The opinion of the court was delivered by: CONNER
CONNER, Senior District Judge:
This is an action for alleged infringement of three United States patents on acellular antigens and vaccines for pertussis, or whooping cough. The patents were issued in the name of Pavel Novotny on applications filed by his employer, Burroughs Wellcome Foundation Ltd. ("Burroughs Wellcome"). Plaintiff Medeva PLC ("Medeva") purchased the vaccine business of Burroughs Wellcome and the patents were assigned to Medeva's subsidiary, plaintiff Evans Medical Ltd. ("Evans"), which granted an exclusive license under the patents to plaintiff SmithKline Beecham Biologicals S.A. ("SmithKline"). Plaintiffs charge that the patents are infringed by a composite "DTaP" vaccine for diphtheria, tetanus and pertussis sold in the United States by defendants American Cyanamid Co. ("American Cyanamid") and American Home Products Corp. ("American Home Products") under the brand name ACEL-IMUNE(R), and incorporating acellular pertussis antigens produced in Japan by defendant Takeda Chemical Industries Ltd. ("Takeda"). The action is before the Court on a welter of pretrial motions.
Defendants have moved: (1) for a ruling by the Court under Markman v. Westview Instruments, Inc., 517 U.S. 370, 134 L. Ed. 2d 577, 116 S. Ct. 1384 (1996), construing the patent claims and for summary judgment that the claims, as so construed, have not been infringed by defendants' accused vaccine; (2) for summary judgment that the patents in suit are invalid because their specifications (all of which are identical) fail to disclose the best mode of practicing the invention known to the patentee at the time the applications were filed, as required by 35 U.S.C. § 112; (3) for summary judgment that the patents are invalid under 35 U.S.C. § 102 because the claimed inventions were anticipated by a prior patent of defendant Takeda and by the prior sale and use of Takeda's antigen in this country; (4) for summary judgment that the patents are invalid under 35 U.S.C. §§ 102 and 103 because the claimed inventions were anticipated by or obvious in view of a March 1985 article co-authored by Novotny, Juan Montaraz (a doctoral student under Novotny's supervision), and Juraj Ivanyi; (5) for an order in limine excluding certain testimony of plaintiffs' patent law expert Gerald Bjorge; and (6) for an order in limine excluding certain testimony of Tom Bozzo or any other witness regarding FDA approval of defendants' vaccine.
Plaintiffs have moved: (1) for partial summary judgment that the patents in suit are not anticipated by the prior patents and publications cited by defendants; (2) for partial summary judgment that, for purposes of determining whether the patent specification satisfies the best mode requirement of 35 U.S.C. § 112, the January 1990 deposit in the European Collection of Animal Cell Cultures of a hybridoma which secretes a monoclonal antibody used in purification of the patented antigen relates back to the May 1, 1985 filing of the parent U.S. application; (3) for an order pursuant to 35 U.S.C. § 256 directing correction of the patents in suit to add Montaraz as an inventor; (4) for an order compelling defendants to return certain inadvertently produced documents; (5) for an order in limine excluding the expert testimony of Dr. Alison Weiss; and (6) for an order in limine excluding evidence at trial of related litigation in the United Kingdom.
Following a background discussion, the motions will be discussed serially. Unless otherwise indicated, all of the background facts recited herein are undisputed.
Development of pertussis vaccines
Pertussis, or whooping cough, is one of the most common serious diseases of infants, with an estimated 50 million cases annually causing 600,000 deaths. A vaccine introduced in the late 1940's strikingly reduced the incidence of the disease in developed countries where large scale immunization programs were undertaken. But that vaccine was prepared from chemically killed whole cells of Bordetella pertussis ("B. pertussis"), the bacterium which causes whooping cough, and caused serious side effects in a significant number of those inoculated, including fever and persistent screaming. This resulted in curtailment of the immunization programs and a concomitant increase in the incidence of the disease.
The vaccines involved in the present case are acellular, incorporating not whole bacterial cells but selected proteinaceous material extracted from the outer membrane of B. pertussis bacteria by, for example, treatment with an amino acid solution. This breaks down the proteins of the outer membrane into fragments comprising long strands of amino acids connected in a sequence which determines the properties and behavior of the material. The extracted material is then subjected to a series of purification steps designed to increase the concentration of a particular protein, now known as pertactin, which has been found to have excellent immunogenic effect against B. pertussis infection. The pertactin strands have a number of active sites or epitopes which are recognized by the defensive white blood cells, or B lymphocytes, of the inoculated patient as characteristic of B. pertussis bacteria, thereby stimulating the lymphocytes to produce antibodies which will attack B. Pertussis bacteria in the event of a later infection and provide effective immunity without the serious side effects of whole cell vaccines. Acellular antigens containing pertactin are currently in widespread use in vaccines for B. pertussis, frequently in composite DTaP vaccines designed to immunize against diphtheria and tetanus as well.
