Lead Opinion
Plaintiff-Cross Appellant Amgen Inc. (“Amgen”) is the owner of numerous patents directed to the production of erythro-poietin (“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.
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.
BACKGROUND
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.
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 erythro-poietin 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.
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 nat
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.,
1. A non-naturally occurring erythro-poietin 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 glyco-protein product effective for erythro-poietin therapy according to claim 1, 2, 3. 4, 5, or 6 and a pharmaceutically acceptable diluent, adjuvant or carrier.
The '698 patent issued on April 8, 1997, containing nine claims drawn to a process for producing a glycosylated erythropoiet-in 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 er-ythropoietin promoter DNA, opera-tively linked to DNA encoding the mature erythropoietin amino acid sequence of FIG. 6; and
b) isolating said glycosylated erythro-poietin polypeptide expressed by said cells
5. The process of claim 4 wherein said promoter DNA is viral promoter DNA.
6. A process for the production of a glycosylated erythropoietin polypeptide having the in vivo biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells comprising the steps of:
a) growing, under suitable nutrient conditions, vertebrate cells comprising amplified DNA encoding the mature erythropoietin amino acid sequence of FIG. 6; and
b) isolating said glycosylated erythro-poietin polypeptide expressed by said cells.
7. The process of claim 6 wherein said vertebrate cells further comprise amplified marker gene DNA.
8. The process of claim 7 wherein said amplified marker gene DNA is Dihydro-folate 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
2. An isolated erythropoietin glycopro-tein having the in vivo biological activity of causing bone marrow cells to increase production of reticulocytes and red blood cells, wherein said erythropoietin glyco-protein comprises the mature erythro-poietin amino acid sequence of FIG. 6 and is not isolated from human urine.
3. A non-naturally occurring 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.
4. A pharmaceutical composition comprising a therapeutically effective amount of an erythropoietin glycopro-tein 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 er-ythropoietin in the medium of their growth in excess of 100 U of erythro-poietin 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 radioimmu-noassay
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 erythro-poietin 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, ad-juvant or carrier, wherein said erythro-poietin 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,
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
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,
DISCUSSION
I
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.,
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.,
A
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
None of the asserted claims contain either an “exogenous DNA” or “endogenous DNA” limitation.
“It is the claims that measure the invention.” SRI Int’l v. Matsushita Elec. Corp.,
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. 08/468,369, 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)
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 '938 patent, for example, is virtually identical to claim 1, save for the express limitation regarding the use of “exogenous DNA” (underlined portioned indicating differences).
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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,
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
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.
B
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,
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,
We indulge a heavy presumption that a claim term carries its ordinary and customary meaning. CCS Fitness,
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.,
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.
C
The final claim construction issue TKT raises is aimed at the district court’s
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.,
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,
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
II
It is axiomatic that claims are construed the same way for both invalidity and infringement. W.L. Gore & Assoc., Inc. v. Garlock, Inc.,
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,
A
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,
In addressing TKT’s written description arguments, the district court carefully examined whether Amgen’s specification adequately described the full breadth of the
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;
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 Roller,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 in*1332 quiry, 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,
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.
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).
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,
B
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,
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.
But the district court made thorough and complete factual findings
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,
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 reti-culocytes 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 he-matocrit levels in mice and adequately disclosed the sequence of the amino acid resi
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.
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,
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.
C
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,
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.”
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.
In addressing this specific issue, the district court relied principally on two of our precedents: Phillips Petroleum, and Cell-pro. The court construed the former as not requiring the written description to include later-developed methods for making a claimed product. Amgen,
Rather than addressing these precedents, the dissent makes broad arguments that are not specifically grounded in our precedent. The dissent asks whether Am-gen’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.
Ill
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,
Amgen asserted the following three claims of the '933 patent against TKT:
1. A non-naturally occurring erythro-poietin 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 glyco-protein product effective for erythro-poietin therapy according to claim 1, 2, 3. 4, 5, or 6 and a pharmaceutically acceptable diluent, adjuvant or carrier.
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 er-ythropoietin, having in mind that the patent holder, Amgen, taught the use of this Western blot, SDS-PAGE and monosac-charide test.” Amgen,
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 gly-coprotein, 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,
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,
The claim language of the '933 patent, however, presupposes that the glyeosy-lation of urinary erythropoietin is a fixed, identifiable marker against which the glyeosylation of recombinant EPOs can be measured. Yet, how can one prove that a recombinant EPO has gly-cosylation which differs from that of urinary EPO when the glyeosylation 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 glyeosylation 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,
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 glyeosy-lation 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 gly-cosylated 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 glyeosylation of uEPO is with certainty before one can determine whether the claimed glycoprotein has a glyeosylation different from that of uEPO. In its discussion characterizing recombinant glycopro-tein 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 glyeosylation. For example, EPO purified from the urine of a single patient (“Lot 82”) using a modified Miyake procedure was shown to have a different glyeosylation from other human uEPO (taken from Goldwasser). Amgen,
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*1342 ... 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 gly-cosylation.
