Full opinion text
FINDINGS OF FACT AND CONCLUSIONS OF LAW DAVIS, District Judge. I. INTRODUCTION AND PROCEDURAL HISTORY.......................269 II. THE PATENTS........................................................271 A. The ’431 Patent..................................................271 1. Background................................................271 2. Subject Matter Jurisdiction Over the ’431 Patent.............272 a. Prior motions for summary judgment as to the ’431 Patent....................................................272 b. The renewed motion for summary judgment as to the ’431 Patent................................................273 B. The ’790 Patent..................................................273 1. The significance of pH.....................................273 2. The claims of the ’790 Patent...............................274 3. Prosecution History........................................275 C. The ’249 Patent..................................................277 1. Introduction...............................................277 2. The addition of ethanol achieves surprising results............278 3. The claims of the ’249 Patent...............................279 4. Prosecution History........................................279 III. PHARMADYNE’S DEVELOPMENT OF THE ACCUSED PRODUCT......281 A. Introduction......................................................281 B. The Effort to “Design Around” the Glaxo Patents ..................282 IV. ANALYSIS OF LEGAL CLAIMS AND DEFENSES......................283 A. Infringement of the ’249 Patent....................................283 1. Doctrine of Equivalents.....................................283 2. Application to the facts in the case at bar...................284 B. Affirmative Defenses and Declaratory Judgment Issues..............293 1. Obviousness: The ’790 and ’249 Patents.....................293 a. Presumption of Validity.................................293 b. ’790 Prior Art..........................................294 i. Differences........................................298 c. ’249 Prior Art..........................................300 i. Differences........................................301 d. Secondary Considerations ...............................303 e. Ordinary Skill in the Art ...............................303 2. Inequitable Conduct........................................305 a. Misconduct in Prosecuting the ’431 Patent................306 b. Misconduct in Prosecuting the ’790 Patent................307 i. Buffer Concentration...............................307 ii. The Padfield Article...............................308 Hi. The Padfield Declaration.........................309 c. Misconduct in Prosecuting the ’249 Patent................310 i. Failure to Disclose the Use of Ethanol in Tagamet . .310 ii. The Hempenstall Declaration......................311 V. CONCLUSION .........................................................313 Glaxo Wellcome, Inc. and Glaxo Group Limited (together “Glaxo”), instituted this action against Pharmadyne Corporation and several affiliated entities for infringement of patents related to its Zantac medication. Defendants counterclaimed for a declaratory judgment on several grounds. A bench trial commenced on November 12, 1997, and concluded on February 5, 1998. The parties have submitted post-trial briefs, which have been carefully considered. I have carefully considered the entire evidentiary record of the case, and render herein findings of fact and conclusions of law in accordance with Fed.R.Civ.P. 52(a). 1. INTRODUCTION AND PROCEDURAL HISTORY Glaxo develops and manufactures ethical pharmaceutical drugs. Over the last decade, Glaxo’s premiere product has been the anti-ulcer medication Zantac. Zantac became the largest selling drug in the world and has enjoyed unparalleled commercial success in the pharmaceutical industry. Glaxo’s sales of the various forms of its Zantac product have grossed in excess of $100 million annually for several years. In fact, Glaxo’s profits from the sale of Zantac medications have been in the billions of dollars and have helped catapult Glaxo into the position of one of the largest pharmaceutical companies in the world. The active ingredient in Zantac is the ami-noalkyl furan derivative ranitidine hydrochloride. Glaxo scientists were the first to synthesize the chemical compound ranitidine. For several years, Glaxo has fought numerous battles in courtrooms all over the country in a largely successful effort to preserve its property in a series of patents expressed in the Zantac mark. See, e.g., Glaxo Group Ltd. v. TorPharm, Inc., 153 F.3d 1366, 1367 (Fed.Cir.1998) (“This is yet another appeal in the ongoing litigation between the holder of patents on a popular medication, Zantac, and a number of generic drug companies who are attempting to sell a generic equivalent of the drug. . . .”); Glaxo, Inc. v. Novopharm, Ltd., 110 F.3d 1562 (Fed.Cir.1997); Glaxo Inc. v. Novopharm Ltd,., 52 F.3d 1043 (Fed.Cir.1995). In 1977, Glaxo’s Dr. David Collin synthesized the crystalline-salt form of the ranitidine now used in Glaxo’s Zantac drug products. Ranitidine’s unique qualities make it a highly marketable drug. Ranitidine is more potent than other anti-ulcer medications on the market. In addition, ranitidine does not cause some of the side effects produced by other anti-ulcer drugs, such as impotence, breast formation in males, and certain endocrine problems. Glaxo Group Limited holds the three United States patents which are the subject of this litigation — U.S. Patent Nos. 4,521,431 (“the ’431 patent”), 4,585,790 (“the ’790 patent”), and 5,068,249 (“the ’249 patent”). All three patents include ranitidine in a pharmaceutical formulation. In the formulations at issue in this case, Glaxo’s ranitidine hydrochloride is dispensed as an oral syrup and injectable product. The syrup formulation is particularly important for children, the elderly and infirm, and adults who are not able to take medication in pill form. Injectable, i.e., intravenous, formulations of Zantac (hereafter “Zantac injection”), covered by the ’790 patent, are used particularly for patients who are otherwise receiving intravenous fluids, or those who are unconscious or comatose. Defendants UDL Laboratories, Inc., Florida, AndaPharma Corporation, and Pharmadyne Corporation are subsidiaries of UDL Laboratories, Inc., Illinois. Defendant UDL Laboratories, Inc. is an Illinois corporation. UDL Laboratories, Inc., Illinois repackages and markets generic pharmaceuticals. Its counterpart in Florida manufactures and packages liquid generic pharmaceuticals. Pharmadyne and AndaPharma were created by UDL for the sole purpose of developing a ranitidine hydrochloride oral solution. Pharmadyne contracted with UDL to have UDL research, develop, manufacture, test and ultimately distribute Pharmadyne’s ranitidine hydrochloride oral syrup in the United States. Pharmadyne also contracted with UDL to act as its agent to prepare an Abbreviated New Drug application (“ANDA”) concerning ranitidine hydrochloride oral syrup solely for filing by Pharmadyne with the Food and Drug Administration (“FDA”). In November 1995, Pharmadyne submitted its ANDA No. 74-794 seeking approval from the FDA to market ranitidine oral solution USP in the United States, pursuant to 21 U.S.C.A. § 355(j). Pharmadyne’s ANDA contained a paragraph IV certification and thus Pharmadyne committed a “highly artificial act of patent