Ex Parte 6,964,850 et alDownload PDFBoard of Patent Appeals and InterferencesMay 19, 201195001032 (B.P.A.I. May. 19, 2011) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 95/001,032 03/17/2008 6,964,850 506612800900 3059 52059 7590 05/20/2011 LIFE TECHNOLOGIES CORPORATION C/O INTELLEVATE P.O. BOX 52050 MINNEAPOLIS, MN 55402 EXAMINER PONNALURI, PADMASHRI ART UNIT PAPER NUMBER 3991 MAIL DATE DELIVERY MODE 05/20/2011 PAPER Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES ____________ XDx, INC. Requester and Respondent v. Patent of SOURCE PRECISION MEDICINE, INC. Patent Owner and Appellant ____________ Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 Technology Center 3900 ____________ Before ROMULO H. DELMENDO, SALLY G. LANE, and RICHARD M. LEBOVITZ, Administrative Patent Judges. LEBOVITZ, Administrative Patent Judge. DECISION Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 2 This is a decision on appeal in an inter partes reexamination of U.S. Patent No. 6,964,850 B2. The Patent Owner appeals the Examiner’s decision to reject claims as obvious under 35 U.S.C. § 103. The Board’s jurisdiction for this appeal is under 35 U.S.C. §§ 6(b), 134, and 315. We affirm. STATEMENT OF THE CASE The patent in dispute in this appeal is U.S. Patent No. 6,964,850 B2, issued November 15, 2005 (hereinafter, “the ‘850 patent”). A request for inter partes reexamination of the ‘850 patent was filed on February 15, 2008 by a Third-Party Requester under 35 U.S.C. §§ 311- 318 and 37 C.F.R. §§ 1.902-1.997 (Request for Inter Partes Reexamination). The claims of the ‘850 patent involve methods of providing an index that is indicative of inflammation. The index is a numerical value which is derived from RNA measurements of various RNAs in a sample taken from a subject. There is one rejection in this appeal which is as follows: Claims 1, 2, and 27 stand rejected under 35 U.S.C. § 103(a) as obvious in view of Bull,1 Dugré,2 Bustin,3 and the Baker Declaration4 (Right 1 U.S. Patent No. 5,506,145, issued Apr. 9, 1996. , ,2 Francine J. Dugré et al., Cytokine and Cytotoxic Molecule Gene Expression Determined in Peripheral Blood Mononuclear Cells in the Diagnosis of Acute Renal Rejection, 70 TRANSPLANTATION 7, 1074-1080 (2000). 3 S.A. Bustin, Absolute Quantification of mRNA Using Real-time Reverse Transcription Polymerase Chain Reaction Assays, 25 J. MOLECULAR ENDOCRINOLOGY 169-193 (2000). 4 Declaration of Dr. Joffre Baker in Support of Request for Inter Partes Reexamintion, executed Jan. 4, 2008.. Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 3 of Appeal Notice (“RAN”) 4, dated February 26, 2010, incorporated by reference into the Examiner’s Answer, dated September 2, 2010). FINDINGS OF FACT5 (“FF”) Bull Patent 1. Bull teaches “a method for determining the presence or absence of an inflammatory condition in an individual by quantifying both the fibrinogen content and hematocrit in a sample of the individual’s blood, and calculating a composition Inflammation Index . . . derived from the two aforesaid variables.” (Col. 1, ll. 8-14.) 2. Bull discloses a general equation I = a(f) + b(h) + c for determining an individual’s inflammation index using fibrinogen level f, hematocrit or hemoglobin h, and empirically derived constants a, b, and c (col. 3, ll. 17- 22). 3. Bull teaches that the Inflammation Index is indicative of systemic inflammation in the donor of the blood sample (col. 4, ll. 7-10). Dugré 4. Dugré used RT-PCR (reverse transcriptase-polymerase chain reaction) to measure cytokine and cytotoxic mRNA expression in kidney transplant patients (p. 1074). 5. Dugré normalized the mRNA levels by beta-actin mRNA (p. 1076). 5 The findings of fact in this Decision are not limited to those enumerated in this section but may also be found in our Discussion below. Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 4 6. Dugré found “that acute rejection episodes in renal transplant recipients were associated with an increase in mRNA expression of cytokines” in blood cells (p. 1074, col. 1). Increased expression, or up regulation was measured for a given patient by comparing values at early post transplantation and at rejection episodes to produce differential expression values (p. 1076). 7. Dugré wrote that “Figure 1 shows that expression of IL-4, IL-5, and IL-6 mRNA measured in patients’ PBMC was significantly higher . . . at the time of acute rejection diagnosis compared with the signal levels determined in the first few days posttransplantation (early post-TX).” (P. 1077, col. 1.) 8. Dugré concluded that the “evaluation of pro-inflammatory cytokines and cytotoxic molecules prove useful in the clinical identification of acutely rejecting transplant recipients.” (P. 1074, col. 1.) Bustin 9. Bustin is a review article discussing quantification of mRNA using real-time RT-PCR (p. 169). 10. Bustin discloses that “[s]pecificity, sensitivity and reproducibility will be the most important qualitative characteristics for clinical diagnostic purposes (p. 170, col. 1). 11. Bustin teaches that the Mg2+ and dNTP concentrations require “strict control” and explains that Mg2+ dNTP mixtures affect the PCR reaction (p. 172, col. 1). Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 5 12. Bustin discussed non-competitive procedures in which “quantification can be unreliable, as the efficiencies of both the RT and PCR steps are likely to vary” and competitive PCR methods in which amplification is achieved “with the same efficiency” when the same primer recognition and internal sequences are shared between the internal standard and primary (p. 172, col. 2). 