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Application Of Jean P Rosselet Oldrich K Sebek and George B Spero

347 F2d 847

This appeal is from the decision of the Patent Office Board of Appeals affirming the examiner's rejection of product claims 3 and 5 in application serial No. 701,967, filed December 11, 1957, for "Organic Compounds and Process." No claims have been allowed.

The invention relates to steroid compounds and, according to the application, is "particularly concerned with 6-methyl-16α-hydroxyhydrocortisone, 1-dehydro-6-methyl-16α-hydroxyhydrocortisone, 6-methyl - 9α - fluoro - 16α - hydroxyhydrocortisone, 1-dehydro-6-methyl-9α - fluoro-16α - hydroxyhydrocortisone, the 16, 21-diesters thereof, the 11-keto analogues and the esters thereof and a method for the production thereof. " The application further says:

The new compounds * * * are highly active adrenocortical hormones having greater glucocorticoid activity than hydrocortisone or cortisone. In addition these compounds have diuretic activity and have saltlosing properties which make them especially well suited in the management of chronic congestive heart failure and in the treatment of cirrhosis of the liver, the nephrotic and adrenogenital syndromes and the treatment of eclampsia and preeclampsia.

The claimed invention, however, is narrower than the above broad description, the two claims reading:

3. 1 - dehydro - 6α methyl - 16α - hydroxyhydrocortisone.

5. 1 - dehydro - 6a - methyl - 9α - fluoro - 16α - hydroxyhydrocortisone.

Thus, claim 5 defines the compound of the formula

NOTE: OPINION CONTAINING TABLE OR OTHER DATA THAT IS NOT VIEWABLE

and claim 3 defines the compound of the same formula except that the 9α-fluoro atom is replaced by hydrogen.

Bernstein (IV) 2,789,118 Apr. 16, 1957

Bernstein (V) J. Am. Chem. Soc. Nov. 5, 1956

78, 5693-4

Spero (I) J. Am. Chem. Soc. Dec. 5, 1956

78, 6213-4

Spero (II) J. Am. Chem. Soc. Mar. 20, 1957

There are four separate rejections: The rejection of claim 3 "as unpatentable over Spero (I) in combination with Bernstein (IV)"; the rejection of claim 5 "as unpatentable over Spero (II) in combination with Bernstein (V)"; and the rejection of claim 5 "as unpatentable over each of the two Bernstein references * * *. "

Spero (I) reports the results of studies on the 6-methylation of various steroids. The reference discloses 1-dehydro-6α-methyl-hydrocortisone which was found to be "sixteen times as active as hydrocortisone" in the "glycogen deposition (glucocorticoid) assay" without showing "salt retaining (mineralocorticoid) activity." This compound differs from the compound of claim 3 in lacking the 16α-hydroxy substituent. The reference says:

* * * demonstration of the absence of mineralocorticoid activity in the presence of high glucocorticoid activity for 6-methylhydrocortisone, the synthesis of which is presently described, was unpredictable and is of considerable interest. Extension of the study to the 1-dehydro series has resulted in the most pronounced selective enhancement of cortical activities reported to date. [Footnotes omitted. ]

Spero (II) refers to Spero (I) as having "reported * * * the preparation of a number of 6-methylated analogs of adrenal hormones which show unusual potentiation of glucocorticoid activity with no sodium-retaining properties" and says that "The group of 9α-fluoro- and 21-fluoro-6-methyl steroids reported herein represents a continuation of this work." 1-Dehydro-6α-methyl-9α-fluoro-hydrocortisone is disclosed and is included among those compounds showing "considerably greater glucocorticoid and anti-inflammatory activity * * * than does hydrocortisone in animal assays." This compound differs from the compound of claim 5 in lacking the 16α-hydroxy substituent.
 

