Application of Bergstrom

• Decision Date: 16 July 1970
• Docket Number: Patent Appeal No. 8256.
• Citation: 427 F.2d 1394
• Parties: Application of Sune BERGSTROM and Jan Sjovall.
• Court: U.S. Court of Customs and Patent Appeals (CCPA)

427 F.2d 1394 (1970)

Application of Sune BERGSTROM and Jan Sjovall.

Patent Appeal No. 8256.

United States Court of Customs and Patent Appeals.

July 16, 1970.

Earl C. Spaeth, Kalamazoo, Mich., attorney of record, for appellants. Eugene O. Retter, George T. Johannesen, Kalamazoo, Mich., Sidney W. Russell, Arlington, Va., of counsel.

Joseph Schimmel, Washington, D. C., for the Commissioner of Patents. Fred W. Sherling, Washington, D. C., of counsel.

Before RICH, ALMOND, BALDWIN and LANE, Judges, and McMANUS, Chief Judge, Northern District of Iowa, sitting by designation.

ALMOND, Judge.

This appeal is from the decision of the Patent Office Board of Appeals affirming the examiner's rejection of claims 23 and 53 in appellants' application¹ for "PGE Type Compounds" "as lacking in novelty under 35 U.S.C. 101."

The invention relates to two chemical compounds, as reflected in the claims:

23. 7-3-hydroxy-2(3-hydroxy-1-octenyl)-5-oxocyclopentyl-5-heptenoic acid, said acid being sufficiently pure to give a substantially ideal curve on partition chromatography using an ethylene chloride:heptane:acetic acid: water (15:15:6:4) solvent system.

53. A composition of matter consisting essentially of 7-3-hydroxy-2-(3-hydroxy-1,-5-octadienyl)-5-oxocyclopentyl-5-heptenoic acid.

Both compounds, termed PGE2 and PGE3, respectively, are members of a family of compounds known collectively as prostaglandins. According to the specification, both are useful in stimulating smooth muscle and in lowering blood pressure.

Some background information will be helpful in understanding the issues raised by the decisions below.

It appears from the record that scientists have known for many years that certain secretions and extracts obtained from human and animal male accessory genital glands possessed the pharmacodynamic effects of lowering blood pressure and stimulating smooth muscle. One Kurzrok, for example, observed in 1930 that human seminal plasma augmented or decreased tone and spontaneous movements in isolated strips of human uterus. A few years later, Goldblatt and von Euler observed that human seminal fluid, human prostate secretions, and secretions of the vesicular gland of sheep produced hypotensive activity and stimulated the smooth muscle in isolated rabbit's intestine. Von Euler also examined extracts of prostate gland and sheep vesicular gland (obtained by subjecting the organ to alcohol extraction, concentrating the extract by evaporation of alcohol and eliminating lipoids, as required, by a further ether extraction) and found similar pharmacodynamic activity. As von Euler then noted, "the attempt to identify the active substance with known substances has thus far been unsuccessful," although he thought that "to all appearances the substance is an independent basic compound." Shortly thereafter, von Euler appears to have determined that the "active principle" in the above secretions and extracts "had acidic character," and he named it "prostaglandin." He was able to free it from associated material "to a certain extent" to obtain "semipurified extracts," having found that,

after extraction with ethanol and evaporation of the ethanol, prostaglandin could be taken up in ether from an acid solution and subsequently extracted with alkaline water.

In the late 1950's, appellants Bergstrom and Sjovall isolated two distinct chemical compounds in essentially pure crystalline form "from crude materials, such as von Euler prostaglandin, or directly from accessory genital materials such as prostate glands and sperm." Their discovery of those compounds, which were originally known as PGE and PGF (now PGE1 and PGF1) is described in their earlier application serial No. 738,514, now patent No. 3,069,322, issued Dec. 18, 1962, and the two pure compounds form the subject matter of some of the claims of that patent. Both compounds were found to have a smooth muscle stimulating effect, but only PGE has hypotensive activity. As described in similar language both in the patent and in the present application:

These compounds PGE1 and PGF1 are associated in the source materials and in crude extracts thereof with antigens and pyrogens, for example, tissue fragments, lipids, cellular debris, foreign proteins, and the like, and are not useful for parenteral applications. The isolation of these compounds free of antigens and pyrogens made it possible to utilize their pharmacodynamic effects without undesirable side effects or reactions.²

To isolate PGE1 and PGF1, it appears from the Bergstrom et al. patent and the present application that appellants first prepared a crude extract containing PGE1 and PGF1 by subjecting sheep prostate gland to alternate alcohol, ether and alkaline phosphate buffer extractions somewhat in the manner of von Euler. A solid residue obtained upon drying a final ether extraction was then given a preliminary purification by subjecting it to a "five stage countercurrent distribution" between ether and phosphate buffer, and the resultant ether and buffer phases were dried. Certain of the dried ether and buffer phases were then pooled and subjected to two different "reversed phase partition chromatography" procedures employing two different solvent systems. Certain fractions of the eluate obtained from that purification procedure yielded crystals of essentially pure PGE1 and PGF1.