13. Bustin teaches that “[s]horter amplicons amplify more efficiently than longer ones and are more tolerant of reaction conditions.” (P. 178, col. 2.) 14. Bustin explained that the “concept of threshold cycle (Ct) is at the heart of accurate and reproducible quantification using fluorescence-based RT-PCR” (p. 179, col. 2). 15. Bustin “constructed standard curves for many target amplicons [regions amplified by PCR primers] and detected differences in both their amplification efficiencies and their sensitivities.” (P. 180, col. 2.) Bustin found that the amplification efficiency for eIF4e was similar to that of GAPDH (id.). 16. Bustin acknowledged that RT-PCR is characterized by variation and non-reproducibility, but describes parameters which influence it (p. 180- 181). 17. Bustin stated that “real-time RT-PCR assays are significantly less variable than any conventional RT-PCR procedure,” with a low coefficient of variation and with “variability . . . between 0 and 5%” (p. 181, cols. 1-2). 18. In describing multiplex RT-PCR – a process in which more than one target mRNA is detected by PCR in the same reaction using multiple Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 6 primer sets – Bustin stated that “successful multiplexing is never trivial and requires careful consideration about the suitability of both chemistry and instrumentation.” (P. 185, col.1.) 19. Bustin reported that the Taqman multiplex PCR system “has been used successfully to quantitate up to three . . . targets, with no apparent reduction in sensitivity compared with the individual reactions” (p. 185, col. 2). 20. Bustin concluded: The final difficulty is associated with limitations caused by mutual interference of multiple sets of PCR primers, which can reduce the dynamic range of the sensitivity and make quantification unreliable. (Id.) 21. Furthermore, the efficacy of multiplex detection is significantly affected by the extension time and the concentrations of dNTPs, primers and MgCl2. (Id.) 22. Vastly different levels of mRNA will cause quantification problems even for real-time detection . . . . (Id.) 23. Therefore, in practice, if the accurate quantification is the main aim, it is probably best to limit multiplexing to the detection of two or three transcripts. (Id.) Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 7 Perkin-Elmer User Bulletin #26 24. Perkin-Elmer describes methods for quantitating sample RNA or DNA using PCR and multiplex PCR (p. 1). 25. Before using the . . . method for quantitation, perform a validation experiment like that in Figure 6 to demonstrate the efficiencies of target and reference are approximately equal . . . If the efficiencies of the two systems are not equal, perform quantitation using the standard curve method. Alternatively, new primers can be designed and synthesized for the less efficient system to try to boost efficiency. (P. 14.) DISCUSSION Claim 1, which we have selected as representative of the claimed subject matter, is drawn to a method “of providing an index that is indicative of the state of a subject, as to a biological condition characterized by inflammation.” The method comprises: • “using amplification for measuring the amount of RNA of constituents from the sample of the subject” where the measurements of the constituents form a first dataset; • “wherein the measures for each constituent are performed under measurement conditions that are substantially repeatable”; • “the efficiencies of amplification for all constituents are substantially similar”; and 6 APPLIED BIOSYSTEMS, USER BULLETIN #2: ABI PRISM 7700 SEQUENCE DETECTION SYS. (1997). Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 8 • “applying values from said first profile to an index function . . . thereby providing a single-valued measure of the biological condition so as to produce art index pertinent to the biological condition of the subject.” The claim thus requires measuring more than one RNA (“RNA . . . constituents”) level in the same sample and using the measurements to create a single-value. The Examiner determined that the claimed method was obvious in view of the Bull patent and the Dugré and Bustin journal articles. The Examiner also relied upon a written declaration by Dr. Joffre Baker, a Ph.D. scientist who is currently Chief Scientific Officer of a company that conducts genomic research (Declaration of Dr. Joffre Baker, dated January 4, 2008). The Examiner found that the Bull patent described an “index function” (“Inflammatory Index”), derived from protein measurements, which served as a “single-valued measure of a biological condition” related to inflammation as required by claim 1 (RAN 5-7). The Examiner found that Bull differed from the claimed invention in measuring blood proteins rather than RNA constituents as in the claim (Id.). The Examiner found that the Dugré publication described measuring RNA of genes (“gene expression”) involved in inflammation by PCR amplification (id. at 7-8). The Examiner concluded that it would have been obvious to the ordinary skilled worker to use the method of studying gene expression levels taught by Dugré in the method of constructing an Inflammatory Index as taught by Bull, since both Dugré and Bull taught measuring gene expression levels for the purpose of detecting or predicting inflammation. (Id. at 8.) Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 9 The Examiner acknowledged that neither Bull nor Dugré taught the limitations of claim 1 “wherein the measures for each constituent are performed under measurement conditions that are substantially repeatable and the efficiencies of amplification for all constituents are substantially similar.” (RAN 8.) However, the Examiner found that these limitations would have been obvious in view of Bustin’s teaching about quantifying RNA levels and optimizing reactions to ensure efficient RNA amplification (id. at 8-9). In reaching this determination, the Examiner cited Dr. Baker’s written testimony about what Bustin taught (id. at 8). Appellant contends that the Examiner erred in determining that the claimed subject matter would have been obvious to the ordinary skilled worker in view of the cited prior art. Appellant contends: 1. None of the cited prior art references discloses or suggests the claim limitation “the efficiencies of amplification for all constituents are substantially similar” (App. Br. 11). 2. The combination of Bull with Dugré is internally inconsistent and based on hindsight (id. at 19). 3. Evidence of unexpected results in the patent was not appreciated by the Examiner (id. at 33). 1. The “efficiencies of amplification” limitation The ‘850 patent does not explicitly define the phrase “the efficiencies of amplification for all constituents are substantially similar.” However, the following disclosure in the ‘850 patent provides guidance: “Amplification” here refers to a degree of sensitivity and specificity of a quantitative assay technique. Accordingly, Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 10 amplification provides a measurement of concentrations of constituents that is evaluated under conditions wherein the efficiency of amplification and therefore the degree of sensitivity and reproducibility for measuring all constituents is substantially similar. (‘850 patent, col. 9, ll. 17-23.) it is desirable that a second criterion also be satisfied, namely that quantitative measurement of constituents is performed under conditions wherein efficiencies of amplification for all constituents are substantially similar (within one to two percent and typically one percent or less). When both of these criteria are satisfied, then measurement of the expression level of one constituent may be meaningfully compared with measurement of the expression level of another constituent in a given sample and from sample to sample. (Id. at col. 12, ll. 18-27.) Given a defined efficiency of amplification of target transcripts, the point (e.g., cycle number) that signal from amplified target template is detectable may be directly related to the amount of specific message transcript in the measured sample. (Id. at col. 14, ll. 26-30.) Based on the above disclosures, the ordinary skilled worker would have interpreted the claimed requirement that the amplification efficiencies are substantially similar to mean that the amplification reaction produces the same amount of product (e.g., DNA in PCR) for each RNA target (“within one to two percent” (col. 12, ll. 18-27)). When the efficiencies are comparable, “expression level of one constituent may be meaningfully compared with measurement of the expression level of another constituent in a given sample and from sample to sample.” (‘850 patent, col. 12, ll. 18-27.) There is sufficient evidence that the objective of achieving substantially similar amplification efficiencies for RNA constituents in the Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 11 same sample was taught in the prior art. Bustin described procedures in which amplification of more than one target RNA is achieved with the same efficiency (FF12) and described using shorter amplicons to amplify targets more efficiently (FF13). Bustin also taught detecting differences in “amplification efficiencies” for “many target amplicons” and found efficiencies similar for at least two different target RNAs (FF15). In multiplex RT-PCR, where more than one target RNA (i.e., “RNA constituents”) is measured in the same sample, Bustin reported success and discussed parameters for increasing efficacy and reliability of PCR detection (FF18, FF19, & FF21). Perkin-Elmer also described determining amplification efficiency of a target and reference, and to design new primers if “the efficiencies of the two systems are not equal” (FF25). Thus, the evidence shows that the ordinary skilled worker recognized amplification efficiency as a goal when measuring different RNA constituents from the same sample. Appellant contends that the Bull and Dugré publications are “utterly lacking in any teaching or suggestion” of the efficiency requirement (App. Br. 11). This argument has little merit since the Examiner acknowledged this difference, but rather relied on Bustin for this teaching. (RAN 8.) As for Bustin, Appellant contends that Bustin used normalization procedures in which an internal control is used to correct variations in PCR (App. Br. 12). Appellant also argues: Other than in connection with Fig. 6, where Bustin shows differing efficiencies of amplification for different genes, Bustin never addresses this circumstance in relation to measuring the amount of RNA amplification for each constituent in a panel of constituents. Bustin references Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 12 amplification efficiency only in the context of measuring transcription of a single target or a single PCR reaction. (Id.) Appellant contends