infringement” under 35 U.S.C.A. § 271(e)(2). Under 35 U.S.C.A. § 271(e)(2)(A): It shall be an act of infringement to submit (A) an application under section 5050 of the Federal Food, Drug, and Cosmetic Act or as described in section 505(b)(2) of such Act for a drug claimed in a patent or the use of which is claimed in a patent, ... if the purpose of such submission is to obtain approval under such Act to engage in the commercial manufacture, use, or sale of a drug ... claimed in a patent or the use of which is claimed in a patent before the expiration of such patent. See generally Eli Lilly and Co. v. Medtronic, Inc., 496 U.S. 661, 676, 110 S.Ct. 2683, 110 L.Ed.2d 605, reh’g denied, 497 U.S. 1047, 111 S.Ct. 11, 111 L.Ed.2d 825 (1990); Glaxo v. Novopharm, Ltd., 110 F.3d 1562, 1568-69 (Fed.Cir.1997), aff'g, 931 F.Supp. 1280 (E.D.N.C.1996). On December 27, 1995, Pharmadyne notified Glaxo that Pharmadyne was seeking approval from the FDA to market ranitidine oral solution USP in the United States, prior to the expiration of Glaxo’s ’431 and ’790 patents. Pharmadyne stated that both patents were invalid, unenforceable and/or will not be infringed by Pharmadyne’s drug product. Subsequently, Glaxo added the ’249 patent to the FDA’s list of patents in the “Orange Book.” Pharmadyne responded by sending Glaxo a supplemental notice of its intent to market its oral solution and asserted that the ’249 patent is likewise invalid, unenforceable, and/or will not be infringed. Upon receipt of Pharmadyne’s first notice, Glaxo instituted this action against Pharmadyne for infringement of Glaxo’s ’790 patent. Pharmadyne answered the complaint and counterclaimed, seeking a declaratory judgment that Glaxo’s ’790 and ’431 patents are invalid, unenforceable, or not infringed. When Glaxo received the second notice, Glaxo filed a second action against Pharmadyne for infringement of its ’249 patent. Pharmadyne answered the second complaint and counterclaimed seeking a declaratory judgment that Glaxo’s ’249 patent is invalid, unenforceable, and/or not infringed. The cases were consolidated for all purposes. Prior to trial, I entered an order dated July 31, 1997, resolving the infringement issues on the ’790 and ’431 patents. I granted Glaxo’s motion for summary judgment in ruling that Pharmadyne’s ANDA product infringes claims 1-5, 9-11 and 13 of the ’790 patent. In addition, I entered a summary declaratory judgment that the ANDA product does not and will not infringe the ’431 patent, and the making, using, selling, offering for sale, sale or importation of the ANDA product does not and will not infringe the ’431 patent. As a result of these interlocutory orders, the only issue. remaining for trial related to the infringement issues under the ’249 patent and the validity and enforceability issues related to all three patents attacked by Pharmadyne in its various counterclaims and requests for declaratory judgments. As explicated immediately below, I now conclude that the ’431 patent is not properly before me. II. THE PATENTS A. The ’431 Patent 1. Background Glaxo scientists Price, Clitherow and Bradshaw, discovered ranitidine in 1976. In 1977, Glaxo’s David Collin made the hydrochloride salt which is covered by Glaxo’s now-expired ’658 patent. Subsequently, Dr. Crookes, another Glaxo scientist, developed a different crystalline form of ranitidine hydrochloride while preparing batch “3B13” of ranitidine hydrochloride. After analyzing the resulting product, Dr. Crookes discovered that, indeed, he had produced a form of ranitidine hydrochloride that was different from all of the other batches previously produced. Infrared spectroscopy and x-ray powder diffraction analysis of batch “3B13” confirmed Dr. Crookes’s observations. Dr. Crookes had invented a polymorph of ranitidine hydrochloride denominated as Form 2. The earlier form of ranitidine hydrochloride covered by the ’658 patent was then denominated Form 1. In 1985, Glaxo obtained the ’431 patent for Form 2 ranitidine hydrochloride. The ’431 patent covers a chemical compound in a “crystal form of ranitidine ... hydrochloride, designated Form 2----” (DX-40.) Claim 1 of the ’431 patent claims Form 2 ranitidine hydrochloride by its infrared spectrum, and lists the main peaks of the infrared spectrum of Form 2. Claim 2 is dependent upon Claim 1, and characterizes Form 2 by its x-ray powder diffraction pattern and lists the characteristic “d” spaeings and relative intensities of Form 2. The ’431 patent expires in 2002. 2. Subject Matter Jurisdiction Over the ’431 Patent Twice prior to trial and then again during trial, Glaxo moved for summary judgment seeking to dismiss the ’431 patent from the lawsuit on the ground that the court lacked subject matter jurisdiction. Glaxo asserted that the court lacked subject matter jurisdiction primarily on the basis that Glaxo had not sued Pharmadyne for infringement of the ’431 patent. In fact, Pharmadyne introduced the ’431 patent into the case when it sought a declaratory judgment under its counterclaim that the ’431 patent is invalid and/or not infringed and under its counterclaim that under collateral estoppel or laches principles, Glaxo should be eternally barred from suing Pharmadyne for infringement of the ’431 patent. a. Prior motions for summary judgment as to the ’431 Patent Glaxo first moved for partial summary judgment for lack of subject matter jurisdiction over the ’431 patent on May 24, 1996. Glaxo contended that there was no controversy surrounding the ’431 patent because Glaxo ■ had not alleged infringement and Pharmadyne claimed that its ANDA product did not infringe the patent. I denied Glaxo’s motion for partial summary judgment on the ground that at that time there was a controversy surrounding the ’431 patent. Pharmadyne had a reasonable apprehension that Glaxo, would sue it for infringement of the ’431 patent. At that time, the evidence before the court reflected that the bulk active ingredient Pharmadyne was using in the manufacture of its product was ranitidine hydrochloride and might possibly fall into the category of Form 2 ranitidine hydrochloride covered by the ’431 patent. Furthermore, there was evidence indicating that Glaxo would initiate suit against Pharmadyne for infringement of the ’431 patent if Glaxo determined that Pharmadyne was using Form 2 ranitidine hydrochloride in its ANDA product. Glaxo had publicly stated its policy to use patent infringement litigation to prevent generic competitors from marketing ranitidine products, particularly products using Form 2. Additionally, there was evidence demonstrating that Glaxo had actually pursued litigation in this area. Moreover, Glaxo made statements — pregnant with ominousness — that it had no basis for determining whether Pharmadyne was infringing the ’431 patent. In April 1997, after some discovery and further factual development of the case, Pharmadyne moved for summary judgment that its ANDA product would not infringe the ’431 patent. At a hearing held on July 29, 1997, Glaxo conceded non-infringement. Glaxo cross-moved for summary judgment as to the ’431 patent, however, once again, on the ground that the Court lacked subject matter jurisdiction. Glaxo sought to remove the issues of invalidity and unenforceability of the ’431 patent from the case. Glaxo argued that dismissal of Pharmadyne’s counterclaim seeking declaratory relief was warranted because Pharmadyne’s concession that its ANDA product as formulated at that time did not infringe the ’431 patent resolved any controversy over the ’431 patent. Ultimately, I found that there were disputes of material fact with “respect to whether or not there was a icase or controversy between the parties on the ’431 patent.” (Trans. 