Imperial Chemical Industries, PLC v. Danbury Pharmacal, Inc. (777 F. Supp. 330, 1991)

OPINION

CALEB M. WRIGHT, Senior District Judge.

The plaintiff-patentee Imperial Chemical Industries, PLC (“ICI”), is a British corporation having its corporate offices and principal place of business in Imperial Chemical House, Millbank, London, England. Consolidated Pretrial Order (“P.T. Order”) filed March 6, 1991 at p. Ill — 1. The defendant Danbury Pharmacal, Inc., (“Danbury”), is a corporation organized and existing under the laws of the State of Delaware having its principal place of business at Stoneleigh Avenue, Carmel, New York. Id. ICI has charged Danbury with infringement of ICI’s U.S. Patent No. 3,934,032, (“the ’032 patent”) and Danbury has asserted the invalidity of this patent as an affirmative defense in Civil Action Nos. 89-575 and 90-736. P.T. Order at p. 1-1. The subject ’032 patent was issued to ICI on January 20, 1976 with two claims directed to a method for the treatment of hypertension in a warm-blooded animal by the administration of a particular alkanolamine derivative. The preferred compound covered by the ’032 patent is generically known as “atenolol”. P.T. Order at p. 1-3.

On June 30, 1989, Danbury filed two abbreviated new drug applications (“AN-DAs”)' Nos. 73-352 and 73-353. The two ANDAs which are the subject of Civil Action No. 89-575, seek authorization from the U.S. Food and Drug Administration (“FDA”) to sell a generic version of the drug atenolol in 50 mg and 100 mg tablets, respectively, after the expiration date of the ’032 patent. P.T. Order at p. 1-2. Atenolol is marketed for the treatment of hypertension by ICI under the trademark TENORMIN. P.T. Order at p. 1-3. On September 5, 1989, Danbury amended AN-DAs Nos. 73-352 and 73-353 and simultaneously submitted a patent certification which alleged, pursuant to 21 U.S.C. § 355(j)(2)(A)(vii) (1988), that the ’032 patent and ICI’s U.S. Patent No. 3,836,671 (“the ’671 patent”) were invalid. Further, Danbury sought approval to market ateno-lol immediately, without regard to the expiration date of the ’032 and ’671 patents. P.T. Order at p. 1-2.

On November 5, 1990, Danbury filed an ANDA (number unspecified) which is the subject of Civil Action No. 90-736, seeking authorization from the FDA to sell a generic version of the drug atenolol/chlorthali-done. P.T. Order at p. 1-2. Atenolol in combination with chlorthalidone is marketed for the treatment of hypertension by ICI under the trademark TENORETIC. P.T. Order at p. 1-3. Concurrent with the filing of this ANDA, Danbury submitted a patent certification which alleged, pursuant to 21 U.S.C. § 355(j)(2)(A)(vii) (1988), that the ’032 patent was invalid, and that Dan-bury sought approval to market the combined drug atenolol/chlorthalidone commencing September 17, 1991 (after the expiration of the ’671 patent) without regard to the expiration date of the ’032 patent. P.T. Order at pp. 1-2, 3.

Danbury’s submission of the ANDAs and the patent certification challenging the validity of the ’032 patent, constitutes infringement of the ’032 patent under 35 U.S.C. § 271(e)(2)(A) (1988). Danbury has admitted infringement with respect to both atenolol per se and atenolol/chlorthalidone combinations, and raised the affirmative defense of invalidity. FDA approval of Danbury’s ANDAs could have been effective immediately (assuming the ANDAs are otherwise in compliance with FDA requirements) except that ICI brought suit within forty-five days of its receipt of the patent certification notices. P.T. Order at pp. I-3. 4. Since ICI filed suit within the forty-five day period, the FDA may not permit Danbury to market its generic drug for a period of thirty months from the date of the receipt of the patent certification notices unless both claims of the ’032 patent are finally adjudicated to be invalid before the respective thirty month periods expire. P.T. Order at p. 1-4.

This Court has jurisdiction under the United States Patent Laws, Title 35, and under 28 U.S.C. §§ 1331, 1338(a). In addition, this action is authorized under the Food and Drug Law, Title 21, and specifically 21 U.S.C. § 355(j)(4)(B) (1988). Venue is found under 28 U.S.C. § 1400(b) since the defendant Danbury is a Delaware corporation. P.T. Order at p. II — 1.

The Court held an eight day bench trial from April 1 through April 5 and April 8 through April 10,1991. Since Danbury has admitted infringement of the '032 patent and has not engaged in any commercial activity relating to the ’032 patent the sole issues for determination at trial were the validity and enforceability of claim 2 of the ’032 patent. After trial, the parties submitted proposed findings of fact and conclusions of law. The Court has considered the parties’ post-trial submissions along with the testimony and documentary evidence presented at trial. After this review the Court renders this Opinion containing its Findings of Fact and Conclusions of Law pursuant to Rule 52(a) of the Federal Rules of Civil Procedure.

Danbury seeks a declaration that claim 2 of the ’032 patent is invalid and grounds its attack on validity upon 35 U.S.C. § 103 (1988) (“section 103”) and 35 U.S.C. § 112 (1988) (“section 112”). The basis of Dan-bury’s § 103 defense of obviousness is that “given the scope and content of the prior art, the nature of the differences between atenolol and the prior art and level of skill in the art, a medicinal chemist of ordinary skill in the art in February, 1969 would reasonably have expected that atenolol because of its R-ABC structure and the close similarity of its R group to known R groups would also be a beta-blocker and, therefore, be useful as an antihypertensive agent.” Defendant Danbury’s Proposed Findings of Fact and Conclusions of Law (“DFC”) at p. 32, 11 50.

The basis for Danbury’s § 112 defense is “the patent specification’s alleged failure to disclose adequately to one of ordinary skill in the art ‘how to use’ the invention without undo experimentation.” DFC at p. 71, ¶ 86. It is Danbury’s position that “the ’032 patent in suit does not disclose, and would not teach, a person of ordinary skill in the art how to use atenolol to treat hypertension in the manner ultimately approved by the FDA [and that] extensive experimentation with atenolol over a period of many years was required by those skilled in the art before they ultimately learned of the possibility of using atenolol to treat hypertension at a dose as low as 100 mg. taken once-a-day.” DFC at p. 28, 1144.

