LIFE SCIENCES! LAW & INDUSTRY

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1 A BNA, INC. LIFE SCIENCES! LAW & INDUSTRY VOL. 1, NO REPORT AUGUST 17, 2007 Reproduced with permission from Life Sciences Law & Industry Report, Vol. 1, No. 12, 08/17/2007, pp Copyright 2007 by The Bureau of National Affairs, Inc. ( ) Recent Trends in Patent Practice: The Federal Circuit s Treatment of Pharmaceuticals BY ROBERT SCHULMAN, DAVID KELLY, AND ALEXANDER SPIEGLER D uring 2005 and much of 2006, the Federal Circuit invalidated or held unenforceable nearly every pharmaceutical patent it reviewed. 1 In the past year, the court largely has continued this practice. In a previous article in 2006, the authors posed the question whether this spate of invalidations was simply the Federal Circuit s proper policing of a particular weak crop of patents, or alternatively, signaled a tectonic shift in the legal landscape. 2 With yet an additional year of data available, including an increasing number of pharmaceutical invalidations, the authors now conclude that there has indeed been a shift in the Federal Circuit s application of the law. In particular, we have identified three areas where the Federal Circuit 1 See Robert Schulman, Is it Harder to Enforce Pharmaceutical Patents? The National Law Journal, Aug. 28, 2006, at S3-S4. 2 See id. at S3. Robert Schulman is a partner in the Washington office of Hunton & Williams. He co-chairs the life sciences practice group. David Kelly is an associate in the Atlanta office of Hunton & Williams. Alexander Spiegler is an associate in the Washington office of Hunton & Williams. All of the opinions expressed herein are those of the authors and do not reflect the opinions of Hunton & Williams or its clients. has disregarded its own precedent and changed the legal landscape to make it much more difficult to defend a pharmaceutical patent. This shift is one that took place before the Supreme Court s decision in KSR Int l Co. v. Teleflex Inc. 3 If one looks at the few cases where the Federal Circuit has upheld the validity of a pharmaceutical patent, it has nearly always been in the context of novel active compounds. By contrast, the court has invalidated nearly every case in the last three years where the patent related to new forms of old actives (e.g., controlled release or novel salts) or to second uses of old actives. These results have led the authors to propose the following thesis: One can predict, with reasonable precision, the outcome of a case before the Federal Circuit simply by determining whether the claim at issue relates to a novel active or to a repackaging or second use of a known active. While we cannot predict how long this bifurcated and admittedly arbitrary treatment will persist, it represents a disturbing trend since it is completely divorced from the statute, which mandates a review of anticipation and obviousness and not a value judgment as to whether later generation embodiments are less worthy from a public policy point of view. 4 This article discusses in Section I how the court: 1) is expanding the doctrine of inherency to include a new form of obvious inherency ; 2) is lowering the bar with respect to the standard of enablement that a prior art reference must meet for purposes of being an anticipa S.Ct (2007). 4 If a new and unobvious form or a second use of an old active represents only a marginal commercial improvement over the original form, then the court should allow the marketplace to judge the value of that patent. COPYRIGHT 2007 BY THE BUREAU OF NATIONAL AFFAIRS, INC. ISSN

2 2 tory reference under 35 U.S.C. 102(b) (which is significantly lower than the standard of enablement that the patent itself must meet for purposes of satisfying 35 U.S.C. 112, 1); and 3) even prior to the Supreme Court s recent KSR decision, was lowering the evidentiary standard required to establish a prima facie case of obviousness. Section II of this article canvases those pharmaceutical patents whose validity has been sustained by the Federal Circuit. These cases suggest that the court s recent shift in its obviousness jurisprudence will not be severely affected by KSR. I. The Federal Circuit Continues to Invalidate Pharmaceutical Patents By Modifying Well-Entrenched Patent Doctrines A. The Federal Circuit Has Expanded the Inherency Doctrine to Include a Novel Theory of Obvious Inherency A patent is invalid for anticipation if a single prior art reference discloses, either expressly or inherently, each and every limitation of the claimed invention. 5 Under the doctrine of inherency, if the missing characteristic is necessarily present in or is the natural result flowing from the explicit disclosure of a prior art reference, the missing element is inherently disclosed by the prior art reference. 6 For example, the discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art s functioning, does not render the old composition patentably new to the discoverer. 