7/29/97 at 7-8.) Accordingly, I granted summary judgment of non-infringement of the ’431 patent to Pharmadyne, but denied without prejudice Glaxo’s cross-motion with respect to subject matter jurisdiction. b. The renewed motion for summary judgment as to the ’431 Patent Once the trial commenced in November 1997, it became apparent that the court lacked subject matter jurisdiction over the ’431 patent. It was evident that Pharmadyne no longer had reason to fear that it would be held liable for practicing the invention claimed in the ’431 patent. At trial, the reality was that Pharmadyne’s fear and apprehension of a lawsuit were centered on highly contingent future, not present, activity. Pharmadyne, however, desired to continue litigating issues related to the ’431 patent because it feared that Glaxo would sue it at some future time if it decided to use Form 2 ranitidine. Pharmadyne also was concerned that Glaxo would institute actions against its suppliers resulting in Pharmadyne being left without a supplier for Form 1 ranitidine hydrochloride. When Glaxo renewed its motion at trial, I held that Pharmadyne’s desire to use Form 2 at some uncertain future date, and its fear that litigation by Glaxo would make it difficult to obtain Form I ranitidine from its suppliers, was not enough to confer jurisdiction on the court to decide the validity and/or enforceability of the ’431 patent. See Super Sack Mfg. Corp. v. Chase Packaging Corp., 57 F.3d 1054, 1058 (Fed.Cir.1995) (Jurisdiction over a declaratory judgment action requires that “[tjhere must be both (1) an explicit threat or other action by the paten-tee, which creates a reasonable apprehension on the part of the declaratory plaintiff that it will face an infringement suit, and (2) present activity which could constitute infringement or concrete steps taken with the intent to conduct such activity.”) (emphasis in original) (citation omitted), cert. denied, 516 U.S. 1093, 116 S.Ct. 815, 133 L.Ed.2d 760 (1996); Spectronics Corp. v. H.B. Fuller Co., Inc., 940 F.2d 631, 635 (Fed.Cir.) (noting that a party seeking a declaratory judgment pursuant to 28 U.S.C.A. §§ 2201, 2202 must establish that subject matter jurisdiction over its action existed at the commencement of the action, and continues after the complaint is filed), cert. denied, 502 U.S. 1013, 112 S.Ct. 658, 116 L.Ed.2d 749 (1991); see also Super Sack; 57 F.3d at 1058 (“[T]he ‘actual controversy must be extant at all stages of review, not merely at the time the complaint is filed.’”) (quoting Preiser v. Newkirk, 422 U.S. 395, 401, 95 S.Ct. 2330, 45 L.Ed.2d 272 (1975)); but see Arrowhead Industrial Water, Inc. v. Ecolochem, Inc., 846 F.2d 731, 736 (Fed.Cir.1988) (test for evaluating whether court has subject matter jurisdiction in a declaratory judgment action is applied to the facts existing at the time the complaint was filed). For these reasons, Glaxo’s renewed motion for summary judgment is granted as to the ’431 patent and any and all claims related thereto are dismissed without prejudice for lack of subject matter jurisdiction. B. The ’790 Patent 1. The significance of pH In the late 1970’s and early 1980’s, Glaxo scientists experimented with different pharmaceutical formulations of ranitidine, including a simple injection solution. The first injection solutions, at concentrations of 2 mg/ml and then 10 mg/ml, were adjusted to a pH of 5.0. Through further experimentation, Glaxo scientists concluded that a ranitidine injection solution was most stable between pH 5-5.5, which they termed its “natural pH.” Glaxo produced a ranitidine injection solution with a “natural pH” in the United Kingdom, and it was first sold there beginning in October 1981. In an effort to develop an intramuscular ranitidine injection solution containing a higher concentration of ranitidine hydrochloride (25 mg/ml) and with an adequate shelf-life, i.e., a product suitable for storage conditions in the U.S. market, Glaxo’s Drs. Pad-field and Winterborn conducted an investigation of the effect of a variety of factors, including pH, on the stability of solutions of ranitidine hydrochloride. Drs. Padfield and Winterborn concluded that the shelf-life of aqueous based formulations containing ranitidine and/or ranitidine hydrochloride was significantly improved if the pH of the formulation is increased from the “natural pH” to a pH in the range of 6.5-7.5. Accordingly, the ’790 patent claims an improved formulation of ranitidine and/or its physiologically acceptable salts, including ranitidine hydrochloride. The invention claimed is that the higher pH range significantly increases the shelf-life of an aqueous ranitidine hydrochloride solution as compared to the shelf-life of the product at its “natural pH” of 5.5. Although Glaxo filed its U.S. patent application on May 11,1984, it claimed the benefit of the earlier filing date of May 13, 1983, for its corresponding British patent application. The ’790 patent issued on April 29, 1986, but only after extensive evaluation by the patent examiner, rejection of the patent application, and reconsideration of the application as discussed below. 2. The claims of the ’790 Patent The claims of the ’790 patent are as follows: Claim 1 A pharmaceutical composition which is an aqueous formulation containing an effective amount of ranitidine and/or one or more physiologically acceptable salts thereof for treatment of conditions mediated through histamine H2 receptors, said formulation having a pH within the range of 6.5-7.5. Claim 2 A pharmaceutical composition according to claim 1 having a pH in the range 6.7 to 7.3. Claim 3 A pharmaceutical composition according to claim 1 having a pH in the range 6.8 to 7.1. Claim k A pharmaceutical composition according to claim 1 in which said pH is adjusted by means of suitable buffer salts. Claim 5 A pharmaceutical composition according to claim 4 in which said buffer salts are potassium dihydrogen orthophosphate and disodium hydrogen orthophosphate or citric acid and disodium hydrogen orthophosphate. Claim 6 A pharmaceutical composition according to claim 1 in a form suitable for parenteral administration. Claim 7 A pharmaceutical composition according to claim 6 in a form suitable for injection and containing 10 to 100 mg/ml ranitidine, expressed as free base. Claim 8 A pharmaceutical composition according to claim 6 in a form suitable for continuous infusion and containing 0.1-2.0 mg/ml ranitidine, expressed as free base. Claim 9 A pharmaceutical composition according to claim 1 in a form suitable for oral administration. Claim 10 A pharmaceutical composition according to claim 9 containing 20 — 400 mg per 10 ml dose. Claim 11 A pharmaceutical composition according to claim 1 containing ranitidine in the form of its hydrochloride salt. Claim 12 A process for the production of a composition of claim 1 suitable for parenteral administration, which comprises dissolving ranitidine and/or one or more physiologically acceptable salts thereof and said remaining constituents in water suitable for injection, followed by sterili[z]ation. Claim 13 A process for the production of a composition of claim 1 suitable for oral administration which comprises adding an aqueous solution of ranitidine and/or one or more physiologically acceptable salts thereof to an aqueous solution or dispersion of a viscosity enhancing agent. (PX-1, column 4.) 