Plaintiff-Cross Appellant Amgen Inc. ("Amgen") is the owner of numerous patents directed to the production of erythropoietin ("EPO"), a naturally occurring hormone that controls the formation of red blood cells in bone marrow. Amgen markets and sells EPOGEN®, a highly successful commercial embodiment of the patented erythropoietin. Seeking to impede defendants-appellants Hoechst Marion Roussel, Inc. and Transkaryotic Therapies, Inc. (collectively "TKT") from commercializing a competitive EPO product, Amgen filed a declaratory judgment action in the United States District Court for the District of Massachusetts in April 1997, alleging that TKT's Investigational New Drug Application ("INDA") infringed United States Patent Nos. 5,547,933 ("the '933 patent"); 5,618,698 ("the '698 patent"); and 5,621,080 ("the '080 patent"). The complaint was amended in October 1999 to include United States Patent Nos. 5,756,349 ("the '349 patent") and 5,955,422 ("the '422 patent"), which issued after suit was filed.

After a three-day Markman hearing, the case was tried to the court for 23 days over the course of four months. In January 2001, the district court issued an exhaustive 244-page opinion in which it: (i) construed the disputed claims; (ii) held each of the patents enforceable; (iii) held the '080, '349 (product claims), and '422 patents valid and infringed; (iv) held the '698 patent not infringed; and (v) held the '933 patent not infringed or, in the alternative, invalid for failure to satisfy 35 U.S.C. § 112. Amgen, Inc. v. Hoechst Marion Roussel, Inc., 126 F.Supp.2d 69, 57 USPQ2d 1449 (D.Mass.2001). On appeal, TKT urges reversal on the grounds that the patents in suit are all unenforceable, that the district court's claim construction was erroneous, and alternatively, if that claim construction was correct, that the court's validity determinations were erroneous. Amgen asserts, in its cross appeal, that the district court committed error: (i) by comparing the accused process to the examples in the specification rather than the limitations of the method claims of the '349 and '698 patents; and (ii) by holding the '933 patent invalid for failure to comply with § 112. We heard oral argument on May 7, 2002.

We commend the district court for its thorough, careful, and precise work on what is indubitably a legally difficult and technologically complex case. There is no doubt that the court marshaled tremendous time and resources in its effort to reach correct results. Nevertheless, because we must conclude that the court committed certain errors of law in certain of its validity and infringement determinations, we cannot affirm the judgment in its entirety.

We affirm in toto the district court's claim construction. We also affirm: (i) its determination that none of the patents in suit is unenforceable for inequitable conduct; (ii) its contingent determination that the '933 patent is invalid under § 112 ¶ 1; (iii) its grant of summary judgment of infringement of '422 patent claim 1; (iv) its determination that the '080, '933, '349, and '698 patents are not anticipated by the Sugimoto reference; and (v) its determination that '349 patent claims 1, 3-4, and 6 are infringed. Because the district court misapplied the law, however, we vacate: (i) its determination that the '933 patent is not infringed; (ii) its determination that the '080 patent is infringed under the doctrine of equivalents; (iii) its determination that the '080, '349, and '422 patents are not invalid; and (iv) its determination that the asserted method claims of the '698 patent and '349 patent claim 7 are not infringed. Accordingly, we remand for the district court to reconsider: (i) whether the '080, '349, and '422 patents are obvious in light of the Sugimoto prior art or anticipated or obvious in light of the Goldwasser prior art; (ii) whether the '422 patent is anticipated by Sugimoto reference (and whether Amgen can prove its nonenablement); (iii) whether the asserted claims of the '698 patent and '349 patent claim 7 are infringed by the accused method; and (iii) whether the '080 patent is infringed under the doctrine of equivalents. In sum, as further explained in detail below, we affirm in part, vacate in part, and remand for further proceedings consistent herewith.

As the district court set out in painstaking detail the basics of the underlying technology, we will provide only a brief summary here. The reader's familiarity with the fundamentals of molecular biology, genetics, and recombinant DNA technology necessary to this appeal is presumed.1

EPO is a naturally occurring protein that initiates and controls erythropoiesis, the production of red blood cells in bone marrow. Red blood cells are critical because they contain hemoglobin, a protein responsible for transporting oxygen from the lungs to peripheral tissues. Because EPO is produced in the kidney, patients with chronic kidney (renal) failure lack normal levels of EPO and, as a result, have a sub-optimal number of red blood cells — a condition called anemia. The therapeutic goal for treating anemic patients is to increase the "hematocrit level," which represents the ratio of red blood cells to total blood volume, to normal or near-normal levels. This is accomplished through the introduction of additional EPO into the patient's system.

The implementation of this seemingly simple solution, introduction of exogenous EPO, proved to be difficult. Because human EPO is produced in very small amounts (even from the healthy human kidney), it is difficult to obtain by conventional methods. Early attempts to recover EPO from plasma or from human urine ("urinary EPO" or "uEPO") were unsuccessful because such recovery employed techniques that were complicated, yet still resulted in a low-yield, high-impurity, or unstable EPO end product. '933 patent, col. 6, line 60 — col. 7, line 42. Similar attempts using antibody techniques failed because of difficulty in providing for the large-scale isolation of quantities of EPO from mammalian sources sufficient for further analysis, clinical testing, or therapeutic use. Id., col. 9, lines 2-8. The first successful method of production of a therapeutically effective amount of erythropoietin used recombinant EPO ("rEPO") techniques; Amgen is recognized as the pioneer. See, e.g., Molecular Biology and Biotechnology at 108.

Amgen scientist Dr. Fu-Kuen Lin is the named inventor on all five patents in suit. Instead of attempting to purify EPO from natural sources, Lin isolated and characterized monkey and human EPO genes, then used conventional recombinant DNA technology to produce large amounts of rEPO. '933 patent, col. 13, lines 50-53. Lin was able to determine the entire DNA sequence of human EPO and from that, its predicted amino acid sequence. Id., Fig. 6; col. 10, lines 65 — col. 11, line 2. Using the isolated human EPO gene, Lin described several methods for producing therapeutically effective amounts of human EPO using an expression vector.2 Id., col. 21, line 42—col. 25, line 27.

EPOGEN®, the commercial embodiment of Amgen's patented EPO product, is produced by the method disclosed in patent specification Example 10. That example describes the production of human EPO through transfection (introduction) of exogenous DNA into host Chinese hamster ovary ("CHO") cells. The CHO host cell, using its own transcription machinery, then expresses human rEPO in abundance, which then accumulates in the host cell cytoplasm or in the culture media. Id., col. 37, lines 43-49. The rEPO so recovered has the same or similar amino acid sequences and biological properties as naturally occurring human EPO, but differs in its "glycosylation," i.e., in the patterns of branched carbohydrate chains that attach to the protein. '933 patent, col. 10, lines 34-41.

The patents in suit, which all claim priority to a December 1983 application long since abandoned, are continuations of a common ancestor — United States Patent No. 4,703,008 — which was at issue in this court's landmark decision in Amgen, Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed.Cir.1991).3 The '933 patent issued on August 20, 1996, containing 14 claims drawn primarily to a non-naturally occurring EPO product with certain characteristics. At issue in this lawsuit are claims 1, 2, and 9 (with the disputed claim terms here and below underscored):

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

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

9. A pharmaceutical composition comprising an effective amount of a glycoprotein product effective for erythropoietin therapy according to claim 1, 2, 3, 4, 5, or 6 and a pharmaceutically acceptable diluent, adjuvant or carrier.

The '698 patent issued on April 8, 1997, containing nine claims drawn to a process for producing a glycosylated erythropoietin polypeptide. At issue are claims 4-9:

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

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

b) isolating said glycosylated erythropoietin polypeptide expressed by said cells

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

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

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

b) isolating said glycosylated erythropoietin polypeptide expressed by said cells.

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

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

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

The '080 patent, which issued with seven claims on April 15, 1997, claims both an isolated erythropoietin glycoprotein and a method for therapeutically administering a pharmaceutical composition thereof. Only product claims 2-4 are at issue:

2. An isolated erythropoietin glycoprotein having the in vivo biological activity of causing bone marrow cells to increase production of reticulocytes 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.

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

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

The '349 patent, which issued on May 26, 1998, contains one method claim and six product claims that are drawn generally to types of vertebrate cells grown in culture. At issue are claims 1, 3-4, and 6-7:

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 erythropoietin per 106 cells in 48 hours as determined by radioimmunoassay, said cells comprising non-human DNA sequences that control transcription of DNA encoding human erythropoietin.

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

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

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

7. 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.

Last, the '422 patent, containing two claims directed to therapeutically effective pharmaceutical compositions of EPO, was granted on September 21, 1999. Only claim 1 is in dispute:

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

The district court conducted the Markman hearing in late March and early April 2000 in advance of Amgen's motion for summary judgment of infringement. The court entertained oral argument, aided by demonstrative exhibits, but heard no witness testimony and received no evidence. Amgen, 126 F.Supp.2d at 81, 57 USPQ2d at 1455. At the close of the hearing, the court announced its claim constructions from the bench; these oral rulings were included and expounded upon in the written opinion ruling on the merits following trial. Id. at 84-94, 57 USPQ2d at 1457-64.

