Janssen Pharmaceutica N v. v. Mylan Pharmaceuticals., Inc.

456 F. Supp. 2d 644, 2006 U.S. Dist. LEXIS 74582

• Court: District Court, D. New Jersey
• Decided: October 13, 2006
• Docket: Civil Action 03-6220 (JCL), 03-6185(JCL)
• Status: Published

Opinion

OPINION

LIFLAND, District Judge.

I. Introduction

Plaintiffs, Janssen Pharmaceutica, N.V., a Belgian corporation, and its New Jersey-based subsidiary, Janssen Pharmaceutica, L.P. (collectively “Janssen”), are the inventors and producers of risperidone, the active ingredient in Janssen’s successful drug for the treatment of schizophrenia, Risperdal. It is perhaps an understatement to describe Risperdal as merely “successful.” The drug has been described by the American Chemical Society as “a standard in the treatment of psychosis, revolutionizing anti-psychotic treatments.” Pl.’s Ex. (“PX”) 309. In 2005 alone, Risperdal accounted for over $3 billion in worldwide sales for Janssen’s parent company, Johnson & Johnson. Vergis Tr. 78:9-16.

Defendants, Mylan Pharmaceuticals, Inc. (“Mylan”), a West Virginia corporation, Dr. Reddy's Laboratories, Ltd., an Indian corporation, and its New Jersey-based subsidiary, Dr. Reddy’s Laboratories, Inc. (collectively, “DRL”), are drug manufacturers seeking to market a generic version of risperidone. Janssen filed this suit claiming infringement of its U.S. Patent No. 4,804,663 (“the '663 patent”), which claims risperidone, among other chemical compounds. Mylan and DRL concede they have infringed the '663 patent; they counter, however, that the '663 patent is invalid due to obviousness, and alternatively, Mylan argues that the '663 patent is unenforceable due to Janssen’s alleged inequitable conduct.

The parties tried the case before the Court from June 28, 2006 through June 30, 2006 and on July 5, 2006. Thereafter, they submitted proposed findings of fact and conclusions of law. The parties’ submissions and the record evidence have been carefully considered. For the reasons set forth below, 1 the Court finds that Mylan and DRL have failed to prove by clear and convincing evidence that the '663 patent is obvious under 35 U.S.C. § 103(a), and that Mylan has failed to prove by clear and convincing evidence that Janssen engaged in inequitable conduct. Thus, the '663 pat ent is neither invalid nor unenforceable, and as a result, Mylan and DRL have infringed that patent under 35 U.S.C. § 271(e)(2).

II. Background

A. The '663 Patent

On February 14, 1989, the United States Patent and Trademark Office (“PTO”) issued the '663 patent to its inventors Ludo E.J. Kennis and Jan Vandenberk and as-signee, Janssen. PX 1. The '663 patent originated from a patent application filed with the PTO on March 27, 1985. Stipulations of Fact (“SF”) 14-15; PX 1.

The '663 patent’s 18 claims encompass compounds “having useful antipsychotic properties and being useful in the treatment of a variety of complaints in which serotonin release is of predominant importance.” PX 1. Among those compounds are risperidone and compound 11, which are included in each of the patent’s 18 claims. 2 SF-17. There is no claim in the '663 patent in which risperidone is the only compound. PX 1; Wolff Tr. 546:1-10.

The compounds claimed in the '663 patent were the result of Janssen’s efforts to invent an effective antipsychotic drug, with few side effects, for the treatment of Schizophrenia. Tamminga Tr. 53:4-22.

B. Schizophrenia

Schizophrenia is a debilitating disease of the brain characterized by hallucinations, delusions and other symptoms that impair a person’s capacity for thought, attention, memory, emotion and social functioning. Tamminga Tr. 46:19-47:1. Despite much research, the cause, mechanism, and etiology of the disease remain unknown. Tam-minga Tr. 47:2-3.

People who suffer from schizophrenia exhibit a wide array of symptoms that can be classified into three major categories: positive symptoms, negative symptoms, and cognitive symptoms. Tamminga Tr. 47:4-7.

Positive symptoms include extreme hallucinations and paranoid delusions. Hallucinations are auditory, visual or both. Schizophrenics do not just hear voices in their mind, “they believe that there are people actually talking to them.” Tam-minga Tr. 47:8-16. In addition, schizophrenics believe in the false realities created by their delusions, sometimes causing the delusions to take over their lives. Id. at 47:17-18.

Negative symptoms include the complete loss of all emotion and lack of spontaneous thought, both of which “result in a loss of social skills and really an entire loss of social functioning.” Tamminga Tr. 47:19-24.

Cognitive symptoms include the impairment of memory and attention. These cognitive deficits cause schizophrenics to become unable to use information and to have great difficulty making decisions. Tamminga Tr. 47:25-48:4.

These symptoms can entirely take over the lives of persons with schizophrenia, preventing them from working or developing social networks. Less than 20 percent of schizophrenics have jobs, less than 15 percent ever marry, and approximately 10 percent eventually commit suicide. Tam-minga Tr. 48:5-15.

C. Early Treatments

Schizophrenia is a disease as old as mankind. For most of that time, there were no effective medical treatments. The only option was compassionate care, placing schizophrenics into protected environments such as government hospitals that quickly became overcrowded. But compassionate care did nothing to treat the symptoms and the patients did not get better. Tamminga Tr. 48:18-49:2.

Beginning in the 1930s, doctors attempted medical treatments. These treatments included induced fever, electroconvulsive shock therapy and frontal lobotomy. None of these attempts to treat the disease was effective. To the contrary, these treatments could even worsen the symptoms of schizophrenia. Tamminga Tr. 49:3-12.

D. First Generation, “Typical” Anti-psychotic Drugs

The lack of effective treatment options continued into the 1950s. Then, for the first time, doctors developed an antipsy-chotic drug to treat schizophrenia, called chlorpromazine. Tamminga Tr. 49:13-18. The discovery that chlorpromazine could treat some symptoms of schizophrenia was accidental. Physicians were testing chlor-promazine as a sedative when they noticed that chlorpromazine significantly reduced the hallucinations and delusions of their schizophrenic patients. Tamminga Tr. 49:19-25.

As the first pharmaceutical treatment for schizophrenia, chlorpromazine was rapidly adopted for use throughout the medical community. Pharmaceutical companies quickly began searching for similar drugs. This led to the development of new antipsychotics such as Janssen’s haloperi-dol, marketed under the trade name, Hal-dol. Chlorpromazine, haloperidol, and other similar drugs became known as first generation, or typical, antipsychotics. Tamminga Tr. 50:12-16, 21-25.

While chlorpromazine and the other typical antipsychotics were an improvement over compassionate care and the early ineffective treatments, they were not perfect. A typical antipsychotic improved the positive symptoms of schizophrenia, but it had no effect on the negative or cognitive symptoms that severely impaired the emotions, thoughts, and social functioning of schizophrenics. In fact, in some cases a typical antipsychotic could even worsen these symptoms. Tamminga Tr. 50:1-3.

More significantly, even when typical antipsychotics were successful at treating the positive symptoms of schizophrenia, they had many unwanted and serious side effects, including sedation, cardiac side effects, and motor side effects. The motor-related side effects were the largest drawback. Tamminga Tr. 51:1-5.

For example, typical antipsychotics caused extrapyramidal symptoms (“EPS”) that caused patients to experience rigidity and tremors similar to those of Parkinson’s disease. The rigidity and tremors brought on by EPS were always uncomfortable and often painful. EPS symptoms tended to cease when a patient stopped taking the medication. Tamminga Tr. 51:6-52:2.

Even worse, EPS symptoms could also gradually develop into a more serious motor syndrome called “tardive dyskinesia” (“TD”), characterized by motor difficulties such as, repetitive, involuntary, and purposeless movements. Unlike EPS, tardive dyskinesia was frequently irreversible even after the medication was discontinued. Tamminga Tr. 51:13-23.

These side effects had significant repercussions in the treatment of schizophrenia. Not surprisingly, patients disliked these motor side effects so much that they some times stopped taking their medication altogether. Tamminga Tr. 52:3-5.

E.Second Generation, “Atypical” Antipsychotic Drugs

In the 1960s, scientists’ search for an improved antipsychotic resulted in the development of the first second generation or “atypical” antipsychotic, clozapine. Cloza-pine was introduced in the 1960s in Europe. Unlike the typical antipsychotics, clozapine had reduced motor side effects. Tamminga Tr. 52:6-9, 52:25-53:1.

Soon after clozapine was introduced, however, researchers discovered that while it had reduced motor side effects, it had a significant toxicity issue. It was found that clozapine could cause agranulocytosis, a sometimes deadly blood disorder. Due to its toxicity, the Food and Drug Administration (“FDA”) did not approve clozapine in the United States until 1990. And even then, it was not approved for general use; its approval was limited to use only with treatment-resistant patients. Tamminga Tr. 52:10-24.

Despite this drawback, the discovery of clozapine demonstrated that it was possible to treat the positive symptoms of schizophrenia without serious motor side effects. It gave the medical community renewed hope for developing improved an-tipsychotic drugs. Tamminga Tr. 53:2-8. For that reason, clozapine became the focus of researchers looking for new drugs that would incorporate clozapine’s improvements without its toxicity. Strup-czewski Dep. (11/16/2004) Tr. 82:4-12. For example, both Eli Lilly and Sandoz spent years on research programs to modify clozapine to create a drug that would retain clozapine’s benefits and eliminate its toxic effect. Meltzer Tr. 250:3-17; Tam-minga Tr. 53:2-8.

F. Risperidone

Janssen was one of the companies attempting to develop a safe atypical anti-psychotic. Following years of research and the testing of many potential compounds, two Janssen scientists, Kennis and Vandenberk, discovered risperidone. When approved by the FDA, risperidone became the first atypical antipsychotic available for general use that effectively treated symptoms with reduced side effects. Risperidone, sold by Janssen under the trademark Risperdal, was approved by the FDA in late 1993 and was first sold in the United States in 1994. Tamminga Tr. 53:9-13; Vergis Tr. 76:6-7, 13-15, 76:24-77:5.

Risperidone was a major advance over the typical antipsychotic drugs. Tam-minga Tr. 55:19-56:5. Like the typical antipsychotics, risperidone has a potent effect in treating the positive symptoms of schizophrenia. However, unlike the typical antipsychotics, risperidone also improves the negative and cognitive symptoms of schizophrenia. Moreover, risperidone also has an extremely low side effect profile, with reduced EPS and almost no TD. Tamminga Tr. 53:14-22, 55:19-56:5.

Risperdal had a revolutionary impact on the treatment of schizophrenia. Once ris-peridone entered the market, the medical community “set aside” the typical antipsy-chotics. Tamminga Tr. 55:19-25.

G. Mylan & DRL’s Abbreviated New Drug Applications

Following Janssen’s success with Ris-perdal, generic manufacturers began filing Abbreviated New Drug Applications (“ANDA”) with the FDA under the Hatch-Waxman Act, 28 U.S.C. § 355(j)(l), seeking approval to sell generic risperidone products. Most of those companies chose not to challenge Janssen’s '663 patent and included a “paragraph III” certification under 28 U.S.C. § 355(j)(2)(A)(vii)(III), indicating that the FDA should not approve their applications until after the expiration of the '663 patent. Vergis Tr. 82:9-13; PX 75, PX 76, PX 77, PX 78, PX 85; PX 396.

On November 29, 2001, Mylan submitted an ANDA (No. 76-288) to the FDA seeking approval to market a generic risperi-done tablet in various doses. Initially, Mylan also chose not to challenge the '663 patent by including a paragraph III certification with its ANDA. SF 21.

On October 24, 2003, DRL submitted an ANDA (No. 76-879) to the FDA also seeking to sell a generic version of risperidone. SF-27. DRL’s ANDA, however, contained a “paragraph IV” certification pursuant to 28 U.S.C. § 355<j)(2)(A)(vii)(IV), challenging the validity of the '663 patent. 3 SF 29. On November 19, 2003, Mylan followed DRL’s lead and amended its ANDA (No. 76-288) to include a paragraph IV certification. SF-23. Both Defendants informed Janssen of its paragraph IV certifications shortly thereafter. SF 24, 29.

H. The Current Litigation

On December 30, 2003, Janssen filed separate patent infringement actions against Mylan (Civil No. 03-6220) and DRL (Civil No. 03-6185) under 35 U.S.C. § 271(e)(2). 4 On March 8, 2004, the two actions were consolidated for discovery and pre-trial purposes. Two additional actions filed by Janssen against DRL (Civil Nos. 05-0884, 5826) based on the filing of additional paragraph IV certifications for different forms of risperidone were consolidated with No. 03-6185 on March 9, 2006.

