©2021. Published in Landslide, Vol. 13, No. 3, January/February 2021, by the American Bar Association. Reproduced with permission. All rights reserved. This information or any portion thereof may not be copied or disseminated in any form or by any means or stored in an electronic database or retrieval system without the express written consent of the American Bar Association or the copyright holder.
In the high-stakes field of abbreviated new drug application (ANDA) litigation, and the patentability of chemical compounds in general, a court uses the lead compound analysis to determine whether claims directed to chemical compounds are obvious.1 In ANDA litigation, a challenger will often make a paragraph IV certification under the Hatch-Waxman Act to certify that the patent at issue “is invalid or will not be infringed by the manufacture, use, or sale of the new drug” covered by the ANDA.2 Accordingly, the challenger commonly attacks the validity of the patent, which may turn on the obviousness of a claimed compound that is a blockbuster drug. The stakes for the outcome of the lead compound analysis are high because patentees may lose billions of dollars in revenue from the loss of patent protection for a blockbuster drug.
The lead compound analysis uses the activity of prior art compounds as possible motivation to select and modify these prior art compounds in order to ascertain the obviousness of a claimed compound. Importantly, in applying this analysis, the Federal Circuit Court of Appeals has focused on the activities disclosed for the claimed compounds as opposed to other activities disclosed in the prior art. Patentees and challengers should take into consideration this tendency of the Federal Circuit in applying the lead compound analysis.
Lead Compound Analysis
In the first inquiry of the analysis, “the court determines whether a chemist of ordinary skill would have selected the asserted prior art compounds as lead compounds, or starting points, for further development efforts.”7 A lead compound is “a compound in the prior art that would be most promising to modify in order to improve upon its . . . activity and obtain a compound with better activity.”8 “[M]ere structural similarity between a prior art compound and the claimed compound does not inform the lead compound selection.”9
“The second inquiry in the analysis is whether the prior art would have supplied one of ordinary skill in the art with a reason or motivation to modify a lead compound to make the claimed compound with a reasonable expectation of success.”10
With respect to motivation, the U.S. Supreme Court in KSR stated that “[i]n determining whether the subject matter of a patent claim is obvious, neither the particular motivation nor the avowed purpose of the patentee controls.”11 To this end, the Federal Circuit in Eisai broadly stated that the motivation in the lead compound analysis is “some motivation that would have led one of ordinary skill in the art to select and then modify a known compound.”12 These statements suggest that the activity selected in the lead compound analysis should be able to encompass any activity disclosed in the prior art.
In applying the lead compound analysis, a lead compound from the prior art is selected for advantageous activity, and the motivation to modify the lead compound is based on improving this activity of the lead compound. Therefore, selection of this activity is critical in the outcome of the lead compound analysis because it determines which prior art compounds could be lead compounds and whether lead compounds would be modified to make the claimed compound.
In practice, however, a challenger applying the lead compound analysis initially selects a prior art compound as a lead compound that is closely structurally related to the claimed compound. Then, the challenger argues for the selection of the prior art compound as the lead compound based on the superior activities of the prior art compound. Next, the challenger argues that one skilled in the art would make the necessary specific molecular modifications to the prior art lead compound to make the claimed compound. Here, the activity applied by the court to the lead compound analysis places constraints on this process as to which prior art compounds are candidates for lead compounds and whether the specific molecular modifications would be made to the lead compound. The challenger faces a difficult argument if the activity narrowly selected by the court is different from the superior activities of the prior art compound that is the asserted lead compound.
Disregarding KSR, the Federal Circuit has consistently limited the activity for the lead compound analysis to the activity for the claimed compound, as demonstrated in the opinions discussed below. The court has even taken this reasoning so far as identifying new lead compounds based on the disclosed activity of the claimed compound. In other examples, the court requires the challenger to satisfy the stringent requirements for preparing prodrugs, which are biologically inactive compounds that are metabolized in the body to active drugs.
In many instances, structurally similar compounds have the same or similar activities disclosed in the prior art. However, compounds with close structural attributes do not necessarily have the same disclosed activities in the prior art. Therefore, it would be a false assertion that structurally similar prior art compounds that are candidates for lead compounds would necessarily have the same disclosed activities as the claimed compound. As discussed above for KSR and Eisai, arguably the activity selected in the lead compound analysis need not be constrained to the disclosed activities of the claimed compound.