Plaintiffs have sued on three U.S. patents: No. 5,237,052 (the "'052 patent"), No. 5,438,120 (the "'120 patent") and No. 5,648,080 (the "'080 patent"). (Exhs. 1-3 to Defs.' Motions for Summ. J.
) All three patents have identical specifications and are based upon the same parent U.S. application, Serial No. 929,257, filed May 1, 1985, which claims priority based upon the United Kingdom specification Serial No. 8,412,207, filed May 12, 1984.
The patents were issued in the name of Pavel Novotny and were based in part on work done in the laboratory of Burroughs Wellcome by Novotny's student assistant, Juan Montaraz, who used the research as the basis for his doctoral thesis and as the subject of an article entitled "Identification of a 68-Kilodalton Protective Protein Antigen from Bordetella bronchiseptica," published in the March 1985 issue of INFECTION AND IMMUNITY in the names of Montaraz, Novotny and Juraj Ivanyi (the "Montaraz et al. article").
The common specification of the patents in suit identifies the desired antigen as "proteinaceous material associated with adenylate cyclase activity" (referred to by the acronym ACAP) and as having an isoelectric point ("pI")
of "about 7," "a relative molecular weight of about 67,000 to 73,000, particularly 69,000"
and a "proline:glutamic acid ratio of about 1:1."
The specification discloses a preferred process of preparing the patented antigen. The first step of this process, denominated "Example 1," involves incubating a culture of B. pertussis cells with an aqueous amino acid buffer with a pH of about 3 for 10-20 hours at 30-45 [degrees] C. The mixture is centrifuged at 100,000g to separate the cells and particulate matter. The supernatant extract is then subjected to a multi-step purification process, the several steps being respectively denominated "Examples 2(a), 2(b) and 3."
"Example 2(a)" consists of separating the fractions of the extracted outer membrane material by chromatography in a DEAE-Trisacryl column.
The retained protein molecules are eluted from the column by flushing with an 0.2M NaCl buffer.
"Example 2(b)" consists of preparative flat-bed isoelectric focusing ("IEF") in a granulated gel.
The eluate from Example 2(a) is embedded in the gel. After electrophoresis, the material which collects in the band at a pI of 7 is scraped from the field and dissolved in distilled water. The gel suspensions are placed in columns and eluted with an 0.2M ammonium bicarbonate buffer at pH 7.0 to produce a gel-free eluate.
"Example 3" consists of further purification of the separated protein material in an immunosorbent chromatographic column charged with "a monoclonal immunoglobulin specific for ACAP." In the parent U.S. application filed May 1, 1985, the monoclonal antibody employed in this final purification step was not otherwise described. It was not until September 21, 1992, over seven years after the filing of the application, and over eight years after the claimed U.K. priority date, that a fifth-generation continuation of the parent U.S. application was amended to add the following reference for identification of the key monoclonal antibody:
The hybridoma which secretes the monoclonal immunoglobulin was deposited under the Budapest Treaty at the European Collection of Animal Cell Cultures, Proton Down, United Kingdom on Jan. 5, 1990 under accession number 90010501.
As the final step in the process of preparation described in the patent specification, denominated "Example 4," the purified ACAP is cultured in a liquid medium containing 2% agar and 5% horse blood for 48 hours at 36-37 [degrees] C while agitating to provide a gas exchange rate of 20-40 [mu] M oxygen/hr. The liquid cultures are then used to inoculate the medium in a glass fermentor, with the pH maintained at 7.6 by the controlled addition of 2M HCl and the oxygen saturation maintained at 5-10% by impeller agitation. The cultures are harvested before the end of the exponential growth phase, or after approximately 36 hours of incubation.
"Example 5" consists of verifying the protective potency of the antigen by employing it in a standard Kendrick test on mice.
"Example 6" involves analysis of the ACAP to ascertain its relative content of the respective amino acids of which it is composed. Sixteen different amino acids had measurable residues after hydrolysis and dessication. Proline and glutamic acid had relative amino values of 60 and 62, respectively.