Immediately following the Markman hearing, the court turned to Amgen's pending motion for summary judgment of infringement of '422 patent claim 1 and '349 patent claims 1, 3-4, and 6. As to the '422 patent, the district court found: (1) that it was uncontradicted that the accused product, HMR4396, was a pharmaceutical composition; (2) that it necessarily contained a therapeutically effective amount of human erythropoietin (otherwise, the filing of an INDA would be pointless); and (3) that the record evidence demonstrated that HMR4396 contained a pharmaceutically acceptable diluent, adjuvant, or carrier as claimed in claim 1. Id. at 94-95, 57 USPQ2d at 1455-56. The sole remaining question was whether the accused erythropoietin product had been "purified from mammalian cells grown in culture." The court found, in light of its claim construction that the term "mammalian" comprises human cells, that the last limitation had been met. Id. at 95-96, 57 USPQ2d at 1466. The court therefore granted summary judgment of infringement of '422 patent claim 1.

Trial commenced on May 15, 2000. When Amgen rested at the close of its infringement case, the court granted TKT's motions for judgment of non-infringement of the '698 patent and literal non-infringement of the '080 patent. Id. at 99-104, 57 USPQ2d at 1469-73. At the close of TKT's rebuttal case, the court granted Amgen's motion for judgment of validity, finding that TKT had not carried its burden of clearly and convincingly proving anticipation or obviousness. Id. at 104-17, 57 USPQ2d at 1473-82. The remaining issues were taken under advisement. The court's opinion issued on January 19, 2001, and these timely cross-appeals followed. Vested with jurisdiction under 28 U.S.C. § 1295(a)(1), we address below the myriad issues before us.

* The rules are by now well known. Because claim language defines claim scope, the first step in an infringement analysis is to construe the claims, i.e., to determine the scope and meaning of that which is allegedly infringed. Markman v. Westview Instr., Inc., 52 F.3d 967, 976, 34 USPQ2d 1321, 1326 (Fed.Cir.1995), aff'd, 517 U.S. 370, 116 S.Ct. 1384, 134 L.Ed.2d 577, 38 USPQ2d 1461 (1996). 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, 39 USPQ2d 1573, 1576-77 (Fed.Cir.1996). Thereafter, the properly construed claims are compared to the accused product or process to determine whether each of the claim limitations is met, either literally or equivalently. CCS Fitness, Inc. v. Brunswick Corp., 288 F.3d 1359, 1365, 62 USPQ2d 1658, 1662 (Fed. Cir.2002).

There are two general areas of dispute TKT raises regarding the district court's claim construction. First, TKT urges that the court erred by failing to limit the asserted claims to exogenous DNA, despite the fact that none of the claims in suit contain an "exogenous DNA" limitation. Second, TKT asserts that the court erred by refusing to limit the terms "vertebrate," "mammalian," and "non-naturally occurring" — each of which appear in varying degrees within the asserted claims — such that they exclude host human cells which, of course, are used by the accused infringers. We consider the trial court's claim construction — a matter of law — afresh on appellate review. See Cybor Corp. v. FAS Techs., Inc., 138 F.3d 1448, 1455, 46 USPQ2d 1169, 1173 (Fed.Cir.1998) (en banc).

* We turn first to address a threshold definitional dispute that carries with it important consequences for the infringement issues decided by the district court and facing us on appeal, to wit, what is the distinction between exogenous, as opposed to endogenous, DNA in recombinant DNA parlance? According to TKT, it practices an innovative process using homologous recombination: it takes the ordinarily unexpressed endogenous (or "native") EPO gene in human cells and transfects "a viral promoter and certain other DNA" that does not encode EPO. That "other" DNA is inserted into the chromosome at a pre-determined, targeted location upstream from the endogenous EPO gene to produce what TKT has termed "Gene-Activated EPO," or "GA-EPO." TKT contrasts this method with that of Amgen, which TKT asserts undeniably uses exogenous DNA.

None of the asserted claims contain either an "exogenous DNA" or "endogenous DNA" limitation.4 Based upon representations allegedly made by Amgen during the prosecution of the patents in suit, however, TKT argues that many of the claims the district court construed should have been defined narrowly to include only exogenous DNA. The district court rejected this argument, as do we.

"It is the claims that measure the invention." SRI Int'l v. Matsushita Elec. Corp., 775 F.2d 1107, 1121, 227 USPQ 577, 585 (Fed.Cir.1985) (en banc). Because the claims are best understood in light of the specification of which they are a part, however, courts must take extreme care when ascertaining the proper scope of the claims, lest they simultaneously import into the claims limitations that were unintended by the patentee. See, e.g., Hoganas AB v. Dresser Indus., Inc., 9 F.3d 948, 950, 28 USPQ2d 1936, 1938 (Fed.Cir.1993) ("It is improper for a court to add extraneous limitations to a claim, that is limitations added wholly apart from any need to interpret what the patentee meant by particular words or phrases in the claim." (citation omitted)). The danger of improperly importing a limitation is even greater when the purported limitation is based upon a term not appearing in the claim. "If we once begin to include elements not mentioned in the claim in order to limit such claim ..., we should never know where to stop." Johnson Worldwide Assocs., Inc. v. Zebco Corp., 175 F.3d 985, 990, 50 USPQ2d 1607, 1610 (Fed.Cir.1999) (quoting McCarty v. Lehigh Val. R.R., 160 U.S. 110, 116, 16 S.Ct. 240, 40 L.Ed. 358 (1895)).

Amgen's inventive EPO product, according to the disclosure in the '933 patent, is "uniquely characterized by being the product of prokaryotic or eucaryotic host expression (e.g., by bacteria, yeast and mammalian cells in culture) of exogenous DNA sequences obtained by genomic or cDNA cloning or by gene synthesis." '933 patent, col. 10, lines 15-20. In discussing United States Patent No. 4,237,224 (issued to Cohen), the '933 patent defines "exogenous DNA" by reference as DNA that is foreign to the host organism. See id. col. 2, lines 41-47 ("[T]he Cohen et al. patent first involve[s] manufacture of a transformation vector by enzymatically cleaving viral or circular plasmid DNA to form linear DNA strands. Selected foreign (`exogenous' or `heterologous') DNA strands usually including sequences coding for desired product are prepared in linear form through use of similar enzymes."). During the prosecution of Serial No. XX-XXX-XXX, which became the '349 patent, the examiner commented that the application "teaches and enables only cells that have been transformed with exogenous DNA that encodes erythropoietin (EPO) that have the high EPO production required by the claims." TKT asserts, as a result, that its GA-EPO product and process fall outside the scope of the asserted claims because Amgen repeatedly has characterized its claimed products and processes as requiring the use of exogenous EPO DNA, and hence the claims should be limited thereto.

Guided by our principles of claim construction, we agree with the district court that TKT improperly seeks to import the "exogenous" limitation into the claims. The plain meaning of the claims controls here, and they plainly are not so limited. The statement that the invention is "uniquely characterized" by the expression of exogenous DNA sequences does not impel us to accept TKT's position when the asserted claims do not contain such an express limitation. In fact, TKT's position is undermined by the doctrine of claim differentiation, as reference to other claims clearly indicates that Amgen did not intend to limit the invention to the use of exogenous DNA. Unasserted claim 3 of the '933 patent, for example, is virtually identical to claim 1, save for the express limitation regarding the use of "exogenous DNA" (underlined portioned indicating differences).

        Claim 1                                  Claim 3
        
          A non-naturally occurring                A non-naturally occurring
          erythropoietin glycoprotein product      glycoprotein product of the
          having the in vivo biological activity   expression in a mammalian host
          of causing bone marrow cells to          cells of an exogenous DNA
          increase production of reticulocytes     sequence comprising a DNA
          and red blood cells and having           sequence encoding human
          glycosylation which differs from that    erythropoietin said product
          of human urinary erythropoietin.         possessing the in vivo biological
                                                   activity of causing bone marrow
                                                   cells to increase production of
                                                   reticulocytes and red blood cells
                                                   and having glycosylation which
                                                   differs from that of human urinary
                                                   erythropoietin.

Our court has made clear that when a patent claim "does not contain a certain limitation and another claim does, that limitation cannot be read into the former claim in determining either validity or infringement." SRI Int'l, 775 F.2d at 1122, 227 USPQ at 586; see also O.I. Corp. v. Tekmar Co., Inc., 115 F.3d 1576, 1582, 42 USPQ2d 1777, 1781 (Fed.Cir.1997) (expressing the notion that there are practical limits to the doctrine of claim differentiation: "the doctrine cannot alter a definition that is otherwise clear from the claim language, description, and prosecution history."). There is a rebuttable presumption that different claims are of different scope. See Kraft Foods, Inc. v. Int'l Trading Co., 203 F.3d 1362, 1366-67, 53 USPQ2d 1814, 1817 (Fed.Cir.2000); Multiform Desiccants, Inc. v. Medzam, Ltd., 133 F.3d 1473, 1479-80, 45 USPQ2d 1429, 1434 (Fed.Cir.1998).