In Eisai, claims 1–6 of U.S. Patent No. 5,045,552 (’552 patent) covered the pharmaceutical rabeprazole, and the challenger argued that the claims were obvious over compounds disclosed in the prior art based on the lead compound analysis.13 The sodium salt of rabeprazole is the active ingredient in Aciphex®, which suppresses gastric acid, and Aciphex® had over $1 billion in worldwide yearly sales.14
Claim 1 of the ’552 patent is silent on the activity of the recited compound. This is common to the claims considered here. However, any activity that would be recited in a compound claim may be considered an intended use or inherent feature.15 Therefore, such an activity would not be a feature that could distinguish the compound claim over the prior art. Accordingly, activity of the claimed compound for the lead compound analysis is read by the court from the disclosure of the patent or approved treatment of a drug and not the claims themselves.
The following activities apply in Eisai. Rabeprazole has the activity of a proton pump inhibitor, which suppresses gastric acid production by inhibiting the enzyme H+K+ATPase.16 The ’552 patent recites the activities of inhibition of gastric acid secretion, H+K+ATPase inhibition, and the treatment and prevention of peptic ulcers.17 The court applied the activity of gastric acid inhibition to the lead compound analysis.18
The challenger advanced lansoprazole as a lead compound.19 Lansoprazole differs from rabeprazole in that lansoprazole has a trifluoroethoxy substituent and rabeprazole has a methoxypropoxy substituent (see fig. 1). The chemical structures are annotated with dashed boxes to identify the structural differences between prior art compounds and claimed compounds.
Omeprazole is a pharmaceutical with proton pump inhibitory activity, and lansoprazole is 20 times superior to omeprazole for anti-ulcer action.20 The court considered the differences between anti-ulcer action and gastric acid inhibition. The court found that “lansoprazole’s candidacy as a starting point to develop new anti-ulcer compounds versus new gastric acid inhibitors does not resolve the lead compound analysis, at least not in the absence of any contrary indications.”21 Therefore, the advantageous anti-ulcer data for lansoprazole, according to the court, did not support lansoprazole as a lead compound because it did not include the activity of gastric acid inhibition. Note, however, that anti-peptic ulcer activity was recited in the ’552 patent of rabeprazole. Regardless, the court stated that there was no motivation in the second inquiry to replace the trifluoroethoxy substituent with a methoxypropoxy substituent even if lansoprazole were selected as a lead compound in the first inquiry because the prior art taught the need for a lipophilic substituent such as trifluoroethoxy.22
Daiichi: Olmesartan Medoxomil
In Daiichi, claim 13 of U.S. Patent No. 5,616,599 (’599 patent) covered the pharmaceutical olmesartan medoxomil, and the challenger argued that claim 13 was obvious over compounds disclosed in the prior art based on the lead compound analysis.23 Olmesartan medoxomil is the active ingredient in Benicar®, Benicar HCT®, and Azor®, which are angiotensin receptor blockers.24
The following activities apply in Daiichi. Olmesartan medoxomil is a prodrug of olmesartan (see fig. 2), which has the activity of an angiotensin receptor blocker (ARB).25 The ’599 patent recites the activities of angiotensin II receptor antagonists as well as treatment and prophylaxis of hypertension and heart diseases.26 The court applied the activity of ARBs to the lead compound analysis.27
The challenger argued that compounds in U.S. Patent No. 5,137,902 (’902 patent) should be used as lead compounds. Example 6 of the ’902 patent differs from olmesartan, the bioactive compound from the olmesartan medoxomil prodrug, in that Example 6 has an isopropyl substituent while olmesartan has a hydroxyisopropyl substituent (see fig. 3).
Although the challenger only presented compounds in the ’902 patent as lead compounds, the Federal Circuit approved the district court’s selection of the activity of ARBs to identify new potential lead compounds to undermine the legitimacy of the compounds in the ’902 patent as lead compounds. The district court found “that a medicinal chemist of ordinary skill would not have been motivated to select the ’902 compounds over other second-generation ARBs, including L-158,809, DuP 532, the Eisai compounds, and valsartan, because many of the latter ARBs demonstrated greater potency and all had been more thoroughly studied than the ’902 ARBs.”28 The Federal Circuit saw no clear error in the district court’s findings.