7 The discoverer, however, may obtain a patent on a new method of using the old compound. In 2003, the Federal Circuit expanded the inherency doctrine by holding that the inherently anticipatory subject matter need not have been recognized in the prior art. 8 In Schering Corp. v. Geneva Pharmaceuticals, 9 the patentee claimed a metabolite of the compound commercially known as CLARITIN. When a patient ingested the drug, it inherently formed the metabolite in vivo. The court invalidated the patent on inherency grounds, noting, for example, that if Schering had claimed the metabolite in isolated form the patent may have been valid. 10 Following up Schering, the Federal Circuit in SmithKline Beecham Corp. v. Apotex Corp, 11 held that a claim directed to paroxetine hydrochloride (PHC) in hemihydrate form was inherently anticipated by prior art showing the PHC in anhydrous form because a small fraction of the anhydrous form spontaneously converted to the hemihydrate form. As in Schering, the court held that since the claims covered compounds that were the natural and necessary result of prior art processes, notwithstanding 5 See e.g., Schering Corp. v. Geneva Pharmaceuticals 339 F.3d 1373, 1377 (Fed. Cir. 2003). 6 Id. at 1377, Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999). 8 See Schering Corp., 339 F.3d at The court also held that it is permissible to rely on inherency for the entirety of the claimed subject matter, or even a single claim limitation. Id. at F.3d 1373 (Fed. Cir. 2003). 10 Id. at F.3d 1331 (Fed. Cir. 2005). that the art may not have recognized or appreciated the compounds, the claims were inherently anticipated. 12 Starting in 2005, however, the Federal Circuit commenced an expansion of the doctrine of inherency to situations where the product claimed was not the natural or necessary result of following the prior art teaching. For example, in Upsher-Smith Laboratories Inc. v. PamLab LLC, 13 a claim directed to vitamin supplement compositions consisting of vitamin B12 and folate but excluding antioxidants (which the inventor discovered destroy some of the vitamin B12 and folate) was anticipated by prior art disclosing compositions optionally including antioxidants. What makes this case interesting is that there was no actual example of the composition being made without the antioxidant. Rather, the court found inherency simply because the composition without antioxidants was enabled. It is submitted that in a previous incarnation, the court in this situation would have found the invention to have been obvious rather than inherently anticipated. This is a significant distinction because an applicant or patentee facing an anticipation rejection cannot rebut it with evidence of secondary considerations (such as unexpected results or commercial success) in contrast to an obviousness rejection where such secondary considerations are relevant. Similarly, in Perricone v. Medicis Pharmaceutical Corp., 14 claims directed to treating aged skin by applying a particular ascorbic acid-containing composition were found to be inherently anticipated by a prior art teaching disclosing compositions comprising various alternative skin benefit ingredients, including ascorbyl palmitate as one of 14 possible ingredients. The prior art did not include an example actually using the ascorbyl palmitate in a compostion. Rather, relying on the fact that the prior art enabled a composition including ascorbyl palmitate and that it was specifically enumerated in a list of ingredients, the court found inherent anticipation: In total, Pereira teaches a total of fourteen skin benefit ingredients. This court rejects the notion that one of these ingredients cannot anticipate because it appears without special emphasis in a longer list. To the contrary, the disclosure is prior art to the extent of its enabling disclosure. 15 This case demonstrates well the paradigm shift exhibited by the Federal Circuit that something is inherent simply because it is an enabled embodiment included in the prior art teaching. Unlike previous cases, such as Schering and SmithKline, there was no evidence in Perricone that the compound had actually been formed in the prior art. Interestingly, the court distinguished In re Baird, 16 which likewise involved a selection from a list of compounds, because that case involved obviousness, not anticipation. 17 This is a remarkable way to distinguish precedent: simply turn what used to be an obviousness rejection into an inherent anticipation rejection and then conclude that prece- 12 Id. at F.3d 1319 (Fed. Cir. 2005) F.3d 1368 (Fed. Cir. 2005). 15 Id. at F.3d 380 (Fed. Cir. 1994). 17 Perricone, 432 F.3d at COPYRIGHT 2007 BY THE BUREAU OF NATIONAL AFFAIRS, INC. LSLR ISSN

