Merck & Co., Inc., In re
| Decision Date | 08 September 1986 |
| Docket Number | No. 85-2740,85-2740 |
| Citation | 231 USPQ 375,800 F.2d 1091 |
| Parties | , 231 U.S.P.Q. 375 In re MERCK & CO., INC. |
| Court | U.S. Court of Appeals — Federal Circuit |
Charles M. Caruso of Merck & Co., Inc., Rahway, N.J., argued for appellant. With him on brief was Nels T. Lippert, of Fitzpatrick, Cella, Harper & Scinto, New York City. Of counsel were Mario A. Monaco and Michael C. Sudol, Jr., of Merck & Co., Inc., Rahway, N.J.
Richard E. Schafer, Associate Sol., Office of Sol., Arlington, Va., argued for appellee. With him on brief were Joseph F. Nakamura, Sol., and Fred E. McKelvey, Deputy Sol.
Donald R. Dunner of Finnegan, Henderson, Farabow, Garrett & Dunner, Washington, D.C., argued for intervenor Biocraft Laboratories, Inc. With him on brief were Robert D. Bajefsky and Carol P. Einaudi of Finnegan, Henderson, Farabow, Garrett & Dunner, Washington, D.C. Of counsel was Beryl L. Snyder, of Biocraft Laboratories, Inc., Elmwood Park, N.J.
Before DAVIS, BALDWIN and ARCHER, Circuit Judges.
This is an appeal from a final decision of the United States Patent and Trademark Office (PTO) Board of Patent Appeals and Interferences (Board), sustaining the rejection of claims 1 through 3 in the reexamination application 1 of U.S. Patent No. 3,428,735 2 (the '735 patent) as unpatentable under 35 U.S.C. Sec. 103. We affirm.
The invention is directed to a method of treating human mental disorders; the method involves treating depression in humans by the oral administration of 5-(3-dimethylaminopropylidene)dibenzo[a, d][1, 4]cycloheptadiene (commonly known as and hereafter referred to as "amitriptyline"), or the hydrochloride or hydrobromide salts thereof, in a particular dosage range. Amitriptyline has the following chemical structure:
NOTE: OPINION CONTAINS TABLE OR OTHER DATA THAT IS NOT VIEWABLE
As representative of the invention, claim 1 reads:
1. A method of treating human mental disorders involving depression which comprises orally administering to a human affected by depression 5-(3-dimethylaminopropylidene) dibenzo[a, d][1, 4]cycloheptadiene or its non-toxic salts in daily dosage of 25 to 250 mg. of said compound.
Remaining claims 2 and 3 are dependent from claim 1 and add limitations pertaining to the use of the hydrochloride and hydrobromide salts of amitriptyline, respectively.
On March 10, 1977 an application, Serial No. 776,464 (the '464 application), was filed for reissue of the '735 patent. 3 All the claims of the '464 application were finally rejected by the examiner under section 102 of title 35, United States Code, and alternatively under section 103 of that title. Subsequently, an appeal (Appeal No. 424-40) was taken to the Board 4 which affirmed the examiner's rejections. Additionally, the Board entered a new rejection under 35 U.S.C. Sec. 103 over a combination of references not previously cited by the examiner. In accordance with 37 C.F.R. Sec. 1.196(b) (1985) 5, appellant elected reconsideration of the '464 application by the examiner. The examiner maintained the rejection entered by the Board; in Appeal No. 480-01, the Board affirmed the examiner. The Board's decision was appealed to the Court of Customs and Patent Appeals (CCPA). Upon the motion of the Commissioner of Patents and Trademarks and on the authority of In re Dien, 680 F.2d 151, 214 USPQ 10 (CCPA 1982), the appeal was dismissed for lack of subject matter jurisdiction. 6
The reissue application was protested by Biocraft Laboratories, Inc. (Biocraft), intervenor in the current appeal. Biocraft is also the plaintiff in a related litigation pending in the U.S. District Court for the District of New Jersey in which the validity and infringement of the '735 patent is in issue. See Biocraft Laboratories Inc. v. Merck & Co., Civil Action No. 77-0693 (D.N.J.). The district court has stayed further action in that case pending the final outcome of the pending PTO proceedings.