These other second-generation ARBs have the ARB activity of the compounds of the ’902 patent. But the issue is that the court is using the activity disclosed in the patent to extend the lead compound search to the structurally dissimilar compounds of L-158,809, DuP 532, the Eisai compounds, and valsartan, which extends beyond the prior art compounds asserted by the challenger. It is unclear whether a lead compound must have substantially the “most promising” activity from a reference or the higher bar of substantially the “most promising” activity throughout the prior art. The court’s selection of the structurally dissimilar more potent compounds suggests that lead compounds should have superior activity across the prior art. Such an interpretation would be a substantially high bar for a challenger in asserting a lead compound. Finally, the court found that the challenger failed to prove the predictability of a prodrug in reference to the medoxomil group on olmesartan medoxomil.29
In Otsuka, claim 12 of U.S. Patent No. 5,006,528 (’528 patent) covered the pharmaceutical aripiprazole, and the challenger argued that claim 12 was obvious over compounds disclosed in the prior art based on the lead compound analysis.30 Aripiprazole is the active ingredient in Abilify®, which is an atypical antipsychotic, and Abilify® had over $3.3 billion in yearly sales.31
The following activities apply in Otsuka. Aripiprazole has the activity of an atypical antipsychotic.32 The ’528 patent recites the activities of treating schizophrenia.33 The court applied the activity of antipsychotics to the lead compound analysis.34
The challenger argued that three prior art compounds should each be considered as a lead compound.35 The court determined that the first prior art compound, the unsubstituted butoxy disclosed and claimed in Otsuka’s earlier U.S. Patent No. 4,734,416 (’416 patent) (see fig. 4), would not be a lead compound.36 In this instance, the Federal Circuit agreed with the district court in that the “‘laundry list’ of potential central nervous system controlling effects” would not “mean that every carbostyril derivative disclosed in the ’416 patent is a potential antipsychotic.”37 The court also discounted the first prior art compound because the ’416 patent clearly teaches antihistaminic effects as opposed to antipsychotic activity.38 Separately, the court appeared willing to disregard mouse jumping data unless it was indicative of antipsychotic activity.39 The first prior art compound was ultimately not accepted as a lead compound particularly because it also had inferior activity in the mouse jumping data regardless of the significance of this data.40 The best compounds had a propoxy linker and not the butoxy linker of aripiprazole.41 Even if the first prior art compound was selected as a lead compound, the court stated that one skilled in the art would not make the necessary specific molecular modifications to make aripiprazole.42
The court also did not find that the second prior art compound, the 2,3-dichloro propoxy (see fig. 5), could be a lead compound.43 The patent disclosing the second prior art compound lists numerous central nervous system effects including antischizophrenia agents.44 The court stated that this patent failed “to tie the 2,3-dichloro propoxy to any meaningful suggestion of antipsychotic activity” because it did not identify antipsychotic activity with particularity.45 Therefore, individually or collectively, these central nervous effects were insufficient as activities for the lead compound analysis even though they included antipsychotic activity. Another patent listed the second prior art compound among 96 example compounds.46 Even if the second prior art compound were selected as a lead compound, the court stated that one skilled in the art would not make the necessary specific molecular modifications to make aripiprazole.47
Further, the court did not agree that the third prior art compound, OPC-4392 (see fig. 6), would be a lead compound.48 Unlike the first two prior art compounds, OPC-4392 was known in the prior art as a potent antipsychotic.49 However, the compound had the adverse side effects of “sleeplessness, stagger, weakness, fatigability, heavy headedness, lack of motivation and disturbed concentration, which were so severe that [subjects] were not able to perform daily routine work.”50 The court stated that “[t]aken as a whole, however, the prior art taught away from using OPC-4392 as a starting point for further antipsychotic research.”51 The Federal Circuit concurred with the district court that there was insufficient motivation to make the specific molecular modifications to the third prior art compound to make the claimed compound, and there was insufficient evidence that “the skilled artisan would have known how to modify OPC-4392 to increase antipsychotic activity.”52 Therefore, the court ultimately held that all three compounds failed the first and second inquiries in the lead compound analysis.53
As in Daiichi, the court in Otsuka used the activity of the claimed compound to extend the lead compound search to structurally dissimilar compounds beyond the prior art compounds asserted by the challenger. The Otsuka court approved of the district court’s conclusion that
two compounds—clozapine and risperidone—would have been considered viable lead compounds. These were the only promising antipsychotic compounds at the time the present inventors began their work. They were the natural and obvious lead compounds whose structures one would have considered to modify to obtain improved antipsychotic compounds. At the relevant time, there were no carbostyril compounds that were marketed as antipsychotics or were publicly known to have potent antipsychotic activity with minimal side effects.54
The court was clear in stating that the search for a lead compound was limited by antipsychotic activity, because any carbostyril compounds in the prior art without antipsychotic activity were eliminated from consideration as lead compounds. This conclusion is further supported by the fact that the court would not consider antihistaminic activity for the first prior art compound as an activity for the lead compound analysis.
