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How to Determine the Obviousness of Chemical Compounds in Patent Applications

                                                                                   

 

Introduction

 

A patentable invention is an invention that is “novel” under 35 U.S.C.A. § 102, “useful” under 35 U.S.C.A. § 101, and “nonobvious” under 35 U.S.C.A. § 103. Section 103(a) of the Patent Act sets forth the parameter of the obviousness requirement:

A patent may not be obtained though the invention is not identically disclosed or described as set forth in Section 102 of this title, if the differences between the subject matter sought to be patented and the prior art must not be 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 to which said subject matter pertains.

 

 In Graham v. John Deere Co., 383 U.S. 1, 17 (1966), the United States Supreme Court interpreted this language to mean that the ultimate determination on the issue of obviousness is treated as a question of law but is based on factual inquires that include (1) the scope and content of the prior art; (2) the differences between the prior art and the claimed invention; (3) the level of skill in the art; and (4) the objective evidence of non-obviousness.

To obtain a patent on a new chemical compound, the compound must meet the nonobviousness requirement at the time it is invented. Special issues, however, arise with chemical patents because unlike electrical and mechanical sciences, chemistry is an unpredictable art. Minor changes in structures can dramatically affect a compound's properties. Thus, it is inherently difficult for a court to determine the obviousness of a claimed compound with a similar structure to that of a prior art.

The extent of the challenge to determine the obviousness of chemical compounds can be illustrated by the issues faced by the court in Yamanouchi Pharmaceutical Co. v. Danbury Pharmacal, 231 F.3d 1339 (Fed. Cir. 2000).  In  Yamanouchi, the dispute centered on whether one skilled in the art would have considered it obvious to make the drug Famotidine by (1) combining the polar tail from lead compound 44 with the modified heterocycle from Tiotidine to form an intermediate compound, and (2) substituting the carbamoyl group in the intermediate compound with a sulfamoyl group to create Famotidine as shown below in Scheme 1. It was well known that both Tiotidine and Tagamet were prior compounds, of which Tagamet was a successful drug in market place while Tiotidine failed in preclinical trials due to its high toxicity. Both compounds, however, showed high efficacy as inhibitors of gastric acid secretion.

 

 

                                    Scheme 1

 

The court in Yamanouchi upheld the patent against an assertion of obviousness. Id. at 1345. The court explained, “For a chemical compound, a prima facie case of obviousness requires a showing of ‘structural similarity between claimed and prior art subject matter … where the prior art gives reason or motivation to make the claimed compositions.’”  Id. at 1343 (quoting In re Dillon, 919 F.3d 688, 692 (Fed. Cir. 1990)). Even though the claimed compound failed the test of structural similarity, the Yamanouchi court invalidated a prima facie case of obviousness based on a lack of motivation to combine the prior art to make the claimed invention with similar biological function to that of the prior art.

 

A. Structural similarity

            Structural similarity between chemical compounds has effectively created a unique and troublesome area of patent law. In re Jones, 958 F.2d 347, 350 (Fed. Cir. 1992). In determining the obviousness of a traditional chemical compound, courts previously focused on the similarity between the structures of a claimed compound and that of a compound disclosed in the prior art. In re Hass, 141 F.2d 122 (C.C.P.A 1944); In re Henze, 181 F.2d 196 (C.C.P.A. 1950).

 

 

            General formula:                    A—(CH2)n—B           

 

 

Prior art compound:   A—CH2—B (n=1)

Claimed compound:               A—CH2—CH2—B (n=2)

                                    Scheme 2

            In Hass, the claimed compound was a homolog of a prior art compound (Scheme 2). See Hass, 141 F.2d at 125. There was only one more carbon unit in the claimed compound than that in the prior art. The Court of Claims and Patent Appeals held that the claimed compound was not patentable unless it revealed “some nonobvious or unexpected beneficial properties not possessed by the homologous compound disclosed in the prior art.” Id. The general principle behind the court’s decision was that chemical and physical properties vary only slightly between members of a homologous series. Id. The Henze case transformed this principle into a presumption that was rebuttable if the applicant showed “that the claimed compound possesses unobvious or unexpected beneficial properties not actually possessed by the prior art homologues.” In re Henze, 181 F.2d at 201. Clearly both courts perceived chemical structure and chemical properties as two different considerations. Therefore, for structurally similar chemical homologues, a new compound was deemed prima facie obvious because a chemist could expect or predict that the new chemical compound would have the same properties in a given system as did a similar prior art compound.

