Leo Pharmaceutical Products, Ltd. v. Rea (Fed. Cir. 2013)

By Kevin E. Noonan --

The Federal Circuit's jurisprudence regarding obviousness as determined by the U.S. Patent and Trademark Office continues its post-KSR development in Leo Pharmaceutical Products, Ltd. v. Rea, which involves an obviousness determination by the Office in an inter partes reexamination.  The Court reversed the Office's obviousness rejection as a matter of law as not being supported by the facts and for the Office's failure to construe certain claims terms according to their broadest reasonable meaning (ironic, in view of the Office's penchant to take that claim construction rubric to extreme and unreasonable lengths).

The case involved U.S. Patent No. 6,753,013 owned by Leo Pharmaceutical Products that covers its Taclonex® ointment product.  The product comprises a combination of a corticosteroid and vitamin D or a vitamin D analog, used to treat psoriasis and other skin ailments.  The prior art taught that these two drugs could be used to treat psoriasis but prescribed individual topical application of the drugs at different times (such as one in the morning and the other at night), a regimen that raised patient compliance issues.  The basis of Leo's invention was its discovery that that corticosteroids (that are stable at a pH of about 4) and vitamin D or analogs (that are stable at a pH of about 8) could be combined in stable, single formulation.  Leo's formulation combined the two drug compounds with polyoxypropylene 15 stearyl ether (POP-15-SE), which was found to provide conditions where both drug compounds were chemically stable.

Claim 1 of the '013 patent is representative of Leo's claims at issue (emphasis added):

1.  A pharmaceutical composition for dermal use, said composition comprising:
    a first pharmacologically active component A consisting of at least one vitamin D analogue selected from the group consisting of seocalcitol, calcipotriol, calcitriol, tacalcitol, maxacalcitol, paricalcitol, falecalcitriol, 1α,24S-dihydroxy-vitamin D2, 1(S),3(R)-dihydroxy-20(R)-[((3-(2-hydroxy-2- propyl)-phenyl)-methoxy)-methyl]-9,10-seco- pregna-5(Z),7(E),10(19)-triene and mixtures thereof; and
    a second pharmacologically active component B consisting of at least one corticosteroid, wherein the difference between the maximum stability pH of said first component A and the maximum stability pH of said second component B is at least 1; and
    at least one solvent component C selected from the group consisting of:
        (i) compounds of the general formula R3(OCH2C(R1)H)xOR2 (I) wherein x is in the range of 2-60, R1 in each of the x units is CH3, R2 is straight chain or branched C1-20 alkyl or benzoyl, and R3 is H or phenylcarbonyloxy;
        (ii) straight or branched C2-4-alkyl esters of straight or branched C10-18-alkanoic or -alkenoic acids;
        (iii) propyleneglycol diesters with C8-14-alkanoic acids; and
        (iv) branched primary C18-24 alkanols,

wherein said pharmaceutical composition is storage stable and non-aqueous.

The limitation that the pharmaceutical composition was "storage stable and non-aqueous" was entered into the claim during the reexamination, and the Board construed "storage stable" to mean "non-aqueous."

Using this claim construction, the Board found Leo's claims obvious over three references:

• U.S. Patent No. 4,083,974 (the Turi reference), which was filed in 1977 and taught pharmaceutical compositions comprising a steroid contained within a solvent, POP-15-SE" (falling within the ambit of the excipients in Leo's claims) but did not teach the combination with vitamin D.  This reference also expressly disclosed that the formulations in the '974 patent did not contain "water, gels, or alcohols," and the benefits of using POP-15-SE to be that it "reduces exposure of tissue to chemical compounds and reduces manufacturing costs."  There was no disclosure regarding stability issues with a combination of corticosteroids and vitamin D (which combinations were not disclosed) or for treating psoriasis.