ICI counters that “[i]n light of the significant structural differences between ateno-lol and the prior art, the lack of any teachings in the prior art which would have suggested the modifications required to make atenolol, atenolol’s unexpected, qualitatively different combination of pharmacological properties, and its advantages over the prior art in the treatment of hypertension, and the other objective evidence of nonobviousness (i.e., the invention’s outstanding commercial success, the pharmaceutical industry’s acquiescence in the ’032 patent’s validity, and Danbury’s copying of atenolol), the invention of claim 2 of the ’032 patent would not have been obvious to one of ordinary skill in the art when the invention was made on February 21, 1969.” Plaintiff ICI’s Findings of Fact and Conclusions of Law (“PFC”) at pp. 238-39, 1197.

ICI argues in opposition to Danbury’s § 112 defense, that “the disclosure of the ’032 patent specification would have enabled one skilled in the art, without undue experimentation, to practice the invention of claim 2 and to obtain atenolol's benefits of betarselectivity, lack of ISA, and hydrophilicity.” PFC at p. 243, 11107.

In the first part of this Opinion, “Findings of Fact”, the following areas will be discussed: (a) The Patent In Suit; (b) The Scope and Content of the Prior Art; (c) The Differences Between the Prior Art and the Claimed Invention; (d) The Development of the Patent in Suit; (e) The Level of Skill in the Art; (f) The Teachings of the '032 Patent; (g) Superior or Unexpected Results; (h) The Commercial Records of TENORMIN and TENORETIC. In the second part of this Opinion, “Conclusions of Law”, the Court will address and state its conclusions of law in reference to the parties’ legal theories and the pertinent case law regarding the following issues: (a) Burden of Proof; (b) Obviousness: 35 U.S.C. § 103; and (c) Adequate Disclosure: 35 U.S.C. § 112.

I. FINDINGS OF FACT

A. The Patent in Suit

The validity of claim 2 of U.S. Patent No. 3,934,032, entitled “Alkanolamine Derivatives for Treating Hypertension” is at issue in this case. This patent was issued to ICI on January 20, 1976 on application Serial No. 461,262 naming Arthur Michael Barrett, John Carter, Roy Hull, David James LeCount, and Christopher John Squire as inventors. Application Serial No. 461,262 was filed on April 15, 1974 as a division of Serial No. 233,781 filed March 10, 1972 (which is now U.S. Patent No. 3,836,671). Application Serial No. 233,781 was, in turn, a continuation-in-part of Application Serial No. 199,011 filed November 15, 1971 (now abandoned) and Application Serial No. 9451 filed February 6,1970, which issued as U.S. Patent No. 3,633,607. P.T. Order at p. Ill— 1.

Three separate patents were issued to ICI as a result of restriction requirements by the United States Patent and Trademark Office (“PTO”) and double patenting is not an issue in this action. These patents are the expired ’607 patent which claims, inter alia, atenolol, per se, as a chemical compound, the ’671 patent which expired on September 17, 1991, and claims inter alia, pharmaceutical compositions containing atenolol as the active ingredient and the use of atenolol to treat angina pectoris and the '032 patent. P.T. Order at pp. III-l, 2.

The ’032 patent contains two claims which read as follows:

1. A method for the treatment of hypertension in a warm-blooded animal in need of such treatment which comprises administering orally, parenterally or by inhalation to said animal an effective amount of at least one alkanolamine derivative selected from the group consisting of a compound of the formula:

wherein R1 is isopropyl or t-butyl, R2 is carbamoyl or alkylcarbamoyl of up to 4 carbon atoms, A is alkylene of 1 to 5 carbon atoms or alkenylene of 2 to 5 carbon atoms and R3 is hydrogen, halogen or alkyl, alkenyl, or alkoxy each of up to 4 carbon atoms: and a non-toxic, pharmaceutically acceptable acid-addition salt thereof.

2. The method of claim 1 wherein the alkanolamine derivative is 1-p-carbamoyl-methylphenoxy-3-isopropyl amino-2-pro-panol or a non-toxic, pharmaceutically acceptable acid-addition salt thereof.

Claim 2, the only claim at issue in this case, is directed to, and specifically covers the use of atenolol to treat hypertension. P.T. Order at p. Ill — 2.

B. The Scope and Content of the Prior Art

1. Background Facts

The body’s autonomic nervous system prepares it to deal with physical exertion and various stressful and emotional conditions. The autonomic nervous system works through two different systems; the parasympathetic system and the sympathetic system. The relevant focus for this discussion is on the sympathetic nervous system. When this system is activated by impulses it releases certain neurohormones which trigger the release of two neuro-chemicals, adrenaline and noradrenaline, collectively referred to as catecholamines. Adrenaline is released into the bloodstream and noradrenaline is released at the nerve endings. Thadani, Tr. at p. 21; P.T. Order at p. Ill — 3.

These catecholamines act at structures called receptors which lie on the cell surface of almost all organs and systems in the body. There are two kinds of receptors which are designated as alpha-receptors and beta-receptors. Our focus for purposes of this case is on the beta-receptors. The interaction between the catecholamines and the receptors produce a response in the associated cells and organ to facilitate the body’s reaction to physical and emotional stress. Thadani, Tr. at pp. 21-23.

When the beta-receptors are stimulated by the catecholamines, they produce a response in the heart in that they increase the force and rate of contraction of the heart which increases the blood flow from the heart (cardiac output). In addition, stimulation of the beta-receptors causes dilation of the arteries to the heart and the peripheral arteries so more blood can be accommodated in these vessels and dilation of the bronchial passages so that the flow of air to and from the lungs is enhanced and thus the flow of blood to critical organs and muscles is facilitated. Thadani, Tr. at pp. 21-23; P.T. Order at p. Ill — 3.

2. The Function and Use of Beta-Blockers

Claim 2 of the ’032 patent claims a method of use of the compound atenolol in the treatment of hypertension. Atenolol is a beta-blocker. P.T. Order at p. Ill — 3. At trial, Danbury’s expert witness on the clinical uses of beta-blockers, Dr. Thadani, described the function of a beta-blocker. He explained that beta-blocker drugs are synthetic chemicals which have a similar structure to the naturally occurring cate-cholamines and can, therefore, occupy a receptor site and block the catecholamine’s reaction with the receptor site. By blocking the catecholamines from interacting with the receptor site, the beta-blockers decrease heart stimulation because the stimulating effects of the catecholamines which normally would increase the force and rate of contraction on the heart are reduced. This reduction in the force and rate of the heart’s contraction then lowers the oxygen demands of the working heart. Thadani, Tr. at pp. 25, 26.

This blockade by a beta-blocker is competitive in that total or complete beta-blockade is never achievable since the inhibitory effect of the beta-blocker or beta-antagonist can always be overcome by increasing the concentration of the endogenous cate-cholamine or agonist. Nevertheless, the level of the body’s response to the endogenous catecholamines is lessened by the presence of a beta-blocker. This lessened response is desirable under certain circumstances. P.T. Order at p. Ill — 3—4.

