Application of Herman Hoeksema

332 F.2d 374, 51 C.C.P.A. 1474

• Court: Court of Customs and Patent Appeals
• Decided: June 4, 1964
• Docket: Patent Appeal 7050
• Status: Published

Opinions

. T , WORLEY, Chief Judge,

Hoeksema appeals from an affirmanceby the board of the rejection of claims 1 to H, 13 to 15 and 17 to 19 of his application¹ for a patent on “Composition, of Matter and Process.”

The invention relates to the antibiotic-dihydronovobiocin and its preparation. According to appellant’s specification novobiocin exists in two crystalline forms-with only one structural formula, but-somewhat different physical properties. Appellant explains that Form 1 is readily absorbed into the blood stream fromaqueous vehicles, but Form 2 is not. Since administering novobiocin in aqueous vehicles is said to be desirable, Form 1 is more desirable than Form 2. How-ever, the application states that Form 1 “has been difficult to prepare in good' yields since crystalling Form 2, the morestable form, became available.”

Claims 1 and 13 read:

“L Dihydronovobioein.

“13. A process which comprises contacting an organic solvent solution of 7-[4-(carbamoyl-oxy)-tetra-hyro-3-hydroxy-5-methoxy-6, 6-di-methylpy ran-2-yloxy ] -4-hydroxy-3-[4-hydroxy-3- (3-methyl-2-butenyl) - benzamido’-8-methyl-coumarin with hydrogen in the presence of a hydrogenation catalyst effective to hydrogenate an ethenoid double bond and recovering the formed 7-[4-(carbam-oyl-oxy) tetrahydro-3-hydroxy-5-methoxy-6,6-dimethylpyran-2-yloxy]4-hydr oxy-3- [4-hydroxy-3- (3-methyl-•butyl) benzamido] -8-methyIcoumar-in.”

The references are:

Peck 2,498,574 February 21, 1950. Hoehstein et al., 76 J. Am. Chem.

Soc. 5080-2, October 1954.

Berger et al., 73 J. Am. Chem. Soc. 5295-7, November 1951.

Flynn et al., 76 J. Am. Chem. Soc. 3126, June 1954.

The Peck patent discloses the conversion of streptomycin salts to the corresponding dihydrostreptomyein salts by reacting an aqueous solution of the streptomycin salt with hydrogen in the presence of a catalyst of a noble metal such as platinum, palladium or platinum oxide. The dihydro compounds are said to be approximately as active antibiotically as the streptomycin salts and are equally suitable for clinical application. Peck also teaches that the dihydro salts are more stable in the presence of substances ■capable of reacting with carbonyl groups and also are stable for twenty-four hours in a designated buffered aqueous solution while the corresponding streptomycin salts are completely inactivated therein.

Hoehstein discloses two antibiotics, ■magnamycin and magnamycin B, both •elaborated from a strain of streptomyces bacteria, and states that the “Catalytic hydrogenation of Magnamycin B shows the presence of two carbon-carbon bonds.” The article specifically describes the preparation of tetrahydromagnamycin B by hydrogenating magnamycin B in anhydrous ethanol in the presence of a palladium-charcoal catalyst.

Berger discloses isolation of crystalline antibiotics from three strains of streptomyces, the antibiotics being identified as X-206, X-464 and X-537A, which are said to be organic acids. The Berger article describes hydrogenation ■ experiments carried out with the antiibiotic X-206 with prehydrogenated platinum oxide as a catalyst, which resulted in the absorption of 1.2 moles of hydrogen in methanol and 3 moles of hydrogen in acetic acid. The products are said to be amorphous and biologically inactive.

Flynn discloses hydrogenation of erthromycin in the presence of a platinum catalyst with glacial acetic acid as the solvent, and states that one mole equivalent of hydrogen is absorbed.

The board stated:

“* * * Each of these references discloses hydrogenation of streptomyces-derived antibiotics such as streptomycin, magnamycin and erythromycin to produce the corresponding hydrogenated compounds. Peck in hydrogenating streptomycin obtained a compound of greater stability. The procedure carried out in these references is the usual one with the aid of catalysts and solvents. The examiner held that since it was routine practice to hydrogenate various antibiotics, particularly in order to determine structural configuration, appellant’s hydrogenation of novobiocin was obvious and routine.”

On that ground the board affirmed the examiner’s rejection of process claims 13 to 15 and 17 to 19, but disagreed with the ground of rejection of product claims 1 to 11, saying:

“ * * * As to these product claims, it would appear that the Examiner is rejecting because he considers the manner in which the product was obtained is obvious which is contrary to 35 U.S.C. 103. Ex parte Burtner et al., 89 USPQ 547, and Ex parte Mowry, Patent No. 2,617,831 are illustrative of this Board’s position on the independence of product and process claims for purposes of determining patentability.”

Thus the board regarded the examiner as considering dihydronovobiocin obvious because it was known to hydrogenate antibiotics generally, i. e. to determine the presence of unsaturation, and novobiocin was a known antibiotic.

