Board of Patent Appeals and Interferences
Patent and Trademark Office (P.T.O.)
GIESA ET AL.
Interference No. 101,584
July 17, 1989
Final Hearing February 15, 1989
Attenuated Hepatitis A Virus
Patent granted to Bertram Flehmig on March 19, 1985, Patent No. 4,506,016 filed September 7, 1982, Serial No. 415,524.
Application of Paula A. Giese, Maurice R. Hilleman and Philip J. Provost filed May 14, 1984, Serial No. 609,677. Accorded benefit of U.S. Serial No. 437,095 filed October 27, 1982 and Serial No. 071,648 filed September 4, 1979.
Donald J. Perrella, Hesna J. Pfeiffer and Julian S. Levitt for Giesa et al. Oral argument by Raymond M. Speer
Before R. Smith, Sofocleous and W. Smith
This interference involves a patent of Flehmig, which is unassigned according to the records of the PTO, and an application of Giesa et al. (Giesa), which is assigned by an unrecorded assignment to Merck & Co., Inc.
The subject matter at issue relates to a process for culturing hepatitis A virus (HAV). The sole count at issue reads as follows:
The claims of the parties which correspond to the count are:
Claims 1 to 4 and 7 to 9.
Claims 13 to 19.
In the decision on motions (Paper No. 35), the Examiner-in-Chief (EIC) denied (i) Flehmig's preliminary motion (Paper No. 12) for judgment under 37 CFR 1.633(a) and (ii) Flehmig's preliminary motion under 37 CFR 1.633(g) to deny Giesa the benefit of his parent application Serial No. 437,095 and his grandparent application Serial No. 071,348. At the same time as he rendered his decision on motions, the EIC ordered Flehmig to show cause why judgment pursuant to the provisions of 37 CFR 1.640(d)(3) should not be rendered against him because his preliminary statement did not overcome the effective filing date of Giesa. Flehmig responded to the order by filing a request for final hearing and a motion for a testimony period. Thereafter, Giesa filed an opposition to the motion for testimony and a belated preliminary motion (Paper No. 45) for judgment. In the decision (Paper No. 47), the EIC granted the Giesa motion for judgment holding that Flehmig's involved claims 1 to 4 and 7 to 9 corresponding to the count were unpatentable over prior art and placed Flehmig under an order to show cause why judgment should not be rendered against him in view of the unpatentability of his claims. In response to the order, Flehmig requested a testimony period and final hearing on the issues raised in his opposition (Paper No. 46) to the Giesa motion for judgment and on the issues raised in his preliminary motions under §§ 1.633(a) and 1.633(g) (Paper Nos. 11 and 12). The EIC granted the Flehmig requests. Flehmig presented testimony and Giesa presented rebuttal testimony.
*2 Both parties filed briefs and appeared, through counsel, at final hearing.
The Flehmig brief raises the matter of whether Giesa has complied with its duty of disclosure under 37 CFR 1.56. We, however, are without authority to consider this matter. See the Commissioner's Notice, dated September 8, 1988, 1095 O.G. 16, as clarified in his Notice, dated October 17, 1988, 1096 O.G. 19. Accordingly, this issue is dismissed.
The following issues are before us:
1. Are Flehmig's involved claims 1 to 4 and 7 to 9 unpatentable over prior art as urged in Giesa's preliminary motion for judgment [FN1]?
2. Are Giesa's involved claims 13 to 19 unpatentable as urged in Flehmig's preliminary motion for judgment?
Giesa's Preliminary Motion for Judgment
Giesa's preliminary motion for judgment under 37 CFR 1.633(a) urges that Flehmig's involved claims 1 to 4 and 7 to 9 are unpatentable under 35 USC 102(b)/103 over Provost, European Patent Application (EP-A)-0 025 745, a patent application published more than one year before the filing date of Flehmig's involved application, which motion was granted by the EIC for the reasons set forth by Giesa. Since Flehmig did not file a motion under 37 CFR 1.633(c)(4) to redefine the interference by designating any of those claims as not corresponding to the count, he is not entitled to argue at this stage of the proceeding that there is a patentable distinction between any of the claims designated as corresponding to count 1 (37 CFR 1.655(b)). Consequently all the claims stand or fall together with the count. Lamont v. Berguer, 7 USPQ 2d 1581 (BPAI 1988) and Kwon v. Perkins, 6 USPQ 2d 1747 (BPAI 1988).
