Obviousness of chemical structures is premised on the principle that compounds that are similar in structure are predicted to have similar properties. As a result, when a compound is disclosed in the prior art and an utility for that compound is also disclosed or predicted, the motivation for modifying that structure is usually found in the desire to obtain additional compounds having the previously disclosed activity.Thus, for example, if the prior art disclosed a compound as its methyl ester and explained that compound was useful as an analgesic, than one of ordinary skill in the art might surmise that an ethyl ester homologue would also be active. An applicant who later attempts to claim that ethyl ester in a patent application would have to deal with the fact that the prior art already disclosed the homologue as well as an activity for that homologue. As a result, the patent examiner could make a persuasive argument that the close structural similarity of the prior art compound together with the disclosure of its activity would have made the homologue an obvious analogue to make; one of ordinary skill in the art would have been so motivated because he could make additional compounds with analgesic activity.

Until now, our primary organizing principle has been understanding a prima facie case of obviousness, the TSM test, and rebutting the prima facie case with unexpected or superior results. To enhance our understanding further, we will see how this obviousness framework has been implemented in regard to different types of chemical subject matter. By presenting the remaining material in this fashion, we can expand on the analytical concepts we have already introduced as well as provide additional specific examples of how that those concepts have been interpreted and applied in the chemical arts.

8.9.a Isomers and Homologues

Isomers in the broadest sense are compounds with the same molecular formula but different structures. Isomers are most broadly categorized as either structural isomers or stereoisomers. Compounds that are structural isomers have a different arrangement of atom connectivity relative to each other,whereas compounds that are stereoisomers have the same atom connectivity but the atoms still arrange differently in a spatial sense. We’ll begin this section with structural isomers, for which one example is shown in Figure below.
Despite the fact that the simple compounds in the figure have the same formula,their properties differ very significantly one from another. Dimethyl ether is a highly flammable gas at room temperature, whereas ethanol is a semi consumable liquidat room temperature. Even though these two compounds have the same formula,the connectivity of the atoms results in very different properties. For an indication of how some structural isomers might be treated, let’s briefly review the case of Ex parte Mowry, which concerned an appeal to the Board of Patent Examiners at

Isomers and Homologues

FIGURE :Two formula isomers.

Two formula isomers.

FIGURE :Claimed styrene and prior art styrenes.

USPTO over rejected claims directed to, inter alia, monocyclohexylstyrene isomers(-ortho, -meta, and -para) of the type shown in Figure 8.16.59
The claimed structures were disclosed as having utility in polymerization reactions(with other monomers) for the preparation of various plastic copolymers. The applicant’sclaims were rejected by the examiner under certain grounds, including alleged obviousness. The obviousness argument made by the examiner cited the disclosure of generic structures having an allegedly isomeric relationship with applicant’s claimed structures (cited structure also shown in Figure above). In other words, the patent examiner’s view was that the cyclohexylstyrenes were prima facie obvious due to the existence of the prior art isohexylstyrene genus.Despite having the same alleged molecular formulae, the Board found that the claimed structures were patentable and that “that isomers in the broad sense, that is, those having the same empirical formula but with different radicals, would not necessarily be equivalent, or that one would be suggestive of the other.” In its opinion,the Board appears to suggest that a different treatment might be afforded to the compounds in suit where the compounds are “positional isomers” rather than isomers of formula only. If we glance back to the basic formula isomer compounds shown in Figure above, we can appreciate that one of ordinary skill in the art would not per se assume formula isomers to be obvious in view of each other, given the poor relationship between a chemical formula as written and its actual structure and especially its function. The chemical formula is much too basic a level to apply any broad rule regarding obviousness.
In contrast to chemical formula isomers, positional isomers are a narrower subclass where the compounds contain the same appending groups, but those groups may be connected in a different manner one from another. Positional isomers must have the same sub stituents, but those substituents occupy a different position on the molecule.

Claimed styrene and prior art styrenes.

FIGURE :Claimed compound and prior art compounds from ’808 reference.