When a person is exercising or experiencing a stressful situation the heart muscle will be stimulated by the release of adrenaline and noradrenaline, as described previously, and it will pump harder in order to accommodate the increased demands for blood flow and oxygen by the muscles. Under normal circumstances this response by the heart is tolerable but in certain situations such a response can be detrimental. For example, in a patient with angina pectoris the coronary arteries which supply blood to the heart muscle are narrowed with fatty deposits or cholesterol accumulation. When the patient exercises the heart is being stimulated and is trying to contract faster but the blood flow cannot increase because the arteries are narrowed and the patient experiences chest pain. A beta-blocker can be used in a patient with angina pectoris to decrease the stimulation of the heart thereby reducing the force and rate of contraction of the heart and lowering the oxygen demands of the heart. Tha-dani, Tr. at pp. 25, 26.

In addition, beta-blocker drugs are useful for the treatment of hypertension. Hypertension is a condition of increased blood pressure. At trial Dr. Thadani testified that beta-blockers lower blood pressure in about sixty percent of hypertensive patients but that the manner in which they accomplish this, even at present, is not known. Thadani, Tr. at p. 28.

Dr. Thadani testified at trial that the functions and uses of beta-blockers, outlined above, were all known prior to February of 1969. Thadani, Tr. at p. 29. Dr. Thadani supported this statement by referring to several prior art articles that he had read and was familiar with and by indicating as to each article any reference it had to a description of the general function and uses of beta-blockers. As to the uses of beta-blockers he specifically identified those articles which mentioned the use of beta-blockers for the treatment of hypertension.

Dr. Thadani discussed DX 504 at trial which is a 1966 article by Doctors Epstein and Braunwald entitled “Beta-Adrenergic Receptor Blocking Drugs: Mechanisms of Action and Clinical Applications” published in the New England Journal of Medicine. The first part of this article describes how beta-blockers function and their effect on various parameters such as heart rate. On page 1179 of this article appears a discussion of the use of beta-adrenergic receptor drugs (beta-blockers) for the treatment of hypertension. In this discussion of hypertension the article makes reference to a 1964 article by Dr. Brian Prichard entitled “Hypotensive Action of Pronethalol” published in the British Medical Journal. Dr. Thadani also referred to this article which is PX 26. Thadani, Tr. at pp. 29-31, 33.

In this article (PX 26), the hypertensive action of a beta-blocker known by the name of “pronethalol” was described. Dr. Prich-ard found that this beta-blocker drug lowered the blood pressure in patients with hypertension. Further work on pronethal-ol was discontinued when experiments in mice showed that it produced carcinogenic effects. However, on page 1228 of PX 26, Dr. Prichard does state that “when a non-carcinogenic beta-receptor-blocking drug is produced it would be worth trying in the treatment of hypertension.” Thadani, Tr. at pp. 33-34.

The Epstein and Braunwald article (DX 504 referred to previously) at p. 1179 states that Prichard’s observations contained in his 1964 article (PX 26) were extended to another beta-blocker, “propranolol” which was found to be effective as a blood-pressure-lowering agent. Dr. Thadani also referred to Dr. Prichard’s work with propra-nolol at trial, in discussing PX 314 a 1969 article co-authored by Dr. Prichard and Dr. Gillam entitled “Treatment of Hypertension with Propranolol” published in the British Medical Journal. Dr. Thadani stated that this article’s authors found that propranolol, a beta-blocker, was effective in the treatment of hypertension. Thadani, Tr. at 35-37.

Dr. Thadani also referred to DX 505 at trial, a 1969 article by Dollery entitled “Clinical Pharmacology of Beta-receptor-blocking Drugs”. This article discusses and describes the clinical pharmacology, properties, function and uses of beta-blocking drugs. The fifth section of the article which deals with the clinical use of beta-blocking drugs, describes the value of these drugs in the treatment of hypertension as giving rise to controversy (at page 785) and indicates that further work will need to be done in order to define the position of beta-blocking drugs in such treatment (at page 787). The article does, however, offer a thorough review of the studies concerned with the blood pressure lowering effect of beta-blocking drugs, and many of the cited studies show successful results. Dr. Thadani characterized this article as describing what he and other physicians were aware of at this time, in 1969, as to beta-blocker drugs. Thadani, Tr. at pp. 31-33.

The Court finds that it was known prior to February of 1969 not only how beta-blockers functioned but that they could be used to lower blood pressure.

3. The Development of Beta-Blockers

In 1948 Dr. R.P. Ahlquist published a paper describing the effect of sympathetic amines (two endogenous catecholamines, adrenaline and noradrenaline, and four synthetic analogues, one of which was isopre-naline) in producing responses in a variety of different animal tissues. The chemical structures of adrenaline, noradrenaline and isoprenaline are as follows:

All three compounds have a benzene ring on which hydroxyl (-0H) groups are substituted at the 3- and 4- positions, and an ethanolamine side-chain at the 1-position. The only difference in structure between these three compounds is the amino group of ethanolamine side-chain. P.T. Order at p. Ill — 6—7.

Upon finding that there were two distinct rankings of relative potency of these sympathetic amines for producing responses depending on the organs tested, Dr. Ahlquist concluded that there were two distinct types of adrenoceptors in the body which could be affected by this class of compound. He referred to these as alpha and beta adrenoceptors. Dr. Ahlquist found that beta-receptors were associated with most of the inhibitory functions such as dilation of the vascular system and inhibition of the bronchial muscles and one excitatory function that of myocardium or heart muscle stimulation. Isoprenaline was found to stimulate these beta-receptors the most, followed by adrenaline and then noradrenaline which stimulated the beta-receptors the least. P.T. Order at p. III-7-8.

In 1958, a report was published by Eli Lilly showing that certain adrenoceptors in animals could be blocked by a chemical compound known as dichloroisoprenaline (DCI). The structure of DCI is as follows:

As in adrenaline, noradrenaline and isopre-naline, DCI has a benzene ring with an ethanolamine side-chain at the 1-position. Unlike the other three compounds, DCI is substituted at the 3- and 4- positions with chlorine (Cl) instead of hydroxyl groups. However, DCI has the same amino group of the ethanolamine side-chain as isoprena-line, a hydrogen and an isopropyl group. P.T. Order at p. Ill — 8.