Id. at 129,
Under 35 U.S.C. § 112 ¶2, a patent applicant is required, at the close of his specification, to “particularly point[ ] out and distinctly elaim[ ] 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.,
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 fight 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.,
B. The '080 Patent
Claims 2-4 of the '080 patent are at issue:
2. An isolated erythropoietin glycopro-tein having the in vivo biological activity*1343 of causing bone marrow cells to increase production of reticulocytes and red blood cells, wherein said erythropoietin glyco-protein comprises the mature erythro-poietin amino acid sequence of FIG. 6 and is not isolated from human urine.
3. A non-naturally occurring 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.
4. A pharmaceutical composition comprising a therapeutically effective amount of an erythropoietin glycopro-tein product according to claim 1, 2, or 3.
The critical limitation of the asse^ed 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 erythro-poietin 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,
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 erythro-poietin. 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 er-ythropoietin molecules therein have a methionine at residue 126 as opposed to a serine as shown in the Figure.
'080 patent, col. 21, fines 29-40.
When the district court revisited the “Figure 6” issue, it concluded that the
The issue of infringement under the doctrine of equivalents was much closer, and likewise centered on the “Figure 6” limitation.
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, ie., 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.
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.
Turning to the finding of infringement under the doctrine of equivalents, TKT asserts that Amgen should be es-topped from obtaining such coverage under Festo. Specifically, TKT alleges that the “mature amino acid sequence of Figure 6” limitation that appears in the '080 patent was added to overcome a double-patenting rejection, and therefore constitutes an amendment related to patentability. We agree.
The district court correctly found that the amendment, although voluntary, was made to avoid a “same invention” double patenting rejection, Amgen, 126 F.Supp.2d at 135,
C. The '698 Patent
The '698 patent is directed generally to a process for producing a glycosylated er-ythropoietin polypeptide. Claims 4-9 are at issue. Independent claims 4 and 6 read as follows:
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 er-ythropoietin promoter DNA, opera-*1346 tively linked to DNA encoding the mature erythropoietin amino acid sequence of FIG. 6; and
b) isolating said glycosylated erythro-poietin polypeptide expressed by said cells
6. A process for the production of a glycosylated erythropoietin polypeptide having the in vivo biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells comprising the steps of:
a) growing, under suitable nutrient conditions, vertebrate cells comprising amplified DNA encoding the mature erythropoietin amino acid sequence of FIG. 6; and
b) isolating said glycosylated erythro-poietin polypeptide expressed by said cells.
Infringement of dependent claims 5 and 7-9 rises or falls with the analysis that applies to independent claims 4 and 6.
The district court granted TKT summary judgment of non-infringement of independent claims 4 and 6 (and hence dependent claims 5 and 7-9) of the '698 patent because it found that Amgen had failed to carry its Rule 52(c) burden. Id. at 102,
The district court properly recognized that the infringement analysis of process claims is necessarily different from that for product claims. See id. at 102,
For example, the court concluded that a fundamental distinction between the respective processes was that TKT employs homologous rather than heterologous recombination, whereas “[i]n order to make EPOGEN®, Amgen transfects [CHO] cells with a vector that contains both viral promoter DNA and the human EPO gene.” Id. This clear reference to the preferred embodiment of Example 10, which the district court considered “the process most heavily relied upon by Am-gen in its patent,” id. at 103,
The district court likewise found material the fact that TKT places its promoter and enhancer farther upstream than does Amgen. In light of the court’s claim construction, however, it would seem TKT satisfies the “operatively linked” limitation, as there is no question that TKT’s promoter causes its intended functional effect. In any event, the trial court once again compared the accused process by reference to an example rather than the claimed process:
As explained in Example 7 and illustrated in Figure 4, Amgen created the vector by cleaving, with BstEII restriction endonucelases ... ‘at a position which is 44 base pairs 5' to the initiating ATG coding for the pre-peptide and approximately 680 base pairs 3' to the Hindlll restriction site’.... TKT’s process has within the DNA sequence upstream of the codons that express the EPO polypeptide several ATG sites.... The court finds that such a process is sufficiently different from that encompassed by Am-gen’s invention that judgment of non-infringement should follow.
Id.
Again, this was legal error insofar as the infringement analysis is not tied to the asserted claims. We therefore vacate and remand so that the court may conduct a proper infringement inquiry in the first instance, comparing the accused device to the properly construed claims without limiting their scope to the examples in the specification or other limitations that are not properly a part of claims 4-9.