In Bristol-Myers, claim 8 of U.S. Patent No. 5,206,244 (’244 patent) covered the pharmaceutical entecavir, and the challenger argued that claim 8 was obvious over compounds disclosed in the prior art based on the lead compound analysis.55 Entecavir is the active ingredient in Baraclude®, which is for the treatment of hepatitis B.56
The following activities apply in Bristol-Myers. Entecavir has the activity of treatment of hepatitis B.57 The ’244 patent recites the activities of antiviral agents against viruses, including herpes simplex virus, vaccinia virus, and hepatitis B virus.58 The court applied the activity of antiviral properties to the lead compound analysis.59
The court found that 2’-CDG would be selected as a lead compound.60 Next, the court stated that “the Madhavan reference demonstrated that adding an exocyclic methylene group to a carbocyclic nucleoside analog can result in a lead compound with improved antiviral activity.”61 The court held that “[w]ith 2’-CDG as a lead compound, the record here amply supports the conclusion that one of ordinary skill in the art would have had a motivation to modify 2’-CDG’s carbocyclic ring by substituting an exocyclic methylene group at the 5’ position to make the patented compound, entecavir”62 (see fig. 7).
The court noted the herpes virus activity and hepatitis B virus activity of 2’-CDG in the prior art as motivation to use 2’-CDG as a lead compound.63 In contrast, Madhavan discloses that “[n]one of the compounds [such as compound 30] displayed significant activity against herpes simplex virus type 1 or type 2, but several demonstrated potent inhibition of vaccinia virus replication.”64 As discussed above, vaccinia virus was part of the antiviral activity in the patent disclosure; therefore, Madhavan compound 30 did have antiviral activity according to the patent disclosure. However, it may have been possible to discount the teachings in Madhavan, and specifically Madhavan compound 30, if vaccinia virus was not encompassed in the patent disclosure because Madhavan arguably taught away from an exocyclic methylene incorporating herpes simplex virus activity.
In Amerigen, claims 1–5 and 21–24 of U.S. Patent No. 6,858,650 (’650 patent) covered fesoterodine, and the challenger argued that these claims were obvious over compounds disclosed in the prior art based on the lead compound analysis.65 Fesoterodine is the active ingredient in Toviaz®, which is used to treat urinary incontinence.66
The following activities apply in Amerigen. Fesoterodine has the activity of an antimuscarinic prodrug and treats urinary incontinence.67 The ’650 patent recites the activities of treating urinary incontinence.68 The court applied the activity of a prodrug with antimuscarinic action to the lead compound analysis.69
The Federal Circuit upheld the Patent Trial and Appeal Board’s (PTAB’s) findings that 5-HMT would be a lead compound because it was known as an active metabolite of tolterodine in the prior art.70 The court stated that “[t]he issue before us is whether it would have been obvious to modify the 2-position hydroxy group of 5-HMT to an alkyl ester of six carbons or less as in fesoterodine”71 (see fig. 8).
The PTAB found that “a skilled artisan would ‘seek some degree of certainty that a prodrug of a particular molecule would be inactive.’”72 Therefore, the PTAB suggested requiring some evidence from the challenger that fesoterodine would be inactive and that fesoterodine would be metabolized into an active compound. “[T]he Board found no evidence of prodrugs in the same chemical class, with the same mechanism of action, or in the same field of treatment. . . . Altogether, the Board found that the petitioners neither established a general motivation to make a 5-HMT prodrug nor proved that the specific claimed modifications would have been obvious.”73 The Federal Circuit concluded “that Amerigen’s factual challenges to the Board’s decision are without merit and that substantial evidence supports the Board’s findings.”74
Therefore, the PTAB as upheld by the Federal Circuit was requiring that prodrug activity factor into the lead compound analysis. Arguably, the challenger only needed to provide motivation for the specific molecular modification of an alkyl ester at the 2-position hydroxy group of 5-HMT without regard to any inherent prodrug activity. The challenger did however make an argument that increasing lipophilicity would be motivation for the alkyl ester even though 5-HMT did not have a bioavailability problem.75 The court undermined this assertion with the uncertainty of developing prodrugs.76
In summary, the activity selected by the Federal Circuit substantially affects the outcome of the lead compound analysis. Although the court is not bound to the motivation or activity of the claimed compound, these cases present examples where the Federal Circuit chose to limit the activity in the lead compound analysis to the activity of the claimed compound. First, the court in Eisai did not give weight to anti-ulcer data on prior art compounds when the claimed compound instead has gastric acid inhibition activity, and the court in Otsuka did not give weight to antihistaminic activity of prior art compounds. Second, the courts in Daiichi and Otsuka identified new and assertedly superior lead compounds because these asserted lead compounds have the activity of the claimed compound. Third, the court in Bristol-Myers did not give weight to a teaching away disclosure in a reference because the activity selected for the analysis was broadly defined as antiviral action. Finally, designating a compound as a prodrug describes its biological activity and not its chemical structure per se. The courts in Daiichi and Amerigen required the challenger to incorporate evidence of prodrug activity into the motivation for the lead compound analysis, when such properties need not calculate into motivation because they would necessarily be inherent.