"Example 7" involves use of the ACAP antigen in aqueous solutions to form pertussis vaccine or, in combination with diphtheria and tetanus antitoxins, to form composite DTaP vaccines.
The '052 patent has only two claims. Claim 1 reads as follows:
A purified Bordetella pertussis antigen characterized by the following features:
a relative molecular weight of between 67,000 to 73,000 as determined by 12% (w/w) polyacrylamide gel electrophoresis;
a ratio of proline to glutamic acid of substantially 1:1 as determined by amino acid analysis.
Claim 2 is identical to Claim 1 except that it specifies "a relative molecular weight of 69,000."
The '120 patent contains only one claim, which is identical to Claim 1 of the '052 patent except that it specifies "a relative molecular weight of between 67,000 and 69,000."
The '080 patent contains fourteen composition claims (Nos. 1-14) directed to a vaccine incorporating the antigen of the '052 and '120 patents and fourteen method claims (Nos. 15-28) directed to inducing an immune response in a patient by administering the vaccine of Claims 1-14.
Claim 1, the only independent composition claim of the '080 patent; reads as follows:
A vaccine which comprises a proteinaceous material, which is derived from the outer membrane of Bordetella pertussis and is characterized by a relative molecular weight of about 67,000 to about 73,000 as determined by 12% (w/w) polyacrylamide gel electrophoresis and a proline:glutamic acid ratio of about 1:1 as determined by amino acid analysis in a pharmaceutically acceptable carrier or adjuvant.
Claim 15, the only independent method claim, reads as follows:
A method of inducing an immune response in a patient, which method comprises administering to said patient a vaccine which comprises a proteinaceous material, which is derived from the outer membrane of Bordetella pertussis and is characterized by a relative molecular weight of about 67,000 to about 73,000 as determined by 12% (w/w) polyacrylamide gel electrophoresis and a proline:glutamic acid ratio of about 1:1, as determined by amino acid analysis in a pharmaceutically acceptable carrier or adjuvant.
Prosecution history of the patents in suit
The U.K. application from which priority is claimed for the patents in suit was filed May 12, 1984. Its disclosure differed somewhat from that of the parent U.S. application. It began by acknowledging that acellular pertussis vaccines containing antigens extracted from the outer membrane of B. pertussis bacteria were known in the prior art, but asserted that "we have now discovered that adenylate cyclase, an enzyme found in the cultures of B. pertussis. . . . is a major protective antigen against B. pertussis," a discovery which "permits the preparation of vaccine formulations comprising antigenic preparations which are free from, or contain reduced amounts of, other B. pertussis components which are responsible for the toxic side-effects demonstrated by whole-cell vaccines." The U.K. specification thus proceeded to describe a procedure for preparing "an antigenic preparation comprising adenylate cyclase . . . . [which] generally has a molecular weight of about 69,000 and an isoelectric point of 7.6-7.2 under preparative conditions. . . . [and which] may, if desired, contain minor quantities of other antigenic compounds . . . . [but is] preferably substantially free from other antigenic components."
It is therefore clear that at the time the U.K. priority application was filed, Novotny and his associates believed that the antigenic enzyme critical to effective protection against B. pertussis infection was adenylate cyclase, and they accordingly described a method of extracting it, along with other proteinaceous material, from the outer membrane of B. pertussis bacteria and purifying it to substantially eliminate the other proteinaceous material. Indeed, Novotny admitted this in an Addendum to his 1995 paper "Identification of 68, 69 and 71 kDa Proteins of Bordetella Species," and added that it was not until after a visit by Professor Erik Hewlett and Dr. Alison Weiss from the United States in October 1984 that he "started to have serious doubt" that the protective enzyme was adenylate cyclase. (Exh. 22, Addendum.) He ultimately concluded that the effective 69 kDa antigen was not adenylate cyclase, but a different enzyme with "adenylate cyclase activity." (See Novotny Dep., June 4, 1997, Exh. 50 at 7, 43-44.)
Novotny's original U.S. application, filed May 1, 1985, accordingly described the key antigen less specifically as "proteinaceous material associated with adenylate cyclase activity (abbreviated to 'ACAP' hereinafter)" and added that it "may comprise the adenylate cyclase enzyme per se or a binding protein for the enzyme."
