# Petition for Writ of Certiorari — Bristol-Myers Squibb Co. v. Zenith Laboratories, Inc. > Briefs, arguments, decisions, and more. URL: https://www.frixlaw.com/law-library/documents/brief%3Amicro_IA40386012_0456%3A1 ## Record - **Collection:** Supreme Court brief - **Document type:** Petition for Writ of Certiorari - **Published:** January 1, 1994 - **Citation:** 513 U.S. 995 ## Text ‘Supreme Court, y FILED -S. No. 94 494 SEP 1 4 1994 OFFICE OF THE CLERK IN THE Supreme Court of the United States OCTOBER TERM, 1994 BRISTOL-MYERS SQUIBB COMPANY, ‘ Petitioner, ZENITH LABORATORIES, INC., Respondent. Petition for a Writ of Certiorari to the United States Court of Appeals for the Federal Circuit PETITION FOR A WRIT OF CERTIORARI H. BARTOW FARR, III (Counsel of Record) RICHARD G. TARANTO FARR & TARANTO 2445 M Street, NW Washington, DC 20037 (202) 775-0184 S. LESLIE MISROCK BRIAN D. CocGcio STEVEN I. WALLACH KENT H. CHENG PENNIE & EDMONDS 1155 Avenue of the Americas New York, NY 10036 hearse MRR WILSON - EPes PRINTING Co., INC. - 789-0096 - WASHINGTON, D.C. 20001 QUESTIONS PRESENTED 1. Whether proof of literal infringement of a patent for a new composition of matter (e.g., a chemical compound ) requires examination of each item of information in the patent claim, even when that information consists of scientifically redundant, overinclusive “fingerprint” data included for evidentiary identification of the patented composition, rather than restrictive conditions that pre- cisely define and limit the patented aspects of the com- position. 2. Whether a valid patent lacks protection against infringement under the doctrine of equivalents except to the extent the invention performs a function not previ- ously performed by any prior art. (i) ii RULE 29.1 STATEMENT Petitioner Bristol-Myers Squibb Company has no parent company. Its non-wholly owned subsidiaries are the fol- lowing: Laboratoires UPSA; Nyagen; RCS Realty Cor- poration; Sino American Shanghai Squibb Pharma Ltd.; Squibb Nigeria Limited; UPSA Investissements; 2309 Realty Corporation; Bristol-Myers Lion Ltd.; Bristol- Myers Squibb G.M.B.H.; P.T. Squibb Indonesia; Squibb of Bangladesh Limited; Synbiotics Limited; Mead John- son. TABLE OF CONTENTS Page QUESTIONS PRESENTED ..........--:.i el sat ata bts dts Syne Ale called tee 25 The protection stripped from a large range of inven- tions is of dramatic significance. Many and perhaps most patents involve inventions that perform old functions: again, that is what makes pioneer patents distinctive.” And the doctrine of equivalents, far from being a minor ap- pendage to the guarantee against literal infringement, is so fundamental to patent law that it has been described as stating “[t]he critical test in any infringement suit.” A. Miller & M. Davis, Intellectual Property: Patents, Trade- marks, and Copyright in a Nutshell 124 (2d ed. 1990); see id. at 126. Indeed, this Court has said that, without the “wholesome realism” of the protection furnished by the doctrine of equivalents, a patent would be a “hollow and useless thing.” Graver Tank, 339 U.S. at 608, 607. Because “minor deviations in the structure of almost any invention could be devised to elude the reach of the patent’s protection, . . . a patent would be virtually worth- less if it did not protect against devices which incorporate unimportant variations of the patented device.” Ziegler, 483 }.2d at 868; see Graver Tank, 339 U.S. at 607 (“Outright and forthright duplication is a dull and very rare type of infringement. To prohibit no other would place the inventor at the mercy of verbalism and would be subordinating substance to form.”). The Federal Circuit’s ruling is anything but the sort of finetuning of patent-law principles, or settling of rules where clarity is as important as content, that this Court should leave to that court for final determination. Rather, the ruling destroys a fundamentally important protection not.”); SRI Int’l, 775 F.2d at 1123. In this case, the Federal Circuit, while recognizing the validity of the ‘657 patent, denied Bristol-Myers the right to control one use of that very invention— as medicine in vivo. 22 Most patents are not pioneer patents and hence do not perform “a function never before performed” (Westinghouse, 170 U.S. at 561-62). See National Hollow Brake-Beam Co. v. Interchangeable Brake-Beam Co., 106 F. 693, 710-11 (8th Cir. 1901); 6. E. Lipscomb, Walker on Patents § 22:41, at 557-58 (3d ed. 1987). 26 for a significant class of valid patents. This Court should grant the petition to review and reverse the Federal Cir- cuit’s ruling. CONCLUSION The petition for a writ of certiorari should be granted. Respectfully submitted, H. BARTOW FArR, III (Counsel of Record) RICHARD G. TARANTO FARR & TARANTO 2445 M Street, NW Washington, DC 20037 (202) 775-0184 S. LESLIE MISROCK BRIAN D. CoGGIo STEVEN I. WALLACH KENT H. CHENG PENNIE & EDMONDS 1155 Avenue of the Americas Dated: September 14, 1994 New York, NY 10036 APPENDICES la APPENDIX A UNITED STATES COURT OF APPEALS FOR THE FEDERAL CIRCUIT 92-1527 ZENITH LABORATORIES, INC., Plaintiff-A ppellant, Vv. BRISTOL-MYERS SQUIBB COMPANY, Defendant-A ppellee. Appealed from U.S. District Court for the District of New Jersey Judge Wolin Decided: March 24, 1994 [corrected March 31, 1994] Before PLAGER, CLEVENGER, and SCHALL, Circuit Judges. PLAGER, Circuit Judge. The question in this declaratory judgment action is whether a drug compound, which in its manufactured state does not infringe the patent in suit, becomes in- fringing as a result of transitory chemical changes that occur in vivo, that is, as a result of ingestion by the patient. There are fact issues—what changes actually occur when the drug is ingested, and how do we know; 2a there are legal issues—does a compound that changes in the human body into the patented product on its way to becoming the active ingredient in the drug (the original patent on the active ingredient having earlier expired) literally infringe, infringe under the doctrine of equiva- lents, or infringe by inducement. The District Court for the District of New Jersey, Civil Action No. 91-3423, entered judgment, following a bench trial, that plaintiff/appellant Zenith Laboratories, Inc.’s (Zenith) commercial sale of cefadroxil DC induces infringement of U.S. Patent 4,504,657 (the ’657- patent),* the patent at issue. Zenith Lab. Inc. v. Bristol-Myers Squibb Co., 24 USPQ2d 1652 (D.N.J. 1992) (Zenith II). The ’657 patent is owned by Bristol-Myers Squibb Co. (Bristol). For the reasons set forth, we reverse. BACKGROUND The chemical compound cefadroxil, an antibiotic of the cephalosporin family effective against bacteria that are resistant to penicillin, was described and claimed in United States Patent No. 3,489,752 (the ’752 patent), which issued in 1970; the owner was Bristol. The claims of the ’752 patent covered any and all forms of cefa- droxil—they described the chemical compound per se. The ’752 patent expired in 1987. In the meantime, Bristol set to work to find a com- mercially useful crystalline form of the compound that would overcome problems related to manufacture of the product so that it would be usable by humans. The task of developing a commercial production process was as- signed to certain of Bristol’s chemists. They developed what became known as the Bouzard monohydrate, named after one of the discoverers—a new crystalline form of cefadroxil. Unlike prior forms of cefadroxil, Bouzard 1That patent issued March 12, 1985, and thus will expire on March 12, 2002. 3a monohydrate possesses certain characteristics in its pre- ingested, powdered form, related to bulk density, solu- bility, and stability (manufacturing-related characteris- tics), which make it particularly suitable for packaging into capsules. The Bouzard monohydrate was the subject of the single claim in the ‘657 patent: 1. Crystalline 7 - [D-a-amino-«-(p-hydroxyphenyl-) acetamido]-3-methyl-3-cephem-4-carboxylic acid mon- ohydrate exhibiting essentially the following x-ray diffraction properties: [a 37-line table of relative intensities exhibited by Bouzard monohydrate at various scan angles]. In July 1988, Zenith, the plaintiff in this declaratory judgment action, contracted with a Spanish company, Gema, S.A. of Barcelona (Gema), to become the exclu- sive United States distributor of the form of cefadroxil manufactured by Gema and known as cefadroxil DC. Cefadroxil DC is a hemihydrate form of cefadroxil and thus differs structurally from Bouzard monohydrate.” Zenith and Gema then undertook to obtain approval from the Food and Drug Administration (FDA) for commer- cial marketing in the United States of cefadroxil DC. Pursuant to FDA regulations, Zenith and Gema sought abbreviated approval on the grounds that cefadroxil DC was bioequivalent to a form of cefadroxil monohydrate (other than Bouzard monohydrate) which had already been approved by the FDA for commercial sale. In Octo- ber 1990, the FDA granted approval.* 2The difference is the number of water molecules which are paired with each cefadroxil molecule. 8The record suggests that the FDA subsequently reconsidered and rescinded this approval after Bristol filed with the FDA a citizens petition seeking to block approval on the grounds cefa- droxil DC was a hemihydrate and thus not bioequivalent to cefa- droxil monohydrate. The record does not indicate whether the FDA thereafter approved Zenith’s application. ——— 4a In June 1991, after learning of Zenith’s and Gema’s efforts to obtain FDA approval, Bristol filed suit against Gema (and Gema’s affiliates) in the District Court for the District of Maryland, Civil Action No. HAR 91-1765 (the Maryland action), alleging infringement of the ’657 patent. Subsequently, when Gema announced it was abandoning its plans to manufacture cefadroxil DC, that Suit was dismissed upon stipulation of the parties. Zenith then, in August 1991, filed the present declara- tory judgment action against Bristol in the District Court for the District of New Jersey. Zenith’s complaint con- tained four counts. In count one, Zenith sought a decla- ration that cefadroxil DC does not infringe the ’657 patent, and in count two, a declaration that Bristol is equitably estopped from asserting that cefadroxil DC in- fringes the ‘657 patent. In count three, Zenith alleged that Bristol, by initiating the Maryland action, violated a consent decree previously entered in settlement of prior litigation between the parties; and in count four, that Bristol had engaged in unfair competition. (Zenith subse- quently added a fifth and still pending count alleging that Bristol had committed antitrust violations. ) Bristol then moved to dismiss counts one and two, and for summary judgment on counts three and four. Zenith filed cross-motions for summary judgment on these counts. On December 12, 1991, the trial court granted Bristol’s motion to dismiss count three (concerning the prior con- sent decree) on the ground that the count was moot in view of the previous dismissal of the Maryland action. Zenith Lab. Inc. v. Bristol-Myers Squibb Co., 24 USPQ 2d 1641, 1651 (D.N.J. 1991) (Zenith 1). As to Zenith’s motion for summary judgment on count one (the infringe- ment count), the court stayed that motion pending an oral hearing. 7d. at 1648. The court denied all other motions. Jd. at 1648, 1650-51. At the hearing on the infringement count, Bristol con- ceded that cefadroxil DC, being a hemihydrate, did not 5a literally infringe the ’657 patent in its pre-ingested form. Bristol nevertheless argued that Zenith was liable under the patent on two grounds; Zenith’s product infringed under the doctrine of equivalents; and Zenith’s product converted into the patented compound in the patient's stomach, and thus the sale of cefadroxil DC would induce infringement of the ‘657 patent under 35 U.S.C. § 271(b) (1988). The trial court concluded that summary judg- ment was appropriate since Bristol had not raised a genuine factual dispute on these issues; and on March 4, 1992, the court granted Zenith’s motion for summary judgment on count one. However, subsequently, on April 16, 1992, upon Bris- tol’s motion for reconsideration, the court vacated its March 4, 1992 decision. The court denied Zenith’s mo- tion for summary judgment on count one on the basis that Bristol, through two declarations submitted with its motion for reconsideration, had demonstrated a genuine dispute on the in vivo conversion issue. Consequently, it ordered that that count be severed from the remaining counts and tried separately. From May 26, 1992 through June 5, 1992, the court conducted a bench trial on count one. Following the trial, the court rejected Bristol’s theory of infringement under the doctrine of equivalents. It found that Bristol, through prosecution history estoppel, had relinquished coverage of cefadroxil DC. However, the court found that cefadroxil DC converts to Bouzard monohydrate in the patient’s stomach. Since an act of literal infringement thus occurs in the patient’s stomach as a result of ingestion of cefadroxil DC, the court concluded that Zenith’s sale of cefadroxil DC would induce infringement of the ‘657 patent. On August 6, 1992, the court, in accordance with its findings and conclusions, entered judgment for Bristol. Zenith II, 24 USPQ2d 1652. The court, pursuant to 35 U.S.C. § 271(e)(4) (A) (1988), ordered that the effec- ———E—EE—— 6a tive date of any approval by the FDA of cefadroxil DC for commercial distribution and sale by Zenith could be no earlier than March 12, 2002, the expiration date of the ‘657 patent. Jd. at 1676. It subsequently certified the finality of that judgment pursuant to Rule 54(b) of the Federal Rules of Civil Procedure. Zenith then filed this appeal. DISCUSSION Zenith presents five separate grounds on which the judgment of the trial court should be reversed. First, the claim of the ‘657 patent, properly construed, does not cover Bouzard crystals which might form momentarily in a patient’s stomach. Second, even assuming conversion in vivo is within the scope of the claim, there was a failure of proof as to whether any crystals, formed in the stomach from ingested cefadroxil DC, literally infringe the ‘657 patent. Third, even if such crystals formed, there would be no infringing “use” within the meaning of 35 U.S.C. § 271(a) (1988). Fourth, the doctrine of equiva- lents, applied in reverse, precludes a judgment of literal infringement. And fifth, the court erroneously declined to grant summary judgment that Bristol was equitably es- topped from asserting that cefadroxil DC infringed the Bouzard patent. 