D. The %22 Patent
Claim 1 of the '422 patent, the only one in dispute, claims “[a] pharmaceutical composition comprising a therapeutically effective amount of human erythropoietin and a pharmaceutically acceptable diluent, adjuvant or carrier, wherein said erythropoietin is purified from mammalian cells grown in culture.” In the Markman hearing, Amgen contended the phrase “purified from mammalian cells grown in culture” meant “purified from the in vitro culture in which the mammalian cells have been grown,” whereas TKT argued that it meant “obtained in a substantially homogeneous state from the mammalian cells in which it was produced and not from the cell culture media.” Concluding that TKT’s construction would exclude the patent’s preferred embodiment (Example 10), the court read the phrase “mammalian cells grown in culture” as a whole to encompass purification techniques from the
According to the district court, it was clear from the beginning that the accused product met most limitations of claim 1. That HMR4396 was a pharmaceutical composition that contained a therapeutically effective amount of human erythropoietin was plain, in view of the Investigational New Drug Application (“INDA”) that TKT filed with the Food and Drug Administration. Id. at 94-95,
TKT tries three different tactics on appeal to escape this concession of infringement. First, TKT argues that “mammalian cells,” as the phrase is used in the '422 patent, do not include its cells because Amgen excluded the use of human cells to produce human EPO from its invention. Second, TKT asserts that the finding of infringement was in error because the patent specification defines pharmaceutical compositions “as comprising ‘polypeptides of the invention’,” and HRM4396 is not a “polypeptide of the invention” inasmuch as the invention is “uniquely characterized” by (and hence limited to) exogenous EPO DNA. Finally, TKT challenges the finding of infringement because, it asserts, the intrinsic evidence limits the phrase “purified from mammalian cells grown in culture” to purification that takes place inside the cells, and not — like TKT — from the culture media.
We cannot accept, for the reasons already stated, TKT’s proposed reading of the claim term “mammalian” and its attempt to import the term exogenous into the claims; we therefore reject out of hand the contention that Amgen expressly excluded the use of human cells to express EPO and the use of endogenous DNA from the scope of its invention. Thus, the issue resolves to a narrow one: the accused product, HRM4396, infringes '422 patent claim 1 unless TKT is correct that the claim limitation “purified from mammalian cells grown in culture” means that the EPO product must be recovered directly from the cell, and not from the culture medium.
At the Markman hearing, Amgen contended the phrase means “purified from the in vitro culture in which the mammali
Example 10 “describes expression systems employing Chinese hamster ovary (CHO) DHFR cells and the selectable marker, DHFR.” '422 patent, col. 25, lines 38-40. As a part of the description, the example discloses that gene amplification in cell culture media is possible to increase productivity of the targeted recombinant EPO product. After describing an example of such a gene amplification system, the specification goes on to state: “The productivity of the EPO producing CHO cell lines described above can be improved by appropriate cell culture techniques. The propagation of mammalian cells in culture generally requires the presence of serum in the growth media. A method for production of erythropoietin from CHO cells in media that does not contain serum greatly facilitates the purification of er-ythropoietin from the culture media.” Id., col. 27, lines 8-14 (emphasis added). We agree with the district court that this disclosure — the undisputed preferred embodiment of the invention — contemplates purification of erythropoietin from the culture media. See also '933 patent, col. 28, lines 28-32 (“Mammalian cell expression products may be readily recovered in substantially purified form from culture media using HPLC (C4) employing an ethanol gradient, preferably at pH7.” (emphasis added)).
TKT does not challenge the district court’s conclusion regarding the disclosure of Example 10. Accordingly, TKT’s challenge ultimately must fail unless we read the preferred embodiment out of the claims, but rare is the case where we should or will do so. A claim interpretation that reads out a preferred embodiment “i§ rarely, if ever, correct and would require highly persuasive evidentiary support.” Vitronics Corp. v. Conceptronic, Inc.,
E. The '319 Patent
The '349 patent 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 er-ythropoietin in the medium of their growth in excess of 100 U of erythro-poietin 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 transcrip*1350 tion 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 radioimmu-noassay.
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 erythro-poietin comprising the step of culturing, under suitable nutrient conditions, vertebrate cells according to claim 1, 2, 3, 4, 5, or 6.
Each of the claims contain the limitation “non-human DNA sequences that control transcription” that appears in claim 1 of the '349 patent or the limitation “transcriptional control DNA sequences, other than human erythropoietin transcription control sequences” that appears in claim 4 of the '349 patent. Transcription is the process whereby RNA polymerase copies genetic information contained in a DNA nucleotide sequence into an RNA sequence. It is a critical step in the expression of proteins like erythropoietin and is itself controlled by specific DNA sequences. According to the patent, “transcription control sequences” is the collective term for DNA sequences that not only “provide a site for initiation of transcription into mRNA,” but also are capable of binding proteins that determine “the frequency (or rate) of transcriptional initiation.” '349 patent, col. 2, lines 3-12.