We have carefully reviewed the evidence [FN2] and the arguments [FN3] in the parties' briefs and we find that we agree with the decision of the EIC that the claims are unpatentable to Flehmig under 35 USC 102(b)/103 over Provost. Accordingly, we hold that Flehmig's claims 1 to 4 and 7 to 9 corresponding to the count are unpatentable to Flehmig. Kwon v. Perkins, supra.
It is Flehmig's position that Provost is not an effective reference against the claims because Provost does not sufficiently describe and lacks an enabling disclosure for the subject matter of the count. Contrary to Flehmig's arguments, we find that Provost sufficiently describes the invention of the count and contains an enabling disclosure.
Adverting to the Provost patent application [FN4], we note that it contains the following relevant disclosure:
*3 It is an object of the present invention to provide an improved method for the in vitro cell culture of hepatitis A virus. Another object is to provide a method for propagation of hepatitis A virus which does not require the use of primates. A further object is to provide a method for the preparation of hepatitis A antigen for use in human vaccines and as a diagnostic antigen. Still another object is to provide an in vitro method for attenuating the virulence of hepatitis A antigen. [Page 2, lines 4 to 13]
The present invention provides a method for propagating hepatitis A virus wherein passage of the virus in a susceptible non-human primate prior to in vitro cell culture is not required. [Page 2, lines 28 to 31]
According to the present invention a clinical specimen containing hepatitis A virus, e.g. stool extract, saliva, urine, or blood, is used as inoculum to infect a susceptible in vitro cell. The cell culture may be formed of primary, continuously cultivated, or transformed cells derived from kidney or liver of human or non-human primate origin, specific examples of suitable cell cultures are those derived from fetal or newborn kidney cells from rhesus monkey (FRhK6), cynomolgus monkey, or cercopithecus monkey, or diploid fibroblast cells derived from human or non-human primate lung tissue such as, for example WI-38 or MRC-5 cell lines. The inoculated cell culture is incubated for an extended period of time until positive results are obtained for the presence of hepatitis A antigen. By an extended period of time is meant an incubation of at least about 25 days, and preferably from about 25 up to about 100 days. The incubation is carried out in the presence of a nutrient medium which maintains the cells at temperatures permitting propagation of the virus in the cell culture.... The cultures are subsequently harvested and serial passages of the viral agent are carried out. As indicated above the virus may be propagated by serial passages in diploid fibroblast cells derived from human or non-human primate lung tissue.... Preferably propagation is effected through from about 5 to about 50 passages in the diploid fibroblast cells. Most preferably, prior to passage in the diploid fibroblast cells the virus is propagated in a cell-culture derived from primary, continuously cultivated or transformed cells derived from kidney or liver of human or non-human primates. Propagation is effected through from about 5 to about 25 passages in the kidney or liver of human or non-human primates. [Page 2, line 32 to page 4, line 5]
The patent also contains 5 examples. Example 1 shows that hepatitis A virus obtained from human stool is inoculated into fetal rhesus kidney (FRhK6) cells. On day 33, a first clear positive result is obtained; the cultures are harvested at day 37 and the cells are disrupted by freeze-thawing and sonication. The supernatant product gives a positive result by radioimmunoassay for hepatitis A antigen. In example 5, the hepatitis A virus derived as in Example 1 is serially passaged a total of 15 times in fetal rhesus monkey kidney cells at 35<<degrees>> C. The virus harvest from passage 15 is then successfully propagated in human diploid lung (HDL) cell cultures at 32<<degrees>>>>> C. A total of 55 serial in vitro passages of the virus in HDL are carried out. After such passage the hepatitis A virus is attenuated in virulence for both marmosets (S. labiatus) and chimpanzees.