1. We begin with claim construction: whether the claim of the ’657 patent, properly construed, covers Bouzard crystals which might form momentarily in a patient’s stomach. Zenith argues that, due to statements made by Bristol during the ’657 prosecution, the ‘657 claim is limited to the pre-ingested, powdered form of Bouzard monohydrate. In those statements Bristol particularly emphasized the superior manufacturing-related benefits of the pre-ingested form of Bouzard monohydrate in relation to prior forms of cefadroxil. Bristol, it is argued, thus relinquished coverage of any forms of cefadroxil DC that do not exhibit these manufacturing-related characteristics =< ee ee ee Ja —that would obviously include any Bouzard monohydrate formed in a patient’s stomach. Zenith has a point. Prosecution history serves as a limit on the scope of claims by excluding any interpreta- tion of the claim language that would permit the patentee to assert a meaning for the claim that was disclaimed or disavowed during prosecution in order to obtain claim allowance. Standard Oil Co. v. American Cyanamid Co., 114 F.2d 448, 452, 227 USPQ 293, 296 (Fed. Cir. 1985). The prosecution history in this case is replete with arguments by Bristol that the importance of this invention was the discovery of a way to manufacture the known compound so as to make it commercially available for medical treatment. The difficulty with Zenith’s argument, however, is in the nature of the’sole claim in the patent. The claim as written and allowed simply describes a compound having specified chemical properties. The question before us is not one of validity: whether the claim would be pat- entable over the prior art if the suggested restriction were not applicable. The question here is one of infringement: whether there is anything in the claim as issued that limits it to the pre-ingested form, keeping in mind the principle that it is improper to read a limitation into a claim “wholly apart from any need to interpret what the pat- entee meant by particular words or phrases in the claim.” E.I. Du Pont de Nemours & Co. v. Phillips Petroleum Co., 849 F.2d 1430, 1433, 7 USPQ2d 1129, 1131 (Fed. Cir.), cert. denied, 488 U.S. 986 (1988). Zenith nonetheless argues that the term “properties” in the claim is the vehicle for incorporating its proposed restriction into the claim. But that term plainly refers to x-ray diffraction properties. X-ray diffraction properties have nothing to do with the manufacturing benefits which Bristol highlighted. Zenith’s argument suffers from additional infirmities. The ’657 claim is a claim for a compound. Its patentabil- 8a ity thus derives from the structure of the claimed com- pound in relation to prior compounds. See In re Spada, 911 F.2d 705, 708, 15 USPQ2d 1655, 1657 (Fed. Cir. 1990). The relevance to patentability of the properties or characteristics exhibited by the compound is limited to assessing the significance of the structural distinctions of the claimed compound over the prior art. Second, as we later note in more detail, it is not at all clear that the statements concerning these characteristics played a de- terminative or even significant role in the Patent and Trademark Office’s (PTO’s) decision to grant the patent. We conclude, therefore, that while the claim as issued is limited to the crystalline form of cefadroxil exhibiting the specified x-ray diffraction pattern, it is not limited to the compound in its pre-ingested form with the manufacturing characteristics which Bristol emphasized during prosecu- tion.* y We turn next to the question of whether Bouzard mono- hydrate is actually found in the stomach of patients who ingest cefadroxil DC. One answer is that no one knows— the scientific fact appears to be that there is no known way to actually sample the contents of patients’ stomachs at the precise moment and conduct the x-ray diffraction analyses required to ascertain if all 37 lines described in the patent are present. ; For its proof Bristol offered instead the testimony of its principal scientific witness, Dr. Harry Brittain, who de- scribed various studies and experiments simulating the environment of the human stomach which were conducted under his auspices; Zenith countered with the testimony of its principal scientific witness, Dr. Martha Greenblatt. The trial judge, after hearing all the evidence, concluded 4The trial court apparently reached the same conclusion: “use of converted Bouzard monohydrate by a patient who ingests cefa- droxil DC is an infringing use.” (But see note 6 regarding the significance of the term ‘use.’) 9a that the Bouzard monohydrate in fact does inevitably form in the patient’s stomach after ingestion of cefadroxil DC. In deciding this issue, the court specifically resolved the conflicting testimony presented by Dr. Brittain and Dr. Greenblatt: [T]he Court finds that Brittain has established by a preponderance of evidence, well within his range of expertise, that cefadroxil DC in fact converts in vivo to Bouzard monohydrate. The strength of Brittain’s experiments and results is their totality. Piece by piece, Brittain built an im- pressive collection of data. The results of each series of experiments strengthen the results of each other set of experimental results. The total effect of the experiments is to prove with sufficient certainty the fact of conversion in vivo. * * * * [A]lthough she may have significant expertise in fields of inquiry unrelated to the issues in this case, Greenblatt demonstrated little understanding of the problem at issue in this case or the reason for her procedures and thus played no role in the design of her experiments, . . ., was lax in her methodology, particularly in the recording of her procedures and observations, and in fact did not even participate in the second series of experiments. The Court finds that Brittain’s . . . results are simply better supported and vastly more credible. According, those findings are adopted by the Court. Zenith I], 24 USPQ2d at 1664, 1668. Courts of law are not the optimal fora for trying ques- tions of scientific truth; even less are appellate courts equipped to choose among conflicting scientific theories. Judges are dependent on the quality and strength of the scientific evidence brought before them. The trial judge who hears the witnesses and does the initial assessment of ee 10a the evidence deserves considerable latitude in eventually choosing sides based on what is ultimately an educated guess—that is what judging is about. However, in determining whether a claim in a patent has been infringed, the scientific theories utilized must establish the presence of the limitations recited in the claim. In this case, Dr. Brittain based his scientific con- clusions on three kinds of tests—visual observation (ob- tained through optical microscopy), birefringence com- parison, and x-ray diffraction pattern comparison. The trial judge explained: Brittain first established indisputably through photo- micrography that cefadroxil DC crystals are much smaller than Bouzard monohydrate crystals, and are much different in shape. He also established that cefadroxil DC crystals exhibit a much weaker bi- refringence than do crystals of Bouzard monohydrate, which are highly birefringent. Thus, through micro- scopy, Brittain could determine with a high degree of certainty whether a sample of wetted cefadroxil DC had changed its crystalline form, and could con- clude to a lesser extent that the form to which it had changed was Bouzard monohydrate. Although changes in the physical properties of shape, size and birefringence of the cefadroxil DC crystals could be conclusively determined through microscopy, Brittain could not determine by observation clone that the larger, more birefringent crystals were necessarily Bouzard. To determine conversion to Bouzard with great certainty, Brittain ran x-ray powder diffraction patterns, a technique that in essence takes the “finger- print” of a crystalline compound. Through x-ray dif- fraction analysis, Brittain determined with much greater confidence that all of the conversions sus- pected after optical examination had in fact been to Bouzard monohydrate. (Emphasis added). Id. at 1665. lla The key piece of evidence, then, was the x-ray diffraction pattern analysis. This is also what the claim in the patent requires. The first two kinds of tests are only inferen- tially relevant given that the claim is drafted in terms of x-ray diffraction lines. Thus they cannot substitute for a proper comparison of those lines. And here a major problem arises. In order to establish its case, Bristol had to show that the accused compound infringed the claim contained in the patent.© This re- quired Bristol to show that the diffraction pattern of cefadroxil DC following its conversion in vivo displayed the same diffraction pattern as that of the claimed com- pound. The district court, instead of requiring the com- parison of the accused compound following conversion to be made with the lines specified in the claim, allowed Bristol to make the comparison with the diffraction pat- tern exhibited by a sample (the reference pattern) of a material considered by Bristol to be the patented com- pound. As we have repeatedly said, it is error for a court to compare in its infringement analysis the accused product or process with the patentee’s commercial embodiment or other version of the product or process; the only proper comparison is with the claims of the patent. E.g., Martin v. Barber, 755 F.2d 1564, 1567, 225 USPQ2d 233, 235 (Fed. Cir. 1985). The difficulty was compounded. The x-ray diffraction pattern exhibited by Bristol’s sample (the reference pat- tern) consisted of a table of only 30 lines of relative intensities. Of this total, the court only compared 22 lines to corresponding lines recited in the claim. Zenith II, 24 USPQ2d at 1665. Based on its comparison, the court concluded the two were sufficiently similar to per- 5 A finding that a claim is infringed is a necessary prerequisite to a finding that there has been an act constituting inducement to infringe under § 271(b). See Met-Coil Sys. Corp. v. Korners Un- limited, Inc., 803 F.2d 684, 687, 231 USPQ 474, 477 (Fed. Cir. 1986). 12a mit Bristol to use the reference pattern in its infringe- ment analysis. In fact, the number of lines recited in the claim is 37. Thus, 15 of the lines recited in the claim (representing about 40% of the total) were not consid- ered by the court in its comparison. Although the term “essentially” recited in the claim permits some leeway in the exactness of the comparison with the specified 37° lines of the claim, it does not permit ignoring a substan- tial number of lines altogether. It is the claim that sets the metes and bounds of the invention entitled to the protection of the patent system. On the basis of this evidence the trial court concluded that when cefadroxil DC is ingested Bouzard monohy- drate is created in a patient’s stomach, that that con- stitutes an infringing use, and that therefore the sale of cefadroxil DC by Zenith would constitute inducement of infringement under 35 U.S.C. § 271(b). Since the find- ing of infringement was based on testimony which incor- porated an improper comparison, and since that com- parison was an essential element in the conclusion that infringement occurred, the conclusion that Zenith by sell- ing cefadroxil DC would engage in inducement of in- fringement is insupportable. Zenith is correct that there was a failure of proof as to whether any crystals, assumed to form in the stomach from ingested cefadroxil DC, lit- erally infringe the ’657 claim. In the absence of evidence comparing the “657 claim with the cefadroxil DC after ingestion Bristol has failed to establish any infringing use and therefore we must reverse the district court’s con- clusion that Zenith’s sale of cefadroxil DC induces in- fringement of the ’657 patent.® 6 As noted previously, Zenith offered three other grounds on which the judgment of the trial court could be reversed: an inci- dental conversion to Bouzard crystals does not “use” the claimed compound; the reverse doctrine of equivalents forecloses literal infringement by conversion; and equitable estoppel. In view of our disposition of the appeal we need not address these other grounds for reversal. 13a 3. On the question of infringement under the doctrine of equivalents, the trial court decided for Zenith, finding that Bristol, through statements it made during the “657 prosecution, was estopped via prosecution history estoppel from asserting that cefadroxil DC infringed under the doctrine of equivalents. According to Bristol, this was error, because the statements relied on by the district court do not support a finding that there was an estoppel; thus the doctrine of equivalents, properly applied, pro- vides an alternative ground on which the judgment for Bristol could be affirmed. Bristol’s point has merit. The essence of prosecution history estoppel is that a patentee should not be able to obtain, through litigation, coverage of subject matter re- linquished during prosecution. See Loctite Corp. v. Ultra- seal Ltd., 781 F.2d 861, 870, 228 USPQ 90, 96 (Fed. Cir. 1985). The legal standard for determining what sub- ject matter was relinquished is an objective one, meas- ured from the vantage point of what a competitor was reasonably entitled to conclude, from the prosecution his- tory, that the applicant gave up to procure issuance of the patent. See Prodyne Enters., Inc. v. Julie Pomerantz, Inc., 743 F.2d 1581, 1583, 223 USPQ 477, 478 (Fed. Cir. 1984); Kinzenbaw v. Deere & Co., 741 F.2d 383, 389, 222 USPQ 929, 933 (Fed. Cir. 1984), cert. denied, 470 U.S. 1004 (1985). Here, we do not believe a com- petitor would have been reasonably justified in concluding that Bristol, through the statements in question, gave up coverage of those forms of Bouzard monohydrate other than the pre-ingested form. There is nothing in the record indicating that the state- ments about manufacturing benefits played any role in the procurement of the ‘657 patent. As noted earlier, in these statements Bristol argued the superior manufacturing- related characteristics exhibited by Bouzard monohydrate in relation to prior forms of cefadroxil. Yet, these prior 14a forms of cefadroxil were never asserted as prior art by the examiner, and the examiner expressly indicated that Bristol’s assertions were not a factor in determining pat- entability. Moreover, according to the examiner’s state- ment of reasons for allowance, the sole basis upon which allowance was challenged, and upon which the ’657 pat- ent was eventually issued, was related to a single prior art reference, Garbrecht, U.S. Patent No. 3,781,282," and Bristol’s successful showing that the claimed compound was not inherent in that reference. There is no indication the examiner ever relied on the statements regarding manufacturing-related characteristics in allowing the pat- ent to issue.