3 3 dent is inapposite because it relates to a different section of the statute. Last November, the Federal Circuit invalidated a patentee s claims to an anesthetic composition and methods of combining the composition with Lewis acid inhibitors. In Abbott Laboratories v. Baxter Pharmaceutical Products Inc., 18 Abbott claimed: An anesthetic composition comprising: a quantity of sevoflurane; and a Lewis acid inhibitor in an amount effective to prevent degradation by a Lewis acid of said quantity of sevoflurane, said Lewis acid inhibitor selected from the group consisting of water. In the course of making sevoflurane, the prior art carried out a purification process involving saturating the sevoflurane with water and admixing it with a specific compound, followed by a distillation of product and removal of water. The district court affirmed the validity of the patent since the prior art s formation of the sevoflurane/water admixture was merely an intermediate step in the manufacture of sevoflurane and the patent s purpose was not to produce sevoflurane in its final useable form. 19 The Federal Circuit reversed. The court acknowledged that prior to Abbott s patent no one was aware of the stabilizing effect water would have to prevent Lewis acid degradation. 20 On the contrary, water was considered an impurity and was removed from sevoflurane to the extent possible during the manufacturing process, including by the teachings of the [prior art]. 21 Nonetheless, referring to this water-saturated intermediate, the court noted that its cases have consistently held that a reference may anticipate even when the relevant properties of the thing disclosed were not appreciated at the time and that the general principle that a newly discovered property on that same art is not avoided if the patentee explicitly claims that property. 22 Accordingly, even though Abbott was correct that nobody knew that the water-saturated sevoflurane of the prior art had the property of resisting the Lewis acid degradation reaction, it was to no avail since the prior art disclosed sevoflurane saturated with water. 23 In terms of the composition, it seems that the case easily could have gone the other way because Abbott claimed an anesthetic composition, whereas the water-saturated intermediate of the prior art included the impurities that made the composition ill-suited for administration to a patient. More disturbing is the fact that the court also found the method of preventing degradation by a Lewis acid of sevoflurane to be inherently anticipated. 24 Although the court acknowledged that new uses of known processes may be patentable, here it concluded that the processes were directed to the same purpose. 25 The same purpose the court cited was that the prior art, like Abbott, was seeking the delivery of safe, effective sevoflurane. 26 But this holding begs the inevitable question: when does a process for making a pharmaceutical ever have a purpose other than making a safe and effective pharmaceutical? The court just as easily could have defined the purpose of the prior art addition of water as being related to purification of the drug, whereas the claimed method related to stabilization of the drug, which is clearly a different purpose. Defining purpose so broadly is yet another example of how the court is finding ever more expansive ways to invalidate patents based on inherency. In 2007, the Federal Circuit continues to rely on this novel application of the doctrine of inherency to invalidate pharmaceutical patents. In In re Omeprazole Patent Litigation, 27 Astra claimed a process for preparing an oral pharmaceutical formulation for, inter alia, Omeprazole, the generic form of Prilosec. 28 Omeprazole inhibits the production of gastric acid. Omeprazole, however, degrades in acidic and neutral environments of the digestive tract. Therefore, any Omeprazole formulation must be protected from contact with gastric juices. Astra discovered and claimed a method of preparing a formulation that provides such protection. Astra determined that under certain conditions a core material comprising Omeprazole and an alkaline reactive compound would react in situ with an enteric coating polymer so as to form a separating layer (the third layer ). 29 Astra discovered this when it tried to show that a Korean competitor (CKD) was infringing an earlier Astra patent that separately coated the core with two successive layers. 30 CKD insisted that they were making only a single enteric coating layer, as disclosed in their patent, but Astra found a third layer in some CKD product and reported this to the Korean court. CKD then disclosed their process, which Astra realized used different temperature conditions than Astra had used. 31 At this different temperature, only two layers formed. 32 Astra filed an application that matured into U.S. Patent No. 6,013,281 based on its discovery that a third layer could be formed in situ. Claim 1 of Astra s patent recites a process for preparing an oral pharmaceutical composition by: forming a core material comprising a proton pump inhibitor and at least one alkaline reacting compound, wherein the concentration of the alkaline reacting compound is about 0.1 mmol/g dry ingredients in the alkaline containing part of the core material, and applying an enteric coating polymer layer so as to surround the core material thereby forming in situ a separating layer as a water soluble salt product between the alkaline compound and the enteric coating polymer. 33 The Federal Circuit held that CKD s patent application anticipated the Astra claim because, inter alia, As F.3d 1363 (Fed. Cir. 2006). 19 Id. at Id. at Id. 22 Id. at Id. at Id. at Id. at Id. at F.3d 1364 (2007). 28 Id. at Id. 30 Id. at Id. at Id. 33 Id. at (emphasis added). LIFE SCIENCES LAW & INDUSTRY REPORT ISSN BNA

