Ex Parte 7462489 et alDownload PDFPatent Trial and Appeal BoardJan 9, 201590011666 (P.T.A.B. Jan. 9, 2015) Copy Citation UNITED STATES PATENT AND TRADEMARKOFFICE 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. 90/011,666 05/02/2011 7462489 MPL-001-US 9737 27326 7590 01/09/2015 VANCE INTELLECTUAL PROPERTY, PC 5467 HILL TOP STREET CROZET, VA 22932-3167 EXAMINER CAMPELL, BRUCE R ART UNIT PAPER NUMBER 3991 MAIL DATE DELIVERY MODE 01/09/2015 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 PATENT TRIAL AND APPEAL BOARD __________ Ex parte MICROPARTICLES PROTEOMICS, LLC 1 APPELLANT __________ Appeal 2015-000153 Reexamination Control No. 90/011,666 Patent US 7,462,489 B2 Technology Center 3900 __________ Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and ROBERT A. POLLOCK, Administrative Patent Judges. POLLOCK, Administrative Patent Judge. DECISION ON APPEAL Appellants appeal under 35 U.S.C. §§ 134(b) and 306 from the Examiner’s rejections of claims 1–20. We have jurisdiction under 35 U.S.C. §§ 6(b)(2) and 306. We affirm. STATEMENT OF THE CASE A request for ex parte reexamination of the Ley Patent2 was filed on May 2, 2011. The request for ex parte reexamination was assigned 1 Appellant asserts that Microparticles Proteomics, LLC is the Real Party in Interest and assignee of the patent under reexamination. (App. Br. 3.) 2 Ley et al., US 7,462,489 B2, entitled “METHODS FOR IDENTIFYING AND ANALYZING BIOMARKERS FROM PLASMA-DERIVED MICROPARTICLES,” issued Appeal 2015-000153 Reexamination Control No. 90/011,666 Patent US 7,462,489 B2 2 Reexamination Control No. 90/011,666 on July 1, 2011. Claims 1–20 are on Appeal and can be found in the Claims Appendix of Appellant’s brief. The detection of proteins in human blood plasma is an important tool for evaluating the predisposition, presence, and progression of numerous clinical conditions. (Spec. 1:14–18.) However, common plasma proteins, such as albumin, fibrinogen, immunoglobulins, and transferrin, interfere with the detection of less abundant proteins and “[r]emoval of the ten most abundant proteins only increases the sensitivity by one order of magnitude, still leaving most proteins undetected.” (Id. at 1:32–42). Thus, although there may be 40,000 different proteins present in normal plasma, and another 500,000 proteins which may be present under a variety of clinical conditions, current methodology, based on 2D gels, liquid chromatography, and /or mass spectroscopy, has led to the detection of only about 500 different plasma proteins. (Id. at 1:18–32.) This “appears to be the limit of detection for the analysis of unfractionated plasma due to the dynamic range of these analytical methods.” (Id. at 1:29–34.) “The present invention provides methods for isolating, identifying, and analyzing microparticles derived from plasma, particularly platelet-poor plasma.” (Id. at 2:32–35). “Microparticles (MPs) are small subcellular membranous vesicles released by essentially all cell types, especially when activated or under stress.” (Id. at 1:43–45). “[S]ignificant evidence has accumulated to indicate that MPs contain a unique set of proteins and inflammatory factors that have important biological functions.” (Id. at 2:1– December 9, 2008, to Klaus F. Ley and David M. Smalley, based on Application No. 11/935,048, filed November 5, 2007. Appeal 2015-000153 Reexamination Control No. 90/011,666 Patent US 7,462,489 B2 3 3). “Many microparticles in plasma are derived from platelets, but it is believed that valuable information resides in plasma microparticles derived from other cells as well.” (Id. at 2:23–25.) “It is therefore desirable to find methods of identifying biomarkers in plasma microparticles that can be useful for diagnosing various diseases, disorders, and conditions.” (Id. at 2:26–28). Representative claim 1, the sole independent claim on appeal, reads as follows: 1. A method of identifying candidate biomarkers in the plasma microparticle sub-proteome, comprising: (a) isolating proteins from blood plasma microparticles obtained from at least one blood sample from a case and at least one blood sample from a control; (b) identifying the proteins; (c) applying a statistical test to measure the abundance of each protein identified; and, (d) determining the presence of positive and negative biomarkers by comparing the abundance of each protein identified in at least one case blood sample with the abundance of the same protein in at least one control blood sample. The following grounds of rejection are before us for review: The Examiner rejects claims 1–4, 6, 7, 9, 10, and 13–17 under 35 U.S.C. § 103(a) as unpatentable over the combination of Jin3 and Simak.4 3 Ming Jin, et al. Distinct Proteome Features of Plasma Microparticles, 5 PROTEOMICS 1940–1952 (2005). 