With the discovery of DCI, the classification scheme of alpha and beta, adopted by Dr. Ahlquist for adrenoceptors, became more widely accepted and was extended to certain drugs which were classified as either alpha or beta according to the type of receptor for which they had the greatest affinity. Thus, DCI was described as a “beta-adrenergic blocking drug” in 1961 and was the first beta-blocker discovered. P.T. Order at p. Ill — 8.

In 1958, Dr. J.W. Black, who had been working on drug treatments for angina pectoris suggested an alternative approach to the treatment of angina pectoris. He suggested reducing the stimulation of the heart so that the heart would need less oxygen. Aware that stress, either emotional or exercise-induced, played a role in bringing about an angina attack and that the release of noradrenaline (from the nerve endings adjacent to the heart muscles) and adrenaline (into the bloodstream from the adrenal gland) acted to stimulate the heart by stimulating the beta-receptors, Dr. Black suggested that by blocking the beta-receptors in the heart muscle the harmful effects of this stimulation could be overcome. P.T. Order at pp. Ill — 9—10.

DCI as a beta-blocker with the ability to block beta-receptors from stimulation by adrenaline and noradrenaline had the potential of being the type of drug that could be used to treat angina pectoris in the alternative way suggested by Dr. Black. However, DCI was found to be a very potent beta-agonist in that it had a strong stimulating effect on the same beta-receptors that it blocked such that it was considered an unsuitable drug for use in the treatment of angina. This led Dr. Black and his colleagues at ICI in 1958 to begin searching for a beta-blocker free from the stimulating effect possessed by DCI. P.T. Order at p. Ill — 10.

In 1960, Drs. Black and Stephenson of ICI discovered, pronethalol, the first clinically useful beta-blocker. The chemical structure of pronethalol is as follows:

A comparison of the structural formulae of pronethalol, DCI, isoprenaline, adrenaline and noradrenaline reveals that each possesses an ethanolamine side chain and that the differences among these compounds include differing amino group substituents of the ethanolamine side chain (hydrogen, methyl and isopropyl), differing ring systems (benzene and double or naphthyl ring structures) and differing substituents on their respective ring structures when comparing DCI and pronethalol with each other and with the sympathetic amines, adrenaline, noradrenaline and isoprenaline. It is these differences that account for the significantly different behavior and clinical utility of these drugs. P.T. Order at p. Ill — 10—11.

Pronethalol was fully developed through pre-clinical testing and clinical trials which showed it to be a successful beta-blocking drug in the treatment of angina pectoris by improving these patients exercise tolerance, though a fairly high dose was needed. These results seemed to support Dr. Black’s hypothesis of an alternative treatment approach for angina. P.T. Order at p. III-ll.

As discussed previously in reference to Px 26, Dr. Prichard found that pronethalol also had blood pressure lowering capabilities. The use of pronethalol, however, was associated with various side-effects, mostly of central nervous system (“CNS”) origin, which seemed unrelated to its beta-blocking effect. Its use was further complicated by its carcinogenic potential in humans such that in 1965 it was withdrawn from human use. P.T. Order at p. Ill — 11—12.

In 1962 propranolol, another beta-blocker drug, was discovered. This compound proved to be not only successful in clinical use, but safe. The structural formula of propranolol is as follows:

Propranolol has a naphthyl ring structure like pronethalol but unlike pronethalol, between the ring and the ethanolamine group (-CH(OH)-CH2-NH-CH(CH3)2), proprano-lol has an oxymethylene group -(OCH2) to form an “oxypropanolamine” group. This oxypropanolamine group was found to give rise to compounds 10-20 times as potent as the corresponding ethanolamine analogues. Propranolol was fully developed through preclinical testing and clinical trials and, in 1965, ICI commenced selling propranolol and it became important in the treatment of hypertension and angina. P.T. Order at p. Ill — 12.

The history as to the development of beta-blockers further supports the Court’s finding that it was known prior to February, 1969 that beta-blocker drugs functioned to block beta-receptors from the stimulating effects of adrenaline and noradrenaline and that these drugs could be used successfully to treat hypertension.

4. The Structural and Pharmacological Properties of Beta-Blockers

Atenolol is a novel compound. P.T. Order at p. Ill — 17. Atenolol is a beta-blocker. P.T. Order at p. Ill — 3. ICI contends that the use of atenolol, acknowledged to be a novel compound and a beta-blocker, in the treatment of hypertension is not obvious in view of the prior art. ICI supports this position primarily by focusing on the structural differences between atenolol and the prior art beta-blockers. ICI claims that the prior art would not have suggested the modifications necessary to make atenolol and that the combination of pharmacological properties possessed by atenolol are unexpected and qualitatively different. Based on the findings discussed in the following sections “a” through “e” of this Opinion, the Court is convinced that ICI’s reliance on structural differences is without merit.

a. The Common Molecular Structure of Beta-Blockers

The prior art includes numerous patents and publications which discuss the structural features of beta-blocker compounds. The basic molecular structure of these compounds can be represented as follows:

made up of the following chemical groups or moieties:

“B” represents oxymethylene group (-OCH2-) which may, but need not, be present for beta blocking activity;

“C” represents an ethanolamine group (-CH(OH)-CH2-NH-), wherein the amine (NH-) may, but need not, be attached to an isopropyl group (- CH(CH3)2), as shown;

“R” represents one or more substituents which may be attached to the aryl group at one or more positions which are labeled on the benzene ring — the 2- and 6- positions are also termed “ortho”, the 3- and 6- positions “meta”, and the 4- position “para”;

“BC” collectively represents an oxypropa-nolamine group (-OCH2-CH(OH)-CH2-NH-CH(CH_3)2), wherein, as shown, the amine is optionally attached to an isopropyl group, but may alternatively be attached to a t-butyl group;

“AC” collectively (without “B”) would represent an arylethanolamine; and

“ABC” collectively represents an aryloxy-propanolamine.

P.T. Order at p. Ill; ¶ 8. This molecular structure is shown on Px 871.

The following are among the specific beta-blocker structures which are prior art with respect to atenolol.

At trial Dr. Loev, an expert in medicinal chemistry for Danbury, was asked to explain the relationship, if any, between the compounds shown on exhibits Px 872 through PX 874 and the general structure shown on PX 871. Dr. Loev testified that the structure on PX 871 shows a generic structure for beta-blocker compounds and that the letters which are used above the different parts of the structure, “R” and “A” and “B” and “C” are a shorthand to represent different parts of the molecule. He further explained that the structures on PX 872, PX 873 and PX 874, all fit within the general structure shown on PX 871. In reference to Claim 2 of the ’032 Patent Dr. Loev stated that atenolol fits within the R-ABC generic structure shown on PX 871. Loev, Tr. at pp. 287-96.