• U.S. Patent No. 4,610,978 (the Dikstein reference), which was filed in 1984 and taught topical preparations ("including creams, ointments, and lotions") of the combination of a vitamin D analog and a corticosteroid for treating psoriasis.  These formulations used water-based solvents including almond oil or polypropylene glycol, and disclosed no recognition of storage stability problems with these formulations.

• PCT WO 94/13353 (the Serup reference), which was filed in 1994 and taught formulations ("creams, ointments, pastes, or gels") comprising a vitamin D analog and a steroid formulated under aqueous conditions that included almond oil, propylene glycol or alcohols.  The reference noted benefits of using vitamin D analogs to treat skin atrophy, which was recognized as a side effect of steroid treatment.  There was no disclosure of storage stability issues with these combinations in this reference.

The PTO applied the '974 patent as the primary reference, which taught the use of POP-15-SE formulated corticosteroids, combined with either the Dikstein or Serup references that taught the vitamin D/corticosteroid combination.  According to the Board, the skilled artisan would have been motivated to combine these teachings because they were directed to compositions comprising corticosteroids and vitamin D, and the advantages of adding vitamin D to corticosteroids for treating psoriasis was disclosed and known in the art.  According to the Board, any "invention" by the inventors involved merely "picking and choosing" ingredients from a list of known ingredients and this was obvious.  Turning to the distinction regarding stability introduced by amendment during the reexamination, the Board found that evidence about stability was disclosed in the '974 patent, which taught the skilled person to avoid aqueous components.  Finally, the Office rejected asserted Leo's objective indicia of non-obviousness.  The purported unexpected results that corticosteroids and vitamin D could be combined was not surprising in view of '974 patent which taught formulations comprising the component (POP-15-SE) that rendered the drug compounds stable.  That the art did not teach stability as a reason to use POP-15-SE didn't matter, "the Board nonetheless conclud[ing] that 'the reason for utilizing the solvent does not have to be the same reason [the solvent] was employed by the inventors'" (citing KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 419– 20 (2007)).  The Board also found that the compositions "ability to resist degradation" (not, as noted by the Federal Circuit a recited claim term) was enough to find that "that the composition is stable, i.e., not changing or fluctuating because it doesn't significantly degrade."  The Board found support for its definition of stability in one example in the '013 specification relating to a stability study performed on the claimed formulation.

The Federal Circuit reversed, in an opinion by Chief Judge Rader, joined by Judges O'Malley and Reyna.  The Court found fault with the Board's claim construction related to the term "storage stable":

At the outset, the Board's construction of "storage stable" is impermissibly narrow because example two is just one disclosure of an accelerated stability test.  Under its accepted and customary meaning, "storage stable" would include a composition that maintains its stability during its shelf life for its intended use as an approved pharmaceutical product for sale and home use by ordinary customers.  . . .  The Board erred by narrowing the definition of "storage stable" to something far short of its broadest reasonable meaning.  The plain meaning of "storage stable" is broader than the disclosure in example two.

This error was enough for the Court to reverse the obviousness determination (although the opinion expressly declines to independently construe the term), but went on to overturn the Board's obviousness rejection.