4 Jan Simak, et al., Elevated Circulating Endothelial Membrane Microparticles in Paroxysmal Nocturnal Haemoglobinuria, 125 BR. J. HAEMATOL. 804–813 (2004). Appeal 2015-000153 Reexamination Control No. 90/011,666 Patent US 7,462,489 B2 4 The Examiner rejects claims 5, 8, 11, 12, and 18–20 under 35 U.S.C. § 103(a) as unpatentable over the combination of Jin and Simak as applied to claims 1–4, 6, 7, 9, 10, and 13–17 above, and further in view of Garcia,5 Liu,6 and Kim.7 FINDINGS OF FACT We have reviewed Appellant’s contentions that the Examiner erred in rejecting claims 1–20 as obvious in view of the art of record. (App. Br. 6– 20; Reply 5–14.) We disagree with Appellant’s conclusions and adopt as our own the factual findings and well-reasoned analysis set forth in the Examiner’s Answer. For emphasis, we highlight and address the following. FF1. The Examiner finds the claims on appeal drawn to “a method of identifying potentially useful biomarkers by quantitatively comparing the proteins found in plasma microparticles (MPs) of ‘case’ and ‘control’ subjects.” (Ans. 2; see also App. Br. 5.) “Claim 1 sets forth the basic method and dependent claims 2-20 detail specific steps in the isolation, identification and quantitation of the MP proteins (collectively referred to as the MP proteome).” (Ans. 2.) FF2. With regard to the method set forth in independent claim 1, the Examiner finds that “Jin performs all the recited steps except for 5 Benjamin A. Garcia, et al., The Platelet Microparticle Proteome, 4 J. PROTEOME RES. 1516–1521 (2005). 6 Hongbin Liu, et al., A Model for Random Sampling and Estimation of Relative Protein Abundance in Shotgun Proteomics, 76(14) ANAL. CHEM. 4193–4201 (2004). 7 Jeong Whun Kim, et al., Fas Ligand-Positive Membranous Vesicles Isolated from Sera of Patients with Oral Cancer Induce Apoptosis of Activated T Lymphocytes, 11 CLIN. CANCER RES. 1010–1020 (2005). Appeal 2015-000153 Reexamination Control No. 90/011,666 Patent US 7,462,489 B2 5 comparing ‘case’ samples with those obtained from control subjects.” (Id.) Jin isolated plasma MPs from healthy human subjects. The MPs were isolated from an MP-enriched plasma fraction obtained by centrifugation, then proteins were extracted from the MPs, separated by 2-D gel electrophoresis (one dimension being SDS-PAGE), quantified, and the most abundant plasma MP proteins identified by mass spectrometry (MS). Jin suggests that plasma MP proteins might include disease markers (p. 1940, col. 2). (Id.) FF3. Jin states that “The number of observed protein spots from the three MP 2-D gels (1021-1055) was consistently higher than that in each of the three plasma 2-D gels (296-360). Six 2-D gels of three MPs and three plasma were matched to the MP reference 2-D map and the relative densities of all protein spots quantified using ImageMaster software.” (Jin 1942–43.) “For each spot on the 2-D gel, the mean density was obtained along with a standard deviation for calculation of protein quantity.” (Id. at 1943.) The relative amounts of plasma MP proteins (normalized volume of each 2D gel spot by percent and standard deviation) are shown in Jin Figure 2. (Id. at 1944, see also Addendum Table 2.) FF4. Jin suggests the step of comparing “case” samples with those obtained from control subjects. (See id. at Figs. 2, 5.) Accordingly, Jin teaches that “the importance of plasma MPs in the regulation of many physiological processes and their potential values as a source of Appeal 2015-000153 Reexamination Control No. 90/011,666 Patent US 7,462,489 B2 6 disease markers are well-appreciated.” (Id. at 1946). Jin further states that: Proteomics provides a means to globally examine protein features and their changes in different pathophysiological conditions . . . However, the proteome of plasma MPs has yet to be described. Knowledge of basic protein constituents and their characteristics in healthy donors will create a basis for future investigation of MPs’ biology and clinical utility in disease diagnosis and disease prediction. The present study establishes groundwork for analysis of the plasma MP proteome. (Id. at 1941.) In disease states, MPs derived from the injured organ likely contain valuable markers for determining the site, type, and extent