 

Judge(s): Rich
Jurisdiction: U.S. Supreme Court
Related Categories: Immigration , International , Patent , Property
 

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Click the maroon box above for a formatted PDF of the decision.
We will not delve into the question of comparative closeness of the prior art to appellants' compounds as we deem it unnecessary. Suffice it to say that the Spero compounds are, we think, sufficiently close to the claimed compounds to make the claimed invention prima facie obvious and, that being so, a showing of some unexpected effectiveness or property relative to those compounds is required to support a finding of patentability. The reason we believe the Spero compounds render the invention obvious within the meaning of 35 U.S.C. § 103 is that closely related 16-hydroxylated steroids are not unknown in the art, as evidenced by the Bernstein reference, and because all of these compounds are recognized in the art as having a great many physiological properties in common. The invention relates to steroid compounds and, according to the application, is "particularly concerned with 6-methyl-16α-hydroxyhydrocortisone, 1-dehydro-6-methyl-16α-hydroxyhydrocortisone, 6-methyl - 9α - fluoro - 16α - hydroxyhydrocortisone, 1-dehydro-6-methyl-9α - fluoro-16α - hydroxyhydrocortisone, the 16, 21-diesters thereof, the 11-keto analogues and the esters thereof and a method for the production thereof." The application further says: RICH, Judge. Spero (I) reports the results of studies on the 6-methylation of various steroids. The reference discloses 1-dehydro-6α-methyl-hydrocortisone which was found to be "sixteen times as active as hydrocortisone" in the "glycogen deposition (glucocorticoid) assay" without showing "salt retaining (mineralocorticoid) activity." This compound differs from the compound of claim 3 in lacking the 16α-hydroxy substituent. The reference says: Appellants contend that the Patent Office has failed to consider the art which they have presented allegedly to show that 6-methylation or 16-hydroxylation does not always result in steroids having the activity attributed to those groups by the Spero and Bernstein references. We have examined the art of record as a whole but find appellants' cited art alone insufficient to overcome the strong suggestion of appellants' compounds which we see in the art cited by the examiner. We note particularly, for example, the very desirable results of 16α-hydroxylation as noted in our above discussion of Bernstein (V). The following table summarizes the structural relationships between the claimed compounds and the pertinent prior art compounds, the base compound in each instance being 1-dehydrohydrocortisone (prednisolone): We agree with appellants' admonitions against deciding questions of chemical obviousness on the basis of structure alone, whether by means of a "mechanistic overlay" or otherwise. However, we think appellants have failed to present adequate evidence to overcome a prima facie showing of obviousness by reason of the admitted "gross structural similarities" of the art compounds, coupled with the fact those compounds are shown to have utility in the same area of pharmacological activity. * * * * * * 1 Appellants have made no challenge of this statement, and we therefore accept it as correct 6a-methyl 9α-fluoro 16α-hydroxy WORLEY, C. J., concurs in the result. The claimed invention, however, is narrower than the above broad description, the two claims reading: There are four separate rejections: The rejection of claim 3 "as unpatentable over Spero (I) in combination with Bernstein (IV)"; the rejection of claim 5 "as unpatentable over Spero (II) in combination with Bernstein (V)"; and the rejection of claim 5 "as unpatentable over each of the two Bernstein references * * *." Spero (II) J. Am. Chem. Soc. Mar. 20, 1957 The additional rejection of claim 5 on Spero (II) in combination with Bernstein (V) parallels the rejection of claim 3 on Spero (I) in combination with Bernstein (IV). Claim 5 differs from claim 3 in the presence of a 9α-fluoro substituent; the corresponding references differ in exactly the same respect. * * * For reasons which will be evident from our treatment of claim 3, the rejection of claim 5 will likewise be sustained. Finally, appellants contend that the combination of the Spero and Bernstein references "is improper for neither of them suggest the combination * * *." However, in substantial agreement with the solicitor, it is our view that the test of obviousness is not express suggestion of the claimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them. These