The Court's opinion found fault with the Board's application of the facts to the claims in its obviousness assessment, and its disregard for the objective indicia of non-obviousness.  Substantively, the Court disagreed with the Board because the claims were "not simply a combination of elements found in the prior art" because "[t]he inventors of the '013 patent recognized and solved a problem with the storage stability of certain formulations -- a problem that the prior art did not recognize and a problem that was not solved for over a decade."  This recognition of the problem to be solved can be sufficient to be the invention ("As an initial matter, an invention can often be the recognition of a problem itself," citing Cardiac Pacemakers, Inc. v. St. Jude Med., Inc., 381 F.3d 1371, 1377 (Fed. Cir. 2004)).  In this case, "the prior art either discouraged combining vitamin D analogs and corticosteroids in a single formulation, or attempted the combination without recognizing or solving the storage stability problems associated with the combination" in the Court's opinion.  Moreover, "several medical research articles published as early as 1995 discourag[ed] the combination of a vitamin D analog with a corticosteroid because of the stability problems of vitamin D analogs at lower pHs," and "[t]hese articles taught away from mixing topical vitamin D formulations with other drugs."  While the prior art taught that it would be "only natural" for vitamin D to be combined with other drugs for treating psoriasis, the prior art "warned that vitamin D should not be combined with other drugs requiring a low pH (e.g., corticosteroids)."  The Court found that neither the Dikstein nor Serup references recognized, disclosed, or addressed the stability problems that arose using the formulations disclosed in those references that were identified by patentee, which disclosure included experimental evidence that the prior art references taught combinations that were not stable under storage conditions.  Because the prior art did not appreciate the stability issues, it provided "no reason for one of ordinary skill in the art to attempt to improve upon either [the formulations disclosed in] Dikstein or Serup using [the teachings of the] Turi [reference]."

The primary deficiency noted by the Court is that "[t]he ordinary artisan would first have needed to recognize the problem, i.e., that the formulations disclosed in Dikstein and Serup were not storage stable."  This would take "several months [of] storage stability test[ing]" to establish, and "[o]nly after recognizing the existence of the problem would an artisan then turn to the prior art and attempt to develop a new formulation for storage stability" (emphasis in opinion).  That isn't what happened; as noted by the Court, recognition of the problem was not achieved "within months" of the Dikstein or Serup references (which the Court says would be expected "[i]f these discoveries and advances were routine and relatively easy"), but instead took "more than a decade."  In view of this evidence, it was apparent to the Court that what the Board viewed as a straightforward combination of the cited references was instead a "hindsight-guided combination of elements."

The Court found that the record did not support the Board's obviousness determination, based on the facts used by the Board to support its position.  For example, the Board "found motivation to combine Dikstein or Serup with Turi because one of ordinary skill would have used vitamin D to solve the well-known side effects of steroid treatment."  In the Court's view this was hindsight, because "Turi was publicly available in the prior art for twenty-two years before the '013 patent was filed, yet there is no evidence that anyone sought to improve Turi with vitamin D."  "[E]ven when Serup published the well-known side effects of steroid-induced atrophy in 1994, no one -- including Serup -- sought to improve Turi by adding vitamin D to Turi's corticosteroid composition," according to the opinion, even when Serup "targeted the precise side effects that the Board believed would have motivated the addition of a vitamin D analog to Turi's corticosteroid composition"; even Serup "did not seek to improve Turi by adding vitamin D."  This conclusion was further supported by evidence that the Turi reference taught away from the combination formulations disclosed in the Serup and Dikstein references, i.e., the aqueous formulations (which included water and propylene glycol) those references disclose.

With regard to the disclosure in the prior art of "broad and general disclosures" of additives ("e.g., diluents, buffers, thickeners, lubricants") and composition forms ("e.g., liniments, lotions, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments, pastes, or gels"), "the Board reasoned that an artisan would have been able to 'mak[e] choices about what ingredients to include, and which to exclude' in formulating a composition with a vitamin D analog and steroid."  "To the contrary," according to the Court, "the breadth of these choices and the numerous combinations indicate that these disclosures would not have rendered the claimed invention obvious to try" citing See Rolls-Royce PLC v. United Techs. Corp., 603 F.3d 1325, 1339 (Fed. Cir. 2010).

The Court also did not find that combining the '974 Turi patent with the Dikstein patent or Serup application rendered the invention obvious to try:

"[W]here the prior art, at best gives only general guidance as to the particular form of the claimed invention or how to achieve it, relying on an obvious-to-try theory to support an obviousness finding is impermissible," said the Court, citing In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litigation, 676 F.3d 1063, 1073 (Fed. Cir. 2012).  [Further, the opinion asserts that] "KSR did not create a presumption that all experimentation in fields where there is already a background of useful knowledge is 'obvious to try,' without considering the nature of the science or technology," citing Abbot Labs. v. Sandoz, Inc., 544 F.3d 1341, 1352 (Fed. Cir. 2008).