that, in Bustin’s discussion about competitive and non-competitive amplification (FF12), Bustin was only concerned with measuring a single target, not RNA constituents (i.e., more than one target) in a sample, as claimed (App. Br. 13). Appellant contends that Bustin added a “control” to the sample which is “artificial and, therefore” is not an expressed product of a gene.” (Id.) This argument is not persuasive. The Examiner cited Bull and Dugré for suggesting the claimed limitation of “using amplification for measuring the amount of RNA of constituents from the sample of the subject.” (Claim 1, emphasis added.) Thus, even if it is accurate that Bustin did not suggest measuring RNA constituents from a single sample as claimed, this difference does not refute the rejection. Nonetheless, Appellant acknowledged that Bustin “talks about measurement of multiple constituents.” (App. Br. 15.) Appellant attempts to negate this disclosure by pointing out that Bustin shows dissimilar efficiencies of amplification. (Id.) Appellant insists that Bustin actually teaches away from achieving similar amplification efficiency because Bustin characterizes multiplexing as “never trivial” and identifies difficulty in achieving it (id.; FF18, FF20, & FF22). There are two issues here. The first issue is whether the ordinary skilled worker would have had reason to optimize the PCR reaction to achieve amplification efficiency. The second issue is whether optimization was enabled by the prior art at the time of the invention. Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 13 As to the first issue, we have already identified the findings of fact that support the Examiner’s position that amplification efficacy was an objective of the prior art (FF12, FF13, FF15, FF21, & FF25). As to the second issue of enablement, as discussed by the Examiner, there is sufficient evidence that the skilled worker knew how to optimize the amplification efficiency by adjusting magnesium concentrations, dNTP, primers, and amplicon target size (FF11, FF13, FF21, & FF25). Dr. Baker’s written expert testimony supports this position (Baker Decl., ¶ 24). Moreover, while Bustin acknowledges “difficulty” in multiplexing methods for measuring RNA constituents, the authors reported success (FF19) and suggested limiting measurement to two to three targets (“transcripts”) in a single reaction to achieve accuracy (FF23). Thus, while Bustin stated multiplexing was “never trivial,” Bustin went on to temper that statement by explaining that the conditions required “careful consideration” and then identified result-effective parameters (FF18, FF20, and FF21). Thus, it is apparent that Bustin believed it was within the ordinary level of skill in the art to accomplish accurate and efficient measurement of RNA constituents in the same sample. Appellant contends that the written declaration by co-inventor Danute Bankaitis-Davis (Declaration of Danute Bankaitis-Davis, dated July 16, 2008) establishes that “Bustin fails to teach the requirement herein of substantially similar efficiencies for all RNA constituents” (App. Br. 15). Dr. Bankaitis-Davis wrote in the declaration: Bustin notes matter-of-factly that differences in amplification efficiencies for different amplicons is a consequence of performing RT-PCR, and then proceeds to discuss normalization on pages 181-184 for how to correct for this after Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 14 the amplification measurement is already performed. Nowhere in Bustin is there any recognition that this is a problem that should be fixed if one wishes to obtain measurements with predictive value in molecular diagnostics. In addition, nowhere in Bustin is there any suggestion or teaching of how one might overcome such differences so that amplification efficiencies can be obtained that are substantially similar for all constituents. (Bankaitis-Davis, ¶ 12.) Beginning on page 181 of the publication, Bustin discusses normalization techniques for PCR. Dr. Bankaitis-Davis appears to take the position that normalizing values in a sample is an alternative to, or mutually exclusive from, adjusting amplification efficiencies in sample. However, Bankaitis-Davis did not provide an adequate explanation for this conclusion. To the contrary, in view of Bustin’s mention of amplification efficiency more than once, as well as the disclosure of it in Perkin-Elmer, it is evident, even if normalization was an alternative solution, that adjusting amplification efficiency was still recognized as a viable approach. Consistent with this factual evidence, Dr. Baker testified in a second written declaration that persons of ordinary skill in the art would have recognized amplification efficiency as a problem and would have known how to go about correcting it (Second Declaration of Dr. Joffre Baker, ¶¶ 24-34, dated August 18, 2008), a conclusion supported by the findings of fact in this record (FF11, FF13, FF15, FF18, FF21, FF23, & FF25). Appellant argues that Bustin teaches away from any hope that the amplification efficiencies described in the patent could be achieved (App. Br. 18). To support this position, Appellant cites various disclosures in Bustin which are said to establish that existing methods are unsatisfactory and do not achieve similar amplification efficiencies (id.). Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 15 We acknowledge that Bustin, indeed, points to difficulties in quantitating RNA. However, at the same time, Bustin expressly identifies parameters that can be adjusted to achieve better quantitation and amplification efficiency. We are unpersuaded that Bustin only describes quantifying and efficiency for one target, when there is explicit disclosure about multiplexing multiple RNA constituents successfully (FF19). The question, as we already stated, is one of enablement. The applicant has the burden of coming forward with evidence in rebuttal, when the prior art includes a method that appears, on its face, to be capable of producing the claimed composition. This burden may be met by presenting sufficient reason or authority or evidence, on the facts of the case, to show that the prior art method would not produce or would not be expected to produce the claimed subject matter. In re Kumar, 418 F.3d 1361, 1368 (Fed. Cir. 2005). In this case, Bustin reported that multiplexing PCR “has been used successfully to quantitate up to three . . . targets” and identifies factors to adjust PCR efficacy (FF19 & FF21). Similarly, Perkin-Elmer describes factors to boost amplification efficiency and accuracy (FF24 & FF25). Appellant did not provide adequate evidence that such factors would not have enabled the ordinary skilled worker to achieve substantially similar amplification efficiencies. Contrary to Appellant’s statements, Bustin expressly found amplification efficiency of two targets to be similar (FF15), cutting against Appellant’s position that there was no hope of achieving substantially similar amplification efficiencies as claimed. Moreover, as noted by the Requester, it appears that the ‘850 patent used methods in the prior art to achieve amplification efficiency, militating against a conclusion of non-enablement (Respondent Br. 8). For example: Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 16 For measuring the amount of a particular RNA in a sample, we have used methods known to one of ordinary skill in the art to extract and quantify transcribed RNA from a sample with respect to a constituent of a Gene Expression Panel. (See detailed protocols below. Also see PCT application publication number WO 98/24935 herein incorporated by reference for RNA analysis protocols). (‘850 patent, col. 14, ll. 3-10.) 2. The combination of Bull with Dugré is internally inconsistent and based on hindsight (App. Br. 19). a) Appellant contends that Bull’s protein disclosure cannot be combined with references dealing with measuring RNA constituents. Appellant argues that Bull’s test was intended to be “quick and easy,” and that applying it to RNA measurements would have made it “inoperable for its intended purpose.” (App. Br. 20-21.) Appellant asserts that Dugré uses measurements at different times from two different samples, not RNA measurements from a single sample as required by the claim. Appellant also contends that mRNA levels are poorly correlated with proteins levels, teaching away from combining Bull’s protein method with Dugré RNA method (id.). The Examiner’s reason for combining Bull and Dugré was that both prior art references dealt with measuring gene expression for the purpose of diagnosing an inflammatory condition (RAN 8). Bull looked at protein and Dugré looked at RNA. Appellant questions the characterization of Bull as describing “gene expression.” (Source Precision Rebuttal Br. 13.) However, to the extent that a protein is a product of a gene, the Examiner Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 17 correctly found that a protein is expressed by a gene and therefore representative of “gene expression.” Bull produced an “Inflammatory Index” using two protein variables (FF1 & FF2). Bull did not suggest adapting its Inflammatory Index to RNA. However, an obviousness “analysis need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 418 (2007). [T]he teaching, motivation, or suggestion may be implicit from the prior art as a whole, rather than expressly stated in the references. . . . The test for an implicit showing is what the combined teachings, knowledge of one of ordinary skill in the art, and the nature of the problem to be solved as a whole would have suggested to those of ordinary skill in the art. In re Kahn, 441 F.3d 977, 987-988 (Fed. Cir. 2006). Having found an “Inflammation Index” comprising two protein variables useful for determining an inflammatory condition, persons of ordinary skill in the art would have reasonably been motivated to apply the Bull teachings to RNA levels because the latter was another recognized measure of gene expression. Moreover, RNA levels had indeed been used by Dugré to look at inflammation associated with transplantation (FF4-FF8). There is no requirement for an explicit suggestion to have been made, as long as there is rationale for combining the teachings of the prior art, as there was here. The argument that adapting Bull’s protein index to RNA would have run contrary to Bull’s teaching about an easy and quick test puts improper Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 18 emphasis on Bull. The question in an obviousness analysis is what the prior art as a whole would have suggested to the skilled worker. Kahn, 441 F.3d at 987-988. Even were it true that Bull’s protein has certain advantages that would not be achieved with an RNA test, Dugré provides evidence that RNA expression levels were recognized in the prior art as valid markers for predictive diagnosis,7 giving the ordinary skilled worker reason to use it. According to Dr. Sidney Hecht, a Ph.D. scientist “well acquainted