At trial Dr. Loev reviewed several prior art publications which discuss the general structure of the class of compounds known as beta-blockers. In summary he stated that the publications discuss what PX 871 illustrates about structure of the beta-blocker compounds and that many of the publications even use the same R-ABC shorthand to identify the structure. Dr. Loev testified that “[i]n general [these pri- or art publications] say that for a substance to be a beta-blocker it will have a structure corresponding to R-ABC, in some cases using those [specific] identifiers, otherwise showing the structure identical to what is [in PX 871] and saying that this is the general structure.” Loev, Tr. at p. 297.

In addition to examining the prior art publications Dr. Loev examined and discussed several prior art patents in reference to the common structure of beta-blocker compounds. Based on his review of the prior art patents Dr. Loev estimated that thousands of different beta-blocker compounds having the R-ABC structure are disclosed. He further stated that these compounds differ very little from one another and that they all conform to the R-ABC structure. Dr. Loev proceeded to go through each of the prior art patents he examined, indicating for the Court where each patent disclosed a beta-blocker having the R-ABC structure. Loev, Tr. at pp. 312-344. The Court will not reiterate Dr. Loev’s remarks as to each patent since it was made evident to the Court at trial that these prior art patents do refer to a common structure, possessed by the beta-blocker compounds, though not always represented by the R-ABC shorthand.

b. The Necessary Molecular Structure of Beta-Blockers

The common generic structure, often times represented by the shorthand R-ABC, associated with the beta-blocker compounds in the prior art is also necessary in that it enables the compound to act as a beta-blocker. Several prior art publications were introduced at trial which analyzed the structure-activity relationship of beta-blockers and defined the necessary structural elements for this class of compounds.

Dr. Loev testified at trial, in reference to DX 536, a 1967 publication by Ariens entitled “The Structure Activity Relationships of Beta Adrenergic Drugs and Beta Adre-nergic Blocking Drugs”, that the very close structural relationship between the endogenous catecholamines, adrenaline and noradrenaline, and the compounds identified as beta-blockers, both of which fit the R-ABC structure, explains why the beta-blocker compounds are able to fit the beta-receptor site so well. Dr. Loev next summarized what DX 538, a 1966 publication by Brand-strom, et al. entitled “Synthesis of some B-adrenergic blocking agents”, disclosed with respect to the relationship between structure and activity in beta-blockers. He stated that the authors indicated a standard hypothesis in drug-receptor research was that one part of the molecule is responsible for combining with the receptor, the attachment part, while another part is responsible for producing the stimulation effect.

At trial, Dr. Loev focused on the drug-receptor reaction that occurs with a beta-blocker drug. He explained that the beta-blocker compound comes to the receptor site (the beta-receptor) and combines with the site. Specifically, the oxypropanola-mine side chain portion of the beta-blocker compound reacts with the beta-receptor site and acts to attach the compound to the site. The other part of the beta-blocker compound, the “RA” portion, sticks out and physically blocks the site thus preventing the endogenous substances from getting into that site to react and cause beta-stimulation. Loev, Tr. at pp. 298-305.

The Court finds that a compound must possess the requisite molecular structure to be capable of acting as a beta-blocker and that the generic structure denoted by the shorthand R-ABC was both the common and necessary molecular structure possessed by the beta-blocker compounds known in the prior art. Specifically, a prerequisite for beta-blocking activity was an ethanolamine “C” group connected to an aromatic ring “A” preferably linked by an oxymethylene (OCH2-) bridge “B”. The oxymethylene bridge “B” was not necessary for beta-blocking activity but, when present, was found to give rise to compounds 10 to 20 times as potent. P.T. Order at pp. Ill — 5, 12. The ethanolamine side chain was believed to be responsible for a beta-blocker’s affinity to the beta-receptor site while the “R-A” portion physically blocked the endogenous substances from reacting with the receptor site.

c. Variation in the “R-ABC” Structure

The way in which the prior art beta-blocker compounds (see the structures illustrated in section I.B.4.a.) differ is in their respective “R” group substituents or their aromatic ring structures, the “A” group. At trial Dr. Loev presented four exhibits (590A-D) which he had prepared to illustrate the diversity of R group substitu-ents that had been used and reported in beta-blocker compounds prior to 1969. Dr. Loev used prior art publications and patents (referenced on each exhibit for each structure appearing on the exhibit) in preparing these exhibits.

DX 590A focuses on aryl ring variations and shows the variety of different ring systems that have been used which fit the R-ABC beta-blocker structure. DX 590B illustrates R group variations which are all attached to the ring by a methylene group (CH2) or methylene bridge. All of these fit the R-ABC beta-blocker structure. DX 590C illustrates a variety of structures containing the “R” group substituent of an amide functional group, an amide. Each of these compounds shown on DX 590C has either front to back or back to front the (CONH) or (CONH2) groupings. All of these are amides. DX 590D illustrates miscellaneous “R” group variations, little groups, big groups, reactive and nonreactive groups, which do not fit into any particular category and further shows the wide diversity of “R” groups which appear in beta-blocker compounds. Loev, Tr. at pp. 345-49.

These exhibits, prepared by Dr. Loev from the prior art patents and publications, show that wide variations in the “R” group substituent can be tolerated while retaining beta-blocking activity. This level of modification in the “R” group is possible since the “BC” portion of the beta-blocker structure was generally believed to be responsible for the affinity or binding of the beta-blocker compound to the receptor site while the “R” or “RA” portion of the structure resulted in various pharmacological profiles. Loev, Tr. at pp. 297-375.

Dr. Loev testified that it would be a reasonable expectation of a person of ordinary skill in the art that compounds possessing the R-ABC beta-blocker structure would have not only a reasonable likelihood, but a very high likelihood of possessing beta-blocking activity. Further, it was Dr. Loev’s testimony, based on his readings, that the pharmacological implication flowing from this property would be antih-ypertensive activity. Loev, Tr. at pp. 354-56. The Court agrees and finds that there would be a high expectation that a compound of the R-ABC beta-blocker structure would possess beta-blocking activity and thus blood pressure lowering capabilities.

d. Secondary Pharmacological Properties of Beta-Blockers

In the prior art publications which analyzed the structure-activity relationships of beta-blockers it was generally believed that the ethanolamine side chain, the “C” group, preferably linked by an oxymethylene (OCH2-) bridge “B” to the aromatic ring “A”, was responsible for establishing the affinity or binding between the beta-receptor and the beta-blocker compound. The “R”. or “R-A” substituent, which in the endogenous catecholamines causes stimulation by reacting with the receptor site and in the beta-blocker compounds physically blocks the site, was believed to be responsible for the presence or absence of certain secondary pharmacological properties. P.T. Order at p. III-17; DX 529, DX 505, DX 535, DX 536, DX 538, DX 539; Loev, Tr. at pp. 298-306.