Whether in ANDA litigation or other litigation on chemical compounds, the challenger and patentee should be aware of the court’s propensity to use the activity of the claimed compound as the activity selected in the lead compound analysis. Regardless, the challenger should advance analogous structures with various activities and argue against necessarily using the activity of the claimed compound in the lead compound analysis. In the process, the challenger should argue as many reasonable lead compounds and motivations as possible. On the other hand, the patentee is favored by the court’s current jurisprudence of narrowly defining activities in the lead compound analysis, which excludes prior art compounds in this analysis. Additionally, a restricted definition of activities in the patent may avoid the circumstances in Bristol-Myers and make it more difficult for a challenger to establish obviousness.
1. Daiichi Sankyo Co. v. Matrix Labs., Ltd., 619 F.3d 1346 (Fed. Cir. 2010); Eisai Co. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353 (Fed. Cir. 2008); Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350 (Fed. Cir. 2007); Yamanouchi Pharm. Co. v. Danbury Pharmacal, Inc., 231 F.3d 1339 (Fed. Cir. 2000).
2. 21 U.S.C. § 355(j)(2)(A)(vii)(IV).
3. Yamanouchi, 231 F.3d 1339.
4. Takeda, 492 F.3d 1350.
5. Eisai, 533 F.3d 1353.
6. Daiichi, 619 F.3d 1346.
7. Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291 (Fed. Cir. 2012).
9. Id. at 1292.
11. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 419 (2007).
12. Eisai Co. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353, 1357 (Fed. Cir. 2008).
13. Id. at 1355–56.
14. Id. at 1356.
15. U.S. Patent & Trademark Office, Manual of Patent Examining Procedure (MPEP) §§ 2111.02, 2112 (8th ed. Rev. 9, June 2020).
16. Eisai, 533 F.3d at 1356.
17. ’552 Patent at col. 13, ll. 53–58.
18. Eisai, 533 F.3d at 1358.
19. Id. at 1357.
20. Id. at 1358.
22. Id. at 1358–59.
23. Daiichi Sankyo Co. v. Matrix Labs., Ltd., 619 F.3d 1346, 1347–48 (Fed. Cir. 2010).
24. Id. at 1347.
25. Id. at 1347, 1351.
26. ’599 Patent at abstract, col. 2, ll. 14–19.
27. Daiichi, 619 F.3d at 1353.
30. Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1283–85 (Fed. Cir. 2012).
31. Id. at 1284.
33. ’528 Patent at col. 2, ll. 37–39.
34. Otsuka, 678 F.3d at 1293.
35. Id. at 1290–91.
36. Id. at 1294.
38. Id. at 1293.
39. Id. at 1294.
42. Id. at 1295.
44. Id. at 1288.
45. Id. at 1295.
46. Id. at 1288.
47. Id. at 1295.
48. Id. at 1295–96.
49. Id. at 1289.
51. Id. at 1295.
52. Id. at 1296.
53. Id. at 1293–96.
54. Id. at 1293 (citation omitted).
55. Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc., 752 F.3d 967, 969 (Fed. Cir. 2014).
58. ’244 Patent at col. 3, l. 62 to col. 4, l. 51.
59. Bristol-Myers, 752 F.3d at 974.
60. Id. at 973.
61. Id. at 975.
62. Id. at 974–75.
63. Id. at 971–72.
64. G. V. Bindu Madhavan et al., Synthesis and Antiviral Evaluation of 6’-Substituted Aristeromycins: Potential Mechanism-Based Inhibitors of S-Adenosylhomocysteine Hydrolase, 31 J. Med. Chem. 1798 abstract (1988).
65. Amerigen Pharm. Ltd. v. UCB Pharma GmbH, 913 F.3d 1076, 1078 (Fed. Cir. 2019).
68. ’650 Patent at col. 1, ll. 17–18; claims 21–24.
69. Amerigen, 913 F.3d at 1080.
70. Id. at 1081, 1085–89.
71. Id. at 1079.
72. Id. at 1088.
73. Id. at 1088–89.
74. Id. at 1089.
75. Id. at 1087.