Board of Patent Appeals and Interferences
Patent and Trademark Office (P.T.O.)
*1 EX PARTE ALANE M. GRAY AND AXEL ULLRICH
Appeal No. 88-0437
January 17, 1989
Application for Patent filed March 3, 1983, Serial No. 471, 961. Human Nerve Growth Factor by Recombinant Technology.
Max D. Hensley et al. for appellants
Primary Examiner--Howard E. Schain
Before Pellman, Winters and W. Smith
ON REQUEST FOR RECONSIDERATION
Appellants request us to reconsider our holding mailed August 17, 1988 in which we affirmed the examiner's decision rejecting claims 1, 11, 12, 17 and 18.
At page 7 of their request, appellants state that there is no basis in the art of record for reasonably predicting that human beta-NGF could be produced by recombinant host cells. However, appellants appear to misapprehend the basis for our decision. It is our explicit holding that the product to which appellants' claims are directed would have been expected to be the same or substantially the same as that of the human nerve growth factor isolated by Goldstein and by Walker. At page 180 of his article, Goldstein states, under "DISCUSSION" that "we have demonstrated that human placental cotyledons are a suitable source for the purification of human NGF." Likewise, at page 195 of the other publication item cited by the examiner, Walker, in the "Summary", reports "Human ??Missing Text?? -nerve growth factor (hNGF) was purified from term human placenta." In the last six lines of the first paragraph at page 195, Walker discloses that:
Recently, Goldtein and coworkers (14) isolated and purified the biologically active ??Missing Text?? subunit of NGF from term human placenta. The present report confirms the presence of human ??Missing Text?? -NGF (hNGF) in term human placenta and reports the lack of immonocross-reactivity between mouse (mNGF) and hNGF using 6 different antisera to mNGF.
Beginning at page 5 of our decision, we pointed out that the legal principles enunciated in cases involving product-by-process claims are considered to be applicable herein. In support thereof, we cited the decision in In re Brown, which clearly explains the basis for our holding. That is, where the product disclosed in the prior art reasonably appears to be either identical with or slightly different from a product claimed by an applicant, there is pragmatic justification for placing the burden of going forward on the applicant. Furthermore, at page 10 of our decision, after acknowledging the apparent conflict between our opinion and the court's holding in In re Wakefield, we asserted that our decision is consonant with the overwhelming weight of current patent jurisprudence. Nevertheless, at page 16 of the request for reconsideration, appellants contend that they can find no decisions that support our position. Accordingly, appellants' attention is invited to the decisions in In re Thorpe, 777 F.2d 695, 227 USPQ 964 (Fed.Cir.1985); In re Marosi, 710 F.2d 799, 218 USPQ 289 (Fed.Cir.1983); In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980); In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Avery, 518 F.2d 1228, 186 USPQ 161 (CCPA 1975); In re Fessman, 489 F.2d 742, 180 USPQ 324 (CCPA 1974); and In re Luck, 476 F.2d 650, 177 USPQ 523 (CCPA 1973), just to name a few. Additionally, for appellants' convenience, we quote the following passage from In re Best, 195 USPQ 433-434, cited at page 7 of our decision:
*2 Where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. See In re Ludtke, [FNa1] supra. Whether the rejection is based on 'inherency' under 35 USC 102, on 'prima facie obviousness' under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products.
Having disposed of the arguments adverting to the product-by-process rationale, we note that, beginning at page 12 of their petition, appellants contend, in effect, that the pure form of a known substance may be patentable. To support their position, appellants refer to the famous "aspirin" case, cited at page 13 of the petition. Nonetheless, the mere purity of a compound, in itself, does not render the substance unobvious. Compare the decisions in Ex parte Hartop, 139 USPQ 525 (Bd.App.1962); Ex parte Steelmand, 140 USPQ 189 (Bd.App.1962); In re Mehta, 52 CCPA 1615, 347 F.2d 859, 146 USPQ 284 (1965); and In re Avery, supra. Furthermore, with respect to the decision in In re Williams, cited at page 14 of the petition, appellants' attention is invited to the subsequent decision in In re Adamson, 47 CCPA 839, 275 F.2d 952, 125 USPQ 233 (1960), which shows that the Williams decision resulted from the absence of relevant available evidence and does not represent a controlling rule of law. Also compare In re Anthony, 56 CCPA 1443, 414 F.2d 1383, 162 USPQ 594 (1969).