Amgen contended that this phrase means “non-human DNA sequences that are able to initiate or regulate RNA synthesis from EPO DNA.” TKT argued that the phrase means “DNA sequences which did not originate in the human genome, which initiate and regulate RNA synthesis of adjacent DNA, and which replace the human EPO transcription control sequences.” By including the term “adjacent DNA” in its construction, TKT sought to require the DNA sequences that control transcription to be located in a position adjacent to the gene segment intended to be expressed. Furthermore, TKT contended that in order to “control” transcription, the DNA sequences must both initiate and regulate the transcription of a gene. Amgen objected to the use of “and,” preferring a construction that required DNA sequences either to initiate or regulate transcription. Finally, the parties disagreed as to the meaning of “nonhuman.” Amgen argued that “non-human” means “not part of the human genome,” whereas TKT contended it meant “not originating in the human genome.”
First, the court rejected TKT’s position and concluded that “non-human” DNA sequences are DNA sequences that are “not part of the human genome.” The court similarly rejected TKT’s “adjacent” language because “no claim term could reasonably be construed to be limiting the transcription control DNA sequences by their location.” Finally, the court held that DNA sequences that control transcription are DNA sequences that initiate and regulate the processes of transcription. Amgen,
The district court entered judgment of noninfringement for TKT on method claim 7 of the '349 patent under an identical rationale to that used to grant judgment of noninfringement for the method claims of the '698 patent. Id. at 122,
Aside from the challenge, already rejected, to the trial court’s construction of the term “vertebrate cells,” TKT mounts a weak challenge to these findings of infringement apparently under the reverse doctrine of equivalents.
Under the reverse doctrine of equivalents, an accused product or process that falls within the literal words of a claim nevertheless may not infringe if the product or process “is so far changed in principle from a patented article that it performs the same or a similar function in a substantially different way.” Graver Tank & Mfg. Co. v. Linde Air Prod. Co.,
We are not persuaded by TKT that this is a case where equity commands a determination of non-infringement despite its product literally falling within the scope of the asserted claims. TKT relies on findings of the district court regarding differences in the way the accused device controls transcription in the '698 patent. It is true, as Amgen candidly admits, that the method by which TKT controls transcription is not identical. Whereas the patent describes placing the promoter DNA in close proximity, or even adjacent, to the EPO leader peptide, TKT places its promoter further upstream. But again, it is error to conduct infringement analyses in a vacuum, without reference to the claims at issue.
The vertebrate cells of the '349 patent, as claimed, are comprised of non-human DNA sequences that control transcription of DNA encoding human erythropoietin. And “controlling] transcription of DNA encoding human erythropoietin” simply
IV
Our affirmance of the district court’s findings that certain of the asserted claims are infringed is not yet the coup de grace for TKT; non-frivolous validity issues remain. One of the statutory requirements for patentability is that the invention for which a patent is sought was not known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention by the applicant. See 35 U.S.C. § 102(a). Similarly, one is not entitled to a patent if the subject matter of the invention as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which the invention is directed. See id. § 103. TKT relies particularly on two items of prior art that allegedly render certain of the asserted claims anticipated under § 102(a) or obvious under § 103. We discuss each in turn.
A
TKT contends the asserted claims are anticipated by the work of Dr. Eugene Goldwasser (“Goldwasser”). Beginning in 1979-80, Goldwasser conducted a clinical study at the University of Chicago at Illinois in which he obtained a preparation of highly purified erythropoietin derived from human urine and administered approximately 10,000 units of human urinary EPO to three anemic patients. Amgen,
The district court similarly concluded that Goldwasser did not render the patents obvious. Of paramount importance to the court was the fact that the prior art references, including Goldwasser, lacked Am-gen’s disclosure of the genetic sequence of EPO and failed to describe any transcription control sequences. Id. at 115,
TKT assigns error to the district court’s alleged blind acceptance of Goldwasser’s assertion that the test was a failure without considering the contemporane
For the Markman hearing in this case, ten terms were “pre-selected” based upon their relationship to Amgen’s then-pending motion for summary judgment of infringement. Id. at 81,
Such evidence [of, e.g., increased eryth-roid marrow stimulation] should be outweighed by the fact that the achial 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.
Id. at 112,
Although the endgame in the treatment of chronically anemic patients is to increase the hematocrit, as recognized by the district court, the claim term “therapeutically effective” must be understood in light of the specification of which it is a part. And that specification appears to teach that results in addition to simply an increase in hematocrit can provide effective therapy. See '933 patent, col. 33, lines 19-31 (“[The claimed polypeptide products] are conspicuously suitable for use in erythropoietin therapy procedures ... to develop any or all of the effects heretofore attributed in vivo to EPO, e.g., stimulation of reticulocyte response ..., erythrocyte mass changes ..., and, as indicated in Example 10, increasing hematocrit levels in mammals.” (emphasis added)).