The passage of time between public availability of the cited reference was also evidence for invention not being obvious to try, according to the opinion:  "The length of the intervening time between the publication dates of the prior art and the claimed invention can also qualify as an objective indicator of nonobviousness," said the Court, citing Ecolochem, Inc. v. S. Cal. Edison Co., 227 F.3d 1361, 1376–77 (Fed. Cir. 2000):

The elapsed time between the prior art and the '013 patent's filing date evinces that the '013 patent's claimed invention was not obvious to try.  Indeed this considerable time lapse suggests instead that the Board only traverses the obstacles to this inventive enterprise with a resort to hindsight.  It took over a decade -- after Dikstein's disclosure of the benefits of combining vitamin D and corticosteroid treatments into one formulation -- for Dikstein's formulations to be tested for storage stability.  And, until the advancement made by the inventors of the '013 patent, no one had proposed a new formulation that would be storage stable.

Moreover, because the "problem was not known, the possible approaches to solving the problem were not known or finite, and the solution was not predictable.  Therefore, the claimed invention would not have been obvious to try to one of ordinary skill in the art.  Indeed ordinary artisans would not have thought to try at all because they would not have recognized the problem."  In addition, the Court found there could have been no reasonable expectation of success in combining the cited art, because in the absence of "clues pointing to the most promising combinations, an artisan could have spent years experimenting without success."

The opinion distinguished any reading of the Supreme Court's KSR opinion to the contrary, stating that the law "recognizes an important distinction between combining known options into 'a finite number of identified, predictable solutions,' KSR, 550 U.S. at 421, and "'merely throwing metaphorical darts at a board' in hopes of arriving at a successful result," Cyclobenzaprine, 676 F.3d at 1071 (quoting In re Kubin, 561 F.3d at 1359).

Turning to the objective indicia, the Court found that the Board erred in not considering evidence propounded by patentee, citing its Cyclobenzaprine decision for the principal that "consideration of the objective indicia is part of the whole obviousness analysis, not just an after-thought."  The objective indicia "play a critical role in the obviousness analysis" and are "not just a cumulative or confirmatory part of the obviousness calculus but constitute[] independent evidence of nonobviousness," citing Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d 1358, 1365 (Fed. Cir. 2008).  The objective indicia "can be the most probative evidence of nonobviousness in the record, and enables the court to avert the trap of hindsight," citing Crocs, Inc. v. Int'l Trade Comm'n, 598 F.3d 1294, 1310 (Fed. Cir. 2010).

Here, the patentee had asserted unexpected results over two of the cited prior art references (which had significant degradation), commercial success, and long-felt but unfulfilled need in the art.  The Board rejected patentee's assertion of unexpected results, on the grounds that the results obtained by Leo were not unexpected in view of the disclosure of corticosteroid/vitamin D combinations in the Dikstein and Serup references.  The Court disagreed, and found "'extensive experimental evidence"" of unexpected results, including experimental evidence reproducing the formulations disclosed in the Dikstein and Serup references that demonstrated "significant degradation of the vitamin D analog and corticosteroid."  These results of instability were even found (for the corticosteroid) when the Serup formulation was "improved" by the addition of POP-15-SE (i.e., the combination resulting from the Board's combination of the references).

The Court cited Leo's evidence for commercial success as being convincing for overcoming obviousness, based in part on FDA approval (which the opinion states is "not determinative" but can be "relevant" evidence of non-obviousness, citing Knoll Pharm. Co., Inc. v. Teva. Pharm. USA, Inc., 367 F.3d 1381, 1385 (Fed. Cir. 2004)), as well as evidence of long-felt but unmet need.  In this regard, the length of time intervening between the dates the various prior art references became available to the public is relevant evidence according to the Court, because "the researchers were aware of the benefits of using both vitamin D and corticosteroids in the treatment of psoriasis as early as 1986" but "it was not until the '013 patent's filing in 2000 -- twenty-two years after Turi and fourteen years after Dikstein -- that the solution to the long felt but unsolved need for a combined treatment of vitamin D and corticosteroid was created."  This amount of time "speaks volumes to the nonobviousness" of these claims.