At page 11 of our decision, we noted that no objective evidence had been provided establishing that a method was unknown to those skilled in the field whereby the claimed material might have been synthesized. In response thereto, at page 6 of the petition, appellants complain that this improperly shifts the burden of proof to them and places them in the untenable position of having to prove a negative of enormous scope. We disagree. Rather, we are of the opinion that, to raise the question of non-enablement, appellants must, at the very least, provide a declaration by a person having ordinary skill in the subject art that no method was known to him prior to the claimed invention whereby the claimed material might have been synthesized. In this connection, attention is invited to the decision in In re Collins, 59 CCPA 1170, 462 F.2d 538, 174 USPQ 333 (1972). It will be noted that in said decision, not only was an affidavit required, but the court agreed with the board that the submitted affidavit failed to establish that there was no known or obvious way to make heat exchangers falling within the scope of the appealed claims. However, in the interest of reducing the issues in this case, we will agree, arguendo, that the only methods for obtaining human nerve growth factor, other than that of appellants, are those disclosed by Goldstein and by Walker, of record.
*3 At page 11 of the petition, appellants again rely upon Breakefield as casting doubt on the identity of the materials reported in the cited references. At page 12 of said petition, appellants state that the Breakefield reference "serves as expert testimony". We are then requested to provide our own evidence to counter the Breakefield et al. findings. Nevertheless, we will decline appellants' invitation.
The reason for requiring evidence in declaration or affidavit form is to obtain the assurances that any statements or representations made are correct, as provided by 35 U.S.C. 25 and 18 U.S.C. 1001. To permit the Breakefield publication, coauthored by one of the appellants herein, to substitute for expert testimony would circumvent the guarantees built into the statute by Congress. Accordingly, it is clear that we have no duty to offer evidence to counter the statements made by Breakefield. Rather, we are charged with the obligation of balancing all of the cited evidence of obviousness against the submitted evidence of non-obviousness. See the paragraph bridging pages 7 and 8 of our decision. In so weighing the evidence, we determined that the Breakefield publication item was inadequate to counterbalance the factual findings in the two publication items provided by the examiner. Consequently, we are convinced that our decision in the present case fully complies with the requirements of the statute and 37 C.F.R. 1.196(a).
Focusing now on claims 17 and 18, we observe that appellants, beginning at page 17 of their petition, again separately argue the patentability of human methionine beta-NGF. However, appellants have failed to respond to our finding that the protein containing the terminal methionyl group is substantially identical in structure to that purified by Goldstein and Walker. Since the decisions, such as In re Brown, of record, and In re Best, of record, agree that the disclosure of a substantially identical material in a prior art reference is sufficient to establish a prima facie case of obviousness and shift the burden of proof to appellants, we find no reason to arrive at a different conclusion.
At page 21 of their request, appellants acknowledge that the exhibits accompanying said request are newly cited and have not been considered by the examiner. Nonetheless, appellants request us to consider the references to economize our time. Ignoring the submitted publication items, appellants caution, will insure that said items will be presented in a continuing application. However, the same reasoning might be employed to extend the prosecution in any application handled by an examiner or to dispute any decision rendered by this Board. Since there must be an end to prosecution in any particular case, the mere possibility of further prosecution in a continuing application is insufficient reason for us to consider the publications cited by appellants herein. Compare In re Fessman, supra.
*4 Although, to the extent indicated, we have reconsidered our decision, we decline to make any changes therein.
BOARD OF PATENT APPEALS AND INTERFERENCES
Irving R. Pellman
Sherman D. Winters
William F. Smith
August 17, 1988
This is an appeal from the examiner's decision finally rejecting claims 1, 11, 12, 13 and 15 through 18, remaining claims 19 and 20 having been withdrawn from consideration by the examiner. However, since, by amendment, claims 13, 15 and 16 were cancelled, the claims before us for consideration are 1, 11, 12, 17 and 18.
The subject matter on appeal involves the human nerve growth factor B-NGF, identified by the particular amino acid sequence and being free from other proteins of human origin (claim 1). The invention also includes pharmaceutical compositions containing said nerve factor (claims 11 and 12) and said human nerve factor in which the amino acid sequence is preceded by a methionyl group (claims 17), as well as a composition containing the factor of claim 17 (claim 18). The particular human nerve factor of the present invention has been synthesized through the use of recombinant DNA technology and thus, is free from human proteins that would otherwise be expected to contaminate the composition. To describe the invention in greater detail and illustrate the claims on appeal, a copy of claim 1 is appended to this decision.