Amgen asserts that the district court’s construction of “therapeutically effective” is supported by admissions of TKT’s experts that the term means “increasing and maintaining the patient’s hematocrit to normal or near normal levels.” But 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. CCS Fitness,
B
A second item of prior art germane to this appeal is United States Patent No. 4,377,513 (“Sugimoto”), issued in March 1983. Sugimoto discloses a process for producing human erythropoietin “characterized by multiplying human lymphoblas-toid cells capable of producing human er-ythropoietin by transplanting said cells into a non-human warm-blooded animal body, or alternatively multiplying said cells by allowing said cells to multiply with a device by which the nutrient body fluid of a non-human warm-blooded animal is supplied to said cells, and allowing the cells multiplied by either of the above multiplication procedures to release human eryth-ropoietin.” Sugimoto, col. 1, lines 30-38. Given the similarity of Sugimoto’s disclosure to the patents asserted by Amgen, TKT naturally raised Sugimoto as potentially invalidating prior art, even though Sugimoto had been before the examiner.
The district court concluded that Sugi-moto was not prior art under 35 U.S.C. § 102(a) because it was not proven to be enabled. Amgen,
A claimed invention cannot be anticipated by a prior art reference if the allegedly anticipatory disclosures cited as prior art are not enabled. Long ago our predecessor court recognized that a non-enabled disclosure cannot be anticipatory (because it is not truly prior art) if that disclosure fails to “enable one of skill in the art to reduce the disclosed invention to practice.” In re Borst, 52 C.C.P.A. 1398,
On appeal, Amgen argues that there should be no presumption of enablement in this case because under § 282 courts only presume the claimed subject matter in a patent is enabled. Thus, Am-gen argues, because only the unclaimed disclosures of Sugimoto are at issue here, no presumption of enablement should apply. This argument is not relevant, however, because, as reasoned below, we do not only rely on § 282 as the source for a presumption. Instead, relying on our precedent, we hold a presumption arises that both the claimed and unclaimed disclosures in a prior art patent are enabled.
In patent prosecution the examiner is entitled to reject application claims as anticipated by a prior art patent without conducting an inquiry into whether or not that patent is enabled or whether or not it is the claimed material (as opposed to the unclaimed disclosures) in that patent that are at issue.
Turning now to the district court’s opinion, we think a fair reading is that the court, at least implicitly, put a burden of proving enablement of Sugimoto on TKT. The court began its analysis of Sugimoto by discussing evidence from Amgen and concluding “one would imagine that if Sug-imoto’s invention were truly enabling, then he would have won that lucrative race [to make human EPO suitable for treating anemia].” Amgen,
In addition, looking at the evidence Amgen did present, we cannot conclude the district court properly found Am-gen had met any burden that the court did place on it. At trial Amgen’s expert, Dr. Erslev, testified that “no one reported using Sugimoto’s process to make a pharmaceutical composition of human EPO, nor has any patient ever been treated by any EPO produced by the Sugimoto procedure.” Id. at 108,
We must therefore conclude that to the extent it placed a burden on TKT the district court committed error. However, we hold this error to be, for the most part, harmless. After analyzing enablement and apparently finding the relevant unclaimed disclosures of Sugimoto nonena-bled, the court nevertheless conducted a full anticipation analysis. Indeed, the district court performed a detailed analysis of each piece of anticipating prior art — including Sugimoto — asserted against each of Amgen’s claims. Id. at 109-10,
Our review is not yet finished, however, because it is apparent from the
Had the court concluded otherwise [ie., that Sugimoto was enabled], the Sugi-moto patent would go a long way toward proving TKT’s obviousness defense. As explained above, Sugimoto disclosed EPO-producing fused cells and advised that (1) conventional techniques can be utilized to achieve purification and (2) the human EPO produced thereby can be used in pharmaceutical compositions for the treatment of anemia. Thus, the patent itself suggested combining its invention with prior art sources relating to both purification and therapeutic delivery. Provided that one of ordinary skill in the art could actually make the EPO-producing cells described in the Sugimo-to patent, a point on which TKT failed to persuade this court, such a combination of prior art materials might render invalid the pharmaceutical composition claims of the '933, '080, and '422 patents.