The Court credited the objective indicia strongly:

Here, the objective indicia -- taken in sum -- are the most "probative evidence of nonobviousness . . . enabl[ing] the court to avert the trap of hindsight."  Crocs, Inc., 598 F.3d at 1310.  Viewed through the lens of the objective indicia, as opposed to the hindsight lens used by the Board, the '013 patent would not have been not obvious over Turi in combination with Dikstein or Serup.

This regard for the objective indicia is in stark contrast to instances, such as the PharmaStem case shortly after the Supreme Court's KSR decision, where the objective indicia were disregarded in view of "strong" evidence of obviousness.  While this is just one panel opinion, it is possible that the pendulum has begun to swing back towards a more expansive view of non-obviousness after a more rigid application of the doctrine immediately post-KSR.

Leo Pharmaceutical Products, Ltd. v. Rea (Fed. Cir. 2013)
Panel: Chief Judge Rader and Circuit Judges O'Malley and Reyna
Opinion by Chief Judge Rader

Comments

[Dan Feigelson]

Thanks for reporting this refreshing injection of rationality into the CAFC's obviousness jurisprudence and its deft handling of KSR in a way that shows fealty to that decision while effectively shunting it aside. While it's not surprising to see Judge Rader deciding in favor of the applicant in this case, seeing that two of the newer members of the court joined him makes me cautiously optimistic for the future.

[MaxDrei]

Interesting case, on obviousness. Here is a link to the EPO patent file:

https://register.epo.org/application?number=EP00901483

I'm not a chemist so the following might not make much sense, but reply comments would be appreciated.

Commercial success as proof of non-obviousness always troubles me. Rarely is there a Nexus. But here, where the issue was storage stability Y/N, the incontrovertible fact that the stuff was a solid commercial success surely is evidence enough that it is storage-stable enough?

The case reminds me of that old case claiming a paper cup for beverages and amended during prosecution to a disposable water-resistant paper cup for hot beverages. Does a switch to it by McDonalds, away from plastic cups, make it non-obvious? Or was it patentable because all earlier paper beverage cups were not "disposable". It is debatable.

Back to the present case. The EPO noted that the tests in the patent application were of one solvent only, but concluded that Applicant had succeeded by evidence in making it "plausible" that all claimed solvents worked to deliver storage stability.

It is a lively EPO file. Plenty of third party observations from members of the public prior to issue, three post-issue oppositions pending and two divisionals in the pipeline.

[Kevin E. Noonan]

Thanks for this, Max. I agree that the issue is often a nexus with commercial success, and somewhat less so for long-felt need and failure of others. I think the court was convinced that the patentees had solved an unappreciated problem with real-world advantages to patients and that the examiner had merely cherry-picked the prior art to reconstruct the invention using hindsight.

What struck me about the case was the explicit use of the amount of time between the prior art references themselves and the invention date to support non-obviousness. I don't remember a case where the court (or the CCPA) used this reasoning so directly.

Thanks for the comment.

[Skeptical]

I agree Dr. Noonan, as I too was struck with the front and center presentation of "Well, if it was so obvious, it would have been done before" type of reasoning.

[MaxDrei]

Indeed Dr Noonan. When have we ever seen evidence of such persuasive force that i)the objective technical problem was old and had defied solution for many years and ii) the Inventor had solved it? The evidence was not only that the Invention delivered to the market a viable medicament and commercially attractive product but also that the prior teachings over many years did not.

Not sure about your "unappreciated" though. Which did the pharma industry not appreciate: Patient compliance, storage stability, or both?