3. Prosecution History The file wrapper for the ’790 patent discloses Glaxo’s ’658 patent and the so-called “Padfield Article” and explains the content and relevance of the two prior art references as: Ranitidine ... and physiologically acceptable salts are described in British Patent Specification No. 1565966. In that specification there is reference to liquid formulations for oral and parenteral administrations and there is a description of an aqueous based formulation for intravenous administration and another of an oral syrup. Both of these formulations contain sufficient hydrochloric acid to achieve a pH of 5.0. In addition injection formulations are described by Padfield et al (The Chemical Use of Ranitidine, Medicine Publishing Foundation Symposium Series 5, Oxford:Medicine Publishing Formulation 1982 pp. 18-22) in the form of a simple aqueous solution of ranitidine hydrochloride at its natural pH, i.e. about 5.5. Whilst such formulations containing ranitidine and/or its physiologically acceptable salts are therapeutically effective they suffer from the disadvantage of having a relatively short shelf life due to the breakdown of the ranitidine. (PX-2.) The claims of the ’790 patent application were rejected initially by the patent examiner on July 2, 1984. The examiner stated: Claims 1-11 are rejected under 35 U.S.C.A. 103 as being unpatentable over Chem.Abst. all. The art appreciates pharmaceutical formulation of Ranitidine. The compositions are considered as prima facie obvious, the pH range notwithstanding. Said range is within the skill of the art, i.e. neutral, and has not been demonstrated as being critical. (PX-2, p. 26.) Claims 12-14 were rejected as “too broad in not reciting all parameters of production” and for “being indefinite for failing to particularly point out and distinctly claim the subject matter which the applicant regards as the invention ... [a] process which comprises processing is vague and indefinite processing fails to define what is done.” (PX-2, p. 25.) In response, Glaxo filed an amendment to claim 1 in early November 1984 and informed the patent examiner that the prior art does not disclose aqueous based formulations of ranitidine having a pH in the range of 6.5 - 7.5. Glaxo specifically noted that the prior art also did not disclose that the higher pH range would have produced significantly enhanced stability, which improved the shelf-life of the formulation. Glaxo remarked: There is absolutely no suggestion in the prior art of record of aqueous based formulations of ranitidine having a pH in the range of 6.5-7.5 let alone a disclosure that an aqueous based formulation of ranitidine having a pH in this range would have the advantage over the formulation described in the prior art of significantly enhanced stability leading to improved shelf life.... Thus, for example, in the ease of a 25 mg/ml ranitidine hydrochloride injection solution buffered to the appropriate pH with phosphate salts and subjected to a storage of 20"C, the rate of breakdown of ranitidine is about 10 times faster for a solution buffered to pH 5.5 than for a solution buffered to pH 7.0.... Assuming, on the basis of the Chemical Abstracts reference, that one of ordinary skill in the art wishes to produce an aqueous formulation of ranitidine, the skilled person would consider the most relevant art, the prior art discussed above and this would lead him to produce an aqueous formulation with a pH of around 5 to 5.5 ... This is particularly true in view of the teaching in the Padfield et al. Paper which states that the injection was most stable at its natural pH which as already noted, is around 5.5. While there is no doubt that one of ordinary skill in the art would be able to adjust the pH of an aqueous based ranitidine formulation to a pH within the range claimed in the present application, there is nothing to suggest any reason or motivation for one of ordinary skill in the art to do this.... (PX-2, pp. 33-34) (emphasis in original.) Subsequently, the examiner issued a rejection of the patent claims, again raising the question of obviousness. (Id. at 36-37.) On February 21, 1985, Glaxo’s attorney had a personal interview with the examiner to discuss the claims and prior art, including the ’658 patent and the Padfield article. (Id. at 39.) As a result of the interview, the examiner agreed to approve the application if a “side-by-side comparison of Glaxo’s formulations showed unexpected results for pH.” (Id.) In September 1985, Glaxo submitted a Request for Reconsideration. (Id. at 43.) The sworn declaration of Dr. John Padfield (the “Padfield Declaration”) accompanied the request and contains a “side-by-side” comparison of accelerated stability studies performed' on two 25 mg/ml ranitidine hydrochloride injection solutions, one buffered to pH 5.5 and one buffered to pH 7.0. (Id. at 48-57.) In relevant part, the “Padfield Declaration” states, as follows: 9. I would not dispute that the art teaches aqueous based formulations of ranitidine and its physiological acceptable salts at pH 5.0-5.5. Nor would I dispute that it is within the skill of the art to adjust the pH to the range that we claim in the present application. However, there is no teaching that it would be advantageous to adjust the pH to 6.5-7.5; indeed the art clearly leads one away from doing so in that it teaches that aqueous solutions of ranitidine hydrochloride are most stable at a pH of around 5.5. ****** 15. Thus, on the basis of the above calculations a significant increase in shelf life can be achieved if one adjusts the pH of a 25 mg/ml ranitidine injection at normal storage temperatures from 5.5. to 7.0. Long term (three year) stability studies on 25 mg/ml ranitidine injections at pH 6 and 7 and at 20C and 30C have confirmed these predictions of an extended shelf life at pH 7. 16. In my opinion, it was not obvious from the teachings of the art to adjust the pH of aqueous based formulations of ranitidine and/or one or more of its physiologically acceptable salts to within the range of 6.5-7.5 and it is surprising that the shelf life is significantly enhanced, as demonstrated above, by adjusting the pH in this manner. (Id. at 52, 56.) The following data is contained in the declaration: Table 1. The Ranitidine Content of Ranitidine Injection (25mg/ml) expressed as a Percentage of the initial value in formulation at pH 5.5 and pH 7.0 pH 5.5 pH 7.0 Day of Test 70°C 80°C 70°C 80°C 0 100.00 100.00 100.00 100.00 1 98.53 95.22 99.76 96.63 4 93.03 83.02 97.35 92.00 6 76.21 87.96 8 86.77 65.17 94.46 84.16 11 83.10 64.49 92.48 76.51 14 57.87 73.19 15 78.76 90.34 Based on the accelerated temperature studies represented in Table 1, Padfield concluded in the declaration: As demonstration of the improved stability of aqueous based formulations at the higher pH, we have calculated that, at 20C, the rate of breakdown of the ranitidine is about ten times faster for a solution at pH 5.5 than for a solution at pH 7.0. (Id. at 52-53.) Dr. Padfield indicated that the 20C and 25C rate constants for 5% loss of ranitidine hydrochloride were calculated using the Arrhenius equation on the rate constant data from Table 1. (Id. at 55.) These results were tabulated in Table 4 of the declaration: Table 4. Time for 5% Loss Ranitidine to Occur