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TTh e U.S. patent system is designed to promote innovation by rewarding investment in

research, such as that undertaken within the pharmaceutical industry in developing new drugs. Typically, hundreds of millions of dollars are invested to bring a single drug to market, notwithstanding those eff orts which do not result in a marketable product. For pharmaceutical products and therapies, especially blockbuster drugs, patent exclusivity is a primary driver in building and maintaining product revenue stream. So it is a major concern if the patent coverage available for any pharmaceutical becomes more vulnerable to unforeseen legal challenges due to a signifi cant change in the law.

KSR and ObviousnessIn patent law, obviousness is the

concept that a supposed invention is so similar to an earlier technology, although not identical, that it is unworthy of patent protection. Th e U.S. Supreme Court fi rst defi ned the

formal legal test for obviousness in the 1966 decision, Graham v. John Deere Co. of Kansas City.1 As a general matter, establishing obviousness involves proff ering a plurality of evidencefrom various sources such as publications (i.e., prior art) or expert witness testimony.

Th ese sources correspond to teachings, suggestions and motivations (TSM) which must be combined to approximate the claimed invention. Th e combination cannot be unreasonable, but instead must have some reasonable expectation of success. Th is reasonable expectation is in the hypothetical view of a person qualifi ed by having ordinary skill, education and training in the subject matter involved.

In April 2007 the Supreme Court decided KSR Int’l v. Telefl ex, Inc.,2 introducing a major change to the legal concept of obviousness. Th is change restricts the enforceability of many U.S. patents as they are more subject to obviousness challenges to their validity in court. Th e change also inhibits the availability of new patents from the U.S. Patent and Trademark Offi ce (PTO). Since the Graham decision in 1966, a large number of specifi c legal rules had developed in obviousness law by the Federal Circuit3 and other courts, as to how various TSM combinations could be established to prove up obviousness.

In KSR, the Supreme Court rejected a rigid application of the Federal Circuit’s TSM tests. Th e Supreme Court in KSR mandated a more fl exible approach, thus making it easier for a challenger to invalidate a patent for obviousness. Although KSR involved a patent with claims drawn to a mechanical apparatus, it aff ects the obviousness analysis applied to all types of U.S. patents. Th is article focuses on the eff ect KSR has had upon pharmaceutical patents.4

Has KSR Introduced a Major Change for Pharmaceutical Patents?

Th e eff ect of a major departure from prior law is diffi cult to determine until the change is defi ned through subsequent judicial decisions. In general, it is diffi cult to identify trends in patent law, and in particular obviousness law, as these cases tend to be heavily fact-specifi c in nature. But at this point, it is clear that KSR has had some impact on pharmaceutical patents, both in district court patent litigation and in ex parte matters for obtaining new pharmaceutical patents from the PTO.

Shortly aft er KSR was announced in 2007, a number of district court decisions refl ected a liberal interpretation of KSR as a basis for

Pharmaceutical Patentsin the Age of KSRby Patrick R. Delaney

Mr. Delaney

is an independent attorney practic-ing patent law in Alexandria, VA.

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substantial new challenges to the validity of pharmaceutical patents based on obviousness. Th e Federal Circuit, however, has announced a series of decisions since KSR. Th ese appellate decisions suggest the actual impact to pharmaceutical Intellectual Property (IP) portfolios is less substantial than originally expected, albeit with some exceptions depending upon the subject matter of the patent claims.

Pharmaceutical Compounds and Obviousness Based on Chemical Structure

Pharmaceutical patents oft en have claims involving the chemical structure of a pharmaceutically active compound. Many of the relevant Federal Circuit decisions since KSR have acknowledged the highly unpredictable nature of small molecule chemical structures, thus rendering this specifi c type of pharmaceutical patent less vulnerable than other types of patents to obviousness challenge based on KSR.

Th e Federal Circuit decided Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.5 in June of 2007. In Takeda, the court interpreted KSR in a way arguably strengthening, rather than weakening, pharmaceutical patents having claims directed to a chemical structure. Th e drug in Takeda was ACTOS, which contains pioglitazone, a compound used to control blood sugar in Type II diabetes.

In the obviousness determination, the structural diff erence between pioglitazone, the claimed chemical compound, and the proposed chemical compound involved replacing similar alkyl groups (i.e., homology) displaced between neighboring positions on a ring structure (i.e., ring-walking).

In Takeda, the court fi rst acknowledged that KSR did not involve a radical change in the obviousness determination in chemical structure cases stating the test for obviousness of chemical compounds is consistent with earlier legal principles and that the KSR court had merely rejected only a rigid application of the TSM tests in an obviousness inquiry. Th e court in Takeda also emphasized that the KSR decision had acknowledged the importance that a challenger identify a reason that would prompt a person of ordinary skill in the relevant fi eld to combine the elements to meet the claimed new invention.