Let us turn to In re Wilder which focused on the issue of positional isomers.
This decision arose from a patent application with a claim to the structure shown in Figure above.
The applicant stated in the specification that the compound is useful as an antidegradant in rubber and had minimal toxicity to human skin. The USPTO rejected the application asserting that the prior art patent U.S. 2,734,808 (the ’808 reference)rendered the applicant’s claimed compound obvious. The ’808 reference disclosed a genus of compounds and two specific compounds of note, one a positional isomerand one a homologue, all of which are represented in Figure above. The compounds of the ’808 reference were described as having utility as gasoline additives that inhibitgum formation and retard the degradation of tetraalkyl lead in leaded gasoline. The applicant appealed the USPTO rejection to the CCPA.
On the basis of the close structural similarity, the Court found that both the homologue and the structural isomer rendered the applicant’s claimed compound prima facie obvious. The applicant, in an attempt to rebut the alleged prima facie case, submitted evidence that the claimed compound was lacking in skin toxicity,which was a property not demonstrated by the prior art positional isomer. While the Court recognized this difference as being sufficient to rebut the prima facie case with respect to the positional isomer, they still found the claimed compound obvious in view of the homologue. Unlike the positional isomer in this case, the homologue demonstrated the same property as the claimed compound (no skin toxicity) and thus the applicant could not rebut the prima facie case raised by the homologous compound. The claim to the compound was thus denied.

As can be gleaned from the decision in the application of Wilder, homologues and positional isomers might sometimes be treated similarly—in this example, both were deemed sufficient to establish a prima facie case of obviousness. In the case of Wilder, the claimed compound and the prior art positional isomer and homologue were very similar in structure. The homologue is missing one carbon atom and the positional isomer has the methyl group at the five-position of the hexyl chain move dover one carbon so that the chain is no longer branched. However, one should not assume from this example that positional isomers will always lead to a case of prima facie obviousness because both the prior art and the claimed isomer must always be considered as a whole and thus cannot be taken out of context. So while a positionalisomer might be predicted to lend similar properties in general, such a generality can sometimes be overridden by a more specific understanding of how such changes might relate to the specific area being analyzed.
The facts of InreWilder also dealt with a prior art homologue, where a homologue is defined as a compound differing from another by the successive addition(s) of the same chemical group (e.g., CH2). This means that a homologue could be 1 methylenere moved from its comparator or 20 (or even more) methylene groups removed from its comparator. Because a homologue can vary so much in its degree of added repetition, the degree of predictability for homologues further removed in structure would be expected to decrease with the increasing difference in size between the claimed structure and the prior art structure. Although they are still homologues no matter the number of additional repeating units, at some point the tail begins to“wag the dog.”So while homologues or positional isomers are often close enough structurally to create a structural presumption of obviousness, nothing is absolute.As pointed out in the case of Ex parte Blattner discussed earlier, this assumption must still be balanced with all other factors, including the predictability of the art in view of what the art as a whole would teach as well as the particular aspects of the compound being claimed. Thus homologues and positional isomers in the prior art can be significant evidence for prima facie obviousness, but are not always adequate to guarantee that conclusion.

