Combination Drug Patents in the Post-KSR World

As the survey above attests to, traditional themes, such teachings-away, unpredictability in the art, and unexpected showings, remain viable to exploit when defending a claim's non-obviousness in the post-KSR era. Hence, regardless of the posture in which the obviousness issue arises, whether prosecution or litigation, one defending claims to a combination therapy should be mindful to create an appropriate record that draws on such favorable evidence in order to maximize the chances for success.

Yong Chen and Sandra Lee are associates at Baker Botts LLP, in the New York office. Special thanks are extended to Joshua Sibble, a 2009 summer associate, for his assistance with case summaries. The views expressed herein are those of the authors and not necessarily those of their firm, others in that firm, or the firm's clients. Nothing about this article should be construed as legal advice on any particular matter. Each individual case presents its own unique facts that must be carefully analyzed in view of current, applicable law before specific legal advice can be rendered.

Combination drug therapies play an important role in today's pharmaceutical marketplace because they can provide additional protection on therapies developed by a company and access to significant revenue streams. As an example, Advair' (GlaxoSmithKline), a combination drug containing fluticasone and salmeterol, which was covered by U.S. Patent Nos. 4,992,474, 5,126,375, and 5,225,445, earned $5.3 billion in sales in 2007.

Combination drug therapies can present unique patent issues, particularly when they employ individual drug compounds that are known in the art. In such situations, the patentee must demonstrate that the combination is not obvious over the prior art. In KSR International Co. v. Teleflex Inc. , 127 S. Ct. 1727 (2007), the U.S. Supreme Court clarified the paradigm for analyzing a claim's obviousness. Since KSR, the courts have had limited review of cases involving combination drug therapies. However, the Board of Patent Appeals and Interferences (“BPAI”) of the U.S. Patent and Trademark Office (“USPTO”) has reviewed a number of such cases. In this article, we survey post-KSR decisions in an effort to assess what impact, if any, that Supreme Court decision may have had on the patentability/validity of combination drug therapies.

An Evolution of the Law of Obviousness

Before reviewing the post-KSR landscape, it may be helpful to review what the law on obviousness was pre-KSR and how KSR affected that jurisprudence. In Graham v. John Deere Co. , 383 U.S. 1 (1966), the Supreme Court established the traditional framework for analyzing obviousness. Under Graham, determining obviousness of a claimed invention entailed a three-part inquiry: 1) determining the scope and content of the prior art; 2) ascertaining the difference between the claimed invention and the prior art; and 3) resolving the level of ordinary skill in the pertinent art. In addition to these three factors, the Court assessed secondary considerations (such as commercial success, long-felt need, and the failure of others) to shed light on the circumstances surrounding the origin of the claimed subject matter.

Striving to achieve a consistent and objective application of the Graham framework, the Federal Circuit adopted the so-called “teaching-suggestion-motivation” (“TSM”) test, under which some teaching, suggestion, or motivation in the prior art had to exist for combining multiple prior art teachings in such a way that they would produce the claimed invention. See, e.g., Alza Corp. v. Mylan Labs. , 464 F.3d 1286 (Fed. Cir. 2006). The Federal Circuit's traditional jurisprudence also emphasized the importance of secondary considerations and required their careful evaluation when raised.

In KSR, the Supreme Court criticized the Federal Circuit's reliance on the TSM test as unduly rigid and formalistic. Moreover, the Supreme Court deemed that approach to be inconsistent with its precedents, which favored a more “expansive and flexible approach” to combining teachings. In effect, the Federal Circuit's approach was viewed as improperly hindering the fact-finder from using common sense to assess a claim's obviousness. The Supreme Court specifically pointed out that a person of ordinary skill in the art should not be assumed to be an automaton, but rather to have ordinary creativity. The Court also held that “when there is design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions[,]” subject matter directed to the same should be unpatentable/invalid as “ obvious to try.”

Drawing on earlier case law, the Court highlighted additional principles that should be factored into the obviousness analysis where appropriate. For example, “the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Moreover, where there is a “mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.” Also, “when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious.” As a result, satisfaction of the TSM test is no longer a precondition to finding claimed subject matter obvious. Finally, while secondary considerations were still recognized by the Court as relevant to the inquiry, they did not play a significant role in the specific facts of KSR.