*4 We do not agree with Flehmig's position that Provost is not an effective reference because it does not sufficiently describe the subject matter of the count.
It is well settled that prior art under 35 USC 102(b) must sufficiently describe the claimed invention to have placed the public in possession of it. In re Donohue, 766 F.2d 531, 226 USPQ 619 (Fed.Cir.1985); In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). Such possession is effected if one of ordinary skill in the art could have combined the publication's description of the invention with his own knowledge to make the claimed invention. In re LeGrice, 301 F.2d 929, 133 USPQ 365 (CCPA 1962).
In our view, Provost sufficiently describes the invention of the count which is directed to a process which comprises culturing unmodified Hepatitis A virus (HAV) on human kidney cells (HKC) and harvesting the thus-produced viruses.
Provost teaches that an object of his invention is a method for culturing HAV derived from human stool which method does not require the use of primates. In other words, Provost's culturing can be done without the use of an intervening culture of a non-human primate i.e., he discloses culturing unmodified HAV as isolated from the source, e.g. stool, on human kidney cells. Thus, we do not agree with Flehmig's argument that the statement made by Giesa on page 4 of his opposition (Paper No. 22) [FN5] that
... the Senior Party found it necessary to culture HAV on fetal kidney cells in order to adapt it for culturing on diploid lung cells
constitutes an admission (see pages 42 to 46 of Flehmig's brief) that Provost or Giesa's grandparent application (see note 4, supra) does not disclose a method of culturing unmodified HAV. The statement speaks, at best, about an "adapted HAV", not an unmodified HAV, which is the subject matter of the count. Further, Flehmig quoted the statement out of context by omitting the words, "Like the junior party," which make clear that the statement applies to both parties' disclosures. Provost teaches the use of "kidney or liver of human or non-human primate origin" in the method and exemplifies in example 1 culturing HAV obtained from human stool in fetal rhesus kidney (FRhK6) cells. In our view, this description reasonably conveys to one skilled in the art that, regardless of which alternative cultures (kidney of human or non-human primate origin) is used, by following the general teachings of the patent he will be able to culture HAV and harvest the thus-produced viruses.
We do not agree with Flehmig's position that Provost is not an effective reference for lack of enablement.
To be a proper reference, the publication must contain a disclosure sufficient to enable one skilled in the art to reduce the disclosed invention to practice. In re Borst, 345 F.2d 851, 145 USPQ 554 (CCPA 1965), cert. denied, 382 US 973, 148 USPQ 771 (1966). The disclosure must be sufficiently complete to enable one of ordinary skill in the art to make the invention without undue delay and experimentation, although the need for a minimum of experimentation is not fatal. In re Brandstadter, 484 F.2d 1395, 179 USPQ 286 (CCPA 1973); Martin v. Johnson, 454 F.2d 746, 172 USPQ 391 (CCPA 1972) and Fields v. Conover, 443 F.2d 1386, 170 USPQ 276 (CCPA 1971). Undue experimentation is that which would require ingenuity beyond that which is to be expected of one of ordinary skill in the art. Fields v. Conover, supra. Every detail need not set forth in the written specification if the skill in the art is such that the disclosure enables one to make the invention. Martin v. Johnson, supra. The party urging lack of enablement bears the burden of proof.
*5 Flehmig has the burden of persuasion to show that one skilled in the art having the Provost reference before him would not have been able to culture HAV on human kidney cells and harvest the thus-produced viruses. In our view, Flehmig has not sustained his burden of persuasion.
