Different aspects of this ruling are well covered in other blogs, notably The Orange Book Blog (OBB), and Patent Baristas. As OBB noted:

Three different U.S. district courts had previously upheld the validity of Pfizer's Norvasc patent (U.S. Patent No. 4,879,303), making today's appeals court decision somewhat of a surprise.

The examiner had originally rejected the same claims for the same reason that the CAFC did: the salt used in combination with the other ingredients would have been obvious.

In response to a final obviousness rejection by the Examiner, Pfizer filed a continuation application (serial no. 07/256,938) and abandoned the original application. Along with the continuation application, Pfizer submitted a preliminary amendment and statement, and a declaration under 37 C.F.R. § 1.132 by Dr. Wells dated October 3, 1988 (“Wells Declaration”)... Pfizer argued that choosing an appropriate salt is a very difficult task “since each salt imparts unique properties to the parent compound” and that one skilled in the art would “conclude that the besylate salt of amlodipine is a unique compound and not an obvious one.”

The continuation claims were allowed.

The district court found "the besylate salt of amlodipine was unexpectedly superior to the amlodipine salts of the prior art."

The district court had granted Apotex a prima facie basis for anticipation based upon the patent's prosecution history. The CAFC squashed that as legally wrong and pinning the tail on the wrong donkey: a patent is by statute presumed valid.

The district court held that Apotex had established a prima facie case of obviousness because the patent examiner initially rejected the claims to amlodipine besylate for obviousness. Specifically, the district court stated, “The ’303 patent’s file wrapper shows that the examiner originally rejected the claimed invention because of obviousness. Under these circumstances, of course, the Court must accept that the defendant has made a prima facie showing on this question.” Bench Order Tr. 21:20-24. The district court’s ruling must be rejected, not only because it is legally incorrect, but also because it may reflect a serious misconception regarding the proper burden of proof each party bears in a patent litigation.

Our case law consistently provides that a court is never bound by an examiner’s finding in an ex parte patent application proceeding. Fromson v. Advance Offset Plate, Inc., 755 F.2d 1549, 1555 (Fed. Cir. 1985). Thus, it can never be the case that an examiner’s interim finding of prima facie obviousness renders the claims of an issued patent prima facie obvious. Instead, deference to the decisions of the USPTO takes the form of the presumption of validity under 35 U.S.C. § 282. Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1329 (Fed. Cir. 2000). That is, by statute a patent is valid upon issuance, 35 U.S.C. § 282, and included within the presumption of validity is a presumption of non-obviousness. Structural Rubber Prods. Co. v. Park Rubber Co., 749 F.2d 707, 714 (Fed. Cir. 1984). Since we must presume a patent valid, the patent challenger bears the burden of proving the factual elements of invalidity by clear and convincing evidence. That burden of proof never shifts to the patentee to prove validity. Hybritech Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1375 (Fed. Cir. 1986). “The presumption [of validity] remains intact and [the burden of proof remains] on the challenger throughout the litigation, and the clear and convincing standard does not change.” Id.

A legitimate invalidity challenge must be answered, but the burden of proof never shifts, always resting on the shoulders of the challenger.

It is true that once a challenger has presented a prima facie case of invalidity, the patentee has the burden of going forward with rebuttal evidence. See Mas-Hamilton Group v. LaGard, Inc., 156 F.3d 1206, 1216 (Fed. Cir. 1998) (citing Hybritech, 802 F.2d at 1376); Cable Elec. Prods. Inc. v. Genmark, Inc., 770 F.2d 1015, 1022 (Fed. Cir. 1985) (“[I]f evidence is presented establishing a prima facie case of invalidity, the opponent of invalidity must come forward with evidence to counter the prima facie challenge to the presumption of section 282.”). But, all that means is that even though a patentee never must submit evidence to support a conclusion by a judge or jury that a patent remains valid, once a challenger introduces evidence that might lead to a conclusion of invalidity—what we call a prima facie case—the patentee “would be well advised to introduce evidence sufficient to rebut that of the challenger.” Orthokinetics, Inc. v. Safety Travel Chairs, Inc., 806 F.2d 1565, 1570 (Fed. Cir. 1986).