8.9.b Enantiomers

Chirality is a property inherent to certain molecules, both organic and inorganic, in which two molecules, identical in absolute structural terms, are nevertheless nonsuperimposable.The word chirality itself is derived from Greek stems that relate to the term “handedness,” and this is very appropriate as your own two hands are probably the most easy to relate to example of chirality. If you look at your two hands, you can appreciate that they are essentially identical (assuming your manicuring is highly symmetric) but yet, your left hand is not super imposable on your right hand. Instead, they relate as one object relates to its own mirror image. While an enantiomeric pair of molecules (the molecule and its mirror image) have the same gross physical properties, they interact differently with other molecules possessing chirality—think of trying to shake somebody’s left hand with your right hand; it does not work the same way as when shaking their right hand with your right hand.
As a result, two enantiomers may act differently toward important classes of chiralbiomolecules such as receptors, enzymes, and membrane components.Over time, the appreciation of the importance of chirality in drugs has grown. In many circumstances, a drug containing a single enantiomer has a different and, very often, a preferred biological profile over a drug containing both enantiomers in equal amounts (referred to as a racemic mixture). In fact, as our medical sophistication has grown, we increasingly appreciate that an enantiomer and its mirror image rarely have the same pharmacological properties and that administration of a racemic mixture is often tantamount to administering two different drugs or perhaps one drug and an equal amount of an impurity. A technological evolution has enabled the industrial scale production or separation of many single enantiomers, resulting in the revisiting of many older, racemicmixture drugs, this time with an eye to evaluating and possibly redeveloping the mixtures as single enantiomer drug products. By way of example, albuterol has been marketed for some time as a racemic mixture having _2-agonist activity useful for inducing bronchodilation in order to alleviate asthma attacks.The R-enantiomer of albuterol provides the bronchial relaxant activity while the S-enantiomer appears to contribute to side effects only.
The determination of non obviousness with respect to a single enantiomer in view of a prior art racemic mixture requires one to look at the claimed subject matter (in this case, a single enantiomer) in view of the closest prior art (the racemic mixture)and ask the question of whether one of ordinary skill in the art would have been motivated to prepare the enantiomer in view of the prior disclosure(s) of the racemic mixture. Since it has been appreciated for some time that a single enantiomer can have beneficial advantages when compared to a racemic mixture, it is no great leap to predict that the enabled disclosure of a racemic mixture for use in pharmaceuticals will likely provide the motivation for the preparation of each of the single enantiomers for the same use. The motivation would be the close structural similarity coupled with a reasonable expectation that at least one of the enantiomers will provide a similar or superior activity over the racemic mixture. Thus the attempt to patent a single enantiomer when the racemic mixture is known in the art will likely result in a case of prima facie obviousness.68 However, a prima facie case of obviousness can still be rebutted by a secondary considerations of non obviousness (Graham step 4), including the demonstration of unexpected or superior results.
Issues related to prior art enablement, prima facie obviousness and secondary considerations of non obviousness often intertwine in obvious determinations during patent prosecution and litigation since their definitional boundaries are often not well demarcated. In the case Sterling Drug Inc. v. Watson, the USPTO rejected claims to various single enantiomer compounds, and this decision was appealed to the U.S. District Court for the District of Colombia. The claims in question—10, 12, and14—are presented in Figure 8.18 together with the claimed structures (l-arterenol is the neurotransmitter nor epinephrine).


FIGURE :Claims to single enantiomer of l-arterenol (nor epinephrine) and d-arterenol.

In the beginning of its analysis in regard to the three claims, the court summarized the USPTO’s argument that the claims were not patentable in view of (1) aprior art reference that disclosed certain salts of racemic arterenol, (2) l-arterenol(norepinephrine) is naturally present in the human body, and (3) another prior artreference that described the next known homologue of l-arterenol. The court, in finding claims 12 and 14 valid, quickly disposed of the USPTO arguments by first noting that l-arterenol had “phenomenal therapeutic properties” with respect to the treatment of irreversible shock and occluded arteries. The court further noted that it is the l-form and not the d/l(racemic)-form that has the therapeutic value. In dispensing with the closest homologues of the prior art, which apparently had some effect in raising blood pressure, the court noted that “there is a vast amount of difference between the therapeutic value of something that will so control the blood pressure that successful surgery can be accomplished and something else that falls so short of doing so that the patient dies.” In contrast, the court found that claim10 was not patentable as written since the claim was also directed to d-arterenol.
The court remarked that there was no showing of any “unexpected and unobvious properties” of the claimed d-arterenol, and thus apparently that claim could not be considered non obvious in view of the prior art, including the known racemicmixture.Finally, the court noted that the existence of l-arterenol in the human body “ignores the fact that it has no therapeutic value unless isolated and available in its pure

Claimed single enantiomers.

FIGURE :Claimed single enantiomers.

form. . .” and that no compound of the type had ever been derived from its natural source unless seeded with pure crystals of the type claimed in applicant’s invention.It appears implicit from the court’s last finding of non obviousness on the fact that the preparation of pure l-arterenol compound in the prior art was not enabled.
Let’s quickly juxtapose this result with an enantiomer case having a different outcome. In re Adamson resulted from an appeal to the CCPA of denial of patentability by the USPTO Board of Appeals, which rejected claims 1–11 of the applicant’s application directed to compounds having spasmolytic activity and processes for making same. The stated reason for the rejection is that the compounds were obvious in view of the prior art disclosure of the racemic mixture. Claim 1, which was deemed by the court to be a typical claim of the invention, is reproduced in Figure above together with the structures of the claimed compounds.