B. Inseparable structure and its properties

            After section 103 was enacted, courts gradually moved to a more holistic view of chemical compounds that considered chemical properties in addition to chemical structures. In re Papesch, 315 F.2d 381 (C.C.P.A. 1971). In ­Papesch, an applicant claimed a family of compounds including representative compound 2,4,6-triethylpyrazolo(4,3-d)-4,5,6,7-tetrahydropyrimidine-5,7-dione (ethyl = CH2CH3), which was admittedly “structurally obvious” in light of a claimed compound 2,4,6-trimethylpyrazolo(4,3-d)-4,5,6.7-tetrahydropyrimidine-5,7-dione (methyl = CH3) as shown in Scheme 3. Id. at 384.

 

Scheme 3

 

Comparative tests of the trimethyl compound and the applicant’s triethyl compound showed that the latter was an active anti-inflammatory agent while the prior art compound was completely inactive for that utility. The Papesch court stated that the properties of compounds were relevant to obviousness, emphasizing that the invention as a whole was a compound with its own properties. Id. at 390. Additionally, the court found that proof of non-obvious or unexpectedly advantageous properties not shared by the prior art compound may rebut a prima facie case of obviousness. Id. at 391.

A compound and all of its properties are inseparable; they are one and the same thing …. But a formula is not a compound and while it may serve in a claim to identity what is being patented, as the metes and bounds of a deed identify a plot of land, the thing that is patented is not the formula but the compound identified by it. And the patentability of the thing does not depend on the similarity of its formula to that of another compound but of the similarity of the former compound to the latter. There is no basis in law for ignoring any property in making such a comparison.

 

 

Id.  Thus the court generously encouraged chemical patent applications as long as a claimed invention could demonstrate new properties even though the claimed compound shared a similar structure with a prior art compound. The Papesch court, however, did not deal with the requirements for establishing a prima facie case of obviousness. The court only held that, for cases with a presumption of obviousness, an examiner had to consider both the properties of the invention and the structural similarity. Id.

 

C. Structures, properties and motivation

            In re Dillon was the first case to discuss the “motivation” argument, and it established the standard for an examiner's evidentiary burden to show prima facie obviousness in chemical composition cases. In re Dillon, 919 F.2d 688, 692 (Fed. Cir. 1990). Dillon’s patent claimed compositions containing tetra-orthoesters useful as fuel additives to reduce soot emissions during fuel combustion. Id. at 690. In rejecting the application, the court pointed to several earlier patents, and one of which contained tri-orthoesters that was also used as fuel additives, but to obtain a different benefit:  dewatering.  Id. at 694.

The dewatering compounds of tri-orthoesters were structurally similar to the soot-reducing compounds of tetra-orthoester in Dillon’s fuel. Id. Dillon argued that, although her additives were structurally similar to additives in previously patented compositions, her additives had a different use. Id. The court noted that the prior art neither taught nor suggested Dillon’s method of reducing emissions. In re Dillon, 919 F.2d at 692.  The court held, however, that neither what the prior art taught nor the suggested properties of the claimed compound would determine prima facie obviousness. Id. at 695. Consequently, for purposes of establishing a prima facie case of obviousness, it did not matter that the earlier patents had failed to indicate that Dillon’s additives would reduce soot. Instead the Dillon court created a new test for prima facie obviousness:  prima facie obviousness arises where the prior art suggests or motivates the selection of the structurally similar claimed composition. Id. at 693.