with RNA expression and regulation,” “there is a good reason to believe from first principles that the use of proteins as the basis for creating indexes suitable to monitor specific biological conditions will not correlate well in many cases with the results obtained monitoring RNA levels for those proteins.” (Declaration of Sidney M. Hecht, July 17, 2008, ¶¶ 10 & 18.) Dr. Hecht explained this lack of correlation as due to the presence of riboswitches and other RNA types (id.). In this specific case, as noted by Dr. Baker in his written declaration, cytokine protein levels had been known to be associated with inflammation (Baker Decl., ¶ 21). This provided Dugré with a reason to study the corresponding RNA expression levels (p. 1074). Moreover, Dugré wrote: Recently, gene expression of cytolytic molecules as well as the cytokine transcripts [RNA], determined in peripheral blood 7 The ‘850 patent acknowledged that the “prior art has utilized gene expression data to determine the presence or absence of particular markers as diagnostic of a particular condition.” (Col. 1, ll. 21-24.) Gene expression is defined in the ‘850 patent as RNA or protein, and thus the relative interchangeability of the two biomolecules appears to have been recognized by Appellant. Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 19 lymphocytes of patients, have been found correlated with their intragraft mRNA during allograft rejection. (P. 1074, col. 2.) [FF27.] Thus, both proteins and RNA were recognized in the context of inflammation (e.g., transplant rejection) as useful variables to measure. The claims require measuring RNA constituents from one sample and using that information to derive an inflammatory index. Appellant repeatedly argues that Dugré utilized two samples in its analysis, while Bull used only one. For this reason, Appellant contends that it would not have been obvious to have combined the two prior art references for diagnostic purposes. It is true Dugré measured RNA constituent levels from different genes in two different samples (after transplantation and during acute rejection) for the same subject. While Dugré compared the RNA levels in the two different samples to produce a “differential expression” value (p. 1076, col. 2; FF6), it cannot be ignored that Dugré first measured “the amount of RNA of constituents from the sample of a subject,” the same step recited in claim 1. This data was reported by Dugré in Figure 1 and discussed (FF7). In sum, Dugré considered the levels of RNA constituents from one sample relevant to his analysis. b) Appellant contends Dugré’s method “raises a question to the person of ordinary skill in the art whether the gene expression value of a sample from a patient at any given time, taken by itself, is even useful.” (App. Br. 24.) To support this position, Appellant directs attention to Dugré’s Figure 1. Figure 1 shows expression levels of the different genes shortly after kidney transplantation (from a first sample) and then at the time Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 20 of acute rejection (from a second sample). Focusing on the expression levels of IL-4, Appellant asserts that at least one of the baseline values (following kidney transplantation, but before acute rejection diagnosis) was higher than all but one of the RNA levels at the time of acute rejection – and thus is not a reliable baseline.8 Appellant also states that some of the RNA levels at the time of acute rejection were about the same as the baseline level. Because of this variability, Appellant contends that the skilled worker would not have expected any single value to be useful for predicting a disease or condition. We do not dispute Appellant’s observation that Figure 1 of Dugré shows that baselines levels (early post-transplantation) for RNAs said to be up-regulated during an acute transplantation rejection were not uniformly lower than the RNA levels measured at the time of acute rejection. For example, for IL-4, at least one baseline value measured shortly after transplantation was higher than several values measured at acute rejection (App. Br. 23-25). Additionally, several of the acute rejection levels appeared to be about the same as the baseline levels (id.). Based on this data, Appellant argues: Dugré's data do not permit inference about an individual's biological condition based solely on gene expression measurements determined from a single sample from the subject. Consequently, to a person of ordinary skill in the art, Dugré teaches that gene expression measurements from a sample taken on a single occasion are not informative of biological condition because they have too great a range of variation. Dugré further teaches that such measurements need to 8 Appellant’s position is that baseline RNA levels should be lower than all the acute rejection levels in genes characterized by Dugré as being up- regulated. Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 21 be put in context by a comparison with another set of measurements from another sample taken, on a different occasion, from the same subject, so that a comparison can be made to identify a change in gene expression in the subject caused by different conditions on the two occasions. (Id. at 25-26.) Despite the “variation” in data noted by Appellant, there are values in Dugré’s reported experiments in which the individual RNA levels during acute rejection were higher than baseline levels. Appellant did not deny this fact. Thus, in at least several cases, the ordinary skilled worker would have recognized that individual RNA levels for a particular gene were indicative of the inflammatory state. This conclusion is additionally reflected in Dugré’s statement that “Expression of IL-4, IL-5, and IL-6 mRNA was significantly higher at the time of acute rejection than during the first few days post-TX [transplantation].” (Dugré at p. 1078; see also FF7.) There was therefore a general trend in the data in which individual RNA levels during the acute rejection phase were higher for IL-4, IL-5, and IL-6 than at baseline. Based on Dugré’s own conclusion coupled with the general trend in the data, the ordinary skilled worker would have reasonably expected that single values for IL-4, IL-5, and IL-6 RNA would be pertinent to the inflammatory condition of the subject patient. According to Dr. Hecht, “[f]alse positive and negative rates of the order described in [Dugré] argue against the utility of the method as described.” (Hecht Decl. ¶ 19.) We have given consideration to Dr. Hecht’s opinion, but do not find it persuasive. Specifically, statements by Dugré lead the other way. Dugré wrote in the Discussion section (p. 1079) [FF28]: Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 22 The up-regulation of . . . IL-4 [etc.] . . . might be a potential indicator of a rejection event . . . In the perspective of confirming their usefulness as a prognostic tool in clinical rejection, we are applying this protocol to new transplant patients. Thus, while Dugré characterized its results as a “potential indicator of a rejection event,” Dugré still considered the results reliable enough to apply to a new clinical trial. The standard applied by Appellant appears to be too stringent, requiring absolute proof that the prior art method worked 100% of the time to have been considered by the ordinary skilled worker as useful. To the contrary, Dugré’s own statement indicates that even preliminary results were sufficient in this case to give the ordinary skilled worker a reasonable basis to believe that the method was a useful diagnostic tool, including the individual RNA levels measured during acute transplant rejection. 3. Unexpected Results In making an obviousness determination, the Supreme Court instructs us “to look at any secondary considerations that would prove instructive.” KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 415 (2007). Appellant states that the ‘850 patent Specification shows evidence of “unexpected results,” a secondary consideration which Appellant contends was unappreciated by the Examiner (App. Br. 33). According to Appellant, the unexpected results, among other things, show that an inflammatory index requires only a single sample using RNA measurements, and that the index provides a reliable measure of the extent of disease, and enables monitoring, tracking and quantitative assessment of therapies used to treat the disease (id. at 41-42). Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 23 Appellant also contends that the RNA expression levels obtained by its method are tightly regulated and normally distributed (id.). While secondary considerations must always be considered in making an obviousness determination, they are not dispositive, but must be weighed against other indices of obviousness. The existence of such evidence, however, does not control the obviousness determination. See Newell, 864 F.2d at 768 (“First, as indicated, obviousness is not a factual inference; second, although these factors must be considered, they do not control the obviousness conclusion.”) (citations omitted); Ryko, 950 F.2d at 719 (the weight of secondary considerations may be of insufficient weight to override a determination of obviousness based on primary considerations). Therefore, we must consider all of the evidence under the Graham factors before reaching our decision. Richardson-Vicks, Inc. v. The Upjohn Co., 122 F.3d 1476, 1483 (Fed. Cir. 1997). Because Appellant contends that the results obtained by the claimed method are “unexpected,” we first look at the relevant legal principles to be considered when establishing unexpected results. According to In re Soni, 54 F.3d 746, 750-51 (Fed. Cir. 1995), prima facie obviousness can be rebutted with a showing of “unexpected results,” i.e., to show that the claimed invention exhibits some superior property or advantage that a person of ordinary skill in the relevant art would have found surprising or unexpected. The basic principle behind this rule is straightforward - that which would have been surprising to a person of ordinary skill in a particular art would not have been obvious. . . . . Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 24 [W]hen an applicant demonstrates substantially improved results, as Soni did here, and states that the results were unexpected, this should suffice to establish unexpected results in the absence of evidence to the contrary. In this case, there is limited testimony by persons of ordinary skill in the art that the claimed method produced unexpected results. At column 11, lines 61-63 of the ‘850 patent, it is stated: We have found that valuable and unexpected results may be achieved when the quantitative measurement of constituents is performed under repeatable conditions. However, the need for reproducibility was recognized by Bustin (Abstract; FF10, FF14, & FF17). Bustin stated that optimization and consistency were critical for obtaining reproducible results, and