Board of Patent Appeals and Interferences
Patent and Trademark Office (P.T.O.)
*1 EX PARTE KURT W. NAUJOKS, WILLIE GERHARDT, CHRISTA HUBNER-PARAJSZ, KARL
WULFF, HERBERT JUNGFER HELMUT LENZ, WINFRIED ALBERT AND AUGUST W. WAHLEFELD
Appeal No. 89-0652
February 24, 1989
Application for Patent filed November 21, 1984, Serial No. 06/673,855. Process For Reagent For The Specific Determination of Pancreas Alpha-Amylase In The Presence Of Saliva Alpha-Amylase.
Stephen B. Shear et al. for appellants
Primary Examiner--David M. Naff
Before Seidleck, Rollins and W. Smith
This is an appeal from the final rejection of claims 1 through 17, 19 through 22 and 24, the only claims remaining in the application.
Claims 2 and 24 are illustrative of the subject matter on appeal and read as follows:
2. A process for the preparation of a monoclonal antibody which specifically reacts with salivary <<alpha>>-amylase and has a cross-reactivity of 5% or less with pancreatic <<alpha>>-amylase comprising immunizing an experimental animal with salivary <<alpha>>-amylase, fusing B-lymphocytes of the immunized animal with a transforming agent cloning and culturing of the so formed hybrid cells and isolating the monoclonal antibody from the latter.
24. Monoclonal antibody against saliva <<alpha>>-amylase, characterised [sic] by a cross-reaction of 5% or less towards pancreas <<alpha>>-amylase, subclass IgG 2 b kappa.
The references relied upon by the examiner are:
Murad et al. (Murad) 4,474,892 Oct. 2, 1984
(filed Feb. 16, 1983)
Sappo et al. (Sappo) (Japanese) 58-183,098 Oct. 26, 1983
(PTO Translation 86-2782)
Goding, "Antibody Production By Hybridomas", Journal of Immunological Methods, Vol. 39, pages 285-308 (1980).
Mishell et al. (Mishell), "Selected Methods In Cellular Immunology", Generation of Humoral Responses, pages 43-54 (1980).
Hagele et al. (Hagele), "Mechanism of Action of Human Pancreatic and Salivary <<Yen>>-Amylase on <<alpha>>-4-Nitrophenyl Maltoheptaoside Substrate", Clinical Chemistry, Vol. 28, No. 11, pages 2201-2205 (1982).
Whitlow et al. (Whitlow), "Maltotetraose as a Substrate for Enzyme-Coupled Assay of Amylase Activity in Serum and Urine", Clinical Chemistry, Vol. 25, No. 3, pages 481-483 (1979).
The claims stand rejected as follows:
(I) Claims 1 through 7, 9 through 14, 19 and 24 under 35 USC § 103 as unpatentable over Sappo in view of Goding and Pfleiderer and "if necessary" in further view of Mishell.
(III) Claims 15, 17, 20 and 22 under 35 USC § 103 as unpatentable over the references set forth above in (I) in view of Whitlow.
(IV) Claims 16 and 21 under 35 USC § 103 as unpatentable over the references set forth above in (I) in view of Hagele.
We have carefully considered the respective positions of the appellants and the examiner and find that we are in agreement with that of the examiner. Accordingly, we affirm the examiner's rejections set forth above for the reasons set forth in the Examiner's Answer and Supplemental Examiner's Answer. We add the following comments for emphasis only.
While there are claims in the application directed to diagnostic methods and reagents useful in such methods which utilize the monoclonal antibody which is the subject matter of claims 2 and 24, appellants have not separately argued these claims. It is apparent from the statements on page 14 of the Appeal Brief that appellants consider that all the claims shall stand or fall based upon the patentability of claims 2 and 24. Accordingly, we limit our consideration of this appeal to the subject matter of claims 2 and 24. [FN1]
The present invention is directed to the problem of the specific determination of pancreas <<alpha>>-amylase, which is of diagnostic importance, in the presence of saliva <<alpha>>-amylase. These two enzymes occur in the body and are stated by appellants to be immunologically identical (page 2 of present specification) which makes it difficult to analytically differentiate between them. The present invention revolves around the obtention of a monoclonal antibody which specifically reacts with salivary <<alpha>>-amylase and has a cross-reactivity of 5% or less with pancreatic <<alpha>>-amylase. A monoclonal antibody having this specificity is useful in binding salivary <<alpha>>>>>>-amylase in a sample to be tested so that only pancreatic <<alpha>>-amylase is available for testing.
Sappo is directed to the same problem, i.e., how to differentiate between salivary and pancreatic <<alpha>>-amylase in an analytical procedure. Sappo proceeds in the same direction in resolving this problem by utilizing monoclonal antibodies. Specifically, Sappo reports on pages 7 through 9 of the translation the obtention of a monoclonal antibody which reacts with salivary <<alpha>>-amylase and shows zero percent reactivity with pancreatic <<alpha>>>>>>-amylase. The procedure used by Sappo to obtain this monoclonal antibody parallels the classical technique of Kohler-Millstein and that set forth in claim 2 on appeal. Salivary <<alpha>>-amylase was used to immunize the mice in the procedure of Sappo and that of the present invention.