However, this requirement does not “in substance shift the burden of persuasion,” Cable Elec., 770 F.2d at 1022, because “the presumption of validity remains intact and the ultimate burden of proving invalidity remains with the challenger throughout the litigation.” Mas-Hamilton Group, 156 F.3d at 1216; see also Innovative Scuba Concepts, Inc. v. Feder Indus., Inc., 26 F.3d 1112, 1115 (Fed. Cir. 1994); Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281, 287 (Fed. Cir. 1985). The trial court has the responsibility to determine whether the challenger has met its burden by clear and convincing evidence by considering the totality of the evidence, including any rebuttal evidence presented by the patentee. Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 1534 (Fed. Cir. 1983).

A prosecution office action rejection is at best a tidbit of evidence.

The basis (as opposed to the mere existence) of an examiner’s initial finding of prima facie obviousness of an issued patent is therefore, at most only one factual consideration that the trial court must consider in context of the totality of the evidence “in determining whether the party asserting invalidity has met its statutory burden by clear and convincing evidence.” Fromson, 755 F.2d at 1555. It does not, however, lessen or otherwise affect the burden of proof, nor does it require that unless the patentee introduces evidence of secondary considerations to establish non-obviousness, the patent challenger will necessarily prevail.

This case's statement of obviousness, relying up last fall's DyStar ruling -

By statute, a claimed invention is unpatentable if the differences between it and the prior art “are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art.” 35 U.S.C. § 103(a). Subsumed within the Graham factors is a subsidiary requirement articulated by this court that where, as here, all claim limitations are found in a number of prior art references, the burden falls on the challenger of the patent to show by clear and convincing evidence that a skilled artisan would have been motivated to combine the teachings of the prior art references to achieve the claimed invention, and that the skilled artisan would have had a reasonable expectation of success in doing so. DyStar Textilfarben GmbH v. C.H. Patrick Co., 464 F.3d 1356, 1360 (Fed. Cir. 2006); Velander v. Garner, 348 F.3d 1359, 1363 (Fed. Cir. 2003).

The appeals court finds both motivation and expectation of success as compelling evidence in the four-factor Graham obviousness test.

The underlying factual determinations made by the trial court that this court must review for clear error include (1) the scope and content of the prior art, (2) the level of ordinary skill in the art, (3) the differences between the claimed invention and the prior art, and (4) objective indicia of non-obviousness. Graham v. John Deere Co., 383 U.S. 1, 17 (1966).

A difficulty in the district court’s opinion arises because, in assuming a prima facie case of obviousness, the district court did not fully address whether Apotex showed by clear and convincing evidence that a skilled artisan would have been motivated to combine the teachings of the prior art references relied on, especially the ’909 patent and Berge, to achieve the claimed invention. However, the district court’s omission in this case is harmless error because evidence of record easily satisfies us that a reasonable fact-finder could only conclude that Apotex has shown by clear and convincing evidence that the skilled artisan would indeed have been so motivated to combine the prior art to produce the besylate salt of amlodipine. The record also satisfies us that, contrary to the district court’s finding, a reasonable fact-finder could only conclude that the skilled artisan would have had a reasonable expectation of success with the besylate salt form of amlodipine for the reasons elaborated, post.

Pfizer's argument was that using the claimed salt had been a rarity.

Pfizer does not argue that there was no motivation to combine the prior art references per se. Rather, Pfizer argues that (1) the ’909 patent does not suggest or motivate the skilled artisan to make amlodipine besylate because none of the anions listed in the ’909 patent have a cyclic structure as does besylate, and (2) even if the ’909 patent were combined with Berge, the skilled artisan would not have been motivated to make amlodipine besylate because Berge shows that besylate was actually one of the most rarely used anions in the pharmaceutical industry, as only 0.25% of approved drugs as of 1974 were besylate salts. Finally, Pfizer asserts that other prior art references relied upon by Apotex are not relevant because the examples of besylate salts disclosed in these references are limited to pharmaceuticals unrelated to amlodipine.