Thus, Dillon’s structurally similar compounds were prima facie obvious because the prior art provided Dillon with motivation to make them. Therefore, Dillon required that the prior art suggest the structurally similar claimed compound for prima facie obviousness to arise. See Id. at 694. Rather than suggest the utility of the claimed compound, however, the prior art need only motivate one to make the claimed compound. In other words, a prima facie case is made if both structural similarity and some motivation to make the claimed composition are present.  Id.

Once a prima facie case has been established, the applicant has an opportunity to rebut that case in a timely manner. Dillon indicated three methods of rebuttal: (1) a comparison of test data showing that the claimed compositions possess unexpectedly improved properties or properties that the prior art does not have . . . , (2) that the prior art is so deficient that there is no motivation to make what otherwise appear to be obvious changes . . . , or (3) any other argument or presentation of evidence that is pertinent." Id. n re Dillon, 919 F.2d at 692-93.

            Upon rebutting a prima facie case, where the claimed composition has both expected and unexpected properties, a "balancing" or "relative significance" test is applied:  if the unexpected properties, on balance, are of greater significance than the prior art's expected properties, then the claimed invention may be nonobvious.  Id. at 692.  The balancing test attempts to differentiate between the unexpected properties resulting from minor chemical manipulations of the prior art compound and the expected and desirable properties from these minor manipulations. Warner-Jenkinson co. v. Allied Chem. Corp., 477 F. Supp. 371, 388 (S.D.N.Y. 1979). Absent motivation, a change in the chemical structure that may be "obvious-to-try" is not necessarily an obvious change. Hybritech Inc. v. Monoclonal Antibodies, Inc. 802 F.2d.1367 (Fed. Cir. 1986). In other words, a prior art compound must teach toward or suggest adding a substitution, combination, or modification where the end result would be useful. See United States v. Adams, 383 U.S. 39 (1966); W.L. Gore & Associates Inc. v. Garlock, Inc., 721 F.2d 1540 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984).

 

D. Reasonable expectation of success        

            The Dillon court essentially solved the problem regarding a claimed compound and a prior art compound with different properties. The court in Yamanouchi Pharmaceutical Co. v. Danbury Pharmacal, 231 F.3d 1339 (Fed. Cir. 2000), however, had to deal with a case that a claimed compound and a prior art shared the same properties with arguably similar structures:  the claimed compound was a second-generation compound of the prior art.

            In Yamanouchi, Danbury filed an Abbreviated New Drug Application (ANDA) with the Food and Drug Administration seeking approval to market generic Famotidine. Id. at 1342. Danbury made a paragraph IV certification that claim 4 of U.S. Patent No. 4,283,408 (the ’408 patent) was invalid. Id. At the heart of validity dispute was whether one skilled in the art would have considered it obvious to select lead compound 44 from Yamanouchi’s U.S. Patent No. 4,252,819 and Tiotidine from the ’378 patent to use as leads for making Famotidine. Id. at 1343. These compounds, respectively, are three and eleven times more active than Cimetidine (Tagamet), a benchmark compound at the time of invention (Scheme 1). Id.  The polar tail from lead compound 44 was combined with the substituted heterocycle from Tiotidine, thus creating the intermediate compound. Thereafter a bioisosteric substitution of the carbamoyl group (CONH2) in the intermediate compound with a sulfamoyl group (SO2NH2) resulted in a new, successful compound -- Famotidine. Id. at 1344.

The Yamanouchi court found that there was not sufficient motivation for one of ordinary skill in the art at the time of invention to take any one of the following steps, let alone the entire complex combination: (1) selecting lead compound 44 as a starting compound, (2) combining the polar tail from lead compound 44 with the substituted heterocycle from Tiodine, and (3) substituting the carbamoyl group in the intermediate compound with a sulfamoyl group to create Famotidine.  Yamanouchi Pharmaceutical Co. 231 F.3d Id. at 1345.

In addition, the court stated that the prior art offered no suggestion to pursue the particular order of manipulating parts of the compounds, and any deviation in the order of combination would have taught away from Famotidine. Id.  The court further stated that if the sulfamoyl group were substituted for the carbamyl group on lead compound 44 without attaching the substituted hererocycle from Tiotidine, the evidence showed that the resulting compound would have 1/100 times the activity of Cimetidine.  So the court concluded that there was no evidence suggesting what might have led an ordinary artisan in this field to follow the precise steps that produced a remarkable invention. Id.

