Board of Patent Appeals and Interferences
Patent and Trademark Office (P.T.O.)
*1 EX PARTE MICHAEL B. SPORN AND ANITA B. ROBERTS
Appeal No. 88-3036
November 10, 1988
HEARD: October 17, 1988
Application for Patent filed February 16, 1984, Serial No. 581,021, which is a Division of Serial No. 500,833, filed June 3, 1983, now abandoned, which is a Continuation-in-part of Serial No. 468,590, filed February 22, 1983, now abandoned, which is a Continuation-in-part of Serial No. 423,203, filed September 24, 1982, now abandoned. Repair Of Tissue in Animals.
Marvin R. Stern, et al., for appellants
Supervisory Primary Examiner--John Kight
Tarring and W. Smith
This is an appeal from the examiner's final rejection of claim 23, the only claim remaining in the case.
This application was the subject of a previous Board decision in Appeal No. 86-1316 which decision and opinion we incorporate by reference. In that decision, we reversed various rejections while affirming the rejections of all six of the claims therein under:
a) 35 U.S.C. 102 or 103 over Todaro; and
b) 35 U.S.C. 102 or 103 over Childs.
We further affirmed the rejection of four claims under 35 U.S.C. 112, first and second paragraphs, as being indefinite and unduly broad. The prior Board indicated that appellants could treat the affirmance of the above rejections as new grounds of rejection under 37 CFR 1.196(b) since the Board's reasons for affirming did not appear to have been clearly developed in the preceeding prosecution history. Appellants invoked the procedure permitted by 37 CFR 1.196(b) and continued prosecution before the examiner. That prosecution has resulted in the examiner dropping the rejection based on Childs. Appellants have limited their claims to the single claim, Claim 23, which provides:
23. An isolated, purified beta transforming growth factor (TGF-B), said growth factor being acid-stable, having an apparent molecular weight of 12,500 to 13,000 daltons on SDS-PAGE in the presence of a reducing agent and 25,000 to 26,000 daltons in the absence of a reducing agent, requiring epidermal growth factor when inducing non-neoplastic indicator cells (NRK cells) to form colonies in soft agar, being non-competitive with said epidermal growth factor for receptor binding, and having the following partial amino acid sequence in a subunit thereof:
Ala-Leu-Asp-Thr-Asn 5-Tyr-CMC-Phe-Ser-Ser 10-Thr-Glu-Lys-Asn-CMC-%r where CMC is Half-cystine or cysteine, determined as S-carboxy-methylcysteine.
A more complete understanding of the invention and the prosecution history of this application can be provided by the referred to and incorporated prior Board decision (Appeal No. 86-1316, dated December 17, 1986).
Todaro et al (Todaro), "Growth Factors Produced By Sarcoma Virus-transformed Cells, CANCER RESEARCH 38, pp. 4147-4156 (November 1978).
Appellants rely on the following references.
DeLarco et al. (DeLarco), "A Human Fibrosarcoma Cell Line Producing Multiplication Stimulating Activity (MSA)-Related Peptides," Nature, Vol. 272. pp. 356-358 (1978).
Brown et al. (Brown), "Insulin-like Synergistic Stimulation of DNA Synthesis In Swiss 3T3 Cells By The BSC-1 Cell-Derived Growth Inhibitor Related To Transforming Growth Factor Type B, Proc. Natl. Acad. Sci. USA, Vol. 84, pp. 3743-3747 (June 1987).
In this decision the Board refers additionally to the following reference, which is of record:
Marquardt et al. (Marquardt), "Purification And Primary Structure Of A Polypeptide With Multiplication-Stimulating Activity From Rat Liver Cell Cultures," J. Biol. Chem., Vol. 256, pp. 6859-6865 (1981).
Two rejections are presented in this appeal:
a) Claim 23 stands rejected under 35 U.S.C. 102/103 over Todaro; and (b) Claim 23 stands rejected under 35 U.S.C. 112, first and second paragraphs.
In support of the rejection under 35 U.S.C. 112, the examiner, in her Answer, indicates that the claim fails "to set forth the invention in full, clear and concise terms." We note that claims are not required to set forth the invention in the full, clear and concise terms required of the description of the invention in the specification. As set forth in the second paragraph of 35 U.S.C. 112, the claims are required to particularly point out and distinctly claim that which the applicant regards as his invention. From the remainder of the comments pertinent to this rejection in the Examiner's Answer, we construe this rejection to be under the second paragraph based on the claim being indefinite. [FN1] We will not sustain this rejection.
Present claim 23 differs from the claims subject to the corresponding rejection affirmed in our previous decision, in its definition of a 15 member partial amino acid sequence. This sequence was present in the claims which were not subject to the corresponding rejection in the earlier decision. The previously non-rejected claims, however, also included an analysis of the number, per mole, of respective amino acids present in a residue of the growth factor. Appellants have not included the residual amino acid analysis in present claim 23. When they cancelled claim 29, which contained the residual amino acid analysis, appellants stated that early identifications of chemical compositions were notoriously inaccurate due to limitations in analytical techniques and knowledge of the material at that time.