The examiner's statement in the prosecution history gives us no pause, as the basis for his rejection was not because transformation with exogenous DNA was not taught, but because "the high EPO production required by the claims" was not. See J.A. at 1302 ("The instant application does not guide one of ordinary skill in the art in the discovery of non-transformed vertebrate cells that are capable of the high EPO production recited in the instant claims, [as demonstrated in the reference,] each of which discloses levels of EPO production by vertebrate cells in culture that are far below those levels required in the instant claims."). TKT's position is further undermined because the asserted claims issued. We must presume the examiner did his job, and if he truly thought that the specification taught or enabled only the use of exogenous DNA, the asserted claims would not have issued.

In the end, TKT has not directed our attention to anything in the intrinsic record that rebuts the presumption that the plain meaning of the terms controls. Accordingly, we conclude that the scope of the asserted claims should not be limited to the expression of exogenous DNA.

TKT asserts, in addition to the exogenous/endogenous distinction discussed above, that the district court misconstrued the terms "non-naturally occurring," "vertebrate cells," and "mammalian cells" — which appear in many of the asserted claims — to include human cells. Reviving the same argument the district court rejected below, TKT contends Amgen expressly disavowed the use of human cells to make human EPO.

The district court found that the definition of the term "non-naturally occurring" can be discerned through the doctrine of claim differentiation. Specifically, the court concluded that TKT's proffered construction must fail in light of '933 patent claim 3, discussed previously, which claims a "non-naturally occurring glycoprotein product of the expression in a mammalian host cell of an exogenous DNA sequence encoding human erythropoietin...." By its terms, then, this claim would cover the expression of human DNA in a cat host cell, for example, because a cat is a mammal. The court thus concluded that the phrase "non-naturally occurring" would be redundant in claim 3 if the phrase had the meaning TKT sought to ascribe to it. Further, because the patent specification compares the biological activity of synthetic products to "EPO isolates from natural sources" or "natural EPO isolates," the court concluded that non-naturally occurring simply means "not occurring in nature." Amgen, 126 F.Supp.2d at 90-91, 57 USPQ2d at 1462-63.

Similarly, finding that the term vertebrate is widely known and understood to cover anything with "a segmented bony or cartilaginous spinal cord [which obviously includes humans]," id. at 85, 57 USPQ2d at 1457-58, the court adopted Amgen's proposed construction. The court also adopted Amgen's proposed construction of the term "mammalian cells" appearing in '422 patent claim 1 and '698 patent claim 9 under a similar rationale. Id. at 84-86, 57 USPQ2d at 1458.

We indulge a heavy presumption that a claim term carries its ordinary and customary meaning. CCS Fitness, 288 F.3d at 1366, 62 USPQ2d at 1662; see also Gart v. Logitech, Inc., 254 F.3d 1334, 1341, 59 USPQ2d 1290, 1295 (Fed.Cir.2001). Although TKT is correct that the prosecution history is always relevant to claim construction, it is also true that the prosecution history may not be used to infer the intentional narrowing of a claim absent the applicant's clear disavowal of claim coverage, such as an amendment to overcome a rejection. See York Prods., Inc. v. Central Tractor Farm & Fam. Ctr., 99 F.3d 1568, 1575, 40 USPQ2d 1619, 1624 (Fed.Cir.1996). No such clear disavowal occurred here.

We agree with Amgen that the specification expressly describes humans as a subset of mammals, and mammals, in turn, as a subset of vertebrates. See '933 patent, col. 4, lines 47-48; col. 10, line 21. Moreover, the specification can fairly be read to, if not expressly, disclose the use of human DNA in human host cells in culture:

Conspicuously comprehended are expression systems involving vectors of homogeneous origins applied to a variety of bacterial, yeast, and mammalian cells in culture as well as to expression systems not involving vectors.... In this regard, it will be understood that expression of, e.g., monkey origin DNA in monkey host cells in culture and human host cells in culture, actually constitute instances of `exogenous' DNA expression inasmuch as the EPO DNA whose high level expression is sought would not have its origins in the genome of the host.

'933 patent, col. 37, lines 33-43 (emphasis added). The astute reader will observe what appears to be a breakdown in the parallelism of the sentence emphasized in the block quote above. Specifically, the reference to the expression of "monkey origin DNA in monkey host cells in culture and human host cells in culture" seems a bit nonsensical because the expression of monkey origin DNA in human host cells is perforce the expression of exogenous DNA. The original 1983 application from which all the patents in suit claim priority, by contrast, contained language that upholds the parallelism of the sentence and logically makes sense. It read, in pertinent part: "[I]t will be understood that expression of, e.g., monkey origin DNA in monkey host cells in culture and human DNA in human host cells in culture constitute instances of `exogenous' DNA expression." J.A. at 2862 (emphasis added).

TKT boldly asserts that the variance between the original application and the patents in suit bespeaks some volitional act by Amgen to narrow the scope of the asserted claims in light of certain experimental data. In particular, TKT advances a theory whereby Amgen intentionally removed the language from subsequent applications (allegedly) because test results using human cells were not good, and later admitted (during an opposition proceeding against the European counterpart patent) that the omission was not inadvertent. But the record contains a more benign explanation as to what happened. According to the testimony of Dr. Lin, he was unaware of, and therefore did not authorize, the change. Further, the prosecuting attorney testified in his deposition that to the best of his knowledge the error was a typographical error.

But even assuming that the error was intentional, the district court's claim construction would not be foreclosed: our precedent is clear that claims are not perforce limited to the embodiments disclosed in the specification. E.g., Rexnord Corp. v. Laitram Corp., 274 F.3d 1336, 1344, 60 USPQ2d 1851, 1856 (Fed.Cir.2001) ("[A]n applicant is not required to describe in the specification every conceivable and possible future embodiment of his invention."). Here, the patent plainly discloses the use of human host cells in culture, and our review of the record indicates no "clear disavowal" sufficient to undercut the express disclosure in the specification.

As a result, we are satisfied that the terms "non-naturally occurring," "vertebrate," and "mammalian" should be construed as they were by the district court, in a manner consistent with their plain meaning. Accordingly, we reject TKT's attempt to limit the scope of the asserted claims under an unduly constricted reading of the specification.

The final claim construction issue TKT raises is aimed at the district court's alleged failure to discern "source and process" limitations in claims of the '080, '349, and '422 patents. According to TKT, the trial court erred by concluding that the asserted claims are product claims, i.e., that they are directed to a structural entity that is not defined or limited by how it is made. TKT summarily states that this holding must be erroneous because, it asserts, the patentability of the claims depended on the process since "Amgen tried, but failed, to distinguish rEPO from prior art EPOs based on physical differences." We do not agree.

It is telling that neither in the briefing nor at oral argument did TKT direct us to any specific statement in the prosecution history to support the contention that the patentability of the product claims in suit depended upon the process by which those products are obtained. In fact, the original claims of at least one of the patents (the '080 patent) were drafted as product-by-process claims, which claims were cancelled and replaced with "pure" product claims. This is strong evidence that both the patentee and the examiner viewed the claims that ultimately issued as lacking a process component. See Vanguard Prods. Corp. v. Parker Hannifin Corp., 234 F.3d 1370, 1372, 57 USPQ2d 1087, 1089 (Fed.Cir.2000) ("Parker Hannifin argues that the prosecution history shows that the Vanguard inventors viewed co-extrusion as `fundamental' to manufacture of the claimed gasket, thereby imposing this process of manufacture upon the product claims.... However, review of the prosecution history shows that during examination the examiner as well as the applicant treated the product claims as directed to the product itself, and examined the application accordingly.").

In any event, we are not convinced that the source limitations in the asserted claims convert the claims into anything other than product claims. As to the '080 patent, the "non-naturally occurring" limitation in claims 3 and 4 merely prevents Amgen from claiming the human EPO produced in the natural course. By limiting its claims in this way Amgen simply avoids claiming specific subject matter that would be unpatentable under § 101. This court has endorsed this approach, recognizing that patentees can use negative limitations such as "non-human" and "non-natural" to avoid rejection under § 101. See Animal Legal Def. Fund v. Quigg, 932 F.2d 920, 923, 18 USPQ2d 1677, 1680 (Fed.Cir.1991). The district court arrived at a similar conclusion, Amgen, 126 F.Supp.2d at 89, 57 USPQ2d at 1462-63, and TKT has not demonstrated any error in that conclusion. Similarly, the "not isolated from human urine" limitation in claims 2 and 4 of the '080 patent simply requires that the claimed EPO, however made, be obtained from a source other than human urine. Each of these limitations only excludes human EPO from specific sources and does not restrict the claimed EPO to that produced from any particular source or by any particular method. In sum, claims 2, 3, and 4 of the '080 patent remain broadly drawn to the described "erythropoietin glycoprotein" or "pharmaceutical composition" produced by any method, or obtained from any source, other than those specifically excluded.