The impact of KSR on the obviousness inquiry has been the subject of much commentary. The Court's rejection of the Federal Circuit's “rigid and formalistic” approach, in favor of a more flexible or “common sense” one, has been viewed by many as raising the bar for patentability. But has KSR had such a discernible impact on claims directed to combination therapies? As discussed below, the impact may not be as great as imagined.

Combination Drug Patents: Pre- and Post-KSR

In the life sciences arena, during the two years after KSR, the Federal Circuit has only decided one case involving the obviousness of a combination drug therapy, Ortho-McNeil Pharmaceutical, Inc. v. Teva Pharmaceuticals Industries, Ltd., 2009 WL 2604919 (Aug. 26, 2009, C.A.Fed. (N.J.)). In that case, a finding of obviousness on summary judgment was largely overturned in light of material factual disputes as to whether one of ordinary skill would have had a basis for combining the two drugs at issue and expecting them to work in concert. District courts, particularly the District of New Jersey and the Southern District of New York, which are important venues for pharmaceutical cases, have considered the issue with essentially the same frequency. Ortho-McNeil Pharmaceutical Co. v. Kali Labs., Inc, 2008 WL 1782283 (D.N.J.), rev'd, 2009 WL 2604919 (Aug. 26, 2009, C.A.Fed. (N.J.)); McNeil-PPC Inc. v. Perrigo Co. , 516 F.Supp.2d 238 (S.D.N.Y. 2007). The largest body of post-KSR case law actually resides in the jurisprudence of the BPAI. Below we highlight decisions from each of these three tribunals, starting with a review of the few pre-KSR decisions issued by the Federal Circuit on the topic.

Federal Circuit Decisions Pre-KSR

McNeil-PPC Inc. v. Perrigo Co. , 337 F.3d 1362 (Fed. Cir. 2003). The drug at issue was Imodium' Advanced, which is a combination of loperamide (an antidiarrheal) and simethicone (an antiflatulant), separated by an impermeable polymeric barrier coating. Four patents covering the drug were asserted in the litigation. The prior art was extensive, teaching the individual drug components, the presence of the conditions each treats in certain patient populations, combinations of simethicone with antidiarrheals other than loperamide, and the use of polymeric barriers to separate simethicone from other actives in a solid dosage form.

The Federal Circuit agreed with the lower court that substituting loperamide for those antidiarrheals featured in the prior art was obvious. In defense of the claims, the plaintiffs argued that the prior art did not recognize the benefit of using a polymer coating, which prevents the two drugs from directly contacting each other and, in turn, improves the shelf-life of loperamide. The Federal Circuit, however, reasoned that this argument did not provide a sufficient basis for supporting the non-obviousness of the claimed subject matter; a prior art reference taught separating simethicone from other components. According to the appellate court, this teaching provided sufficient motivation for one to apply a polymeric coating to the claimed drug combination.

Regarding secondary considerations, the Federal Circuit considered evidence of commercial success, but found that it lacked the requisite nexus to the merits of the claimed combination product. Further, the court found that the patentee's clinical evidence for unexpected results was not convincing since the evidence only focused on results achieved in a limited patient population. Hence, the evidence was deemed unreliable. Nor was the court convinced by the patentee's argument regarding synergism because the patentee did not compare the collective action of the claimed therapy to the full range of antidiarrheal and antiflatulant combinations taught in the prior art.

Knoll v. Teva , 367 F.3d 1381 (Fed. Cir. 2004). This decision focuses on the pain reliever, Vicoprofen', which is a combination of hydrocodone (an opioid) and ibuprofen (an NSAID). U.S. Patent No. 4,587,252 covered the combination therapy. The prior art taught the combination of the two families of drugs, opioids and NSAIDs, but not the pairing of the hydrocodone and ibuprofen specifically.