of disease pathology. (Id. at Abstract) Attempts to explore the blood plasma proteome and to discover new disease markers were initiated almost 30 years ago . . . Constant improvements in technology have allowed recent studies to resolve unprecedented numbers of plasma and serum proteins by applying various combinations of protein fractionation and analysis strategies (Id. at 1943.) With respect to protein detection sensitivity, 2-D gel analysis of MPs displayed greater than 1000 distinct protein spots, three times the number of protein spots obtained in 2-D gel analysis of whole plasma under analogous conditions. Therefore, it offers a novel method to detect many low-abundant proteins and examine their changes under various pathophysiological conditions. (Id. at 1946.) Appeal 2015-000153 Reexamination Control No. 90/011,666 Patent US 7,462,489 B2 7 It remains, however, undefined yet about the amount and cell origins of MPs in various disease states. Future proteomic analysis of plasma MPs in the patient population will provide significant insight into disease pathophysiology and potentially new diagnostic utilities. (Id.) Under pathological conditions, part of the MP population are cell membrane fragments that may be created by activated, apoptotic, or otherwise damaged cells from the site of injury . . . This exciting fact provides much promise for the clinical application of MP proteomics in the prediction and early diagnosis of diseases. Currently, our laboratories are engaged in establishing the biological variation of major MP proteins in the general population. A future project will be to translate knowledge of the MP proteome into clinical application and practice. (Id. at 1946–1947.) FF5. Simak teaches that MPs contain protein biomarkers for disease states and that “[a]n increasing number of recent studies have analyzed circulating blood cell, platelet, and endothelial cell MP [ECMP] in different vascular pathologies.” (Simak 808.) “MP of endothelial origin are of particular interest because of their possible diagnostic importance as increased counts of these MP could signal endothelial cell injury.” (Id.) FF6. Simak uses flow cytometry and antibodies against specific MP proteins to analyze “endothelial cell membrane microparticles (ECMP) in the peripheral blood of patients with paroxysmal nocturnal haemoglobinuria (PNH) (n = 9), aplastic anaemia (AA) (n = 10), sickle cell disease (SCD) (n = 8), and healthy donors (HD) (n = 11).” Appeal 2015-000153 Reexamination Control No. 90/011,666 Patent US 7,462,489 B2 8 (Id. at Summary.) Applying a “Kruskal-Wallis One Way Analysis of Variance on Ranks” for group comparisons (id. 806), Simak reports that “[t]he population of CD105+AVB+ ECMP was significantly (P < 0.05) higher” in SCD and PNH patients when compared to the healthy donors group (id. at Summary). “Even more pronounced differences were observed in ECMP exhibiting a marker of inflammatory stimulation CD54 (CD105+CD54+). Similarly, ECMP that exhibited endothelial specific and proteolysis-sensitive antigen CD144 were increased in SCD and PNH, but not in AA.” (Id.) FF7. “Simak explicitly compares plasma MPs from case (diseased) and control (healthy) subjects.” (See Ans. 11.) In particular, Simak discloses isolated endothelial cell MPs from healthy donors and donors suffering from various disease states. Endothelial cell MPs are a subset of plasma MPs identified by labeling MPs with antibodies against cellular antigens and quantified by flow cytometry. Several antigens were identified which appear to be markers for certain diseases. While different analytical methods were used, Simak’s results show that disease biomarkers can be found by comparing the proteins found in plasma MPs of healthy and diseased individuals. Specifically, MPs isolated from patients with paroxysmal nocturnal haemoglobinuria were found to contain elevated amounts of AVB and CD54 (p. 812). (Id. at 3) The Examiner concludes that: It would have been obvious to one of ordinary skill in the art to study the plasma MP proteome by the method of Jin in order to identify biomarkers for clinical conditions. It would have been obvious to compare control and “case” samples, given Jin’s explicit suggestion to do so. There Appeal 2015-000153 Reexamination Control No. 90/011,666 Patent US 7,462,489 B2 9 would have been a reasonable expectation of success given the knowledge that plasma MPs do contain proteins that can be used as biomarkers for certain disease states, as shown by Simak. Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made. (Id.) ANALYSIS Appellant’s arguments are directed to the combination of Jin and Simak as applied to claim 1. (See, e.g., App. Br. 5.) Claims 1–4, 6, 7, 9, 10, and 13–17 are argued together. (Id. at 6.) Appellant relies on the same arguments with respect to the rejection of claims 5, 8, 11–12, and 18–20. (Id. at 19–20.) Appellant contends that Jin is “not related to finding biomarkers, but instead is a paper that reported the results of surveying proteins from a pooled plasma sample from healthy donors.” (Id. at 8.) We do not find Appellant’s argument persuasive. “[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom.” In re Preda, 401 F.2d 825, 826 (CCPA 1968). Properly considered, Jin suggests far more than a mere survey of biomarkers in healthy donors. As set forth in FF2–4, and further detailed at pages 4 and 5 of the Examiner’s Answer, Jin emphasizes the importance of MPs “as a source of disease markers,” teaches that “Proteomics provides a means to globally examine protein features and their changes in different pathophysiological conditions,” and that states that “[i]n disease states, MPs derived from the Appeal 2015-000153 Reexamination Control No. 90/011,666 Patent US 7,462,489 B2 10 injured organ likely contain valuable markers for determining the site, type, and extent of disease pathology.” Considering the reference as a whole, we agree with the Examiner that not only does Jin suggest comparing MP protein biomarkers from case and control subjects, but “shows that those skilled in the art expected that disease markers would be found. In fact, the study reported in Jin was intended as the first step in this process.” (Ans. 5.) Moreover, that Simak expressly compares MP protein antigens in the plasma of diseased patients and healthy donors underscores the obviousness identifying candidate biomarkers in the plasma microparticle sub-proteome. (See FF5–7.)8 Appellants contend that “the technology of Jin was crude and extremely limited” as it could only identify 169 of the 260 most abundant MP protein spots on a 2D gel, and this represents only about 17% of the 2D spots from a “pooled sample.” (App. Br. 8–9.) These arguments do not persuade us that the Examiner erred in rejecting the claims on appeal. As an initial matter, we do not read the claims at issue to exclude the use of pooled samples. To the contrary, the language of independent claim 1 (“isolating proteins . . . from at least one blood sample from a case and at least one blood sample from a control”) appear to expressly contemplate such pooling. Nor do the claims require any particular level of sensitivity. 8 Simak assays known proteins in case and control MP populations to determine which, if any, provide biomarkers for diseases of interest, finding, for example, that the abundance of CD105 and AVB antigens were significantly higher in those from SCD and PNH patients as compared to healthy donors. We therefore reject Appellant’s argument that Simak “is entirely unrelated to looking for biomarkers in a case/control method.” (See App. Br. 16–17.) Appeal 2015-000153 Reexamination Control No. 90/011,666 Patent US 7,462,489 B2 11 (See Ans. 6–7.) Indeed, given the Examiner’s finding that the Ley Patent “also excluded unidentified and/or low abundance peptides (col. 11, lines 1– 9) . . . . and only identified 209 gene products (col. 15, lines 14–16)” (Ans. 6) out of more than 40,000 (or 500,000) potential target proteins (Spec. 1:18–23), it is not immediately apparent whether Appellant’s Specification would support an increased sensitivity as compared to the cited art. Finally, with respect to Appellant’s argument that Jin’s 2D gel system is somehow inapplicable because “Jin could only identify 17% of the reported spots” (Reply 7, see also Reply 18), we note that nothing in the claims requires the ability to identify every possible MP protein. Appellant contends that Jin does not “apply a statistical analysis to measure the abundance of each protein identified” as required by claim 1. (App. Br. 9–10; Reply 6–9.) Appellant first argues that the ImageMaster2D software used by Jin is not a statistical analysis at all, but “a straightforward algorithm that converts density of a 2-D gel into protein weight.” (App. Br. 9, 18.) In accord with the Examiner’s findings, we note that the Ley Patent broadly teaches the quantitation of protein abundance (claim step (c)) from mass spectrometer ion currents by “integrating the area under