As to the '422 patent, the limitation "purified from mammalian cells grown in culture" in claim 1 clearly limits the source of the EPO used in the claimed "pharmaceutical composition." The limitation only speaks to the source of the EPO and does not limit the process by which the EPO is expressed. Rather, the claim is broadly drawn to a "pharmaceutical composition" having certain elements, one of those being EPO "purified from mammalian cells in culture." This reading is in line with the district court's construction and, again, TKT directs us to no error.5

It is axiomatic that claims are construed the same way for both invalidity and infringement. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 842 F.2d 1275, 1279, 6 USPQ2d 1277, 1280 (Fed.Cir.1988). But because the features of the accused product or process are often undisputed, this axiom invites a common approach in the appellate arguments by accused infringers: the principal argument challenges the correctness of a trial court's broad claim construction; the contingent argument, assuming the trial court's claim construction is affirmed, challenges validity under 35 U.S.C. § 112 ¶ 1 of the asserted patents in light of that broad construction. See, e.g., Adv. Cardiovascular Sys. v. Medtronic, Inc., 265 F.3d 1294, 60 USPQ2d 1161 (Fed. Cir.2001); PPG Indus. v. Guardian Indus. Corp., 75 F.3d 1558, 37 USPQ2d 1618 (Fed.Cir.1996); Kalman v. Kimberly-Clark Corp., 713 F.2d 760, 218 USPQ 781 (Fed.Cir.1983). TKT employs that approach here. We therefore think it appropriate to address the relevant § 112 issues before turning to the issue of infringement.

Section 112 of the patent statute describes what must be contained in the patent specification. Among other things, it must contain "a written description of the invention, and of the manner and process of making and using it ... [such] as to enable any person of ordinary skill in the art to which it pertains ... to make and use the same...." 35 U.S.C. § 112 ¶ 1. Thus, this statutory language mandates satisfaction of two separate and independent requirements: an applicant must both describe the claimed invention adequately and enable its reproduction and use. See Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563, 19 USPQ2d 1111, 1117 (Fed.Cir.1991). Third, though not in issue here, he must disclose what he considers the best mode of practicing his invention.

* The purpose of the written description requirement is to prevent an applicant from later asserting that he invented that which he did not; the applicant for a patent is therefore required to "recount his invention in such detail that his future claims can be determined to be encompassed within his original creation." Id. at 1561, 935 F.2d 1555, 19 USPQ2d at 1115 (citation omitted). Satisfaction of this requirement is measured by the understanding of the ordinarily skilled artisan. Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed.Cir.1997) ("The description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). "Compliance with the written description requirement is essentially a fact-based inquiry that will `necessarily vary depending on the nature of the invention claimed.'" Enzo Biochem v. Gen-Probe, Inc., 296 F.3d 1316, 1324, 63 USPQ2d 1609, 1613 (Fed.Cir.2002) (citation omitted). Because of its fact intensive nature, we review a district court's decision on the adequacy of written description for clear error. Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1323, 56 USPQ2d 1481, 1483 (Fed.Cir.2000) (citations omitted).

In addressing TKT's written description arguments, the district court carefully examined whether Amgen's specification adequately described the full breadth of the claims. In the end, the district court rejected TKT's written description challenge, finding that TKT had proven its case only by a preponderance of the evidence — not the clear and convincing standard required as a matter of law. Acknowledging the presence of "a genuine dispute between the expert witnesses," the court weighed the testimony and found that the evidence showed that the descriptions adequately described to those of ordinary skill in the art in 1984 the use of the broad class of available mammalian and vertebrate cells to produce the claimed high levels of human EPO in culture. Amgen, 126 F.Supp.2d at 149, 57 USPQ2d at 1507. In so doing, the court credited in particular the testimony of Amgen's expert, Dr. Harvey Lodish, who testified, among other things, that there might be "minor differences" in applying the method of the disclosed examples (utilizing CHO and COS-1 (monkey) cells) to any vertebrate or mammalian cells, but that those of ordinary skill could "easily" figure out those differences in methodology. Id., 126 F.Supp.2d 69, 57 USPQ2d at 1507.

Much of TKT's argument on appeal challenging this finding dovetails with its claim construction arguments we have already found lacking. For example, TKT asserts that the Amgen patents do not satisfy the written description requirement because: (1) Amgen failed to sufficiently describe the use of all vertebrate and mammalian cells; (2) Amgen deleted use of exogenous human EPO DNA in human cells from its applications;⁶ (3) Amgen expressly excluded the use of endogenous EPO DNA; (4) Amgen emphasized that the advantage of its invention was "freedom from association with human proteins"; and (5) in using the "uniquely characterized" language to describe the polypeptides of the invention, Amgen identified exogenous EPO DNA as an essential element of the invention. As a result of these shortcomings, argues TKT, it has clearly and convincingly proven invalidity under Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed.Cir.1997), Gentry Gallery, Inc. v. Berkline Corp., 134 F.3d 1473, 45 USPQ2d 1498 (Fed.Cir.1998), and Enzo Biochem, Inc. v. Gen-Probe, Inc., 296 F.3d 1316, 63 USPQ2d 1609 (Fed.Cir.2002). We are not persuaded that these precedents mandate reversal of the trial court's factual findings as clearly erroneous regarding the written descriptions.

First, in addressing the adequacy of the written description of the '422 patent and with respect to TKT's exogenous DNA arguments, the district court noted:

When the claim is to a composition rather than a process, the written description requirement does not demand that the specification describe technological developments in the way in which the claimed composition is made that may arise after the patent application is filed. See United States Steel Corp. v. Phillips Petroleum Co., 865 F.2d 1247, 1251 [9 USPQ2d 1461, 1465] (Fed.Cir.1989); In re Koller, 613 F.2d 819, 824-25 [204 USPQ 702, 707] (C.C.P.A.1980); see also In re Hogan, 559 F.2d 595, 606 [194 USPQ 527, 538] (C.C.P.A.1977). Instead, section 112 only requires the Court to determine whether the specification conveys to one of ordinary skill in the art as of 1984 that Dr. Lin invented the subject matter claimed in the patents-in-suit. Reiffin, 214 F.3d at 1346 [Reiffin v. Microsoft Corp., 214 F.3d 1342, 1346, 54 USPQ2d 1915, 1917 (Fed. Cir.2000)]. The written description inquiry, therefore, focuses on a comparison between the specification and the invention referenced by the terms of the claim — not comparison between how the product was made as disclosed in the patent and future developments of this process that might alter or even improve how the same product is made.

Amgen, 126 F.Supp.2d at 150, 57 USPQ2d at 1508; see also id. at 152, 57 USPQ2d at 1509 (discussing the '080 patent), at 154 n. 51, 57 USPQ2d at 1510 (discussing the '349 patent). The district court therefore considered TKT's exogenous DNA arguments and, for the reasons stated above, rejected them. On appeal TKT has not argued that its legal analysis was erroneous. Because we have not been directed to any case law to the contrary, we conclude the district court's legal conclusion based on Phillips Petroleum was not erroneous and that it properly handled the exogenous DNA issue.

We move now to TKT's argument that Amgen failed to sufficiently describe all vertebrate and mammalian cells as engineered in the claimed invention. We held in Eli Lilly that the adequate description of claimed DNA requires a precise definition of the DNA sequence itself — not merely a recitation of its function or a reference to a potential method for isolating it. 119 F.3d at 1566-67, 43 USPQ2d at 1406 (holding the disclosure of the cDNA sequence of the insulin gene of a rat did not adequately describe the cDNA sequence of the insulin gene of every vertebrate). More recently, in Enzo Biochem, we clarified that Eli Lilly did not hold that all functional descriptions of genetic material necessarily fail as a matter of law to meet the written description requirement; rather, the requirement may be satisfied if in the knowledge of the art the disclosed function is sufficiently correlated to a particular, known structure. See Enzo Biochem, 296 F.3d at 1324, 63 USPQ2d at 1613. Both Eli Lilly and Enzo Biochem are inapposite to this case because the claim terms at issue here are not new or unknown biological materials that ordinarily skilled artisans would easily miscomprehend.7 Instead, the claims of Amgen's patents refer to types of cells that can be used to produce recombinant human EPO. Thus, TKT can only challenge the adequacy of disclosure of the vertebrate or mammalian host cell — not the human DNA itself. This difference alone sufficiently distinguishes Eli Lilly, because when used, as here, merely to identify types of cells (instead of undescribed, previously unknown DNA sequences), the words "vertebrate" and "mammalian" readily "convey[] distinguishing information concerning [their] identity" such that one of ordinary skill in the art could "visualize or recognize the identity of the members of the genus." Eli Lilly, 119 F.3d at 1567, 1568, 43 USPQ2d at 1406.8 Indeed, the district court's reasoned conclusion that the specification's description of producing the claimed EPO in two species of vertebrate or mammalian cells adequately supports claims covering EPO made using the genus vertebrate or mammalian cells, renders Eli Lilly listless in this case. Amgen, 126 F.Supp.2d at 149, 57 USPQ2d at 1507.