Turning to the source of HAV, Provost, page 2, line 33 to page 3, line 1, teaches that a clinical specimen containing HAV, e.g. stool extract, saliva, urine or blood, is used as inoculum to infect a susceptible in vitro cell culture and exemplifies in example 1 stool as the source of HAV. Flehmig doubts that saliva or urine are useful as a source of inoculum because he is unaware of any publication teaching this. This doubt concerning the usefulness of saliva or urine as a source of inoculum does not persuade us that Provost is not enabling. One skilled in the art would consider the reference as a whole. Although the Provost disclosure teaches various sources of inoculum for HAV, the examples show that Provost prefers stool as a source of the inoculum. Should it have been shown, which Flehmig has not, that saliva or urine were not useful as a source of inoculum, that would not show that Provost is nonenabling, where the reference clearly teaches and exemplifies an operative source for the inoculum. It is not required that every embodiment in a disclosure be operative in order to be enabling under 35 USC 112, first paragraph. Atlas Powder Co. v. E.I. Dupont de Nemours & Co., 750 F.2d 1569, 224 USPQ 409 (Fed.Cir.1984); In re Geerdes, 491 F.2d 1260, 180 USPQ 789 (CCPA 1974).
With respect to culturing HAV on human kidney cells, it is Flehmig's position [FN6] that one skilled in the art could not predict without experimentation whether a specific species of HAV would propagate in a specific cell culture. In support of the position, Flehmig points to his testimony that there are distinct species of HAV isolated from human stool. According to Flehmig, the exhibit (FX 22) is his unpublished manuscript which reports the testing of some 20 different stool samples in three different cell cultures (fetal rhesus kidney cell number four, human kidney cells, primary human kidney cells and primary human fibroblast cells from the lung). Flehmig testified that it was found that one of the stool samples was propagated in fetal rhesus kidney cells and human kidney cell. FR 37 to 39, 44, 54, 56 and 57; FX 22 to 25.
On the other hand, Giesa presented the testimony of Provost, a coinventor, who testified [FN7] that ...
it is my opinion, based on our experience and a careful review of the extensive literature to date on the nature of HAV and its behavior, that even though some minor differences among HAV strains may have been demonstrated thus far, that propagation of HAV in the types of cell cultures set out in the description of THE APPLICATION [Giesa involved application] can be carried out regardless of the HAV strain used. That is, there is no instance, either in our experience or recorded in the literature, of any particular strain of HAV failing to be propagated in any of the cell culture types enumerated in THE APPLICATION, where an attempt to do so has been made using proper experimental (tissue culture) procedures. In fact, a significant number of those cell culture types have already been established in the literature as affording a means for propagating various HAV strains when proper procedures, i.e., those in accordance with the description in THE APPLICATION, were employed. [GR 17 and 18]
*6 He also testified that no valid scientific conclusions could be drawn from the results of Flehmig's experiments because no active control was used by Flehmig side by side with the strains being studied and because the experiments were not repeated, i.e., the data were derived from only single runs of the experiment. GR 17 to 20.
We are not persuaded that one skilled in the art would not have been enabled to culture HAV on human kidney cells in light of the teachings of Provost. Further, we are not persuaded by Flehmig's evidence that HAV is strain specific to the extent that it cannot be cultured on different cell mediums. In this regard we agree with Giesa that no valid scientific conclusions can be drawn from the results of Flehmig's experiments because no active control [FN8] was used by Flehmig side by side with the strains being studied and because the experiments were not repeated, i.e., the data were derived from only single runs of the experiment. See Provost's testimony at GR 19 and 20. Further, we note that Tables II and III of FX 22 show that samples 2/1 and 2/2, taken from the same patient no more than one day apart, gave very different results concerning the amount of HAV present in each sample and concerning propagation of the HAV in human kidney cells. Sample 2/2, but not sample 2/1, could be propagated on human kidney cells. Thus we are not persuaded that Flehmig has sustained his burden to show that HAV is strain specific.
The record contains no evidence to show culturing any strain of HAV on human kidney cells would require ingenuity beyond that which would have been expected of one of ordinary skill in the art. On the contrary such ingenuity would not have been required because, according to Flehmig, the procedures for culturing and the cell cultures themselves were routine and ordinary. FR 68 to 70; FX 6. The mere fact that some experimentation is necessary to determine whether a particular strain of HAV will culture on a particular cell culture is not fatal to enablement where as here the procedures and cultures are routine. Indeed, Flehmig's position is belied by his claims corresponding to the count which do not claim any specific strain of HAV.