Id. at 114 n. 29,
V
The last issue on appeal is inequitable conduct. TKT raised before the district court essentially three instances of allegedly inequitable activities by the patentee: withholding crucial details regarding the Goldwasser study; withholding certain results of its own experiments that undermined the validity of the '933 patent; and failing to disclose to the Patent and Trademark Office the existence of this litigation. The district court found that TKT had not proven inequitable conduct by clear and convincing evidence, and we have not been persuaded on appeal that a contrary result is compelled. In reaching this conclusion, we need look no further than the district court’s determination that TKT’s case was doomed because it was bereft of evidence of intentional deception:
TKT has failed to produce any persuasive evidence that causes the Court to doubt the integrity of the individuals who bore the duty of shepherding the Amgen patent applications through the Patent and Trademark Office, [so] its charge of inequitable conduct utterly fails.... TKT has failed to prove by clear and convincing evidence that this [experimental] data was material or that it was withheld with intent to deceive .... [And] TKT has not even begun to demonstrate that Amgen representatives possessed an intent to deceive the [PTO] in failing to provide specific notification regarding this litigation.... In summary, TKT’s proof of inequitable conduct with respect to each of these charges falls short of the mark. Although the directness of Amgen’s disclosures varies depending on the particular piece of disputed information, one truth remains the same throughout: Amgen’s*1358 representatives never intended to deceive the Patent Office. Consequently, a finding of inequitable conduct would be error and the Court does not so find on the complete record.
Id. at 141, 145, 147,
A patent applicant commits inequitable conduct when, during prosecution of the application, he makes an affirmative representation of a material fact, fails to disclose material information, or submits false material information, and does so with the intent to deceive. Refac Int’l, Ltd. v. Lotus Dev. Corp.,
Here, the district court determined that there was no evidence of intent to deceive, and TKT has directed us to none on appeal. Thus, to conclude the Amgen patents are unenforceable — as TKT requests — we must conclude (1) that the district court clearly erred by failing to find the minimal requisite intent to deceive, and (2) that it abused its discretion in weighing the degree of materiality against the degree of deceptive intent and by not then rendering the patents unenforceable. On the record before us, we decline to do so.
CONCLUSION
We summarize our decision as follows. Affirmed are: the district court’s claim construction; its finding that all of the patents in suit are enforceable; its finding that the '933 patent is invalid; and its finding that the '349 (product claims only) and the '422 patents are infringed. We vacate: its finding that the '933 patent was not infringed; several of its validity findings with respect to the '080, the '349, the '422, and the '698 patents; and its infringement findings with respect to the '698 patent and '349 patent claim 7. On remand, the district court should: construe the claim term “therapeutically effective” and then reconsider validity under §§ 102 and 103 in view of Goldwasser; reconsider validity of all asserted claims under § 103 and claim 1 of the '422 patent under § 102 in view of Sugimoto, with Amgen bearing the burden of proof on its non-enablement (for § 102 purposes only); reassess infringement of the accused method by comparing it solely to the limitations of each of the asserted method claims; and reevaluate its finding of infringement under the doctrine of equivalents of the '080 patent, focusing on the application of prosecution history estoppel.
AFFIRMED IN PART, VACATED IN PART, REMANDED.
No costs.
Notes
. For further reading on these subjects, see generally Robert A. Meyers, ed., Molecular
. An "expression vector” is a circular piece of DNA (or “plasmid”) that is inserted into a host cell to produce (or "express”) a protein. The expression vector carries the gene encoding for the protein of interest (in this case human EPO), a marker that assures that the vector is properly introduced into the host cell, and a promoter site that the host will recognize to transcribe the vector's DNA. See generally Thomas E. Crieghton, ed., Encyclopedia of Molecular Biology, vol. 2, John Wiley & Sons, Inc. (1999) at 883-86.
. Because the patents in suit share an identical disclosure, all citations will be to the '933 specification unless otherwise noted.
. That is not to say that there are no claims that have such a limitation. Unasserted claim 3 of the '933 patent, for example, does contain such a limitation: "A non-naturally occurring glycoprotein product of the expression in a mammalian host cell of an exogenous DNA sequence comprising a DNA sequence encoding human erythropoietin col. 38, lines 26-29.
. We do not hold that these limitations lack meaning, only that they mean just what they say. Accordingly, they limit only the source from which the EPO is obtained, not the method by which it is produced.
. We addressed this point in our claim construction analysis on pages 1328 ante, finding that the written description did not exclude human cells from the scope of the claims. That analysis suffices here as well.
. Indeed, Amgen’s patents appear to satisfy the sequence requirement in Eli Lilly insofar as Figure 6 of the patents expressly discloses the complete (albeit slightly incorrect) sequence of human genomic EPO DNA and the encoded DNA.
. There is no issue here as to in haec verba description because, as stated in the body of the opinion, in contrast to “cDNA” — that clearly does not describe the actual sequence of the cDNA — the words "mammalian cells” and "vertebrate cells” convey exactly what they are. Thus, this aspect of the holding in Eli Lilly is also inapplicable here.