Th e challenger in Takeda had argued that the two compounds were so close in chemical structure so as to be obvious as a matter of law and based this argument upon a prior appellate decision6 that chemical structure similarity, when very close, is suffi cient to establish obviousness as a matter of law. Th e Takeda court, however, distinguished this notion of obviousness as a matter of law.

Th e court fi rst determined that the two compounds were shown to have dissimilar pharmaceutical properties which were not previously known, and emphasized how this established the highly unpredictable nature of chemical structure cases. Th e court then held that obviousness had not been established without some factual showing to support why the diff erences, homology and ring-walking, would have been obvious.

Th e 2008 decision in Ortho-McNeil Pharmaceutical, Inc. v. Mylan Laboratories, Inc.7 also supports the view that pharmaceutical patents involving a chemical structure in the claims are not subject to any new KSR-

type obviousness challenges. Ortho-McNeil involved TOPOMAX, an epilepsy drug containing the chemical compound topiramate. Mylan challenged the validity of the patent covering topiramate citing KSR to support the obviousness challenge. Th e rationale was based on the supposed probability of a person of ordinary skill in the art discovering topiramate from a fi nite number of choices and being motivated merely by design need or market pressure to solve a problem.

Th e court in Ortho-McNeil rejected Mylan’s application of KSR and countered that the discovery process for topiramate did not present a fi nite and small number of options. Th e court held that KSR did not apply as the mechanical case in KSR posited a situation with a fi nite, and in the context of the art, small or easily traversed number of options that would convince an ordinarily skilled artisan of obviousness. Th e court in Takeda also reinforced the distinction for pharmaceutical patents that even small changes in chemical structure were highly unpredictable when the available prior art fails to identify predictable solutions for the pharmaceutical activity involved.

Th e importance of considering unpredictability in determining obviousness was amplifi ed by the court in Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd.8 Th e Eisai case involved ACIPHEX, which contains the proton pump inhibitor rabeprazole, a compound for the treatment of duodenal ulcers and heartburn. Th e structural diff erence between rabeprazole and the proposed compound for comparison, lansoprazole, involved a change in only a single lipophilicity-conferring

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fl uorinated substituent of the proposed lansoprazole molecule.

Th e challenger cited KSR as a basis for challenging the validity of the patent covering ACIPHEX but proff ered no factual evidence to support why one of ordinary skill in the art would be motivated to make the proposed substitution. In line with both Takeda and Ortho- McNeil, the court in Eisai determined that the record contained no reasons a skilled artisan would have considered modifi cation of lansoprazole by removing the lipophilicity-conferring fl uorinated substituent from the proposed compound as an identifi able, predictable solution and as such, the record did not support a case of obviousness.

Th e Federal Circuit has been consistent in advancing unpredictability as a basis for non-obviousness in other recent cases involving closely related chemical structures. Chemical enantiomers are two chemical compounds that are nearly the same with the exception that they are mirror images of each other. For example, a left -hand image and a right-hand image. As such, enantiomers polarize light in opposite directions.

Th e drug Plavix contains clopidogrel, a dextrorotatory (i.e., clockwise polarizing) enantiomer compound for inhibiting the aggregation of blood platelets and used to treat or prevent blood-thrombotic events. Clopidogrel is therapeutically eff ective and completely without certain bad side eff ects which were all found to be associated with the opposite levorotatory enantiomer (i.e., counter-clockwise polarizing) of clopidogrel. In addition, this undesirable enantiomer had no therapeutic effi cacy. In Sanofi -Synthelabo v. Apotex, Inc.,9 the court

affi rmed the validity of the Plavix

patent. Th e court determined the two enantiomeric chemical structures were not obvious variants to each other due to the highly unpredictable fi nding of completely opposite pharmaceutical properties in the two separate enantiomeric compounds.

Similarly, in Proctor & Gamble v. Teva Pharmaceuticals USA, Inc.,10 the court’s decision involved the obviousness of ACTONEL containing the bisphosphonate compound risedronate, a drug for the treatment of osteoporosis. On appeal, Teva contended that, under KSR, the structural similarities between risedronate and another compound, 2-pyr EHDP, rendered the challenged claims of the patent covering ACTONEL obvious. Risedronate and 2-pyr EHDP are positional isomers in that they each contain the same atoms arranged in a slightly diff erent way. Th e court did not agree with Teva and found the patent to be valid on the basis that there was no credible evidence that the structural modifi cation was routine.