 Furthermore, the Yamanouchi court stated that to show obviousness, the level of motivation must be coupled with a “reasonable expectation of success”:  the ordinary medicinal chemist would have expected Famotidine to have the “most desirable combination of pharmacological properties” that it possessed. The court also concluded that there was no evidence suggesting what might have led an ordinary artisan in this field to “follow the precise steps” that produced the claimed invention. Id.

 

E. Flaws in the Yamanouchi court’s arguments                                                      

1. The test of “reasonable expectation of success” might not be applicable to chemical compounds

 

The test of “reasonable expectation of success” was established in In re O'Farrell, 853 F.2d 894 (Fed. Cir. 1988), a landmark biotechnology case. In contrast to the Yamanouchi court, which was asked to determine the obviousness of a new chemical compound, the O’Farrell court faced the obviousness question of a novel genetic engineering method for the synthesis of protein.

Due to the fact that a process rather than a product was under review, the O’Farrell court correctly employed a different test than that of the Dillon court. The O’Farrell court, however, failed to clarify this distinction: “For obviousness under Section 103, all that is required is a reasonable expectation of success.” Id. Thus it seemed that, with respect to prima facie obviousness, the O’Farrell court’s test of “reasonable expectation of success” represented a subtle divergence from that of the prior chemical case law precedent established in Dillon.  Considering that the invention at issue had been clearly suggested in prior art references, the court focused on whether the applicant had a reasonable chance to succeed in carrying out the invention.  The court concluded that the inventions were patently obvious, and hence unpatentable, when the inventor had a reasonable expectation of success in his endeavor even though such an expectation of success did not have to be absolute. Id.

As established in O’Farrell, a prima facie obviousness case is made if a reasonable expectation of success is present. The O’Farrell court arrived at this test not by analyzing compositions of chemical compounds, but by examining the methodology used to isolate the claimed composition. So the application of the reasonable expectation of success to measure the level of motivation might not be appropriate in a chemical compound patent litigation case.

A process or methodology development is similar to electrical or mechanical science, which is predictable, as the use or combination of any components, and the invention as a whole, are readily discernable. Chemistry, on the other hand, is predominantly an unpredictable art.  Small changes in bonding or adding an atom or a molecule to a chemical structure could have dramatic macroscopic and microscopic effects. For example, in biochemistry the change of a double bond between two atoms to a single bond transforms an unsaturated fat to a saturated one, and the property of which would be completely different and affect people’s lives in different ways. As another example in catalytic chemistry, minor changes in a chemical catalyst may produce different types of products. Studiengesellschaft Lohle Mbh v. Eastman Kodak Co, 616 F.2d 1315, 1341 (Fed. Cir. 1980). Thus due to the unpredictability of potentially active chemical compounds, the test of “reasonable expectation of success” becomes inapplicable to the determination of the obviousness of chemical compounds in patent applications.

 

2. “The precise steps to follow” argument from the Yamanouchi court

            The Yamanouchi court also stated that the prior art offered no suggestion to pursue the particular order of manipulating parts of the compounds, and any deviation in the order of combination would have taught away from Famotidine. Yamanouchi Pharmaceutical Co, 231 F.3d at 1345. The court further argued that if the sulfamoyl group were substituted for the carbamyl group on lead compound 44 without attaching the substituted heterocycle from Tiotidine, the evidence showed that the resulting compound would have 1/100 times the activity of Cimetidine. Therefore the court concluded that there was no evidence suggesting what might have led an ordinary artisan in this field to “follow the precise steps” that produced a remarkable invention. Id.

            Here the court’s finding was arguably persuasive to recognize the nonobviousness of a specific chemical compound. Yet iIt failed to consider the fact that one specific chemical compound could be prepared by designing different routes, so it is not necessary to pursue the exact order or particular steps to synthesize that compound.           