4 4 tra had argued to the Korean court that the CDK product had a third layer. 34 The court also reasoned that since the ingredients used by CDK were capable of forming the third layer, the claim was anticipated. 35 The claim element thereby forming in situ a separating layer as a water soluble salt product was not considered to limit the process only to low temperatures where the layer formed as distinct from the higher temperatures routinely used by CKD, where the layer did not form. 36 In her dissent, Judge Pauline Newman charged that the court was applying a novel theory of inherent anticipation. 37 Specifically, she argued that although Astra admitted that it believed that the CKD had made such a product, it is undisputed that such a sublayer does not form under the conditions in the CKD patent application. 38 She suggested that the majority s decision was contrary to a vast body of precedent holding that anticipation cannot be predicted on mere conjecture and that it is insufficient if a material element or limitation is merely probably or possibly present in the prior art. 39 Thus, at present, the Federal Circuit seems intent on invalidating pharmaceutical patents whenever it perceives an enabling combination of elements of a prior art reference, even if it is a far cry from the necessary result of following that teaching. It is submitted that, as Judge Newman noted in her dissent, the court has seriously corrupted the application of the doctrine of inherency, to the detriment of pharmaceutical patentees. B. The Federal Circuit Has Lowered the Enablement Standard for Prior Art References Making It Easier to Invalidate Claims Based on Anticipation It is black letter law that a patent claim cannot be anticipated by a prior reference if the allegedly anticipatory disclosures cited as prior art are not enabled. 40 In recent years, however, the Federal Circuit has relaxed the standard of enablement that a prior art reference must provide. Beginning in 2005, the Federal Circuit repeatedly has held that not all enablement is created equal. Indeed, the degree of enablement required to establish that a prior art reference is anticipatory is much diminished compared to the degree of enablement required for the patent itself. Specifically, the court has held that a prior art reference that is not enabling under 35 U.S.C. 112, 1 may still be an anticipatory reference under 35 U.S.C. 102(b). In Rasmusson v. SmithKline Beecham, 41 the applicant claimed a method of treating prostate cancer by 34 Id. at Id. at Id. at Id. at Id. at Id. at Elan Pharmaceuticals Inc. v. Mayo Foundation, 346 F.3d 1051, 1054 (Fed. Cir. 2003). One possible exception related to the limited situation where an applicant claimed a chemical compound having a given utility in view of prior art disclosing that compound but without any stated utility. Even though such prior art was technically non-enabling, it nonetheless could be cited as an anticipatory reference against the claim. However, even in such instances, the applicant was not precluded from claiming a method of use for the compound. See, e.g., In re Schoenwald, 964 F.2d 1122 (Fed. Cir. 1992) F.3d 1318 (Fed. Cir. 2005). administering a therapeutically effective amount of finasteride. The Board of Patent Appeals and Interferences concluded that the patent applicant s priority applications were non-enabling under 35 U.S.C. 112, The board reasoned that even though finasteride was known as a selective 5aR inhibitor, a person skilled in the art would not have understood that it was effective in treating prostate cancer as claimed. 43 The board also held that a European prior art patent with the same disclosure did not anticipate the claims because it lacked an enabling disclosure since it failed to demonstrate that finasteride was effective in treating prostate cancer. 44 The Federal Circuit upheld the Board s determination that the applicant s priority applications were nonenabling, but reversed the Board s decision that the European equivalent patent was non-enabling for purposes of anticipation. 45 The court explained that [t]he standard for what constitutes proper enablement of a prior art reference for purposes of anticipation under section differs from the enablement standard under section Thus, according to the court, while a reference may be used to show the state of the art does not enable a claimed invention, that same reference may be used to invalidate the non-enabled invention. The court cited In re Hafner for the proposition that a disclosure lacking a teaching of how to use a fully disclosed compound for a specific, substantial utility... is... entirely adequate to anticipate a claim to... the product... and, at the same time, entirely inadequate to support the allowance of such a claim. 