Altana Pharma AG and Wyeth v. Teva Pharmaceuticals USA, Inc., et al.11 is somewhat of an exception to this line of cases. In Altana, the drug Protonix was involved. It contains the compound pantoprazole, which is another proton pump inhibitor and used to treat gastric acid disorders in the stomach. Th e challenger made only a preliminary and partial showing that pantoprazole might be an obvious variant of a proposed chemical compound and the court agreed that the patent might be vulnerable to a validity challenge based on obviousness. However, in Altana, there was no fi nal determination as to the validity of the patent covering

Protonix because the underlying legal context involved only a preliminary injunction, not a full trial on the merits. A preliminary injunction involves only showing the mere potential for a fi nding of invalidity.

So KSR appears to have had only a marginal impact on pharmaceutical patents involving claims directed to a chemical structure. Th at is, when the chemical structure itself is the object of the obviousness inquiry. Th e same, however, cannot be said for other types of pharmaceutical patents.

Therapeutic Methods and Pharmaceutical Compositions or Salts

For the purposes of this article, pharmaceutical patents directed to therapeutic methods and compositions involve something other than a small molecule pharmaceutical compound in the patent claims, such as a cell or an additive. It is the cell or additive which is involved in the obviousness inquiry. In general, this type of subject matter involves properties or characteristics which are relatively more predictable and pharmaceutical patents in this category are more susceptible to an obviousness challenge under KSR. Not surprisingly, the Federal Circuit has confi rmed that these types of patents can be successfully challenged under KSR and found invalid.

In PharmaStem Th erapeutics, Inc. v. Viacell, Inc.,12 the court found two patents to be invalid precisely due to a predictably reasonable expectation of success when combining the separate teachings disclosed in the prior art. Th e challenger proff ered prior art publications which suggested a possibility but did not confi rm whether human stem cells are found in cord blood. An expert testifi ed in the

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patentee’s defense, opining there was no reasonable expectation of success to combine the prior art teachings to arrive at the claimed invention. Th e expert took the position that, based upon the prior art proff ered by the challenger, it would have been unpredictable to a person of ordinary skill at the time of the invention that stem cells were actually present incord blood.

Th e court in PharmaStem did not accept the expert’s position as tenable. Instead, the court reconsidered the prior art and relying on KSR found both patents to be invalid based on obviousness. Th e court determined the inventors had merely used routine research methods to prove what was already believed to be the case. Th e court further held that scientifi c confi rmation of what was already believed to be true may be a valuable contribution, but it does not give rise to a patentable invention.

Although decided one month prior to KSR, the decision in Pfi zer, Inc. v. Apotex, Inc.,13 also illustrates how a pharmaceutical patent might be found invalid under KSR. Th e Pfi zer case involved the drug NORVASC, containing amlodipine, a dihydropyridine compound used for treating hypertension. Th e obviousness determination, however, only involved the choice of the salt, and not the active agent amlodipine compound.

In the new drug application (NDA) history for NORVASC, the Pfi zer scientists had performed the early toxicity and effi cacy testing for amlodipine using the maleate salt of amlodipine. However, when tablet manufacturing diffi culties became apparent for the maleate, Pfi zer switched to the besylate salt of

amlodipine for fi nal FDA approval of the tablet product.

Pfi zer had obtained an initial patent covering, in general, both amlodipine salts. Th is initial patent specifi cally disclosed the maleate salt of amlodipine, but not the besylate salt. Pfi zer subsequently sought an improvement patent directed specifi cally to amlodipine besylate. Th e improvement patent was challenged as invalid based on the maleate and besylate salts of amlodipine being obvious variants. Th e earlier Pfi zer patent had disclosed amlodipine maleate and the challenger established that besylate salts, per se, were known in the prior art.

Pfi zer had countered that it had been unpredictable whether amlodipine would form a stable salt with besylate having good tablet manufacturing properties. Pfi zer further argued that one of ordinary skill in the art had no reasonable expectation of success by combining amlodipine with besylate because there was no reliable way to predict the infl uence of a particular salt species on an active pharmaceutical compound. Pfi zer also furnished evidence that the combination of amlodipine with besylate resulted in favorable tablet manufacturing properties.

Th e court in Pfi zer came to a conclusion completely in line with KSR. Th e Pfi zer court held that the unpredictability of mere salt formation did not reach the level of having an unreasonable expectation of success to a pharmaceutical chemist. Th e court emphasized that besylate was already known in the art and that one of ordinary skill in the art would have had some expectation of successfully forming a stable besylate

salt with amlodipine having good tablet manufacturing properties. At the same time, while fi nding Pfi zer’s improvement patent to be invalid as obvious, the Pfi zer court did not discount that other pharmaceutical salts might still be patentable and not obvious if the salt formulation were not well-known in the prior art or could be shown to aff ect the therapeutic eff ectiveness of the pharmaceutically active compound.