Nor do we agree with Flehmig that Giesa was required in some way to make a deposit of the specific HAV utilized by him. The various exhibits (FX 6 to 22 and GX 2 to 5 and 6 to 9) indicate that HAV is a well known virus which on the record before us appears to be publicly available. Flehmig has not shown otherwise or sustained his burden to show that HAV is strain specific. Under those circumstances, Giesa was not required to make a deposit of the organism. In re Wands, 858 F.2d 731, 8 USPQ 2d 1400 (Fed.Cir.1988).
Adverting to harvesting thus-produced viruses, the count does not specify whether the cultured viruses are cell-free or cell-bound. By its terms, the count embraces both forms of HAV and, according to Giesa, the distribution of the virus as either cell-bound or cell-free is of no practical importance. GR 8. Flehmig does not dispute that Provost is able to harvest HAV by the freeze-thawing and sonication technique. In our view, one skilled in the art would have been able to harvest the HAV cultured by Provost.
*7 For the foregoing reasons, we find that Provost is an effective reference against the Flehmig claims and accordingly hold that the Flehmig claims are unpatentable under 35 USC 102(b)/103 over Provost.
Flehmig's Preliminary Motions
Our holding that Flehmig's claims are unpatentable is dispositive of the interference against Flehmig. For the sake of completeness, we will consider the Flehmig motions.
Flehmig's preliminary motion for judgment urges that Giesa's claims 13 to 19 [FN9] corresponding to the count are not patentable to Giesa because his involved application does not satisfy the written description, the enablement and best mode requirements of 35 USC 112, first paragraph. Flehmig's preliminary motion under 37 CFR 1.633(g) urges that Giesa is not entitled to the benefit of his parent application, Serial No. 437,095, and his grandparent application, Serial No. 071,348, for failure to satisfy the written description and the enablement requirements of 35 USC 112, first paragraph.
As we noted in note 4, supra, the Giesa grandparent application, Serial No. 071,348, contains the same disclosure as the Provost European patent. The grandparent application has substantially the same disclosure as the Giesa's parent and involved applications, the latter two applications having a more extensive disclosure than the grandparent application. Since Flehmig attacks these applications on the same grounds and for the same reasons as he attacked the Provost reference, we direct our discussion, infra, to the Giesa grandparent application (Provost).
With respect to the written description under 35 USC 112, first paragraph, we rely upon sections I and II, supra, of our decision on Giesa's preliminary motion for judgment. We add the following:
In our view, Giesa's grandparent application contains a sufficient written description, within meaning of 35 USC 112, first paragraph, for the subject matter of the count in issue and Giesa's involved application contains a sufficient written description, within meaning of 35 USC 112, first paragraph, for its claim 13 corresponding to the count.
To comply with the written description requirement, an application must reasonably convey to persons skilled in the art that, as of the filing date thereof, the inventor had possession of the subject matter later claimed by him. In re Driscoll, 562 F.2d 1245, 195 USPQ 434 (CCPA 1977).
Giesa teaches that an object of her invention is a method for culturing unmodified HAV derived from human stool which method does not require the use of primates. She specifically teaches the use of "kidney or liver of human or non-human primate origin" in the method and exemplifies in example 1 culturing HAV obtained from human stool in fetal rhesus kidney (FRhK6) cells. In our view, this description reasonably conveys to one skilled in the art that, regardless of which alternative cultures (kidney of human or non-human primate origin) is used, by following the general teachings of the patent one skilled in the art will be able to culture HAV and harvest the thus-produced viruses. On the other hand, Flehmig would require that the Giesa grandparent contain a specific example to the culturing of HAV on human kidney cells in order to satisfy the written description requirement. The law, however, does not require such an example to satisfy the written description requirement of 35 USC 112, first paragraph. In re Strahilevitz, 668 F.2d 1229, 212 USPQ 561 (CCPA 1982).