In February 2004, Mylan and DRL filed separate answers. Both Defendants asserted an affirmative defense claiming that the '663 patent is invalid for obviousness under 35 U.S.C. § 103(a). Both Defendants also asserted a counterclaim seeking a declaration of invalidity.

On June 7, 2006, Mylan amended its answer to include the additional affirmative defense that the '663 patent is unenforceable due to Janssen’s alleged inequitable conduct. Mylan also seeks a declaratory judgment to that effect. DRL did not join Mylan in asserting this defense and counterclaim.

I. Jurisdiction, Venue and Applicable Law

This Court has subject matter jurisdiction over Janssen’s patent infringement claims and Mylan and DRL’s counterclaims pursuant to 28 U.S.C. §§ 1331 and 1338(a). Defendants have waived any objections to this Court’s exercise of personal jurisdiction, SF 11, and venue is proper under 28 U.S.C. §§ 1391(b)(1) and (c), and 1400(b).

Because this action arises under the patent laws of the United States, this Court must apply the precedents of the United States Court of Appeals for the Federal Circuit, which has jurisdiction over any appeal of this judgment. See 28 U.S.C. § 1295(a).

III. Analysis

A. Patent Infringement

One is liable for patent infringement if he or she, “without authority makes, uses, offers to sell, or sells any patented invention ... during the term of the patent therefor....” 35 U.S.C. § 271(a). Additionally, the filing of an application with the FDA under 21 U.S.C. § 355© “for a drug claimed in a patent” is an act of infringement “if the purpose of such submission” — as demonstrated in the applicant’s paragraph IV certification — “is to obtain approval ... to engage in the commercial manufacture, use, or sale of [that] drug ... before the expiration of such patent.” 35 U.S.C. § 271(e)(2)(A).

Defendants concede infringing the claims of the '663 patent with them proposed ANDA products. SF 47. Thus, the only issues before the Court are those raised in Defendants’ affirmative defenses to infringement: (1) whether the '663 patent is invalid due to obviousness, as asserted by Mylan and DRL, and (2) whether the '663 patent is unenforceable due to inequitable conduct, as asserted only by Mylan.

“A patent shall be presumed valid.” 35 U.S.C. § 282. The validity of each claim within a patent must be evaluated independently; the invalidity of one claim does not disturb the presumption of validity of another. Id. The party challenging the patent bears the burden of proving by clear and convincing evidence the invalidity or unenforceability of the claims of a patent. Id. “The ‘clear and convincing’ standard of proof of facts is an intermediate standard which lies somewhere between ‘beyond a reasonable doubt’ and a ‘preponderance of the evidence’ ” and “has been described as evidence which produces in the mind of the trier of fact an abiding conviction that the truth of [the] factual contentions [is] ‘highly probable.’ ” Buildex, Inc. v. Kason Indus., Inc., 849 F.2d 1461, 1463 (Fed.Cir.1988) (internal quotation omitted).

B. Obviousness

“[A] claimed invention is unpatentable if the differences between it and the prior art are ‘such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art.’ ” Alza Corp. v. Mylan Labs., Inc., 464 F.3d 1286, 1289 (Fed.Cir.2006) (quoting 35 U.S.C. § 103(a)). Obviousness is a question of law. Id. at 1289-90. Its resolution depends on four underlying factual inquiries, the so-called Gratem 5 factors: “ ‘(1) the scope and content of the prior art; (2) the level of ordinary skill in the prior art; (3) the differences between the claimed invention and the prior art; and (4) objective evidence of nonobviousness.’” Id. at 1290 (quoting In re Dembiczak, 175 F.3d 994, 998 (Fed.Cir.1999)).

1. The Scope and Content of the Pri- or Art

The scope and content of the prior art is limited to art that is analogous to the claimed invention. See In re Bigio, 381 F.3d 1320, 1325 (Fed.Cir.2004). Analogous art is that which is from the same field of endeavor or, if not within the field of endeavor, is still reasonably pertinent to the particular problem with which the inventor is involved. Id.

The prior art includes (1) analogous patents or printed publications of a person besides the inventor in this or a foreign country before March 27, 1985, (2) analogous patents and printed publications of the inventor in this or a foreign country before March 27, 1984, and (3) analogous U.S. Patents (not invented by Kennis and Vandenberk) that issued after March 27, 1985 but were filed before—or were entitled to rely on a U.S. filing date before— March 27, 1985. 35 U.S.C. § 102(a), (b), and (e).

Defendants argue that the '663 patent is obvious in light of the drug pirenperone, which is covered by U.S. Patent No. 4,342,-870 (“the '870 patent”). Pirenperone was also invented in part by Kennis. The '870 patent was assigned to Janssen, and issued more than one year prior to the filing date of the '663 patent. Thus, it is statutory prior art under 35 U.S.C. § 102(b).

Other patents and publications fall within the scope and content of the prior art, and will be discussed in more detail as necessary below.

2. The Level of Ordinary Skill in the Prior Art

The second Graham factor is the level of ordinary skill in the prior art. The obviousness analysis is conducted from the perspective of a person at that skill level. 35 U.S.C. § 103(a). This hypothetical person of ordinary skill is an objective legal construct who is presumed to be aware of all the relevant prior art. Custom Accessories, Inc. v. Jejfrey-Allan Indus., Inc., 807 F.2d 955, 962 (Fed.Cir.1986).

While the person having ordinary skill knows all of the prior art, he or she is neither a genius nor an innovator. “A person of ordinary skill in the art is also presumed to be one who thinks along the line of conventional wisdom in the art and is not one who undertakes to innovate, whether by patient, and often expensive, systematic research or by extraordinary insights, it makes no difference which.” Standard Oil Co. v. Am. Cyanamid Co., 774 F.2d 448, 454 (Fed.Cir.1985); see also Life Techs., Inc. v. Clontech Labs., Inc., 224 F.3d 1320, 1326 (Fed.Cir.2000).

The parties in this case dispute the appropriate educational background of the person having ordinary skill in the art. Janssen argues such a person would have a master’s degree in chemistry, medicinal chemistry, or pharmacy, or a bachelor’s degree in one of those fields “with at least two years of experience in research in antipsychotic drugs.” Pl.’s FF & CL, at p. 24. Mylan and DRL claim that the person of ordinary skill would have a “Ph.D with at least two years of experience and a record of research success, which is attested to by a small group of publications.” Defs.’ FF & CL, at p. 49. The dispute appears to be somewhat academic (so to speak). 6 Neither party contends that the educational background of the person of ordinary skill is determinative of whether the '663 patent is obvious or nonobvious. See, e.g., Meltzer Tr. 266:2-9, 19-24 (testifying that a person of ordinary skill with either educational background would find the '663 patent nonobvious); Wolff Tr. 530:19-25 (testifying that the person of ordinary skill would have possessed a doctorate, without stating that this educational level was essential to viewing the '663 patent as obvious). Additionally, neither party provided evidence on how specific items of prior art in the record would have been viewed differently depending upon the educational background of the person of ordinary skill.

Furthermore, it appears that few courts conducting an obviousness analysis ever specify the exact level of ordinary skill in the art. In the opinion of one authority, this is because, “[i]n practice, the concept of ‘a person of ordinary skill in the art’ seems more designed to remind judges to put themselves in the shoes of a skilled artisan, rather than to compel a specific factual finding.” Roger Schechter & John Thomas, Principles of Patent Law, § 5.3.2.2 (2d ed.2004). This view of the third Graham factor has some support in Federal Circuit case law. In Environmental Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 697 (Fed.Cir.1983), the Court of Appeals explained that when evaluating the level of ordinary skill in the prior art,

[t]he important consideration lies in the need to adhere to the statute, i.e., to hold that an invention would or would not have been obvious, as a whole, when it was made, to a person of ‘ordinary skill in the art’ — not to the judge, or to a layman, or to those skilled in remote arts, or to geniuses in the art at hand.

With that said, the Federal Circuit has specified several factors to look at in defining the level of ordinary skill in the art. These factors that show that educational background is only part of the story. See Orthopedic Equipment Co. v. All Orthopedic Appliances, Inc., 707 F.2d 1376, 1382 (Fed.Cir.1983). They include: “(1) the educational level of the inventor; (2) types of problems encountered in the art; (3) prior art solutions to those problems; (4) rapidity with which innovations are made; (5) sophistication of the technology; and (6) educational level of active workers in the field.” Environmental Designs, 713 F.2d at 696 (citing Orthopedic, 707 F.2d at 1382).

Here, the '663 patent’s inventor, Kennis, has a degree in industrial engineering from a foreign university that he testified was not capable of comparison to a Bachelor of Science or a Bachelor of Arts. Kennis Dep. (10/20/2004) Tr. 11:19-13:8. In any event, Kennis stated that he is not a doctor. Id. at 11:17-18. Additionally, Dr. Meltzer testified that the actual workers involved in the development of antipsy-chotic compounds have bachelor’s or master’s degrees, not doctorate degrees. Meltzer Tr. 266:15-18; see also Strupczew-ski Dep. (11/16/2004) Tr. 13:15-23. The Court finds this testimony persuasive, and finds that the person of ordinary skill in the art in 1985 searching for an antipsy-chotic compound with reduced EPS would have had a master’s degree in chemistry, medicinal chemistry, or pharmacy, or a bachelor’s degree in one of those fields with at least two years of experience in research in antipsychotic drugs. 7

To the extent the parties presented evidence bearing on the remaining factors articulated in Environmental Designs, 713 F.2d at 696, they are considered in the analysis below in determining whether the person of ordinary skill in 1985 would have found the '663 patent obvious.

3. The Differences Between the Claimed Invention and the Prior Art

“For a chemical compound, a prima facie case of obviousness requires ‘structural similarity between claimed and prior art subject matter ... where the prior art gives reason or motivation to make the claimed compositions. ’ ” Yamanouchi Pharm. Co. v. Danbury Pharmacal, Inc., 231 F.3d 1339, 1343 (Fed.Cir.2000) (emphasis added) (quoting In re Dillon, 919 F.2d 688, 692 (Fed.Cir.1990) (en banc)).

Because 35 U.S.C. § 103(a) orders a Court to determine whether the subject matter was obvious “at the time the invention was made,” the obviousness inquiry cannot be performed using hindsight. Accordingly, this Court must apply the “motivation-suggestion-teaching” test, which asks “whether a person of ordinary skill in the art, possessed with the understandings and knowledge reflected in the prior art, and motivated by the general problem facing the inventor, would have been led to make the combination recited in the claims.” In re Kahn, 441 F.3d 977, 988 (Fed.Cir.2006) (citing Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1321-24 (Fed.Cir.2005)).

It is not enough for a party seeking to defeat a patent on obviousness grounds to merely identify each element of the invention in the prior art. Id. at 986. This can be done for nearly all inventions. Id. Instead, a prima facie case of obviousness requires the party to “explain the reasons one of ordinary skill in the art would have been motivated to select the references and to combine them to render the claimed invention obvious.” Id. (internal quotations omitted).

Evidence of a “motivation to combine” need not be found explicitly in the prior art — it “may be implicit from the prior art as a whole.” In re Kotzab, 217 F.3d 1365, 1370 (Fed.Cir.2000). If such evidence is lacking, however, the use of hindsight will be inferred. Kahn, 441 F.3d at 986.

a. Defendants’ Obviousness Argument

Mylan and DRL do not argue that risperidone would have been obvious; instead they claim that compound 11 would have been obvious in 1985 in light of the prior art. As mentioned earlier, risperidone and compound 11 are embodiments of all 18 claims in the '663 patent. SF 17. The claims are written in the Markush format. “A Markush group is a listing of specified alternatives of a group in a patent claim.” Abbott Labs. v. Baxter Pharm. Prods., 334 F.3d 1274, 1280 (Fed. Cir.2003). “[M]embers of the Markush group are ... alternatively usable for the purposes of the invention.” Id. (internal quotations omitted). Because the '663 patent’s-claims are written-this way, Jans-sen “has made a representation that for the purposes of the claimed invention, the [embodiments] of the groupfs] are equivalents.” In re Skoll, 523 F.2d 1392, 1397 (Cust. & Pat.App.1975). As a result, if one embodiment of a group is obvious, e.g., compound 11, Janssen is precluded from arguing that any other embodiment of the claim, e.g., risperidone, is not obvious. Id.; see also Ecolochem Inc. v. So. Cal. Edison Co., No. 95-1320, 1996 WL 297601, *2, 1996 U.S.App. LEXIS 13330, at *6 (Fed. Cir. June 5, 1996) (not published) (“By claiming a Markush group, [the patentee] has indicated that for the purpose of claim validity, the members of the claimed group are functionally equivalent. Thus if utilizing one element of the' group is anticipated or obvious, the patentee is precluded from arguing that the claim is valid.”).