The Federal Circuit reversed a finding of obviousness on summary judgment, holding that the lower court erred in: 1) precluding the patentee from offering evidence developed after the patent was filed for to support the existence of unexpected results, e.g., synergism between the drugs and accelerated muscle repair; and 2) not giving proper weight to other secondary indicia of non-obviousness. In so ruling, the Federal Circuit was sending the message that evidence relating to such secondary indicia should be considered as part of the obviousness inquiry.

Post-KSR Decisions

As the post-KSR decisions reviewed below reflect, evidence regarding the predictability of the art and the existence of surprising/unexpected results continues to play an important role in the overall inquiry.

Federal Circuit Decision

Ortho-McNeil Pharmaceutical Co. v. Kali Labs., Inc., 2009 WL 2604919 (C.A.Fed. (N.J.)). The drug at issue in this case was Ultracet', which is a combination of tramadol (an opioid) and acetaminophen (an analgesic). The patent covering the drug is RE 39,221, a reissue of U.S. Patent No. 5,336,691. The patent-at-issue was directed to a fixed-dose combination that “consisted essentially of” these two drugs. Two sets of prior art were particularly relevant to the obviousness inquiry. U.S. Patent No. 3,652,589 (“Flick”) taught that, when tramadol is used together with other therapeutic agents, a synergistic effect is frequently observed. Example 22 of the Flick patent taught the combination of tramadol and an analgesic in a two-agent tablet. Example 23 of the Flick patent also taught tramadol and acetaminophen as part of a four-agent tablet. Additional art, including an article by Brinkmann, ZFA Z. Allg. Med. 65:166-68 (1989), disclosed the combination of up to 1 gram of acetaminophen with 40 drops of tramadol.

On summary judgment, the district court found the claims to be obvious over the prior art. With respect to all but one claim, the Federal Circuit reversed, finding that the patentee had raised genuine issues of material fact. First, the Federal Circuit noted that, given the unpredictability in the art, there was a genuine issue as to whether one of skill in the art would have expected a combination lacking the two additional actives featured in example 23 of Flick to produce any therapeutic effect, let alone the synergistic effect actually observed for the claimed combination. Second, the appellate court noted that there was a genuine issue of fact as to whether the remaining art taught away from using the fixed-dosage forms claimed; this art indicated that, when treating a patient, “[drug] combinations and doses [should be chosen] based on individual needs.”

District Court Decisions

McNeil-PPC Inc. v. Perrigo Co. , 516 F.Supp.2d 238 (S.D.N.Y. 2007). In 2007, the Southern District of New York considered the obviousness of claims covering Pepcid Complete', a combination of famotidine and magnesium hydroxide. Famotidine is a histamine H2-receptor antagonist that inhibits stomach acid production, while magnesium hydroxide is an antacid that neutralizes stomach acid. U.S. Patent No. 5,817,340 covers the drug combination. There was an extensive body of prior art regarding the treatment of indigestion with such drugs, and numerous references were cited against the patent including: a PCT publication (WO 92/00102) disclosed a solid oral dosage form containing uncoated famotidine and an antacid; U.S. Patent No. 5,229,137 taught oral administration of an antacid and a histamine H2-receptor antagonist; U.S. Patent No. 5,075,114 taught a method for the granulated coating of a variety of drugs, including famotidine, to mask the taste of active ingredients in chewable tablets; and European Patent No. 0294933 taught the combination of cimetidine (a bitter tasting H2 blocker) and an antacid in a chewable tablet.

The patentee predicated non-obviousness on the surprising observation that a coated form of famotidine, as claimed, degrades more slowly in the presence of magnesium oxide than an uncoated form. Notwithstanding, the court found the claimed combination obvious because the art provided an independent motivation for coating the H2 blocker, i.e., to mask its bitter taste. As fate would have it, McNeil stated in its New Drug Application that “taste masking of famotidine is necessary in [the combination famotidine-antacid product] due to the bitterness of the drug substance.” The court regarded this statement as an admission that famotidine's bitter taste was known in the art and, further, as providing a basis for the person of ordinary skill to employ an impermeable coating. The claims were therefore deemed obvious despite the surprising observation that such a coating also prevents famotidine from degrading.