*8 For the foregoing reasons, we hold that the Giesa benefit applications support an embodiment within the scope of the count and that the involved Giesa application contains a sufficient written description for its claims 13 to 19 corresponding to the count.
Adverting to the enablement issue, we consider that our decision in section III, supra, in our decision on Giesa's preliminary motion for judgment adequately discusses this issue in the context of 35 USC 112, first paragraph. Accordingly, we incorporate herein our discussion in that section and hold that the Giesa benefit and involved applications contain an enabling disclosure to satisfy the requirements of 35 USC 112, first paragraph.
Adverting to the best mode argument, Flehmig's main brief at page 27 urges that Giesa's benefit and involved applications fail to provide a best mode or any mode for the subject matter defined by the count. As we view the argument, we consider that Flehmig's best mode attack is in substance no more than an alternative way of stating the application disclosure is not enabling. See U.S. Department of Energy v. Daugherty, 687 F.2d 438, 215 USPQ 4 (CCPA 1982). Our previous holding that the Provost reference is enabling is, therefore, dispositive of Flehmig's best mode argument.
Bertram Flehmig is not entitled to a patent containing his claims 1 to 4 and 7 to 9; and
Paula A. Giesa, Maurice R. Hilleman and Philip J. Provost are entitled to a patent containing their claims 13 to 19.
BOARD OF PATENT APPEALS AND INTERFERENCES
Ronald H. Smith
William F. Smith
FN1. By granting the motion, the EIC accepted the showing as sufficient to excuse the belatedness. Pursuant to 37 CFR 1.655(a), the EIC's interlocutory order is presumed to have been correct. The Board may consider whether an interlocutory order is manifestly erroneous or an abuse of discretion, and the burden of showing such is on the party attacking the order. Nowhere in the brief has Flehmig addressed his burden.
FN2. Both parties presented expert testimony on the issues before us together with associated exhibits. The Flehmig record will be referred to as FR followed by its page number; each Flehmig exhibit, as FX followed by its number. The Giesa record will be referred to as GR followed by its page number; each Giesa exhibit, as GX followed by its number.
FN3. The Flehmig brief raises numerous objections (see, for example, page 7) concerning the weight to be given to the Giesa evidence and urges that numerous statements (see, for example, page 6) made by Giesa constitute admissions. In the interest of judicial economy, we will consider only those objections and purported admissions which relate to the Giesa evidence relied upon us, bearing in mind that a statement to constitute an admission must be "clear and unmistakable." See 3 Rivise and Caesar, Interference Law and Practice, page 1797 (The Michie Co. 1947).
FN4. The disclosure of Provost is the same as the disclosure of the Giesa grandparent application, Serial No. 071,348, which Giesa has been accorded the benefit of in the notice declaring this interference. Flehmig has attacked this accordation of benefit. See issue 3, supra.
FN6. Flehmig's position concerning strain specificity appears to be inconsistent with his patent specification and his claims corresponding to the count which do not specify any strain specificity for HAV.
FN7. In regard to Flehmig's argument on pages 52 and 64 of his main brief that this testimony constitutes hearsay insofar as Provost's opinion is based on the experience of someone other than Provost, e.g. "our experience," we agree that the issue of hearsay is presented. Since Flehmig did not file a motion to suppress in accordance with 37 CFR 1.656(h), we will not disregard the testimony Since the testimony is based on Provost's own experience, Provost being a part of the "our", the testimony is entitled to consideration in the absence of any evidence to the contrary.
FN8. On page 70 of his main brief, Flehmig urges that given Provost's definition of an "active control," stool sample No. 1 comprising HAV strain GBM, "a well-defined standard HAV," was a control. Regardless of Flehmig's strained definition of a control, we find that no control was used. Our position is consistent with Flehmig's testimony at FR 72 that "[w]e have not used a specific positive control," even though "the GBM strain is included in this work." FR 72.
FN9. Independent claim 13 corresponds exactly to the count. 37 CFR 1.601(f). The remaining claims depend on claim 13.