. TKT refers here to the district court's statement that "it appears that Dr. Lin claimed far more than he delivered." Amgen,
. Following the dissent’s "machine” analogy, the "machine” is a genetically altered vertebrate cell containing transcription control sequences used to transcribe a human EPO gene to express the claimed levels of human EPO. Simply altering the way the human EPO gene is inserted or activated— whether it be through transformation with exogenous DNA or through activation of an endogenous gene — does not make this a different "machine” once built; rather, it only changes the way it was "constructed.”
. In this same vein, the dissent suggests that our court here has somehow "waived” the requirements of § 112 for product claims.
. The court declined to rule on this issue at the Markman hearing, instead choosing to take the matter under advisement. See
. The district court held that every other limitation of the asserted claims in the '698 patent were met literally by the accused product/process. Amgen,
. Amgen argues: "The specification describes the mature amino acid sequence of human EPO as 'including' — not 'limited to’— the 1-166 sequence. Properly construed, Lin's claimed sequence — the mature sequence — includes the fully processed form of any glycoprotein having the Figure 6 sequence. That includes both the 1-165 and the 1-166 amino acid sequences of Figure 6. Only this construction affords 'mature' its proper meaning, and includes Lin's preferred embodiment.”
. Claim 5 claims "[t]he process of claim 4 wherein said promoter DNA is viral promoter DNA.” Claim 7 claims ”[th]e process of claim 6 wherein said vertebrate cells further comprise amplified marker gene DNA.” Claim 8 claims "[t]he process of claim 7 wherein said amplified marker gene DNA is Dihydrofolate reductase (DHFR) gene DNA.” And claim 9 claims ”[t]he process according to claims 2, 4 and 6 wherein said cells are mammalian cells.”
. The basis for this argument is that claim 2 of the '698 patent recites recombinant EPO “isolated from the host cell or the medium of its growth.” Therefore, asserts TKT, “Amgen also knew how to claim what it now seeks, but failed to do so.”
. The importance of this distinction is that, because it is scientifically arguable that viral DNA originates in the human genome, the viral promoter DNA that TKT employs thus might not fall within the meaning of the claim.
. We note also that the trial court granted summary judgment of infringement of the product claims of the '349 patent. It modified its summary judgment finding (but reached the same result) with respect to the "controlling transcription” limitation in light of extensive trial testimony. Amgen,
. The sum total of TKT's challenge to the infringement finding, aside from the "vertebrate” issue, is as follows: “[TKT] also do[es] not use the 'transcription control sequences’ of the '349 patent. As the court found, [TKTj’s transcription control sequences are not only structurally different from Amgen’s sequences but also function in a different way. Because of those differences in structure and function, [TKT] do[es] not infringe the ’transcription control sequences' limitation in the '349 claims.”
. We note also that on remand when considering obviousness and anticipation issues relating to the '080 and '422 patents the district court should be cognizant of the rule that a claimed product shown to be present in the prior art cannot be rendered patentable solely by the addition of source or process limitations. General Electric Co. v. Wabash Corp.,
. Additionally, we think it unwise as a matter of policy to force district courts to conduct a mini-trial on the proper claim construction of a prior art patent every time an allegedly anticipating patent is challenged for lack of enablement. As we frequently revisit district courts’ determinations in matters of claim construction and validity, we are certainly aware that such a task can occupy a great deal of a court's resources. In any event, because the presumption outlined here does not rely on § 282, we see no reason to impose these burdens on litigants and the district courts.
. We note that by logical extension, our reasoning here might also apply to prior art printed publications as well, but as Sugimoto is a patent we need not and do not so decide today.
Dissenting Opinion
dissenting in part.
I join my colleagues’ thorough opinion in all respects save one, albeit significant, exception. Because the claims lack meaningful limitations on the structure of the erythropoietin-producing cells, I cannot
As described by the specifications of the patents in suit, Amgen in 1984 cloned and sequenced the DNA encoding human er-ythropoietin (EPO). Amgen then showed that by introducing the cloned EPO DNA (linked to a promoter sequence) into mammalian cells, those cells could be engineered to express high levels of functional human EPO protein. The parties refer to this as “exogenous DNA” expression of EPO. Amgen obtained several patents that cover the use and manipulation of cloned EPO DNA, and these patents, battle-tested through litigation, have been the foundation of Amgen’s successful business of manufacturing and selling recombinant EPO. But these patents are not in suit here, and TKT’s method for producing EPO does not rely upon manipulation of cloned EPO DNA or “exogenous DNA” expression technology.