47 It also cited Bristol-Myers Squibb Co. v. Ben Venue Labs 48 for the proposition that newly discovered results of a known process directed to the same purpose are not patentable because such results are inherent. 49 The problem with the court s reliance on these two cases is that the prior art in these cases actually prepared the claimed product or carried out the claimed steps whereas the prior art in this instance never treated prostate cancer with finasteride. In Impax Laboratories Inc. v. Aventis Pharmaceuticals Inc., 50 the Federal Circuit, applying the holding in Rasmusson, reversed the district court s finding of validity for Aventis claims to a method of treating amyotropic lateral sclerosis (ALS) with riluzole (6- trifluoromethoxy-2-benzothiazolamine). Impax alleged that U.S. Patent No. 5,236,940 (the 940 patent) and its French priority application anticipated Aventis claims. The 940 patent discloses a formula I that includes many different compounds. 51 Although riluzole literally falls within this formula, the 940 patent specifically excludes it because it was not new at the time of filing the 940 patent Id. at Id. 44 Id. at Id. at 1324, Id. at Id. (quoting In re Hafner, 56 C.C.P.A. 1424, 410 F.2d 1403 (Cust. & Pat. App. 1969)) F.3d 1368 (Fed. Cir. 2001). 49 Rasmusson, 413 F.3d at USPQ2d 1001 (Fed. Cir. 2006). 51 Id. at Id COPYRIGHT 2007 BY THE BUREAU OF NATIONAL AFFAIRS, INC. LSLR ISSN

5 5 The 940 patent discloses that the compounds of formula I: are useful in the treatment of medical conditions associated with the effects of glutamate.... They are active with respect to glutamateinduced convulsions, and are hence useful in the treatment and prevention of convulsive phenomena, schizophrenic disorders, and in particular the deficiency forms of schizophrenia, sleep disorders, phenomena linked to cerebral ischaemia and also neurological conditions in which glutamate may be implicated, such as Alzheimer s disease, Huntington s chorea, amyotrophic lateral sclerosis and olivopontocerebellar atrophy. 53 The district court concluded that Aventis patent was not anticipated by the 940 patent because formula I entails such a large number of compounds... [that] one of ordinary skill in the art would not have recognized that riluzole was effective in treating ALS without additional detail or guidance that is not found in the disclosure of the 940 patent. 54 The district court further concluded that the language indicating that formula I compounds treat neurological conditions in which glutamate may be implicated amounted to speculation that those compounds would be useful in treating ALS. 55 The Federal Circuit reversed. The court noted that while the 940 patent includes riluzole as a formula I compound, suggests that formula I compounds may be used to treat ALS, and provides some dosage information, the district court incorrectly found that the 940 patent did not anticipate the 814 patent because the disclosure of the 940 patent was not enabling at least in part because there was no evidence that it would be effective. 56 The court explained, as we recognized in Rasmusson, proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation. 57 Rather, the proper issue was whether the 940 patent described the claimed invention sufficiently to enable a person of ordinary skill in the art to carry out the invention. It is again submitted that, in its previous incarnation, the inherency doctrine would not have been applied to invalidate this patent, where one had to select a single compound from among many and where the efficacy of such compounds for treating a particular disease was so speculative. It seems that now if there is any discussion of a potential therapeutic use for a class of compounds in the prior art, the Federal Circuit will find it inherently anticipated despite the complete lack of efficacy. In other words, even the most speculative proposal is worth its weight in gold as far as this court is concerned. C. The Federal Circuit Has Watered Down the Standard for Establishing a Prima Facie Case of Obviousness Recently, in KSR Int l Co. v. Teleflex Inc., 58 the Supreme Court rejected the rigid application of the Fed- 53 Id. (emphasis added). 54 Id. 55 Id. at Id. at Id S. Ct (2007). eral Circuit s teaching, suggestion, or motivation (TSM) test in an obviousness inquiry. 59 But even before KSR, the Federal Circuit already was requiring a lower showing to prove a prima facie case of obviousness. Indeed, in several cases, the court went out of its way to point out that its TSM test is flexible, allowing the teaching, suggestion, or motivation to come from a variety of sources, such as expert testimony or even common sense. For example, in Alza Corp. v. Mylan Laboratories Inc., 60 Alza claimed a sustained-release oxybutynin formulation comprising a therapeutic dose of an oxybutynin or its pharmaceutically acceptable salt, in a controlled-release manner, for treating incontinence. Alza argued that its controlled-release oxybutynin formulation was not obvious because the prior art did not provide a reasonable expectation of success that oxybutynin would be colonically absorbed, which is necessary for controlled release. 