 

F. The Proposal: the use of objective evidence of nonobviousness in chemical patent prosecution

           

Objective evidence of nonobviousness has often been described as addressing secondary considerations.  Such evidence is important and must be considered before a court may find a patent claim invalid for obviousness. In re Rouffet, 149 F.3d at 1355. Many courts have gradually realized the importance of objective evidence of nonobviousness in patent prosecution. For example, the Federal Circuit reversed a district court for failing to consider objective evidence of nonobviousness in Demaco corp . v. F.Von Langsdorff Licensing Ltd., 851 F.2d 1387, 1391 (Fed. Cir. 1988).  The Federal Circuit has also stated that objective evidence must be considered before a conclusion on obviousness was reached, and it “was not merely ‘icing on the cake.’” See Hybritech Inc. v. Monoclonal Antibodies, Inc, 802 F.2d 1367, 1380 (Fed. Cir. 1980). Of course, objective evidence requires the establishment of a nexus between the evidence and the merits of the claimed invention. Demaco Corp., 851 F.2d at 1392.

 

1.  Commercial success

            Commercial success has been listed as the first convincing argument among objective evidence. In Yamanouchi, the court could use the success of Famotidine to defeat any case of obviousness.

      Famotidine, an H2 receptor antagonist useful for treating peptic ulcer, has been extremely successful. In 1996, for example, prescription sales of Famotidine in the United States alone reached over 690 million dollars. Yamanouchi, 231 F.3d at 1341. This is a strong evidence of commercial success, especially in a field with other patented competitors. Among companies who tried and failed to develop second generation drugs similar to Famotidine were Bristol-Myers, Merck, Glaxo, Pfizer, and ICI. Their research identified millions of potential candidate compounds, but none turned out to be safe, effective, and successful drugs. Id.

      In the meantime many generic drug manufacturers have great interest in offering their own version of the drug. For example, Danbury Pharmacal, Inc., filed an Abbreviated New Drug Application with the FDA seeking approval to market generic Famotidine. To make a paragraph IV certification under the Hatch-Waxman Act, Danbury claimed that one of Yamanouchi’s patent was invalid, resulting in the Yamanouchi case.

     

2.  Unexpected results

            The Federal Circuit has recognized that unexpected superior results from an invention tend to support a finding that the invention was not obvious to a person of ordinary skills in the art. In re Baxter Travenol Labs, 952 F.2d 388, 392 (Fed. Cir. 1991). The principle may apply most often to the less predictable fields, such as chemistry, where minor changes in a product would yield substantially different results. In re Mayne, 104 F.3d 1339, 1343 (Fed. Cir. 1997). This principle is especially appropriate for medicinal chemistry, because the biological effects of a new compound are often too complex to predict with any accuracy.

           

3. Long-felt need and failure of others

            The failure of others to develop alternatives to the invention may also be an evidence of nonobviousness. Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966). The first successful H2 receptor antagonist was Cimetidine (Tagamet), which was approved by the FDA in 1977, and has remained a commercial product so far. A proposed competing drug, Cimedine, however, turned out to cause some negative side effects, such as interference with liver enzymes that caused the buildup of certain drugs to toxic levels, as well as impotence and breast swelling in men when administered in high doses.  In addition, it was very inconvenient to administer Cimedine, which had to be taken four times a day. More evidence showed that, after the discovery and initial success of Cimetididne, many major pharmaceutical companies all over the world tried to develop improved compounds for the next generation—compounds that would be more effective than Cimetidine and have fewer side effects. So far, Famotidine has been the best one as a second-generation H2 antagonist.

 

G.  Conclusion

            Chemical compounds present special issues that arise from the unpredictable nature of chemistry. A question of obviousness of chemical compounds could be answered if all the following has been considered: (1) a claimed compound and a prior art compound are sufficiently structurally similar; (2) the compounds and all of its properties are inseparable and must be considered as a whole in determining obviousness; (3) any suggestion or motivation is disclosed in the prior art to make the new compound; and (4) objective evidence demonstrates the level of motivation showing a “reasonable expectation of success.”