The claims in suit here contain no significant limitations as to how the recombinant EPO is expressed, or as to the structure of the EPO-producing cells, so long as the EPO is “non-naturally occurring” or produced in “vertebrate cells.” The central question in this case is therefore whether Amgen’s disclosure of one means of producing synthetic EPO in mammalian cells, namely exogenous DNA expression, entitles it to claim all EPO produced by mammalian cells in culture, or all cultured vertebrate cells that produce EPO. I think this is a question of some importance. Yet it is a question that the district court simply refused to consider. Athough the district court admitted that Amgen’s disclosure was limited to exogenous DNA expression, the district court quite clearly and explicitly refused to decide whether the absence of any exogenous DNA limitations rendered the asserted claims vulnerable to the enablement challenge mounted by TKT under section 112. According to the district court, because the asserted claims were to “compositions” rather than “processes,” “the specification need teach only one mode of making and using a claimed composition.” Amgen, Inc. v. Hoechst Marion Roussel, Inc.,
With respect to the '080 and '422 patents, which claim “non-naturally occurring” EPO and EPO “purified from mammalian cells grown in culture,” the majority, like the district court, essentially passes over the question of whether these limitations — which are essential for patentability of the claims — raise issues of compliance with the enablement and written description requirements of section 112. The majority holds that patentees are free to decorate their composition claims with source and process limitations without any concern for whether the full scope of those limitations is enabled or described, and that these requirements of section 112 are waived so long as the patentee succeeds in characterizing its claims as “product” claims. Competent patent attorneys should be quick to take advantage of the majority’s broad exemption from the disclosure requirements by the appropriate phraseology. Rather than endorse the district court’s elevation of form over substance, I would vacate its decision on these issues regarding the '080 and '422 patents, and remand for further consid
With particular reference to the '349 patent, which claims not EPO polypeptides but the cells that produce them, I think the district court’s abstention from scrutiny under section 112 is even more patent error. The majority focuses on the district court’s findings that the invention could readily be practiced in mammalian or vertebrate cells other than the hamster and monkey cells taught by the specification. I agree that TKT has not shown error in these findings. But, as it did for the EPO claims, the district court simply refused to consider whether the absence of any exogenous DNA limitations raised en-ablement issues, “[bjecause Amgen is only required to enable skilled artisans to make its claimed product by only one method. ...” Id. at 164 n. 57,
' Yet that is exactly what the district court and the majority allow the '349 patent to achieve. It claims any or all cultured vertebrate cells that can secrete a defined amount of EPO, with only a single limitation on their structure: that they “comprisfe] non-human DNA sequences which control transcription of DNA encoding human erythropoietin,” or that they “comprise transcription control DNA sequences, other than human erythropoietin transcription control sequences, for production of human erythropoietin.” This is little more precise than a recitation of “A machine that makes polymer X, wherein the machine comprises means for controlling how much polymer X is made.” The specification teaches only a single means by which the use of a transcription control sequence can coax a vertebrate cell to secrete EPO: by transforming that cell with an exogenous expression vector on which the transcription control sequence is linked to cloned EPO DNA. Yet the claims leave this essential aspect of the invention undefined. It is black-letter law that claims failing to recite a necessary element of the invention fail for lack of an enabling disclosure, In re Mayhew,
I must also disagree with the majority that the district court’s approach was faithful to this court’s articulation of the written description requirement of section 112, as expressed in Regents of the University of California v. Eli Lilly & Co.,
Nor am I convinced that the district court’s approach was faithful to Gentry Gallery. In Gentry, only those claims that included limitations such as “wherein the control means are located on the console” satisfied the written description requirement. Because the specification failed to disclose any location for the controls other than on the console, those claims that lacked such limitations were invalid under § 112, ¶1.
Even if we ignore the patents’ statement that the claimed EPO molecules are “uniquely characterized by being the product of ... expression ... of exogenous DNA sequences” (which of course we cannot), I think the parallels between this case and Gentry Gallery are inescapable. The invalid claims in Gentry recited elements that could readily be found in the text of the specification (a couch, controls, a console), but those claims nonetheless failed the written description requirement because they included no limitations on how those elements were arranged. Likewise, the '349 claims' — for which I think it must be conceded that structure of the EPO-secreting cell is a relevant question— recite particular elements found in the specification (cells, non-human control sequences, EPO-coding DNA), but do not include limitations on the arrangement of those elements, e.g. that the non-human control sequences and coding DNA are present on an exogenous expression vector in the cell. I agree that as a matter of claim interpretation there is no justification for importing an “exogenous DNA” limitation into the claims. But the absence of such limitations must weigh heavily in the section 112 inquiry, else we hold that claims become more resistant to written description challenges the more broadly drafted they are.
While I share my colleagues’ admiration for the considerable efforts of the district court in this complicated case, I cannot share their faith that the district court properly and conscientiously applied Eli Lilly and Gentry Gallery, when the district court’s opinion is completely devoid of reference either to those cases or to the principles they espouse. If the district court did not focus on the correct law to be applied, then its factual findings merit no deference, and the correct remedy for this omission is to vacate the district court’s judgment on this point and remand for further consideration. Our precedent has little value if the district courts may overlook its certain pertinence, if not its plain applicability.