Claim 1 of the U.S. application as filed described the antigen merely as "proteinaceous material associated with adenylate cyclase activity (ACAP)." A series of dependent claims respectively added other characteristics of the material, such as "a relative molecular weight (MW) of 67,000-73,000," "an isoelectric point (pI) of 7.0-7.4 under preparative isoelectric focusing (IEF) conditions" and a "ratio of proline to glutamic acid residues . . . [of] substantially 1:1."
All of the claims were rejected by the PTO Examiner as anticipated by or obvious in view of a paper by Erik Hewlett and J. Wolff entitled "Soluble Adenylate Cyclase from the Culture Medium of Bordetella pertussis : Purification and Characterization," published in the August 1976 edition of BACTERIOLOGY (the "Hewlett & Wolff article," Gram Aff., Exh. F). That article disclosed the extraction of adenylate cyclase from B. pertussis and its purification first by DEAE-cellulose chromatography and then by SDS electrophoresis. The purified product had a molecular weight of 69,000. Through some seven years of prosecution, and a series of continuation and divisional applications, the broadest claims were amended to import limitations from the original dependent claims, including those specifying molecular weight and the proline:glutamic acid ratio. Novotny then sought to overcome the rejection based on the Hewlett & Wolff article by filing a declaration under 37 CFR § 1.132 of Erik Hewlett, one of the authors of the article, stating that the adenylate cyclase produced by the process described therein did not have a proline:glutamic acid ratio of substantially 1:1, as called for in the amended claims.
The PTO Examiner also repeatedly rejected all of the claims as anticipated by or obvious in view of the prior U.S. patent No. 3,141,824 to Robert Dahlstrom which was issued July 21, 1964 on an application filed May 29, 1961 (the "Dahlstrom patent," Exh. 6). Dahlstrom disclosed the extraction of a B. pertussis antigen from B. pertussis bacteria by a process which the Examiner concluded would produce some ACAP even if Dahlstrom had not specifically been seeking it.
After the rejection of the claims had been made final, the Examiner suggested that the rejection could be overcome if the claims were further amended to limit them to "A purified. . . antigen." Such an amendment was filed August 22, 1992 (see Exh. 43) and ultimately resulted in the allowance of the applications.
Defendants' accused antigens and vaccine
Takeda has manufactured and sold an acellular pertussis vaccine in Japan since 1981. On September 12, 1980, it filed an application for a Japanese patent on the method of producing toxoid (antigen) for such a vaccine, and filed a corresponding U.S. application on January 30, 1981. U.S. patent No. 4,455,297 (the "Takeda patent") was issued June 19, 1984 on a continuation of the U.S. application. (See Exh. 5.)
Like Novotny, Takeda extracts a mixture of antigens from B. pertussis bacteria and treats the extract with formalin (an aqueous solution of formaldehyde) to remove toxins. Unlike Novotny, however, Takeda does not attempt to purify the mixture to eliminate other antigens and achieve a concentrated pertactin. Thus, pertactin constitutes only about 4% of the Takeda mixture of antigens. The relative molecular weight of the Takeda pertactin is approximately 69 kDa, but its proline:glutamic acid ratio is about 0.86:1, as measured by amino acid analysis. Further, Takeda's tests show that Takeda's pertactin has no adenylate cyclase activity, a finding which plaintiffs have not disputed.
I. DEFENDANTS' MOTION FOR A MARKMAN RULING
Markman v. Westview Instruments, 517 U.S. 370, 134 L. Ed. 2d 577, 116 S. Ct. 1384 (1996), holds that patent claim construction is an issue of law to be resolved by the Court. Injury cases, once the Court has construed the claims, the jury determines as an issue of fact whether the claims, as thus construed, are infringed -- either literally or under the doctrine of equivalents -- by the accused product or method. Wright Med. Tech., Inc. v. Osteonics Corp., 122 F.3d 1440, 1443 (Fed. Cir. 1997).
In determining the meaning of the claims, the Court must first examine the "intrinsic" evidence -- i.e., the claims themselves, the specification and, if in evidence, the prosecution history. Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir. 1996). If this intrinsic evidence permits an unambiguous construction of the claim language, the Court need not, and indeed should not, consider extrinsic evidence, such as testimony from expert witnesses as to special meanings which the terms of the claims have for those skilled in the art. See id. at 1585.