the curve for cases and controls.” (Spec. 6:4–6; Ans. 6–7.) Applying the broadest reasonable interpretation in light of the Specification, we agree with the Examiner that a mean and standard deviation implies a statistical test, such that claim step (c) is satisfied by Jin’s use of “optical density data from multiple gels to determine a mean and standard deviation (statistical Appeal 2015-000153 Reexamination Control No. 90/011,666 Patent US 7,462,489 B2 12 analysis) of the % normalized gel volume for each selected protein spot (see p. 1943, col. 2; pp. 1948–1952, far right column of Table 2).” (Ans. 7.) In the alternative, Appellant argues that, contrary to the language of claim 1, any statistical analysis taught by Jin is used on “unidentified proteins.” (App. Br. 9.) In other words, Appellant contends that the claims require that the identification and statistical quantitation steps be performed in a particular order, “which cannot be reversed.” (Reply 6.) “[T]o apply step (c), the statistical analysis to calculate abundance, the identities of the proteins in the case and control samples must be known.” (Id. at 8.) Moreover, “step (c), a statistical measurement of abundance of each identified protein, requires a comparison. This comparison must be between the case and control proteins in order for one to practice step (d), the determining of a positive or negative biomarker.” (Id.) We do not find Appellant’s arguments persuasive. First, step (c) does not require a comparison between case and control samples. Such a requirement would in fact be duplicative of the express language of step (d): “comparing the abundance of each protein identified in at least one case blood sample with the abundance of the same protein in at least one control blood sample.” Accordingly, the “abundance” of each protein in step (c) need not be measured relative to a case (or control) sample. Moreover, we agree with the Examiner that Appellant has not explained why one of ordinary skill in the art would not consider it obvious to apply a statistical test to measure the abundance of each protein before, as opposed to after, identifying it. (See Ans. 7–8 (“In this case, it does not Appeal 2015-000153 Reexamination Control No. 90/011,666 Patent US 7,462,489 B2 13 appear that the order of steps (quantitation and identification) would affect the results obtained.”).) Appellant fails to provide sufficient evidence or argument that the steps (c) and (d) – in either order–leads to anything other than predictable results. See KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 401 (2007) (the “combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”) We therefore find that the reasoning in Burhans applies. In Burhans, the Appellant identified four process steps, where each of the steps was disclosed in the prior art, differing only order of the steps. In re Burhans, 154 F.2d 690, 692 (CCPA 1946). The court was unpersuaded of patentability, finding that “[t]here is no merit in the point here in the absence of any proof in the record that the order of performing the steps produces any new and unexpected results.” Id. We conclude that the same reasoning applies in the instant case, where Jin teaches the application of a statistical test to measure the abundance of each protein prior to determining its identity. (See Ans 7–8; FF2–3.) In sum, the Examiner’s explanation provides sufficient factual basis and technical reasoning to support a determination that Jin, alone or in combination with Simak, renders obvious claims 1–4, 6, 7, 9, 10, and 13–17. Appellant has not rebutted the Examiner’s prima facie showing. Because Appellant provides no additional arguments with respect to claims 5, 8, 11– 12, and 18–20, which directly or indirectly depend from claim 1, those claims also fall with claim 1. Appeal 2015-000153 Reexamination Control No. 90/011,666 Patent US 7,462,489 B2 14 SUMMARY We affirm the rejection of claims 1–4, 6, 7, 9, 10, and 13–17 under 35 U.S.C. § 103(a) as unpatentable over the combination of Jin and Simak. We affirm the rejection of claims 5, 8, 11, 12, and 18–20 under 35 U.S.C. § 103(a) as unpatentable over the combination of Jin and Simak as applied to claims 1–4, 6, 7, 9, 10, and 13–17 above, and further in view of Garcia, Liu, and Kim. TIME PERIOD FOR RESPONSE Requests for extensions of time in this ex parte reexamination proceeding are governed by 37 C.F.R. § 1.550(c). See 37 C.F.R. § 41.50(f). AFFIRMED bar Copy with citationCopy as parenthetical citation