Pirenperone, of the '870 patent, is structurally identical to compound 11 with one exception: pirenperone has a ketone group, where compound 11 has a benzisox-azole group. Wolff Tr. 547:8-548:24. My-lan and DRL argue that a person of ordinary skill in the art in 1985 would have been motivated from the prior art to start with pirenperone, and take the following series of allegedly obvious steps in order to arrive at compound 11.

First, Defendants claim that pirenper-one would have been chosen as a lead compound by one looking for an antipsy-chotic with minimal side effects, including EPS, because it possessed indicators of those properties. Second, Defendants claim that once pirenperone was chosen, it would have been obvious to the person of ordinary skill in 1985 that its only problem was that it had a short half-life, and thus had to be administered to patients three times per day, which was a problem for schizophrenics. Third, given the prior art, Mylan and DRL believe it then would have been obvious that pirenperone’s ketone group was responsible for this durational problem. Fourth, it then would have been obvious, Defendants assert, to the person of ordinary skill that the solution to this problem was to convert the ketone group to a benzisoxazole, and that this change would permit the compound to retain its desired antipsychotic activity with low side effects.

The Court concludes that Mylan and DRL have failed to prove by clear and convincing evidence that all of these steps would have been obvious to the person of ordinary skill in the art in 1985. Indeed, they have failed to prove that any would have been obvious.

b. The Person of Ordinary Skill Would Not Have Chosen Pirenper-one as a Lead Compound

Defendants argue that the person of ordinary skill in the art in 1985 would have started with pirenperone in attempting to create an antipsychotic with reduced EPS, because pirenperone possessed properties that the prior art taught would be needed for such a drug, namely, dopamine antagonism and serotonin antagonism. 8

As stated earlier, when applying the “motivation-suggestion-teaching” test, the Court must ask whether the person of ordinary skill in the art in 1985, “motivated by the general problem facing the inventor would have been led to make the combination recited in the claims.” Kahn, 441 F.3d at 988 (internal quotations omitted). The “general problem” in 1985 was how to develop a safe and effective antipsychotic with reduced EPS. McMillen Tr. 483:11-484:18; Wolff Tr. 618:5-8. Therefore, Mylan and DRL must demonstrate why the hypothetical person would have been motivated to choose pirenperone as a lead compound in attacking this general problem. 9 See Yamanouehi, 231 F.3d at 1344. First, Defendants argue that tests in the prior art -demonstrate that pirenperone was a dopamine antagonist, and therefore the prior art teaches that pirenperone would be an effective antipsychotic. Second, Defendants claim that pirenperone would have been thought to have a low incidence of EPS due to its serotonin antagonism.

The Court concludes that Defendants are incorrect on both points. First, the prior art teaches that in 1985 pirenperone was an antianxiety drug, not an antipsy-chotic. Second, one following the conventional wisdom in 1985 for choosing a drug with reduced EPS would not have selected pirenperone because that wisdom did not emphasize serotonin antagonism. The pri- or art provided other more likely starting points for the development of an improved atypical antipsychotic drug.

(1) Pirenperone Was Not Considered an Antipsychotic

Pirenperone’s failure of standard tests for antipsychotics indicates that it would not have been considered an antipsychotic and thus, would have made an unlikely choice as a starting point. Meltzer Tr. 274:3-275:5; PX 94; PX 388; PX 389.

As both of Defendants’ experts admitted, no prior art described pirenperone as an antipsychotic. No prior art said that pirenperone was being considered or should be considered as an antipsychotic drug. No prior art tested pirenperone as an antipsychotic in humans. Wolff Tr. 638:23-639:5, 641:6-8, 641:18-20; McMil-len Tr. 511:8-10. Instead, pirenperone was recognized in the literature to be a pure serotonin antagonist that might be clinically useful to treat anxiety. Meltzer Tr. 269:5-8; PX 22; PX 94; PX 96; PX 202; PX 388; PX389.

Janssen — the company that invented pi-renperone and knew it best — did not view pirenperone as a potential antipsychotic drug. Meltzer Tr. 271:18-22.- Indeed, the pirenperone patent does not even mention that pirenperone might be an antipsychotic. PX 80; Wolff Tr. 641:3-5; Meltzer Tr. 269:15-20. Instead, that patent describes the pirenperone family of compounds as “very potent serotoninf ] antagonists” to “be used in the treatment of a variety of diseases in which serotonin release is of predominant importance.” PX 80, col. 11, 11. 11-14; Wolff Tr. 639:15-22. The patent focused on pirenperone’s serotonin antagonist qualities with no indicátion of anti-psychotic potential. Meltzer Tr. 269:12-25; Wolff Tr. 639:6-14; PX 80 (abstract). On the basis of this evidence, the Court concludes that Janssen did not view piren-perone as a potential antipsychotic. '

In addition, the published literature consistently describes pirenperone as a pure serotonin antagonist that could be useful to treat anxiety disorder. Janssen conducted extensive research on pirenperone. In both its published and unpublished research, Janssen studied and described pi-renperone only as a treatment for anxiety. Wolff Tr. 638:1-10, 641:9-17; Meltzer Tr. 270:1-8; McMillen Tr. 508:21-509:4. Janssen’s studies make this clear. See PX 21, 22, 93, 96, 202.

As Defendants’ expert witness Dr. Brian McMillen testified, antianxiety drugs can sometimes be used for antipsychotic purposes, “depending] on the dose and activity” of the drug. McMillen Tr. 470:25-471:5. It is apparent, however, that the two classes of drugs are not interchangeable. The testimony of Dr. Herbert Melt-zer, and the prior art, demonstrated that an antianxiety drug will not always successfully function as an antipsychotic. Meltzer Tr. 272:1-19; PX 94, PX 388, PX 389.

Indeed, prior art was explicit that piren-perone failed to function as an antipsy-chotic. In three published studies on pi-renperone and another of its compounds, setoperone, Janssen told the world that setoperone was an antipsychotic, while pi-renperone was not. PX 94; PX 388; PX 389; McMillen Tr. 509:16-510:11; Meltzer Tr. 272:1-272:19, 273:12-275:5.

Mylan and DRL rely solely on the fact that pirenperone, in addition to its serotonin antagonism, is a dopamine antagonist to support their claim that pirenperone is an antipsychotic. See, e.g., Defs.’ FF & CL, p. 35; McMillen Tr. 479:15-20; Melt-zer Tr. 275:6-11. Not all dopamine antagonists are effective antipsychotics, however. Meltzer Tr. 275:25-276:17. Therefore, companies such as Janssen developed, used, and published tests, in addition to those for dopamine antagonism, to determine whether a compound would be an antipsychotic. Meltzer Tr. 271:18-272:19. While setoperone passed these additional tests, pirenperone failed them. Meltzer Tr. 271:18-272:19, 273:12-275:5; McMillen Tr. 509:16-510:11; PX 94; PX 388; PX 389.

For example, Dr. Janssen tested both setoperone and pirenperone twice using food reinforcement, cocaine discrimination and fentanyl discrimination. Passing the food reinforcement tests as evidenced by suppression of response control is an effect that is characteristic of antipsychotic activity. The published results demonstrated that setoperone passed both tests. By contrast, pirenperone failed the same standard tests for antipsychotic activity. Wolff Tr. 643:9-15; Meltzer Tr. 273:12-274:12; PX 94; PX 388; PX 389. Thus, setoper-one was unique in combining LSD antagonism (i.e., serotonin antagonism, an effect shared with pirenperone) with typical anti-psychotic activity. Wolff Tr. 642:22-25; PX 94. As a result of these studies, Jans-sen studied setoperone, not pirenperone, in humans to treat schizophrenia. PX 391; PX 392; Wolff Tr. 634:12-635:7. It is clear from these test results that a person of ordinary skill would have not considered pirenperone an antipsychotic.

The same studies also tested pirenper-one for antianxiety activity. In those tests, unlike the antipsychotic tests, pirenperone performed better than setoperone. Dr. Janssen reported that pirenperone was effective in the antianxiety tests and had the potential to be another Librium or Valium — known antianxiety drugs. PX 94; Meltzer Tr. 274:13-23. As a result, Jans-sen studied pirenperone only as a treatment for anxiety in humans.

Dr. Janssen’s three publications told one of ordinary skill in the art that pirenper-one is an anxiety drug and that it is not an antipsychotic. A person of ordinary skill in the art in 1985, trying to develop an antipsychotic drug, would not turn to pi- renperone in light of that prior art. Melt-zer Tr. 275:2-5.

Even Dr. Manfred Wolff, Mylan and DRL’s expert witness on obviousness, agreed that one of ordinary skill in the art would hesitate go against Dr. Janssen’s recommendation on pirenperone:

Q. Now, we are talking about the person of ordinary skill and about a compound. Pirenperone is patented as a pure serotonin antagonist, is being studied only in anxiety and Dr. Janssen who you think the ordinary scientist would give so much deference, is telling the world pirenperone is not an antipsychotic, you think a person of ordinary skill would go against Dr. Janssen’s recommendation?

A. Perhaps not.

Wolff Tr. 643:20-644:2 (emphasis added).

Dr. Wolffs “perhaps not” makes it clear that Mylan and DRL have failed to prove by clear and convincing evidence that it would have been obvious for one of ordinary skill in the art in 1985 to select pirenperone as a starting point to develop an antipsychotic drug.

(2) The Conventional Wisdom in 1985 for Predicting Whether a Drug Would Have Reduced EPS Teaches Away From Selecting Pirenper-one as a Lead Compound

There is a second flaw in Mylan and DRL’s argument that pirenperone would have been chosen as a lead compound. They assert that it was well known in 1985 that all that was needed to create an anti-psychotic drug with reduced EPS was to find a compound, like pirenperone, with combined serotonin and dopamine antagonism. See, e.g., Defs.’ FF & CL, pp. 35-37. This, however, was not the conventional wisdom in 1985.

To the contrary, nearly all the prior art typical antipsychotic drugs—drugs that caused debilitating EPS'—were also combined serotonin-dopamine antagonists. Meltzer Tr. 247:2-14, 260:23-261:2; PX 98, p. 170 at Table 2. It was only first demonstrated by Dr. Meltzer much later, in 1989, that a particular ratio of serotonin and dopamine antagonism is critical to creating an atypical antipsychotic. PX 14; Meltzer Tr. 247:20-24. As it happens, the compounds of the '663 patent, risperidone and compound 11, both have the desirable do-pamineserotonin ratio, and that is part of the reason for their effectiveness. PX 1. But simply being a serotonin-dopamine antagonist, like pirenperone, is not enough and knowledge of the desirable ratio comes from pure hindsight; it is not recited anywhere in the prior art.

In the early 1980s, numerous theories were put forward regarding the role of the brain’s receptors in schizophrenia and how to reduce EPS. Meltzer Tr. 237:15-238:11, 242:13-243:1; McMillen Tr. 503:23-504:9.

The prior art demonstrated that the dominant theory in March 1985 was the anticholinergic theory, which focused not on serotonin, but on acetylcholine — another of the brain’s many neurotransmitters. It was believed that the combination of antidopamine and anticholinergic 10 (acetyl-choline-blocking) activities would lead to an atypical antipsychotic with reduced EPS. Meltzer Tr. 262:8-10; 248:3-11.

This theory was developed by comparing the anticholinergic activity of known drugs. Researchers such as Dr. Solomon Snyder found that clozapine, which had the lowest level of EPS, was the strongest anticholi- nergic. Meltzer Tr. 238:2-14, 240:11-241:14; Wolff Tr. 627:23-628:1; PX 265. By contrast, haloperidol, a typical antipsy-chotic that produced the most EPS, was the weakest anticholinergic. Meltzer Tr. 241:19-21; Wolff Tr. 628:2-6.

As Dr. Snyder put it:

There was an inverse correlation between EPS incidence and anticholinergic potency, with clozapine being the most potent anticholinergic and butyrophe-none haloperidol the weakest, findings obtained independently by Miller and Hiley (Table 2).

PX 36 at 988. 11 See also Wolff Tr. 628:7-17.

The theory had strong intuitive appeal. For many years the medical community had used anticholinergic drugs to treat EPS. Patients were given antipsychotic drugs that were dopamine antagonists together with an anticholinergic drug to treat their EPS side effects. Meltzer Tr. 235:18-236:1.

Mylan and DRL were unable to effectively rebut Dr. Meltzer’s testimony and the prior art in the record, which demonstrated that the anticholinergic theory was the conventional wisdom in 1985 for producing a compound with reduced EPS. See Wolff Tr. 631:4-10; McMillen Tr. 503:23-504:9. Neither Dr. Wolff nor Dr. McMil-len was able to disagree with Dr. Meltzer’s assessment that the anticholinergic theory was dominant and that the serotonin theory, which Defendants now claim the person of ordinary skill would have followed, was controversial. Id.