TKT's remaining arguments rely on Gentry Gallery. However, we see Gentry Gallery as similarly inapt. TKT would have us view Gentry as a watershed case, in reliance on an isolated statement — probably only dicta — that one of ordinary skill in the art would clearly understand that the location of the reclining controls on the claimed sectional sofa "was not only important, but essential to [the] invention." 134 F.3d at 1480, 45 USPQ2d at 1503. But as we recently indicated in Cooper Cameron Corp. v. Kvaerner Oilfield Prods., Inc., 291 F.3d 1317, 1323, 62 USPQ2d 1846, 1850-51 (Fed.Cir.2002), "we did not announce [in Gentry] a new `essential element' test mandating an inquiry into what an inventor considers to be essential to his invention and requiring that the claims incorporate those elements." See also Vas-Cath, 935 F.2d at 1565, 19 USPQ2d at 1114; cf. Aro Mfg. Co. v. Convertible Top Replacement Co., 365 U.S. 336, 345, 81 S.Ct. 599, 5 L.Ed.2d 592 (1961) ("[T]here is no legally recognizable or protected `essential element,' `gist' or `heart' of the invention in a combination patent."). Understood in this light, one sees the holding in Gentry for what it really was: an application of the settled principle that a broadly drafted claim must be fully supported by the written description and drawings. See Cooper Cameron, 291 F.3d at 1323, 62 USPQ2d at 1850-51. After considering extensive testimony from both parties, the district court held this principle met and TKT failed to demonstrate that this analysis was clearly erroneous factually or based on an error of law. Amgen, 126 F.Supp.2d at 149-50, 57 USPQ2d at 1507-08.

To the extent the particular facts of Gentry are relevant, we also find it distinguishable. First, there is a fundamental difference between Amgen's patented invention and the invention in Gentry. In Gentry the invention was the placement of reclining controls on a central console on a unit of a sectional sofa so as to allow the sofa to have two independent reclining seats face in the same direction (solving a problem present in the prior art). 134 F.3d at 1475, 45 USPQ2d at 1499. The undisclosed element leading to the Gentry court's holding of invalidity for lack of an adequate description was a location for the controls other than on the console — leading to a different and undescribed product. See id. at 1479, 45 USPQ2d at 1502-03. Amgen's invention is not the location of the control sequences and EPO DNA in relation to the cell, but rather the production of human EPO using those sequences. Thus, the undisclosed element TKT urges invalidates Amgen's product claims is a different method (endogenous activation) of making the claimed compositions. But, as the district court noted, under our precedent the patentee need only describe the invention as claimed, and need not describe an unclaimed method of making the claimed product. Amgen, 126 F.Supp.2d at 150, 57 USPQ2d at 1507 (citing Phillips Petroleum, 865 F.2d at 1251, 9 USPQ2d at 1465; In re Koller, 613 F.2d at 824-25, 204 USPQ at 707); see also Vas-Cath, 935 F.2d at 1563-64, 19 USPQ2d at 1117. This factual difference alone is sufficient to distinguish this case from Gentry.

Second, the statements by the patentee in the written description in this case fall short of what Gentry prohibits. The court in Gentry concluded that the inventor had clearly expressed in the written description that he considered his invention to be limited to the specific location of the controls on the console on the sofa ("the only possible location") and that any variation was "outside the stated purpose of the invention." Gentry Gallery, 134 F.3d at 1479, 45 USPQ2d at 1503. Indeed, in Gentry the inventor testified that he only considered locating the controls outside of the console — and only broadened his application claims accordingly — after seeing Gentry's competitors introduce products with controls located off the console. Id. Here, to be sure, Amgen made statements that its invention is "uniquely characterized" by exogenous expression of DNA. '933 patent col. 10, lines 15-20. When considered in context, however, these statements do not lead to the same conclusion as in Gentry. Amgen's statements simply do not clearly indicate that exogenous expression is the only possible mode of the invention or that other methods were outside the stated purpose of the invention. Instead, Amgen begins the background section of its written description by stating "[t]he present invention relates generally to the manipulation of genetic materials and, more particularly, to recombinant procedures making possible the production of polypeptides possessing part or all of the primary structural conformation and/or one or more of the biological properties of naturally occurring erythropoietin." '933 Patent, col. 1, lines 18-23. Because of this lack of clear statements by the patentee limiting the claimed invention (and in light of the case law discussed, ante), we cannot invalidate a patent for failure to describe a method of producing the claimed compositions that is not itself claimed. Nor could the patentee have described the other method, as it was not developed until 10 years later. We see Gentry Gallery as inapplicable in this regard. In light of the evidentiary record and TKT's inability to persuade us that precedent requires a contrary result, we hold that the district court's finding that Amgen satisfied the written description requirement is not clearly erroneous.

The enablement requirement is often more indulgent than the written description requirement. The specification need not explicitly teach those in the art to make and use the invention; the requirement is satisfied if, given what they already know, the specification teaches those in the art enough that they can make and use the invention without "undue experimentation." Genentech, Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed.Cir.1997); In re Vaeck, 947 F.2d 488, 495, 20 USPQ2d 1438, 1444 (Fed.Cir.1991). Before the district court, TKT bore the burden of clearly and convincingly proving facts showing that the claims were not enabled. E.g., Enzo Biochem, Inc. v. Calgene, Inc., 188 F.3d 1362, 1375, 52 USPQ2d 1129, 1141 (Fed. Cir.1999). Enablement is a question of law; we therefore review the trial court's determination de novo, deferring to its assessment of subsidiary facts underlying the legal question unless clearly erroneous. Bruning v. Hirose, 161 F.3d 681, 686, 48 USPQ2d 1934, 1939 (Fed.Cir.1998).

TKT contends that the asserted claims are invalid for lack of enablement. Taking a position that virtually mirrors the written description (and claim construction) arguments previously rejected, TKT posits that the specifications do not enable an ordinarily skilled artisan to practice the full scope of the asserted claims without undue experimentation because they fail to describe the production of EPO using human cells or endogenous human EPO DNA. At bottom, TKT complains that the court erred by failing to follow its findings to their logical conclusion.9

But the district court made thorough and complete factual findings supporting its holding that the claims were not proven not enabled, expressly incorporating many of its factual determinations made with respect to written description. As to TKT's endogenous/exogenous arguments, the court concluded the arguments were inapplicable as a matter of law for two reasons. First, "where the method is immaterial to the claim, the enablement inquiry simply does not require the specification to describe technological developments concerning the method by which a patented composition is made that may arise after the patent application is filed." Amgen, 126 F.Supp.2d at 160, 57 USPQ2d at 1515 (citing Phillips Petroleum, 865 F.2d at 1251, 9 USPQ2d at 1465; In re Koller, 613 F.2d at 824-25, 204 USPQ at 707; In re Hogan, 559 F.2d at 606, 194 USPQ at 538); see also id. at 161, 57 USPQ2d at 1516 (discussing the '080 patent), at 163-64, 57 USPQ2d at 1518 (discussing the '349 patent). Thus, the specification's failure to disclose the later-developed endogenous activation technology cannot invalidate the patent. Id. at 160, 57 USPQ2d at 1516. Second, "the law makes clear that the specification need teach only one mode of making and using a claimed composition." Id. at 160, 57 USPQ2d at 1515 (citing Johns Hopkins Univ. v. Cellpro, Inc., 152 F.3d 1342, 1361, 47 USPQ2d 1705, 1719 (Fed.Cir.1998); Engel Indus. Inc. v. Lockformer Co., 946 F.2d 1528, 1533, 20 USPQ2d 1300, 1304 (Fed.Cir.1991)); see also Durel Corp. v. Osram Sylvania Inc., 256 F.3d 1298, 1308, 59 USPQ2d 1238, 1244 (Fed.Cir.2001). This conclusion again makes the specification's failure to disclose TKT's endogenous activation technology legally irrelevant. Amgen, 126 F.Supp.2d at 160, 57 USPQ2d at 1515. We reach the same conclusion on appeal, as TKT has not persuaded us that the district court's conclusions in this regard were erroneous.

Focusing specifically on the '422 patent, the enablement inquiry is whether Amgen has enabled all pharmaceutical compositions comprising "a therapeutically effective amount of human erythropoietin," "a pharmaceutically acceptable diluent, adjuvant or carrier," and human erythropoietin "purified from mammalian cells grown in culture." The court found that the specification described and enabled various possible diluents and carriers and provided specific information on effective dosages and therapeutic effect in mice. Id. at 148, 57 USPQ2d at 1506. Amgen also described and enabled at least one way of obtaining EPO purified from mammalian cells in culture: the genetic manipulation of CHO and COS-1 cells, followed by both described and other well known purification techniques. Finally, the court accepted testimony indicating that an ordinarily skilled artisan would infer from the COS-1 (monkey) and CHO cell examples that similar outcomes could be expected from other mammalian cells since all mammalian cells produce and secrete hormones like EPO by means of the same fundamental processes. Id. at 159, 57 USPQ2d at 1514-15. These are all findings of fact and they have not been shown to be clearly erroneous.

