR/TKT’s HMR 4396 infringes claim 7.

2. The Claim at Issue

Claim 7 of the ’349 Patent:

A

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

’349 Patent, Ex. 1, col. 38: 34-36.

3. Summary of the Parties’ Arguments

HMR/TKT, in an effort to establish non-infringement of claim 7, has argued, as it did with claims 4 and 6 of the ’698 patent, that claim 7 is a step-plus-function claim and that 35 U.S.C. § 112 , ¶ 6 therefore applies. As such, it contends that its product does not literally infringe the “step of culturing” because HMR/TKT’s process does not involve the culturing procedures set forth in Amgen’s specification. HMR/ TKT’s Mem. in Supp. [Doc. No. 687] at 12-13. As with the ’698 patent, Amgen argues, as a preliminary matter, that HMR/ TKT is improperly basing its motion under Fed.R.Civ.P. 52(c) on new arguments and defenses, given the previous orders of this Court and Amgen’s lack of opportunity to address these issues. Amgen’s Mem. In Opp’n re ’698 & ’349 [Doc. No. 717] at 3-5. Furthermore, Amgen points out, the procedural context here is different than it was with the ’698 patent, as this Court heard the entirety of both parties’ arguments and evidence concerning ’349 claims 1, 3, 4, 6, and 7. Lastly, Amgen argues, for the same reasons that it did regarding the ’698 patent, that claim 7 is not a step-plus-function claim.

Id.

at 11-14 .

4. Discussion

a. Should the Court Allow HMR/ TKT to Make Its Step-Plus-Function Argument?

Here, there is the same wrinkle that there was with the step-plus-function argument respecting the ’698 patent:

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should the Court permit HMR/TKT to raise this argument at this late stage in the game? There are two differences, however, that make the wrinkle, in the context of this patent, harder to iron out. First, the Court did not remark on the record, as it did with the ’698 patent, that it was making a means-plus-function analogy in ruling on the ’349 patent claims. Second, HMR/TKT has already presented its case of non-infringement regarding all the claims of the ’349 patent.

Neither of these differences, however, prevents the Court from allowing HMR/ TKT to make this argument at this point. The fact that the Court did not make a means-plus analogy to this patent is easily overcome since the Court, in

Amgen I ,

explained that it found non-infringement of claim 7 of the ’349 patent for the same reasons as it did the ’698 patent. Thus, the parties were on notice that any analysis regarding the process claims of the ’698 patent would necessarily apply to the ’349 patent. The procedural landscape ought not prevent the Court from construing whether this is a step-plus-function claim. If it is such a claim, the Court ought not conduct its infringement analysis as though it were not. This claim is here on remand and this Court must construe it in accordance with the law. Thus, the Court reaches the same conclusion as it did with the ’698 patent, that is, that it can and should address HMR/TKT’s step-plus-function argument.

b. Is Claim 7 of the ’349 Patent a Step-PIus-Punction Claim?

The determination of whether claim 7 of the ’349 patent is a step-plus-function claim must be made in the same way as any other determination regarding claim construction. As such, the Court must principally rely on intrinsic evidence and refer to extrinsic evidence only if necessary, with the exception that a dictionary or treatise — which qualifies as extrinsic evidence — can be consulted freely as long as it does not contradict the patent language.

The Court’s assessment of whether “culturing” is a function rather than an act, such that the step-plus-function framework applies, tracks the analysis provided above with respect to the whether “growing” is a function rather than an act in the ’698 patent. Just as the Court ruled that growing is an act, it rules that culturing is an act, and claim 7, therefore, does not state a step-plus-function limitation.

Like the asserted claims of the ’698 patent, claim 7 contains the phrase “step of,” rather than the phrase “step for.” Accordingly, there is a presumption that section 112, paragraph 6 does not apply — that this is not a step-plus-function.