For evidence of obviousness, the references identified below are cited by the examiner.
Goldstein et al (Goldstein) "Isolation of Human Nerve Growth Factor From Placental Tissue", Neurochemical Research 3, 175-183 (1978)
Walker et al (Walker), "Human Nerve Growth Factor: Lack of Immunocrossreactivity with Mouse Nerve Growth Factor", Life Sciences 26, 195- 200 (1980)
All of the claims stand rejected for being unpatentable (35 U.S.C. 103) in view of Goldstein or Walker. The examiner, at page 2 of the answer states that:
"Each of these prior art discloses human B-NGF that appears to be the same as that claimed wherein such was isolated from human placental tissue, versus the claimed B-NGF that was produced by recombinant techniques."
In the sentence bridging pages 2 and 3 of the answer, the examiner notes that the sequencing of a protein does not make the protein different, but merely constitutes a further characterization of the known material.
In response to the examiner's arguments, beginning at page 5 of the brief appellants set forth their own arbuments. Appellants apparently divide their argument into three points. The first is that the human B-NGF of the references is not inherently that of appellants. Second, appellants contend that the reference human nerve growth factor is not free from other human proteins. Finally, we are told that the cited prior art does not teach or suggest methionyl N-terminal human B-NGF.
*5 At page 6 of their brief, appellants refer to the publication edited by Black, Cellular and Molecular Biology of Neuronal Development, Plenum Press, New York, Chapter 20, Breakefield et al, pages 309-328 (1984). Appellants refer specifically to page 310, wherein the author states that:
"To establish whether patients with dysautonomia make an altered form of B-NGF, it is necessary to characterize the human form of this protein. This has been difficult, and although there are a number of reports on preliminary identification of a human NGF-like molecule (Goldstein et al, 1978; Walker et al, 1980), no one has conclusively demonstrated its presence."
Appellants rely upon the foregoing as evidence that the Goldstein and Walker reports are merely preliminary and inconclusive.
At page 8 of their brief, appellants focus on the difference in the interpretation of Walker by the examiner vis-a-vis that by appellants as to the lack of immunological cross-reactivity between the art human B-NGF and murine B-NGF. Appellants conclude that the point is not whose theory is right, but contend that "when legitimate disputes arise about polypeptide identity they must-in view of prior board precedent, be resolved in appellants' favor. Rejections cannot be properly maintained on "maybe" references."
Beginning at page 9 of their brief, appellants raise the question of the purity of the claimed human B-NGF as compared with that of the references. Appellants explain that, due to the method of preparation, their nerve growth factor is free from any other human proteins. At page 10 of the brief, appellants query "why would the art be motivated to attempt to further purify human "B-NGF" beyond the level reported by Goldstein et al and Walker et al? If so motivated, does the art reasonably teach one of ordinary skill how to do do?"
In connection with the foregoing, at page 10 of the brief, appellants suggest that even if art were applied showing recombinant methods for synthesizing proteins, it would be clear from their discussion that more than a conventional recombinant method was involved in the preparation of the claimed human nerve growth factor.
At page 11 of their brief, appellants discuss the methionyl N-terminal human nerve growth factor. We are informed that "no reference of record teaches any reason for wanting to make methionyl B-NGF, and no reference teaches how to do so even if that was an objective. With regard to the therapeutic formulation of claim 18, there is no teaching or suggestion as to what sort of biological activity to reasonably expect from the methionyl N-terminal variant."
Although due consideration has been given to the opposing arguments and supporting evidence of appellants and of the examiner, we are unpersuaded of reversible error in the examiner's rejection, which will be sustained.
While the present claims are drafted in the form of a compound or a composition, the rationale underlying appellants' arguments is founded on the proposition that the claims are directed to a product-by-process. In any event, we are convinced that the legal philosophy employed in rejections involving products-by-process should be employed with respect to the claims before us. That is, insofar as we can observe, the difference between the material of Goldstein and of Walker and that claimed by appellants herein resides in the method of obtaining the human growth factor. The prior art material is recovered from natural sources and purified, while appellants' is produced by recombinant DNA methodology. However, the dispositive issue before us is whether the claimed factor exhibits any unexpected properties compared with that described by the cited publication items.
*6 To answer the foregoing question, we turn to the decision in In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972) wherein, at 59 CCPA 1041, Judge Baldwin, delivering the court's opinion, explains:
"We are therefore of the opinion that when the prior art discloses a product which reasonably appears to be either identical with or only slightly different than a product claimed in a product-by-process claim, a rejection based alternatively on either section 102 or section 103 of the statute is eminently fair and acceptable. As a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith."