In 1960, appellants also published a description of their work relating to the isolation of PGE1 and PGF1 in Acta Chemica Scandinavica, 14, 1693-1705 (1960). The procedure with respect to the isolation of PGE1 was described thus:

We have described the isolation of prostaglandin F from vacuum dried sheep prostate glands in the preceding paper * * *.

In that work it was noticed that a more lipid soluble factor was sometimes present which showed activity both on intestinal strips and on rabbit blood pressure. It has been found that this fraction is responsible for most of the activity of the fresh or frozen glands.

The isolation of this factor, prostaglandin E (PGE) in crystalline form, will be described in this paper.

* * * * * *

Extraction procedure. The frozen glands were minced in a meat grinder. After addition of 4 liters of 95% ethanol per kg, the suspension was stirred mechanically for one hour and then left to sediment over night. The extract was separated and concentrated * * *. The crude concentrate was then extracted into ether and transferred into phosphate buffer * * *.

Partition chromatography. In this work, we left out the counter-current distribution procedure for the preliminary purification of the crude extract. Instead, this extract was directly subjected to reversed-phase chromatography with 50% methanol/water as moving phase and 50% isooctanol/chloform as stationary phase, supported on Hostalen (Hoechst). In most cases the extract from 12.5 kg of prostate glands weighed 5-7 g and this material was put on a column with 67 ml of stationary phase on 100 g of Hostalen. The result of such a chromatography is shown in Fig. 1. The peak of physiological activity appeared at about 1.5 1 effluent. * * * A 10 to 30-fold purification of the active material was obtained with the reversed phase chromatography.

The material obtained was found to lower rabbit blood pressure. This effect is not obtained with previously isolated PGF. It was found, however, that PGE, although being eluted somewhat later than PGF, was not separated from this compound. Therefore, a second reversed-phase chromatography was run using 35% (v/v) methanol/water saturated with 1/10 of its volume of 40% (v/v) isoamyl acetate/chloroform as moving phase. The hydrophobic phase was used as stationary phase, 4 ml being supported on each 4.5 g of silane treated kieselguhr. With this system, PGF is eluted just after the front, separated from PGE which is eluted at about 50 ml effluent from a 4.5 g column. * * * an approximate 4-fold purification was obtained.

* * * * * *

Crystallization of prostaglandin E. The fractions from the second reversed phase chromatography, containing the last half of the active band, were combined as also were those containing the first half. After evaporation to dryness in vacuo, the residues were dissolved in a few ml of ethyl acetate and allowed to stand overnight at room temperature. Needle-shaped crystals were usually obtained from the material contained in the last half of the active band * * *.

In Examples 4 and 5 of the present application, appellants describe a procedure for separate isolation of PGE2 and PGE3 in addition to PGE1 which closely resembles the process described in their 1960 publication up to the point where the second reversed-phase chromatography run was begun. Thereupon, appellants changed their procedure and subjected the pooled effluent fractions from the first chromatography run to a different chromatographic process. They obtained three separate fractions having physiological activity from which pure PGE1, PGE2, and PGE3 were individually isolated.

Faced with that set of facts, the examiner rejected claims 23 and 53 under § 101. Inasmuch as the "claimed compounds are naturally occurring," said the examiner, they therefore "are not `new' within the connotation of the patent statute," citing Ex parte Snell, 86 USPQ 496 (1950). In support of her rejection, and in contrast to appellants' contention that both claims are directed not to naturally occurring materials but to pure compounds which do not exist in pure form in nature, the examiner noted that she could not "determine from the claims exactly what is included or excluded." She thought the language of both claims sufficiently broad to embrace and not distinguish from either (1) the mother liquors which apparently inherently contain PGE2 and PGE3 and from which PGE1 is crystallized, as described in the 1960 Bergstrom et al. publication, or (2) those compounds as they inherently occur in previously known crude extracts or even in nature. In view of that, and because...