In this case, defendants raise three questions concerning the applicability of the language of the broadest patent claims to their accused antigens. They contend (1) that their accused ACELIMUNE(R) vaccine does not include "purified" 69k, as called for in the claims of the '052 and '120 patents, but a mixture of antigens of which 69k constitutes only 4%; (2) that their 69k antigen does not have a proline:glutamic acid ratio of "substantially 1:1" as called for in the claims of the '052 and '120 patents, or "about 1:1" as called for in the claims of the '080 patent, but a ratio of 0.86:1; and (3) that the claims of all three patents in suit must be limited to cover only antigens having adenylate cyclase activity, which their antigens do not have. Thus the Markman issues to be resolved by the Court concern the meaning of the terms "purified" and "substantially 1:1" or "about 1:1," and whether a requirement of adenylate cyclase activity should be read into the claims. These issues will be discussed separately in that order.
A. What does "purified" mean in the context of the patents in suit?
There can be no question as to the critical importance of this limitation which appears in each of the claims of the '052 and '120 patents. All the application claims were repeatedly rejected as unpatentable over the prior art references (especially the Dahlstrom patent) over some seven years of prosecution and through many continuation and divisional applications until, in response to the Examiner's repeated suggestion, the claims were finally amended to limit them to a "purified" 69k antigen. However, the parties hotly dispute the meaning of this limitation.
Plaintiffs contend that it means only that the desired material has been at least partially separated or isolated from an unwanted material -- in other words, that any degree of purification suffices. Defendants urge a construction at the opposite end of the spectrum, one requiring that the extracted proteinaceous material be put through all of the purification steps described in the specification, including the final immunopurification step of "Example 3." On the basis of the intrinsic evidence alone, it is difficult to conclude that either of these extreme positions is the correct one, although that of defendants seems closer to the mark.
Our analysis begins of course with the patent specification, which discloses a vaccine wherein the only active ingredient mentioned is "an antigenic preparation derived from B. pertussis comprising ACAP, optionally toxoided e.g. using formalin, glutaraldehyde or [beta] -propiolactone, together with a pharmaceutically acceptable carrier therefor." ('052, 2/54-59.) All the specific examples of vaccine formulations given include "antigen according to the invention" as the only active ingredient. ('052, 9/36-10/26.)
The specification, after discussing the prior research in "isolating and purifying the 20 or more surface antigens of the B. pertussis organism and characterising their ability to induce immune reactions," states that among the antigens suggested for such investigation is adenylate cyclase. ('052, 1/54-64.) The specification then discusses several prior methods of reducing the toxicity of the extracted proteinaceous material, including that of defendant Takeda's U.K. Patent Specification 2 047 358 A, which discloses production of a B. pertussis extract vaccine "involving removal of endotoxin from culture supernatants." ('052, 2/6-9.)
The specification initiates its discussion of the patented invention by stating:
It has now been discovered that certain proteinaceous material, associated with adenylate cyclase activity, as hereinafter described, found in the cultures of B. pertussis, is capable of providing protection against challenge by B. pertussis when administered to experimental animals. This discovery that the proteinaceous material usually associated with adenylate cyclase activity is a major protective antigen against B. pertussis permits the preparation of vaccine formulations comprising antigenic preparations which are free from, or contain reduced amounts of, other known B. pertussis components which may be responsible for the toxic side-effects demonstrated by whole cell vaccines.
('052 2/28-40; emphasis added.) The specification later adds that although the patented antigenic preparations may have "minor quantities of other antigenic compounds, in addition to the ACAP," they are "preferably substantially free from other antigenic compounds." ('052, 3/34-42; emphasis added.) Then, after describing the disadvantages of prior methods of extracting ACAP from the outer membrane of B. pertussis organisms, the specification states:
We have now discovered that . . . extraction of B. pertussis organisms using regulated, mildly acidic conditions results in the extraction of substantially increased yields (about 40x better than previously reported techniques) of adenylate cyclase from the outer membrane in a form which is water-soluble.
('052, 4/6-12.) The specification then more specifically describes the extraction process, including incubation of the B. pertussis cells with an amino acid buffer and centrifuging to separate the cells from the ACAP-containing supernatant. ('052, 4/13-37.) It continues to describe use of the supernatant extract in the Kendrick test on mice, from which it was learned that
. . . control vaccines containing no adenylate cyclase activity were found to provide little or no protection against challenge with B. pertussis, suggesting that ACAP may, in fact, be the most important factor in immunity. Analysis of batches of non-protective whole-cell vaccine has also shown that non-protection tends to be associated with a lack of adenylate cyclase activity, further suggesting that ACAP may be the key antigen necessary for eliciting an immune response against B. pertussis.