61 Mylan s expert testified that, based on its lipophilicity, he would expect oxybutynin to be a highly permeable compound that is rapidly absorbed along the length of the gastrointestinal tract, including the colon. 62 The court held that under our non-rigid motivationsuggestion-teaching test, a suggestion to combine need not be found in the prior art but rather can be based on the testimony of an expert witness to determine the knowledge that a person of ordinary skill in the art would have possessed at a given time. 63 The court concluded that while colonic absorption was not guaranteed, the evidence, viewed as a whole, is clear and convincing that a person of ordinary skill in the art would nonetheless have perceived a reasonable likelihood of success and that she would have been motivated to combine prior art references to make the claimed invention. 64 The key point of this case is that obviousness can be found absent any prior art and under a very flexible anything goes standard. This is why Alza s evidence of non-obviousness, i.e., that lipophilicity did not necessarily translate into colonic absorption, could be trumped by the testimony of a paid expert in a litigation. Although not involving a pharmaceutical, the case of DyStar Textilfarben GmbH & Co. Deutschland KG. v. C.H. Patrick Co. 65 further illustrates how the court, even before the KSR decision, has practically eliminated the need for a meaningful teaching, suggestion, or motivation to combine references. In DyStar, the court, citing Alza, likewise referred to the flexibility of its teaching-suggestion-motivation test in invalidating a patent directed to an indigo dyeing process even though the prior art provided no explicit motivation for combining references. Dystar had argued that the court s suggestion test for obviousness requires the cited references themselves to contain a suggestion, teaching or motivation to combine them and that it 59 See also Takeda Chemical Indus. Ltd. v. Alphapharm Pty. Ltd., 2007 WL * 5(Fed. Cir. June 28, 2007) USPQ2d 1001 (Fed. Cir. 2006). 61 Id. at Id. at Id. at 1006 (emphasis added). 64 Id. at USPQ2d 1641 (Fed. Cir. 2006). LIFE SCIENCES LAW & INDUSTRY REPORT ISSN BNA

6 6 66 Id. at Id. 68 Id. at Id. at F.3d 1348, 1361 (Fed. Cir. 2007). 71 Id. at Id. at Id. at 1362 (citing DyStar). must be explicitly stated. 66 Dystar also argued that since Brochet does not suggest combining his invention with those of Chaumat or Wimmer to stabilize his leuco indigo solution in oxygen-excluding containers until either using it directly in the dyebath or placing it on the market for sale, the invention cannot be obvious. 67 The Federal Circuit disagreed. The court stated it had repeatedly held that an implicit motivation to combine exists not only when a suggestion may be gleaned from the prior art as a whole, but when the improvement is technology-independent and the combination of references results in a product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient. 68 The court held that an ordinary artisan with knowledge of Chaumat, reading Brochet, would have realized that, by stabilizing catalytic hydrogenated leuco indigo solution in oxygen-excluding containers, he could devise a cheaper, faster, and more convenient indigo dyeing process. 69 So in other words, if a combination results in an invention that is better (e.g., stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient), that is sufficient motivation. It would seem, therefore, that under this court s reading of the law, the only way to avoid prima facie obviousness for a claim directed to a combination is to make an invention which is less efficient and less desirable. Applying the principles of implicit motivation set forth in DyStar, the Federal Circuit recently invalidated yet another pharmaceutical patent. In Pfizer Inc. v. Apotex Inc., 70 Pfizer claimed the besylate salt of amlodipine. The district court found that although amlodipine besylate was not superior to the prior art amlodipine maleate in every category, it nonetheless clearly and unexpectedly illustrates a superior combination of properties such as non-stickiness when compared against the amlodipine maleate. 71 The Federal Circuit reversed and held that the claimed besylate salt would have been obvious over an earlier Pfizer patent to amlodipine and pharmaceutically-acceptable salts thereof in view of a prior art reference disclosing pharmaceutically acceptable anions that could be used to form addition salts. 72 The court rejected Pfizer s argument of lack of motivation to combine references, stating, a suggestion, teaching, or motivation to combine the relevant prior art teachings to achieve the claimed invention does not have to be found explicitly in the prior art references sought to be combined, but rather may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. 