## United States Court of Appeals for the Federal Circuit

2008-1404, -1405, -1406 THE PROCTER & GAMBLE COMPANY, Plaintiff-Appellee,

v. TEVA PHARMACEUTICALS USA, INC., Defendant-Appellant.

William F. Lee , Wilmer Cutler Pickering Hale & Dorr LLP, of Boston, Massachusetts, argued for plaintiff-appellee. With him on the brief were Vinita Ferrera and Allen C. Nunnally . Also on th e brief were David B. Bassett and Christopher J. Meade , of New York, New York. James Galbraith , Kenyon & Kenyon LLP, of New York, New York, argued for defendant-appellant. With him on the brief were Maria Luisa Palmese , and A. Antony Pfeffer

. Appealed from: United States District Court for the District of Delaware Judge Joseph J. Farnan, Jr.

## United States Court of Appeals for the Federal Circuit
2008-1404, -1405, -1406

THE PROCTER & GAMBLE COMPANY, Plaintiff-Appellee,

v. TEVA PHARMACEUTICALS USA, INC., Defendant-Appellant.
Appeal from the United States District Court for the Distric t of Delaware in 04-940, 08- 066, and 08-191, Judge Jos eph J. Farnan, Jr.

__________________________ DECIDED: May 13, 2009

__________________________

Before MAYER, DYK, Circuit Judges , and HUFF, * District Judge

. HUFF, District Judge

. Teva Pharmaceuticals USA, Inc. (“Teva ”) appeals from a final judgment of the United States District Court for the District of Delaware in favor of The Procter & Gamble Company (“P&G”) in three cases uphold ing the validity of P&G’s U.S. Patent 5,583,122 (the “’122 patent”). Procter & Gamble Co. v. Teva Pharmaceuticals USA, Inc. , 536 F. Supp. 2d 476 (D. Del. 2008). A fter a bench trial and a stipulation for

* Honorable Marilyn L. Huff, District J udge, United States District Court for the Southern District of Califor nia, sitting by designation.judgment in the related cases, the district court rejected Te va’s invalidity defenses of obviousness and obviousness-type double patenting. We affirm. I. BACKGROUND The ’122 patent claims the compound rise dronate, the active ingredient of P&G’s osteoporosis drug Actonel®. In August 2004, P&G sued Teva for infringement of the ’122 patent after Teva notified P&G that it planned to market risedronate as a generic equivalent of Actonel®. Specifically, P&G alleged that Teva’s proposed drug infringed claim 4 of the ’122 patent for the compoun d risedronate, claim 16 for pharmaceutical compositions containing ris edronate, and claim 23 for methods of treating diseases using risedronate. In its defense, Teva argued that the ’122 patent was invalid as obvious in light of P&G’s ex pired U.S. Patent 4,761,406 (the “’406 patent”), filed on June 6, 1985 and issued on August 2, 1988. Alternat ely, Teva argues that the ’122 patent is invalid for obviousness-type double patenting. Risedronate, the subject of the contested claims, is a member of a group of compounds referred to as bisphosphonates. Bisphosphonates, in general, are active in inhibiting bone resorption. The first tw o promising bisphospho nates studied for the treatment of metabolic bone diseases, et idronate (EHDP) and clodronate, had clinical problems which prevented their commerciali zation. P&G conducted a significant amount of experimentation involving hundreds of differ ent bisphosphonate compounds, but could not predict the ef ficacy or toxicity of the new compounds. Eventually, researchers at P&G identif ied risedronate as a promising drug candidate. On December 6, 1985, risedronate’s inventors applied for a patent on the compound. P&G is the owner by assi gnment of the ’122 patent, entitled

2008-1404, -1405, -1406 2“Pharmaceutical Compositions Containing Ge minal Diphosphonates, ” which issued on December 10, 1996.