Pirenperone has no anticholinergic activity. Meltzer Tr. 242:10-12, 248:9-13, 267:10-11. Indeed, the anticholinergic theory discounted the relevance of serotonin. Meltzer Tr. 245:5-8; PX 36 at 988.

There were numerous other theories in 1985 in addition to the dominant anticholi-nergic theory. These included: (1) dopamine 1(D1) receptor, (2) norepinephrine, (3) GABA, and (4) glutamate. The D1 receptor and chemicals in the brain (norep-inephrine, GABA, glutamate) were viewed as potentially causative of schizophrenia and researchers tried to find drugs that would antagonize them in order to treat it. Meltzer Tr. 242:13-243:1; McMillen Tr. 504:4-6.

Defendants point to a few papers that suggested that serotonin may play some role in schizophrenia. In particular, Defendants rely on a 1978 study by Dr. Josee Leysen (a Janssen scientist) in support of the idea that serotonin antagonism was important to develop an antipsychotic with reduced EPS and that a dopamineseroto-nin theory would be followed by one of ordinary skill in the art in 1985. PX 98. But as Dr. Wolff conceded, there is no basis for that idea in the Leysen article. Nowhere does Leysen say anything about EPS or whether serotonin is good, bad, or indifferent for EPS. Wolff Tr. 632:6-9.

As reported in that article, Dr. Leysen simply analyzed a large number of antipsy-chotics. PX 98 at Table 2; Wolff Tr. 631:18-20. She determined that many an-tipsychotic drugs had antiserotonin properties, but concluded that “[t]he precise significance of the anti-serotonergic component of neuroleptics, however, requires assessment of its clinical implications.” PX 98 at 171; Wolff Tr. 632:1-5; 634:2-6. As this passage makes clear, Dr. Leysen had no understanding of the clinical relevance of serotonin. Meltzer Tr. 245:12-19.

Defendants also point to a few papers that postulate that antiserotonin properties might contribute to the reduction of EPS and invite further investigation. But even the proponents of serotonin recognized the anticholinergic theory as attractive. Wolff Tr. 626:11-13. At best, these isolated papers invite further experimentation so that the effects of serotonin could also be considered. 12

None of the developing theories on serotonin dislodged the anticholinergic theory as the dominant theory in 1985. Meltzer Tr. 246:24-247:1.

Unlike the anticholinergic theory, the serotonin theory had significant limitations. While the serotonin theory postulated that serotonin antagonism would reduce EPS, typical antipsychotics caused EPS despite their potent serotonin antagonism. There was no explanation for these observations. For example, chlorproma-zine, a typical antipsychotic with a high incidence of EPS, had strong serotonin antagonism. Meltzer Tr. 247:2-14, 260:23-261:2; PX 98, p. 170 at Table 2.

As a result, there was skepticism in the pharmaceutical industry about the value of serotonin antagonism. For example, from 1982 to 1986 Bristol-Myers and Defendants’ expert Dr. McMillen were developing a serotonin agonist, not antagonist. McMillen Tr. 502:15-21, 504:12-19, 505:1-19, 506:20-23. Additionally, Hoeehst-Roussel did not even investigate the serotonin activity of the benzisoxazole compounds from the Strupczewski patent, PX 81, that Defendants rely on. Strupczewski Dep. (11/16/2004) Tr. 113:23-114:6, 115:9-20,116:7-19.

The prior art demonstrates that the serotonin theory was just one of numerous theories, and that it was considered controversial. The articles cited by Mylan and DRL invite further investigation into the role of serotonin in reducing EPS; however, this is not a sufficient reason to select pirenperone — a serotonin antagonist with no anticholinergic activity — as a lead compound. “The prior art must be considered as a whole for what it teaches.” Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1166 (Fed.Cir.2006).

Further, even if the serotonin theory were selected, that was no reason to pick pirenperone among the many possible dopamine-serotonin antagonists. Rather, as noted above, pirenperone would not be selected since it was known neither as an antipsychotic nor as an agent that reduced EPS.

Instead, a person of ordinary skill in the art in 1985 would follow the “conventional wisdom in the art,” Standard Oil, 774 F.2d at 454, and use the anticholinergic theory in order to develop an improved antipsy-chotic with reduced EPS. Meltzer Tr. 267:4-14. That person of ordinary skill in the art following the dominant anticholi-nergic theory would select compounds such as clozapine or thioridazine to develop an antipsychotic drug with reduced EPS. These drugs were known antipsychotics with potent anticholinergic properties. Meltzer Tr. 249:22-250:2. On the other hand, pirenperone would never be selected. Unlike clozapine, pirenperone is not an anticholinergic. Meltzer Tr. 242:10-12, 248:3-13, 267:10-11.

(3) Defendants Admit Using Hindsight to Choose Pirenperone

To avoid using hindsight, a proper obviousness analysis asks whether a person having ordinary skill in the art when “confronted with the same problems as the inventor and with no knowledge of the claimed invention, would select the elements from the cited prior art references for combination in the manner claimed.” In re Rouffet, 149 F.3d 1350, 1357 (Fed. Cir.1998) (emphasis added).

Almost any invention, no matter how nonobvious at the time, will appear obvious when looking backward from the solution. It is for that reason that “[cjare must be taken to avoid hindsight reconstruction by using ‘the patent in suit as a guide through the maze of prior art references, combining the right references in the right way so as to achieve the result of the claims in suit.’ ” Grain Processing Corp. v. Am. Maize-Prods. Co., 840 F.2d 902, 907 (Fed.Cir.1988) (citation omitted, emphasis added).

Mylan and DRL’s experts admit that they went straight to pirenperone solely to advance their theory of obviousness, not because a person of ordinary skill in the art would choose pirenperone. McMillen Tr. 508:12-20; Wolff Tr. 621:14-622:11, 637:9-11. Dr. McMillen did not consider the known antipsychotics in the prior art and did not purport to offer an opinion as to why a person of ordinary skill in the art would have focused on pirenperone. Instead, he focused on pirenperone alone because it was close to the claims in the '663 patent. McMillen Tr. 501:12-502:3, 508:12-20 (“Q. And one of the reasons that you didn’t go and consider setoperone was that pirenperone was closer to all of the claims in the '663 patent and setoperone wasn’t as close to all of the claims in the '663 patent. Correct? A. Correct.”).

Dr. Wolff, Defendants’ only expert to offer an obviousness opinion, was no different. He admitted he did nothing to learn about antipsychotic drug research in the early 1980s. Wolff Tr. 603:18-604:20. This is despite the fact that the prior art includes thousands of actual antipsychotic compounds, falling into numerous broad classes. Meltzer Tr. 249:7-21; PX 16. Dr. Wolff also said he did not know what drugs researchers were looking for to reduce EPS. Wolff Tr. 605:20-606:24. Instead, he testified that his analysis began and ended with pirenperone “because of its relationship to the claims of the patent.” Wolff Tr. 614:17-21, 612:10-13, 637:9-11 On cross examination, Dr. Wolff was asked:

Q. To summarize your approach so far in reaching your conclusion [on selecting a lead compound for your obviousness analysis], you looked at the structure of compound 11, you looked at the structure of the compound pirenperone, and you did the structural analysis.

A. That’s correct.

Wolff Tr. 548:20-24.

This use of the '663 patent as a guide was improper because one of ordinary skill in the art in 1985 would not have the benefit of starting from the '663 patent, in order to choose pirenperone. See Yama-nouchi, 231 F.3d at 1345.

Mylan and DRL’s failure to prove by clear and convincing evidence that the person of ordinary skill in the art in 1985 would have selected pirenperone in attempting to create a safe and effective atypical antipsychotic alone is sufficient to defeat their claims of obviousness. Nevertheless, the Court will describe below why Mylan and DRL have failed to demonstrate, even assuming choosing pirenper-one would have been obvious, that it was obvious to modify it in such a way as to result in compound 11.

c. A Person of Ordinary Skill in the Art in 1985 Would Not Have Been Motivated to Modify Pirenperone’s Ketone Group to Make it Long-Lasting

(1) It Would Not Have Been Obvious That Pirenperone Had a Short-Duration Problem

After choosing pirenperone, Mylan and DRL argue it would have been obvious to one of ordinary skill in the art in 1985 that it was short-lasting, requiring a patient to take it three times per day. This would have been an obvious problem for an anti-psychotic drug, Defendants claim, because a patient with schizophrenia, suffering from its cognitive impairments, may not remember to take the drug that often. See Wolff Tr. 560:15-561:6.

Defendants rely on papers by Meltzer, DX 113, and Green, PX 25, to support their assertion that pirenperone was short-lasting. Green found that at low doses, pirenperone’s ability to affect a particular test result in a rat lasted less than six hours. From this, Green concluded that pirenperone was “fairly short-lasting.” PX 25 at 577. The Meltzer paper, another rat study, looked at pirenperone’s effects on hormonal secretion, and said nothing about pirenperone’s duration at all. McMillen Tr. 511:14-23; PX 25; DX 113.

The first problem with these articles is that they provide rat data, not human data. Dr. McMillen agreed that “the duration of action of a[n antipsychotic drug] may be very different in rat and man[.]” McMillen Tr. 511:24-512:14; Meltzer Tr. 280:4-10. This is supported by prior art. DX 62 at 2213 (“It is known. that the duration of action and oral absorption of neuroleptics may be very different in the rat and man.”).

There are other issues associated with the articles that would cause one of ordinary skill not to focus on them. As for the Meltzer article, it does not describe piren-perone as having a short duration, even in rats. DX 113. The Green article does comment on pirenperone’s duration, but the Court agrees with Dr. Meltzer’s assessment that it would have been discounted by one of ordinary skill for a few reasons. Specifically, Green did not (1) show the data, (2) show the standard error, (3) report how many animals were studied, or (4) study time intervals between 60 minutes and six hours. Given these defects, there was not much to be learned from Green — and the person of ordinary skill would not have relied on it to conclude that pirenperone was short acting in humans. Meltzer 278:17-279:1, 279:15-280:3; PX 25 at 575.

The second problem with Defendants’ approach is that it looks at the rat data to the exclusion of any other references, such as the extremely relevant and important human test data.

In examining the prior art to see what it teaches a person of ordinary skill, references cannot be read in isolation. Instead, they must be read in light of what they fairly teach in combination with the prior art as a whole. Mylan and DRL cannot pick and choose among the prior art references. See, e.g., In re Merck & Co., 800 F.2d 1091,1097 (Fed.Cir.1986).

When all of the prior art available in March 1985 — and not just the rat data relied on by Defendants — is considered, it shows that pirenperone was acceptable for human use without modification. Janssen was going forward with clinical studies of pirenperone in humans using three times a day dosing. Wolff Tr. 646:14-21; PX 202; PX 96; PX 22. No suggestion was made in any of Janssen’s studies with pirenper-one in humans that its duration was inadequate. No suggestion was made that pi-renperone should be modified in any way.

This is not surprising considering, first, the fact that a drug is dosed three times a day in clinical trials does not indicate that it could not be dosed on a less frequent schedule after full testing, particularly in antianxiety drugs. Meltzer Tr. 281:9-20. Second, three times a day dosing has been shown to be perfectly acceptable for anti-psychotic drugs. Testimony from the only two expert witnesses who are medical doctors that prescribe antipsychotics, stated that haloperidol, the leading antipsychotic drug at the time, was dosed three times a day. Meltzer Tr. 281:21-24; Tamminga Tr. 50:17-20, 72:17-19; see also Wolff Tr. 648:5-11.

Defendants’ experts admitted they lacked the expertise to challenge this point. Wolff Tr. 647:16-23; McMillen Tr. 502:4-11. Dr. Wolff conceded that it was not a necessity, but only a choice, to change the dosing on a drug proven effective at three times a day. Wolff Tr. 649:17-20.

This is especially true given that compound modification is an uncertain process that can easily result in reduced efficacy or safety issues. Wolff Tr. 650:8-13, 651:4-8. By Dr. Wolff s own estimate, a compound modification results in a desirable change only five to 10 percent of the time. Wolff Tr. 651:16-24. With that level of risk and uncertainty and with three times a day dosing a medically acceptable alternative, Mylan and DRL failed to provide clear and convincing evidence that a person of ordinary skill would conclude that pirenperone had a short-duration problem that could only be solved by modifying its molecular structure.

In sum, it would not have been obvious to the person of ordinary skill in the art in 1985 that pirenperone was short-lasting and that this was a problem requiring a modification of its molecular structure.