73 According to the court, the motivation existed because Pfizer discovered that amlodipine maleate was susceptible to degradation from a Michael addition reaction in which the double bond of maleate underwent an addition reaction causing the formation of degradation products. 74 The court agreed that testimony from Apotex s expert supports an inference that the skilled artisan actually would have been encouraged, rather than discouraged, to choose an anion without the same double bond, such as benzene sulphonate, in order to avoid the Michael addition reaction. 75 The court also rejected Pfizer s argument that amlopidine in its besylate salt form would be at best obvious to try. 76 The court stated that this is not the case where there are numerous parameters to try. 77 Rather, the court found motivation to narrow the genus of 53 pharmaceuticallyacceptable anions to a few. 78 Although purportedly limited to the particularized facts of [the] case, the Federal Circuit implicitly endorsed the obvious to try standard as a means for challenging the validity of pharmaceutical patents. One particularly disturbing aspect of this case is the court s conclusion that the claimed salt would have been obvious because, in forming the salts, it was conventional to test their properties. 79 So in other words, if one can test the efficacy of that combination, the results of that combination are predictable. Once again, this signals a major departure from precedent. Pfizer was not the first to question the validity of a pharmaceutical patent on obviousness based on inference rather than prior art. In Abbott Laboratories v. Andrx Pharmaceuticals Inc., 80 Abbott claimed a composition for extended release of an erythromycin derivative comprising the derivative, and a pharmaceutically acceptable hydrophilic water-soluble polymer (such as HPMC), which gave rise to the desired release profile. 81 The accused infringer, Teva, alleged that it would have been obvious to use erythromycin in combination with HPMC because Abbott s prior patent disclosed a first erythromycin derivative (clarithromycin) in combination with an alginate carrier, and a secondary reference disclosed HPMC in combination with a compound (azithromycin) related to the first derivative, thus making it obvious to replace the alginate of Abbott s patent with HPMC. 82 Abbott argued, and the district court agreed, that since azithromycin and clarithromycin are so different, there would have been no reasonable expectation of success that the HPMC polymer suitable for azithromycin could be suitably employed with the clarithromycin of the earlier Abbott patent. 83 But on appeal, the Federal Circuit rejected Abbott s contention that erythromycin derivatives (clarithromycin) and azithromycin are so different, and reversed the district court. 84 The court noted that the prior art patent explicitly discloses only clarithromycin controlled release compositions, yet claims azithromycin compositions, and that Abbott had represented to the 74 Id. 75 Id. 76 Id. at Id. at Id. at 1363; see also, Takeda Chemical Indus., Ltd., 2007 WL at *8. 79 Pfizer Inc., 480 F.3d at F.3d 1331 (Fed. Cir. 2006). 81 Id. at Id. at Id. at Id. at COPYRIGHT 2007 BY THE BUREAU OF NATIONAL AFFAIRS, INC. LSLR ISSN

7 7 PTO that the differences between clarithromycin and azithromycin were such that azithromycin could be substituted into a controlled release clarithromycin composition by a person of ordinary skill in the art without undue experimentation. 85 It concluded, therefore, that if a patentee includes two compounds in a single claim, but only explicitly discloses one of them, then that patentee has represented to the PTO that one could be substituted for the other in that same context (e.g., controlled release). II. The Federal Circuit Has Consistently Upheld the Validity of Pharmaceutical Patents Directed to Novel Actives The Federal Circuit recently upheld the validity of several patents directed to novel actives. For example, in Sanofi-Synthelabo v. Apotex Inc., 86 the court reviewed the validity of Sanofi s drug Plavix and, in particular, a claim reciting hydrogen sulfate of the dextrorotatory isomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thienopyridyl) (2-chlorophenyl)-acetate ( MAT- TPCA ) substantially separated from the levo-rotatory isomer. Apotex argued the two missing limitations, the d-enantiomer and the bisulfate salt, were inherently disclosed in the prior art. The district court disagreed and found that of the at least 50 different pharmaceutically acceptable salts that could have been chosen, the skilled artisan actually would have been dissuaded from preparing the bisulfate salt in light of the prior art s disclosure. 87 The Federal Circuit upheld the district court, distinguishing previous cases on grounds that they disclosed a pattern of preferences for the later claimed species, whereas the prior art reference here did not. 88 In Eli Lilly & Co. v. Ivax Pharmaceuticals Inc., 89 the court addressed the validity of claims covering the compound olanzapine (marketed commercially under the name Zyprexa ), pharmaceutical compositions including olanzapine, and methods of treating schizophrenia using olanzipine. Pointing to earlier Federal Circuit precedent, Ivax asserted that a prior art reference anticipated Lilly s patent because it identified compounds from the same family of compounds (thienobenzodiazepines). 