As to the '080 patent, the inquiry is whether Amgen has enabled the production of all EPO glycoproteins having "the in vivo biological activity of causing bone marrow cells to increase production of reticulocytes and red blood cells," "the mature erythropoietin amino acid sequence of FIG. 6," and "[are] not isolated from human urine" or "non-naturally occurring." The court noted that Amgen disclosed the in vivo biological effect of EPO upon hematocrit levels in mice and adequately disclosed the sequence of the amino acid residues in figure 6. Id. at 151, 57 USPQ2d at 1508-09. Amgen also described and enabled at least one method of producing EPO that was both "non-naturally occurring" and "not isolated from human urine": the genetic manipulation of CHO and COS-1 cells. The court noted with particularity that even TKT's witness, Dr. Kingston, agreed that if one of ordinary skill in the art followed the teachings of Example 10, then such a person could successfully practice the claimed invention. Id. at 161, 57 USPQ2d at 1516.

We address the product claims of the '349 patent in more detail, as they differ slightly from the patents we discussed above. The '349 patent claims genetically manipulated "vertebrate cells" — a composition — having certain characteristics and properties, including an ability to produce the claimed levels of human EPO.10 The enablement question thus posed is this: having disclosed one way to make the claimed EPO-producing cell, is Amgen entitled to claim all such cells that "can be propagated in vitro," comprise "non-human DNA sequences that control transcription," transcribe "DNA encoding human erythropoietin," and produce the claimed amount of EPO? While our precedent does hold that disclosure of one or two species may not enable a broad genus, e.g., In re Vaeck, 947 F.2d at 495-96, 20 USPQ2d at 1444-45, the district court made several fact-findings indicating that any gaps between the disclosures and the claim breadth could be easily bridged. See, e.g., Amgen, 126 F.Supp.2d at 149, 57 USPQ2d at 1514 (crediting Amgen's expert Dr. Lodish's statement that "one of ordinary skill in the art, me, my students, would have understood this not to be limited to the specific types of cells that were used in this example, that other vertebrate cells, mammalian cells, could have been used"); cf. Enzo Biochem, 188 F.3d at 1367-68, 1372, 52 USPQ2d at 1133, 1136-37 (affirming nonenablement of claims to anti-sense DNA technology applied to all eukaryotic and prokaryotic organisms because anti-sense was a "highly unpredictable technology" and a "high quantity of experimentation" would be needed to practice the invention outside of the disclosed example); Vaeck, 947 F.2d at 495-96, 20 USPQ2d at 1444-45 (holding the examiner did not err in rejecting as nonenabled claims drawn to all genetically-engineered cyanobacteria expressing a given protein because the claimed 150 genera of cyanobacteria represent a vast, diverse, and poorly understood group; heterologous gene expression in cyanobacteria was "unpredictable"; and the patent's disclosure referred to only a genus). The district court found that a skilled artisan could readily have used various cultured vertebrate and mammalian cells to produce human EPO, and this fact was buttressed by numerous post-filing publications that demonstrated the extent of the enabling disclosure. Amgen, 126 F.Supp.2d at 162, 57 USPQ2d at 1517 (citing Gould v. Quigg, 822 F.2d 1074, 3 USPQ2d 1302 (Fed.Cir.1987) for the proposition that an expert may rely on post-filing publications to show enablement). The court also found that for those skilled in the art it was a relatively simple matter to determine whether a certain promoter would work within a specific vertebrate cell, whether a particular vertebrate cell would produce human EPO in culture, and whether a particular promoter could be operatively linked to control the transcription of the human EPO DNA. Id. In summary, the court once again chose to credit Amgen's witnesses, Drs. Lodish and Wall, on the issue of enablement:

Throughout the testimony of these witnesses, a theme becomes apparent: any challenge which one of ordinary skill in 1984 might have encountered in attempting to make and use the claimed invention using other cultured mammalian cells could be resolved by experimentation falling short of undue.

Id. at 159, 57 USPQ2d at 1515.

With these factual findings before us, TKT cannot prevail simply by reasserting in a conclusory manner that Amgen's disclosure does not enable the transformation of all mammalian or vertebrate cells or the production of human EPO. The district court carefully considered these issues, finding in the end that TKT had not met its clear and convincing burden of proof. Finding no clear error in these factual determinations, and having been directed to no legal error committed by the trial court, we will not disturb its holding that the asserted patents are not invalid for failure to meet the enablement requirement of § 112 ¶ 1.

Certain concerns are raised by the dissent. My brother in dissent sees the district court as having "abstained from fully inquiring" about compliance with the written description and enablement requirements of § 112, ¶ 1. In light of this strong statement, we write here to highlight what the district court did and did not do in deciding the case below. The district court should be seen as deciding the challenges to validity under each requirement as presented to it by the accused infringer. In doing so, the court fully found the facts that under-girded its conclusions on validity and relied on our case law interpreting and applying § 112. We are largely limited on review to deciding whether those findings based on that testimony are clearly erroneous and we cannot so conclude. We may, of course, review de novo the court's interpretation of our precedent.

The dissent, however, does not directly challenge the court's factual findings, nor does it mention the decisions relied on by the district court. Instead, it finds fault in the absence of discussion of other precedents, namely Eli Lilly, Gentry Gallery, In re Mayhew, and In re Vaeck, and makes broader arguments seemingly based upon policy considerations.

The dissent would vacate and remand the written description issue because the district court did not cite our precedents Eli Lilly and Gentry Gallery. According to the dissent, the district court "did not focus on the correct law to be applied" and, for that reason, its "factual findings merit no deference." It is difficult to see how the district court's analysis must be rejected because it did not include discussions of these two decisions or, per the dissent, "the principles they espouse." First, it is far from clear that the defendant based its written description challenge below primarily on these two cases. Second, as we hold above, these cases are simply inapplicable here. Given these considerations, we decline to hold that the failure of the district court to cite these precedents constitutes reversible error.

In addressing the enablement inquiry the dissent looks to two other cases not discussed by the district court. It cites In re Mayhew, 527 F.2d 1229, 1233, 188 USPQ 356, 358 (C.C.P.A.1976), for the proposition that "claims failing to recite a necessary element of the invention fail for lack of an enabling disclosure." There, however, the method claims omitted a step without which the invention as claimed was wholly inoperative (meaning it simply would not work and could not produce the claimed product). Id. Here, the lack of a limitation directed to the exogenous expression vector in the product claims is not a failure to describe the structure of the cell or a necessary element of the claimed EPO. Once inside the cell, the transcription control sequence and the human EPO DNA integrate randomly into the host cell chromosomes. The only required description, then, is of the EPO DNA and the transcription control sequences because it is the presence of these sequences in the cell that causes the cell to produce the EPO as claimed. Thus, the lack of a description of (or a limitation directed to) the expression vector itself (as separate from the EPO DNA and transcription control sequences) does not render the invention inoperable and therefore does not run afoul of In re Mayhew, 527 F.2d at 1233, 188 USPQ at 358 (affirming examiner's rejection of claims not limited to having a cooling zone at the exit of a steel strip from a zinc bath because the specification indicated that without that cooling bath the invented process would not work).

The dissent's reliance on In re Vaeck is also misplaced. Vaeck is cited for the proposition that the disclosure of one or two species (here monkey and hamster cells) "may not enable a broad genus under the circumstances." 947 F.2d at 496, 20 USPQ2d at 1444-45. But then again, it may; the inquiry is fact-specific. Here the district court held the disclosure did enable the genus because the differences between using the two described mammalian (and vertebrate) cells and other such cells were small and easily accommodated by the artisan. Thus, in assessing the evidence, the court found that the defendant's evidence fell short of clear and convincing.

But more fundamentally, we think the dissent unfairly characterizes the district court's careful and reasoned handling of the § 112 issues. The dissent repeatedly suggests that the district court "simply refused" to consider whether, having disclosed only one means to make EPO produced by vertebrate or mammalian cells, Amgen was entitled to claims for all such cells and EPO. Specifically, the dissent asserts that the district court "abstained" from considering whether the absence of a claim limitation on the means of expression raises § 112 issues.11 We find this hard to understand. The district court explicitly analyzed these requirements in addressing defendant's specific challenges to validity. It decided they were not proven sufficiently and its decision is supported both by citations to our precedent and its own factual findings. Thus, rather than refusing to answer the § 112 questions, it seems the district court did answer them affirmatively.

In addressing this specific issue, the district court relied principally on two of our precedents: Phillips Petroleum and Cellpro. The court construed the former as not requiring the written description to include later-developed methods for making a claimed product. Amgen, 126 F.Supp.2d at 150, 160, 57 USPQ2d at 1508, 1515. The court construed the latter as holding that a product claim is supported by adequate written description and enabling disclosure even if it describes only one method of making the claimed product. Id. at 160, 57 USPQ2d at 1515. These cases have not been shown to be incorrectly applied by the district court. And we, like the district court, are obligated to follow them both, as they explicitly support the court's rulings. Phillips Petroleum, 865 F.2d at 1251, 9 USPQ2d at 1465 (holding that the patentee was entitled to a prior filing date because the earlier disclosure of polypropylene as known at that time described and enabled a later claim to "[n]ormally solid polypropylene" even though a new, higher molecular weight form of polypropylene had been subsequently discovered), and Cellpro, 152 F.3d at 1361, 47 USPQ2d at 1719 (affirming summary judgment of enablement of a product claim over a challenge that two alternative embodiments disclosed in the patent were not enabled because "the enablement requirement is met if the description enables any mode of making and using the invention").