The applicants argued that their single enantiomer compounds were non obvious for two reasons. First, they discovered that the racemic mixture of the prior art could be separated. Second, they submitted an affidavit alleging that the claimedlevorotary compounds had substantially higher spasmolytic activity than either the dextrorotary is omer or the racemicmixture while having only slightly higher toxicity.
It was the applicant’s contention that the prior art suggested that the levorotary and dextrorotary forms of the compounds produced should have had similar therapeuticactivity.However, the Court was not persuaded by the applicant’s arguments regarding the unexpected and superior activity of the claimed single enantiomers compared to the racemic mixture. The Court noted that the claimed levo-isomers were only twice as potent as the racemic mixture and that the dextro-isomer was inactive. In regard to enablement, the Court roundly rejected the applicant’s contention, asserting that the prior art of record showed there were numerous techniques for separating aracemic mixture into its constituent enantiomers. Although the reference did not describe compounds of similar structures as those claimed by applicants, the Court held that such specificity was not required. The obviousness rejection was thus upheld.
The difference in facts between cases (stated and especially unstated) always makes generalizations difficult, but it still is worthwhile to consider why the Court in Sterling Drug found one of the enantiomers non obvious in view of the racemicmixture whereas the court in Adamson did not. First, it is useful to appreciate the similarities. In both cases, the Courts indicated that the enantiomers in question would be prima facie obvious absent a showing of useful or unexpected properties.
The motivation to prepare a pure enantiomer is the expectation that the enantiomer will have similar or even somewhat improved properties then the mixture. In Sterling Drug, the Court was very impressed with the “phenomenal therapeutic properties” ofl-artenerol with respect to the treatment of irreversible shock and occluded arteries,and it is important that the court noted that it is the l-form and not the d/l(racemic)-form that has the therapeutic value. In the case of Sterling Drug, it appeared that the difference was not one of degree but rather a difference in kind (the difference between working and not working). In contrast, the Court in Adamson appeared to take the twofold increase in activity of the claimed enantiomer over the racemicmixture as a predictable and not unexpected result. Likewise, the only moderate increase in toxicity relative to the racemic mixture despite having twofold greater activity was also shrugged off. The Court noted that the racemic mixture had toxicity between the two isomers which is “to be particularly expected.”
Beyond the differences in activity between the claimed enantiomers of each case relative to the prior art racemicmixture, there was also the different treatment afforded by the Courts regarding the question of whether the prior art would have enabled the production of the claimed enantiomers. In Sterling Drug, the Court appeared to suggest that the prior art would not have enabled the production of the single enantiomers of the claimed invention whereas in Adamson, the actual production of the individual enantiomers was deemed to be able to be produced by techniques within the purview of those of ordinary skill in the art. Without the actual experimental details involved in both of these cases, it is not possible to make any hard conclusions. Since enablement requires that one take into account whether one of ordinary skill in the art could have made the claimed invention (without undue experimentation) at the time of the invention, the technological time frame must also be considered. From the latter half of the 20th century to the present time, much progress in synthesizing and/or separating racemic mixtures into single enantiomers has taken place. As a corollary, a court or examiner in the patent office is more likely today than several decades ago to find the prior art enabled for a claimed enantiomer in view of the priorart disclosure of a racemic mixture. The decision in Adamson was 5 years after that of Sterling Drug, but from the facts, it is not clear when the inventions were made.
If they were also separated by a similar frame of time, than that fact may also help explain the different findings in enablement between the two cases.
With earlier cases like Sterling Drug and Adamson paving the way for modern determinations of non obviousness in view of prior art disclosures of racemic mixtures,we can discern that the courts are less likely to find the prior art non enabled as they were in the days of Sterling Drug. However, finding that a single enantiomer is non obvious due to unexpected or superior results is still possible, as we will see in are cent case addressing this issue, Ortho-McNeil. This case arose when the generic drug producer, Mylan Laboratories, Inc. (Mylan) filed an ANDA with a paragraph IV certification that asserted, inter alia, that U.S. 5,053,407 (the ’407 patent), which covered the antibiotic levofloxacin, was invalid for alleged obviousness. The plaintiffs in the case, Daiichi Pharmaceutical Co., Ltd., Johnson & Johnson, the parent company of Ortho-McNeil Pharmaceuticals, Inc., and Johnson & Johnson Pharmaceutical Research and Development (Ortho) sued Mylan for constructive patent infringement and the present action ensued. Levofloxacin is the subject of claim 2 of the ’407 patent, which is dependent from claim 1, both of which are reproduced in Figure above.
In its analysis of Mylan’s assertion that levofloxacin was obvious in view of the prior art disclosure of the racemic mixture (oflaxocin), the Court agreed that levofloxacin was enabled as of 1985 (when levofloxacin was prepared). The Court