(2) Even if Pirenperone’s Duration Was a Problem, It Would Not Have Been Obvious That Metabolism at its Ketone Group Was the Cause

As stated above, pirenperone is structurally identical to compound 11 except piren-perone has a ketone group where compound 11 has a benzisoxazole group. Wolff Tr. 547:8-548:24. Mylan and DRL claim that it would have been obvious to the person of ordinary skill in 1985 that pirenperone’s short duration was due to metabolism 13 at this ketone group.

Again, the Court disagrees. Even were the Court to assume that pirenperone had a short-duration problem, and that modifying the compound was the solution, Mylan and DRL have failed to provide clear and convincing evidence that it would have been obvious that metabolism at the ke-tone was the problem.

It was not known in 1985 that pirenper-one metabolized, let alone that it metabolized at the ketone. Abraham Tr. 386:5-10. Because there is no teaching in the prior art that pirenperone had a metabolism issue at the ketone, the person having ordinary skill who follows conventional wisdom would not assume the problem was at the ketone. See Standard Oil, 774 F.2d at 454.

If one concluded that pirenperone was short acting in humans, the problem could be due to any number of factors, such as absorption, distribution, metabolism, or excretion. Abraham Tr. 385:5-386:4. This point does not appear to be disputed. Defendants’ expert Dr. McMillan agreed that short action could be due to at least either metabolism or excretion, if not also absorption and distribution. McMillen Tr. 494:12-22.

.Green, PX 25, the principal reference upon which Defendants rely for pirenper-one’s alleged deficiencies, said nothing about the ketone in pirenperone. Abraham Tr. 384:15-22. Furthermore, it said nothing about pirenperone’s metabolism. Abraham Tr. 384:19-22. From Green, nothing at' all can be concluded about the reasons for pirenperone’s alleged short duration. Abraham Tr. 385:5-8.

If pirenperone’s alleged short duration was due to metabolism, it is undisputed that it could metabolize at numerous places. Abraham Tr. 386:11-19, 387:14-20, 388:10-13; McMillen Tr. 495:19-496:14. Of the possible positions for metabolism, no position is more likely than any other. Abraham Tr. 388:14-20.

Mylan and DRL rely on the metabolism of other compounds to attempt to demonstrate the obviousness of pirenperone’s alleged short activity. But none of the cited references provides the clear and convincing evidence Defendants need. For exam- pie, Defendants examine the metabolism of ketanserin and haloperidol to infer that pirenperone’s ketone could be reduced to an alcohol and could result in a short acting compound. But there was no reason for one of skill in the art in 1985 to make that inference. As Dr. Wolff admitted,, although the antipsychotic drug halo-peridol and the hypertensive drug ketanse-rin had ketones that metabolized to an alcohol, they were both successful commercial products. Wolff Tr. 648:5-8, 652:20-653:3.

Moreover, although ketanserin metabolizes at the ketone to an alcohol, it is then metabolized back to the ketone, which makes ketanserin very long-acting. Abraham Tr. 390:23-391:9, 446:5-25; PX 174 at 342 (“In view of these results it is likely that the terminal ketanserin half-life of 15h is related to slow ketanserin regeneration from the metabolite ketanserin-ol.”). '

Similarly, Defendants rely on the Bac-hur article, PX 26, to contend that ketones metabolize. But Bachur does not predict which ketones are reduced to alcohols. It simply states that reduction to alcohols is a possibility. Abraham Tr. 389:4-8; PX 26. More importantly, Bachur emphasizes that when reduced to alcohols, most ketone-containing compounds usually retain pharmacological activity. Abraham Tr. 389:9-12, 389:22-390:2; PX 26 at 597 (“The alcohol metabolites resulting from carbonyl [ketone] reduction of drugs usually retain pharmacological activity.”). Thus, after reading Bachur’s conclusion that, if metabolized, drugs having ketones retain pharmacological activity, and considering the numerous successful drugs a person of ordinary skill in the art would be aware of that had ketones, that person would not conclude that pirenperone’s ketone was necessarily a part of the molecule that needed to be removed or modified.

' Taken as a whole, none of the cited references would convince the person of ordinary skill in the art that metabolism at the ketone was causing pirenperone to be short acting. For this reason as well, Mylan and DRL have failed to make out a clear and convincing case of obviousness.

d. Defendants’ Solution to Pirenper-one’s Alleged Duration Problem Would Not Have Been Obvious to the Person of Ordinary Skill in the Art in 1985

A further flaw in Mylan and DRL’s obviousness case is their proposed solution to pirenperone’s alleged short-acting problem. If one of ordinary skill in the art wished to eliminate pirenperone’s ketone to create a new, long-acting compound, that person would not have changed the ketone to a benzisoxazole.

(1) A Sustained Release Formulation Would Have Been a More Obvious Solution

If there was a known problem with pi-renperone’s duration, one of ordinary skill in 1985 would have avoided modifying its chemical structure, because such modifications are risky and uncertain. It is undisputed that they can result in loss of efficacy or introduce safety issues. Wolff Tr. 650:8-13.

According to Defendants’ expert Dr. Wolff, only three or four out of hundreds of modifications lead to a commercial product. Wolff Tr. 651:1-8. Dr. Wolff later described a reasonable expectation of success that a modification would result in a commercial product as on the order of five to 10 percent. Wolff Tr. 651:9-24. Even using Dr. Wolff s estimate, the expectation of success from structural modification was unreasonably low in 1985. 14

Given these low odds, it is far more reasonable to expect the person of ordinary skill to pursue one of a number of other safer solutions then available to develop a longer-acting compound. These other solutions included controlled (or extended) release. Abraham Tr. 392:9-23; Wolff Tr. 649:8-16; Meltzer Tr. 282:10-12. By making a controlled or extended release formulation, one would use the same compound, thus avoiding the uncertain risk associated with compound modification.

A number of technologies existed in March 1985 for making controlled or extended release products: persons of ordinary skill in the art could develop a depot (long lasting) injection, a controlled release capsule (such as Contac) or a transdermal patch. Abraham Tr. 392:11-23; Wolff Tr. 649: 8-16; Meltzer Tr. 282:10-12.

Defendants do not dispute the availability of these other solutions. Moreover, Defendants offered no testimony to explain why one of ordinary skill in the art would not pursue these solutions, instead of modifying pirenperone.

(2) It Would Not Have Been Obvious to Replace the Ketone With a Ben-zisoxazole

If the person of ordinary skill in the art wanted to modify pirenperone, he or she would have looked to the most common methods of altering a molecule: classical isosteric replacements.

Classical isosteric replacement follows Grimm’s hydride displacement law. Abraham Tr. 370:12-371:2. Standard isosteric replacements for ketones were available and well-known in and prior to 1985. Abraham Tr. 372:2-6, 372:15-24, 394:20-395:18; Wolff Tr. 658:2-6. These standard replacements, when applied to pirenper-one, would have resulted in changes well-recognized in the prior art, Strupczewski Dep. (11/16/2004) Tr. 155:8-24, and in standard textbooks, PX 141 at 75, PX 158 at 3151.

One of ordinary skill in the art would choose one of these standard replacements, not the replacement of a ketone with benzisoxazole. Abraham Tr. 395:24-396:11. Defendants’ experts provided no testimony — let alone clear and convincing evidence — why these standard replacements would not be pursued first.

Alternatively, one could make “non-classical bioisosteric” replacements. Abraham Tr. 369:7-24. A bioisosteric replacement is a change that is believed to act with the same biological system. Such changes are much riskier than classical isosteric replacements. There is no guarantee that the changed compound will have the same activity as the original compound. Rather, the changed chemical compound could have the same activity, the opposite activity, or no activity at all. Abraham Tr. 369:25-370:10; PX 141 at 73.

There are numerous problems with bioi-sosteric replacement as an approach to drug modification. First, there was no reasonable expectation in 1985 that bioi-sosteric replacement would work. Abraham Tr. 374:3-8.

Second, there was no reasonable expectation in 1985 that bioisosteres would bind to the same receptor. Abraham Tr. 374:10-13.

Third, for bioisosteric replacements there are different degrees of binding even to the same receptor. Abraham Tr. 375:14-17. Or activity on the same receptor can be opposite after a bioisosteric change, such that one chemical compound is an agonist and a compound that is a bioisostere is an antagonist. Abraham Tr. 377:9-19.

Fourth, bioisosteric replacement can also cause issues with absorption, distribution, metabolism, and excretion (“ADME”). Abraham Tr. 377:20-379:6; 379:11-14. These ADME issues can come into play as soon as the drug is given, while the drug is on the receptor, or after it is on the receptor. Abraham Tr. 379:20-25.

Fifth, bioisosteric replacement can cause different results in different animals. Abraham Tr. 380:2-5.

Sixth, even knowing the three-dimensional structure of receptors, one cannot predict which bioisosteres will be active. Abraham Tr. 381:11-14.

Defendants’ experts did not offer evidence that contradicted Professor Abraham’s testimony on these problems that generally occur with bioisosteric replacement.

Notwithstanding these problems, there were in 1985 a few known and recognized bioisosteric replacements. Abraham Tr. 394:20-396:11, 425:10-426:7. Defendants ignore these recognized replacements and insist that it was obvious to use an unrecognized non-classical bioisosteric replacement, one that just happens to be the only replacement that modifies pirenperone to arrive at Defendants’ desired result, compound 11. Such a decision is not based on the science; it is the result of inappropriate hindsight.

Defendants propose replacing the ke-tone with a benzisoxazole, a modification that requires that two extra atoms be added, and that a new ring be formed, to transform pirenperone into compound 11. Abraham Tr. 429:13-22.

As of March 1985, this substitution was not recognized in the art. Abraham Tr. 396:12-17. As of 1985, the benzisoxazole-for-ketone swap appeared in no standard reference as a bioisosteric replacement. Wolff Tr. 659:16-23, 661:8-12.

Instead of looking in standard texts, My-lan and DRL rely on inferences from publications that say nothing about bioisosteric replacement, most of which do not even involve antipsychotics. None of the cited literature describes benzisoxazole as a bioi-sosteric replacement for a ketone. Instead, Defendants merely infer it. Wolff Tr. 664:1 — 4, 667:9-16.

In fact, a person of ordinary skill would consider none of the cited references because (1) they do not discuss bioisosteric replacements, (2) they do not address the problem Defendants identify of making a compound longer-lasting, and/or (3) they are from the wrong field.

Defendants principally rely on the Strupczewski work at Aventis (then Hoechst-Roussel Pharmaceuticals). This work included an abstract, PX 191, and the '811 patent, PX 81. These references simply reported Hoechst’s work on antipsy-chotic compounds. There is not a word in these references about modifying the structures disclosed in them. Wolff Tr. 662:9-11, 663:9-15, 16-25; Abraham Tr. 398:1-15; PX 191; PX 81.

The other references cited by Defendants, the Saunders article, PX 195, and Shutske article, PX 192, are even less relevant. Those articles do not relate to anti-psychotics. Abraham Tr. 396:21-25; Wolff Tr. 665:2-7. Instead, Shutske, PX 192, is about diuretics and Saunders, PX 195, concerns anti-inflammatory agents. Janssen argues that Saunders and Shutske are non-analogous references and thus, are not relevant. See e.g., Litton Sys., Inc. v. Honeywell, Inc., 87 F.3d 1559, 1568 (Fed. Cir.1996).

The Court need not decide this question because even assuming these articles are analogous prior art, they still would not direct the person having ordinary skill in the art to make the change Mylan and DRL propose. As with the Strupczewski work, Saunders and Shutske, PX 195 and PX 192, contain no discussion on bioisos-terism. Abraham Tr. 397:15-25; Wolff Tr. 664:21-23. Nor do they talk about benzi-soxazoles being a bioisosteric replacement for a ketone. Wolff Tr. 664:24-665:1.

As stated earlier, when a chemical compound is at issue, “a prima facie case of obviousness requires ‘structural similarity between claimed and prior art subject matter ... where the prior art gives reason or motivation to make the claimed compositions.’ ” Yamanouchi, 231 F.3d at 1343 (quoting Dillon, 919 F.2d at 692). Mylan and DRL have failed to demonstrate that the prior art would have motivated the person of ordinary skill in the art in 1985, with no knowledge of the '663 patent, to (1) choose pirenperone as his or her lead compound, (2) determine that pirenperone was deficient due to its alleged short duration, (3) determine that this problem was due to metabolism of a ketone, and (4) determine that this problem could be solved by replacing the ketone with a ben-zisoxisole with any kind of reasonable expectation of success. Accordingly, Defendants have failed to present a prima facie case of obviousness.