* Zenith asserts that the statements in question fore- stalled an obviousness rejection of the claim on the basis of the prior forms of cefadroxil. That, however, is at best highly speculative; it is unpersuasive in view of the examiner’s statement of reasons for allowance. Thus, the 7 According to MPEP § 1302.14: One of the primary purposes of [a statement of reasons for allowance] is to improve the quality and reliability of issued patents by providing a complete file history which should clearly reflect, as much as is reasonably possible, the reasons why the application was allowed. Such information facilitates evaluation of the scope and strength of a patent by the patentee and the public and may help avoid or simplify litigation of a patent. The absence of any reference to the manufacturing related char- acteristics in the statement of reasons for allowance supports our conclusion that the examiner did not rely on such characteristics in issuing the patent. 8 Although actual reliance by the examiner need not be shown, if an estoppel is to rest upon argument made during the examina- tion process, the circumstances must be such as to permit the infer- ence that such reliance in fact occurred. A showing that the con- duct in question played a material role in the issuance of the patent usually suffices. See Mannesmann Demag Corp. v. Engineered Metal Prod., 793 F.2d 1279, 1285, 280 USPQ2d 45, 48 (Fed. Cir. 1986). I srs actin AN ar Te 15a court’s conclusion, that the statements in question gave rise to prosecution history estoppel, is insupportable. However, any error in the court's application of pros- ecution history estoppel was harmless; the court’s conclu- sion that the doctrine of equivalents is inapplicable to this case is correct as a matter of law. To prove infringe- ment under the doctrine of equivalents, Bristol bore the burden of showing that cefadroxil DC was the equivalent of Bouzard monohydrate. See Corning Glass Works v. Sumitomo Elec., U.S.A., Inc., 868 F.2d 1251, 1259, 9 USPQ2d 1962, 1967 (Fed. Cir. 1989). A necessary part of the function/way ‘result equivalency analysis is the function of the substituted element as seen in the context of the patent, the prosecution history, and the prior art. Graver Tank & Mfg. Co. v. Linde Air Products Co., 339 U.S. 605, 609 (1950), reh’g denied, 340 U.S. 845 (1950). In view of Bristol’s numerous statements in the prosecu- tion history regarding the superior manufacturing-related benefits of the Bouzard crystal in relation to the prior forms of cefadroxil, it is clear that the primary, if not the only, function of the Bouzard crystal form of the drug as compared to other forms is to facilitate pre-ingestion manufacturing. No other intended function is described or suggested. Since any unanticipated production of the Bouzard crystal in the patient's stomach as a result of ingesting cefadroxil DC does not even remotely perform that function, the “function” part of the function/way/ result test of equivalency is not met. As a matter of law, there can be no infringement under the doctrine of equivalents. Bristol cites a number of cases to demonstrate that the doctrine of equivalents has been applied to find infringe- It is self-evident that the function cannot be described more broadly, i.e. as the delivery of therapeutic value to the patient, for that is the function attributable to cefadroxil per se, which is prior art in relation to Bouzard monohydrate. 16a ment in situations involving in situ or in vivo conversions. However, these cases do not support Bristol’s argument. In two, Broadview Chemical Corp. v. Loctite Corp., 159 USPQ 80 (D. Conn. 1968), aff'd in relevant part, 406 F.2d 538, 160 USPQ 449 (2d Cir.), cert. denied, 394 U.S. 976 (1969) and Studiengesellschaft Kohle, M.b.H. v. Dart Industries, Inc., 549 F. Supp. 716, 216 USPQ 381 (D.Del. 1982), aff'd, 726 F.2d 724, 220 USPQ 841 (Fed. Cir. 1984), the doctrine of equivalents was not the issue in the case.”® In the others, Atlas Powder Co. v. E.I. DuPont de Nemours & Co., 588 F. Supp. 1455, 221 USPQ 426 (N.D. Tex. 1983, aff'd, 750 F.2d 1569, 224 USPQ 409 (Fed. Cir. 1984); Chemical Cleaning Corp. v. Dow Chemical Co., 379 F.2d 294, 155 USPQ 49 (Sth Cir. 1967), cert. denied, 389 U.S. 1040 (1968); Ortho Pharmaceutical Corp. v. Smith, 18 USPQ2d 1977 (E.D. Pa. 1990), aff'd, 959 F.2d 936, 22 USPQ2d 1119 (Fed. Cir. 1992); and Beecham Group Ltd. v. Bristol Lab. Ltd., [1978] R.P.C. 153 (House of Lords 1977), the substituted compound or ingredient converted in vivo or in situ to the compound or ingredient called for by the claim, and performed the same function as that of the claim. The infringer was thus using the equivalent ele- 10 In Broadview, the claimed ingredient was found to be present in the accused product independently of the purportedly substituted ingredient. 406 F.2d at 541-42, 160 USPQ at 451. Thus, that product literally infringed. Equivalence between the two ingredi- ents was not an issue in the case. In Studiengesellschaft, although it was unclear whether the trial judge had made findings on the doctrine of equivalents issue, we concluded on appeal that any such findings were inappropriate and unnecessary insofar as the court’s judgement was sustainable on the basis of literal infringe- ment. 726 F.2d at 728, 220 USPQ at 843. 11J[n Atlas Powder, it was found that the substituted compound— an oil-in-water emulsifier—converted in situ to the claimed com- pound—a water-in-oil emulsifier—which in turn performed its intended function—forming an emulsion between oil and water. 588 F. Supp. at 1472, 221 USPQ at 440, aff’d, 750 F.2d at 1581, 224 USPQ at 417. In Chemical Cleaning, it was determined that the substituted compound—monomethylolthiourea—disassociated in up- | | 17a ment to perform the same function as the claimed com- pound, a typical case for doctrine of equivalents appli- cation. Even assuming that cefadroxil DC converts in vivo to Bouzard monohydrate in measurable amounts, that par- ticular crystalline form does not perform the function of facilitating encapsulation. On the record before us, the trial court was correct in his judgment that Bristol had failed to establish infringement under the doctrine of equivalents. CONCLUSION For the reasons given, the judgment of the trial court in favor of Bristol on count one is reversed. REVERSED eration to form the claimed compound—thiourea—which in turn performed its intended function—acting as a sequestering agent for copper. 379 F.2d at 296, 155 USPQ at 49. In Ortho, it was found that the substituted compound—norgestimate—converted in vivo to the claimed compounds—norgestral and norgestral ace- tate—which in turn performed their intended function—contra- ception. 18 USPQ2d at 1985-86, aff'd, 959 F.2d at 939, 22 USPQ2d at 1122. Finally, in Beecham, it was determined that the substi- tuted compound—hetacillin—converted in vivo to the claimed com- pound—ampicillin—-which in turn performed its intended function —acting as an antibiotic. [1978] R.P.C. at 167, 182-83, 202. 18a APPENDIX B DISTRICT COURT D. NEW JERSEY No. 91-3423 ZENITH LABORATORIES INC. V. BRISTOL-MYERS SQUIBB Co. Decided July 21, 1992 Wolin, J. Bristol-Myers Squibb Company (“Bristol”), a Dela- ware corporation, is the owner of United States Patent No. 4,504,657 (“the ‘657 patent”), issued on March 12, 1985. The ’657 patent includes a single claim for a spe- cific crystalline form of cefadroxil monohydrate (herein- after “Bouzard monohydrate”). Cefadroxil is a ceph- alosporin antibiotic compound that has a number of medical uses. Bristol previously owned the now-expired 1The patent claim reads: We claim: 1. Crystalline 7-[D-c-amino-a- (p- hydroxypheny) I- aceta- mido] -3-methyl-3 -cephem-4- carboxylic acid monohydrate ex- hibiting essentially the following x-ray diffraction properties: [followed by a table of numbers corresponding to the x-ray diffraction characteristics of the Bouzard monohydrate] (United States Patent No. 4,504,657 at page 18, lines 65-69). cli angina Mt ae Nt 19a United States Patent No. 3,489,752, which issued on January 13, 1970 and claimed all forms of cefadroxil. This action was filed by Zenith Laboratories, Inc. (“Zenith”), a New Jersey corporation, against Bristol on August 5, 1991. Among other claims for relief, Zenith seeks a declaration that “cefadroxil DC”, a hemihydrate form of cefadroxil for which Zenith has obtained Food and Drug Administration (“FDA”) approval to market in finished dosage form as a generic equivalent of cefadroxil monohydrate, does not infringe the ’657 patent.? Although Bristol does not contend that cefadroxil DC infringes the ‘657 patent in its manufactured, pre-ingested state, it does contend that after ingestion, the drug “converts” to the Bouzard monohydrate inside the body, or “in vivo,” and that such conversion renders cefadroxil DC an in- fringing compound under the docirine of equivalents, or alternatively, that sales of cefadroxil DC by Zenith would constitute inducement of infringement of the ’657 patent. In an Opinion dated February 21, 1992, the Court granted summary judgment in Zenith’s favor on the issue of in vivo conversion, and found that Zenith was entitled to a declaration that cefadroxil DC does not infringe the ‘657 patent. An Order reflecting this ruling was filed on March 4, 1992. On motion for reconsideration, in an Opinion and Order dated April 13, 1992, the Court vacated its March 4, 1992 Order, motivated in substantial part by the uncommon manner and speed by which the record was created for the motion, and by how early in the proceedings the motion was brought. Recognizing the immediacy of the rights at stake, the Court set down the issue of infringement for trial on an accelerated basis following expedited discovery. 2A hemihydrate is a crystal form containing two molecules of water for each molecule of a chemical compound. A monohydrate contains one water molecule for each molecule of the chemical com- pound. _—— SE ~~--~--~r—Seststt 20a The issue of infringement was tried to the Court be- tween May 26, 1992 and June 5, 1992, during which six days of evidence was received. The primary factual issue at trial was whether cefadroxil DC converted in vivo to the Bouzard monohydrate. Set forth below is a summary of the testimony at trial, and the Court’s findings of fact and conclusions of law as required by Federal Rule of Civil Procedure 52(a). Based on these findings and con- clusions, a judgment will be entered in Bristol’s favor. I. THE EVIDENCE AT TRIAL The evidence at trial consisted for the most part of expert testimony presented by both parties. Both parties’ experts conducted a number of experiments to investigate whether cefadroxil DC converts in vivo to the Bouzard monohydrate. These experts were presented as witnesses to explain their theories of conversion, experimental meth- odologies, test results, and conclusions based on those results. Additional experts were presented to provide foundations for assumptions made by some of the experts who conducted experimental studies, or to rebut the as- sumptions, methodologies, theories, or conclusions of other expert witnesses. The Court will summarize each party’s case in the order presented at trial. A. Zenith’s Direct Case C. David Smith Zenith’s first witness was C. David Smith, its vice- president of quality assurance. Mr. Smith testified as to the status of Zenith’s FDA application, and as to the formulation for Zenith’s cefadroxil DC capsules. He testi- fied that the capsules contain, in addition to the cefadroxil material, lactose, sodium starch glycolate and magnesium stearate. (Tr. 17)*° These nonactive ingredients, known as “excipients”, are included in the capsules for different purposes. Lactose is used as a filler. Sodium starch 3 “Tr, ____” refers to the trial transcript at the page indicated. 2la glycolate swells greatly when exposed to water, and is included as a disintegrant to break apart the capsule. (Tr. 18) Magnesium stearate is a lubricant useful in machin- ing the capsules. (/d.) Edwin C. Rothstein Zenith next presented the testimony of Edwin C. Roth- stein, president of Leberco Testing, Inc. (“Leberco”), an independent testing laboratory located in New Jersey. Leberco was retained by Zenith to perform dissolution and solubility tests on cefadroxil DC and the Bouzard monohydrate, both in their formulated and bulk forms. 1. Dissolution Tests Rothstein testified that Leberco technicians conducted dissolution tests in which they recorded the rates at which 500 milligram capsules of cefadroxil DC and Bouzard monohydrate dissolved into simulated gastric juice. (Tr. 39) The tests were performed by placing 500 milligram capsules in a dissolution basket rotated at 100 revolutions per minute (“rpm”) in 900 milligrams of simulated gastric juice without enzymes. (PX 21)* The percentage of ma- terial dissolved into the dissolution media was measured and recorded at intervals of 3, 5, 7.5, 10 and 20 minutes. (Id.) Six runs were performed and averaged on each sub- stance. From the results of this experiment, Rothstein concluded that between three and five minutes, cefadroxil DC had a higher dissolution rate than the Bouzard mono- hydrate. (Tr. 40) He also concluded that cefadroxil DC had a higher total solubility than Bouzard monohydrate. (Id.) The same tests were run using 1000 milligram tablets. (Id.) Rothstein concluded that the results of this experiment were essentially the same as with the first test. (Tr. 40-41; PX 22) 4“PxX ” refers to plaintiff's exhibit numbered as indi- cated. Likewise, “DX ” refers to the indicated defendant’s exhibit. 