Generation II Orthotics Inc.,

263 F.3d at 1368 ;

Seal-Flex,

172 F.3d at 849 (Rader, J., concurring);

Masco,

303 F.3d at 1326-27 .

HMR/TKT argues that “culturing” is the claimed function of claim 7. HMR/ TKT’s Mem. in Supp. re ’698 & ’349 [Doc. No. 687] at 13. Specifically, it claims that the “what” is “culturing.” In other words, HMR/TKT argues that “culturing” is “what” the claim ultimately accomplishes, and nothing else in the claim describes “how” the culturing is accomplished. HMR/TKT’s Reply Mem. re ’698 & ’349 [Doc. No. 725] at 9. While at first blush this argument makes sense, the Federal Circuit, in

Masco,

interpreted Judge Rad-er’s formulation as requiring analysis of “what th[e] limitations ultimately accomplish in relation to what the other limitations and each claim as a whole accomplish.”

Masco,

303 F.3d 1316 . Although there are no words in claim 7 that state the function, as Judge Rader explained in

Sealr-Flex,

“the function of that element may nonetheless be discernible from the context of the overall claim and the disclo

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sure in the specification.”

Seal-Flex,

172 F.3d at 850 . Here, the claim states in its preamble that it is “a process for producing erythropoietin” suggesting that there is a larger, ultimate function and that “culturing” is merely one act that achieves it. While the “recitation of the overall function of the claim in the preamble does not suffice to convert each element into an act for performing that function so as to preclude application of section 112, paragraph 6,”

Seal-Flex,

172 F.3d at 850 ,

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language in other claims of the patent lends further support to the Court’s conclusion that “culturing” is an act. Here, claim 7 itself refers to,

inter alia,

product claims 1 and 4. Claims 1 and 4 describe the purpose of culturing vertebrate cells as being able to produce erythropoietin at a certain rate:

Claim 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 106 cells in 48 hours ...

Claim 4:

Vertebrate cells which can be propagated in vitro which comprise transcription control DNA 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 eryth-ropoietin per 106 cells in 48 hours ...

’349 Patent, Ex. 1, col. 38: 8-14, 21-27 (emphasis added). Hence, when considering what the “other limitations and each claim as a whole accomplish,” it appears that “culturing” is not the claimed function but instead a single step or act of a process claim that

“ultimately accomplishes

” the production of erythropoietin at a certain rate.

Masco,

303 F.3d at 1327 (emphasis added).

There are two other pieces of support for construing “culturing” as an act. First, both parties agreed that the claim term “culturing under suitable conditions” means “growing in vitro under appropriate [or suitable] conditions.” Amgen’s App. to Mem. in Opp’n re ’698 & ’349, Tab P (9/20/99 App. to Amgen’s Claim Construction Submission) at 7;

id.,

Tab Q (10/18/99 App. to HMR/TKT’s Claim Construction Submission) at 5. Thus, implicitly HMR/ TKT admitted that “culturing” and “growing” are essentially interchangeable terms. This, considered in combination with the Joint Pretrial Memorandum itself, which states that HMR/TKT’s HMR 4396 is produced by “growing, under suitable nutrient conditions R223 cells,” 4/26/00 Corrected Joint Pretrial Mem. at 5, ¶ 25, suggests that even HMR/TKT at one point did not believe that “growing” — and by extension, “culturing” — was a function that needed further explanation. This strongly suggests that the term “culturing” was one reasonably well understood by those skilled in the art, a relevant consideration in determining whether a term is an act.

Cf. Greenberg v. Ethicon Endo-Surgery, Inc.,

91 F.3d 1580, 1582 (Fed.Cir.1996);

see also Watts,

232 F.3d at 881 ;

Caterpillar,

961 F.Supp. at 1256.

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Second, dictionary definitions of “culturing” define this word as an act. A standard medical dictionary,

Dorland’s Medi

*261

cal Dictionary,

defines “culture” as “propagation of ... living tissue cells in special media conducive to their growth.” Amgen’s App. to Mem. in Opp’n re ’698 & ’849, Tab R

(Borland’s Illustrated Med. Dictionary

(27th ed.1988)), at 384; see,

e.g., Masco,

303 F.3d at 1328 (relying on a standard mechanical engineering dictionary definition of “transmitting” to help determine whether it is an act). The

American Heritage Dictionary

describes the verb culturing to mean “to cultivate” or “to develop (microorganisms or tissues, for example) in a culture medium.”