('052, 4/41-50; emphasis added.)
The specification then teaches a multi-step purification process for producing the "purified" ACAP antigen, commencing with the "Crude Outer Membrane Proteins" extracted in the first step, which is described in "Example 1." ('052, 5/54-55.) Plaintiffs have admitted that this "crude" mixture is not a "purified" material. (Exh. 30, Interrog. # 9.)
In support of their contention that the ACAP is "purified" only after it has been put through all the steps of the purification process described in the specification, including the immunopurification step of "Example 3," defendants point out that "Example 3" is entitled "Purification of ACAP Using a Monoclonal Immunosorbent Column," ('052, 7/26-28), and that none of the products of the earlier steps in the process is described as a "purified" material. On the other hand, plaintiffs lay principal stress on the fact that in its initial, summary description of the purification process, the specification states:
The supernatant extract [from "Example 1"] . . . may . . . contain the ACAP in small quantities complexed with other proteins including fragments of LPS [lipopolysaccharide, which is suspected as the cause of toxic side effects], in which case it may be desirable to purify further the material for use in the vaccine formulations according to the invention. Thus, for example, further purification may be effected by ion exchange chromatography and/or by preparative isoelectro-focussing to eliminate complexed material. . . . After the above-described purification steps the ACAP may, if desired, be further purified, for example by passing the material through an immunosorbent column containing an appropriate monoclonal antibody against the ACAP.
('052, 4/51-68; emphasis added.) Since the process steps denominated "Example 2(a)" and "Example 2(b)" are referred to as "purification" of the extract, plaintiffs argue that the product of those steps must be deemed to have been "purified" in the lexicography of the patent. However, this argument proves too much: because these steps are described as "further purification," carrying plaintiffs' argument to its logical conclusion would mean that the crude extract resulting from "Example 1" would likewise have to be deemed "purified." But, as already noted, plaintiffs have admitted that that product is not purified, as indeed they must in view of the prior art and the prosecution history of the applications for the '052 and '120 patents.
The limitation of the broadest claims of those applications to a "purified" ACAP material was added during prosecution to overcome the rejection of the claims as unpatentable over the cited references, particularly the Dahlstrom patent. Dahlstrom discloses the preparation of a B. pertussis antigen by extraction of proteinaceous material from B. pertussis cells in a saline solution (pH 8.5-10.5), which is later neutralized by the addition of sterile acid and centrifuged to separate the cells. The extracted antigen was tested for immunogenic potency by injection into mice and challenge by B. pertussis organisms introduced intracerebrally. Because Dahlstrom's antigen provided excellent immunity, with a 100% survival rate at a dosage of 0.015ml, it must have included a significant amount of ACAP, if we are to believe the teaching of the patents in suit that "vaccines containing no adenylate cyclase activity were found to provide little or no protection against challenge with B. pertussis " and that ACAP "may be the key antigen necessary for eliciting an immune response against B. pertussis." ('052, 4/41-50.) Thus there was ample support for the PTO Examiner's conclusion that the Dahlstrom process "inherently . . . would result in the extraction of Applicant's claimed protein. Note that Applicant's claims 28-32 do not require the antigen to be purified." ( Exh. 41 P 5.) Novotny acquiesced in that conclusion by amending all of the claims of the application for the '052 patent so that they cover only a "purified" 69k antigen.
Nevertheless, in his co-pending application for the '120 patent, Novotny made another effort to obtain the coverage which he had thus relinquished, asserting claims similar to those of the '052 patent except that the word "purified" was replaced with the word "acellular" (See Exh. 31 at 3.) These broader claims were rejected as unpatentable over an article by Novotny and K. Cownley -- "Effect of Growth Conditions on the Composition and Stability of the Outer Membrane of Bordetella pertussis " -- published in 1978 as part of the Proceedings of the Third International Symposium on Pertussis (the "Novotny & Cownley article"). In rejecting the claims, the Examiner stated that "the rejected claims do not contain any limitations which would distinguish the claimed products from the isolated outer membrane of the [Novotny & Cownley] article on the basis of purity." ( Exh. 32 P 6.) Novotny thereafter amended all the claims to limit them to "purified" 69k. (See Exh. 34.)