Following dismissal of the reissue appeal by the CCPA, Merck & Co., Inc. (Merck), the assignee of the '735 patent, filed for and was granted a request for reexamination of the patent. As a result of prosecution before the examiner, claims 1 through 3 of the reexamination application were finally rejected under 35 U.S.C. Sec. 102 as anticipated by prior art references; the claims were also rejected under 35 U.S.C. Sec. 103 as being obvious over references cited by the Board in its new ground of rejection entered during the initial reissue appeal. Finding the '735 patent to be entitled to the benefit of the November 30, 1959 filing date of its parent application, Serial No. 855,981, the Board reversed the section 102 rejection because the effective filing date of the application antedated all the references cited therein. The Board, however, sustained the rejection for obviousness under section 103. Expressly adopting the reasonings of its earlier reissue opinions, the Board took the position that in view of the prior art, in combination and a thorough knowledge of the investigative techniques used in the medicinal chemical art, the skilled artisan would have expected the known tricyclic compound, amitriptyline, to be useful as an antidepressant.
The references relied upon by the Board were:
(1) Rey-Bellet et al. (Rey-Bellet) U.S. Patent No. 3,384,663, May 21, 1968 (application filed Mar. 27, 1959);
(2) Kuhn, Schweizerische Medizinische Wochenschrift, Vol. 87, No. 35-36, pp. 1135-1140 (Aug. 1957);
(3) Lehman et al. (Lehman), Canadian Psychiatric Association Journal, "The Treatment of Depressive Conditions with Imipramine (G 22355)", vol. 3, No. 4, pp. 155-164 (Oct. 1958);
(4) Friedman, First Symposium On Chemical Biological Correlation, "Influence of Isosteric Replacements Upon Biological Activity", pp. 296-358 (May 1950);
(5) Burger, Journal of Chemical Education, "Rational Approaches to Drug Structure", Vol. 33, No. 8, pp. 362-372 (Aug. 1956);
(6) Petersen et al. (Petersen), Arzneimittel-Forschung, Vol. 8, No. 7, pp. 395-397 (1958);
(7) Roche Research Report No. 43,162, pp. 1-9 (Nov. 1957);
(8) Roche Research Report No. 43,169, pp. 1-8 (Apr. 1958);
(9) Roche Research Report No. 52,195, pp. 1-13 (Sept. 1958) (collectively called the "Roche Reports").
The Rey-Bellet patent disclosed amitriptyline and its hydrochloride salt. Properties of amitriptyline taught by the reference included a "manifold activity upon the central nervous system," as well as pharmacological and medicinal properties, such as "narcosis-potentiating, adrenolytic, sedative, antihistaminic, antiemetic, antipyretic and hypothermic." Rey-Bellet did not disclose or otherwise teach that amitriptyline possessed antidepressive properties.
and differs from the structure of amitriptyline only in the replacement of the unsaturated carbon atom in the center ring with a nitrogen atom. Kuhn taught a recommended dosage of 75-150 mg per day--possibly 200-250 mg if the smaller doses proved ineffective.
The Lehman publication disclosed the results of a Canadian study of the effects of imipramine on the symptoms of depression in humans. This article confirmed, for the most part, the teachings of the Kuhn article.
The object of the Friedman publication was "to survey the history of isosterism, to classify the varieties of isosteric replacements which are recorded in the literature, and to note the influence of these replacements on the biological activity of compounds." Friedman defined isosteres as atoms, ions or molecules in which the peripheral layers of electrons can be considered identical. Compounds which fit this broad definition and exhibit the same biological activity were termed "bioisosteric." Further, with respect to the medicinal chemists' use of the theory of "isosteric replacement" or "bio-isosteric replacement" as a tool to predict the properties of compounds, Friedman commented that:
[t]o the synthetic organic chemist interested in medicinal chemistry, every physiologically active compound of known structure is a challenge--a challenge either to better it, or perhaps merely to equal it....
There are numerous ways of attacking such a problem.... One of the methods which has been used frequently, very often with success, is that of isosteric replacement. The examples of this type of replacement in the literature are very numerous, and the fruitful results in the fields of sulfonamides, antimetabolites, and antihistamines are well known.
Friedman at page 296. Finally, Friedman disclosed various atoms or groups of atoms as bioisosteric, including the interchange of oxygen and the unsaturated carbon atom which often resulted in similar biological activity. Friedman, however, did not disclose or otherwise teach as bioisosteric the interchange of the nitrogen and unsaturated carbon atoms.
The Burger publication also discussed the theory of "bioisosterism" and its usefulness in designing new drugs based upon the knowledge of "lead" compounds.
The Petersen publication taught, inter alia, the properties of chlorpromazine (a phenothiazine derivative) and chlorprothixene (a 9-amino-alkylene-thioxanthene derivative), these compounds having the following structural formulas:
Petersen concluded that, when the nitrogen atom located in the central ring of the phenothiazine compound is interchanged with an unsaturated carbon atom as in the corresponding 9-amino-alkylene-thioxanthene compound, the pharmacological properties of the thioxanthene derivatives resemble very strongly the properties of the corresponding...
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