Claims to levofloxacin.

FIGURE :Claims to levofloxacin.

noted that one of the compound’s own inventors, in a chapter written for a book,stated:
[W]ith the development of synthesis methods via stereo selection and improvement in the analytical methods of optical isomers in the recent years, many came to believe that only one of the enantiomers is the important substance and that the other one is, if bluntly said, an almost impure substance. Influenced by ideas like these, we decided to focus on the antibacterial activity of the two [ofloxacin] enantiomers, resulting in the application of optical resolution.
To the Court this was an important admission as it rebutted an earlier assertion by the inventor’s representatives that structure–activity relationship principles would have completely discouraged skilled artisans from preparing the separate isomers of theracemicmixture (ofloxacin) or from reasonably expecting that one enantiomer would exhibit greater activity than the racemic mixture. The publication also indicated that the prior art adequately enabled methods of preparing the compound, so one of ordinary skill in the art would therefore have been motivated to make levofloxacin.
The Court next turned to the properties of levofloxacin itself. From our previous enantiomer cases where prima facie cases of obviousness were held to exist, the actual properties of the enantiomer,when compared to the prior art racemic mixture, held the key to success or failure in the patentee’s bid to either get a patent issued or to defend its validity. Like the other two enantiomer cases we have examined, the decision in the instant case also came down to the actual properties of the enantiomer compared to the racemic mixture of the prior art. In this regard, the Court was persuaded that the properties of levofloxacin were sufficiently unexpected to find the invention non obvious. In particular, the solubility of levofloxacin was highlighted as being especially surprising given that the patent assignees provided evidence demonstrating levofloxacin to be approximately 10 times more soluble than the racemic mixture.
In addition to expert witness testimony documenting the significance of this large difference, the court noted that prior to the discovery of levofloxacin, the largest reported difference in solubility between an enantiomer and its racemate was fivefold. This difference alone, the Court indicated, was an unexpected result and presumably sufficient by itself to rebut the prima facie evidence presented against its patentability.
The Court also documented the fact that levofloxacin was approximately two times more potent than the racemateofloxacin. While this fact alone might not have been persuasive, it was persuasive to the court when coupled with the fact thatlevofloxacin is less toxic than ofloxacin. This appeared to contradict the conventional scientific wisdom in the art that the toxicity of the tricyclic quinolone antibiotics moved in parallel with the therapeutic activity. The Court also noted levofloxacin’s un expectedly higher effectiveness against S. pneumoniaewhen taking into account its exposure levels compared to oflaxocin as well as levofloxacin’s unexpected potency against quinolone-resistant S. pneumoniae.
While we have focused extensively on unexpected results as one of the secondary considerations of non obviousness, there are several additional considerations that can be argued. In this opinion, the Court addressed these several additional secondary considerations of non obviousness as well. These additional important factors include commercial success, simultaneous invention, fulfillment of long-felt need,prior failure, others copying of the invention, third-party praise and recognition, and skepticism of persons skilled in the art.
Commercial success of an invention can be useful secondary evidence of non obviousness.
The logic is that a putatively obvious invention would be less likely to experience commercial success since the preexisting, obvious progenitors would be too competitive in the market place.Absent some advantage in marketing or other factors,it is sometimes possible to assign the success of the product to its advantageous and non obvious properties (letting the market speak). To establish the commercial success of a product for purposes of providing evidence to help rebut a prima facie case of obviousness, the applicant or patentee must establish a nexus between the merits of the invention in view of the prior art and that product’s commercial success.
As a procedural matter, the party wishing to establish the commercial success firsts needs to demonstrate that the “product enjoys significant sales in a relevant market,and that the successful product is the invention disclosed and claimed in the patent.”