Consistent with the court's holding, we find that, in the present case, the Office does not have the facilities for examining and comparing appellants' growth factor with that disclosed by Walker and by Goldstein. It is therefore entirely proper that appellants should have shouldered their burden of persuasion and made some comparison between the two materials to establish unexpected properties for the claimed factor. Having failed to do so, appellants are in a poor position now to contend that any doubt as to the difference between the two materials should be resolved in favor of patentability. Appellants do not inform us of the legal basis for their conclusion that this Board has held that doubt should be resolved in favor of an applicant and we are aware of no such recent decision. On the other hand, our reviewing tribunal, the United States Court of Customs and Patent Appeals, in In re Mixon, 59 CCPA 1996, 470 F.2d 1374, 176 USPQ 296 (1973), responsive to Chief Judge Worley's discussion of the "rule of doubt", Judges Rich, Almond, Baldwin and Lane, in their concurring opinion state:
"Since we have not been following any 'rule of doubt' policy and since that question is not involved in the present case we do not agree with the additional comments of the author."
In fact, rather than resolving doubt in favor of the applicant, the court has often held that obviousness does not require absolute predictability. See the decisions in In re Merck and Company, Inc., 800 F.2d 1091, 231 USPQ 375 (Fed.Cir.1986) and In re Lamberti, 545 F.2d 747, 192 USPQ 278 (CCPA 1976).
At page 5 of their brief, appellants contend that human B-NGF, as described by Walker or Goldstein, is not "inherently" that of appellant. However, this has not been established. Appellants' attention is invited to the decision in In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977), wherein the court held that the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. Accordingly, since the issue in the present appeal is whether the prior art factor is identical or patentably indistinct from that of the material on appeal, appellants have the burden of showing that inherency is not involved.
*7 Following the court's guidance in In re Johnson, 747 F.2d 1456, 223 USPQ 1260 (Fed.Cir.1984), we have weighed the examiner's evidence of obviousness against appellants' countervailing evidence to determine whether the claims are patentable notwithstanding the references of record. It appears that appellants rely heavily upon the publication item by Breakefield, particularly pages 310 and 311. We are well aware that the author dismisses the "preliminary identification of a human B-NGF-like molecule" by Goldstein and Walker and concludes that no one has conclusively demonstrated its presence. Nevertheless, we do not interpret the subjective statement by Breakefield as adequate to overcome the specific findings reported by Goldstein and Walker. Mere conclusory statements in a publication item are no more probative of nonobviousness than would be said statements in appellants' specification. Compare In re D'Ancicco, 59 CCPA 748, 452 F.2d 1060, 172 USPQ 241 (1972). Moreover, even if we were to consider the unverified statements in the publication article as those of an expert in the art, the statements would be inadequate because of the lack of factual supporting evidence. Compare In re Grunwell, 609 F.2d 486, 203 USPQ 1055 (CCPA 1979).
The present situation is somewhat similar to that confronting the court in Scripps Clinic & Research Foundation v. Genentech Inc., ______ F Supp. ______, 3 USPQ 2nd 1481 (DC NCalif 1987) wherein human blood-clotting factor VIII:C was involved. At page 3 USPQ 2nd 1487, the court points out that:
Scripps also alleges infringement of product claims 24 through 29 covering concentrated preparations of "human Factor VIII:C.
According to Scripps, these claims cover preparations, in the specified ranges of purity and potency, of Factor VIII:C with the functional and structural characteristics of the protein as it occurs naturally in humans.@6 Genentech, on the other hand, argues that Scripps' claims are limited to Factor VIII:C derived from human blood plasma. The issue posed is whether the asserted product claims must be interpreted to apply solely to concentrates of Factor VIII:C derived directly from human blood plasma or whether they extend also to other concentrates of Factor VIII:C having the same characteristics as those derived from human blood plasma.
In the paragraph bridging pages 1488-1489, the court explains that:
"the excerpts quoted by Genentech from deposition testimony of Drs. Katzmann and Zimmerman, Scripps' experts, that 'human' means 'obtained from human blood', are not probative on the issue of interpreting the claims. Dr. Katzmann's answer related to Factor V, not Factor VIII, and Dr. Zimmerman's answer did not purport to give an interpretation of the particular claim language. Human factor VIII:C as claimed in the patent therefore applies to any Factor VIII:C preparation, regardless of how produced, having the same material structural and functional characteristics as the plasma-derived preparation."