The CAFC rejects that logic - who cares how rarely used in the past!, figuring that, looking at the nature of the problem, the solution would naturally arisen to one skilled in the art.

We reject Pfizer’s first argument, since 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.” DyStar, 464 F.3d at 1361; see also Ormco Corp. v. Align Tech., Inc., 463 F.3d 1299, 1307-08 (Fed. Cir. 2006). In other words, it is irrelevant that none of the anions specifically listed in the ’909 patent have a cyclic structure, because the motivation to make amlodipine besylate here is gleaned not only from the prior art as a whole rather than the ’909 patent alone, but also from the nature of the problems encountered with the amlodipine maleate tablet formulations sought to be solved by the inventors of the ’303 patent.

Concomitantly, the number of salts approved for use by the FDA is small, limiting available choices.

This is true especially given the fact that the genus of FDA-approved anions at the time was small, i.e., only 53. That benzene sulphonate was only used in creating 0.25% of FDA-approved drugs is not highly probative, much less dispositive. Indeed, beyond hydrochloride, which was used in approximately 43% of approved drugs, almost all other salts could be characterized as “rarely used.”

To the CAFC, one of out 53 is obvious enough; no "undue experimentation" required, especially when considering that stability and solubility were the traits sought, and which besylate salt of amlodipine was known to provide.

But the outcome of this case need not rest heavily on the size of the genus of pharmaceutically-acceptable anions disclosed by Berge because clear and convincing evidence establishes that, out of the list of 53 anions, one of ordinary skill in the art would have favorably considered benzene sulphonate because of its known acid strength, solubility, and other known chemical characteristics as reported in several other publications Pfizer has admitted are prior art.

The district court ignored the significance of these other prior art references suggesting the besylate salt because the pharmaceuticals disclosed in those prior art references were not described as useful to treat hypertension or angina, as is amlodipine. By not considering these references in its obviousness analysis, however, the district court clearly erred. As here, the besylate acid addition salt form was described in these prior art references as useful in promoting stability and solubility, as well as improving other physicochemical characteristics. That none of these references discloses a medication for treating hypertension or angina like amlodipine is therefore unimportant, if not actually irrelevant. As Pfizer concedes, the besylate part of the acid addition salt has no therapeutic effect, but merely serves as a means to deliver the amlodipine part of the molecule to the body. Prior art disclosing the use of benzene sulphonate for improving the bioavailability of other pharmaceuticals—especially a dihydropyridine as disclosed by Carabateas—is therefore highly relevant in weighing the factors relating to obviousness.

Now to the nut of it with regard to experimentation: what constitutes a "reasonable probability of success"? The CAFC dismisses unpredictability as factoring in, failing to see any relationship between predictability and probability.

The problem with the district court’s ultimate conclusion of non-obviousness based on that factual finding, however, is that case law is clear that obviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success. See In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985) (“Although [the inventor] declared that it cannot be predicted how any candidate will work in a detergent composition, but that it must be tested, this does not overcome [the prior art’s] teaching that hydrated zeolites will work.”); see also Brown & Williamson Tobacco Corp. v. Philip Morris Inc., 229 F.3d 1120, 1125 (Fed. Cir. 2000); Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 809 (Fed. Cir. 1989); In re Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986). Indeed, a rule of law equating unpredictability to patentability, applied in this case, would mean that any new salt—including those specifically listed in the ’909 patent itself—would be separately patentable, simply because the formation and properties of each salt must be verified through testing. This cannot be the proper standard since the expectation of success need only be reasonable, not absolute. Merck, 874 F.2d at 809; In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988).

The evidence would convince a reasonable finder of fact that the skilled artisan would have had that reasonable expectation of success that an acid addition salt of besylate would form and would work for its intended purpose. See In re Rinehart, 531 F.2d 1048, 1053-54 (C.C.P.A. 1976).