The ancillary pharmacological properties associated with the beta-blocker compounds, in addition to their beta-adrenergic receptor blocking activity, include cardiose-lectivity, intrinsic sympathomimetic activity (“ISA”) and membrane stabilizing activity (“MSA”). By 1967 it was a generally accepted practice to classify the beta-blockers by the ancillary pharmacological properties which they possessed. P.T. Order at pp. Ill — 13—15.

Cardioselectivity refers to the preference or selectivity certain beta-blockers demonstrate for the beta-receptors predominantly located in the cardiac muscle, called betai-receptors, as opposed to those beta-receptors, referred to as beta2-receptors, predominantly located in the muscles of the peripheral vascular or bronchial systems. Thus, the beta-blocking effects on the muscles in the peripheral vascular or bronchial system are significantly reduced with a cardioselective beta-blocker. Beta-blockers which are cardioselective are referred to as being betai-selective. ISA, also known as partial agonist activity or PAA, refers to the fact that some beta-blockers provide some degree of stimulation to the beta-receptor while simultaneously blocking that receptor from stimulation by the endogenous catecholamines. P.T. Order at pp. Ill — 13—15.

Variations in the “R” or “RA” portion of the R-ABC beta-blocker generic structure could be expected to produce a compound possessing beta-blocking activity and some combination of the secondary pharmacological properties associated with the beta-blocker compounds as described above. The only structural difference between the cardioselective prior art beta-blocker, prac-tolol, and the non-selective prior art beta-blockers such as alprenolol and oxprenolol is the nature of the “R” group substituent. In addition, the only structural difference between the prior art beta-blocker propra-nolol which lacks ISA and the prior art beta-blockers oxprenolol and alprenolol which possess ISA is the nature of the aromatic ring “A” and the “R” group sub-stituent. P.T. Order at p. Ill — 17.

e. Beta-Blockers as a Class of Compounds

It is the Court’s finding that the beta-blocker compounds define a class of compounds and that atenolol’s inclusion in this class is appropriate. The prior art patents and publications along with the expert testimony given at trial, all discussed in the proceeding sections I.B.4.a. through d., support the Court’s characterization of the beta-blocker compounds as a class. All three chemical experts, Dr. Rees, Dr. Hirschmann and Dr. Loev, and the co-inventor on the ’032 Patent, Dr. LeCount, appear to recognize that there was an established class of chemical compounds known as aryloxypropanolamines and that this class was known to possess beta-blocking activity in conjunction with other common characteristics. Loev, Tr. at pp. 286-311; LeCount, Tr. at pp. 484-86; Rees, Tr. at pp. 684-85; Hirschmann, Tr. at pp. 872-73.

The prior art teaches the way in which this class of compounds functions and the uses for this class of compounds. In addition, it is apparent to the Court that the prior art teaches that there were certain common and necessary structural elements which the prior art beta-blockers possessed that enabled this class of compounds to perform the function of a beta-receptor blockade. The review of the prior art further reveals that as long as the necessary structure was maintained, wide variations of the non-requisite structural elements of this class of compounds could be tolerated. These variations would not result in a loss of beta-blocking activity but only in a variety of secondary pharmacological properties exhibited by the class of compounds of beta-blockers.

Atenolol is a novel compound and admittedly does possess structural differences from the prior art beta-blockers, but it is still a beta-blocker and a member of this class of compounds. Atenolol retains the generic structure common and necessary to the class’ function. Atenolol’s structural variation appears only in the non-requisite portions of the molecule which results in its combination of secondary pharmacological properties.

C. Differences Between the Prior Art and the Claimed Invention

Atenolol possesses the common and necessary R-ABC structure of the class of beta-blocker compounds known to possess beta-blocking activity. Atenolol is a novel compound. It differs from the prior art compounds by the structure of its “R” group only or by the structure of its “A” group in addition to its “R” group. Through the testimony of Dr. Loev it was seen that a wide variation in the structure of the “R” group can be tolerated with a retention of beta-blocking activity such that there is an expectation that almost any “R” group would result in a beta-blocker. P.T. order at pp. Ill — 15, II26 and III — 17, ¶ 30; Loev, Tr. at pp. 297-375. This expectation of beta-blocking activity is further enhanced if the modifications in the “R” group substituent are minor such as where an “R” group structure close to that of a prior art “R” group is retained. Such is the case when atenolol is compared to the prior art beta-blocker practolol. At trial Dr. Loev demonstrated by using three dimensional scale models, the very similar size and shape of these two compounds. Loev Tr. at pp. 272-82, 375-85.

Atenolol and practolol are structural isomers in that they each have the same number of carbon, hydrogen, nitrogen and oxygen atoms. They each have the identical aryloxypropanolamine structure, the common and necessary “ABC” structure of the class of beta-blockers. They differ in structure in their respective “R” group substituents at the para position on the aryl ring. The “R” group of each is an acetamide (CH3-CO-NH2-) but in the case of atenolol this group is linked to the aryl ring, the “A” group, through a methyl (CH3) group and in the case of practolol, the acetamide is linked to the aryl group through an amino (NH) group. Dr. Loev explained that if one were seeking a car-dioselective beta-blocker the fact that prac-tolol possessed an amide (NH-CO) functional group as its “R” group and it was cardioselective, the expectation would be that retention of such an amide group would result in a cardioselective beta-blocker and, if one were asked to get a beta-blocker, you could “stick almost anything [in the R group position.]” Loev, Tr. pp. 397-98. P.T. Order at p. III-18, ¶ 31; Loev, Tr. at pp. 297-375; Rees, Tr. at p. 636; DX 596; DX 600.

The expectation of beta-blocking activity is also enhanced if modification to the “R” group is in accord with the guidelines developed for “isosteric” and “bioisosteric” replacements. These established replacements are published into tables. Such a table appears on page 75 of DX 545 as table 8-1. According to this table a known isosteric replacement is the substitution of CH2 for NH or NH2 for CH3. Such exchanges would result in atenolol from practolol. As Dr. Loev testified, these tables have limits since it is recognized that there is no guarantee that a particular molecular modification will produce a desired result. However, it is reasonable, in the case of a beta-blocker compound, where the prior art discloses such compounds as possessing “R” groups which vary greatly in steric and electronic configurations, that an “R” group selection which results in a compound that is isosteric or isomeric with known beta-blockers having established activity, that the likelihood of beta-blocking activity is greater than if the “R” group is selected at random. Loev, Tr. at pp. 273-77, 374-378.