22a. Rothstein testified that Leberco performed an addi- tional experiment designed to determine whether the dis- solution rates observed were affected in any way by any difference between the Zenith gelatin capsule and the Bristol gelatin capsule. The experiment consisted of com- paring the dissolution rate of 350 milligrams of cefadroxil DC in a Zenith capsule with the dissolution rate of 350 milligrams of cefadroxil DC in a Bristol capsule. (PX 23) From the measured results of this test, Rothstein con- cluded that the gelatin capsule shell had no effect on the dissolution rates of the two cefadroxil materials. (Tr. 41) One further dissolution experiment was conducted by Leberco. A comparison was made of the dissolution of capsules of cefadroxil DC and Bouzard monohydrate in 30 milliliters of simulated gastric juice at 37° C in a dis- solution basket rotated at three rpm. (PX 24) Rothstein testified that the dissolution test could not be performed due to the small quantity of fluid used. (Tr. 42) There- fore, only visual observations could be made. (Jd.) Roth- stein testified that after three minutes, the Zenith capsule had released most of its contents, but that the Bristol capsule still contained most of its contents. (/d.) 2. Solubility and Bulk Density Tesis Rothstein testified that Leberco technicians performed solubility tests on cefadroxil DC and Bouzard mono- hydrate. Solubility is a measure of the quantity of a given material that can be dissolved in a given solvent at a given temperature and pressure in a given volume. (Tr. 46) Rothstein testified that five grams of a material was placed in 100 milliliters of deionized water that was maintained at a specific temperature and intermittently agitated for ten hours. Undissolved materials were then filtered, and the clear filtrate was then spectrophotometrically analyzed: to determine its cefadroxil content. (Jd.) This was done for each cefadroxil material at three temperatures: 4°C, 23a room temperature (between 23°C and 25°C) and 50°C. (Id.) From the test results obtained (see PX 25, 26), Rothstein concluded cefadroxil DC is “clearly more solu- ble” than the Bouzard monohydrate under the conditions utilized. (Tr. 43) Leberco also measured the bulk densities of cefadroxil DC and Bouzard monohydrate. (PX 25) From the tests, Rothstein concluded that cefadroxil DC has a bulk density considerably lower than that of Bouzard monohydrate. Dr. Martha Greenblatt The testimony of Dr. Martha Greenblatt was offered into evidence on Zenith’s direct case through deposition transcript. Greenblatt was deposed by Zenith de bene esse on May 21, 1992. The transcript was accepted into evidence without objection. On Zenith’s rebuttal case, Greenblatt testified in court. Greenblatt is a professor at Rutgers University in New Jersey who teaches solid state chemistry, and is an expert in x-ray crystallography. (Deposition Tr. 5) She was asked to perform an experiment that was intended to determine whether, at the time a capsule of cefadroxil DC bursts in simulated gastric acid, cefadroxil DC has already converted to Bouzard monohydrate. This was ac- complished by Greenblatt placing a Zenith capsule in simulated gastric acid until the capsule breached, and at the moment that cefadroxil began to pour out of the cap- sule, she froze the material in liquid nitrogen. (Dep. 11) This experiment was repeated. She then freeze-dried the frozen samples, and recorded the x-ray powder diffraction patterns of two samples. (Dep. 15-16; PX 31) In the first experiment, Greenblatt placed a Zenith capsule in a dissolution basket that was then immersed in 100 milliliters of simulated gastric acid maintained at 37°C and rotated at six rpm. At one minute, 54 seconds, Greenblatt observed that the capsule had burst, and re- 24a moved the basket from the beaker and placed it into the liquid nitrogen within five seconds. A second experiment was performed in which Greenblatt observed a burst in the capsule at approximately two minutes. Both frozen- samples were placed in a freeze-drier overnight. The next day, 20 hours after the samples were frozen (Tr. 894), x-ray diffraction patterns of the samples were recorded and designated Z1 and Z2. (PX 31) These pat- terns were compared to “standard” patterns made from samples of cefadroxil DC and Bristol’s Bouzard monohy- drate.’ According to Greenblatt, the patterns for Z1 and Z2 were “identical” to the standard cefadroxil DC pat- tern. (Dep. 17) From the comparison, Greenblatt con- cluded that the cefadroxil DC samples she placed in acid and freeze-dried had not undergone any structural change in their crystal form. (Dep. 22) Dr. Ralph R. Pfeiffer Dr. Pfeiffer is a consultant at Purdue School of Phar- macy in the solid state drug chemistry group. (Tr. 65) He also does consulting and teaches seminars on poly- morph formation and solvate formation, most recently for the F.D.A. (Tr. 66) He has extensive experience, in- cluding 30 years at Eli Lilly Company, in x-ray powder diffraction analysis, in the identification of polymorphs and solvates of drugs, and in other areas related to crystal formation and behavior. (Tr. 66) Pfeiffer was offered as an expert in x-ray powder diffraction analysis, crystal theory and the behavior of oral drug dosages in the hu- man body. Pfeiffer testified as to his comparison of x-ray diffrac- tion patterns of cefadroxil DC and a prior art form of cefadroxil known as “Gottstein” cefadroxil. (Tr. 71-2) For the Gottstein pattern, Pfeiffer relied on the pattern attached to the declaration of Timothy Marr, which was 5 Greenblatt verified that the patterns obtained from bulk cefa- droxil DC and formulated DC with excipients were identical. 25a filed with the United States Patent and Trademark Of- fice in 1982. (Tr. 71; PX 33) Zenith also offered the declaration of David Whitehead, which was also filed with the United States Patent and Trademark Office, in which Whitehead declared that the Gottstein material utilized by Mar had not changed in the eleven years since it was first prepared. (PX 37) Pfeiffer used one of Dr. Greenblatt’s patterns as representative of cefadroxil DC. (Tr. 71) He concluded, after comparing the patterns, that cefadroxil DC and Gottstein cefadroxil “are of the same crystal structure.” (Tr. 72) Based on this conclusion, Pfeiffer also concluded that the structure-dependent properties of both materials—including equilibrium solubility, melting point and density—would be the same. (Tr. 82-83) Pfeiffer further opined that if one material converted to the Bouzard monohydrate when exposed to an aqueous environment, so would the other. (Tr. 83) Dr. Pfeiffer testified that in his opinion, it was unlikely that cefadroxil DC could convert in vivo to the Bouzard monohydrate. (Tr. 83-84) He believed that a number of conditions existed in tre stomach that would preclude the dissolution and recrystallizatton processes that would be required for conversion. (Tr. 84) Specifically, he be- lieved that cefadroxil DC would dissolve very quickly in the stomach and prevent the creation of a super-saturated environment needed for recrystallization. (Tr. 88-89) In addition, Pfeiffer believed that the mixing action of the stomach would tend to disperse any super-saturated region that might otherwise form. (Tr. 89) Dr. Pfeiffer testified further as to the conditions that he believed were necessary for conversion to occur. In addition to the super-saturated solution, he testified that nucleation must occur. (Tr. 89) Conditions that could produce nucleation include evaporation, cooling of the solution, and inducement of mechanical stress. (Tr. 90) Recrystallization could also occur if nuclei were already present. (Tr. 90) Pfeiffer opined that none of these con- ditions are present in the stomach. (Tr. 91) SER ee eT as | 26a Pfeiffer testified as to the conclusions that he drew from the tests performed by Leberco, introduced through Dr. Rothstein. He concluded from the results of the equilibrium solubility tests performed by Leberco that cefadroxil DC did not convert to Bouzard monohydrate because at the end of ten hours in simulated gastric acid, different amounts of the two material dissolved into iden- tical volumes of the fluid. To Pfeiffer, this indicated that no conversion occurred because if it had, equal amounts of material would have dissolved. (Tr. 92) This is true even though, in their dissolved states, cefadroxil DC and Bouzard monohydrate are identical—they are simply the compound cefadroxil. (Tr. 92) On one-last topic, Pfeiffer opined that Dr. Greenblatt’s experiments minimized the chance that changes would occur in cefadroxil DC after it had been removed from the dissolution medium. (Tr. 93) He further agreed with her conclusion that no conversion had occurred. (Tr. 93) B. Bristol’s Case Dr. Howard Goldin Bristol’s first witness, Dr. Goldin, is a Board-certified doctor of internal medicine and gastroenterology. (Tr. 246) He was offered as an expert on the conditions that exist inside the human stomach. Goldin was asked to provide a protocol for simulating stomach conditions, which could be used in in vitro experiments intended to determine whether cefadroxil DC converted in vivo to the Bouzard monohydrate. (Tr. 253) According to Goldin, ethical constraints precluded actual in vivo experiments from being conducted for this purpose. (Tr. 253) The protocol provided by Goldin consisted of the use of 30 milliliters of actual gastric juice maintained at body temperature (37°C) and gently agitated at three rpm. (Tr. 254, 264) Goldin also recommended that simulated gastric juice (a 0.1 solution of hydrochloric acid) could be EAI MARE IRN Rp eo 27a used. (Tr. 255) The stirring rate was chosen as an approximation of the agitation that occurs in the stomach. Goldin testified that for the most part, the stomach is in a flaccid state, with only intermittent gentle waves that “barely agitate the contents of the stomach.” (Tr. 265) For only approximately five out of every 90 to 120 min- utes are there- vigorous contractions in the stomach. (Tr. 265) An in vitro stirring rate of 100 rpm, in Dr. Goldin’s opinion “far exceed[s] the physiologic spectrum of the human stomach.” (Tr. 270) Samples of actual gastric juice provided to Bristol for experimentation uses by Dr. Goldin were obtained from Goldin’s patients during a routine suction of the contents in preparation for an endoscopic examination. (Tr. 265- 66) The patients had all fasted prior to the examination. (Tr. 265) Most of the gastric acid obtained had a pH of between one and two. (Tr. 266) The average volume of acid suctioned from the patients was 30 milliliters. (Tr. 267) Essentially all of a stomach’s contents are removed by the suctioning. (Tr. 267) The pH of gastric acid in a non-fasting patient is generally higher (less acidic) due to neutralization by the ingested solids or liquids. (Tr. 266) Goldin opined that experiments utilizing his specified conditions would simulate in vivo conditions. (Tr. 270) He further opined that he did not believe that much of a difference would be observed if gastric acid from non- fasting patients were used, even if it consisted of a greater volume of fluid. (Tr. 274-75) Goldin opined that a vol- ume of gastric acid between 30 and 240 milliliters was within the physiologic range of the human stomach. (Tr. 278) He also opined that a stirring rate between three and ten rpm would also be within that range, but that 25 rpm would fall outside of the range. (Tr. 281-82) Goldin ultimately concluded that he would expect con- version to occur in vivo if it occurred in vitro under the conditions that he specified. (Tr. 284-85) 28a Dr. Robert J. Levine The testimony of Dr. Levine was offered into evidence by Bristol through deposition transcript. Levine was deposed by Bristol de bene esse on May 11, 1992. The transcript was accepted into evidence without objection as defendant’s exhibit 20. (Tr. 317-18) Levine is a professor of medicine at Yale University School of Medicine in Connecticut, specializing in medical ethics. (Dep. 5) His previous experience included serving as chief of the clinical pharmacology section at Yale Uni- versity School of Medicine. (Dep. 11) He has reviewed more than 5,600 proposals to do medical research on human subjects. (Dep. 13) In Levine’s opinion, no insti- tutional review board would approve research on human subjects solely to defend a patent. (Dep. 14-15) He further opined that he did not believe that an in vivo experiment could be designed to test whether cefadroxil DC converts to Bouzard monohydrate that would not be subject to the same criticisms to which the in vitro experi- ments have been subjected. (Dep. 15) Dr. Gerond V. Lake-Bakaar Dr. Lake-Bakaar is a } sician who, like Dr. Goldin, specializes in internal medicine and gastroenterology. (Tr. 318-19) He teaches medicine at the State University of New York at Stony Brook. (Tr. 319) Bristol offered Lake-Bakaar as an expert in gastroenterology. (Tr. 320) Lake-Bakaar testified that he conducts research in gas- troenterology and has on a number of occasions designed in vitro studies that were intended to simulate in vivo con- ditions, (Tr. 320, 326), and that such tests are frequently relied on by gastroenterologists to predict in vivo results, (Tr. 327). In his opinion, the in vitro conditions em- ployed by Dr. Harry Brittain, a witness for Bristol dis- cussed infra, of 30 milliliters of 0.1 N HCl maintained at 37°C with gentle agitation, closely simulates conditions 29a in the human stomach. (Tr. 332-33) In his experience, Dr. Lake-Bakaar has encountered varying volumes of gastric acid in patients, ranging between 20 and 80 milli- liters. (Tr. 333) He also opined that mixing rates between three rpm and 100 rpm covered a range that exceeded the range of agitation that he believes occurs in the human stomach. (Tr. 336) In his opinion, 10 rpm is the average rate of mixing in the human stomach, to the extent it can be quantified in those terms. (Tr. 336, 369- 70) Lake-Bakaar further opined that little difference exists between the gastric juice of fasted and non-fasted patients. (Tr. 337) Dr. Lake-Bakaar testified that, in his opinion, Dr. Brit- tain’s failure to account for emptying and replenishment of stomach juices does not affect the validity of his simula- tions, because the emptying rate of the human stomach is sufficiently slow such that it would be minimal over the short time interval that elapsed before Brittain observed conversion in his experiments. (Tr. 334-35). Lake- Bakaar estimated that in five minutes, the human stomach replaces approximately five percent of its gastric acid. (Tr. 334). This rate remains constant without regard to whether additional fluid has been ingested. (Tr. 358-59) He further opined that Brittain’s failure to take into account absorption of materials through the stomach wall did not affect the validity of his simulation, because, with the exception of extremely acidic compounds, such absorp- tion is minimal. (Tr. 335) He also testified that he did not believe “sink” conditions existed in the human stomach. (Tr. 337) In his understanding, “sink” conditions exist when the concentration of a solvent is altered by, for example, emptying and replacement. (Tr. 337-38) For his final conclusion, Lake-Bakaar opined that, if conversion actually occurs under the range of conditions observed by Dr. Brittain in his in vitro experiments, he believes that conversion would also occur in vivo. (Tr. 339-40) 30a Dr. Harry G. Brittain Dr. Brittain has a doctorate in chemistry, has done extensive post-doctoral fellowship work, taught chemistry at several colleges, and has, since 1985, worked for Bristol or one [of] its predecessor corporations. Brittain was of- fered as an expert in physical-chemistry, x-ray powder diffraction analysis and optical microscopy. (Tr. 384) As part of his job responsibilities at Bristol, Dr. Brittain examines, compares and analyzes x-ray powder diffraction patterns on a regular basis. (Tr. 630-31) Relying on the conditions specified by Drs. Goldin and Lake-Bakaar, Dr. Brittain conducted numerous experiments that were de- signed to determine whether cefadroxil DC converts to Bouzard monohydrate in vivo after ingestion. He designed all of his own experiments. (Tr. 495) The conditions and results of these experiments are summarized in tables received into evidence as defendant’s exhibits 42a-d. 1. Brittain’s Theory of the Conversion Mechanism Dr. Brittain testified that he believes conversion occurs because cefadroxil DC, when wetted, partially dissoives and forms a saturated layer around the undissolved