Once the applicant or patentee has established the commercial success, the burden then switches to the party asserting that the patent is obvious to prove that the commercial success is actually due to other factors such as, for example, effective marketing. In Ortho-McNeil, the Court highlighted the fact that levofloxacin (soldas Levaquin_R ) was a very good selling antibiotic with tremendous growth in sales from $170 million in its launch year 1997 to more than $1 billion in 2003. Further noting that the successful product was the compound claimed in the patent in suit, the Court then allocated the burden to Mylan to prove that the commercial success wa sin fact due to “extraneous factors” separate from the virtues of the compound itself.
Although Mylan presented “voluminous data” attempting to demonstrate that levofloxacin’s commercial success was due to other factors, the Court discounted their evidence as being insufficient to “sever the nexus between the merits of levofloxacin and its commercial success.” In particular, the Court noted numerous statistics demonstrating that levofloxacin was much more successful than the racemate (marketed as Floxin), a difference that could not be explained by marketing muscle alone.
In its conclusion to the portion of its decision recognizing levofloxacin’s commercial success, the Court stated:
the Court is un persuaded by Mylan’s exogenous forces arguments. In the competitive anti-infective market, the overwhelming response by doctors and hospitals to levofloxacin cannot be attributed exclusively to clever marketing strategies and a “perfectstorm” of unforeseen FDA delays and regulatory changes. Levofloxacin was a commercial success on its own merits, a factor which weighs in favor of un obviousness.
The next secondary consideration that the Court took up was near simultaneous invention. If two or more separate inventors almost simultaneously discover an invention,this can be regarded as secondary evidence that the invention is obvious.
My lan presented evidence that multiple other groups had synthesized levofloxacin with in one year after the inventors of the challenged patent. The Court only assigned moderate emphasis to this secondary evidence, however, because My lan provided no corroborating evidence as to the exact date of four out of five of the near simultaneous discoveries. This was an issue because one of the inventors of the patents in suit published on some of levofloxacin’s properties and general resolution methods soon after they made their discovery of levofloxacin. Thus it was not clear whether the near-simultaneous invention from the other four groups was due to the obviousness of the invention at that time or because of the inventor’s own disclosure.
Secondary evidence of non obviousness can also be found where an invention fulfills a long-felt need. Where a long-felt need has existed, presumably any obvious solutions would have already been tried and from a strict policy perspective,fulfilling the long-felt needs of society should rank pretty high on the things that should be encouraged. There was significant evidence of the limitations in fluoroquinolones(the class of molecules that includes levofloxacin) before the invention date of levofloxacin. For example, it had been noted that the fluoroquinolones to date had efficacies against gram-positive bacteria that were “less than optimal.” Levofloxacin fulfilled that need “in light of the drug’s demonstrated effectiveness againstS. pneumoniae(a gram positive bacteria).”
Evidence that others had tried to make the invention at issue and failed is also probativeas secondary evidence of non obviousness. The fact that others had failed where the patentee or applicant has succeeded can persuasively argue that the invention was not so obvious, and in particular, its enablement or reduction to practice required skill beyond what is ordinary in the art. It is interesting, in the present case, that Ortho presented evidence that the inventors themselves had failed in numerous attempts to produce the claimed invention. The Court rejected this evidence, pointing out that previous courts had generally focused on the failure of others and not the applicants or patentees themselves. As a result, the Court did not consider this evidence.
It has been said that imitation is the sincerest form of flattery, and apparently this is true for inventions as well. If others attempt to copy an invention after it is made public, this can be taken as a sign that the invention bears copying due to some meritorious aspect of that invention that was unavailable for copying prior to the disclosure of the invention itself. Here the Court focused on the fact that the recreate had been known as a drug for some time, yet My lan chose levofloxacin as the drug it wished to make as a generic. Thus the Court asserted that, not with standing this fact, My lan wished to copy levofloxacin despite Mylan’s contention that levofloxacin and oflaxocin were “virtually indistinguishable.” My lan countered that it chose levofloxacin because it was sold in tablet form, was manufacturable at My lan, and presented a “good business opportunity, was available from a quality raw material provider, and provided a first-to-file Paragraph IV opportunity for exclusivity.”