in a 25 mg/ml Ranitidine Injection at pH 5.5 and 7.0 at 20C and 25C Storage pH 5.5 PH 7.0 Temperature 20° 23.7 months 276 months 25° 12.7 months 122.8 months On September 27, 1985, the examiner issued an Advisory Action indicating that claims 13 and 14 would be allowable. Although he acknowledged the “unexpectedness” of the results, the examiner still rejected claims 1-11. He reasoned that Dr. Padfield’s remarks in the declaration “it is within the skill of the art to adjust the pH to the range that we claim in the present application,” indicated that “any benefits would logically flow and are inherent.” (Id. at 58-59.) In October 1985, Glaxo filed a response to the Advisory Action pointing out that the examiner had misconstrued the “Padfield Declaration” and emphasizing that the prior art did not teach or suggest any advantage in adjusting the pH of ranitidine solutions to the range of 6.5-7.5. (Id. at 61-63.) Glaxo asserted that “[t]he test of obviousness is not ‘obvious to try various pH ranges, but the obviousness of the invention in its entirety. (Id. at 63.) Following Glaxo’s last communication, the examiner, on December 6, 1985, allowed claims 1-11 and 13-14. (Id. at 65-70.) C. The ’249 Patent 1. Introduction In the early 1980’s, Glaxo began development of an aqueous ranitidine hydrochloride oral syrup product for commercial release, i.e., Zantac syrup. The original formulation was based on the Zantac injectable product covered by the ’790 patent. (Long Tr. at 277-79.) In November 1983, Glaxo submitted to the FDA a “Notice of Claimed Investigational Exemption for a New Drug for Zantac (ranitidine hydrochloride) Syrup.” (PX-63; Long Tr. at 276.) As described in the application, the original formulation for Zantac syrup included a preservative system composed of three parabens: methylparaben, propylparaben and butylparaben, but it did not contain any alcohol. The original syrup formulation met the requirements of the Antimicrobial Preservative Effectiveness test of the United States Pharmacopeia (USP). As work progressed on the syrup formulation, it however, became apparent that the formulation was prone to contamination with a microbial known as pseudomonas cepacia. Dr. David Long, a research scientist at Glaxo in the United Kingdom, discovered the contamination problem. Ultimately, through analysis and experimentation, he discovered that adding ethanol to the formulation killed the pseudomonas cepacia. Interestingly, as well, as he testified at trial, it was surprising to discover that the addition of ethanol also increased the stability of the ranitidine hydrochloride in the syrup formulation without requiring a change in the preferred pH of 6.5-7.5 of the base formula. (Long Tr. at 425.) It is the claim of the patent for this “improved” syrup formulation that Glaxo asserts is infringed by the ANDA 74-794 product that Pharmadyne proposes to manufacture and distribute for sale. 2.The addition of ethanol achieves surprising results In 1985, Dr. Long was conducting in-use testing on the original syrup formulation when he discovered that it was contaminated with the microbial pseudomonas cepacia. (Long Tr. at 280-81.) He had noticed that there was a decrease in the concentration of one of the parabens. Dr. Long considered this decrease a surprise because there was data from a study of the formulation in sealed bottles showing that there was little change in the product over a two year period. (Long Tr. at 280.) Additionally, the degradation of the paraben concentration did not fit any known law of degradation of parabens. (Long Tr. at 281.) Dr. Long had the product analyzed by Glaxo microbiologists who discovered that it contained pseudomonas cepacia. (Long Tr. at 281.) At the time of this discovery, Glaxo had submitted a product license application to the regulatory authorities in the United Kingdom, and Dr. Long was in the process of transferring the process of manufacture of the syrup formulation to the Glaxo factory in Liverpool. (Long Tr. at 280-81.) Dr. Long testified that the project came to a “screeching halt” when he discovered the contamination problem. (Long Tr. at 280.) Glaxo delayed the development of the syrup formulation in order to further investigate the microbial contamination problem. To combat the contamination problem, Dr. Long devised a strategy that included the exploration of the use of ethanol, chlorhexidine, phenoxyethanol, benzalkonium chloride, and propylene glycol. He also considered requiring that the product be refrigerated or packaged in single dose creamer packs. Dr. Long finally decided to use ethanol because it is a known and effective preservative for aqueous pharmaceutical products. He testified that he felt comfortable using ethanol because it was contained in a similar product on the market, Tagamet. In early October 1985, Dr. Long tested the effects of a little less than 1%, 3% and a little over 5% ethanol on the formulation. Because 5% ethanol was successful in killing the pseudomonas cepacia, Dr. Long decided to use 7.5% ethanol (weight/volume) to ensure that a minimum of 5% ethanol (weight/volume) would remain in the product throughout its assigned shelf-life. (Long Tr. at 421-22.) Glaxo’s modified formulation containing 7.5% ethanol met the USP’s Antimicrobial Preservative Effectiveness test and was effectively preserved against pseudomonas cepacia. As finally constituted, Glaxo’s ethanol syrup formulation contains the following ingredients: 1. Ranitidine hydrochloride 2. Hydroxypropyl Methylcellulose 2906 or 2910 USP (viscosity type 4000cp) 3. Alcohol USP 4. Propylparaben NF 5. Butylparaben NF 6. Monobasic Potassium Phosphate NF 7. Dibasic Sodium Phosphate (dried) USP 8. Sodium Chloride USP 9. Saccharin Sodium USP 10. Sorbitol Solution USP 11. Mint Flavour IFF 17:42:3632 12. Purified Water USP (PX-64, p. Y060572; Long Tr. at 285.) Between April and October 1986, the 7.5% ethanol formulation was placed on stability review to determine whether the formulation was chemically stable throughout the assigned shelf-life as necessary for regulatory approval. (PX-238, p. Y084402; PX-116.) In December 1986, Glaxo submitted an amended NDA for the syrup reflecting the new formulation containing ethanol. (Long Tr. at 286.) Using the 6 month stability data on the product containing ethanol in combination with the 12 month stability study data on the syrup without ethanol, Glaxo proposed an 18 month shelf-life for the new syrup formulation at storage temperatures between 2-30C. (Long Tr. at 286-87.) In the stability studies submitted with the NDA in December 1986, Glaxo concluded as follows: Our assignment of the shelf-life for Zantac syrup is based on the acceptance of up to a 5% loss of ranitidine on storage. The supporting stability data for the formulation without ethanol, ..., allow a predicted shelf-life of eighteen months when stored at 2-30 degrees centigrade for that formulation. A comparison of the results for Zantac Syrup with ethanol ... and ranitidine syrup without ethanol ... shows that the addition of ethanol does not adversely affect the stability of. ranitidine. Consequently, the shelf-life predicted for the formulation with ethanol should be similar to that of the formulation without ethanol. (PX-64, p. Y060620.) Ultimately, Dr. Long inadvertently discovered the significant enhancing effect of ethanol on the stability of ranitidine hydrochloride while evaluating comparative stability data of the nonethanol formulations with the ethanol formulations in preparation for filing the NDA. Indeed, this was a surprise to Dr. Long. At most, Dr. Long had hoped that the addition of ethanol would cure the contamination problem without altering the stability of the formulation. (Long Tr. at 425-26.) 