ma- terial, and then recrystallizes as the Bouzard monohydrate. (Tr. 510) He opined that when liquid enters a cefadroxil DC capsule, a micro-environment of saturation is created that allows partial dissolution of cefadroxil DC crystals that act as nuclei for the formation of Bouzard mono- hydrate crystals. (Tr. 629, 806) He does not believe that the beaker in which he conducted his experiments had any effect on the conversion because he believes that con- version occurs inside of the capsule. (Tr. 510) 2. Initial Experiments The first experiments undertaken by Brittain to investi- gate conversion are summarized in defendant’s exhibit. By placing a range of weights of cefadroxil DC in a series of test tubes with one milliliter of water and observing in 3la which tubes all of the drug dissolved, Brittain determined that the equilibrium solubility of cefadroxil DC was ap- proximately between 10.1 and 16.3 milligrams per milli- liter. (Tr. 390; DX 17) This was considered consistent by Brittain with his understanding that cefadroxil DC has an equilibrium solubility of 12 milligrams per milliliter. (DX 17) Brittain also observed that the fine cefadroxil DC povw- der that he placed in the test tubes turned granular in appearance after being in contact with the water for one minute. (Tr. 390; DX 17) Upon examination by optical microscope at 400 magnification, Brittain observed that the granular solids in the solution had a significantly dif- ferent appearance from the unwetted cefadroxil DC. The initial cefadroxil DC consisted of small needle-shaped crystals, but the wetted cefadroxil consisted of much larger rhombic crystals. (Tr. 396-97; DX 17) The larger rhom- bic crystals are characteristics, in Brittain’s opinion, of crystals of Bouzard monohydrate. (Tr. 400) A significant difference was also observed between the birefringence of both samples. The wetted sample was significantly birefringent, but the unwetted sample was only slightly birefringent. (DX 17) The phenomenon of birefringence is the degree to which the indices of refrac- tion in a given material scatters light passed through the material. By passing polarized light through a substance and then observing the substance through a second polar- ‘zer rotated 90° from the initial polarizer, the relative degree to which light is scattered as it passes through different substances can be observed as varying intensities of brightness. (Tr. 383) Birefringence can be a useful test for identifying crystals, or comparing whether two substances are the same crystal. (Tr. 383) If the same crystals are present, they will have the same birefringent characteristics. According to Brittain, the birefringence of cefadroxil DC is “extremely weak”. (Tr. 401) 32a 3. Second Series of Experiments The next series of experiments performed by Dr. Brit- tain is summarized in defendant’s exhibits 14 and 18, but is described in greater detail in Brittain’s laboratory note- book, offered into evidence as defendant’s exhibit 16. In that experiment, he initially photomicrographed dry cefadroxil DC to reconfirm its particle size and shape as small needles, and verified that it exhibited weak bire- fringence. (Tr. 405) He also ran an x-ray powder diffraction analysis of a sample of dry cefadroxil DC that he possessed, to obtain a diffraction pattern for use as a reference in his future experimentation. (Tr. 406- 07) He also obtained an x-ray diffraction pattern for Bouzard monohydrate. (Tr. 410) For this experiment, Brittain placed a dry 10 milligram sample of cefadroxil DC on a microscope slide, wetted it with water, and observed it under a microscope. (Tr. 411-12; DX 14) He observed that the cefadroxil material transformed from very small crystals to large block-like crystals. (Tr. 412) In a second experiment, Brittain placed 100 milligrams of cefadroxil DC on a slide, and wetted it with 0.1 N HC1 solution. (Tr. 413) He ob- served the same phenomena as in the prior experiment, except that the crystal faces appeared better formed, and the birefringence was more distinctive. (Tr. 413) The transformation of the crystals occurred within 30 seconds of being wetted. (DX 14) The sample remained in the solution for five minutes before it was removed and sub- jected to x-ray diffraction analysis. When the x-ray powder diffraction pattern obtained from the wetted cefadroxil DC was compared to the reference patterns, Brittain observed that the pattern for the wetted cefadroxil was equivalent to the reference pattern for Bouzard monohydrate. (Tr. 415) A third experiment in this series was performed to de- termine whether cefadroxil DC converted to Bouzard monohydrate within a capsule immersed in fluid. In two separate runs, handfilled capsules of cefadroxil DC were 33a placed respectively in 250 milliliters of water and in 250 milliliters of 0.1 N HC1 solution and allowed to sit for respectively four and ten minutes, and were then removed, sliced open, and examined under the microscope for crys- tal shape and size, and for birefringence. (Tr. 416-18, 423: DX 16) These visual tests confirmed that the ma- terial had converted to Bouzard monohydrate. (/d.) X-ray diffraction analysis further confirmed that conversion had occurred. (Tr. 418, 424, 425) 4. Dissolution Experiments In a series of dissolution experiments, Dr. Brittain utilized the in vivo conditions specified by Dr. Goldin, in an attempt to determine with more certainty whethe= conversion would occur in the human stomach. Those conditions consisted of 30 milliliters of simulated gastric juice maintained at 37°C and stirred at three rpm. In the first experiment, approximately 300 milligrams of cefadroxil DC was placed in a clear capsule and low- ered into a dissolution kettle that contained 30 milliliters of simulated gastric juice stirred at three rpm for a period of eight minutes. (Tr. 438) Optical microscopy was per- formed on the capsule, which revealed to Brittain, con- sistent with previous experiments, that the crystals had changed from small needles to large monohydrate crystals, and that the birefringence had also increased significantly. (Tr. 439) The same conditions were repeated and the same results were obtained. (Tr. 441-42) X-ray powder diffraction patterns were not run because the x-ray unit was not operating on that day. (Tr. 442) Brittain later ran many other dissolution experiments, using varied condition of temperature, volume dissolu- tion medium, and stirring rate. Tests were performed on handfilled capsules containing between 300 and 500 milligrams of cefadroxil DC, as well as on actual formu- lated Zenith cefadroxil DC 500 milligram capsules in- cluding excipients. Capsules were immersed in media 34a maintained at 37°C and at 25°C. Dissolution media vol- umes were varied between 30 and 900 milliliters. Both simulated gastric juice and actual gastric acid provided by Dr. Goldin were used as dissolution media, with pHs ranging between 1 and 6.5. Stirring rates were varied between zero and 100 rpm. Brittain testified at length during trial as to the conditions of these experiments. His laboratory notebook provides a contemporaneous rec- ord of the details of these experiments. (DX 16) The re- sults of these experiments are summarized in table form in defendant’s exhibits 42a-42c. For all of these experi- ments, similar tests were performed to reach uniform re- sults. Optical microscopy observation of crystal size and birefringence, together with x-ray powder diffraction analyses, uniformly indicated to Dr. Brittain that conver- sion of cefadroxil DC to Bouzard monohydrate occurred under all of the varied experiment conditions. Brittain concluded that the pH of the dissolution medium had little or no effect on whether conversion would occur. (Tr. 533) He also concluded that the volume of the dissolu- tion medium and stirring rate had little or no effect on whether conversion would occur. (Tr. 540-41) 5. Protonation Experiment One of the claims raised by Zenith on motion for sum- mary judgment was that cefadroxil DC wetted with acid could not recrystallize once dissolved, because the cefa- droxil would become protonated as it reacted with the acid. Protonation occurs when a compound binds with free hydrogen ions as the acid reacts with the compound. (Tr. 468) To test this assertion, Brittain ran fourier trans- form infrared reflectance (“FTIR”) analyses of the ma- terial he believed was converted cefadroxil and of un- wetted Bouzard material, to obtain FTIR spectra. (Tr. 466-67) FTIR analysis is commonly used to determine whether a material has protonated. (Tr. 467) Brittain concluded from a comparison of the two spectra that the cefadroxil DC material had converted to the Bouzard monohydrate, and that it was not protonated. (Tr. 467) ew tes ‘ets 35a 6. Light Scattering Experiments Although he did not believe that removing cefadroxil from the dissolution medium had any effect on the con- version process, Dr. Brittain designed a light-scattering experiment with which he could investigate whether con- version could be observed without removing a sample from the dissolution medium. (Tr. 548) The apparatus used to conduct the light-scattering ex- periments consisted of a laser light source that was passed through a square cuvette containing three milliliters of liquid. (Tr. 550-52) On an adjacent side of the cuvette was a photomultiplier tube that received the light passing through the cuvette at a right angle to the laser source, and converted it to an electrical current that varied in proportion to the intensity of the scattered light. (Tr. 552) The electrical current was then converted to a voltage output that also varied in proportion to the scat- tered light intensity, which was amplified and displayed on an output device. (Tr. 552) To isolate the laser light passing through the cuvette, and to minimize the effect of changes in ambient light levels, the laser light source was pulsed at a chosen fre- quency. Through use of a lock-in implifier, which ampli- fied only the converted voltage signal with the same fre- quency as the pulsed laser source, the final displayed out- put, as recorded on a strip chart recorder, measured es- sentially just light that had originated from the laser light source. (Tr. 553) This apparatus was designed and built by Dr. Brittain. To validate the system, Brittain mixed twenty milli- grams of microcrystalline cellulose, a water insoluble sub- stance, with water in a cuvette. (Tr. 554) The mixture was alternatively stirred with a magnetic stirrer, then allowed to settle, while the laser source passed through the cuvette. (Tr. 554-55) The output recorded on the 36a strip chart recorder showed changes in negative voltage that varied from a lesser negative voltage when the ma- terial was completely settled, to a maximum negative voltage when the stirring occurred. (Tr. 555) This indicated that the apparatus measured changes in the in- tensity of light scattered from the original laser source. (Tr. 555) When more particles are suspended in solu- tion, more light is scattered. Brittain then used the apparatus to determine whether changes in light could be detected as the cefadroxil DC was mixed in simulated gastric juice. To separate the possible effect on the test that dissolution, as opposed to conversion, would have on the light-scattering measure- ment, Brittain started with a filtered saturated solution of cefadroxil DC, because no further dissolution could occur if the saturated solution was held at a constant tempera- ture. (Tr. 557) In the first series of runs, he added 25 milligrams of Bouzard monohydrate to the saturated solu- tion, which was mixed vigorously while the scattered light intensity was measured by the light-scattering apparatus. (Tr. 558-59) Three strip chart traces were obtained in three separate runs, which revealed a fairly constant nega- tive output. (Tr. 539) The materials in the cuvettes were examined by microscopy to verify that the Bouzard ma- terial was still present. (Tr. 561). In the next series of runs of the experiment, Brittain replicated the conditions used in the first series, except that he used cefadroxil DC instead of Bouzard monohy- drate. (Tr. 562) This experiment was also run and re- corded three different times. (Tr. 563) The curves plotted in all three runs were essentially the same. (Tr. 568) They show a sharp arc-shaped decrease in negative volt- age output through most of the first minute of the experi- ment, and then a gradual steady increase in negative volt- age intensity through the remainder of the experiment. (DX 16, pages 148-49) Dr. Brittain believed that the initial decrease in intensity was due to dissolution of the cefadroxil DC crystals, which resulted in less scattering — vee ee ee eee 37a of the laser signal because fewer solid particles were pres- ent to scatter the light. (Tr. 565) He also believed that the later increase in the scattered light intensity was con- sistent with conversion, because it indicated that some physical change had occurred in the tube at the approxi- mate time that he had observed conversion in his other experiments. (Tr. 566-67, 569) Another experiment was conducted in which Brittain used the same conditions of solution and stirring as used in the light-scattering experiment, but instead of measur- ing light intensity with the light scattering apparatus, he took a series of nine photomicrographs -of material ex- tracted out of the cuvette at different time intervals dur- ing a four minute period. (DX 16, pages 150-53) Bire- fringence was also examined. (Tr. 573) Brittain observed very small Bouzard crystals in the first photograph taken at 14 seconds. (Tr. 573) In each successive photograph, he observed larger and more crystals up until approxi- mately two minutes, after which the appearance did not change significantly. (Tr. 575) From this, he concluded that evaporation did not play any role in conversion, be- cause if the material converted only due to evaporation on the slide, each photograph would look the same. (Tr. 575) Brittain related these results to the light-scattering measurements by observing that the Bouzard crystals only began to aggregate at approximately one minute, the time at which the light scattering intensity began to in- crease. (Tr. 576) He opined that the aggregation of crystals at one minute was consistent with the change in light-scattering intensity that was observed beginning at that time interval. (Tr. 576) Brittain conducted another series of light-scattering ex- periments in which he re-ran the first two series of experi- ments except that instead of using a saturated cefadroxil solution as the dissolution medium, he used only simulated gastric juice, in which he placed a greater quantity of cefadroxil material. (Tr. 577) This was done so that he could determine whether conversion occurred in an un- saturated solution. (Tr. 579-80) 38a When Brittain recorded the light scattering intensities of the Bouzard