 The inventor, Dr. Wells, on reasonable expectation, having narrowed the possibilities to seven -

Specifically, the evidence clearly shows that as soon as tablet processing problems arose with the amlodipine maleate tablet formulations, Dr. Wells readily compiled a list of seven alternative anions—including the besylate—each of which he expected would form an amlodipine acid addition salt:

Q. And one of the reasons why you chose these various salts [sic], or suggested these various salts [sic], is because you expected that they would be able to make a salt of them, correct?
A. There was an expectation, but that wasn’t guaranteed.

But, once again, only a reasonable expectation of success, not a guarantee, is needed. O’Farrell, 853 F.2d at 903; Brown & Williamson, 229 F.3d at 1125. That reasonable expectation of success is further amply reflected in Dr. Wells’ further testimony that he expected these seven amlodipine acid addition salts would show improved physicochemical characteristics over the maleate salt, including improved stability and non-stickiness...

Finally, there is a suggestion in Pfizer’s supplemental filing with the FDA that it was known that the besylate salt of amlodipine would work for its intended purpose: “We feel that the change in salt form [from maleate to besylate] is justified since benzenesulfonate is a commercially acceptable salt, as exemplified by the tranquilizer mesoridazine (Serentil).” Thus, although Dr. Wells testified that it was not guaranteed whether amlodipine besylate would form and what its salient characteristics would be, “this does not overcome [the prior art’s] teaching that [amlodipine besylate] will work.” Corkill, 771 F.2d at 1500.

Considering all of the evidence, we conclude that the district court clearly erred in finding that Apotex failed to produce clear and convincing evidence that one skilled in the art would have had a reasonable expectation of success with the besylate salt of amlodipine.

Would besylate salt of amlodipine have been obvious to try? What is the threshold for undue experimentation? The CAFC figures it must be case by case, leaving prior art anticipation a crap shoot for high-rolling litigation.

To be sure, “to have a reasonable expectation of success, one must be motivated to do more than merely to vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result, where the prior art gave either no indication of which parameters were critical or no direction as to which of many possible choices is likely to be successful.” Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006) (internal quotations omitted). Pfizer argues that, if anything, amlodipine in its besylate salt form would at most be “obvious to try,” i.e., to vary all parameters or try each of numerous possible choices to see if a successful result was obtained. O’Farrell, 853 F.2d at 903.

Parties before this court often complain that holdings of obviousness were based on the impermissible “obvious to try” standard, and this court has accordingly struggled to strike a balance between the seemingly conflicting truisms that, under 35 U.S.C. § 103, “obvious to try” is not the proper standard by which to evaluate obviousness, In re Antonie, 559 F.2d 618, 620 (C.C.P.A. 1977), but that, under O’Farrell and other precedent, absolute predictability of success is not required. 853 F.2d at 903. Reconciling the two is particularly germane to a situation where, as here, a formulation must be tested by routine procedures to verify its expected properties. The question becomes then, when the skilled artisan must test, how far does that need for testing go toward supporting a conclusion of non-obviousness?

As we have said before, “[e]very case, particularly those raising the issue of obviousness under section 103, must necessarily be decided upon its own facts.” In re Jones, 958 F.2d 347, 350 (Fed. Cir. 1992). Consequently, courts cannot decide the obviousness or non-obviousness of a patent claim by proxy. Undue dependence on mechanical application of a few maxims of law, such as “obvious to try,” that have no bearing on the facts certainly invites error as decisions on obviousness must be narrowly tailored to the facts of each individual case. As we stated in DyStar,

Obviousness is a complicated subject requiring sophisticated analysis, and no single case lays out all facets of the legal test. [There is] danger inherent in focusing on isolated dicta rather than gleaning the law of a particular area from careful reading of the full text of a group of related precedents for all they say that is dispositive and for what they hold. When parties . . . do not engage in such careful, candid, and complete legal analysis, much confusion about the law arises and, through time, can be compounded.