BPAI Decisions

Ex parte Lee, Appeal No. 2007-1033, 2007 WL 1766990 (Bd. Pat. App. & Int. Jun. 19, 2007). In this case, the claims were directed to methods of treating a cancer by administering capecitabine and Compound 1. Two prior art references were cited as teaching compositions containing Compound 1, while a third prior art reference was cited as teaching capecitabine. The BPAI agreed with the Examiner that a prima facie obviousness case existed for administering the claimed combination to treat cancer. However, the BPAI reversed the rejection, noting that evidence of an unexpected result (a surprising synergy between the two actives) rebutted the prima facie case.

The Examiner had rejected such evidence on the ground that it was not commensurate with the scope of the claims. The Examiner noted that the claims were directed to treating various cancers, but the evidence only supported the treatment of colon cancer. Moreover, the claims focused on a broad dosage range, while the data relied upon only focused on two discrete dosage combinations. Notwithstanding these observations, the BPAI held that the Examiner had not provided any reason as to why a synergistic effect would not also be expected when treating other cancers and at the other dosages claimed. In this regard, the BPAI placed the burden on the Examiner to demonstrate that the unexpected showing was not commensurate with the scope of the claims.

Ex parte El-Naggar, Appeal No. 2007-2834, 2007 WL 2814131 (Bd. Pat. App. & Int. Sep. 20, 2007). A representative claim at issue (claim 18) was directed to a pharmaceutical composition for treating inflammatory disorders that comprises three ingredients: 1) a COX-2 inhibitor (selected from celecoxib and rofecoxib); 2) low dose aspirin; and 3) an antioxidant (selected from a flavonoid, a flavonoid, and a combination thereof). Three references were relied upon in the Examiner's obviousness rejection, which individually taught the use of one of the three claimed components in compositions to treat inflammation (Hedden (WO 01/14705A1) taught celecoxib as anti-inflammatory agent; Lanhoff (DE 198 55 426 A1) taught the incorporation of aspirin in a multi-ingredient composition; and Shapiro (U.S. Patent No. 6,444,221) disclosed certain flavonones among antioxidants suitable for combination with benzoic acid derivatives for treating chronic inflammatory disorders including arthritis). By combining these references, the Examiner deemed the claim to be obvious.

The BPAI disagreed with the Examiner and overturned the rejection. According to the BPAI, “one of ordinary skill reading the cited prior art as a whole would have reasoned from these teachings that obtaining a therapeutic effect ' would have required at least four ingredients in addition to those recited in claim 18 ' ' cod liver/linseed oil, vitamin C, ' vitamin E, and ' [a] benzoic acid derivative, where both the cod liver/linseed oil and benzoic acid derivative are administered in multi-gram quantities to achieve a therapeutic effect.” Furthermore, given that claim 18 requires all of the ingredients to be present in a single composition, the BPAI held that the Examiner had not adequately explained why one of ordinary skill would have formulated the ingredients required by the prior art, in the quantities disclosed, to form a single composition.

Ex parte Warren, Appeal No. 2007-4515, 2008 WL 1706584 (Bd. Pat. App. & Int., Apr. 11, 2008). In this case the claims at issue were directed to an absorbent article comprising a skin care composition containing hexamidine, zinc oxide, and niacinamide, with each present within specified weight percent ranges. In making the obviousness rejection, the Examiner relied on two main references: Ehrnsperger (U.S. Patent No. 6,160,200) and Vega (U.S. Patent No. 6,153,209). Ehrnsperger disclosed absorbent articles containing suitable skin care compositions, such as Category I actives defined by the FDA, which include zinc oxide. Ehrnsperger also taught that other agents, such as hexamidine derivatives, could be present in such compositions. Vega taught that a skin care composition can include an emollient (such as vitamin A, B3, B5, niacinamide), and agents such as antimicrobials, zinc oxide, and hexamidine. The Examiner considered both references as teaching absorbent articles and skin care compositions that included the claimed ingredients. In addition, the Examiner asserted that it would have been within the scope of a skilled artisan to choose amounts for each ingredient that would fall within the ranges claimed.

Citing KSR, the BPAI focused its analysis on whether the claimed combination was “more than the predictable use of prior art elements according to their established functions.” The BPAI concluded that the combination was not. Therefore, the claims were deemed obvious.