Risedronate is neither claimed nor disclosed in the ’406 patent. Instead, the ’406 patent, entitled “Regimen for Treating Ost eoporosis,” claims an intermittent dosing method for treating osteoporosis. As the tr ial court noted, the ’406 patent “addresses the central problem seen in bisphosphonates at the time, namely that they inhibited bone mineralization, by teaching the use of a cyclic administr ative regimen to achieve a separation of the benign effect of anti-resorption from the unwanted side effect of antimineralization in patient s.” Procter & Gamble , 536 F. Supp. 2d at 492. The ’406 patent lists thirty-six polyphosphonate molecules as treatment candidates and eight preferred compounds for intermittent dosing, includi ng 2-pyr EHDP. Teva contends that the structural similarities bet ween risedronate and 2-pyr EHDP render the challenged claims of the ’122 patent obvious. From the testimony at trial, the district court conc luded that the ’4 06 patent would not have led a person of ordinary skill in t he art to identify 2-pyr EHDP as the lead compound. In light of the extremely unpredic table nature of bisphosphonates at the time of the invention, the dist rict court also found that a per son of ordinary skill in the art would not have been motivated to make the specific molecu lar modifications to make risedronate. The district court conclude d that unexpected results of risedronate’s potency and toxicity rebut a claim of obvi ousness. The district court found that secondary considerations of non -obviousness supported its conc lusions. Similarly, the court found that the ’122 patent was not invalid for obvious ness-type double patenting.

2008-1404, -1405, -1406 3This consolidated appeal follo wed. We have jurisdiction pursuant to 28 U.S.C. § 1295(a)(1).

II. DISCUSSION I. Standard of Review “On appeal from a bench trial, this court reviews the district court's conclusions of law de novo and findings of fa ct for clear error.” Golden Blount, Inc. v. Robert H. Peterson Co. , 365 F.3d 1054, 1058 (Fed. Cir. 2004). Whether the subject matter of a patent is obvious is a question of law and is reviewed de novo. PharmaStem Therapeutics, Inc. v. ViaCell, Inc. , 491 F.3d 1342, 1359 (Fed. Cir. 2007). Factual determinations underlying the obviousness iss ue are reviewed for cl ear error. Alza Corp. v. Mylan Labs., Inc. , 464 F.3d 1286, 1289 (Fed. Cir. 2006). The evidentiary burden to show facts supporting a conclusion of invalidity is one of clear and convincing evidence. AK Steel Corp. v. Sollac & Ugine , 344 F.3d 1234, 1238-39 (Fed. Cir. 2003). Non-statutory double patentin g is a legal question revi ewed without deference. Georgia-Pacific Corp. v. U.S. Gypsum Co. , 195 F.3d 1322, 1326 (Fed. Cir. 1999). II. Patent Obviousness – Legal Standard Under the U.S. Patent Act, an invention cannot be patent ed if “the subject matter as a whole would have been obvi ous at the time the invention was made to a person having ordinary skill in the art to which sa id subject matter pertains.” 35 U.S.C. § 103(a). Patents are presumed to be va lid. Kao Corp. v. Unilever U.S., Inc. , 441 F.3d 963, 968 (Fed. Cir. 2006). A party seeking to invalidate a patent based on obviousness must demonstrate “by clear and convincing evidence that a skilled artisan would have been motivated to combine the teachings of the prior art references to achieve the

2008-1404, -1405, -1406 4claimed invention, and that the skilled artisan would hav e had a reasonable expectation of success in doing so.” Pf izer, Inc. v. Apotex, Inc. , 480 F.3d 1348, 1361 (Fed. Cir. 2007). Clear and convincing evidence places in the fact finder “an abiding conviction that the truth of [the] factual contentions are highly probable.” Colorado v. New Mexico , 467 U.S. 310, 316 (1984) (quot ation marks omitted). The obviousness determination turns on under lying factual inquiries involving: (1) the scope and content of prio r art, (2) differences betw een claims and prior art, (3) the level of ordinary skill in pertinent art, and (4) sec ondary considerations such as commercial success and satisfaction of a l ong-felt need. Graham v. John Deere Co. , 383 U.S. 1, 17 (1966). The Supreme Court has explained that t he Federal Circuit’s “teaching, suggestion or motivation” test prov ides helpful insight into the obviousness question as long as it is not applied rigi dly. KSR Int’l Co . v. Teleflex Inc. , 550 U.S. 398, 127 S. Ct. 1727, 1741 (2007). Accordingly, under KSR , “it remains necessary to identify some reason that would have led a chemist to modify a known compound in a particular manner to establish prima facie obvious ness of a new claimed compound.” Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd. , 492 F.3d 1350, 1357 (Fed. Cir. 2007). If a patent challenger makes a prima faci e showing of obviousness, the owner may rebut based on “unexpected results” bydemonstrating “that t he claimed invention exhibits some superior property or advantage that a person of ordinary skill in the relevant art would have found surpri sing or unexpected.” In re Soni , 54 F.3d 746, 750 (Fed. Cir. 1995). We consider the relevant factors in turn.