464 F.3d at 1367. On the facts of this case, however, we are satisfied that clear and convincing evidence shows that it would have been not merely obvious to try benzene sulphonate, but would have been indeed obvious to make amlodipine besylate.

First, this is not the case where there are “numerous parameters” to try. Rather, the only parameter to be varied is the anion with which to make the amlodipine acid addition salt. Although we recognize some degree of unpredictability of salt formation, see, e.g., Sanofi-Synthelabo v. Apotex, Inc., 470 F.3d 1368, 1379 (Fed. Cir. 2006), the mere possibility that some salts may not form does not demand a conclusion that those that do are necessarily non-obvious. This is especially true here, where (1) as noted above, the skilled artisan had a reasonable (although not guaranteed) expectation that amlodipine besylate would form; (2) Pfizer conceded in prior litigation that the type of salt had no effect on the therapeutic effect of the active ingredient, amlodipine, and was practically interchangeable, Pfizer v. Dr. Reddy’s Labs., 359 F.3d at 1365-66; and (3) numerous other publications (described above) clearly directed the skilled artisan to a pharmaceutically-acceptable acid addition salt made from benzene sulphonate, including, significantly, the Carabateas patent which taught the besylate acid addition salt form of another dihydropyridine pharmaceutical compound.

Second, this is not the case where the prior art teaches merely to pursue a “general approach that seemed to be a promising field of experimentation” or “gave only general guidance as to the particular form of the claimed invention or how to achieve it.” O’Farrell, 853 F.2d at 903; Medichem, 437 F.3d at 1167. Here, as admitted by Mr. Davison, in selecting an acid addition salt formulation, one skilled in the art looked to pharmacopoeias and compendia to find a salt that was previously approved by the FDA and used successfully within the pharmaceutical industry. Berge clearly pointed the skilled artisan to 53 anions that, as of 1974, were pharmaceutically acceptable. As Dr. Wells’ testimony and the Carabateas patent demonstrated, one of ordinary skill in the art was capable of further narrowing that list of 53 anions to a much smaller group, including benzene sulphonate, with a reasonable expectation of success.

The CAFC becomes profoundly inarticulate through muddled verbiage, approaching inscrutability, but basically postulates that verification testing does not qualify as undue experimentation. Hence, if you think it would work ("reasonable expectation of success") that it tests out doesn't mean anything with regard to obviousness, regardless of how expensive or laborious the testing is. Incremental improvements of a known process are not generally patentable - "discovery of an optimum value of a variable in a known process is usually obvious."

Finally, Pfizer protests that a conclusion that amlodipine besylate would have been obvious disregards its “discovery” because it was obtained through the use of trial and error procedures. While the pharmaceutical industry may be particularly adversely impacted by application of an “obvious to try” analysis, see, e.g., In re Merck, 800 F.2d at 1100 (Baldwin, J., dissenting), that Pfizer had to verify through testing the expected traits of each acid addition salt is of no consequence because it does not compel a conclusion of non-obviousness here. In coming to this conclusion, we have not ignored the fact that “[p]atentability shall not be negatived by the manner in which the invention was made.” 35 U.S.C. § 103(a). Nor are we ignorant of the fact that reference to “routine testing” or “routine experimentation” is disfavored. See, e.g., In re Yates, 663 F.2d 1054, 1056 n.4 (C.C.P.A. 1981) (“The Solicitor . . . argues that it is ‘not unobvious to discover optimum or workable ranges by routine experimentation.’ In many instances, this may be true. The problem, however, with such ‘rules of patentability’ (and the ever-lengthening list of exceptions which they engender) is that they tend to becloud the ultimate legal issue—obviousness—and exalt the formal exercise of squeezing new factual situations into preestablished pigeonholes. Additionally, the emphasis upon routine experimentation is contrary to the last sentence of section 103.”) (internal citation omitted); In re Saether, 492 F.2d 849, 854 (C.C.P.A. 1974) (“In his argument that ‘mere routine experimentation’ was involved in determining the optimized set of characteristics, the solicitor overlooks the last sentence of 35 U.S.C. § 103 . . . . Here we are concerned with the question of whether the claimed invention would have been obvious at the time it was made to a person having ordinary skill in the art—not how it was achieved.”) (internal citation omitted); In re Fay, 347 F.2d 597, 602 (C.C.P.A. 1965) (“[W]e do not agree that ‘routine experimentation’ negatives patentability. The last sentence of section 103 states that ‘patentability shall not be negatived by the manner in which the invention was made.’ To support the board’s decision that ‘routine experimentation within the teachings of the art’ will defeat patentability requires a primary determination of whether or not appellants’ experimentation comes within the teachings of the art. Whether the subsequent experimentation is termed ‘routine’ or not is of no consequence.”).