3. The claims of the ’249 Patent The claims of the ’249 patent are as follows: Claim 1 A pharmaceutical composition which is an aqueous formulation for oral administration of an effective amount of ranitidine and/or one or more physiologically acceptable salts thereof, said formulation comprising a stabilizing effective amount of ethanol and said composition having a pH in the range of 6.5-7.5. Claim 4 A pharmaceutical composition according to claim 1 having a pH in the range 6.8 to 7.4. Claim 5 A pharmaceutical composition according to claim 1 having a pH in the range of 7.0 to 7.3. Claim 6 A pharmaceutical composition according to claim 1 wherein said pH is obtained by the use of buffer salts. Claim 7 A pharmaceutical composition according to claim 1 prepared using ranitidine in the form of the hydrochloride salt. Claim 8 A pharmaceutical composition as claimed in claim 1, wherein the effective amount is 20-400 mg ranitidine per 10 ml dose expressed as free base. Claim 9 A pharmaceutical composition as claimed in claim 1 wherein the effective amount is 20-200 mg ranitidine per 10 ml dose expressed as free base. Claim 10 A pharmaceutical composition as claimed in claim 1, wherein the effective amount is 150 mg ranitidine per 10 ml dose expressed as free base. (PX-3.) The specification of the ’249 patent states: We have now surprisingly found that the stability of ranitidine in aqueous based formulations and more particularly aqueous based formulations for oral administration may be substantially enhanced by the addition of ethanol to the formulation. 4. Prosecution History On December 12, 1986, Glaxo filed British Patent Application No. 86 29781. Glaxo filed its corresponding United States patent application Serial No. °ftsi,422 on December 11, 1987 in the name of the inventor David R. Long. Two continuation applications were filed as discussed below. An information disclosure statement was filed in the initial patent application referencing Glaxo’s ’658 and ’790 patents, and two Chemical Abstract references, 97,61014G (1982) and 104,102280Z (1986). (Stipulation 70.) Although Glaxo informed the FDA that ethanol was added to its formulation to kill pseudomonas cepacia, Glaxo never told the PTO why ethanol was added. On May 5, 1988, the patent examiner rejected all of the originally-filed claims, as indefinite and non-enabling under 35 U.S.C.A. § 112 and as obvious under 35 U.S.C.A. § 103 over both Chemical Abstract references. The examiner reasoned that the Chemical Abstracts taught the cojoining of ranitidine and alcohol (e.g., ethanol) and that he did not find the additional pH limitations to be patentable. (Stipulation 71.) On November 7,1988, Glaxo filed an amendment to Claim 1 to particularize that the formulation would include a “stabilizing effective amount” of ethanol. (Stipulation 72.), Following this submission, the examiner issued a final rejection of the patent claims, -again raising the question of obviousness under 35 U.S.C.A. § 103. (Stipulation 73.) On April 27, 1989, Glaxo filed a continuation application serial no. -%4,620, abandoning the ’422 application. (Stipulation 74.) In an Office Action dated June 6, 1989, the examiner- again rejected the claims as being obvious under 35 U.S.C.A. § 103 and stated that: The art teaches the cojoined use of ranitidine and an alcohol (ethanol). The claims also teach ranitidine and ethanol. The various parameters of the claims; i.e. pH and amounts, are considered as choices to one skilled in the art. Such parameters have not been demonstrated as being critical and as such are to be considered to be within the skill in the art. (Stipulation 75.) To counter this rejection, Glaxo filed an additional amendment and advised the examiner that: [T]he art does not teach the cojoining of ranitidine and an alcohol in a pharmaceutical composition which is an aqueous formulation for oral administration. These references do not lead one of ordinary skill in the art [in] any way to expect that the stability could be enhanced by the presence of ethanol and does not suggest the presence of ethanol in such compositions. (Stipulation 76.) Once again, Glaxo received a rejection of the claims as being obvious under 35 U.S.C.A. § 103, based on the Chemical Abstracts. Glaxo filed another continuation application on March 4, 1990. On May 4, 1990, Glaxo was faced with the same rejection. The examiner stated that the art teaches cojoined use of ranitidine and an alcohol (ethanol). (Stipulation 79.) On October 31,1990, Glaxo filed yet another amendment and advised the examiner that a declaration was being prepared. (Stipulation 80.) Some claims were allowed based on the amendment. However, new rejections were issued based upon additional documents ■ filed by Glaxo on January 10, 1991. (Stipulation 81.) On May 10, 1991, Glaxo filed a “Request for Reconsideration” and in support of the application filed the declaration of Dr. John Hempenstall (the “Hempenstall Declaration”). (Stipulation 82.) Glaxo advised the patent examiner: Applicant acknowledges that ethanol has previously been used in pharmaceutical compositions. However, the purpose for which ethanol has been included has been either as a solvent or as a preservative against bacterial contamination. There was, however, no reason to suppose that either of these functions of ethanol would have had any beneficial effects in terms of limiting the degradation of ranitidine and aqueous formulations thereof. For this reason, there would have been no skill in the art to include ethanol in an aqueous ranitidine formulation. Ranitidine is very soluble in water and ethanol is quite unnecessary to assist in the dissolution of ranitidine in the formulation. In addition, other and better preservatives are available. (PX-4A, pp. 84.) The “Hempenstall Declaration” contained the following pertinent statements and data: In my laboratory it was found that for an aqueous based ranitidine formulation, a significant and surprising enhancement in the stability of the ranitidine is achieved by the addition of ethanol to the formulation. The advantageous effect resulting from the addition of ethanol to an aqueous based ranitidine formulation can readily be determined by comparing the stability of the ranitidine in a formulation according to the present invention and the same formulation but without the added ethanol. ****** Stability studies were carried out comparing this formulation with a formulation that was identical except that it did not contain ethanol. Samples of each formulation were stored at 30C, 37C, and 45C for approximately 3 years ... At each temperature 2 samples of the formulation without ethanol, identified as Batches 1 and 2 were analysed with 3 samples of the formulation with ethanol identified as Batches 3, 4 and 5 ... The acceptable shelf life for an aqueous formulation containing ranitidine hydrochloride is considered to be the time at which no more than 5% of the ranitidine present in the formulation has degraded. Accordingly, the figure determined from the stability studies was the time (in months) for 5% ranitidine loss calculated as the lower 95% confidence limit. The results are as follows: Without Ethanol With 7.5% Ethanol Temperature Batch 1 Batch 2 Batch 3 Batch 4 Batch 5 30°C 12.5 13.6 19.5 17.0 20.8 37°C 5.4 4.7 7.8 7.1 7.5 45°C 1.8 2.3 2.9 2.9 ' 2.8 From this data, Dr. Hempenstall concluded: Thus the formulation with ethanol has an average shelf life at 30C of 19 months compared with 13 months when ethanol is excluded from the formulation. This is a highly significant and valuable improvement. Dr. Hempenstall also included the following table to demonstrate the beneficial effect of ethanol on the stability of ranitidine in aqueous based formulations. The table gives the time (in months) for 5% ranitidine loss (calculated as the lower 95% confidence limiO:_ Temperature % Ethanol _0 2.5 5.0 . 