Dr. Sporn, by declaration, has stated that the recitation of the first fifteen amino acids defines the claimed substance from a possible set of over 1020 substances and that there is no other known substance in the physical world that corresponds to this substance. He further stated that present claim 23 defines a single unique substance.
*3 Dr. Matthew Rechler, an expert in the field, has provided a declaration wherein he generally corroborates Dr. Sporn's statements and, additionally, indicates that the amino acid sequence is a more accurate indication of the material than is the amino acid residue composition.
We are satisfied that the above noted evidence of record adequately establishes that the partial amino acid sequence provided in claim 23, along with the other provisions of the claim, is sufficient to particularly point out and distinctly claim appellants' invention. We note that the examiner also criticizes the term "isolated" and "purified" as being relative terms which are not sufficient to establish the exact level of purity for TGF-B. The use of relative terms does not necessarily render the claim indefinite. Clearly, TGF-B as it exists in nature is not covered by the claim. Naturally occurring TGF-B would have to be isolated and purified before it would correspond to the claimed factor. We are unaware of any requirement that the claims recite the exact level of purity of isolated and purified substances. Accordingly, we see nothing indefinite resulting from the claims use of the terms "isolated" and "purified".
The previous Board decision found that the four isolates from human fibrosarcoma cells described by Todaro at pages 4150, 4151 are, prima facie, sufficiently similar to appellants' TGF-B, to shift to appellants the burden of proving that differences, in fact, do exist between the isolates and the claimed TGF-B. The prior decision more completely explains the rationale underlying that holding.
Appellants have not provided side-by-side comparisons of TGF-B with the four isolates. They contend that it might be impossible to again isolate the same materials and, moreover, such is not necessary to demonstrate the required differences. Appellants contend that Todaro clearly discloses that the isolates therein are structurally homologous to MSA (multiplication-stimulating activity), that the chemical structure both of MSA and of TGF-B is now known and comparison of these known structures demonstrates that there is no identity, homology or relationship between these peptides. The argument continues that since Todaro's isolates are structurally homologous to MSA, the total lack of a relationship between MSA and TGF-B establishes that the isolates cannot be the same as TGF-B. Appellants further contend that TGF-B does not bind to MSA-specific receptors in the manner disclosed by Todaro for the relevant four isolates. Appellants rely on declarations by Dr. Sporn and Dr. Matthew Rechler as providing the necessary factual support for the above arguments.
The examiner has not found appellants' showings and arguments sufficient to establish actual differences, in fact, between the relevant four isolates and the presently claimed TGF-B. She notes that appellants contention that the isolates are structurally homologous to MSA constitutes unsupported allegation. She points out that the prior art merely states that the "disclosed protein is related to MSA." She further pointed out that the comparison relied on is with MSA and not the closest prior art, the isolates which are said to be related to MSA.
*4 We have carefully considered the respective positions of the examiner and the appellants, as well as the evidence relied on by each, in reaching our determination that the rejection over Todaro is free of reversible error and shall, therefore, be sustained.
Specifically with respect to appellants' position that the isolates are homologous with MSA, we note that the factual evidence in support thereof relies on the reported isolates capability "of reacting with the MSA-specific receptors and serving as a signal for cell division," and the assertion that the interaction with MSA-specific receptors suggests, to one of ordinary skill in the art, the homology of these isolates with MSA (Dr. Rechler's Declaration, Paragraph 8). The application file includes a Declaration of the inventors signed on January 17, 1986. Included as Exhibit B to that Declaration is a document which compares the chemical structure, including the sequencing of amino acids, of Epidermal Growth Factor (EGF) and Transforming Growth Factor- Alpha (TGF-a). A comparison of the amino acid sequencing of these materials establishes that there are no extensive areas of identical sequencing in the respective materials, indeed it is difficult to locate identical sequencing of any more than two adjacent amino acids in the respective materials. Exhibit A to that Declaration provides a tabulation of the chemical and physical properties of TGF-a and TGF-B. This tabulation reports that TGF-a "binds to EGF receptor" and is "homologous" with EGF. In view of the very limited degree of similar amino acid sequencing demonstrated by the provided structural formulas of, the designated "homologous", EGF and TGF-a compounds, we find that the isolates of Todaro could structurally differ substantially from MSA, even though they are related to the extent that they both compete for at least some of the same receptors (as do TGF-a and EGF). Accordingly, we find that the recognized structural differences between MSA and TGF-B are not probative of actual differences between Todaro's four isolates and the claimed TGF-B.