Rather than addressing these precedents, the dissent makes broad arguments that are not specifically grounded in our precedent. The dissent asks whether Amgen's disclosure "entitles it to claim all EPO produced by mammalian cells in culture, or all cultured vertebrate cells that produce EPO." (emphasis in original). While this broad entitlement question may be important as a policy matter, where, as here, we have applicable precedents, we are bound by the specific inquiries they mandate. Here, we, as did the district court, look to the requirements of § 112 as interpreted by our precedent. In short, the district court cannot have committed legal error by faithfully following controlling precedent of this court.

Lastly, the dissent emphasizes that omissions in the claim limitations and in the disclosures of the specifications "raised enablement issues." If the claims were still in prosecution before the PTO, perhaps the examiner could make an issue of such omissions. The dissent talks of what is "essential for the patentability of the claims." (emphasis added). But the question here is not patentability of application claims, but validity of issued claims that are presumed valid by statute. Now a heavy burden falls on the challenger. The district court found that the challenger had not carried that burden. It admitted that the questions were close—indeed, it found invalidity proven, but only by a preponderance. Hence, rather than refusing to decide questions of validity under § 112, it did decide them under the proper standard of proof. We see no reversible error.

Having addressed the claim interpretation and § 112 issues, we move to the second step of the infringement analysis: comparison of the properly construed claims to the accused product or process. See, e.g., CCS Fitness, 288 F.3d at 1365, 62 USPQ2d at 1662. Our review of this step differs depending upon whether the issue of infringement was resolved on summary judgment or after a full trial. See Cole v. Kimberly-Clark Corp., 102 F.3d 524, 528, 41 USPQ2d 1001, 1004 (Fed.Cir.1996). In the case of summary judgment, as with claim 1 of the '422 patent, we review de novo the trial court's finding that there was no genuine issue as to any material fact regarding infringement. Id., 102 F.3d 524, 41 USPQ2d at 1004; Fed.R.Civ.P. 56(c). After a full bench trial, infringement is a question of fact that we review, of course, for clear error. Ultra-Tex Surfaces, Inc. v. Hill Bros. Chem. Co., 204 F.3d 1360, 1363, 53 USPQ2d 1892, 1895 (Fed.Cir.2000). When JMOL is entered under Fed.R.Civ.P. 52(c), as with the '698 and '080 patents, we review the district court's determination for clear error, as if it had been entered at the close of all the evidence. Yamanouchi Pharm. Co. v. Danbury Pharmacal, Inc., 231 F.3d 1339, 1343, 56 USPQ2d 1641, 1643 (Fed.Cir.2000). Anchored in the proper scope of review for each claim in dispute, we now address the trial court's infringement analysis.

Amgen asserted the following three claims of the '933 patent against TKT:

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

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

9. A pharmaceutical composition comprising an effective amount of a glycoprotein product effective for erythropoietin therapy according to claim 1, 2, 3, 4, 5, or 6 and a pharmaceutically acceptable diluent, adjuvant or carrier.

Critical for our purposes is the final limitation of claim 1, which states that the claimed glycoprotein has "glycosylation which differs from that of human urinary erythropoietin." Glycosylation is the addition of carbohydrate side chains to amino acid residues in protein sequences to form glycoproteins. Encyclopedia of Molecular Biology at 1047. At the Markman hearing, Amgen asserted that the phrase meant "the attached carbohydrate groups differ when analyzed by standard prior art techniques known as of 1983-84." TKT argued, by contrast, that it meant "the carbohydrate groups attached to side chains of the erythropoietin polypeptide backbone differ by Western blot analysis and SDS/PAGE and carbohydrate composition analysis from those of human urinary erythropoietin to at least the degree described in the patents-in-suit."

Thus, the primary difference concerned which, if any, techniques were acceptable to determine whether the glycosylation was different. The district court found that the examples in the specification teach three measurement methods, but that they failed to limit "glycosylation which differs" to those methods. The court ruled, therefore, that the phrase means: "Glycosylation as to which there is a detectable difference based upon what was known in 1983-1984 from that of human urinary erythropoietin, having in mind that the patent holder, Amgen, taught the use of this Western blot, SDS-PAGE and monosaccharide test." Amgen, 126 F.Supp.2d at 91-92, 57 USPQ2d at 1463.

It is undisputed that in 1983, there were at least two analytical techniques available for detecting differences in glycosylation between two glycoproteins. SDS-PAGE is a type of gel electrophoresis in which the glycoprotein of interest is bound to a charged compound that denatures the glycoprotein, which in turn is subjected to an electric field; glycoproteins of different molecular weight (reflecting their different glycosylations) will migrate through the electric field at different speeds. Id. at 124, 57 USPQ2d at 1488. Isoelectric focusing ("IEF"), a second technique known to artisans in 1983, is similar to SDS PAGE except that it determines the pH at which a protein is electrically neutral because the charge is placed in the gel in the form of a pH gradient, rather than on the glycoprotein itself. Id. at 125, 57 USPQ2d at 1488. The data obtained by both these methods can be visualized by Western blot, allowing an approximation of the molecular weight.

There was little dispute that any of these tests could be used to determine the glycosylation of a glycoprotein. Indeed, the district court noted that the testimony of an Amgen witness, Dr. Cummings, "would discharge Amgen's duty of showing by a preponderance of the evidence that HMR4396 has glycosylation which differs from that of human urinary EPO." Id. at 127, 57 USPQ2d at 1490. However, the court also credited evidence that indicated two uEPO preparations produced from the same batch of starting materials could nevertheless have different glycosylation patterns. Id. at 129, 57 USPQ2d at 1492 ("[A] skilled artisan in 1984 would have understood that urinary erythropoietin samples obtained using different purification methods could have different glycosylation. As a result, the glycosylation of human urinary erythropoietin was in 1984, and continues to be, a moving target."). Consequently, because the district court concluded that the patent failed to identify a single standard by which the "difference" could be measured, it held that TKT did not infringe and the '933 patent was invalid for failure to satisfy 35 U.S.C. § 112:

The claim language of the '933 patent, however, presupposes that the glycosylation of urinary erythropoietin is a fixed, identifiable marker against which the glycosylation of recombinant EPOs can be measured. Yet, how can one prove that a recombinant EPO has glycosylation which differs from that of urinary EPO when the glycosylation of urinary EPO itself varies? The Court need not answer this conundrum. All that need be said is that Amgen's showing that GA-EPO has glycosylation which differs from but one of the many heterogeneous urinary EPOs is insufficient to carry its burden of proving infringement by a preponderance of the evidence that TKT infringes the claim limitation.

Id. at 129, 57 USPQ2d at 1492.

Amgen argues on appeal that an ordinarily skilled artisan in 1984 would have understood, based upon the patent disclosure, that there were two principal processes for purifying uEPO, with the technique taught by Miyake (SDS-PAGE) recognized as the standard. It asserts that it carried its burden of proving infringement because its empirical evidence "unequivocally demonstrated the glycosylation difference between Miyake-purified uEPO and the accused product." But it seems to us that Amgen has failed to address the trenchant question on this issue, i.e., whether uEPO is necessarily glycosylated in the same way. Amgen deals rather cavalierly with the question in both its principal and reply brief, stating summarily that the district court erred and suggesting that the question is unimportant.

By definition, one must know what the glycosylation of uEPO is with certainty before one can determine whether the claimed glycoprotein has a glycosylation different from that of uEPO. In its discussion characterizing recombinant glycoprotein products, the specification of the '933 patent does not direct those of ordinary skill in the art to a standard by which the appropriate comparison can be made. See '933 patent, col. 28, line 33—col. 29, line 7. The district court considered evidence that experiments conducted by Amgen in 1984 showed that different urinary EPO preparations had different glycosylation. For example, EPO purified from the urine of a single patient ("Lot 82") using a modified Miyake procedure was shown to have a different glycosylation from other human uEPO (taken from Goldwasser). Amgen, 126 F.Supp.2d at 129, 57 USPQ2d at 1491-92. And so, even assuming that Amgen is correct that one of ordinary skill in the art would have understood the benchmark test for glycosylation to be Miyake, its contention still fails. As the district court noted, the Miyake article provides a method of purification, but hardly suggests uniformity of glycosylation of the human uEPO studied:

The 1977 Miyake et al. publication, for example, describes the purification from the same starting material of two homogeneous urinary EPO preparations (Fraction II and Fraction IIIA) that had about the same potency in terms of biological activity. Fractions II and IIIA ... had different carbohydrate compositions and, therefore, differed from each other in glycosylation. Thus, these two uEPO preparations, though produced by the same procedure (*Miyake) and derived from the same batch of starting material, nonetheless had different glycosylation.

Id. at 129, 57 USPQ2d at 1491; see also Miyake, Purification of Human Erythropoietin, J. Bio. Chem. 5558, 5562 (1977) ("In spite of our finding of similar potency and molecular size, these two preparations [Fractions II and IIIA] must be considered different. The chemical basis for this difference is now being studied."). Amgen fails to controvert or otherwise address this evidence in its cross-appeal.