2008-1404, -1405, -1406 5III. Identification of a Lead Compound An obviousness argument based on structur al similarity between claimed and prior art compounds “clearly depends on a pr eliminary finding that one of ordinary skill in the art would have select ed [the prior art compound] as a lead compound.” Takeda , 492 F.3d at 1359; see also Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd. , 533 F.3d 1353, 1359 (Fed. Cir. 2008) (stating that “post-KSR , a prima facie case of obviousness for a chemical compound still, in general, begins with the reasoned identif ication of a lead compound” in the prior art). Teva argues that the ‘406 patent identi fies 2-pyr EHDP as the most promising molecule for the inhibition of bone resorption. The trial court disagreed and concluded fr om the evidence that a person of ordinary skill in the art would not have identified 2-pyr EHDP as a lead compound for the treatment of osteoporosis. We need not reach this question because we conclude that even if 2-pyr EHDP was a lead compound, the evidence does not establish that it would have been obvious to a person of ordinary skill at the time of the invention to modify 2-pyr EHDP to create risedronate. IV. Obviousness of Risedronate in Light of the Prior Art To decide whether risedronate was obvious in light of the prior art, a court must determine whether, at the time of invention, a person havi ng ordinary skill in the art would have had “reason to attempt to make t he composition” known as risedronate and “a reasonable expectation of success in doing so.” PharmaStem T herapeutics, Inc. v. ViaCell, Inc. , 491 F.3d 1342, 1360 (Fed. Cir. 2007).

2008-1404, -1405, -1406 6The district court concluded that, even if 2-pyr EHDP were a lead compound, it would not render the ’122 patent’s claims on risedr onate obvious because a person having ordinary skill in the ar t would not have had reason to make risedronate based on the prior art. The district court’s findings also support the conclusion that there could have been no reasonable expectation as to risedronate’s success. The question of obviousness “often turns on the structural similarities and differences between the claimed compound and the prior art compound[].” Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd. , 533 F.3d 1353, 1356-57 (Fed. Cir. 2008); see also Sanofi-Synthelabo v. Apotex, Inc. , 550 F.3d 1075, 1086 (Fed. Cir. 2008) (“Precedent establishes the analytical proc edure whereby a close structur al similarity between a new chemical compound and prior art compounds is generally deemed to create a prima facie case of obviousness . . . .”); In re Mayne , 104 F.3d 1339, 1343 (Fed. Cir. 1997) (“Structural relationships o ften provide the requisite mo tivation to modify known compounds to obtain new compounds.”); In re Payne , 606 F.2d 303, 313-15 (CCPA 1979) (discussing the presumpti on of obviousness based on close structural similarity). In this case, risedronate and 2-pyr EHDP ar e positional isomers; they each contain the same atoms arranged in different ways. In risedronate, the hydroxy-ethanediphosphonate group is connected to the #3 carbon of a pyri dine ring, while in 2-pyr EHDP, the hydroxy-ethane-di phosphonate group is connected to the #2 carbon. Because the nitrogen atom is in a different position in the tw o molecules, they differ in three dimensional shape, charge distri bution and hydrogen bonding properties. To successfully argue that a new compound is obvious, the challenger may show “that the prior art would hav e suggested making the specific molecular modifications