7.5 10,0 37°C 5.9 7.2 7.6 7.7 6.4 45°C 2,1 2,4 2.4 2.6 2.7 (PX-4A, pp. 93-95.) The data provided in the Hempenstall declaration proved persuasive. A Notice of Allowance was issued to Glaxo on June 3, 1991. (Stipulation 83.) Subsequently, on November 26, 1991, U.S. patent number 5,068,249, entitled Aqueous Ranitidine Compositions Stabilized with Ethanol issued to Glaxo. III. PHARMADYNE’S DEVELOPMENT OF THE ACCUSED PRODUCT A. Introduction Pharmadyne’s Ranitidine Oral Solution USP product covered by ANDA No. 74-794 (the “accused product”) contains 12.5% propylene glycol and 25% sorbitol, by weight/volume of the total formulation. The accused product as filed under the ANDA No. 74-794 is a generic ranitidine oral solution composed of the following: Ingredient_Quantity per 1 mL 1. Ranitidine Hydrochloride 16.8 mg (equiv. to 15 mg/ml ranitidine) 2. Dibasic Sodium Phosphate 13.61 mg 3. Citric Acid Anhydrous 1.0 mg 4. Saccharin Sodium 1.0 mg 5. Sorbitol Solution 250 mg 6. Propylene Glycol 125 mg 7. Methylparaben 1.8 mg 8. Propylparaben 0.2 mg 9. Natural Peppermint Extract 5.0 mg 10.Purified Water Q.S. The regulatory specification for the pH of the ANDA product is 6.7 to 7.5. (PX-71, p. P01515.) Samples from a 500 liter batch of the ANDA product achieved a pH of 7. (PX-71, pp. 01559-60.) Samples from the 500 liter ANDA batch were packaged in (i) 16 oz. PET bottle containers and (ii) 10 ml HDPE cups. (PX-71, pp. 01563-64.) The samples were tested for stability of the ranitidine active ingredient and for pH over time at 40C at 75% relative humidity. (PX-71, pp. P01565-85.) Samples from the 500 liter ANDA batch consistently maintained a pH between 6.8 to 7. (PX-71, pp. P01571-85.) The results of Pharmadyne’s testing of the accused product (over an 18 month period) for ranitidine content established a 29-month shelf-life for the ANDA product at 25-30C. (PX-94; PX-105; Wray Tr. at 835; Cartstensen Tr. at 2052-55.) B. The Effort to “Design Around” the Glaxo Patents Dr. Anita K, Runyan, Director of Research and Development at UDL from October 1994 through September 1996, was in charge of Pharmadyne’s development project for the ranitidine hydrochloride oral pharmaceutical formulation. She assigned to Dr. Prasad Gullapalli the task of developing the formulation. Dr. Gullapalli worked on the development project from 1994 until he left UDL in the summer of 1995. His job was to develop a ranitidine hydrochloride syrup formulation that had similar stability characteristics to that of Zantac syrup. To avoid infringing Glaxo’s product, Dr. Gullapalli was instructed to stay outside the pH values claimed in the ’249 patent, that is, 6.5-7.5, and to avoid using ethanol. Instead of using ethanol, Dr. Gullapalli began developing a ranitidine syrup formulation using another alcohol, propylene glycol, and, at a pH of 6. Dr. Gullapalli’s pH 6 formulation failed to meet UDL’s stability criteria because the stability of the formulation failed to equal that of Zantac syrup. However, Dr. Gullapalli developed the pH 7 formulation that became the accused product. In a report dated March 7, 1995, Dr. Gullapalli concluded that “[sjtability improved with increase in pH of medium as expected, stability was not affected by type of buffer; [cjhange in pH of formulations with time was larger with increase in temperature and decrease in pH; [sjtability was not affected by buffer strength; [ajll the solutions were stable for at least 5 days at 60C in the presence of various polyols. However, more data has to [be] collected to make a positive conclusion.” (PX-85, p. 11984.) In Fall 1995, Dr. Gullapalli left UDL and Dr. Nathan Pathak assumed responsibility for the development project. He had joined the company in early 1995. Dr. Pathak’s role was two-fold. First, he was asked to write a report on Dr. Gullapalli’s pH 7 formulation, in the event it was needed by Pharmadyne to obtain approval of the accused product from the FDA. Second, Dr. Pathak was asked to reformulate Dr. Gullapalli’s failed pH 6 formulation. Dr. Pathak’s work on the accused product included reviewing and analyzing Dr. Gullapalli’s work. He produced two development reports: the Ranitidine Oral Solution USP Pre-Development Report, (PX-91), and the Product Development Report. (PX-92; Pathak Tr. at 4056-59.) Pharmadyne’s “Pre-Development Report” on the accused product, dated June 19, 1996, which was approved by Dr. Runyan, contains the following conclusions: As illustrated ... pH-rate profile of ranitidine HC1 in solution suggests the pH of optimum stability in the proximity of 7.3 Formulations with different co-solvents suggest.... Increase in sorbitol concentration from 12.5% to 50% ... leads to decrease in overall pH of solution, and also results in reduced shelf-life ... However, sorbitol solution at 25% level appears to be satisfactory in masking the taste of ranitidine and propylene glycol in the formulation ... Increase in propylene glycol (>12.5%) improves the stability (better shelf-life), however, it contributes to the bitterness in the formulation. (PX-91, P19024.) IV. ANALYSIS OF LEGAL CLAIMS AND DEFENSES A. Infringement of the ’249 Patent 1. Doctrine of Equivalents Glaxo had the burden of proving by a preponderance of the evidence that Phar-madyne’s generic ranitidine oral solution, as specified and formulated in accordance with their ANDA No. 74-794, infringes claims 1 and 4-10 of the ’249 patent. (The parties stipulated that ANDA No. 74-794 infringes claims of the ’790 patent, and I make no findings as to that claim.). SmithKline Diagnostics, Inc. v. Helena Laboratories Corp., 859 F.2d 878, 889 (Fed.Cir.1988); Uniroyal, Inc. v. Rudkin-Wiley Corp., 837 F.2d 1044, 1054 (Fed.Cir.), cert. denied, 488 U.S. 825, 109 S.Ct. 75, 102 L.Ed.2d 51 (1988). The parties agree that the accused product does not literally infringe the claims of the ’249 patent. Literal infringement requires that every limitation found .in the patent claim exist in the accused product. Graver Tank & Mfg. Co. v. Linde Air Products Co., 339 U.S. 605, 607, 70 S.Ct. 854, 94 L.Ed. 1097 (1950). Here, the accused product does not literally infringe the ’249 patent because the accused product does not contain the identical alcohol — ethanol. Instead, the accused product contains propylene glycol, a substance that is both an alcohol and a polyol. The Supreme Court has explained that limiting infringement analysis to literal infringement “would place the inventor at the mercy of verbalism and would be subordinating substance to form.” Id. The Court reasoned as follows: to permit imitation of a patented invention which does not copy every literal detail would be to convert the protection of the patent grant into a hollow and useless thing. Such a limitation would leave