4. Secondary Considerations: Objective Evidence of Nonobviousness

An obviousness analysis requires a Court to also examine objective evidence of nonobviousness in the record. Graham, 383 U.S. at 17-18, 86 S.Ct. 684; Ruiz v. A.B. Chance Co., 234 F.3d 654, 667 (Fed. Cir.2000). Such objective evidence includes, inter alia, commercial success, long felt, but unsolved need, the failure of others, copying, and unexpected results. Graham, 383 U.S. at 17-18, 86 S.Ct. 684; Ruiz, 234 F.3d at 662-63, 667.

Defendants insist that there is no need for them to refute the secondary considerations with respect to risperidone. Rather, Defendants insist that they can focus their obviousness case solely on compound 11.

This is legally incorrect. The fact that risperidone was chosen for further commercialization while compound 11 was left as a back-up drug does not mean that evidence regarding risperidone’s commercial success is irrelevant. It is entirely appropriate, as the Federal Circuit has held, for the patent owner to point to secondary considerations with respect to any commercial embodiment of the claim. Applied Materials, Inc. v. Advanced Semiconductor Materials Am., Inc., 98 F.3d 1563, 1570 (Fed.Cir.1996); see also See Jackson Jordan, Inc. v. Plasser Am. Corp., 747 F.2d 1567, 1578 (Fed.Cir.1984) (“The claims [of a patent], not particular embodiments, must be the focus of the obviousness inquiry.”).

Both parties agree that the commercial embodiment of the '663 patent, Risperdal, is risperidone and is encompassed by each and every claim of the '663 patent in addition to compound 11. SF 17. Thus, secondary considerations with respect to ris-peridone are relevant here.

Objective evidence of nonobviousness “may often be the most probative and cogent evidence in the record.” Stratoflex Inc. v. Aeroquip Corp., 713 F.2d 1530, 1538 (Fed.Cir.1983). Indeed, secondary considerations “may be sufficient to overcome a prima facie case of obviousness.” In re Beattie, 974 F.2d 1309, 1313 (Fed.Cir. 1992). Of course, here, Mylan and DRL have failed to make out a prima facie case. Nevertheless, the Court will examine the secondary considerations, as it must.

a. Commercial Success

Commercial success of an invention is evidence that it would not have been obvious. Demaco Corp. v. F. Von Langsdorff Licensing Ltd., 851 F.2d 1387, 1391-92 (Fed.Cir.1988). Risperidone, sold as Ris-perdal, is an incredible commercial success. Sales have increased every year since it was first sold in 1994, and it experienced double digit growth in most years. PX414; PX730; Vergis Tr. 77:6-10.

Within three years it became the most prescribed antipsychotic, quickly overtaking clozapine (sold as Clozaril) and halo-peridol (sold as Haldol). PX 744; Vergis Tr. 78:17-79:9.

Today, a decade after launch, it is still the second most prescribed antipsychotic. PX 417; PX 673; Vergis Tr. 79:18-80:10; Tamminga Tr. 55:19-56:5; Meltzer Tr. 283:4-22.

Risperdal has been used to treat at least five million people. Meltzer Tr. 283:4-22. Last year, Risperdal was Johnson & Johnson’s largest product, accounting for just under $3 billion in worldwide sales. Ver-gis Tr. 78:9-16.

b. Long Felt, But Unsolved Need

Evidence of a long-felt but unsolved need in the industry for the solution offered by the patented invention supports a finding that the invention would not have been obvious at the time the invention was made. Monarch Knitting Machinery Corp. v. Sulzer Morat GmbH, 139 F.3d 877, 884 (Fed.Cir.1998). “[L]ong-felt need is analyzed as of the date of an articulated identified problem and evidence of efforts to solve that problem.” Texas Instruments Inc. v. ITC, 988 F.2d 1165, 1178 (Fed.Cir.1993).

In this case it is undisputed that there was a long-felt but unsolved need for a safe, atypical antipsychotic that did not cause EPS or TD from at least the 1960s until 1985 and beyond. Tamminga Tr. 49:19-50:16, 51:1-52:5; Meltzer Tr. 283:4-22; Wolff Tr. 648:18-20.

The invention and eventual approval of Risperdal solved this long felt, but unfilled need. Risperidone was the first compound available to physicians for general use that safely combined the efficacy of a typical antipsychotic with reduced EPS. Its development “has been very exciting to the medical field.” Tamminga Tr. 52:25-53:13, 53:23-54:2; Meltzer Tr. 253:17-20, 254:14-255:9.

c.Failure of Others

Evidence of failed attempts by others supports a finding that the patented invention would not have been obvious. Advanced Display Sys., Inc. v. Kent State Univ., 212 F.3d 1272, 1285 (Fed.Cir.2000).

From the discovery of clozapine in the late 1960’s through 1985, the scientific community was unsuccessful in developing an antipsychotic with reduced EPS for general use. Meltzer Tr. 253:13-16. During that time period, many pharmaceutical companies made such attempts. For example, Dr. McMillen worked with Bristol-Myers to develop an atypical antipsychotic. McMillen Tr. 504:12-25. Yet no approved drug resulted from those years of research.

Many pharmaceutical companies identified promising atypicals, such as fluperla-pine, remoxipride, and serotonyl, that all failed to result in an approved drug — until risperidone. Meltzer Tr. 282:22-283:3.

Most telling is the work of Hoechsb-Roussel. Beginning in the 1970s, Hoechst-Roussel had a program to develop improved antipsychotic drugs with reduced EPS. Strupezewski Dep. (11/16/2004) Tr. 101:2-21, 151:2-12, 198:4-199:16.

As part of this program, Hoechst-Rous-sel developed compounds relied on by Defendants — the Strupezewski '811 patent, PX 81, and abstract, PX 191. Strupezew-ski Dep. (11/16/2004) Tr. 151:14-152:15, 105:12-23, PX 81, PX 191.

One of the Hoechst-Roussel compounds that Defendants rely on is HRP913. Hoechst-Roussel filed an Investigational New Drug Application (“IND”) with the FDA to conduct clinical trials on HRP-913, but those trials were a failure. Strup-ezewski Dep. (11/16/2004) Tr. 213:8-24, 188:16-21. HRP-913 caused marked adverse side effects in healthy volunteers on whom it was tested and had little useful therapeutic effect. Strupezewski Dep. (11/16/2004) Tr. 217:24-218:22; Strupezew-ski Dep. (11/17/2004) Tr. 27:8-18, 28:11-30:2. As a result, Hoechst-Roussel discontinued its development. Strupezewski Dep. (11/17/2004) Tr. 11:10-16, 21:2-13; Meltzer Tr. 252:22-253:12.

Similarly, in the early 1980s, Hoechst-Roussel developed a chemical compound it called HR 592. Strupezewski Dep. (11/17/2004) Tr. 39:11-23. HoechsNRous-sel believed that HR 592 would have useful antipsychotic properties and the company submitted an IND to investigate HR 592 in humans. Strupezewski Dep. (11/17/2004) Tr. 42:2-21, 47:13-48:10, 50:21-51:11. But, as with HRP-913, HR 592 was not effective against schizophrenia in patients. To the contrary, it exacerbated patients’ symptoms, and one patient even committed suicide when administered HR 592. Strupezewski Dep. (11/17/2004) Tr. 61:10-18. 69:24-70:8. As a result, Hoechst-Roussel discontinued development of HR 592. Strupezewski Dep. (11/17/2004) Tr. 73:2-74:7.

To this day, Hoechst-Roussel (now Aventis) has never succeeded in bringing an antipsychotic drug to market. Strup-ezewski Dep. (11/16/2004) Tr. 108:9-15.

The evidence establishes that there was a failure of others to develop a safe, atypical antipsychotic prior to the time Janssen filed its risperidone patent application.

d. Copying

Copying the patented invention is also evidence that the invention would not have been obvious. Dow Chem. Co. v. American Cyanamid Co., 816 F.2d 617, 622 (Fed.Cir.1987).

Janssen received certification letters from ten different generic manufacturers that they filed ANDAs with the FDA in order to market generic risperidone products. Vergis Tr. 82:2-15; Meltzer Tr. 283:4-22. There has been undisputed copying of risperidone, a compound covered by the claims of the '663 patent.

e. Respect by the Industry

Respect of the industry for the validity of the patent is also evidence of nonobvi-ousness. E.g., WMS Gaming, Inc. v. Int’l. Game Tech., 184 F.3d 1339, 1359 (Fed.Cir. 1999) (“Objective evidence of nonobviousness may include ... licenses showing industry respect.”).

Of the ten companies that have sought permission from the FDA to market a generic risperidone product, six have respected the validity of the '663 patent and have not asked for permission to sell their products before the expiration of the patent. Vergis Tr. 82:9-13; PX 75, PX 76, PX 77, PX 78, PX 85; PX 396.

f. Acclaim

Appreciation of the invention is further evidence that the invention would not have been obvious. E.g., Vulcan Eng’g Co. v. Fata Aluminium, Inc., 278 F.3d 1366, 1373 (Fed.Cir.2002); In re Piasecki, 745 F.2d 1468, 1473-74 (Fed.Cir.1984).

Risperdal and its active ingredient ris-peridone have received numerous awards from the industry. Vergis Tr. 81:2-4. In 1995, Risperdal received the Prix Galien awards in Canada and France. Vergis Tr. 81:5-18. In 1996, Risperdal received the International Prix Galien. The International Prix Galien is the pharmaceutical industry’s equivalent to the Nobel Prize. Vergis Tr. 81:5-18; Meltzer Tr. 283:4-22.

And in 2005, Kennis, one of the inventors of the '663 patent, was named a Hero of Chemistry by the American Chemical Society. The Heroes of Chemistry program recognizes “the vital role of industrial chemical scientists and their companies in improving human welfare through successful commercial innovations and products.” Kennis received this award “for the development of Risperidal [sic], a standard in the treatment of psychosis, revolutionizing antipsychotic treatments.” PX 309; Vergis Tr. 81:5-82:1.

Additionally, Risperdal has had a tremendous effect on the patients who have taken it, and their families. Risperdal gets schizophrenic patients back into the work place and allows them to reintegrate themselves into their families and society. Ken Steele authored a memoir, The Day the Voices Stopped, PX 68, in which he describes his struggle with schizophrenia and the dramatic impact Risperdal had on his life. Vergis Tr. 84:22-85:24; Tammin-ga Tr. 54:6-55:18. See also PX 67 at 381.

g. Unexpected Results

The final relevant secondary consideration is unexpected results. Unexpected superior properties of an invention support the conclusion that the invention was not obvious to one of ordinary skill in the art. Knoll Pharm. Co. v. Teva Pharms. USA, Inc., 367 F.3d 1381, 1385 (Fed.Cir.2004). In making this determination, the Court should look at the evidence from both before and after the patent application was filed. Id.

Risperidone was the first antipsychotic drug available for general use whose anti-psychotic activity was equivalent to a typical antipsychotic but that did not cause significant EPS. Meltzer Tr. 253:17-254:9.

Risperidone had a number of unexpected benefits: (1) cognitive improvements, (2) improvement in negative symptoms, (3) reduction in tardive dyskinesia and (4) less metabolic side effects. Typical antipsy-chotic drugs either did not improve the cognition of schizophrenic patients or they made it worse. They also did not improve the negative symptoms of schizophrenia (social withdrawal, lack of motivation). By contrast, risperidone improved the cognition of schizophrenic patients. It also showed modest improvement of negative symptoms and did not have the disabling sedation of typical antipsychotic drugs. In addition, risperidone reduced both the frequency of tardive dyskinesia and its symptoms. Also, after subsequent atypical anti-psychotic drugs were developed, it was discovered that they cause weight gain and increase the risk of diabetes and cardiovascular disease. Risperidone, by contrast, produces minimal side effects of this kind. Meltzer Tr. 254:14-255:9; PX 46; PX 50; PX 51; PX 54.

5. Defendants Have Failed to Prove Obviousness of the '663 Patent

In sum, Mylan and DRL have failed to demonstrate that the prior art gave reason or motivation to one of ordinary skill in the art to create the claimed compositions. In addition, the secondary considerations overwhelmingly demonstrate the nonobvi-ousness of the '663 patent. Mylan and DRL have therefore failed to meet their burden of proving by clear and convincing evidence that the '663 patent is obvious under 35 U.S.C. § 103(a).

IV. Inequitable Conduct

“Patent applicants and those substantively involved in the preparation or prosecution of a patent application owe a ‘duty of candor and good faith’ to the PTO.” M. Eagles Tool Warehouse, Inc. v. Fisher Tooling Co., 439 F.3d 1335, 1339 (Fed.Cir.2006) (quoting 37 C.F.R. § 1.56(a) (2004)). Breaching this duty can constitute “inequitable conduct,” which renders the patent unenforceable. Id. at 1340.