references are closely related in the same art. The new compounds * * * are highly active adrenocortical hormones having greater glucocorticoid activity than hydrocortisone or cortisone. In addition these compounds have diuretic activity and have saltlosing properties which make them especially well suited in the management of chronic congestive heart failure and in the treatment of cirrhosis of the liver, the nephrotic and adrenogenital syndromes and the treatment of eclampsia and preeclampsia. This appeal is from the decision of the Patent Office Board of Appeals affirming the examiner's rejection of product claims 3 and 5 in application serial No. 701,967, filed December 11, 1957, for "Organic Compounds and Process." No claims have been allowed. Spero (I) J. Am. Chem. Soc. Dec. 5, 1956 July 1, 1965} 5. 1 - dehydro - 6a - methyl - 9α - fluoro - 16α - hydroxyhydrocortisone. Thus, claim 5 defines the compound of the formula The decision of the board is affirmed. Clarence W. Moore, Washington, D. C. (J. E. Armore, Washington, D. C., of counsel), for Commissioner of Patents. Claim 3 X X Application Of Jean P Rosselet Oldrich K Sebek and George B Spero Case No.Patent Appeal 7334. Spero (II) X X During prosecution, appellants presented two affidavits, both by William E. Dulin, an employee of appellants' assignee, The Upjohn Company, Kalamazoo, Michigan, which convincingly establish that the compound of claim 3 is 4.7 times more effective as an anti-inflammatory agent than the closest compound of Bernstein (IV) and that the compound of claim 5 is 1.6 times more effective as an anti-inflammatory agent than the closest 9α-fluoro compound of Bernstein (V), also disclosed in Bernstein (IV). The board, after first finding the claim 3 compound to be structurally obvious, said: Appellants contend that a comparison with the Spero compounds is unnecessary since the Bernstein compounds are "closer" and a comparison with these compounds, showing greater effectiveness, has been presented. Their basis for this contention is two-fold. First the examiner has rejected one of the claims as unpatentable over each of the Bernstein references alone, but not on the basis of the Spero references alone. Second, a methyl substituent allegedly constitutes a smaller difference (chemically speaking, we presume) than does a hydroxy substituent. Appellants are quite emphatic, however, in urging that the addition of a methyl substituent to an otherwise unsubstituted carbon atom does not set up a "homologous series" and, consequently, so the argument goes, the issue here is unlike those found in cases in this court dealing with "homology" or "isomerism." Before WORLEY, Chief Judge, and RICH, MARTIN, SMITH and ALMOND, Judges. While the issue could be stated, alternatively, as the converse of the above, we see no reason why our statement is not a proper interpretation of the examiner's rejection. 78, 5693-4 Bernstein (IV) 2,789,118 Apr. 16, 1957 78, 6213-4 Bernstein (IV) X Bernstein (V) J. Am. Chem. Soc. Nov. 5, 1956 ---------------------------------------------------------------------- 347 F2d 847 Bernstein (V) additionally discloses that the 9α-fluorocompound of Bernstein (IV), is "about 13 times more active than hydrocortisone" in the rat liver glycogen assay and is one of "the most active glucocorticoids hitherto reported which * * * [is] devoid of sodium-retaining properties." The conclusion is reached that "16α-hydroxylation abolishes the sodium-retaining property of 9α-fluorosteroids without destroying their glucocorticoid activity." Spero (I) X 3. 1 - dehydro - 6α methyl - 16α - hydroxyhydrocortisone. Eugene Retter, Gerard A. Blaufarb, Kalamazoo, Mich., for appellants. Affirmed. In view of the many factors bearing on decisions of this kind and because of the frequency of appeals in this area of the law, we think it desirable, lest we be misunderstood, to point out some things this opinion does not hold. We do not herein hold, impliedly or otherwise, that any compound differing from the prior art solely by a hydroxy or methyl group is deemed prima facie obvious in view of that art and thus necessitates a showing of an unexpected effectiveness or property; that affidavits must be presented comparing the claimed compounds with both the primary and secondary reference compounds; that a showing of activity 4.7 and 1.6 times that of the prior art is insufficient as a matter of law to establish patentability; and that prior art cannot be effectively cited by appellants to rebut teachings or suggestions in prior art cited by the examiner. United States