The American Heritage Dictionary, supra,

at 348;

see, e.g., Masco,

303 F.3d at 1328 (relying on standard unabridged dictionary definition of “transmitting” to help determine whether it is an act);

Vitronics,

90 F.3d at 1584 . None of these definitions contradicts what is described in the patent.

In sum, HMR/TKT has failed to show that the “limitation contains nothing that can be construed as an act.”

Sealr-Flex,

172 F.3d at 850 . On the contrary, “culturing” — that is, developing cells in a certain medium — can logically be construed as an act because it describes

how

the EPO is produced (i.e., by culturing the cells), and because “culturing” is itself a term well understood by those skilled in the art.

As a final matter, the Court notes the same concerns it had with construing “growing” as a step-plus-function limitation. If the Court were to construe “culturing” as a step-plus-function limitation, it would run the risk of interpreting the process claim of the ’349 patent in a way that Congress never intended, rendering the scope of coverage of the patent uncertain and disrupting the patentee’s settled expectations regarding the scope of the claims.

Masco,

303 F.3d at 1328 ;

O.I. Corp.,

115 F.3d at 1583 .

5. Conclusion and Claim Construction

Accordingly, the Court rules that claim 7 of the ’349 patent does not contain a step-plus-function limitation and that the regular framework for assessing infringement therefore applies.

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IV. VALIDITY CHALLENGES UNDER 35 U.S.C. § 112

When claims are construed broadly, alleged infringers commonly challenge validity under 35 U.S.C. § 112 , ¶¶ 1, 2 in light of the broad construction.

Amgen II,

314 F.3d at 1330 . This is exactly what HMR/ TKT does here. It argues that certain of Amgen’s claims are now invalid because of how broadly the Court construed them. Because these validity challenges relate directly to this Court’s claim construction and claims are construed the same way for both invalidity and infringement,

see, e.g., W.L. Gore & Assocs., Inc., v. Garlock, Inc.,

842 F.2d 1275, 1279, 1280 (Fed.Cir.1988), this Court now addresses the relevant section 112 issues before turning to the infringement issues.

See Amgen II,

314 F.3d at 1330 (addressing section 112 issues before infringement for the same reasons).

As with any validity challenge, the Court begins by presuming that the patents are valid.

Amgen II,

314 F.3d at 1335 ; 35 U.S.C. § 282 (2000).

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As a result, HMR/TKT bears the burden of going

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forward and a “heavy burden” of persuasion, one that requires proof by clear and convincing evidence.

Amgen II,

314 F.3d at 1335 . 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. Definiteness

1. The ’698 and ’349 Patent

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a. Discussion

Paragraph 2 of section 112 requires that a patent specification include one or more claims “particularly pointing out and distinctly claiming subject matter which the applicant regards as his invention.” 35 U.S.C. § 112 , ¶ 2 (2000). The Federal Circuit has stated that the standard for determining whether a claim is sufficiently definite is “[i]f one skilled in the art would understand the bounds of the claim when read in light of the specification.”

Exxon Research and Eng’g Co. v. United States,

265 F.3d 1371, 1375 (Fed.Cir.2001);

Union Pac. Res. Co. v. Chesapeake Energy Corp.,

236 F.3d 684 , 692 (Fed.Cir.2001) (“The definiteness inquiry focuses on whether those skilled in the art would understand the scope of the claim when the claim is read in light of the rest of the specification.”). Although the definiteness requirement is meant to protect public notice of the scope of the patentee’s right to exclude,

Honeywell Int’l, Inc. v. Int’l Trade Comm’n,

341 F.3d 1332, 1338-39 (Fed.Cir.2003), the Federal Circuit has made clear that the standard for indefiniteness is rather high. A claim is not indefinite merely because its scope is not ascertainable from its face. Instead, it is indefinite if it is “insolubly ambiguous and no narrowing construction can be properly adopted.”