The Court is aware that the prior art patents do not actually disclose the specific molecular modifications required to synthesize atenolol from any prior art beta-blocker, including praetolol (which is considered to be the closest prior art by ICI). (PFC at p. 55). The Court can’t agree, however, with ICI’s position that the general prior art gave no guidance to persons of ordinary skill in the art seeking to make a new beta-blocker. Loev, Tr. at 411; PFC at p. 59. The Court finds that the physical and chemical relationships between atenolol and the prior art beta-blockers (i.e. the common and necessary R-ABC structure and an “R” group substituent structurally related to known beta-blockers with activity), would enhance the expectation, in 1969, that atenolol would be an active beta-blocker and, thus, a member of the recognized class of beta-blocker compounds disclosed in the prior art as having antihyper-tensive utility. Loev Tr. at pp. 272-82, 375-85.

D. The Development of the Patent in Suit

1. ICI’s Research Interests and Goals

In 1968, ICI’s cardiovascular team’s research included research into beta-blockers. When Dr. LeCount, a co-inventor of the ’032 patent, joined the Pharmaceutical Division of ICI this research involved exploration of the chemistry of compounds related to the prior art beta-blocker, practo-lol. Praetolol is a cardioselective beta-blocker which has ISA. The interest at ICI, and one of Dr. LeCount’s goals, was to find a beta-blocker that was cardioselec-tive, like praetolol, but which lacked the ISA of praetolol. At this time, however, it was not clear whether the presence or absence of ISA was desirable. Thus one of the objectives in making a cardioselective beta-blocker without ISA was to permit clinical evaluation of the effectiveness of this combination of properties. LeCount, Tr. at pp. 476-484, 489, 497, 499-504. No beta-blocker existed in the prior art which had cardioselectivity but lacked ISA to serve as a reference. P.T. Order at p. HI-15.

In reference to the upper left hand drawing on PX 892, Dr. LeCount explained that the changes to the praetolol compound being explored at ICI included those positions marked as follows: 1) “R”, which indicates the terminal amino group on the oxypropa-nolamine side chain; 2) “Ri”, which indicates the terminal portion of the praetolol side chain; and 3) “R2”, which indicates other substituents at various positions on the aryl ring. He also explained that the (-NHCOR1) group (of the praetolol compound) was being kept constant in an effort to retain its overall properties while attempting to enhance its level of activity. Research was also being done to explore changes in the prior art beta-blocker pro-pranolol, in which the double ring structure was held constant while variations were made to other parts of the molecule. Le-Count, Tr. at pp. 497, 499-503.

Throughout his testimony Dr. LeCount referred to the “praetolol series” when discussing the research involved in making the above modifications to the praetolol compound, and to the “propranolol series” in reference to the modifications being made to the propranolol compound. He concluded from the prior work in modifying praetolol and propranolol that the desired “series” of improved beta-blocker would not be found in either the propranolol series or the praetolol series, but that it would be necessary to devise a new series having the most desirable properties of each. Affidavit of David James LeCount (DX 503) at p. 34, 1142.

The Court does not agree with Dr. Le-Count’s characterization of the prior art compounds as belonging to different series. The Court has found that they are all part of the class of compounds of beta-blockers for which the prior art defines a generic structure and the permissible modifications that can be made to this structure without a loss of beta-blocking activity. In fact, Dr. LeCount was aware of the teachings of the prior art relating to beta-blocker structures and recognized that because his objective was to make a beta-blocker the R-ABC structure would have to be retained since it was a prerequisite to obtaining a compound which possessed beta-blocking activity. Also based on his knowledge of the prior art, Dr. LeCount believed that the R group was the only part of the molecule that could potentially make a difference with respect to cardioselectivity since he knew that the only structural difference between the cardioselective prior art beta-blocker, practolol, and the non-selective pri- or art beta-blockers, alprenolol and oxpre-nolol, was the nature and location of the “R” group substituent on the “A” ring. These are the very portions of the structures of practolol and propranolol that the ICI work, discussed above, centered on. LeCount, Tr. at pp. 482, 486-90.

In the Court’s view, Dr. LeCount’s description of the ICI research team’s goal as a departure from the “practolol series” with the objective of finding a new series, is misleading. This characterization creates the impression that in embarking on the synthesis of a new beta-blocker with the desired combination of properties, that the prior art with respect to the chemical structure of beta-blockers created no expectation that a new compound, with the R-ABC structure and an “R” group close to that of prior art “R” groups, would be a beta-blocker. The Court is convinced that this was not the case. In fact, to the contrary, ICI’s focus in synthesizing a new beta-blocker was on modifications of the “R” group of practolol. This is hardly a major departure from what is disclosed in the prior art to warrant classifying the resulting compound as a member of a “new series”. Dr. LeCount described the rationale which led to the synthesis of atenolol as follows:

“Clearly, it is a simple matter to synthesize a molecule that looks like a beta-adrenoceptor blocking agent, and not too difficult to synthesize one that is active.... The only difference between the selective practolol and its nonselec-tive relatives was the presence of the acetylamino group in practolol; therefore it was toward this group that our attention turned.”

LeCount, Tr. at pp. 482, 488-89; DX 532 at p. 126.

2. The Synthesis of Atenolol By ICI — A Chance Discovery

It is contended by ICI that the compound that became atenolol was not the target of the synthesis intended by Dr. LeCount and Dr. Hull. It is asserted that the biological activity of atenolol was purely a chance discovery. LeCount, Tr. at pp. 515-517; Rees, Tr. at pp. 613-14, PX 82. Further, it is asserted that making the structure of atenolol would have been inconsistent with Dr. LeCount’s goal, because if he was trying to disclose acidity on the carbon adjacent to the aromatic ring, it would not have been sensible to have amide hydrogens present nearby, as is the case in the structure of atenolol. This is because amide hydrogens are inherently more acidic, since they are hydrogens on nitrogen as opposed to hydrogens on carbon. Rees, Tr. at p. 614.