Court of Customs and Patent Appeals. and claim 3 defines the compound of the same formula except that the 9α-fluoro atom is replaced by hydrogen. We agree with the board's analysis and decision. Clearly, the Spero references, especially in view of the Bernstein disclosures, give rise to a presumption of obviousness under section 103. The law, under such circumstances, is clear in requiring a showing of an unexpected property or properties compared to those prior art compounds which otherwise render the claimed compound obvious. Appellants have not made such a showing. Claim 5 X X X * * * demonstration of the absence of mineralocorticoid activity in the presence of high glucocorticoid activity for 6-methylhydrocortisone, the synthesis of which is presently described, was unpredictable and is of considerable interest. Extension of the study to the 1-dehydro series has resulted in the most pronounced selective enhancement of cortical activities reported to date. [Footnotes omitted.] Since we agree with the examiner's rejections of claims 3 and 5 on the combination of references, it is unnecessary to consider his rejection of claim 5 on each Bernstein reference alone. Bernstein (IV) discloses, inter alia, 1-dehydro-16α-hydroxyhydrocortisone and 1-dehydro - 9α-fluoro - 16α-hydroxyhydro-cortisone and says the compounds "are useful as anti-inflammatory agents in the treatment of arthritis, asthma, burns, bursitis, and the like, and also in the treatment of skin disorders and collagen diseases." Although appellants have submitted data, in the Dulin affidavit filed January 6, 1960 * * * to show that the claimed compound has an anti-inflammatory activity 470% that of the Bernstein (IV) compound, they have made no comparison with the Spero (I) compound. In view of the fact that the Spero (I) compound is the well-known commercial product "Medrol" of appellants' assignee, there appears to be no justification for appellants' failure to compare the claimed compound with the Spero (I) compound. It may be assumed that comparative data was either available to appellants or readily obtainable. Lacking such comparison, there is no foundation for concluding that the claimed compound is an unobvious improvement over the Spero (I) compound. * * * v. Spero (II) refers to Spero (I) as having "reported * * * the preparation of a number of 6-methylated analogs of adrenal hormones which show unusual potentiation of glucocorticoid activity with no sodium-retaining properties" and says that "The group of 9α-fluoro- and 21-fluoro-6-methyl steroids reported herein represents a continuation of this work." 1-Dehydro-6α-methyl-9α-fluoro-hydrocortisone is disclosed and is included among those compounds showing "considerably greater glucocorticoid and anti-inflammatory activity * * * than does hydrocortisone in animal assays." This compound differs from the compound of claim 5 in lacking the 16α-hydroxy substituent. It should now be clear that the rejection of claim 3 as unpatentable over Spero (I) in combination with Bernstein (IV) and the rejection of claim 5 as unpatentable over Spero (II) in combination with Bernstein (V) present parallel issues, viz., obviousness of the claimed compounds in view of the respective Spero compounds, which differ from the claimed compounds solely in the absence of a 16α-hydroxy substituent, and in view of the respective Bernstein teachings which show that 16α-hydroxy substituents are found on closely related steroids, the Bernstein compounds themselves differing from the claimed compounds solely in the absence of a 6α-methyl substituent. Thus appellants are not, nor do they pretend to be, the first to 6-methylate or 16-hydroxylate steroids of the type here involved. What appellants have done is to provide hydrocortisones bearing both these substituents and, accordingly, novelty of the claimed compounds has been conceded. Appellants admit there are "gross structural similarities" between the compounds of claims 3 and 5 and the compounds of Spero and Bernstein, but argue that "one need look only to the recent decisions of this Honorable Court to ascertain that the obviousness of chemical compounds, even of homologs * * *, is no longer to be predicated solely on structural similarity. * * * Here, the superimposition or `mechanistic overlaying' of the compounds of Bernstein and Spero is clearly inappropriate to render the claimed compounds obvious * * *," citing In re Riden, Jr., 318 F.2d 761, 50 CCPA 1411 for the latter proposition. NOTE: OPINION CONTAINING TABLE OR OTHER DATA THAT IS NOT VIEWABLE


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