In reaching this conclusion, the BPAI rejected the Applicants' argument that there must be a specific “suggestion, teaching or other 'indicator' for the skilled artisan to produce the specific combination claimed” as inconsistent with KSR, inasmuch as: “the obviousness analysis cannot be confined by a formalistic conception of the words teaching, suggestion, and motivation.” In addition, the BPAI pointed to the fact that the prior art in this case did not merely disclose skin care ingredients in a generic fashion. Instead, it disclosed niacinamide, hexamidine, and zinc oxide with particularity, albeit within lists of skin care ingredients. According to the BPAI, the specific listing of these ingredients in the prior art was more supportive of an obviousness finding than the mere reference to a broad genus embracing the same.

Ex parte Stokes, Appeal No. 2008-0226, 2008 WL 1806822 (Bd. Pat. App. & Int. Apr. 22, 2008). In Ex parte Stokes, the BPAI affirmed the Examiner's obviousness rejection of claims directed to treating hypertension with a combination of 8 to 600 mg of an angiotensin II inhibitor and 1 to 200 mg of a nitric oxide donor. One prior art reference differed from the claimed invention only in the specific dosage amounts of each active ingredient it taught and the conditions to be treated by the claimed drug combination. Nonetheless, the Examiner concluded that the claims were obvious. There were additional prior art references reflecting that the claimed dosage ranges suitable for hypertension overlap with the dosage ranges of the primary reference. Because the sets of art were directed to similar fields and problems, the Examiner concluded that one of ordinary skill would have been motivated to apply the dosages taught in the secondary art to the primary reference.

The Applicant countered by arguing that the Examiner was engaging in impermissible hindsight. The BPAI, citing KSR, disagreed. Even though the primary reference was directed to treating a disease other than hypertension, the BPAI noted that it taught dosage ranges comparable to those used to treat a comparable disease. This connection, according to the BPAI, was sufficient to make the other references “relevant to the problem addressed by [the prior art],” and therefore obvious to combine. Such an analysis seems to reflect the kind of “flexible approach” to the obviousness inquiry advocated by KSR by taking into consideration “the interrelated teach[ings] of multiples references; the effects of demands of the marketplace; and the background knowledge possessed by a person of ordinary skill.”

Ex parte West, Appeal No. 2008-4224, 2008 WL 4570287 (Bd. Pat. App. & Int. Oct. 10, 2008). The BPAI affirmed the Examiner's obviousness rejection of claims directed to treating gastro-esophageal reflux disease with a composition consisting of a chewing gum base, an acid neutralizing agent, an anti-gas agent, and an acid production inhibitor. According to the BPAI, the claims were directed to elements that were known in the art and whose combination resulted in nothing “more than the predictable use of prior art elements according to their established functions.”

To rebut the Examiner's prima facie case, the Applicant argued that the art taught away from the claims by expressly identifying other drug combinations to the exclusion of the very combination claimed. The BPAI rejected that argument, noting that the mere failure of the art to list a particular combination does not per se teach away from that combination.

Ex parte Patel, Appeal No. 2008-5302, 2009 WL 476124 (Bd. Pat. App. & Int. Feb. 24, 2009). In this case, the BPAI affirmed the Examiner's obviousness rejection of claims to a topical skin composition comprising a retinoid (tretinoin) encapsulated in a discontinuous lipid phase and an antibiotic (clindamycin) unencapsulated in a continuous aqueous phase. Notwithstanding the Applicant's arguments that the technology was complex and unpredictable, both the Examiner and the BPAI found the claims obvious. Based on its review of the record, the BPAI concluded that nothing more than the exercise of ordinary creativity was needed to arrive at the claimed subject matter. The use of a combination of tretinoin and clindamycin for treating skin conditions was evident from the prior art. Moreover, the art provided a reasonable expectation that those two drugs could be administered in an efficacious manner, even with one present in free form in an aqueous phase, and the other encapsulated in a lipid phase.