Amgen II,

314 F.3d at 1342 ;

Honeywell,

341 F.3d at 1338-39 ;

Amgen Inc. v. Chugai Pharm. Co.,

927 F.2d 1200, 1218 (Fed.Cir.1991);

Standard Oil Co. v. Am. Cyanamid Co.,

774 F.2d 448, 453 (Fed.Cir.1985).

HMR/TKT argues that under the Court’s construction of “DNA encoding” the asserted claims of the ’698 patent and claim 7 of the ’349 patent are invalid as indefinite because they include within their scope many embodiments that will not make EPO. HMR/TKT’s Opening Br. After Trial [Doc. No. 808] at 47-48. Specifically, it argues that the Court’s construction of the term requires only that the DNA provide the requisite letters or co-dons, regardless of what protein is actually made, and that the evidence demonstrates that while many cells contain the same DNA codons, only those in which certain particular DNA codons are contiguous will actually produce EPO. Further, it asserts that Amgen has changed its stance and now claims that “genetic instructions for” includes not only the codons but also the splicing instructions for putting those co-dons together in the correct order.

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The claims, it asserts, say nothing about splicing instructions or messages and, as such, are indefinite and inoperative.

*263

Amgen responds primarily by arguing that the evidence demonstrates that skilled artisans using the teachings of Amgen’s patents would have been able to produce EPO using cells comprising non-contiguous DNA encoding the “mature erythro-poietin amino acid sequence of FIG. 6.” Amgen’s Reply to HMR/TKT’s Opening Br. After Trial [Doc. No. 815] at 33-34.

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Further, it claims that this very evidence establishes that those skilled in the art would have known how to determine which processes fell within the ’698 and ’349 claims.

The primary dispute, then, is whether the specification teaches skilled artisans to splice the codons into the correct order when the codons are not contiguous but need to be in order to make EPO. If it does, then the claims are not indefinite as they do not cover embodiments that do not make EPO.

While it may be true, as Dr. Kingston originally stated, that “only those cells in which the DNA letters were contiguous would actually produce EPO,” Kingston Test., R. Trial Tr. at 56-60, 164: 2-7, Dr. Kingston admitted that the cells from Example 10 of Amgen’s specification produce EPO even though the Figure 6 codons for the mature erythropoietin sequence in the Example 10 cells are not contiguous.

Id.

at 164: 8-22; 170: 4-10. Either Dr. Kingston was blatantly contradicting his original statement, or — as the Court concludes is more likely — Example 10 and Figure 6 communicate to Dr. Kingston, one skilled in the art, how non-contiguous codons can be manipulated to produce EPO. This belies HMR/TKT’s argument that the claims are vague or indefinite for not including splicing instructions and for covering contiguous and noncontiguous codons because the specification provides the information that Dr. Kingston believed was missing from the claims.

This deduction — that the specification makes the term “DNA encoding” understandable to the skilled artisan,

Exxon Research and Engineering Co.,

265 F.3d at 1375 ;

Union Pacific Resources Co.,

236 F.3d at 692 — is supported by expert testimony from Dr. Lodish and by other testimony from Dr. Kingston.

According to Dr. Lodish, Dr. Lin’s patent taught those skilled in the art in 1983 to produce DNA sequences encoding EPO that are either contiguous

or noncontiguous.