2008-1404, -1405, -1406 7necessary to achieve the claimed invention.” Takeda , 492 F.3d at 1356 (quotation marks omitted). “In keeping with the flex ible nature of the obv iousness inquiry, the requisite motivation [to modify] can come from any number of sources.” Eisai , 533 F.3d at 1357 (citation omitted). T hus, in addition to structur al similarity between the compounds, a prima facie case of obviousness may be show n by “adequate support in the prior art” for the change in structure. In re Grabiak , 769 F.2d 729, 731-32 (Fed. Cir. 1985). As we noted in Takeda : A known compound may suggest its homol og, analog, or isomer because such compounds often have similar pr operties and therefore chemists of ordinary skill would ordinarily contempl ate making them to try to obtain compounds with improved prope rties. . . . [However,] it remains necessary to identify some reason that would hav e led a chemist to modify a known compound in a particular m anner to establish prima facie obviousness of a new claimed compound. 492 F.3d at 1356-57 (citation omitted). At trial, P&G’s expert witnesses testifi ed that, in 1985, a person having ordinary skill in the art realized that the properties of bisphosphonates could not be anticipated based on their structure. Additionally, the tr ial court relied on cont emporaneous writings from Herbert Fleisch, the preeminent author ity on bisphosphonates during the relevant time period. Dr. Fleisch wr ote in 1984 that “every compound, while remaining a bisphosphonate, exhibits its own physical- chemical, biological and therapeutic characteristics, so that eac h bisphosphonate has to be considered on its own. To infer from one compound the effect s in another is dangerous and can be misleading.” Herbert Fleisch, Chemistry and Mec hanisms of Action of Bisphosphonates , in Bone Resorption, Metastasis, and Diphosphonates 33- 40 (S. Garattini ed., 1985). In this case, P&G synthesized and tested 2-pyr EH DP, risedronate (3-pyr EHDP) and 4-pyr

2008-1404, -1405, -1406 8EHDP, another structural isomer . Confirming the unpredictability of bisphosphonates, test results for 4-pyr EHDP reve aled that it was not active in inhibiting bone resorption despite its close relationshi p with potent compounds. In li ght of the Supreme Court’s instruction in KSR , the Federal Circuit has stated that, “[t]o t he extent an art is unpredictable, as the chemic al arts often are, KSR ’s focus on [] ‘identified, predictable solutions’ may present a difficult hurdle becaus e potential solutions are less likely to be genuinely predictable.” Eisai , 533 F.3d 1353, 1359 (quoting KSR , 127 S. Ct. at 1742). The district court found that Teva failed to clear that hurdle, establishing insufficient motivation for a person of ordinary skill to synt hesize and test risedronate. This finding was not clearly erroneous. Additionally, there was an insufficient show ing that a person of ordinary skill in the art would have had a “reasonable expec tation of success” in synthesizing and testing risedronate. PharmaStem , 491 F.3d at 1360. In KSR , the Supreme Court stated that when an obvious modification “leads to the anticipated success,” the invention is likely the product of ordinary sk ill and is obvious un der 35 U.S.C. § 103. 127 S. Ct. at 1742. “[O]bviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success.” Pfizer , 480 F.3d at 1364 (citing In re Corkill , 771 F.2d 1496, 1500 (Fed. Cir. 1985)). Here, the district court’s findings indicate that there was no reasonable expectation in 1985 that risedronate would be a successful compound. Cases following KSR have considered whether a gi ven molecular modification would have been carried out as part of routine testing. See, e.g. , Takeda , 492 F.3d at 1360 (discussing the district court’s finding that a modification was not known to be

2008-1404, -1405, -1406 9beneficial and was not considered “routine”). When a person of ordinary skill is faced with “a finite number of identif ied, predictable solutions” to a problem and pursues “the known options within his or her technical gr asp,” the resulting discovery “is likely the product not of innovation but of ordinary skill and common sense.” KSR , 127 S. Ct. at 1742. So too, “[g]ranting patent protection to advances that would occur in the ordinary course without real innovatio n retards progress.” Id. at 1741. In other cases, though, researchers can only “vary all parameters ortry each of numerous possible choices until one possibly arrive[s] at a successful resul t, where the prior art [gives] either no indication of which parameters [are] critical orno direction as to which of many possible choices is likely to be su ccessful.” In re O’Farrell , 853 F.2d 894, 903 (Fed. Cir. 1988). In such cases, “courts should not succumb to hindsight claims of obviousness.” In re Kubin , __ F.3d __, No. 2008-11 84, slip op. at 14 (Fed. Cir. Apr. 3, 2009). Similarly, patents are not barred just because it was obv ious “to explore a new technology or general approach that seemed to be a promising field of experimentation, where the prior art gave only general guidance as to the particular form of the claimed invention or how to achieve it.” In re O’Farrell , 853 F.2d at 903. In this case, there is no credible evidenc e that the structural modification was routine. The district court found that the appellee’s expert was evasive on this topic, stating that the witness “did not directly respond to most questions posed to him about whether it would be common for a chemist who develops a pyridine compound to conceive of and make [2-pyr EHDP, 3-pyr EHDP, and 4-pyr EHDP] isomers.” Procter & Gamble , 536 F. Supp. 2d at 486. But evidence ofevasion is not necessarily evidence that the testimony would otherwise have been fa vorable. The only direct evidence that