90 While acknowledging some of its prior cases had found a particular species anticipated by a broad genus in the prior art, the court in Eli Lilly found these holdings inapposite. In Petering, the prior art disclosed a limited number of specific preferences from a specifically defined group of [the genus]. 91 Similarly, the prior art in another case disclosed 14 compounds, later further narrowed to seven, considering express preferences. 92 By contrast, the number of compounds actually disclosed in the prior art reference asserted against Lilly numbers in the millions (including all proposed alternative substituents). 93 The court found that [n]o possible combination of those preferred substituents would lead to the components that make up olanzapine, because each would contain a fluorine or a chlorine. 94 Indeed, the court stated that one would have to depart from the teaching of the article and recombine the components of the specific illustrative compounds with hindsight. 95 In Takeda Chemical Indus. Ltd. v. Alphapharm, 96 decided after KSR, the Federal Circuit upheld the validity of claims directed to the compound pioglitazone a thiazolidinedione having a 5-ethyl-substituted 2-pyridyl ring. The prior art taught a thiazolidinedione compound having a 6-methyl-substituted 2-pyridyl ring. The accused infringer, Alphapharm, argued that one of skill in the art would have made two obvious changes: 1) replacing the methyl with an ethyl (resulting in the 6-ethyl compound); and 2) moving the ethyl substituent to the 5-position, thereby leading to the discovery of pioglitazone. 97 The district court found that the claims were nonobvious. It held that Alphapharm failed to demonstrate why a person skilled in the art would have chosen the particular 6-methyl-substituted pyridyl thiazolidinedione of the prior art as the lead compound for further development. 98 The court found that the prior art disclosed millions of thiazolidinediones and did not provide guidance that would lead the skilled artisan to select the disclosed 6-methyl-substituted pyridyl thiazolidinedione as a lead compound. 99 Sustaining the validity of the claims on appeal, the Federal Circuit distinguished precedent by suggesting that structural similarity (e.g., homologs, analogs, or isomers of known compounds) creates prima facie obviousness only if the prior art would have suggested the specific modifications to make to the claimed compound. 100 The court held that this test was consistent with KSR, as the Supreme Court acknowledged the importance of identifying a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does in an obviousness determination. 101 The court continued: in cases involving new chemical compounds, 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 obviousness of a new claimed compound. 102 Accordingly, as can be seen in the Federal Circuit s decisions in Sanofi-Synthelabo, Eli Lilly, and Takeda, the court appears more willing to sustain the validity of novel actives, even when these compounds are homologs to prior art compounds. III. Conclusion Over the past year, the Federal Circuit has persisted in closely scrutinizing pharmaceutical patents. Relying on novel applications of old doctrines, the court has continued to invalidate the overwhelming majority of pharmaceutical patent claims before it. For example, the court has broadened the doctrine of inherent an- 85 Id. at F.3d 1368 (Fed. Cir. 2006). 87 Id. at Id. at F.3d 1369 (Fed. Cir. 2006). 90 Id. at Id. 92 Id. 93 Id. 94 Id. at Id WL (Fed. Cir. June 28, 2007). 97 Id. at*5. 98 Id. 99 Id. at* Id. at *4, *9, * Id. at* Id. LIFE SCIENCES LAW & INDUSTRY REPORT ISSN BNA

8 8 ticipation to include a novel theory of obvious inherency so as to expand the doctrine of inherency to situations involving selecting from among many variables. Moreover, the court has lowered the standard of what is considered to be an enabling prior art reference well beyond the previous limit. Finally, the court has diminished the motivation required to prove a prima facie case of obviousness and has suggested that obvious to try is enough to invalidate a pharmaceutical patent. Analyzing these trends, a common theme seems to be emerging. The court seems much more willing to invalidate patent claims directed to novel formulations and administration methods of old actives than claims directed to novel actives. We have no way of knowing if this result is due to concern that claims to new forms or second uses of old compounds represent an attempt by pharmaceutical companies to wrongly expand their patent monopoly. What we do know is that neither the court s own precedent nor the statute mandate such result COPYRIGHT 2007 BY THE BUREAU OF NATIONAL AFFAIRS, INC. LSLR ISSN