Lodish Test., R. Trial Tr. at 1061: 4-1063: 4. In other words, Dr. Lodish testified that those skilled in the art would not

*264

consider the phrase “DNA encoding” to require the presence of contiguous codons of the mature EPO sequence of Figure 6. The main support for this contention stems from the fact that the codons were non-contiguous in Figure 6 of the patent. As mentioned earlier in the claim construction portion of this memorandum and order, Dr. Lodish testified that those of ordinary skill in the art at the time would have understood the disputed term to mean “a DNA which when copied into RNA, and

if necessary

spliced, specifies the order of amino acids that are the mature erythro-poietin amino-acid sequence depicted in Figure 6 of the patent.” Lodish Test., R. Trial Tr. at 1054: 17-22 (emphasis added);

id.

at 1058: 10-1059: 3. He explained that Figure 6 disclosed to those skilled in the art the codons for the mature EPO amino acid sequence, the introns, exons, and splice donor and acceptor sites of the human genomic EPO sequence.

Id.

Indeed, Dr. Kingston admitted that Lin’s specification discloses the EPO gene sequence, the EPO splice donor and acceptor sites, and the linkage of a non-human promoter with the EPO gene. Kingston Test., R. Trial Tr. 116: 23-117: 2. According to Dr. Lodish (and not directly disputed by Dr. Kingston), this information, along with what was known in the art, enabled skilled artisans to alter the codons, to alter or eliminate the introns, and to make many DNA sequences that would encode human EPO and work in the claimed processes.

Id.

Thus, contrary to HMR/TKT’s assertions, expert testimony from both sides shows that those skilled in the art would understand the claims to cover contiguous and non-contiguous DNA sequences that when necessary could be spliced into a correct and contiguous order to produce EPO.

Union Pacific Resources Co.,

236 F.3d at 692 (“The definiteness inquiry focuses on whether those skilled in the art would understand the scope of the claim when the claim is read in light of the rest of the specification.”).

b. Conclusion

HMR/TKT has failed to establish by clear and convincing evidence that “DNA encoding” is a vague, ambiguous, or undefined term not understandable to a skilled artisan when read in light of the specification. Accordingly, the Court rejects HMR/TKT’s argument that the disputed claims of the ’349 and ’698 patent are indefinite.

B. Written Description

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1. The ’698 and ’349 Patents

a. Discussion

The basic requirements for the content of a patent specification are found in 35 U.S.C. § 112 , ¶ 1:

The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains ... to make and use the same ....

35 U.S.C. § 112 , ¶ 1 (2000). “The purpose of this provision is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.”

Reiffin v. Microsoft Corp.,

214 F.3d 1342 ,

*265

1345 (Fed.Cir.2000). Therefore, the specification must communicate clearly to those skilled in the art that the inventor invented what is claimed.

In re Gosteli

872 F.2d 1008, 1012 (Fed.Cir.1989). Specifically, the disclosure as originally filed must explicitly or inherently convey to the skilled artisan that the inventor had possession at that time of the later claimed subject matter.

Reiffin,

214 F.3d at 1346 ;

In re Kaslow,

707 F.2d 1366, 1375 (Fed. Cir.1983);

see generally

Guang Ming Whitley,

A Patent Doctrine without Bounds: The “Extended” Written Description Requirement,

71 U. Chi. L.Rev. 617 (2004). Compliance, however, is to be judged as of the date the application is filed.

United States Steel Corp. v. Phillips Petroleum Co.,

865 F.2d 1247, 1251 (Fed.Cir.1989);

Application of Roller,

613 F.2d 819, 824 , 204 U.S.P.Q. 702 (1980). Thus, the critical inquiry is whether the specification clearly communicated to those skilled in the art what was claimed based on what was known in the art at the time of the filing — in this case, 1983-84. Only if the claims would have been, at the time of filing, correctly rejected for inadequate support will a court find that the claims are now invalid for lack of support.

See Roller,

613 F.2d at 824 .

HMR/TKT contends that Amgen’s claims, as construed by the Court, have a scope far greater than the written description of Amgen’s patents and are, therefore, invalid. HMR/TKT’s Opening Br. After Trial at 47-48. Primarily, it makes two arguments in support of this contention. First, HMR/TKT argues that the specification “repeatedly describes [the] DNA, cells, processes and proteins in terms of

only

exogenous DNA and heterologous recombination,” whereas the Court construed the asserted claims in the ’698 and ’349 patents to cover both exogenous and endogenous DNA and homologuous and heterologous recombination.