2008-1404, -1405, -1406 10the structural modification was routine was presented byan expert witness that the district court judge discredited. 1 Accordingly, we conclude that the district court did not clearly err in finding that Teva had not established a prima facie case of obviousness as to the challenged claims of the ’122 patent. V. Unexpected Results The district court found that, even if Te va could establish a prima facie case of obviousness, P&G had introduced sufficient ev idence of unexpected results to rebut such a showing. Such evidence includ ed “test data showing that the claimed composition[] possess[es] unexpectedly improved properties or properti es that the prior art does not have.” In re Dillon , 919 F.2d 688, 692-93 (Fed. Cir. 1990). Because Teva did not establish a prima facie case of obv iousness, P&G need not rely on this evidence to defend the ’122 patent. Nonetheless, we note that P&G’s witnesse s consistently testified that the properties of risedronate were not expected. For example, Dr . Benedict testified that he and other researchers did not pr edict the potency of risedronat e. Ms. McOsker testified that she was “very surprised” by the low dose at which risedronate was effective. Dr. Miller stated that the superior properties of risedronate were unexpected and could not have been predicted. In a test to determine the lowest dose at which these compounds

1 Appellant’s expert testified that “i f someone was aware that [2-pyr EHDP] was safe and effective, they would immediately in terms of the drug discovery effort, make the [3-pyr EHDP].” However, the distri ct court concluded that this witness “had no specialized experience in t he area of bisphosphonates” asid e from his preparation to testify in the litigation. Procter & Gamble , 536 F. Supp. 2d at 480. Additionally, the expert prepared his opinion by reviewing drug profiles in the current version of the Physician’s Desk Reference inste ad of drug profiles from the relevant time, causing his opinions to be “marred by hindsight.” Id. at 495.
2008-1404, -1405, -1406 11caused toxic reactions, ris edronate outperformed 2-pyr EHDP by a substantial margin. Risedronate showed no obser vable toxic effect at a dose of 0.75 mg P/kg/day, while 2- pyr EHDP’s “no observable effect level” was only 0.25 mg P/kg/day. In another test involving live animals, 2-pyr EHDP was let hal at a dose of 1.0 mg P/kg/day while risedronate was not. Ultimately, the distri ct court weighed the evidence and evaluated the credibility of the witnesses in conclu ding that P&G had in troduced sufficient evidence of unexpected results to rebut any finding of obviousness. VI. Secondary Considerations of Non-Obviousness Secondary considerations of non-obviousness include the commercial success of the invention at issue and its satisfaction of a long-felt need. B.F. Goodrich Co. v. Aircraft Braking Sys. Corp. , 72 F.3d 1577, 1582 (Fed. Cir. 1996). The district court found that secondary consider ations supported a finding of non-obviousness. When present, such factors “may often be the mo st probative and cogent evidence [of nonobviousness] in the record.” Stratoflex, Inc. v. Aeroquip Corp. , 713 F.2d 1530, 1538 (Fed. Cir. 1983). The district court found that risedronat e, marketed as Actonel, has been an undisputed commercial success and sa tisfied a long-felt unmet need. 2 This conclusion was based on the testimony of Dr. Daniel C. Smith, who stated that risedronate experienced favorable growth and had ama ssed $2.7 billion in aggregate domestic