material, he plotted a different tracing from that obtained in the first series of experiments. In- stead of a constant light-scattering intensity, he recorded a pattern that began as a maximum negative voltage and gradually decreased to a constant intensity value. (Tr. 580) Brittain opined that the initial maximum scattered light intensity was consistent with the fact that none of the cefadroxil had yet dissolved, and that the gradual decrease in intensity represented the dissolution of the Bouzard monohydrate until it reached an equilibrium, at which point the light scattering intensity remained constant. (Tr. 580; DX 16, pages 155-56) In the next experiment, Brittain plotted scattered light intensities over time for light passed through simulated gastric juice in which he placed cefadroxil DC. The scattered light intensity curves he obtained in these experi- ments were more complex than in the other light scatter- ing experiments. The initial intensity was not as great as the initial intensity of the Bouzard material suspended in the gastric juice. Brittain believed that this was consistent with the fact that cefradoxil DC crystals are smaller than Bouzard crystals, and hence would not refract as much light. (Tr. 581) Over the first minute, the scattered light intensity decreased, consistent with dissolution of the cefa- droxil DC crystals into the gastric juice. (Tr. 581) At approximately one minute and eighteen seconds, however, the scattered light intensity increased steadily, surpassing the initial intensity, until the four and one-half minute mark, at which point the intensity remained relatively constant, decreasing only slightly. (Tr. 581) Brittain concluded from the fact that the final intensity was greater tham the initial intensity that a definite change had occurred m the physical characteristics of the cefadroxil DC. (Tr. 581-82) This was consistent with his observa- tions in other experiments that conversion to Bouzard had occurred. (Tr. 582) Brittain conducted microscopy ex- periments similar to those run in connection with the 39a first set of light-scattering experiments, in which he repro- duced the conditions of the light scattering experiment this time cefadroxil DC in simulated gastric juice—and took a series of microphotographs to record visual and birefringence changes in the crystals over time. (Tr. 587- 88) Brittain observed that as early as 12 seconds into the experiment, Bouzard crystals were evident. (Tr. 588) From the strength of the birefringence of the crystals, and from the depth of the crystals, Brittain opined that evap- oration could not have been the cause of the formation of the crystals. (Tr. 589) 7. Sealed System Experiments A further set of experiments was performed in an at- tempt to minimize the effects that evaporation could have on cefadroxil solution observed microscopically. Brittain observed cefadroxil DC in simulated gastric juice placed in the well of a thick miscroscope slide over which he had placed a slide cover that was sealed with nail polish. (Tr. 593) This experiment was a standard laboratory technique for creating a sealed system that can be ob- served by microscope. (Tr. 593) Photomicrographs were taken at approximately two, four, six and eight minutes. (Tr. 594; DX 37) In each successive photograph, dis- tinctive large triangular crystals believed by Brittain to be Bouzard crystals can be seen in greater quantity. (DX 37; Tr. 595) Brittain conducted a second type of sealed system ex- periment, in which he filled test tubes that could be sealed by screwing on a threaded cap with cefadroxil DC in approximately 23 milliliters of water or simulated gas- tric juice. (Tr. 600-02) The goal of this experiment was to determine whether cefadroxil DC converted in a larger quantity of fluid in a sealed environment. (Tr. 601) Samples were maintained in a bath at 37°C and allowed to equilibrate for one half hour. (Tr. 601-02) Samples were then examined by microscopy and x-ray powder 40a diffration. Again, Brittain concluded that Bouzard crys- tals had formed. (Tr. 603, 605) These results were believed consistent with the sealed slide tests, and caused Brittain to conclude that evaporation played no role in the conversion of cefadroxil DC to Bouzard monohy- drate. (Tr. 605) 8. Freeze-Drying Experiments Brittain simulated the freeze-drying experiments of Dr. Greenblatt, with minor variations. He placed a Zenith cefadroxil DC capsule in 30 milliliters of simulated gas- tric juice maintained at 37°C and stirred at 10 rpm. (Tr. 606-07) At approximately two and three quarters min- utes, instead of Dr. Greenblatt’s one and three quarters minutes. Brittain removed the capsule from the dissolu- tion apparatus and, within five to ten seconds, as op- posed to Dr. Greenblatt’s approximately five seconds, plunged the sample into liquid nitrogen. (Tr. 607) Dr. Brittain opined that the five second difference had no scientific significance. (Tr. 618) After five minutes in the nitrogen, Brittain removed the sample and place it in a freeze-drying (“lyophiliza- tion”) apparatus that he had constructed himself. (Tr. 608) The following day, he removed the contents and conducted microscopy and x-ray powder diffraction anal- yses of the sample. (Tr. 613) From these tests, Brittain concluded that the samples he observed contained Bou- zard monohydrate. (Tr. 613) Brittain conducted another experiment in which he replicated the dissolution and sample removal aspects of Dr. Greenblatt’s experiment, removing the sample at one and three quarters minutes. (Tr. 619) He then sliced the capsule and performed microscopy and x-ray powder diffraction analyses of the contents. Brittain first ob- served that the contents of the capsule did not appear sufficiently wetted, in his opinion, for conversion to occur. (Tr. 620) The results of his microscopy examination “a ied 3 : 3 tsi mat 4la was that although some Bouzard crystals were present, the bulk of the sample was cefadroxil DC with weak bire- fringence. (Tr. 612) Likewise, the x-ray powder diffrac- tion analysis yielded a pattern that signified to Brittain a mix of cefadroxil DC and Bouzard crystals. (Tr. 621- 22) Brittain concluded that if a sample of cefadroxil DC is not sufficiently wetted, no conversion will occur. (Tr. 622-23) 9. Gottstein Comparison To rebut Dr. Pfeiffer’s testimony, Dr. Brittain made an independent comparison of the Gottstein and Zenith cefadroxil DC x-ray powder diffraction patterns. (Tr. 642) He concluded that the two patterns were on the border between being considered by him “similar” or “equivalent”. (Tr. 642) From this, he did not believe that he could conclude that Gottstein would convert to Bouzard monohydrate. (Tr. 644-45) Brittain recorded an x-ray diffraction pattern of a com- pound represented to him by Bristol to be Gottstein cefa- droxil. When he compared the pattern obtained from the Bristol sample to the Marr pattern relied on by Dr. Pfeiffer, Brittain found that 21 of 24 peaks matched, and concluded that the patterns were equivalent. (Tr. 819-20) He then wetted 200 milligrams of the substance he believed was Gottstein cefadroxil and, after eight minutes, recorded another x-ray powder diffraction pat- tern. (Tr. 821) Brittain concluded from the second x-ray pattern that the Gottstein material had not changed, and that no Bouzard monohydrate could be detected. (Tr. 822) After another fifteen minutes had elapsed, which would have allowed evaporation to have occurred, he ran another powder pattern, which again remained un- changed. (Tr. 822-23) Yet another x-ray powder pattern was made after one hour had elapsed, with similar re- sults. (Tr. 823) From this Britain concluded that Gott- stein cefadroxil does not convert to Bouzard monohy- drate when wetted. (Tr. 824) 42a C. Zenith’s Rebuttal Case Dr. Martha Greenblatt Greenblatt was presented as a live witness on Zenith’s rebuttal case. She testified that at the time of her initial experiments and deposition, she had not considered whether leaving the capsules in the simulated gastric acid for a longer period of time would have had any impact on the results of her tests. (Tr. 846) Since it was brought to her attention, Greenblatt had formed the opinion that leaving the capsules immersed for a longer period of time would not have changed her results, because the capsules had already opened and she ‘believed that the capsules’ contents had already been wetted. (Tr. 847) To verify this opinion, Greenblatt instructed a graduate student to conduct a further experiment in which he replicated her earlier experiments except that he increased the length of time in which the capsule remained in the gastric fluid before they were removed, from approximately two min- utes to almost three minutes. (Tr. 864-65; PX 46) Green- blatt concluded that the results of this experiment were no different than the results of her earlier experiments— no conversion could be detected from the x-ray powder patterns. (Tr. 865) Dr. Anthony P. Simonelli Dr. Simonelli, the last witness to testify at trial, is a professor emeritus at the University of Connecticut. (Tr. 929) Dr. Simonelli performed no experiments of his own that were introduced at trial, but only gave his expert opinions based on the experiments of others. He was offered as an expert in biopharmaceutics, which is the study of how formulations of drugs interact with a bio- logical environment/system (otherwise known as a body, be it human or other animal), and how changes in drug formulations affect their absorption by the biological sys- tem. (Tr. 929-30) Simonelli was also offered as an ex- 43a pert in the identification and analysis of polymorphic and solvate transformation in solid state and heterogeneous systems, and in the fields of nucleation and crystal growth, and x-ray diffraction analysis and optical microscopy (Tr. 931-33, 935) Simonelli testified at length about the nucleation process that must precede any recrystallization of dissolved cefa- droxil DC. He differed substantially with the theories of Dr. Brittain. Simonelli opined that Dr. Brittain’s ex- periments did not prove that conversion occurred in the dissolution beaker. (Tr. 958) He instead believed that the recrystallization occurred on the microscope slide after a sample was removed from the beaker, because the conditions for nucleation and crystal growth are “fan- tastically higher on the slide than they are in the beaker,” due to the greater saturation on the slide, (Tr. 959), and the cooling effect of evaporation, which aids precip- itation of solids from a solution, (Tr. 980-81). Simonelli testified that Brittain’s slide observations would not be representative of in vivo conditions, because evaporation and cooling, factors present on the slide that he believed greatly enhance crystal growth, are not present in the human stomach. (Tr. 981) He also believed that the stirring motion present in the stomach would diminish the possibility of nucleation and crystal growth. (Tr. 981) Simonelli further opined that other factors present in the stomach but not on a slide that might inhibit nucleation and crystal growth include the dissolved gela- tin capsule, (Tr. 982-83), excipients, (Tr. 984), and the presence of macromolecules such as proteins and en- zymes, (Tr. 1008, 1018). Simonelli believed that Brittain’s sealed system experi- ments are not conclusive because they at most eliminate only one factor as a possible explanation for the conver- sion: evaporation. (Tr. 986) He was at a loss to explain the difference in results between Dr. Brittain’s and Dr. Greenblatt’s second freeze-drying test results. He postu- 44a lated that the difference in time it took Brittain to re- move the sample from the dissolution beaker and plunge it in the liquid nitrogen—at most five seconds—may ac- count for the difference. (Tr. 987-88) Simonelli opined that Brittain’s light-scattering experi- ments also did not establish that conversion occurred in solution as opposed to on the slide, but were merely inconclusive. (Tr. 993, 995) He further opined that “sink” conditions present in the stomach would also in- hibit nucleation and crystal growth. (Tr. 1012) Accord- ing to Simonelli, sink conditions exist when the concen- tration of a compound is negligible in the bulk of a dis- solution medium and is high near the surface of the compound being dissolved. (Tr. 1013-15) He believed that Dr. Lake-Bakaar was wrong in concluding that the rapidity of the conversion would counteract the sink effect, because he believes that the speed of the conver- sion does not affect the action of the sink conditions in preventing a localized supersaturation zone. (Tr. 1015- 17) Simonelli conceded that the speed of the reaction is not unimportant, but, all else being equal, the presence of sink versus non-sink conditions would impact on the likelihood of nucleation and crystal growth. (Tr. 1017) In general, Simonelli concluded that Brittain’s experi- ments did not sufficiently simulate in vivo conditions to be indicative of nucleation and crystal growth in the human stomach. (Tr. 1008-09) He did not disagree with the conditions in the human stomach specified by Drs. Goldin and Lake-Bakaar, but disagreed that the beaker experiments of Dr. Brittain adequately accounted for other factors present in the stomach that would adversely affect the likelihood of conversion. (Tr. 1018-19) Il. FINDINGS OF FACT The central fact issue that the Court must determine is whether the cefadroxil DC in Zenith’s formulated cap- sules converts to Bouzard mpnohydrate in vivo. This 45a one issue was the focus of much scientific theorizing and experimentation, and has resulted in a trial record that contains a number of theories and abundance of data. A subsidiary issue that Zenith asserts circumscribes the breadth of the claim in the ’657 patent is whether “Gott- stein” cefadroxil is in fact cefadroxil DC, and whether Gottstein cefadroxil converts in vivo to the Bouzard mon- ohydrate. This issue accounted for a minor portion of the evidence presented at trial. A. In Vivo Conversion Zenith’s position on the conversion of cefadroxil DC into Bouzard monohydrate rests on the results it obtained from several experiments, and on expert opinion testi- mony that attempted to refute the results obtained by Bristol from its experiments. Zenith had three sets of experiments conducted to support its position that con- version does not occur. First, Dr. Rothstein supervised an experiment to mea- sure and compare the dissolution rates of cefadroxil DC and Bouzard monohydrate. Second, Dr. Rothstein super- vised an experiment to measure and compare the equilib- rium solubility and bulk density of those two compounds. Both the dissolution rates and equilibrium solubilities, as well as initial bulk densities, were found by Rothstein to be different for both compounds. In reliance on this data, Zenith expert Dr. Pfeiffer opined that conversion did not occur. His theory was that