75

HMR/TKT’s Opening Br. After Trial at 47-48. Second, HMR/TKT points to the undisputed fact that the specification provides only an example of a process which places the promoter just upstream of the ATG initiation codon of a cloned and isolated EPO gene, although the Court construed “operatively linked,” as found in the ’698 patent,

76

to cover placement much farther upstream.

Id.

77

As such, HMR/ TKT argues, the asserted process claims of the ’698 patent fail to provide adequate written description.

Id.

(1) HMR/TKT’s First Argument: Endogenous DNA and Homologous Recombination

Although HMR/TKT’s first argument is, in part, factually correct — the specification explicitly discloses only exogenous EPO DNA expression systems and heterologous recombination techniques

78

— it is misdirected. The section

*266

112 inquiry focuses on what was known by those skilled in the art at the time of the filing of the application. Here, it is undisputed that in 1983-84 (the time period of the application filing date), endogenous activation technology and homologous recombination were not known to skilled artisans. HMR/TKT’s Findings of Fact ¶ 488; Amgen’s Reply to HMR/TKT’s Opening Br. After Trial at 34-35.

79

Therefore, this technology is irrelevant to the written description analysis, and for good reason. “If later states of the art could be employed as a basis for rejection under 35 U.S.C. § 112 , the opportunity for obtaining a basic patent upon early disclosure of pioneer inventions would be abolished.”

Application of Hogan,

559 F.2d 595, 606 , 194 U.S.P.Q. 527 (1977);

see also Koller,

613 F.2d at 825 (same).

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HMR/TKT incorrectly assumes that the Court’s construction of Amgen’s claims to cover this later developed technology changes the analysis.

Application of Koller,

a case similar to this one, shows the fallacy of HMR/TKT’s assumption. In that case, the Federal Circuit upheld a broad construction of the term “liquid medium” that covered all solvents (including the later developed water-immiscible solvents) despite a specification that only described water and water-miscible solvents — and not water-immiscible solvents. It reversed, however, the decision of the United States Patent and Trademark Office Board of Appeals that had found,

inter alia,

that the claims failed to provide adequate description. The Federal Circuit conducted its section 112 analysis based on what was claimed and known at the time of the application filing date. Because water-immiscible solvents were not known at the time of the application filing date, the Federal Circuit found that the term “liquid medium” was adequately described.

Koller,

613 F.2d at 823-25 .

Here, the situation is very similar. Because homologous recombination and use of endogenous DNA were not known to those skilled in the art at the time of the application, HMR/TKT’s first argument

*267

for inadequate written description fails. As the Federal Circuit explained in

Application of Hogan ,

“the Courts have consistently considered subsequently existing states of the art as raising questions of infringement but never of validity.”

Hogan,

559 F.2d at 607 (noting that the PTO’s concern that allowance of the claims might lead to enforcement efforts against later developers is “both irrelevant and unwarranted” because “[t]he business of the PTO is patentability, not infringement”);

United States Steel Corp.,

865 F.2d at 1251 (stating that the fact that “claim[s] may cover a later version of the claimed [invention] relates to infringement not to patentability”).

HMR/TKT’s arguments are more properly reserved for invoking the judicially developed reverse doctrine of equivalents defense which allows interpretation of the claims in light of the specification,

inter alia,

and precludes improper enforcement against later developers.

Hogan,

559 F.2d at 607 . This argument alone fails to establish this defense. Because this is the only argument presented with respect to the sufficiency of the written description of claim 7 of the ’349 patent, the Court holds that HMR/TKT has failed to meet its burden with respect to this defense.