Therefore, there can be no dispute that the claim limitation to a "purified" material requires, at the least, sufficient purification to distinguish it from the extracted ACAP-containing material of the prior art, including the Dahlstrom patent and the Novotny & Cownley article, which was cited in rejecting the claims. It is clear that a "purified" ACAP is one that results from subjecting the mixture of proteins extracted from the outer membrane of B. pertussis bacteria to one or more purification steps which, to a substantial degree, isolate ACAP and eliminate the other antigens in the mixture. The only remaining question is how much purification is required for the material to be deemed "purified" within the meaning of the claims?
Defendants' argument that the third step (immunopurification), "Example 3," is necessary to achieve a "purified" material runs contrary to the specification's statement that the final step is optional:
After the above-described purification steps ["Example 2(a)" and "Example 2(b)"] the ACAP may, if desired, be further purified by passing the material through an immunosorbent column containing an appropriated monoclonal antibody against the ACAP ["Example 3"].
('052, 4/64-68; emphasis added.)
In opposition, plaintiffs argue that, because the limitation to a "purified" 69k was added to the broadest claims of the '052 and '120 patents to overcome their rejection as anticipated by or obvious in view of the prior Dahlstrom patent, the limitation should be construed as narrowing the claims only to the minimum extent necessary to overcome the rejection based on Dahlstrom. At the oral argument of the motions, plaintiffs' counsel conceded that the extraction and centrifugation steps of Dahlstrom constitute "purification." (Transcript of May 26, 1998 Oral Argument at 27.) Yet he argued that the claims of the '052 and '120 patents must be construed so as to cover antigens which have undergone any degree of purification beyond that performed by Dahlstrom.
However, that argument considers only one type of intrinsic evidence -- the prosecution history -- and ignores the equally important intrinsic evidence of the specification itself, which contains strong indications as to the meaning of the term "purified." The specification teaches that ACAP may be the "key antigen" for immunization against B. pertussis, that "the vaccine formulations according to the invention may, if desired, contain minor quantities of other antigenic compounds, in addition to the ACAP . . . . [but are] . . . preferably substantially free from other antigenic components." ('052, 3/33-42; emphasis added.)
Moreover, the only antigen that is described in the specification as "purified" is the product of the immunopurification step of "Example 3." At the oral argument, plaintiffs' counsel contended, with impressive ingenuity, that this step is unnecessary to produce a safe and effective antigen and was disclosed only so that Novotny "could characterize and identify [69k] as part of his teaching." (Tr. at 26-27.) But Novotny's specification taught immunopurification as the final step in producing an "antigen according to the invention." There is not the slightest suggestion that it was disclosed only as a means of identifying the new antigen which Novotny claims to have discovered.
After thorough consideration of all the intrinsic evidence, the Court concludes that the term "purified" in the claims of the '052 and '120 patents means that the mixture of proteins extracted from the outer membrane of B. pertussis has been treated to reduce the concentration of antigens other than 69k at least to the point where they are "minor" ingredients and 69k is the major remaining antigen. In other words, 69k must constitute, at the minimum, more than half of the extracted proteinaceous material present in the mixture.
If there were any doubt about this conclusion, resort to the most persuasive extrinsic evidence -- the testimony of the patentee Novotny against his own interest -- would only narrow the definition further in favor of the defendants. In pretrial depositions, Novotny stated unequivocally that the extracted material is not "purified" even after it has been subjected to the preliminary purification steps of "Example 2(a)" and "Example 2(b)" and not until it has gone through the final immunopurification step of "Example 3":
Q: At the end of Example 2(a), after you have performed that procedure, do you have something that is purified, as you understand the meaning of that term?
A: No, it was crude separation of some components which we weren't interested in, and some components which we wanted to proceed further, which was made, at that time, electrofocusing.
Q: What about the procedure of Example 2(b), which is: "Preparative flat bed isoelectrofocusing [in] granulated gel" . . . . At the end of that procedure, do you have something that was purified, as you understand that term?
A: No, it was still complex.
Q: Turning to Example 3 in column 7, that example is entitled: "Purification of ACAP using a monoclonal immunosorbent column."
Q: What were you trying to achieve in that procedure?
A: No, that's the final step of the purification which started in column 5, because [the] immunosorbent column was specific for the protein. So, it stuck to the column and was then eluted from the immunosorbent and you obtained a variety of a very pure preparation.
Q: So, according to your understanding, it is only after someone completes the procedure of Example 3, with monoclonal antibodies, that you have a purified ...