*8 We are convinced that our decision herein is completely consistent with and supported by the above-noted holding of the District court in Northern California.
In the interest of completeness, we call attention to two other decisions that appear relevant to our present holding. The first of these is In re Bergstrom, [FNa1] 57 CCPA 1240, 427 F.2d 1394, 166 USPQ 256 (1970), involving a rejection of certain pure prostaglandin compounds for not being novel in light of the material from which it was extracted. At page 57 CCPA 1250, the court held as follows:
"We need not decide the merits of that matter, for the fundamental error in the board's position, as we see it, is the analysis and answer it gave to the sole issue it accurately posed--'whether the claimed pure materials are novel as compared with the less pure materials of the reference.' [emphasis supplied.] It seems to us that the answer to that question is self-evident: by definition, pure materials necessarily differ from less pure or impure materials and, if the latter are the only ones existing and available as a standard of reference, as seems to be the situation here, perforce the 'pure' materials are 'new' with respect to them."
The other decision relevant to the facts before us, is In re Wakefield, 57 CCPA 959, 422 F.2d 897, 164 USPQ 636 (1970). In the Wakefield case, the claimed subject matter was synthetic rubber, while the prior art showed the corresponding naturally occuring product. At page 57 CCPA 966, Judge Lane, speaking for the court, disagreed with the board that the word "synthetic" as used in the claims would be applicable to purified natural product. In delivering the court's opinion, Judge Lane held that:
"we now turn to the examiner's view adopted by the Board, that the synthetic product is so similar to the natural product, purified to the extent allegedly shown in Davis, as to be 'prima facie obvious'. We would agree with this conclusion as a tentative one based on similarity of structure and gross characteristics. However, such tentative conclusions of obviousness are rebutted in those instances where there was, at the time the invention was made, no known or obvious method of making the claimed composition, or where the claimed composition is found to possess unexpected characteristics. At least the first situation is present in the case before us, since it cannot be said that a method of making the claimed synthetic product would be known or obvious from Davis."
Although we acknowledge that our holding in the present case appears to be in conflict with the court's limited holding in the Wakefield appeal, we are convinced that our decision is consonant with the overwhelming weight of current patent jurisprudence involving questions of the type posed by appellants. Moreover, we point out that no objective evidence has been provided establishing that no method was known to those skilled in this field whereby the claimed material might have been synthesized. Therefore, although we have weighed all of the evidence and legal authorities, both pro and con, concerning the patentability of the claims on appeal, we find that the evidence and the weight of legal authority compels an affirmance of the examiner's rejection.
*9 With respect to claims 17 and 18, the mere presence of a single methionyl moiety in a sequence of over 100 amino acids would not have been expected to alter the properties of the compound in a significant respect, in the absence of evidence to the contrary. It is our view that a minor inactive substituent on an otherwise unpatentable complex compound will not necessarily impart patentability to said compound. Thus, since we find claims 17 and 18 to be directed to an unpatentable modification of the compound to which the remaining claims are directed, these claims are held to be properly rejected for the same reasons as claims 1, 11 and 12.
For the reasons expressed above and those set forth in the answer, the examiner's decision rejecting claims 1, 11, 12, 17 and 18 is affirmed.
37 CFR 1.136(a) does not apply to the times for taking any subsequent action in connection with this appeal.
Irving R. Pellman
Sherman D. Winters
William F. Smith
FN1a. Cited by the court in footnote 6 in the Scripps Clinic decision.
1. Human B-NGF comprising the amino acid sequence ser-ser-ser-his-pro-ile-phe-his-arg-gly-glu-phe-ser-val-cys-asp-ser-val-ser-val-trp-val-gly-asp-lys-thr-thr-ala-thr-asp-ile-lys-gly-lys-glu-val-met-val-leu-gly-glu-val-asn-ile-asn-asn-ser-val-phe-lys-gln-tyr-phe-phe-glu-thr-lys-cys-arg-asp-pro-asn-pro-val-asp-ser-gly-cys-arg-gly-ile-asp-ser-lys-his-trp-asn-ser-tyr-cys-thr-thr-thr-his-thr-phe-val-lys-ala-leu-thr-met-asp-gly-lys-gln-ala-ala-trp-arg-phe-ile-arg-ile-asp-thr-ala-cys-val-cys-val-leu-ser-arg-lys-ala-val-arg and which is free of other proteins of human origin.