In comparing the monoclonal antibody reported by Sappo and the method used to obtain this monoclonal antibody with that set forth in claims 2 and 24 on appeal, it is apparent that Sappo would have, at the least, rendered the subject matter of these claims prima facie obvious to one of ordinary skill in the art. Indeed, appellants do not dispute that Sappo discloses a monoclonal antibody having the claimed specificity and a method which encompasses that set forth in claim 2 on appeal. Rather, appellants argue that the monoclonal antibody disclosed in Sappo could not be reproduced by them using the method disclosed in the reference. Appellants also argue that the assignee of Sappo recognized this in a letter to the present assignee. These arguments are supported by a declaration filed under 37 CFR 1.132 by co-appellant Kurt Walter Naujoks on July 21, 1987 (Paper No. 11). We have carefully considered these arguments and supporting evidence, but find that they are insufficient to rebut the prima facie case established by the examiner.
*3 In considering appellants' position, we note that the disclosure of a reference "must be taken at face value in the absence of evidence or reasoning inconsistent therewith." In re Donohue, 632 F.2d 123, 207 USPQ 196 (CCPA 1980). Thus, we take as a given that the method disclosed in Sappo will produce the monoclonal antibody specifically identified in that reference. In the Test Report attached to Dr. Naujoks's declaration, Dr. Naujoks reports the results obtained when he repeated the procedure described in Sappo to form the described monoclonal antibody. Dr. Naujoks reports that, contrary to the disclosure of Sappo, he did not find a high number of hybridomas which recognize specifically only salivary <<alpha>>-amylase. He reports that the cross-reaction of the sera was about 95 to 100%. Dr. Naujoks reports that even when cloning was carried out with the help of a fluorescence-activated cell sorter, which is stated to be superior in method over the method mentioned in Sappo, he did not succeed in isolating hybridomas whose cross-reaction in respect to pancreatic <<alpha>>-amylase was better than 80%. Dr. Naujoks goes on the conclude that these results were consistent with former tests carried out in assignee's laboratory facility in 1981 (prior to the present invention) which show that:
"after a short-term immunisation [sic], differentiating antisera or monoclonal antibodies cannot yet be obtained. Moreover, I refer to the literature already cited at that time, this literature establishing an increase in specificity of the antisera after immunisation [sic] for a longer time."
Sappo immunized the mice twice over a period of two weeks with the spleens being harvested three to four days after the second immunization, which is the immunization procedure used by Dr. Naujoks in his Test Report.
We are not persuaded that the Test Report by Dr. Naujoks is sufficient to establish that the specific method disclosed by Sappo is not reproducible or that the reference as a whole is nonenabled. As set forth above, we take at face value that the disclosed procedure in Sappo produces the monoclonal antibody disclosed in this reference. In re Donohue, supra. In considering similar circumstances involving the alleged nonenablement of a U.S. patent to produce a disclosed product, the court stated in In re Michalek, 34 CCPA 1124, 162 F.2d 229, 74 USPQ 107 (1947):
With respect to the experiments described in the affidavits it must be said that in a patent it is to be presumed that a process, if used by one skilled in the art, will produce the product alleged by the patentee and such presumption is not overcome by a mere showing that it is possible to operate within the disclosure without obtaining the alleged product. Skilled workers would as a matter of course, in our opinion, if they do not immediately obtain desired results, make certain experiments and adaptations and we agree with the argument of the solicitor that it is not a difficult matter to carry out a process in such fashion that it will not be successful and, therefore, the failures of experimenters who have no interest in succeeding should not be accorded great weight, citing Bullard Company et al. v. Coe, 147 F.2d 568, 64 USPQ 359. Possibly more extensive experiments than were made by the affiants herein might have produced a different result.
*4 While the reference before us is a Japanese Patent Publication, not a U.S. patent, we find that similar considerations should apply in evaluating appellants' evidence. Dr. Naujoks apparently faithfully performed the method of Sappo using an improved screening technique in order to find the desired monoclonal antibody. However, Dr. Naujoks did not take into account knowledge which he admits those of ordinary skill in the monoclonal antibody art had at the time this invention was made, i.e., a longer immunization protocol will result in a more specific monoclonal antibody being produced. Under these circumstances, we find that one of ordinary skill in the art, in attempting to obtain the specific monoclonal antibody disclosed by Sappo, would adapt the procedure disclosed in that reference to include a longer immunization protocol in order to achieve a more specific monoclonal antibody if one was not obtained in an initial trial in accordance with the knowledge available at that time. Further, Dr. Naujoks does not set forth what significance, if any, an initial "failure" to reproduce the monoclonal antibody of Sappo would have to one of ordinary skill in the art.
Appellants argue that the assignee of Sappo has recognized that the method disclosed in that reference is not reproducible. In support of this argument, Dr. Naujoks attached to his declaration filed under 37 CFR 1.132 a copy of a letter to present assignee from the director of the planning department of the assignee of Sappo. In relevant portion, the letter reads as follows:
Our examination of the technique according to the Patent Application has proved now, that in a process of developement [isc] for marketing after filing the Application, the method had not sufficient repeatability and an inhibition of the definite desired isoenzyme was not complete.