The board substituted its own ground of rejection of the product claims, under Rule 196(b), stating that

“However, insofar as this case is concerned novobiocin is a known material and its structure is set out by formula on page 1 of the specification. This is necessary background for claims 1 through 11; otherwise they would be indefinite if not meaningless in “novobiocin.” However, the structure of novobiocin clearly indicates to the chemist that it may be hydrogenated because of the carbon to carbon unsaturation which also happens to be the type of unsaturation hydrogenated by Hochstein etal. * * *”

The board thus regarded dihydronovobiocin to be obvious in view of the structure of novobiocin and the conventionality of hydrogenation. In other words, the presence of unsaturation in novobiocin suggested hydrogenation thereof because other unsaturated antibiotics have been similarly hydrogenated in the prior art.

We agree with appellant that the board erred in two respects, namely, in assuming that the structure of novobiocin was known to the prior art, and in neglecting to consider the properties of dihydronovobiocin vis-a-vis novobiocin.

We observe that, at the time appellant made his invention, those skilled in this art knew that novobiocin existed and that it possessed certain antibacterial properties; its structure, however, was unknown. As we have pointed out, from the teachings of the cited references, a person skilled in this art would have been expected to know also that other antibiotics had been hydrogenated, and that such hydrogenation had produced varying results with respect to the bacterial activity, stability and absorption characteristics of the resulting product. Those facts do not, we think, support the board’s conclusion that it would be obvious that hydrogenation of novobiocin would produce the claimed novel compound which appellant produced and which he found to possess antibacterial activity and stability in aqueous vehicles, as well as to be readily absorbed with unusually high blood levels following either, oral or parenteral administration.

In In re Viktor Papesch, 315 F.2d 381, 50 CCPA 1084, this court said:

“->:■ •>:• * a formula is not a compound and while it may serve in a claim to identify 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. * * *»

Comparing the compounds involved, and not merely their structural formulae, the unexpected properties of dihydronovobiocin persuade us that that product is not obvious in view of the cited prior art. Thus we are obliged to reverse the board’s rejection of product claims 1 to-11.

Process claims 13 to 15 recite the production of dihydronovobiocin by “contacting” novobiocin, in an organic solvent, with hydrogen “in the presence of a hydrogenation catalyst effective to hydrogenate an ethenoid double bond.” Claims 14 and 15 specify the catalyst and solvent respectively. Claims 17 to 19 define the actual reaction steps as simply “hydrogenating the said novobiocin in an organic solvent in the presence of a hydrogenation catalyst effective to hydrogenate the ethenoid double-bond” but state in the preamble:

“17. A process for converting novobiocin in the crystalline form which is not readily absorbed into the readily absorbable and biologically active product * *

Thus claims 17 to 19 are directed to converting Form 2, which is readily absorbable into the blood stream, to dihydronovobiocin whereas claims 13 to 15 are directed to converting novobiocin, in either crystalline form, to dihydronovobiocin. But whatever the starting material, the specification points out that

“ * * * The same product is obtained whether novobiocin Form 1 or Form 2 crystals are used as the starting product or whether a crude novobiocin is hydrogenated and then purified.” (Emphasis supplied)

The product, dihydronovobiocin, is said to possess the advantages of novobiocin “ * * * and, at the same time, is stable in aqueous vehicles and readily absorbed therefrom.”

As may be seen from the references, .and as pointed out by both the examiner ■and the board, it is conventional to hy■drogenate antibiotics to determine the presence of unsaturation and thus, in part, determine the structure of the antibiotic molecule. While process claims 13 to 15 and 17 to 19 recite no special conditions or critical limitations to distinguish them from the usual prior art catalytic hydrogenation, the question arises whether the preamble of claims 17 to 19, .supra, imparts such a limitation. The latter claims recite the conversion of Form II to dihydronovobiocin whereas the former claims do not define the form ■of the starting material.

Since the process is otherwise identical, we cannot distinguish between ■claims 13 to 15 and 17 to 19, on the basis ■of the starting material as urged by appellant. Indeed, the product is the same regardless of which form of novobiocin is hydrogenated.

We find the instant process to be ■obvious from the clear teachings'of record that hydrogenation of antibiotics to •elucidate their structure is conventional, and appellant did just that.²

Here the instant product is unobvious because of its unexpected properties. In In re Larsen, 292 F.2d 531, 49 CCPA 711, this court held a process to be obvious although it produced a product which, because of its unexpected properties, was unobvious.

While the instant process produces a compound, the properties of which are unexpected, that fact does not necessarily make the process itself unobvious because it is not unexpected that hydroge.nation of novobiocin produces dihydronowobiocin. Indeed, appellant’s purpose in hydrogenating was to produce a dihydro derivative of novobiocin, since obtaining such a product would demonstrate unsaturation in the parent compound.2 ³ Hochstein is an example of the practice of hydrogenating an antibiotic to determine unsaturation.

As this court stated in Larsen, a process may or may not be obvious once “given the idea of the compound” to be produced. Whether the instant hydrogenation process is viewed from the vantage point of the compound to be produced, namely dihydronovobiocin, or as having been conducted for the purpose of elucidating structure, the claimed process, nonetheless, constitutes the conventional hydrogenation of a known antibiotic.

The rejection of claims 1 to 11 is reversed.

The rejection of claims 13 to 15 and 17 to 19 is affirmed.

Modified.

1 . Serial No. 592,212, filed June 18. 1950.

2 . Appellant, in Ms brief, states:

“Appellant in attempting to elucidate the structure of novobiocin found that on hydrogenation in alcohol solution novobiocin was converted to a new crystallizing form having all the advantages of novobiocin in regard to antibacterial activity but being free of the disadvantage noted above.”

3 . See fn. 2, supra.