described real-time RT-PCR Taqman assays as having a low coefficient of variation (p. 181; FF10, FF16, & FF17). Thus, as found by the Examiner, Bustin described a reproducible method for measuring RNA levels (RAN 8), the same result which Appellant now characterizes as “unexpected.” Therefore, the property characterized as “unexpected” would have been possessed by the prior art and consequently is not a persuasive basis to establish non- obviousness. As stated in In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991): Baxter argues that the unexpected hemolysis-suppression quality of DEHP rebuts any prima facie showing of obviousness. However, when unexpected results are used as with the closest prior art. . . . Since the prior art bags plasticized with DEHP were inherently suppressing hemolysis, albeit unknown at the time of the Becker document, this hemolysis-suppressing function is not a basis for rebutting a prima facie finding of obviousness. Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 25 Appellant’s “unexpected results” boil down to the demonstration that a method of providing an inflammatory index, based on RNA constituents in a single sample from a subject, predicts inflammation in a specific disease with a high degree of confidence. The issue is whether there was a reasonable expectation that the claimed method, using RNA, could be arrived at successfully based on the prior art. The evidence put forward by the Examiner shows: • Bull’s teaching of an Inflammatory Index based on two protein variables; • Dugré’s teachings that RNA levels had been used as a marker for inflammatory disease, albeit not as a composition index as shown in the Bull patent publication; and • The prior art (Dugré and Bustin) enabled producing reproducible quantification of mRNAs with similar amplification efficiencies. Bustin, contrary to Appellant’s arguments, describes reproducibility and amplification efficiency as desired outcomes in PCR (FF10, FF13, FF17), identified process parameters (FF11, FF13, FF21), and acknowledged that multiplexing had been used “successfully to quantitate up to three . . . targets, with no apparent reduction in sensitivity as compared with the individual reactions” (FF19). In view of such disclosures, the Examiner had a credible basis to shift the burden to Appellant to show evidence of a lack of expectation of success. We find Appellant’s evidence unavailing. As already discussed, Dugré showed a general trend in its single-point data toward high RNA Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 26 levels during acute rejection, providing evidence that success would be expected. Success does not have to be guaranteed as long as the skilled worker would have perceived a reasonable likelihood of success. Alza Corp. v. Mylan Labs., Inc., 464 F.3d 1286, 1295 (Fed. Cir. 2006). Secondly, both Bustin and Perkin-Elmer, as mentioned above, provided evidence that parameters were known in the prior art about how to achieve reproducibility and amplification efficiency. Appellant has not established through objective evidence that such parameters would not work. We have considered the testimony of Dr. Bankaitis-Davis and others on this issue, but do not find that it outweighs the factual evidence in the Bustin and Perkin-Elmer publications. For example, Dr. Bankaitis-Davis stated that “Bustin never discusses or suggests measurements conditions wherein the efficiencies for all constituents are substantially similar, except to teach away from this claim limitation” (Bankaitis-Davis Decl. ¶ 9). However, Bustin, in fact, refers to targets having similar amplification efficiency (FF15), a statement that Dr. Bankaitis-Davis did not address in the declaration. Dr. Bankaitis-Davis also said that “even today the industry still does not understand that amplification efficiencies for all constituents should be substantially similar.” (Bankaitis- Davis Decl. ¶ 14). However, this conclusion appears inconsistent with statements in Bustin about efficiencies, and Perkin-Elmer’s instruction (FF24): If the efficiencies of the two systems are not equal, perform quantitation using the standard curve method. Alternatively, new primers can be designed and synthesized for the less efficient system to try to boost efficiency. Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 27 The Bankaitis-Davis Declaration reported that amplification efficiencies were not consistent across ABI reagent lots (¶ 19). This evidence does not establish a lack of a reasonable likelihood of success. First, Dr. Bankaitis-Davis did not indicate that the ABI lots and experiments were prior art. Second, and independently, both Bustin and Perkin-Elmer recognized that amplification efficiency might be different for different samples, and indicated that optimization had to be done if such differences were found. SUMMARY We affirm the Examiner’s rejection of claims 1, 2, and 27 under 35 U.S.C. § 103(a) as obvious in view of Bull, Dugré, Bustin, and the Baker Declaration. TIME PERIOD FOR RESPONSE Requests for extensions of time in this inter partes reexamination proceeding are governed by 37 C.F.R. § 1.956. See 37 C.F.R. § 41.79. AFFIRMED bim Appeal 2011-005235 Reexamination Control 95/001,032 Patent 6,964,850 B2 28 FOR PATENT OWNER: SUNSTEIN, KANN, MURPHY & TIMBERS, LLP 125 SUMMER STREET BOSTON, MA 02110 FOR THIRD-PARTY REQUESTER: MORRISON & FOERSTER, LLP 1650 TYSONS BOULEVARD SUITE 400 MCLEAN, VA 22102 Copy with citationCopy as parenthetical citation