In reply the Court deflected My lan’s arguments by asserting that the fact that levofloxacin was a good business opportunity was evidence that the compound had special properties that accounted for its business success, thus supporting the non obviousness of the compound. The Court further noted that it would be hard to believe that My lan would not copy a compound without “heavily weighing its respective properties.” The Court further noted that My lan had previously attempted to market its own proprietary antibiotic sparfloxacin (Zagam), which apparently did not achieve much commercial success due to phototoxicity and the fact that the drug was potentially cardiotoxic. As a result of these factors, the Court decided that My lan’s choice to copy levofloxacin was significant secondary evidence of non obviousness.
Another category of secondary evidence of non obviousness considered by the Court was the extent of third-party praise and recognition for levofloxacin and its discovery. For support, the Court quoted from a recent CAFC case that discussed this factor, stating “Appreciation by contemporaries skilled in the field of the invention is a useful indicator” of nonobviousness.90 Finding that this factor weighed in the favor of non obviousness, the Court recited some awards the inventor had received, including the Molecular Chirality Award and recognition of the inventor by the Pharmaceutical Society of Japan, an Education Science Minister Award, and the“prestigious purple ribbon medal” from the Emperor of Japan for his outstanding contributions. According to the Court, My lan’s rebuttal contention that all of the awards were for the development of the racemateofloxacin (which was invented by the same person) suggested but did not prove the whole of their contention, and accordingly, the evidence of recognition of the inventor and invention were also indicative of non obviousness of the invention.
Expressions of skepticism toward an invention by those of skill in the art can bemused as secondary evidence of nonobviousness.91 However, evidence of skepticism in the form of an article presented by the inventor’s representatives was deemed by the Court to be not relevant. Despite the fact that the presented article was pessimistic about the possibility that an optically pure tricyclic fluoroquinolone antibacterial would obtain certain desired properties, the Court found that it could not have discouraged an inventor at the time of levofloxacin’s invention since the article was published 4 years after the date of the invention. As a result, the article could not accurately reflect or influence the state of mind of one of ordinary skill at the time of the invention and thus skepticism of those of skill in the art was not established.
Finally, the Court opened its findings for the last indicia of secondary evidence that would be contemplated in the instant case by quoting from precedent: “Licenses taken under the patent in suit may constitute evidence of non obviousness; however, only little weight can be attributed to such evidence if the patentee does not demonstrate‘a nexus between the merits of the invention and the licenses of record.” The levofloxacin patent was licensed to Ortho-McNeil/Johnson & Johnson, Glaxo and Hoechst. However, the Court largely discounted this evidence by noting the fact that all three companies also owned licenses to ofloxacin, and My lan offered evidence that the three companies bought licenses to levofloxacin for its extended patent life as well as other reasons. The Court held that the inventor’s representative had failed to show that the licenses were purchased because of the superior properties of levofloxacinitself and thus placed little or no weight on the license evidence.
As a result of its analysis, the Court concluded that the relevant claims to levofloxacin were non obvious over the prior art (including the racemate). The Court, in reaching its decision, systematically reviewed and applied the obviousness/ non obviousness factors and weighed these in view of the claims to levofloxacin.It is not surprising that the Court spent a considerable amount of time reviewing secondary evidence of non obviousness, since, as we saw before, the likelihood of finding a prima facie case that an enantiomer is obvious is high so the consideration of the compound’s properties as well as other secondary indicia becomes a central concern.

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