BiologicalsBiologicals oft en involve

macromolecular chemical structures such as DNA sequences or a structurally-related protein coded by a DNA sequence. KSR was relied upon by the court in the recent In re Kubin14 decision involving this type of biological. Th e case in Kubin involved a patent application that had been denied a patent grant at the PTO due in part to obviousness.15

Th e patent applicant appealed the case to the Federal Circuit. Th e claims in the appealed application were directed to new DNA sequences having a chemical structure corresponding to coding for a known protein. Th e court fi rst found that the specifi cation in the patent application used a conventionally known method of molecular cloning to derive the claimed DNA sequences from the known protein.

In relying on KSR, the court in Kubin affi rmed the PTO’s conclusion of obviousness. In the decision, the court noted that the protein was known in the prior art and that the method of molecular cloning was a conventional method oft en used by a molecular biologist as a person of ordinary skill in this area. Given these preliminary fi ndings, the court held there was a

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reasonable expectation of success in developing the claimed DNA sequences from the known protein using a method of molecular cloning which, at the time of the invention, had been merely a conventional method in the art.

KSR Presents a Higher Bar to Obtaining New Patents from the U.S. PTO

Undoubtedly, KSR has increased the basis for validity challenges to at least some pharmaceutical patents in U.S. District Courts. But the overall effect of KSR upon pharmaceutical patent litigation is less than was originally anticipated. On the other hand, KSR has significantly impacted the availability for obtaining new U.S. patents from the PTO.

The PTO generally construes the U.S. patent laws regarding patentability (including obviousness) more conservatively than the U.S. courts. This is due to the necessary deference the PTO, as a regulatory agency, must show the Federal Circuit and U.S. District Courts. It is also due

to the nature of the patent application process. The PTO puts the initial burden of proof upon all patent applicants to establish patentability as part of the quid pro quo between the applicant and the U.S. public. If successful, the applicant obtains a grant of exclusivity in an issuedU.S. patent.

In response to KSR, the PTO has established patent examination guidelines for implementing how KSR is to be applied in the examination of all types of patent applications, including pharmaceuticals. These examination guidelines call for a range of approaches by which applicants may respond in obtaining the grant of a patent. As with any obviousness inquiry, the best approach will depend heavily on the specific factual circumstances involved. Explaining the many possible approaches pharmaceutical patent applicants might take to successfully overcome KSR-type obviousness issues raised in ex parte matters at the PTO is beyond the

scope of this article. These are the subject of a subsequent publication.

1 Graham v. John Deere Co. of Kansas City, 383 U.S. 1, 86 S.Ct. 684, 148 U.S.P.Q. 459 (1966).

2 KSR Int’l Co. v. Telefl ex Inc., et al., 550 U.S. 398, 127 S.Ct. 1727, 82 U.S.P.Q.2d 1385 (2007).

3 Th e Court of Appeals for the Federal Circuit (Federal Circuit) is the only appellate circuit court having subject matter jurisdiction for matters involving U.S. patents. Although Supreme Court decisions take precedence over Federal Circuit decisions, the Supreme Court hears relatively few patent cases which must be appealed from the Federal Circuit. So most legal decisions of national signifi cance having patent issues relating to obviousness are fully developed at the Federal Circuit level.

4 Th is article builds upon a related article published in the (Sept./Oct. 2007) edition of Update Magazine shortly aft er the decision in KSR was announced.

5 Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350 (Fed. Cir. (2007)).

6 In re Wilder, 563 F.2d 457 (CCPA (1977)).7 Ortho-McNeil Pharmaceutical, Inc. v. Mylan

Laboratories, Inc., 520 F.3d 1358 (Fed. Cir. (2008)).8 Eisai Co. Ltd. v. Dr. Reddy’s Labs, Ltd., 533 F.3d

1353 (Fed. Cir. (2008)).9 Sanofi -Synthelabo v. Apotex, Inc., 550 F.3d 1075

(Fed. Cir. (2008)).10 Proctor & Gamble v. Teva Pharmaceuticals USA,

Inc., Nos. 2008-1404, -1405, -1406 (Fed. Cir.(May 13, 2009)).

11 Altana Pharma AG v. Teva Pharmaceuticals USA, Inc., No. 2008-1039 (Fed. Cir. (May 14, 2009)).

12 PharmaStem Th erapeutics, Inc. v. Viacell, Inc., 491 F.3d 1492 (Fed. Cir. (2007)).

13 Pfi zer, Inc. v. Apotex, Inc., 480 F.3d 1348(Fed. Cir. (2007)).

14 In re Kubin, et al., No. 2008-1184 (Fed. Cir.(Apr. 3, 2009)).

15 Ex parte Kubin, Appeal No. 2007-0819, 2007 WL 2070495 (BPAI (May 31, 2007)) “Board Decision.”

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