The Court does not see the significance to be given to ICI’s assertion that atenolol was a chance discovery. Atenolol fits the R-ABC structure of the class of beta-blocker compounds. The net result of the synthesis of atenolol was a compound in which there is a modification of the “R” portion of the generic R-ABC structure of prior art beta-blockers. In fact, if the “R” group of practolol is turned around, the resulting compound is atenolol. As discussed previously, the prior art publications and patents and the opinion of Dr. Loev based on these prior art items, shows that there was a recognized class of beta-blocker compounds having a generic R-ABC structure in which a diverse array of “R” groups could be put into the R-ABC structure and beta-blocking activity still retained. It was also disclosed in the prior art (and discussed previously), that compounds of this class were useful antihypertensive agents. Therefore, a determination as to whether atenolol resulted from an unintended synthesis route or was simply the rearrangement of the “R” group of an existing prior art beta-blocker is not a necessary finding this Court must make in deciding this case.

E. The Level of Skill in the Art

Atenolol possesses an aryloxypropanola-mine group, the “ABC” structural component of the generic beta-blocker structural formula. The “AC” portion is required for beta-blocking activity and the “B” portion, the oxymethylene bridge, is desirable as it is attributable to additional potency. Aten-olol differs from the prior art beta-blockers in the structure of its “R” group and/or in the modification of the “A” group. Structural differences in the nature of the aromatic ring “A” and the “R” group substi-tuent distinguish a cardioselective prior art beta-blocker from a non-selective one, specifically cardioselective practolol and non-selective alprenolol and oxprenolol and a prior art beta-blocker lacking ISA from a beta-blocker possessing ISA, specifically ISA lacking propranolol and ISA possessing oxprenolol and alprenolol. P.T. Order at p. Ill — 17, 1128, 11 29. Therefore, it was apparent that variations in the nature of the “A” portion and the “R” portion of the beta-blocker basic molecular structure, R-ABC, could result in beta-blockers with varying pharmacological profiles. P.T. Order at p. Ill — 5, ¶ 8; p. III-17, ¶ 29. Therefore, the level of ordinary skill in the art in this case involves the research and development of beta-blockers for use in the treatment of hypertension as of February, 1969, since the claimed invention is a method for the use of a novel beta-blocker compound, atenolol, for treating hypertension. P.T. Order at p. IV-4, H 14; p. Ill — 3 at II7; p. Ill — 17 1130.

1. A Medicinal Chemist

ICI was interested in developing a beta-blocker with varying pharmacological properties from the prior art beta-blockers when atenolol was discovered. ICI sought to develop a beta-blocker which was car-dioselective like practolol but, unlike prac-tolol, lacked ISA. LeCount, Tr. at pp. 478-84. Therefore, a determination of how to modify the “R” and “A” portions of the R-ABC structure of existing beta-blockers was required in order to produce a beta-blocker compound with the desired properties. The Court finds that the art involved in such a determination and thus of the invention in the ’032 patent is that of medicinal chemistry and that the person of ordinary skill in the art would be a medicinal chemist. Loev, Tr. at pp. 350-52; Hirschmann, Tr. at p. 839.

The person of ordinary skill in the art would be an individual with a PhD degree in organic chemistry, with an emphasis in medicinal chemistry (i.e. the application of organic chemistry to the development of pharmaceutical products), who would have some experience with the development of beta-blockers, and would be thoroughly familiar with the prior art which discusses the structure-activity relationships of the existing beta-blockers and have knowledge of the methodologies of drug development (i.e. lead following, isosterism, and bioisos-terism, discussed in the following section of this Opinion). Loev, Tr. at pp. 282-85; Hirschmann Tr. at pp. 726-28.

ICI has asserted that the level of ordinary skill in the art involved in the research and development of beta-blockers for use in the treatment of hypertension as of February, 1969, would be that possessed by a hypothetical person or team having a PhD in organic chemistry and advanced degrees in pharmacology and medicine. P.T. Order at IV-4, II14. The Court does not agree that either a team or an individual possessing the above advanced degrees, in addition to a PhD degree in organic chemistry, is necessary. The educational degree of necessity for developing a new beta-blocker compound for hypertension, would be in organic chemistry as applied to pharmaceutical product development (medicinal chemistry) since the alteration of a requisite and common chemical structure is involved in achieving this invention. Guidance from other individuals with degrees in pharmacology and medicine could be accessible and useful to this medicinal chemist for obtaining information from a clinician’s point of view as to optimal properties. The medicinal chemist himself, however, would not need to possess this additional training in order to pursue the necessary development work.

Dr. LeCount, a co-inventor of the ’032 patent, is himself an individual with a PhD degree in organic chemistry who fits the other criteria the Court has assigned to the level of ordinary skill in the art in this case. Dr. LeCount’s reliance on input from biologists and physicians is the type of guidance foreseen by the Court and does not alter the characterization of the level of ordinary skill in the art as previously described. Hirschmann, Tr. at pp. 726-729; LeCount, Tr. at pp. 451, 453-54, 466, 469, 493-500.

2. Methodology Employed in Drug Research

Prior to 1969 two strategies were known with respect to drug development. These two strategies were referred to as “lead-seeking” and “lead-following”. The lead-seeking strategy is employed when a researcher’s area of interest is new and no useful compounds for treatment have previously been found. Thus, there exists no class of compounds or specific compounds which are effective and the aim under this strategy is to find a prototype compound, a first compound, which is effective. Once a compound is found it must be screened to determine if it possesses the desired activity. If it is active, which many times the compounds are not, it is then subjected to in-depth evaluation to determine if it has problems with side effects, toxicity, potency etc. Loev, Tr. at pp. 261-62; DX 597.

The other strategy called lead-following, is a later step after the lead-seeking stage. This strategy involves taking a prototype or lead compound which has been found and following it and modifying it in an attempt to get rid of certain deficiencies it may have and improve it. In doing this, one makes other compounds related to this lead compound, such as analogs and homo-logs. Any of these related compounds will have to be screened initially for activity. Even though a lead compound or prototype which possesses activity is being followed, it does not necessarily mean that the related compound will also be an active compound. However, there is a reasonable likelihood that active compounds will be produced since a lead compound which possesses activity is being followed. Once this strategy produces an active molecule, further modifications will most likely be necessary because this compound will still have certain deficiencies or not meet the researcher’s criteria for one reason or another. Continual modifications, with subsequent screenings for activity, will occur until a compound is produced which is determined to be suitable for marketing or the search following this lead compound is abandoned. Loev, Tr. at pp. 262-64; DX 597.

Prior to 1969, the lead-following strategy was the more common strategy in the development of drugs. Loev, Tr. at p. 264. A 1960 textbook entitled “Chemobiodynam-ics and Drug Design” (DX 550) by F.W. Schueler, PhD, states at page 405 that “[t]he most widely used mode of approach today in the design of new drugs devolves upon the use of some drug of known structure as a model or prototype from which congeners, or homologues and analogues are designed.” In explaining why this approach is