2 The court rightly gave little weight to risedronate’s commercial success because the prior art ’406 patent was also a ssigned to P&G. As of December 6, 1985, the filing date of the ’122 patent, 2-pyr EHDP could be found only in a pending application for the ’406 pat ent, which was not available to the public. See Merck & Co., Inc. v. Teva Pharma. USA, Inc. , 395 F.3d 1364, 1377 (Fed. Cir. 2005) (holding that commercial success is not significantly pr obative of non-obviousness where others are barred from acting on the prior art).
2008-1404, -1405, -1406 12sales. The district court based its finding of a long-felt unmet need on the fact that, in the mid-1980s, osteoporosis was recogniz ed as a serious disease and existing treatments were inade quate. However, because the co mpeting drug alendronate was available before risedronate, Teva contends that risedronate could not have satisfied any unmet need. Teva argues that the long-felt need must be unmet at the time the invention becomes available on the market, w hen it can actually satisfy that need. To support this argument, Teva cites Monarch Kn itting Mach. Corp. v. Sulzer Morat GmbH , 139 F.3d 877 (Fed. Cir. 1998). In fact, Monarch rejects a similar argument partly because the competing inventions were not actually produced until after the claimed invention’s filing date. Id. at 884. Here, alendronate was not produced until ten years after the filing of the ’122 patent. Under Monarch , we look to the filing date of the challenged invention to assess the pr esence of a long-felt and unmet need. Accordingly, it was not clear error for the di strict court to conclude that risedronate met such a need and that secondary considerati ons supported a finding of non-obviousness. VII. Whether the ’406 Patent is Prior Art As an alternative to its position that risedronate was not obvious, P&G argues that the ’406 patent should not be considered prior art with respect to the ’122 patent because risedronate was first synthesized by P&G before the ’406 patent was filed. At trial, Dr. Benedict, one of the inventors nam ed in the ’122 patent, testified that he synthesized risedronate in May 1985. P&G submitted a portion of Dr. Benedict’s laboratory notebook which cont ains a May 3, 1985 entry det ailing the structure of risedronate and the procedure for its synthesis , but this entry was unwitnessed and was not corroborated by any other evidence.

2008-1404, -1405, -1406 13“It is well established that when a party seeks to prove conception via the oral testimony of a putative inv entor, the party must proffe r evidence corroborating that testimony.” Shu-Hui Chen v. Bouchard , 347 F.3d 1299, 1309 (Fed. Cir. 2003). The inventor “must provide independent corrobor ating evidence in addition to his own statements and document s.” Hahn v. Wong , 892 F.2d 1028, 1032 (Fed. Cir. 1989). Because P&G did not provide adequate corrobor ating evidence of an earlier invention date for risedronate, the distri ct court correctly concluded t hat the ‘406 patent qualifies as prior art for purposes of this inquiry. VIII. Obviousness-Type Double Patenting In addition to its obviousness defense, Teva also asserted that the ’122 patent was invalid for double patenting. The double pat enting doctrine is designed to prevent a patent owner from extending hi s exclusive rights to an in vention through claims in a later-filed patent that are not patentably distinct from claims in the earlier filed patent. Geneva Pharm., Inc. v. GlaxoSmithKline PLC , 349 F.3d 1373, 1378 (Fed. Cir. 2003.) In general, the obviousness analysis applies to double patenting, except for three distinctions. First, statutory obviousness co mpares claimed subject matter to the prior art, while non-statutory double patenting compares claims in an earlier patent to claims in a later patent or application. Id. at 1377 n.1. Second, double patenting does not require inquiry into a motivation to modify the prior art. Id. Finally, double patenting does not require inquiry into objective criteria suggesting non-obviousness. Id. Having concluded that ris edronate was not obvious u nder 35 U.S.C. § 103, we similarly conclude that the ’122 patent is not invalid for obviousness-type double patenting. Additionally, we agr ee with the district court that the claims of the ’122 patent

2008-1404, -1405, -1406 142008-1404, -1405, -1406 15 are distinct from the claims of the ’406 patent. Comparing t he claims of the ’122 patent to those of the ’406 patent, we note that, while claims 4 and 16 of the ’122 patent explicitly claim the risedr onate compound, the ’406 patent claims an intermittent dosing regimen for the treatment of osteoporosis and claims no new compounds. Accordingly, Teva failed to present clear and convinci ng evidence of overlap between the claims of the two patents to invalidate the ’122 patent based on obviousness-type double patenting. III. CONCLUSION For the foregoing reasons, we affirm. AFFIRMED