(2) HMR/TKT’s Second Argument: Placement of the Promoter

HMR/TKT’s second argument and Amgen’s response thereto, as they relate to the ’698 patent, render determination of the written description a bit more squirrelly. As stated above, HMR/TKT correctly argues that the specification only describes insertion of the promoter just upstream of the ATG initiation codon of the EPO gene to be expressed while the Court construed the claims to cover HMR/ TKT’s process of inserting the promoter far upstream leaving multiple ATGs between the promoter and the gene to be expressed.

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Instead of counter-arguing, as it did in response to HMR/TKT’s first argument, that HMR/TKT’s placement technique was a post-filing advance which need not be described, Amgen contends that by 1984, artisans of ordinary skill could have placed a promoter DNA in such a position that multiple ATGs would exist between it and the gene to be expressed, and they knew how to express proteins in vertebrate cells by positioning a promoter upstream of exon coding sequences and removing unwanted DNA by manipulating splice sites. Amgen’s Reply to HMR/ TKT’s Opening Br. After Trial at 34-35; Amgen’s Reply to HMR/TKT’s Findings of Fact ¶ 67. Further, Amgen asserts, evidence shows that those of skill in the art would have understood the patent to describe operative linkages of far greater distances than 44 pairs and that skilled artisans would have understood from Lin’s patent how to avoid potentially interfering ATG sequences and thereby successfully position the promoter further upstream of DNA encoding EPO.

Id.

¶ 68, ¶ 342.

82

*268

This argument is curious because the easier path would have been to argue that placement so far upstream was a post-filing advance. Indeed, the Court’s factual findings in

Amgen I

would have supported such an argument.

See, e.g., Amgen I,

126 F.Supp.2d at 160 (concluding that placing the promoter farther upstream works to make HMR/TKT’s process more “technologically advanced” than that in Amgen’s patent and commenting that there was no evidence implying that “one of ordinary skill in the art would dare to place a promoter sequence in such a position that multiple ATGs would exist between it and the gene to be expressed”). Such an argument, however, would have weakened Am-gen’s position with respect to the reverse doctrine of equivalents. In other words, urging that this technique was a post-filing advance would work against Amgen’s argument that HMR/TKT’s product and process is not so far changed in principal that the Court ought find that it does not infringe under the reverse doctrine of equivalents.

Stuck in a similar catch-22, HMR/TKT argues with respect to section 112 that Amgen should have described upstream placement of the promoter, yet, in furtherance of its reverse doctrine of equivalents argument, HMR/TKT argues with equal passion that a process for producing EPO by linking the promoter and transcription control sequences far upstream of the EPO gene had never been done before HMR/TKT developed its patented gene activation process. HMR/TKT’s Reply Br. After Trial [Doc. No. 819] at 29, 34. Further, it argues that those skilled in the art recognized that promoter linkages further upstream of the initiation codon would

not

work to produce EPO. HMR/TKT’s Findings of Fact ¶493. Thus, HMR/TKT’s reverse doctrine of equivalents argument belies its argument that Amgen should have described placement of the promoter further upstream of the EPO gene to be expressed since, according to HMR/TKT, this had never been done before. Thus, both parties, to a degree, have argued against their best interests on this issue because to do otherwise would weaken their positions with respect to application of the reverse doctrine of equivalents.

However the parties may frame the issue, this Court, as trier of fact in this case, must determine whether placing the promoter farther upstream was a concept sufficiently known to those skilled in the art at the time of filing such that the claims would have been understood to encompass such a technique.

United States Steel Corp.,

865 F.2d at 1251 (“ ‘[L]engage in a specification is to be understood for what it meant to one having ordinary skill in the art at the time the application was filed’ ... and ... support need be found for only the claimed invention, in view of how one skilled in the art at that time would construe the claims and would read its specification.” (quoting

Koller,

613 F.2d at 824 ) (internal citation omitted));

United States Steel Corp.,

865 F.2d at 1252 (considering the state of the art in 1983-84, the level of sufficiency and the condition of knowledge about all art-related facts at the time of filing

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