Appellants contend that side-by-side comparisons of Todaro's four isolates may be impossible due to the lack of certainty that the same isolates could again be extracted. Basically the argument is directed to the unavailability of these isolates for testing. However, it is clear from the record that Todaro's paper is based on work performed at The National Institutes of Health (NIH), which is within the Department of Health and Human Services, the assignee of the present case. Moreover, various bibliographies in the record show that the inventors, individually and jointly, have collaborated with Drs. Todaro and DeLarco on various technical publications in the past. [FN2] Appellants have not indicated why the four isolates might not be available for testing from Dr. Todaro or his associates, or, if they are no longer with NIH, from the laboratory at which they previously worked.
*5 While we do not mean to imply that side-by-side comparison to Todaro's isolates with TGF-B is absolutely necessary to establish the existence of differences in fact, we do feel that such is usually the most direct and, for that reason, most objective technique to establish such actual differences. We note appellants' contention herein that TGF-B does not bind to MSA-specific receptors in the manner disclosed by Todaro for the four isolates and that, therefore, the isolates must be different from TGF-B. To the extent that it is established that TGF-B performs differently than the isolates in procedures identical to those reported in Todaro, such would be indicative that the isolates are, in fact, different from TGF-B.
However, we find the evidence to be insufficient to establish that TGF-B performs differently than the isolates in the described tests. While Dr. Rechler, at paragraph 9 of his Declaration, states that "TGF-B does not bind to MSA-specific receptors in the manner disclosed by Todaro, et al. for the four (4) human fibrosarcoma cell isolates referred to above", the Declaration fails to provide any experimental or other support for the statement. In the absence of a showing of the experimental procedure and results on which Dr. Rechler's opinion is based, we are unable to conclude that actual differences between TGF-B and the subject isolates are established by the Declaration alone. See In re Thompson, 545 F.2d 1290, 192 USPQ 275 (CCPA 1976). Appellants, in their brief, cite the Brown publication (June 1987) as support for Dr. Rechler's statement. We have several problems with the sufficiency of the required support provided by this publication. The statement relied on states:
In addition, TGF-B failed to compete with 125 I-labeled IGF-I for binding to Swiss 3T3 cells (A.N. Corps. and K.D.B., unpublished observation). Page 3746.
In their brief, appellants state that 125 I-labeled IGF-I corresponds to MSA (Br-17). The record does not support appellants position that IGF-I corresponds to MSA. The record includes the previously referenced Marquardt publication which reports the authors comparison of MSA to two insulin-like growth factors (IGF-I and IGF-II). These authors report that the "absence of methionine in MSA and IGF-II distinguished these peptides from IGF-I" (page 6861). The authors went on to propose the term rat IGF-II for the MSA polypeptide. Therefore, the statement in the Brown publication, involving IGF-I, does not appear relevant to a demonstration that TGF-B does not perform in the same manner as reported for the four subject isolates. Moreover, we note that the statement relied on in Brown appears to be based on "unpublished observations." We are not willing to hold that opinions based on such "unpublished observations" are entitled to substantial weight in establishing the accuracy of the opinion stated. In the absence of a disclosure of the procedure leading to the observations, independent meaningful assessment of the probable validity of such observations is not possible. Just as with affidavits under 37 CFR 1.132, we are unable to assign conclusive weight to statements or opinions as to empirical results when the data supporting such statements is not provided for critical evaluation by the public or scientific community.
*6 Accordingly, we find that there is insufficient evidence of record to establish that TGF-B differs in fact from each of the four isolates described by Todaro. The rejection over Todaro is therefore affirmed.
We note that applicants have submitted several disclosure statements subsequent to the entry of the Examiner's Answer. We have not attempted to fully assess the relevance of the various disclosures provided in these statements, inasmuch as it is preferable that the examiner assess such in the first instance. We note, however, that the Moses and Leof, 1986 publication, indicates that TGF-B was first described in the Moses et al. 1981 article in Cancer Research. The examiner should fully consider the relevance of these publications in any further prosecution of the invention involved herein.
The examiner's decision is affirmed.
BOARD OF PATENT APPEALS AND INTERFERENCES
Saul I. Serota
Henry W. Tarring, II
William F. Smith
FN1. In the earlier Board decision, the rejection under 35 U.S.C. 112, was based, in part, on the first paragraph thereof, because the involved claims were drafted to include a class or family of isolated compounds, while the evidence indicated that the same compound was produced from the various isolates. The specification was found to not support claims directed to a family of compounds since only one compound was produced according to the preparation techniques described. The examiner does not appear to contend that the present claim is directed to a family of compounds, thereby exceeding the scope of enablement provided.
FN2. For instance,
Nature (Lond.), 295, pp. 417-419 (1982); N.Eng.J.Med., 303, pp. 878-880 (1980); J.Supramol.Struc., 15, pp. 287-301 (1981).