if cefadroxil DC first converted to Bouzard monohydrate before dissolving, the equilibrium solubility for the two materials would be identical, because in essence the same material would be dissolving into the dissolution medium. POSTE The third set of experiments offered into evidence by Zenith were the freeze-drying experiments of Dr. Green- blatt. Greenblatt conducted two sets of experiments, dif- fering only in the time at which the dissolving capsule was removed from the dissolution vat and frozen in liquid ii aie 46a nitrogen. The first set of experiments, with the shorter dissolution period, was offered into evidence on Zenith’s direct case through deposition transcript with exhibits. The second set of experiments was offered into evidence on Zenith’s rebuttal case through Greenblatt’s live testi- mony and exhibits. The results obtained by Greenblatt were the [ ] same for both experiments: no conversion occurred. Bristol’s position with respect to Zenith’s experiments is that they were scientifically inaccurate and otherwise flawed. Bristol’s position on the conversion of cefadroxil DC into Bouzard monohydrate rests on the results it ob- tained from a number of experiments conducted by Dr. Brittain, and on expert opinion testimony that laid a foundation for some of the assumptions made by Brit- tain in attempting to simulate in vivo conditions. Drs. Levine and Goldin were offered as experts to support Bristol’s position that actual in vivo experiments could not be conducted due to medical ethics constraints, and that no satisfactory in vivo experiment could be designed to test the conversion hypothesis that would be any more probative of the issue than are in in vitro experiments of Dr. Brittain. Drs. Goldin and Lake-Bakaar were offered as experts in gastroenterology to lay the founda- tion for the conditions utilized by Dr. Brittain to simulate conditions inside the human stomach. The bulk of Bistol’s evidence consists of the numerous experiments conducted by Dr. Brittain to verify that cefadroxil DC converts to Bouzard monohydrate. Brit- tain designed and conducted a variety of experiments to test different aspects of the conversion issue, all of which confirmed in his opinion that conversion would in fact occur in vivo. Zenith’s position with respect to Bristol’s experiments is that they at best prove that conversion occurs on a microscope slide under conditions different from those present in the human stomach. Zenith’s ex- perts opined that Bristol did not even prove that conver- sion occurs in a dissolution beaker, much less in vivo. ‘47a The Court finds that Bristol presented by far the more compelling case on the issue of conversion. 1. Use of In Vitro Experiments The opinions of Drs. Levine and Goldin that, given the nature of the experiments which would be required, in vivo experimentation could not be justified under med- ical ethics constraints merely to prove patent infringe- ment, stands unrefuted by Zenith. Both doctors were adequately qualified to give this opinion and were credible witnesses. Therefore, the Court finds that Bristol’s use of in vitro experiments to establish in vivo events is in prin- ciple a valid methodology. Cross v. lizuka, 753 F.2d 1040, 1050 [224 USPQ 739] (Fed. Cir. 1985); Nelson v. Bowler, 626 F.2d 853, 856 [206 USPQ 881] (C.C.P.A. 1980). 2. Validity of Brittain’s Simulated In Vivo Condi- tions The conditions prescribed by Drs. Goldin and Lake- Bakaar to simulate conditions in the human stomach, i.e., 30 milliliters of simulated or actual gastric juice main- tained at 37°C and stirred at three to ten rpm, were also unrefuted by Zenith. Further substantialy unrefuted was Dr. Lake-Bakaar’s opinion that the emptying rate of the stomach and the secretion rate of additional gastric juice are sufficiently slow in comparison to the rate at which Brittain believed conversion occurred such that failure to account for those factors would not constitute a flaw in Brittain’s experiments. Both doctors were adequately qualified to give these opinions and were credible wit- nesses. Therefore, to the extent Bristol established the oc- currence of conversion under these conditions that was not attributable to some other condition present in the in vitro experiment that is not present in vivo, it has proved that in vivo conversion also would occur. 48a 3. Brittain’s Experiments Dr. Brittain spent far more time on the witness stand during this trial than did any other witness. Over the course of nearly three full days of testimony, the Court had the opportunity to observe and listen to Brittain at great length. The Court’s impression of Dr. Brittain is that he is a talented research chemist, who possesses a significant ability to thoroughly understand a problem and, through his broad knowledge of laboratory instrumenta- tion, design multiple experiments to test many aspects of that problem. He was also, for the most part, a very credible witness. Dr. Brittain’s explanation of the reason that conversion occurs, and the process by which it @oours, however, seemed to be somewhat beyond the scope of his expertise. On this point, Zenith’s Dr. Simonelli seemed more knowl- edgeable. In fact, though, the Court does not believe ~ that any witness presented in this case has anything more than a superficial understanding of the “mechanism” or “pathway” by which conversion occurs. At issue in this case, however, is not “why” conversion occurs, but only “whether” it occurs. Thus, although Dr. Brittain’s ex- planation of the conversion process seemed beyond the ken of his expertise and was somewhat lacking in credi- bility, the Court finds that Brittain has established by a preponderance of evidence, well within his range of ex- pertise, that cefadroxil DC in fact converts in vivo to Bouzard monohydrate. The strength of Brittain’s experiments and results is their totality. Piece by piece, Brittain built an impressive collection of data. The results of each series of experi- ments strengthen the results of each other set of experi- mental results. The total effect of the experiments is to prove with sufficient certainty the fact of conversion in vivo. In support of its motion for summary judgment, Zenith submitted expert affidavits that concluded that the pro- 49a tonation of cefadroxil DC molecules dissolved in gastric acid would prevent recrystallization of dissolved cefadroxil DC. At trial, Bristol introduced testimony and test re- sults by Brittain to refute this claim. Those experiments tested for protonation, and the results indicated that pro- tonation did not occur. Zenith offered no evidence at trial to refute this evidence. Accordingly, the Court finds that protonation plays no role in inhibiting conversion. The largest number of experiments conducted by Brit- tain were the dissolution experiments in which he placed both bulk powder or formulated capsules in varied amounts of water or simulated or actual gastric juice and later tested the samples for conversion. The dissolution medium volume and stirring rate conditions employed en- compassed and exceeded the wide range of possible condi- tions in vivo. Through the use of three tests—visual ob- servation, birefringence comparison and x-ray diffraction pattern comparison—Brittain concluded uniformly that under any of the conditions used, he detected conversion. Brittain first established indisputably through photo- micrography that cefadroxil DC crystals are much smaller than Bouzard monohydrate crystals, and are much dif- ferent in shape. He also established that cefadroxil DC crystals exhibit a much weaker birefringence than do crystals of Bouzard monohydrate, which are highly bire- fringent. Thus, through microscopy, Brittain could de- termine with a high degree of certainty whether a sample of wetted cefadroxil DC had changed its crystalling form, and could conclude to a lesser extent that the form to which it had changed was Bouzard monohydrate. Al- though changes in the physical properties of shape, size and birefringence of the cefadroxil DC erystals could be conclusively determined through microscopy, Britain could not determine by observation alone that the larger, more birefringent crystals were necessarily Bouzard. To deter- mine conversion to Bouzard with great certainty, Brittain ran x-ray powder diffraction patterns, a technique that in essence takes the “fingerprint” of a crystalline compound. 50a Through x-ray diffraction analysis, Brittain determined with much greater confidence that all of the conversions suspected after optical examination had in fact been to Bouzard monohydrate. Zenith contends that Brittain failed to establish that any of the x-ray diffraction patterns, including his Bouzard monohydrate reference pattern, conform to the x-ray dif- fraction pattern that forms the claim of the ’657 patent. The Court disagrees, with respect to the reference pattern, Bristol has put into evidence numerical tables represent- ing both the patent pattern and Brittain’s reference pat- tern. (DX 1; DX 16 at 19) According to Zenith’s own expert, Dr. Pfeiffer, differences of 0.2 or less are insig- nificant in comparing x-ray diffraction patterns. (Tr. 233) According to Dr. Brittain, whose expertise on X-ray powder diffraction pattern analysis the Court accepts, patterns with at least a 95% match of peaks are “iden- tical” compounds. (Tr. 633). Using Dr. Pfeiffer’s mar- gin of error, a simple comparison of the tables reveals that 21 out of 22 peaks in the patent pattern are matched by peaks in Brittain’s reference pattern. Although Pfeiffer would find a “match” even with a variation of up to 0.2, most of the matches have differences of less than 0.05. In fact, only one match even approaches, but does not exceed 0.1. Thus, there are 21 clear matches out of 22 peaks in the patent pattern. The ratio of 21/22 exceeds the 95% peak matches Brit[t]ain would require to con- clude that two compounds are identical. The Court thus concludes that Zenith’s claim that Brittain’s reference pat- tern is not of the same compound claimed in the ’657 patent is without any merit. The Court further finds credible Brittain’s conclusions that the patterns obtained from wetted cefadroxil samples recovered from his experiments are equivalent to the refer- ence pattern for Bouzard monohydrate. Dr. Brittain’s ex- pertise with the analysis and comparison of x-ray diffrac- tion patterns was amply demonstrated, and the Court ac- cordingly adopts Brittain’s conclusions. Zenith’s assertion S5la that the comparison are inconclusive because Brittain con- cluded only that the patterns were “equivalent” and not “identical” is rejected by the Court. Although under Brittain’s rating system “identical” is the higher rating, the Court accepts Brittain’s opinion that a finding of “equivalance” is sufficient to support his conclusion that conversion had occurred. The standard of proof in this case is not the “beyond a reasonable doubt” standard. The Court finds that Brittain’s laboratory procedures for the dissolution experiments were consistent, well- documented and highly credible. Zenith has not with any force directly refuted the results of Brittain’s microscopy and x-ray diffraction tests. Zenith’s criticisms of Brittain’s results are based on contentions that the conversion oc- curred not in the dissolution beaker, but on the micro- scope slide, under conditions greatly different from ac- tual in vivo conditions. Alternatively, Zenth contends that even if conversion does occur in the beaker, the beaker conditions are significantly different from in vivo condi- tions. The Court finds these contentions also without merit. A major basis for Zenith’s contention that conversion occurs on a slide and not in a beaker or the stomach is that on the slide, a much more saturated solution ex- ists, which Dr. Simonelli opined was much more conducive to nucleation and crystal growth. The Court finds that Bristol demonstrated with a high degree of certainty that conversion occurs inside of an ingested capsule, and that the environment inside of a capsule penetrated by gastric liquid would be of a similar or greater saturation level to that existing on a slide. Thus, the Court finds that Zenith’s distinction between beaker and slide conversion is meaningless to the extent it is based on differences in saturation levels. To the extent that the beaker/slide ar- gument is premised on conditions present on a slide that are not also present inside of a capsule ingested in vivo, it has adequately been overcome by Bristol’s affirmative proofs. 52a Zenith, through Drs. Simonelli and Pfeiffer, posited that several material differences exist between the condi- tions present on a slide and those present in vivo, which impact greatly on the question of in vivo conversion. First, both Pfeiffer and Simonelli identified evaporation and cooling as two factors present on a slide but not in the stomach. They opined that evaporation is conducive of cooling, which is conducive of precipitation of crystals out of solution. As will be discussed below, Brittain con- ducted experiments that refuted the significance of either of these factors. Simonelli and Pfeiffer further opined that the stirring action and replenishment of fluids in the stomach would adversely affect the occurrence of nucleation and crystal growth. Dr. Simonelli assumed that conversion occurs after the cefadroxil DC leaves the capsule, because the “dynamic situation” he discussed was based on the move- ment of the capsule contents as they poured out of the capsule. (Tr. 981) Dr. Pfeiffer’s opinion was similarly flawed. Because the Court finds that conversion occurs inside of an ingested capsule, it finds that stomach agita- tion as an inhibitor of conversion is of minimal signifi- cance, and opinions relying on it are not entitled to much, if any, weight. Further, the Court finds that Simonelli’s suggestion that the replenishment of fluids in the stomach is similarly without credibility. Dr. Lake-Bakaar’s testi- mony as to the extremely slow rate of stomach emptying and replenishment was highly credible and stands unre- futed. The Court therefore finds Simonelli’s opinion as to this factor to be lacking in credibility. Other factors identified by Simonelli as existing in the stomach but not on a slide include the presence of gelatin, excipients and macromolecules such as food particles, pro- teins and enzymes. The Court finds this testimony to be worthy of no weight. First, on cross-examination, Simonelli conceded that macromolecules such as food particles or proteins could it 53a enhance nucleation and crystal growth, as well as in- hibit them. (Tr. 1026-27) Second, excipients were pres- ent on the slide as well as in vivo in those dissolution ex- periments conducted by Brittain that used Zenith capsules. Dr. Simonelli’s attempted explanation of why excipients would have a lesser impact on a slide than they would in a capsule, (Tr. 984), seemed contrived and