There are three steps in the inequitable conduct analysis. See Floffmann-La Roche, Inc. v. Promega Corp., 323 F.3d 1354, 1359 (Fed.Cir.2003). First, there must have been a “misrepresentation or omission of a material fact.” Id. Second, the misrepresentation or omission must have been made “with an intent to deceive the PTO.” Id. Materiality and intent to deceive must be shown by clear and convincing evidence. Id. Third, assuming the first two requirements have been met, “the district court must determine whether the equities warrant a conclusion that the pat-entee has engaged in inequitable conduct.” Id. (citing Molins PLC v. Textron, Inc., 48 F.3d 1172, 1178 (Fed.Cir.1995)). 15

Mylan 16 argues that Janssen withheld material information concerning the dopamine antagonism of pirenperone from the PTO during its prosecution of the '663 patent, and that it did so intentionally. Mylan’s arguments focus on the representations made by Janssen patent attorney Geoffrey Dellenbaugh, who prosecuted the '663 patent, CEO Paul Janssen, and scientist Dr. Frans Awouters.

A. Materiality

Under the regulations in place during prosecution of the '663 patent, “information is material where there is a substantial likelihood that a reasonable patent examiner would consider it important in deciding whether to allow the application to issue as a patent.” 37 C.F.R. § 1.56(a) (1984). This is often referred to as “the Rule 56 standard.” Dayco Prods., Inc. v. Total Containment, Inc., 329 F.3d 1358, 1363-64 (Fed.Cir.2003); Digital Control, Inc. v. Charles Mach. Works, 437 F.3d 1309, 1313-19 (Fed.Cir.2006).

Materiality does not require that any withheld information, if it had been provided, would have resulted in a rejection of the patent claims by the patent examiner. On the contrary, information can be “material” even if a patent examiner would find the claimed invention to be patentable after considering such information. See Digital Control Inc. v. Charles Machine Works, 437 F.3d 1309, 1313-19 (Fed.Cir.2006).

Mylan claims that prior art regarding the dopamine antagonism of piren-perone was material information that Jans-sen failed to disclose to the PTO during the '663 patent prosecution. While the '870 patent for pirenperone was disclosed to the PTO, it only discloses pirenperone’s activity as a serotonin antagonist. PX 80, Dellenbaugh Tr. 138:9-19. Specifically, Mylan points to seven prior art papers, three of which were co-authored by Dr. Janssen, and one which was co-authored by Dr. Awouters. These papers allegedly disclose pirenperone’s effectiveness as a dopamine antagonist. DX 86, 89, 112, 120. Among these references are the results of Janssen’s clinical trials of pirenperone performed in humans. DX 116,102.

Mylan’s assertion that pirenperone’s dopamine antagonism was material rests on communications between Janssen and the PTO during the '663 patent’s prosecution. The PTO initially rejected the claims of the application as obvious over U.S. Patent No. 4,335,127 (“the '127 patent” or “the Vandenberk patent”), PX 223, which disclosed a Janssen compound called ketanse-rin, in view of U.S. Patent No. 4,352,811 (“the '811 patent” or “the Strupczewski patent”), a patent owned by Hoechsfc-Roussel, PX 81. PX 2 at 113; Dellen-baugh Tr. 129:15-20. The examiner claimed that it would have been obvious to combine the two in order to produce a compound within the claims of the pending application. Dellenbaugh Tr. 163:9-19, DX 173. Dellenbaugh, on behalf of Jans-sen, replied that a motivation to combine would not exist with respect to the Van-denberk patent because the compounds claimed therein did not possess antipsy-chotic activity. Dellenbaugh Tr. 165:21-25; DX 176, at 4-5. Dellenbaugh claimed that this was so, in part, because ketanse-rin “does not antagonize apomorphine[ 17 ] — induced agitation in rats ... as do the compounds claimed” in the application that would eventually become the '663 patent. DX 176, at 5-6; see also DX 178, at 1.

Additionally, Janssen submitted a declaration by Dr. Awouters comparing ke-tanserin’s apomorphine test results with those of risperidone. DX 178. Janssen’s submissions apparently satisfied the PTO, as it passed its application to issue, resulting in the '663 patent. PX 2. Mylan claims this interaction demonstrates the materiality of dopamine antagonism.

It is clear however, that the material issue for the examiner in the above correspondence was antipsychotic activity, not dopamine antagonism per se. The PTO’s initial rejection of Janssen’s application rested on its belief that the compounds of the '127 and '811 patents had antipsychotic activity: “Since the compounds of both the above references have ‘antipsychotic’ activity it would not be unreasonable to expect the product to also possess ‘antipsychotic’ activity.” PX 2 at 114; Dellenbaugh Tr. 129:21-130:8. The PTO made no mention of pirenperone or dopamine antagonism. Dellenbaugh Tr. 130:9-11.

Dellenbaugh’s response focused on Jans-sen’s belief that the compounds in the '127 patent were not antipsychotics, PX 2 at 123-24, and submitted the data contained in the Awouters declaration to corroborate this claim. PX 2 at 187; see also PX 2 at 195-197.

While it is tree that this data relied on ketanserin’s lack of dopamine antagonism to support this conclusion, dopamine antagonism with regard to pirenperone was not similarly relevant because pirenperone is demonstrably not an antipsychotic in humans.

As the examiner knew from the piren-perone patent itself, pirenperone was not claimed to be an antipsychotic compound. PX 80.

Defendants rely solely on the fact that pirenperone is a dopamine antagonist for their argument that pirenperone is an anti-psychotic. But, as Dr. Meltzer testified, being a dopamine antagonist does not mean that a compound will be an antipsy-chotic. Instead, there are many reasons why a compound could act as a dopamine antagonist and not be an antipsychotic. Meltzer Tr. 275:25-276:17. It is for that reason that companies such as Janssen developed, used, and published additional tests to determine whether a compound would be an antipsychotic. Meltzer Tr. 271:18-272:19.

Janssen tested pirenperone with these additional tests. The studies and their published results demonstrated that piren-perone, in contrast to setoperone, was not effective as an antipsychotic. Meltzer Tr. 271:18-272:19, 273:12-275:5; McMillen Tr. 509:16-510:22; PX 94/DX 141; PX 388; PX 389.

Pirenperone had failed two standard tests for antipsychotics, it was being studied in humans for anti-anxiety, not as an antipsychotic, and it was reported in the literature not to be an antipsychotic. Wolff Tr. 638:23-639:5, 641:6-8, 641:18-20; McMillen Tr. 511:8-10; Meltzer Tr. 269:5-8; PX 22; PX 94; PX 96; PX 202; PX 388; PX 389.

Far from supporting any theory of obviousness, disclosure of more information about pirenperone would only have further demonstrated its lack of materiality. The additional pirenperone information teaches away from the invention, not towards it. Halliburton, 925 F.2d at 1441 (finding information in reference that taught away from the invention non-material).

Mylan has failed to present clear and convincing evidence that prior art regarding pirenperone’s dopamine antagonism was material.

B. Intent to Deceive

Even if there were a material omission, there is no clear and convincing evidence that anyone acted with an intent to deceive the PTO. Without an intent to deceive, there can be no inequitable conduct. Kingsdown Med. Consultants, Ltd. v. Hollister, Inc., 863 F.2d 867, 872 (Fed.Cir. 1988). Even grossly negligent failures to disclose material information are not sufficient to render an otherwise valid patent unenforceable. Id. at 876.

In ascertaining intent, the court must consider the totality of the circumstances. Id. This includes any evidence of good faith, which militates against a finding of intent to deceive. Id.

“Intent need not, and rarely can, be proven by direct evidence.” See Merck & Co., Inc. v. Danbury Pharmacal, Inc., 873 F.2d 1418, 1422 (Fed.Cir.1989). Instead, an intent to deceive may be inferred from a failure to credibly explain a “knowing failure to disclose material information.” Bruno Indep. Living Aids, Inc. v. Acorn Mobility Sens., Ltd., 394 F.3d 1348, 1354 (Fed.Cir.2005) (emphasis added).

1. Dr. Paul Janssen

With respect to patents in which he was not an inventor — such as the '663 patent— Dr. Janssen’s role was simply to request the Janssen patent department to begin preparing applications when the scientific research had reached the appropriate point. Dellenbaugh Tr. 106:1-7. He was not involved in the prosecution of patents filed on behalf of Janssen in the United States. Dellenbaugh Tr. 105:22-25, 106:8-11.

Nor is there any reason to believe that Dr. Janssen ever reviewed the application for the '663 patent, the prosecution history or the references that were disclosed to the Patent Office. Those activities fell outside the scope of Dr. Janssen’s responsibilities and his normal practices at the time. Dellenbaugh Tr. 106:12-22.

Because Dr. Janssen was not substantively involved in the prosecution of the '663 patent, he had no disclosure obligations imposed on him by the United States Patent Office and could not have committed inequitable conduct. 37 C.F.R. § 1.56(a) (1985) (only inventors, prosecuting attorneys, or people substantively involved in the prosecution owe a duty of candor to the PTO). 18

2. Dr. Frans Awouters

Second, Mylan accuses Dr. Awouters, 19 who, as mentioned above, submitted a declaration to the PTO regarding the characteristics of the compound ketanserin. PX 2 at 195-197.

Mylan faults Dr. Awouters for not volunteering information about pirenperone. Under the circumstances-a rejection concerning ketanserin-there was no need whatsoever for him to do so. Dellenbaugh Tr. 136:19-23. There is no proof — let alone clear and convincing proof — that Dr. Awouters knew anything about the prosecution of the '663 patent other than the submission of his declaration. In particular, there is no proof that he ever saw the prosecution history (other than the '517 application itself, PX 2 at 4-28, which later published as the '663 patent) or the references that were cited, or knew whether information about pirenperone was, or was not, either submitted or material. Dellen-baugh Tr. 135:9-136:7. All his declaration states is that he had read “the specification and claims of U.S. patent Application Serial No. 826,517 and fully understood] the contents thereof.” PX 2 at 176.

The undisputed evidence shows that in the normal course, Dr. Awouters would have not been shown any other information. When a declaration was needed from a non-inventor to support a technical point, it was the normal practice of Dellenbaugh and the Janssen patent department simply to explain to the declarant the objection raised by the PTO and to ask whether there was any evidence that would help to disprove it. Dellenbaugh Tr. 133:17-134:7. There was no reason to show the scientist all of the unrelated communications with the PTO or the prior art that had been submitted during prosecution. There was certainly no reason to discuss with the declarant a reference the examiner had not relied upon. Dellenbaugh Tr. 134:8-135:8.

The only obligation that Dr. Awouters assumed was to submit a truthful declaration. 37 C.F.R. 1.56(a) (1985) (the duty to the PTO is “commensurate with the degree of involvement in the preparation or prosecution of the application”). This he did, swearing to its truthfulness, and the accuracy of his declaration is unchallenged. PX 2 at 197. There is no evidence — let alone clear and convincing evidence — that Dr. Awouters ever was in a position to assess whether pirenperone data was even relevant to the prosecution of the patent, let alone that he formed an intent to deceive the PTO about such information. Without such knowledge, Dr. Awouters could not form an intent to deceive the PTO.

3. Geoffrey Dellenbaugh

Finally, Mylan accuses Dellenbaugh of harboring an intent to deceive. Dellen-baugh testified that he relied on Janssen counsel in Europe to prepare the application and that he had no reason to doubt the veracity or completeness of any statement contained therein. Dellenbaugh Tr. 107:16-108:2, 108:18-21, 117:12-118:11.

There is no evidence that he knew that pirenperone was a dopamine antagonist. 20

“[T]here can not have been culpable intent in withholding information that the inventor did not have.” Hebert v. Lisle Corp., 99 F.3d 1109, 1115-16 (Fed.Cir. 1996) (quoting Thermar-Tru Corp. v. Peachtree Doors, Inc., 44 F.3d 988, 996 (Fed.Cir.1995)).

While there is no evidence of an intent to deceive, there is affirmative evidence of Dellenbaugh’s good faith. Kingsdown, 863 F.2d at 876 (evidence of good faith must be considered). Most notably, Dellenbaugh cited the examiner to the setoperone patent — the closest prior art. During the prosecution of the '663 patent, Mr. Dellen-baugh expressly disclosed the '451 patent, which describes setoperone and includes both its dopamine and serotonin antagonism. He discussed the setoperone '451 patent in the '663 patent as well. PX 1 at 8:20-29. If Dellenbaugh or other Janssen employees were seeking to conceal from the PTO that prior art Janssen patents described antipsychotic compounds with dopamine and serotonin antagonism, the setoperone patent would never have been disclosed. Yet the setoperone patent was disclosed and it prompted no comments from the PTO.

C. Balancing

Had Mylan proved both materiality and intent, the Court would then balance the degree of materiality and degree of intent to make an equitable judgment as to whether the conduct was so culpable that the patent should be barred from enforcement. See Life Techs., 224 F.3d at 1324. Mylan, however, has failed to carry its burden. Thus, the '663 patent is not unenforceable for inequitable conduct.