Under 35 U.S.C. § 112 ¶ 2, a patent applicant is required, at the close of his specification, to "particularly point[] out and distinctly claim[] the subject matter the applicant regards as his invention." The requirement of claim definiteness set out in § 112 ¶ 2 assures that claims in a patent are "sufficiently precise to permit a potential competitor to determine whether or not he is infringing." Morton Int'l, Inc. v. Cardinal Chem. Co., 5 F.3d 1464, 1470, 28 USPQ2d 1190, 1195 (Fed.Cir.1993). The standard of indefiniteness is somewhat high; a claim is not indefinite merely because its scope is not ascertainable from the face of the claims. Cf., e.g., LNP Eng'g Plastics, Inc. v. Miller Waste Mills, Inc., 275 F.3d 1347, 1359-60, 61 USPQ2d 1193, 1202 (Fed.Cir.2001) (affirming district court finding that patent was not indefinite, despite testimony from a co-inventor that he did not understand what the claim limitation "substantially completely wetted" meant). Rather, a claim is indefinite under § 112 ¶ 2 if it is "insolubly ambiguous, and no narrowing construction can properly be adopted." Exxon Research & Eng'g Co. v. United States, 265 F.3d 1371, 1375, 60 USPQ2d 1272, 1276 (Fed.Cir.2001); Allen Eng'g Corp. v. Bartell Indus., Inc., 299 F.3d 1336, 1349, 63 USPQ2d 1769, 1776 (Fed.Cir.2002) ("It is not our function to rewrite [indefinite] claims to preserve their validity."). Applying these legal maxims to the facts of this case, we agree with the district court that the claims requiring "glycosylation which differs" are invalid for indefiniteness.

We find erroneous, however, its conclusion that invalidity for indefiniteness should be found only in the alternative. A claim is indefinite if, when read in light of the specification, it does not reasonably apprise those skilled in the art of the scope of the invention. See Solomon v. Kimberly-Clark Corp., 216 F.3d 1372, 1378, 55 USPQ2d 1279, 1282 (Fed.Cir.2000) (citing Personalized Media Comm., LLC v. ITC, 161 F.3d 696, 705, 48 USPQ2d 1880, 1888 (Fed.Cir.1998)). So it is here. Recognizing that it was faced with a "conundrum" regarding claim construction, the court held that the patent was not infringed because Amgen could not meet its burden simply by showing "that GA-EPO has glycosylation which differs from but one of the many heterogeneous urinary EPOs." Amgen, 126 F.Supp.2d at 129, 57 USPQ2d at 1492. That the court recognized that one of ordinary skill in the art would have been faced with this "conundrum" should have ended the inquiry, for such ambiguity in claim scope is at the heart of the definiteness requirement of 35 U.S.C. § 112 ¶ 2. One cannot logically determine whether an accused product comes within the bounds of a claim of unascertainable scope. Accordingly, the finding that TKT does not infringe the '933 patent is vacated and the finding that the '933 patent is invalid under § 112 is affirmed.

Claims 2-4 of the '080 patent are at issue:

2. An isolated erythropoietin glycoprotein having the in vivo biological activity of causing bone marrow cells to increase production of reticulocytes 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.

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

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

The critical limitation of the asserted claims in the '080 patent is the requirement that the erythropoietin glycoprotein "comprise[] the mature erythropoietin amino acid sequence of Fig. 6." The court construed the claim term "mature erythropoietin amino acid sequence of Figure 6" that appears in claims 4 and 6 of the '698 patent and claims 2 and 4 of the '080 patent. The dispute here arises out of a mistake in the specification. At the time the patent was drafted, it was believed that the sequence included 166 amino acids, and this belief is depicted in Figure 6. In fact, later research demonstrated that the full sequence was actually 165 amino acids; the last (arginine) is actually cleaved off prior to the protein's secretion from the cell. Amgen argued that the reference to Figure 6 was irrelevant, even if the figure had too many amino acids, because it still showed the "mature [i.e., 165] erythropoietin amino acid sequence." TKT argued that the reference to Figure 6 required the term to be construed as depicted in Figure 6, and thus with 166 amino acids. Following trial,12 the court adopted TKT's proposal, relying on what it considered key language in the specification supporting that construction: "Fig. 6 thus serves to identify the primary structural conformation (amino acid) sequence of mature human EPO as including 166 specified amino acid residues ...." '080 patent, col. 12, lines 3-5. Amgen, 126 F.Supp.2d at 86-87, 57 USPQ2d at 1459.

In total, Figure 6 consists of five separate figures denominated Figs. 6A through 6E, which collectively disclose the sequence of human genomic EPO DNA and the encoded EPO. The detailed description in the '080 patent indicates that the specificity of Figure 6 is not to be lightly disregarded:

Fig. 6 thus serves to identify the primary structural conformation (amino acid sequences) of mature human EPO as including 166 specified amino acid residues (estimate M.W.=18,399). Also revealed in the Figure is the DNA sequence coding for a 27 residue leader sequence along with 5' and 3' DNA sequences which may be significant to promoter/operator functions of the human gene operon. Sites for potential glycosylation of the mature human EPO polypeptide are designated in the Figure by asterisks. It is worthy of note that the specific amino acid sequence of Fig. 6 likely constitutes that of a naturally occurring allelic form of human erythropoietin. Support for this position is found in the results of continued efforts at sequencing of urinary isolates of human erythropoietin which provided the finding that a significant number of erythropoietin molecules therein have a methionine at residue 126 as opposed to a serine as shown in the Figure.

'080 patent, col. 21, lines 29-40.

When the district court revisited the "Figure 6" issue, it concluded that the language of the claims, read in conjunction with the portion of the specification excerpted above, clearly identified the mature erythropoietin amino acid sequence as exactly depicted in Figure 6. In so doing, the court expressly rejected Amgen's contention that the claim should be read as covering the mature amino acid sequence, of erythropoietin, whatever its number of amino acids. Amgen, 126 F.Supp.2d at 100, 57 USPQ2d at 1470 ("Had Amgen claimed only `the mature erythropoietin amino acid sequence' without associating or linking that amino acid sequence to Figure 6 its argument that its claims cover whatever sequence (whether it contained 165 or 166 amino acids) is ultimately secreted by the cell might have more momentum."). The district court therefore found at the close of Amgen's case that HMR4396 does not literally infringe the asserted claims of the '080 patent.

The issue of infringement under the doctrine of equivalents was much closer, and likewise centered on the "Figure 6" limitation.13 The district court concluded that Amgen had proven by a preponderance of the evidence that the 165 amino acid sequence satisfied the function-way-result test, crediting in particular the testimony of Dr. Lodish that TKT's missing arginine residue (the 166th amino acid appearing in Figure 6) does not affect the in vivo biological activity of its EPO product. Id. at 133, 57 USPQ2d at 1495. In reaching its conclusion, the court rejected TKT's argument that Amgen was not entitled to any range of equivalents under Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki, 234 F.3d 558, 566, 56 USPQ2d 1865, 1870 (Fed. Cir.2000), because during prosecution it had narrowed the scope of the claim for reasons related to patentability. The parties have cross-appealed on this patent, with Amgen asserting that the district court erred by finding no literal infringement and TKT continuing to press its estoppel theory as a basis for denying any range of equivalents.

Naturally, Amgen continues to focus on the "mature" portion of the relevant claim limitations to support its argument that the trial court erred by finding no literal infringement. According to Amgen, the practical result of the trial court's conclusion is to read out from the claims the preferred embodiment of the invention because the specification makes clear that "mature" human EPO is that form which circulates in the blood, i.e., the 165 amino acid form that has already been secreted. This argument strains reason to its breaking point; our reading of the patent, like the district court's, will support no such interpretation.

Amgen's argument is based upon a misconstruction of the term "including" that evinces a misunderstanding of the plain meaning of that term, as well as the term "comprise," which appears in the '080 patent claims.14 "Comprising is a term of art used in claim language which means that the named elements are essential, but other elements may be added and still form a construct within the scope of the claim." Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1633 (Fed.Cir.1997). The word "include" means the same thing. See Hewlett-Packard Co. v. Repeat-O-Type Stencil Mfg. Corp., Inc., 123 F.3d 1445, 1451, 43 USPQ2d 1650, 1655 (Fed.Cir.1997) ("The claim term `including' is synonymous with `comprising,' thereby permitting the inclusion of unnamed components."); see also Webster's II New Riverside University Dictionary 619 (1984) ("include: 1. To have or take in as a part or member: CONTAIN; 2. To put into a group class, or total."). Thus, a claim reciting "a widget comprising A and B," for example, would be infringed by any widget containing A and B, no matter that C, D, or E might be present.

If, then, as the specification states, "the primary structural conformation (amino acid sequence) of mature human EPO as including 166 specified amino acid residues," it is simply illogical for Amgen to argue that that means anything other than, at minimum, the 166 amino acids shown in Figure 6. This is verified by the fact that '080 claims 2 and 3 claim an erythropoietin glycoprotein "compris[ing] the mature erythropoietin amino acid sequence of Fig. 6...." Again, read properly in light of the term "comprising," this means that the claimed glycoprotein must have — at minimum — all 166 amino acids shown in Figure 6.