Additional BPAI cases that are relevant to post-KSR obviousness analysis in combination drug therapies include the following 12 cases: Ex parte Davis, Appeal No. 2007-0181, 2007 WL 1874810 (Bd. Pat. App. & Int. Jun. 28, 2007); Ex parte Patten, Appeal No. 2007-2721, 2007 WL 5063478 (Bd. Pat. App. & Int. Dec. 3, 2007); Ex parte Robinson, Appeal No. 2007-4455, 2008 WL 558042 (Bd. Pat. App. & Int. Feb. 26, 2008); Ex parte Podolski, Appeal No. 2007-4486, 2008 WL 559565 (Bd. Pat. App. & Int. Mar. 3, 2008); Ex parte Chen, Appeal No. 2008-1880, 2008 WL 1318584 (Bd. Pat. App. & Int. Apr. 7, 2008); Ex parte Davis, Appeal No. 2007-4484, 2008 WL 1706582 (Bd. Pat. App. & Int. Apr. 11, 2008); Ex parte Junien, Appeal No. 2008-0971, 2008 WL 3276243 (Bd. Pat. App. & Int. Aug. 8, 2008); Ex parte Meade, Appeal No. 2008-3535, 2008 WL 4418280 (Bd. Pat. App. & Int. Sep. 29, 2008); Ex parte Medicis Pharm. Corp., Appeal No. 2008-5830, 2009 WL 160224 (Bd. Pat. App. & Int. Jan. 21, 2009); Ex parte Zohoungbogbo, Appeal No. 2008-5274, 2009 WL 357790 (Bd. Pat. App. & Int. Feb. 12, 2009); Ex parte Davis, Appeal No. 2009-1214, 2009 WL 383725 (Bd. Pat. App. & Int. Feb. 13, 2009); Ex parte Morimoto, Appeal No. 2009-1838, 2009 WL 1111591 (Bd. Pat. App. & Int. Apr. 23, 2009).

Drug Combinations in the Post-KSR World

Given the limited case law that is available, particularly at the district court and Federal Circuit level, it is difficult to reach definitive conclusions about KSR's impact on the patentability/validity of claims directed to combination therapies. While a number of BPAI decisions have found claims to combination therapies obvious, their resolution tends to turn on the state of the art and the absence of any evidence regarding secondary considerations rather than any paradigm shift imposed by KSR. Moreover, the Federal Circuit has cautioned that, even in the post- KSR world, the obviousness of a claim “must be decided in a particular context, including the characteristics of the science or technology, the nature of the choices available to one skilled in the art, the specificity of the prior art, and the predictability of results in the area of interest.” Ortho-McNeil Pharmaceutical, Inc. , 2009 WL 2604919 *6 (citing Abbott Labs. v. Sandox, Inc. , 544 F.3d 1341, 1352 (Fed. Cir. 2008)). Thus, despite the “flexibility” KSR brings to the obviousness analysis, the obviousness inquiry remains intrinsically fact-specific and broad enough to embrace a host of considerations that can be drawn upon to support the non-obviousness of claims directed to combination therapies.

In view of the above observations, it is important to highlight that KSR did not abandon the fundamental premise underlying obviousness: Courts must still determine whether there is an apparent reason to combine prior art elements in the fashion claimed. Likewise, certain practices are still followed even in light of KSR. It still remains that practitioners are served well to thoroughly consider all available defenses regarding secondary consideration factors with their requisite burdens of proof, and to present the pertinent evidence effectively to the fact-finder.

As the survey above attests to, traditional themes, such teachings-away, unpredictability in the art, and unexpected showings, remain viable to exploit when defending a claim's non-obviousness in the post-KSR era. Hence, regardless of the posture in which the obviousness issue arises, whether prosecution or litigation, one defending claims to a combination therapy should be mindful to create an appropriate record that draws on such favorable evidence in order to maximize the chances for success.

Yong Chen and Sandra Lee are associates at Baker Botts LLP, in the New York office. Special thanks are extended to Joshua Sibble, a 2009 summer associate, for his assistance with case summaries. The views expressed herein are those of the authors and not necessarily those of their firm, others in that firm, or the firm's clients. Nothing about this article should be construed as legal advice on any particular matter. Each individual case presents its own unique facts that must be carefully analyzed in view of current, applicable law before specific legal advice can be rendered.