However, on the particularized facts of this case, consideration of the “routine testing” performed by Pfizer is appropriate because the prior art provided not only the means of creating acid addition salts but also predicted the results, which Pfizer merely had to verify through routine testing. Merck, 874 F.2d at 809. The evidence shows that, upon making a new acid addition salt, it was routine in the art to verify the expected physicochemical characteristics of each salt, including solubility, pH, stability, hygroscopicity, and stickiness, and Pfizer’s scientists used standard techniques to do so. These type of experiments used by Pfizer’s scientists to verify the physicochemical characteristics of each salt are not equivalent to the trial and error procedures often employed to discover a new compound where the prior art gave no motivation or suggestion to make the new compound nor a reasonable expectation of success. This is not to say that the length, expense, and difficulty of the techniques used are dispositive since many techniques that require extensive time, money, and effort to carry out may nevertheless be arguably “routine” to one of ordinary skill in the art. Rather, our conclusion here relies on the fact that one skilled in the art would have had a reasonable expectation of success at the time the invention was made, and merely had to verify that expectation.

We find this case analogous to the optimization of a range or other variable within the claims that flows from the “normal desire of scientists or artisans to improve upon what is already generally known.” In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003) (determining where in a disclosed set of percentage ranges the optimum combination of percentages lies is prima facie obvious). In In re Aller, 220 F.2d 454, 456 (C.C.P.A. 1955), our predecessor court set forth the rule that the discovery of an optimum value of a variable in a known process is usually obvious. See also In re Boesch, 617 F.2d 272, 276 (C.C.P.A. 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”). Similarly, we hold that the optimization of the acid addition salt formulation for an active pharmaceutical ingredient would have been obvious where as here the acid addition salt formulation has no effect on the therapeutic effectiveness of the active ingredient and the prior art heavily suggests the particular anion used to form the salt. Cf. In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997) (“‘[I]t is not inventive to discover the optimum or workable ranges by routine experimentation.’” (quoting Aller, 220 F.2d at 456)); In re Kulling, 897 F.2d 1147, 1149 (Fed. Cir. 1990) (finding no clear error in Board of Patent Appeals and Interferences’ conclusion that the amount of eluent to be used in a washing sequence was a matter of routine optimization known in the pertinent prior art and therefore obvious).

Thus, while patentability of an invention is not negated by the manner in which it was made, “the converse is equally true: patentability is not imparted where ‘the prior art would have suggested to one of ordinary skill in the art that this process should be carried out and would have a reasonable likelihood of success.’” Merck, 874 F.2d at 809 (quoting In re Dow Chem. Co., 837 F.2d 469, 473 (Fed. Cir. 1988)).

The CAFC on the unexpected being based upon what would have expected at the time:

Evidence of unexpected results can be used to rebut a prima facie case of obviousness. Peterson, 315 F.3d at 1330.

(“‘[W]hen unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art.’” (quoting In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991)).

Another defect in the district court’s reasoning is its failure to recognize that by definition, any superior property must be unexpected to be considered as evidence of non-obviousness. In re Chupp, 816 F.2d 643, 646 (Fed. Cir. 1987). Thus, in order to properly evaluate whether a superior property was unexpected, the court should have considered what properties were expected. Merck, 874 F.2d at 808.