V. Conclusion

For the foregoing reasons, the Court finds that Mylan and DRL have failed to prove by clear and convincing evidence that the '663 patent is obvious or that Janssen engaged in inequitable conduct. Thus, the '663 patent is neither invalid nor unenforceable, and as a result, Mylan and DRL have infringed that patent under 35 U.S.C. § 271(e)(2).

1 . This opinion shall constitute the Court's findings of fact and conclusions of law pursuant to Federal Rule of Civil Procedure 52(a).

2 . In the '663 patent, the chemical name for Risperidone is 3-[2-[4-(6-fluoro-l,2-benzi-soxazol-3-yl)- 1-piperidinyl] ethyl]-6,7,8,9tetrahydro-2-methyl-4H-pyrido[l,2-a]-pyri-midin-4-one; the chemical name for Compound 11 is 3-[2-[4-(6-fluoro-l,2-benzisoxa-zol-3-yl)-l-piperidinyl] ethyl]-2-methyl-4Hpyrido[l, 2-a]pyrimidin-4-one. Defs.’ Ex. ("DX”) 1.

3 . DRL twice amended its ANDA to include different doses and variations of a generic risperidone.

4 . Upon receiving notice of an applicant's paragraph IV certification, 35 U.S.C. § 271(e)(2) permits the patent holder to immediately bring an action in a U.S. District Court for a determination that the application infringes the patent. See, e.g., SmithKline Beecham Corp. v. Apotex Corp., 439 F.3d 1312, 1314 (Fed.Cir.2006).

5 . Graham v. John Deere Co., 383 U.S. 1, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966).

6 . The Court assures the reader that this is the only pun to be found in this lengthy opinion.

7 . The Court stresses however, that its ultimate ruling — that the '663 patent is nonobvious and therefore not invalid — is not contingent upon this finding. Indeed, the Court would find the '663 patent nonobvious even were it to hold that the person of ordinary skill in the art possessed a doctorate degree. As stated above, the parties have not presented any evidence that particular pieces of prior art would have been viewed any differently if the person evaluating it had a bachelor's, master’s or doctorate.

8 . A short biochemistry lesson, provided by the parties, is in order. Dopamine and serotonin are hormones that, when found in the brain, act as neurotransmitters. A neurotransmitter is a chemical that permits the billions of nerve endings in the brain to communicate with each other. In turn, this communication enables a human being to function.

Each nerve ending in the brain contains dozens of different "receptors.” Neurotransmitters attach to the receptors and cause a chemical reaction. However, in the same way that only certain keys will open certain locks, only certain neurotransmitters will attach to certain receptors. For example, there are receptors that will only allow dopamine (and similar chemicals) to attach, and receptors that will only allow serotonin to attach. Receptors are categorized by what neurotransmitter can attach to it, and within these categories, there are further subcategories. For example, there are five types of dopamine receptors.

Pharmaceutical companies can create drugs that mimic the actions of neurotransmitters. These drugs attach to receptors and behave like a particular neurotransmitter. Such drugs are called "agonists.” For example, a drug that mimics the functioning of dopamine is called a "dopamine agonist.”

Conversely, drugs can be created that block the actions of neurotransmitters. These drugs attach to particular receptors and prevent neurotransmitters from attaching. Such drugs are called "antagonists.” For example, a drug that blocks the functioning of dopamine is called a "dopamine antagonist.” Meltzer Tr. 227:20-232:24; PL’s FF & CL, at app. A.

9 . Mylan and DRL dispute that Yamanouehi 'mandates’ the identification of 9 a lead compound as a predicate to an obviousness analysis,” and suggest that they need not demonstrate why one of ordinary skill in the art in 1985 would start with pirenperone. Defs.' Findings of Fact and Conclusions of Law ("FF & CL”) 61-62. The Court disagrees. The Federal Circuit’s statement in Yamanouehi that "[a]t the outset, [the Defen dant] did not show the required motivation for selecting example 44 as a lead compound,” 231 F.3d at 1345, was not the creation of a new legal requirement, but merely a factually-specific application of the ''motivation-suggestion-teaching” test. As explained earlier, in cases involving chemical compounds, the party alleging the obviousness of the patent must demonstrate that " 'the prior art gives reason or motivation to make the claimed compositions.' ” Id. at 1343 (quoting In re Dillon, 919 F.2d at 692). The Yamanou-chi Court faulted the Defendant there for failing to show motivation for selecting example 44 as a lead compound because it was the Defendant's own allegation that "one of skill in the art would have considered it obvious to select the example 44 compound from [a pri- or art patent] and [a compound from another prior art patent] to use as leads for making [a compound in the disputed patent].” Id. at 1343-44. Similarly here, it is Mylan and DHL which allege that one of ordináry skill in the art in 1985 would have started with piren-perone, see, e.g., Defs.’ FF & CL, p. 34; Defs. Post-Trial Br. 6-7, and that is precisely why this Court is requiring Defendants to prove that the prior art teaches the motivation to do so. See In re Dillon, 919.F.2d at 692.

10 . The term anticholinergic is sometimes also referred to as antimuscarinic, Meltzer Tr. 240:20-21, because a subclass of acetylcho-line receptors are also sensitive to the neurotransmitter muscarine. Pl.’s FF & CL, at app. A.

11 . Indeed, the prior art in evidence is replete with teachings that the anticholinergic theory was the conventional wisdom in the 1970s, 1980s and beyond: Snyder wrote in 1974 that "[t]he most potent anticholinergics should evoke the fewest extrapyramidal effects; conversely, drugs with the highest incidence of these side effects should be the weakest anti-cholinergics.” PX 265 at 1248 (emphasis added).

Miller and Hiley concluded in 1974 that "[t]he results obtained here support the hypothesis that the antimnscarinic activity of these drugs is related to the frequency of extrapyramidal side effects.” PX 725 at 596 (emphasis added).

Creese said in 1976: "The anticholinergic properties of these drugs may well account for their low incidence of extrapyramidal effects.” PX 178 at 482 (emphasis added).

Neumeyer — one of Defendants’ experts — reported in 1981: "The most potent anticholi-nergics should evoke the fewest extrapyrami-dal effects; conversely, drugs with the highest incidence of these side effects should be the weakest anticholinergics.” PX 728 at 215 (emphasis added).

Chakrabarti — an Eli Lilly researcher' — reported in 1982: "In fact, neuroleptics, which possess anticholinergic properties (clozapine, thioridazine), produce a reduced incidence of EPS in the clinic.... Thus, in order to achieve a maximum reduction in side effects, it is important to obtain a correct balance of the antidopaminergic and anticholinergic activities." PX 753 at 1133 (emphasis added).

The anticholinergic theory continued to be important well after 1985. For example, Neumeyer continued to emphasize it in 1989 and 1995 texts: "With the phenothiazines and butyrophenones, and virtually all other classes of antipsychotic drugs, extrapyramidal side effects vary directly with the ratio of their anti-D-2; anti-Achn [anti-acetylcholine] potency." PX 754 (1989) at 198 (emphasis added); PX 274 (1995) at 208; Wolff Tr. 629:21-630:1.

The anticholinergic theory was used by scientists such as Strupczewski and his co-workers at Hoechst-Roussel (Aventis) as well as Eli Lilly and Sandoz. Hoechst-Roussel based its drug design program in the 1980s on the anticholinergic theory. As part of this program, Hoechst — Roussel developed compounds disclosed in its U.S. Patent No. 4,352,-811 ("the '811 patent”), PX 81, and in the 1982 Strupczewski Abstract, PX 191. Strup-czewski Dep. (11/16/2004) Tr. 151:14-152:15, 105:12-23. Eli Lilly and Sandoz followed the anticholinergic theory by working with its premiere example — clozapine. Meltzer Tr. 249:22-250:17.

12 . For example, Anthony Sulpizio, et al., PX 38, wrote that clozapine's antiserotonin properties might contribute to its overall pharmacological profile, but he did not discount the need for anticholinergic properties. Meltzer Tr. 246:5: — 18. Rather, Sulpizio called the anti-cholinergic theory "important”: “[S]ome authors have suggested that clozapine’s potent muscarinic blocking activity explains its lack of EPS liability.... [IJnvestigations into the anti-dopamine and anti-cholinergic activity of clozapine are obviously important in elucidating its overall pharmacological profile, our data suggest that the study of cloza-pine’s anti-serotonin activity is of equal importance.” PX 38 at 1445.

Similarly, Dr. Lai, PX 37, wrote that ”[w]hile the intrinsic anticholinergic activity hypothesis offers an attractive explanation for the lower EPS of thioridazine and clozapine, the possible role of serotonergic mechanism in this phenomenon is also worthy of consideration.” PX 37 at 347; Wolff Tr. 626:6-10.

13 . The term "metabolism” comprises the sum of the physical and chemical processes in an organism by which its material substance is produced, maintained, and destroyed, and by which energy is made available. See Pl.’s FF & CL, app. A.

The liver is responsible for metabolizing foreign substances that enter the body, like pharmaceuticals. The liver "[tjries to get rid of drugs, anything foreign in the body that is not normally, should be there, the job of the liver is tp either make it more soluble, cut it apart, get rid of it, make it nontoxic, if possible.” Abraham Tr. 387:22-25. ‘ Certain drugs are metabolized, and others are not. Id. at 388:3-4.

14 . Cf. Abraham Tr. 374:3-8 ("Q. So what would a person of ordinary skill in the art expect to happen if they made one of these changes, would they expect to have a successful drug? A. There would be ... no reasonable expectation you would come up with a drug using this method.”).

15 . See also Kemin Poods, L.C. v. Pigmentos Vegetales Del Centro, 464 F.3d 1339, 1346 (Fed.Cir.2006) ("Even when a court finds that the patentee failed to disclose material information to the PTO and acted with deceptive intent, the court retains discretion to decide whether the patentee’s conduct is sufficiently culpable to render the patent unenforceable.”).

16 . DRL does not join Mylan in alleging Jans-sen engaged in inequitable conduct.

17 . Apomorphine is used in testing as a surrogate for dopamine because it is more chemically stable, but will still bind to dopamine receptors. Thus, a test compound that functions to inhibit the ability of apomorphine to bind to a dopamine receptor will also inhibit the ability of dopamine to bind to that same receptor, i.e., it will function as a dopamine antagonist. Wolff Tr. 543:2-544:13.

18 . See, e.g., Schreiber Foods, Inc. v. Beatrice Cheese, Inc. 92 F.Supp.2d 857, 872, n. 16 (E.D.Wis.2000), rev'd on other grounds, 31 Fed.Appx. 727 (Fed.Cir.2002) ("Any attempt by an alleged infringer to conflate an opponent's corporate actors with the opponent's applicant group represents a distortion of the patent law, and also signals to a court that clear and convincing evidence of materiality and intent may be lacking.”).

19 . Dr. Awouters is a retired Janssen employee who was medically unable to participate in the trial. Declaration of Dr. Denis Wuyts dated June 19, 2006.

20 . Dellenbaugh testified that he had no knowledge of the references Mylan alleges were withheld from the PTO. Dellenbaugh Tr. 144:22-25 (no knowledge of DX 86), 145:19-146:3 (no knowledge of DX 89); 147:18-20 (no knowledge of DX 112), 149:2-8 (no knowledge of DX 120), 153:7-10 (no knowledge of DX 116), 193:14-194:6 (no knowledge of DX 203).

Mr. Dellenbaugh did not have any discussions with any the authors of these references, including Dr. Awouters, Kennis, Dr. Janssen and Dr. Gelders, about dopamine activity of pirenperone. Dellenbaugh Tr. 154:14-25.

Dellenbaugh had no recollection of meeting with or talking to Kennis, Dr. Awouters or Dr. Janssen during the time period the '663 patent was prosecuted and it would have been contrary to his normal practice to have done so. Dellenbaugh Tr. 109:8-19, 117:8-11; 105:22-25.

Mr. Dellenbaugh had no knowledge of whether pirenperone was an antipsychotic, was a dopamine antagonist or passed apo-morphine tests. Dellenbaugh Tr. 114:12-20. Nor was he likely to have learned of that information since he did not follow the literature or Janssen's research. Dellenbaugh Tr. 108:22-109:4.

Mr. Dellenbaugh's knowledge of pirenper-one was based solely on the pirenperone patent itself, which contained no information about dopamine antagonism, apomorphine tests, and antipsychotic ability. PX 80; Del-lenbaugh Tr. 113:3-14. Had he been aware of any of that information, he testified that he would have included it in the pirenperone’s patent application. Dellenbaugh Tr. 112:3— 23.