lacked credi- bility. Third, macromolecules of the variety identified by Simonelli were present on the slide in those dissolution experiments conducted by Brittain that used actual gastric juice. Last, Simonelli’s testimony that dissolved gelatin may inhibit nucleation and crystal growth, though prob- ably true in the abstract, does little to refute the results of Brittain’s experiments. According to Simonelli, Brit- tain’s experiments failed to account for the presence of gelatin because his samples were taken from the inside of the capsule. (Tr. 983) Because the Court finds that conversion occurs inside the capsule, it finds Simonelli’s criticism to lack merit. Yet another factor Simonelli identified as present in the stomach but not on a slide was “sink” conditions. Simonelli’s opinion, however, was premised on conver- sion occurring outside of the capsule, in a low concen- tration solution. Because the Court finds that conversion occurs inside of the capsule, this factor is of little conse- quence. Moreover, Brittain demonstrated that conversion occurs even under conditions that Simonelli agreed would constitute sink conditions. (Tr. 1022-23) Although Dr. Simonelli impressed the Court as a scientist of distinction with vast experience, his opinion testimony in this case was not supported by any experimental data, was in good measure highly speculative in nature, and did not cast significant doubt on Bristol’s experimental evidence of conversion. One of several series of experiments conducted by Brit- tain to verify the occurrence of conversion in the dissolv- tion beaker instead of on a slide, free from the effect of 54a evaporation and cooling, was Brittain’s series of light- scattering experiments. Those experiments cast great doubt on Zenith’s contention that conversion occurs only as a result of the greater saturation levels, cooling and evaporation present on a slide. Although Zenith contends that the light-scattering experiments do not prove beaker conversion because the saturation levels in the cuvettes used in those experiments were closer to slide saturation conditions than to beaker saturation conditions, this argument is not supported by the record. The light-scattering experiments used 25 milli- grams of cefadroxil DC placed in a cuvette holding three milliliters of simulated gastric juice. This represents a ratio of solvate to solvent only one half that of the ratio of solvate to solvent that existed in Brittain’s dissolution experiments that used 500 milligrams of cefadroxil DC in capsule form placed in 30 milliliters of simulated gastric juice. If, as Zenith contends, conversion does not occur inside the capsule because its contents leave too rapidly, then the resulting solution would be adequately proxied by the cuvette in the light-scattering experiments. Accord- ingly, to the extent that the light-scattering experiments prove conversion inside the cuvette, they also prove beaker conversion. The scattered light traces recorded by Brittain are also highly corroborative of Brittain’s opinion that conversion occurs free from the effects of evaporation and tempera- ture cooling. Through several runs of the light-scattering experiment, Brittain established that undissolved Bouzard monohydrate crystals floating in a dissolution medium maintained at a constant temperature scatter more light than do undissolved cefadroxil DC crystals. This is con- sistent with the greater size and birefringence of Bouzard monohydrate crystals. The Court finds that the trace at page 157 of Brittain’s laboratory notebook (DX 16) establishes that conversion occurred in the cuvette, as opposed to on the slide. There, ooo z Lie chiar: cre Ta 55a the undissolved cefadroxil DC initially placed in simu- lated gastric juice reflected a certain intensity of light, before it diminished and then, at approximately one min- ute, gradually increased in intensity, reaching a level in excess of the initial level of scattered light. This trace proves without question that some physical change oc- curred inside the cuvette. Dr. Brittain opined that this curve is consistent with an initial dissolution phase in which the scattered light intensity declined as the cefa- droxil DC dissolved, and then increased as conversion occurred and Bouzard crystals precipitated out of solu- tion, resulting in a scattered light intensity exceeding the initial intensity reflected by Cefadroxil DC crystals. The Court finds this explanation highly credible and corroba- rative of Brittain’s other experiments. Further corraborative of the occurrence of conversion before a sample was placed on a slide, and perhaps more revealing, are the series of photomicrographs recorded by Dr. Brittain over time under the conditions used in the light scattering experiments. Over time, Dr. Brittain ob- served greater numbers in larger sizes of Bouzard-shaped crystals. The appearance of these crystals in the photo- graphs is identical to crystals observed in other experi- ments in which they were identified by x-ray diffraction analysis as Bouzard crystals. Accordingly, the Court finds credible Brittain’s conclusion that these crystals were also Bouzard crystals. The increase and size and quan- tity of Bouzard crystals over time in the photographs would not be possible if, as Zenith contends, conversion occurred on the slide. Instead, each slide would have an equal amount of Bouzard crystals of equal size. There- fore, the Court finds that this experiment further but- tresses the conclusion that conversion occurs even under conditions free from the effects of evaporation and cool- ing. The Court finds that Dr. Brittain’s light-scattering ex- periments were highly probative of the issue of conversion 56a in solution versus on the slide. Zenith’s only witness who addressed the results of this experiment, Dr. Simonelli, had no adequate explanation for these results. His con- jecture that an aggregation and dispersion of cefadroxil DC particles, or the presence of excipients in the solution may have been the cause of changes in light-scattering intensity was speculative, and unsupported by any experi- mental data or literature, and is accorded little weight. The Court also finds that Brittain’s sealed system ex- periments prove that evaporation played little, if any, role in the microscopy observation made by Brittain. By seal- ing slides and test tubes, and then recording conversion over time, Brittain has refuted Zenith’s claim. If evap- oration played a significant role in the observed conver- sion, a sealed slide or test tube system should contain only those converted crystals that had already precipitated out of solution before the slide was sealed. Instead, Brit- tain observed continuing precipitation of Bouzard crys- tals long after the slide was sealed. Thus, the Court finds that evaporation, a condition that both parties agree does not exist in the stomach, was not a substantial cause, if it was a cause at all, of conversion on the micro- scope slide. Last, Brittain’s freeze-drying experiments also corrobo- rate his other findings that conversion occurs inside of a capsule cefadroxil DC capsule if enough time is allowed to elapse. His findings will be compared to those of Dr. Greenblatt below. 4. Greenblatt’s Freeze-Drying Experiments Differences between Dr. Greenblatt’s first series of freeze-drying experiments and Dr. Brittain’s freeze-drying experiments could be accounted for by differences in the length of time that capsules were left in the dissolution beakers before being removed and frozen. The results of Greenblatts second series of experiments, however, appear to directly conflict with the results of Brittain’s erie a dee \ eee 57a experiments. The Court finds unlikely, and unsupported by credible evidence. Zenith’s suggestion that a difference of at most five seconds between the length of time it took Greenblatt to remove a capsule from the beaker and place it in liquid nitrogen and the length of time it took Brittain to do the same could account for the difference in results. Zenith’s own witness, Dr. Pfeiffer, opined that a difference of two or three seconds would be insignificant. (Tr. 188-89) The Court also finds unlikely Bristol’s sug- gestion that grinding and desiccation of the recovered sample could cause converted Bouzard to revert to cefa- droxil DC, a more unstable form of cefadroxil. Thus, the Court can only resolve this conflict by resort to an evalu- ation of credibility. On this count, the Court must con- clude, on the basis of its observations of both witnesses and scrutiny of their testimony, that Brittain’s results are significantly more credible. Brittain demonstrated repeat- edly during trial his consistency in laboratory method, his understanding of the problem he was investigating, his knowledge of laboratory equipment and the ability to design and verify experiments. By contrast, although she may have significant expertise in fields of inquiry unrelated to the issues in this case, Greenblatt demon- strated little understanding of the problem at issue in this case or the reason for her procedures and thus played no role in the design of her experiments, lacked any prior experience in freeze-drying techniques, was lax in her methodology, particularly in the recording of her pro- cedures and observations, and in fact did not even par- ticipate in the second series of experiments. The Court finds that Brittain’s freeze-drying results are simply better supported and vastly more credible. Accordingly, those findings are adopted by the Court. - 5. Rothstein’s Dissolution Rate and Equilibrium Solubility Experiments Zenith contends that Dr. Rothstein’s experiments prove that conversion does not occur. Specifically, Zenith con- 58a tends that the observed differences in dissolution rates between cefadroxil DC and Bouzard monohydrate are in- consistent with conversion, because if conversion occurred within the capsule, similar equilibrium solubility results would be observed after the contents of the capsule were released and dissolved into solution. For this conclusion, Zenith relies on the testimony of Dr. Pfeiffer, and an arti- cle from a medical journal annexed as Exhibit B to De- fendant’s Exhibit 13. (Tr. 92) Though the Rothstein results may support Zenith’s posi- tion that conversion does not occur, the Court does not find that those results overcome the extensive proofs con- tained in Brittain’s experiments. The Court is hard- pressed to reconcile the conflict between Rothstein’s ex- perimental results and Brittain’s. An explanation prof- fered by Bristol is that the-Rothstein results are inconclu- sive because of the possibility of a significant degree of experimental error. The margins of error recorded by Rothstein with respect to the dissolution rate experiments support Bristol’s contention. (See Tr. 54; PX 21) The absence of any effort by Rothstein to account for margin of error as to the equilibrium solubility experiments leaves the issue unresolvable. On the basis of the trial record, the Court can neither conclude that the experiment re- sults are tainted by error, nor exclude experimental error as an explanation for the discrepancy. Thus, at bottom, the-€ourt can only find that the powerful proofs by Bristol of the occurrence of conversion are simply much more persuasive, and greatly outweigh the Rothstein results, from which the non-occurrence of conversion is merely a possible inference. B. Gottstein Findings A subsidiary fact issue raised by Zenith is whether cefadroxil DC is in fact a form of cefadroxil prior in the art to Bouzard monohydrate. Zenith contends that this issue bears on the interpretation of the claim in the ’657 patent, and on the ultimate issue of infringement. Based 59a on its review of the evidence, the Court finds that Zenith has adequately demonstrated that Gottstein cefadroxil and cefadroxil DC are similar crystalline forms of cefadroxil. The Court finds, however, that although the x-ray dif- fraction patterns of Gottstein cefadroxil is similar to the x-ray diffraction pattern for cefadroxil DC, Bristol has proved that cefadroxil DC converts to Bouzard mono- hydrate when wet, and that Gottstein cefadroxil does not. The only evidence Zenth relies on to support its posi- tion that the two materials are the same is Dr. Pfeiffer’s comparison of the two respective compounds’ x-ray dif- fraction patterns, and his opinion that, based solely on this comparison, if one material converted, the other would also. This opinion is completely refuted by the results of an experiment in which Brittain attempted with- out success, under conditions stated by Zenith’s exper‘s to be highly conducive of conversion, to make Gottstein convert to Bouzard monohydrate. Given this result, in contrast to Brittain’s proof that cefadroxil DC converts to Bouzard monohydrate, the Court finds that Gottstein cefadroxil is distinctly different from cefadroxil DC. Zenith’s further contention that Bristol has not proved that the material it claims is in fact Gottstein materials is also without merit. Brittain relied on a comparison of an x-ray diffraction pattern that he obtained from his Gott- stein sample with the same pattern Zenith relied on as representative of Gottstein, and concluded credibly that his Gottstein sample matched the Gottstein pattern relied on by Zenith. The Court finds that Bristol has proved that the material it used to test for conversion was in fact Gottstein cefadroxil. Ill. CONCLUSIONS OF LAW A. Jurisdiction and Burden of Proof Count I of Zenith’s complaint arises under the patent laws of the United States, 35 U.S.C. §§1 et seq. For reasons stated by the Court on previous occasions, a jus- ticiable controversy has existed and continues to exist -_aenennnieteini 60a between the parties. Therefore, the Court has subject matter jurisdiction over this action pursuant to 28 U.S.C. § 1338(a). As a declaratory judgment plaintiff, Zenith had the burden to prove the existence of an actual controversy, which in this case required proof that Bristol posed a threat that it would sue Zenith for infringement based on acts in which Zenith had a present intention and capacity to engage. Indium Corp. of America v. Semi-Alloys, Inc., 781 F.2d 879, 883 [228 USPQ 845] (Fed. Cir. 1985), cert. denied, 479 U.S. 820, 107 S. Ct. 84 (1986). This burden was met. As a patent owner who has been proved in a declaratory judgment action to have posed a threat to sue for infringement, Bristol bears the burden to prove infringement. Advance Transformer Co. v. Levinson, 837 F.2d 1081, 1084 [5 USPQ2d 1600] (Fed. Cir. 1988) (trial court did not err in finding that patent owner- defendant in declaratory judgment action had not met his burden to prove infringement); United Sw [Text truncated at 120,000 characters. The full text is on the page linked above.] --- Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/brief%3Amicro_IA40386012_0456%3A1. Public record. Not legal advice.