room — indeed encourage — the unscrupulous copyist to make unimportant and insubstantial changes and substitutions in the patent which, though adding nothing, would be enough to take the copied matter outside the claim, and hence outside' the reach of the law. One who seeks to pirate an invention, like one who seeks to pirate a copyrighted book or play, may be expected to introduce -minor variations to conceal and shelter the piracy. Outright and forthright duplication is a dull and very rare type of infringement. Id. (emphasis added); see Laitram Corp. v. Cambridge Wire Cloth Co., 863 F.2d 855, 859 (Fed.Cir.1988), cert. denied, 490 U.S. 1068, 109 S.Ct. 2069, 104 L.Ed.2d 634 (1989). Accordingly, even though the accused product does not meet all of the express terms of the ’249 patent claims, the accused product can still infringe the patent under the dob-trine of equivalents. Id. The doctrine of equivalents protects the patent owner against infringers who make insubstantial changes to the claimed invention, so that the accused product may not literally read on the claims, but nonetheless appropriates the invention. See Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 117 S.Ct. 1040, 137 L.Ed.2d 146 (1997); Graver Tank, 339 U.S. at 607, 70 S.Ct. 854; London v. Carson Pirie Scott & Co., 946 F.2d 1534, 1538 (Fed.Cir.1991) (“[W]here an infringer ... merely makes an insubstantial change, essentially misappropriating or even ‘stealing’ the patented invention, infringement may lie under the doctrine of equivalents.”). Patent protection is extended beyond the limitations set forth in the claims and specification to prevent competitors from making insubstantial changes by substituting equivalent ingredients that do not alter the function or properties of the patented composition. Gillette Co. v. S.C. Johnson & Son, Inc., 12 U.S.P.Q.2d 1929, 1942 (D.Mass.1989), aff'd, 919 F.2d 720 (Fed.Cir.1990); Continuous Curve Contact Lenses, Inc. v. National Patent Development Corp., 214 U.S.P.Q. 86, 117 (C.D.Cal.1982). In Graver Tank, the Supreme Court set forth the “function-way-result” test which applies in determining infringement under the doctrine of equivalents. In applying the test in this case, the primary issue that must be addressed is whether the propylene glycol in the accused product performs the same function in the same way to obtain the same result as the 7.5% ethanol in the ’249 patent. Recently, the Supreme Court reaffirmed the validity of the doctrine of equivalents and clarified the scope of the doctrine. See Warner-Jenkinson Co., 520 U.S. 17, 117 S.Ct. 1040, 137 L.Ed.2d 146. The Court held that the doctrine requires an evaluation of the accused product to determine whether it contains elements equivalent to each claimed element of the patented invention. Warner-Jenkinson, 520 U.S. at -, 117 S.Ct. at 1054. “An analysis of the role played by each element in the context of the specific patent claim will thus inform the inquiry as to whether a substitute element matches the function, way, and result of the claimed element, or whether the substitute element plays a role substantially different from the claimed element.” Id. In the context of this case, additional factors that need to be considered under the doctrine include: 1) whether persons skilled in the art knew that propylene glycol was interchangeable with ethanol; 2) whether there is substantial evidence that Pharmadyne simply copied the ’249 patent; 3) whether there is evidence of independent development by Pharmadyne; and 4) whether Pharmadyne designed around the ’249 patent. See Warner-Jenkinson, 520 U.S. -, 117 S.Ct. at 1052-53, 137 L.Ed.2d 146. 2. Application to the facts in the case at bar Here, Glaxo met its burden of establishing that the propylene glycol in the accused product performs the same work in substantially the same way and accomplishes the same result as the ethanol in Glaxo’s ’249 patent. Determination of whether an accused product infringes requires a two step analysis. First, the court must construe the claims of the allegedly infringed patent. Maxwell v. J. Baker, Inc., 86 F.3d 1098 (Fed.Cir.1996). cert. denied, — U.S. -, 117 S.Ct. 1244, 137 L.Ed.2d 327 (1997); Tanabe Seiyaku Co., Ltd. v. U.S. International Trade Comm’n, 109 F.3d 726, 729-30 (Fed.Cir.), cert. denied, — U.S. -, 118 S.Ct. 624, 139 L.Ed.2d 605 (1997). Second, the Court must compare the claims of the patent to the accused product to see if they fall within the scope of the claims. Id. Construing the claims of a patent is left to the Court because it is always a question of law. Markman v. Westview Instruments Inc., 517 U.S. 370, 116 S.Ct. 1384, 134 L.Ed.2d 577 (1996). In this instance, however, there is no dispute as to the construction of the claims of the ’249 patent. The parties agree that the key claim limitation is Claim 1 and the critical dispute revolves around whether Pharmadyne’s use of propylene glycol in the accused product is a mere substitution of the stabilizing ingredient, ethanol, in Claim 1 of the ’249 patent. In their post trial memoranda on infringement of the ’249 patent, the parties deal exclusively with claim 1. Accordingly, I shall focus on the issue of infringement of claim 1 only. Glaxo charges that the accused product is nothing more than a copy of the ’249 patent. I so find. Throughout the litigation, Pharmadyne has maintained that the sole function of propylene glycol in the accused product is to act as a solvent for the paraben preservative system. A plethora of evidence in the record indicates this is not so. Despite Pharmadyne’s claimed efforts to avoid copying the claims of the ’249 patent, Pharmadyne has developed a formulation that is not substantially different from Glaxo’s ’249 patent. Convincing evidence of this fact is found in the stability studies conducted by Dr. Gullapalli. (PX-85.) Glaxo proved its case primarily through its expert, Dr. Paul Eugene Wray. He presented the most compelling analysis and evaluation of the data demonstrating that propylene glycol functions to stabilize ranitidine hydrochloride in the accused product in a manner similar to ethanol stabilizing the compound in the ’249 patent. The invention of the ’249 patent is that ethanol enhances the chemical stability of ranitidine hydrochloride by retarding the degradation rate of ranitidine through hydrolysis. In turn, the physical stability of ranitidine hydrochloride is increased and ultimately results in an extended shelf-life of the drug product. Dr. Wray described physical stability in terms of the maintenance of the physical characteristics of a drug product over the shelf-life of the product. For example, taste, color, odor, sedimentation, and pH are factors that should remain constant over the shelf-life of the product. (Wray Tr. at 481-82.) On the other hand, chemical stability is a measurement of the degradation rate of the active ingredient in a drug product: [a]ll the drugs I have ever worked with in my career have finite degradation rates. They will last for a certain amount of time and be considered subpotent ... [Degradation rates are affected by ... temperature ... the higher the temperature quite often the faster the chemical degradation ... [t]he pH of the solution ... because ... pH can affect the stability of the active ingredient as well as the stability of the excipients ... ionic strength and dielectric constant ... oxygen generally causes compounds to degrade. (Wray Tr. at 482-84.) In