Application of Warren Francis Carey

392 F.2d 646, 55 C.C.P.A. 1146

• Court: Court of Customs and Patent Appeals
• Decided: June 20, 1968
• Docket: Patent Appeal 7923
• Status: Published

Opinions

ALMOND, Judge.

This is an appeal from the decision of the Patent Office Board of Appeals affirming the rejection of the sole remaining claim of appellant’s application entitled “Urological Compositions.”¹

The invention is adequately described in the claim:

6. The method of combating bacterial urinary tract infection in a host subject thereto which comprises orally administering to said host in dosage unit form about 100 to about 400 mg. of 1- (5-nitrof urylideneamino) -2-imi-dazolidone.

The references relied upon are:

Gever et al. (Gever) 2,746,960 May 22 1956

Mintzer et al. (Mintzer), Antibiotics and Chemotherapy, Vol. 3, No. 2, January 1953, pages 151-157.

Paul et al. (Paul) Antibiotics and Chemotherapy, Vol. 10, No. 5, May 1960, pages 287-302.

Claim 6 stands rejected as unpatentable over Gever considered with Paul and Mintzer under 35 U.S.C. § 103 on the ground that in view of the close structural relationship of the nitrofuran recited in appellant’s claim (designated herein as NF-246) and nitrofurantoin (NF-153),² a well known urinary tract

antibacterial, it would be obvious that NF-246 would possess similar properties as NF-153, and its use in the treatment of urinary tract infections would be obvious. The Gever patent discloses and claims as a compound the nitrofuran NF-246 here involved. The patent further discloses that this compound is effective against infections caused by both gram positive and gram negative organisms and has a surprisingly low level of toxicity when orally administered.

Mintzer discusses the use of NF-153 in the treatment of urinary tract infections. According to Mintzer, NF-153 is practically completely absorbed by the body, as evidenced by low fecal concentration, is excreted in the urine to about 45% of the dosage given, and has bactericidal levels below urinary concentrations when tested in vitro against organisms commonly implicated in urinary tract infections. The article reports clinical studies showing effectiveness of this compound in treatment of patients having urinary tract infections caused by various organisms.

The Paul article is directed to a study of the distribution of certain nitrofurans in the body. The reason for and purpose of the study is stated by the authors:

The effective spectrum of these compounds against such a wide variety of invading microorganisms, and the apparent lack of toxicity at chemotherapeutic levels in an equally wide range of hosts, has led to inquiries in regard to the physiological disposition of these compounds.

Paul compares NF-153 and NF-246, among other nitrofurans. This comparison shows that both compounds have low blood and fecal concentrations. It also shows that NF-153, when administered in a dosage level of 25 mg./Kg. of body weight, is 52% excreted in the urine, while NF-246, administered in a dosage level of 276 mg./Kg., is 10% excreted in the urine.

The examiner expressed his rejection as follows:

In view of the facts that (1) NF-153 is useful combatting urinary tract infections, (2) NF-246 is structurally closely related to NF-153, and (3) NF-246 possesses the same qualities which are indicated as being responsible for the success of NF-153 as a urinary tract antiseptic, it is believed that one of ordinary skill in the art would consider that it was logical to anticipate with a high degree of probability that a trial of NF-246 as a urinary tract antiseptic would be successful. Thus, appellant’s invention is presumed obvious.

Appellant attacks the rejection on several grounds. He first asserts that since the assignee of this application ³ had conducted considerable research work on both NF-153 and NF-246 from 1952 to 1959 with no suggestion of its use as a urinary tract antibiotic until appellant’s application was filed in February 1963, this should be taken as evidence of unobviousness. We can dispose of this argument by noting that the rejection is based upon obviousness in view of a combination of three references, one of which was not published until May 1960. We further note that this record does not show when appellant made his invention —for all we can discern from the record, it could have been made contemporaneously with the discovery of NF-246 by Gever.

Appellant argues also that no citation has been advanced to establish the equivalency of carbonyl and methylene groups. He feels such citation is necessary since a substitution of one group for the other is the sole difference between NF-153 and NF-246. We think this statement of the issue misses the point. The question before us is not the obviousness of substituting a methylene for a carbonyl; Gever had already done that. Our question is whether it would be obvious to substitute in this particular application a compound having one methylene and one carbonyl group for a compound having two carbonyl groups in view of the secondary reference teachings of certain physiological and antibacterial similarities between the two.

Appellant argues that the examiner and the board failed to give proper weight to an affidavit filed by Dr. Mary Paul, one of the authors of the Paul reference. This affidavit discussed the factual showings in the art of record, and then concluded:

From the data presented there I would not expect, with a high degree of probability, that a trial of NF-246 as a urinary tract agent would be successful. * * * On their face these values would not convince me that a trial of NF-246 as a urinary tract agent could have any better than hope of success.

The opinion of an expert in the art on the question of obviousness of an invention is only one bit of evidence to be considered along with other evidence in the record, including the prior art. In re Weber, 341 F.2d 143, 52 CCPA 1015. The opinion of the board makes it clear that the board did not summarily dismiss the affidavit, but did consider it and found it lacking in persuasive effect. We find no error here.

Appellant has also argued that he has shown unexpected and surprising results in the use of NF-246, based upon the showing of the Regan affidavit. That affidavit reports clinical tests on the treatment of urinary tract infections in human patients. The board was unimpressed by this affidavit, noting that it reports that of 30 patients treated with 39 courses of the drug, 21 were unsuccessful. The board also noted that only 8 of 24 patients had good results at a daily dosage of 200 mgm, and that the investigators seem to have been mainly impressed with the lack of toxicity of NF-246, a characteristic already noted by Gever.

Appellant criticizes the board for failing to recognize that the reported clinical studes were run, as is customary with most initial drug investigations, at dosages well below the recommended levels. Appellant argues that even at this dosage level, which is from % to y2 the recommended dosage of NF-153, good results were obtained in 60% of the cases. He argues this to be a surprisingly good result, particularly since NF-246 is excreted in the urine at far lower levels than NF-153.

The trouble with appellant’s arguments on this point is that they require us to guess what effect NF-153 would have at % to y2 the recommended level. It is only when the performance of the reference compound under similar conditions is established that it becomes possible to compare the performance of the claimed compound to show improved or unexpected results. From all that is shown in the affidavit, NF-246 may have been grossly inferior to NF-153 in these particular clinical tests.

The Regan affidavit does appear to establish that several organisms are sensitive to NF-246 but not NF-153 in tests conducted in vitro. However, since the claimed invention is a method of combating bacterial urinary tract infections in a host, this showing is an inadequate substitute for comparative in vivo tests.

We agree with the examiner that one skilled in the art, knowing of the prior use of NF-246 as an orally administered antibacterial agent having a broad spectrum of antibacterial activity, including activity against E. coli, identified by Mintzer as one causitive organism in urinary tract infections, knowing of the low toxicity and substantial urinary excretion of NF-246, and knowing of its striking structural similarity to the known urinary tract antibacterial agent NF-153, would expect NF-246 to have utility in combating urinary tract infections. There is nothing in the affidavits which persuades us that the results achieved were unexpected in view of the prior art.

The decision of the board is therefore affirmed.

Affirmed.

1 . Serial No. 259,403 filed February 18, 1963.

2 . The structures of these two compounds are:

(NF-246)

(NF-153)

3 . The Norwich Pharmacal Company, which is also assignee of the Gever reference, employer of the authors of the Paul artiele, and sponsor of the authors of the Mintzer article.