Thus, it has been already decided, that the examination for application should not be requested, because an improvement of the technique was necessary.
Therefore, we can declare herewith that (1) we do not make a complain to any person, who puts the method into practice, (2) We can not give the materials related for the method of anyone at the present time, because an improving the method now in progress, (3) We will take your interests about this kind of the technique into consideration in future, as the improved method will be applied for a patent in near future.
As mentioned above, we would like to inform you of the results of our investigation. We are pleased, however, to keep the contents of our report secret to a third person.
Appellants assert that the statement which appears in the first quoted paragraph of the letter, "[T]he method had not sufficient repeatability and an inhibition of the definite desired isoenzyme was not complete.", is an admission that the Japanese inventors themselves could not reproduce the teachings of Sappo. We disagree.
Our evaluation of this letter is hampered because appellants have chosen not to make of record the letter written by the present assignee which precipitated the response from the assignee of Sappo. Thus, it is not clear in what context or environment this response was made. When it is considered that these two assignees are commercial entities and apparently competitors, it is difficult to determine what weight should be given to this letter when only half of the correspondence is of record since the overall context of the correspondence is unknown. Further, the statement in the letter relied upon by appellants is in the context of developing the process of Sappo "for marketing". When this paragraph is read in its entirety, it appears that any problem in regard to repeatability of the method disclosed in Sappo was of concern to the assignee of Sappo in regard to commercially marketing that invention. As stated by the court in In re Sivaramakrishnan, 673 F.2d 1383, 213 USPQ 441 (CCPA 1982): "... [the] patent statute does not require commercial use of subject matter of a prior-art disclosure for that disclosure to qualify as a reference", citing In re Blake, 53 CCPA 720, 724, 352 F.2d 309, 312, 147 USPQ 289, 291 (1965).
*5 A reasonable conclusion from reading the letter in its entirety is that the assignee of Sappo is only stating that the method disclosed in that reference did not have sufficient repeatability for that invention to be commercially marketed. We do not find that it establishes that the specific method disclosed in Sappo is not repeatable or that the reference is nonenabled or inoperative.
The examiner has relied upon Goding as evidence that immunization and other conditions used in producing monoclonal antibodies can vary and be selected to provide a desired monoclonal antibody. Appellants refer to the statement at page 286 of Goding that:
"[F]inally, it should be stressed that the production, testing, cloning and characterisation [sic] of monoclonal antibodies is not a trivial procedure. It should not be undertaken without an appreciation that it will involve some months of fairly continuous bench works."
On the basis of this statement of Goding and the alleged non-repeatability of the procedure disclosed in Sappo, appellants conclude that Sappo would be, at best, an invitation to experiment and that the rejection amounts "obvious to try" to get the desired antibodies. Appellants rely upon Hybritech Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 231 USPQ 81 (Fed.Cir.1986). We have considered Hybritech and the most recent case involving monoclonal antibody technology, In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed.Cir.1988). Both of these cases involved uses of monoclonal antibodies and did not relate directly to the production of the monoclonal antibody of interest as appellants have limited the consideration of this appeal. To the extent that these cases were concerned with producing an individual monoclonal antibody of the specificity of interest, the following passage from wands is to be noted:
The PTO concedes that the methods used to prepare hybridomas and to screen them for high-affinity IgM antibodies against HBsAg were either well known in the monoclonal antibody art or adequately disclosed in the '145 patent and in the current application. This is consistent with this court's recognition with respect to another patent application that methods for obtaining and screening monoclonal antibodies were well known in 1980. [Citing Hybritech, 802 F.2d at 1384, 231 USPQ at 94]
To the extent that appellants argue that the present rejection is based upon an impermissible "obvious to try" standard, we think such argument is misplaced in that it is predicated upon the assumption that the method set forth in Sappo is not reproducible. Appellants' evidence has not substantiated this assumption. The present issue does not revolve around "trying" anything different in Sappo, as Sappo essentially discloses what is claimed in claims 2 and 24. To the extent that appellants' position can be regarded as being that the present method differs from that disclosed in Sappo by the immunization used, we note that claim 2 on appeal is not specific to the immunization protocol. Indeed, the present specification sets forth at pages 5 and 6 that the immunization of this invention takes place by the conventional administration of the native or modified enzyme and that the immunization preferably takes place over the course of at least nine months with at least seven immunizations. The immunization step recited in claim 2 on appeal is inclusive of that specifically disclosed by Sappo and does not serve as a point of distinction.
*6 The decision of the examiner is affirmed.
37 CFR 1.136(a) does not apply to the times for taking any subsequent action in connection with this appeal.
BOARD OF PATENT APPEALS AND INTERFERENCES
James A. Seidleck
Alton D. Rollins
William F. Smith
FN1. 37 CFR 1.192 provides in pertinent part that the Appeal Brief "... must set forth the authorities and arguments on which the appellant will rely to maintain the appeal."