Exosomics Siena S.p.A.

Patent Trials and Appeals Board

Mar 14, 2022

2021001628 (P.T.A.B. Mar. 14, 2022)

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. 15/316,188 12/05/2016 Francesco LOZUPONE PI100294 1057 136012 7590 03/14/2022 Berggren LLP Leea S Somersalo 802 Lincoln ave Palmyra, NJ 08065 EXAMINER HALVORSON, MARK ART UNIT PAPER NUMBER 1642 NOTIFICATION DATE DELIVERY MODE 03/14/2022 ELECTRONIC 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. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): email@berggren-usa.com susanne.somersalo@berggren-usa.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte FRANCESCO LOZUPONE, ANTONIO CHIESI, PAOLO GUAZZI, NATASA ZAROVNI, PIETRO FERRUZZI, and DAVIDE ZOCCO Appeal 2021-001628 Application 15/316,188 Technology Center 1600 Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and RACHEL H. TOWNSEND, Administrative Patent Judges. TOWNSEND, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims to a diagnostic method for determining the presence of a tumor in a subject as being directed to patent ineligible subject matter and claims to a method for detecting and quantifying TM9SF4 and CD9 positive exosomes in a subject as being obvious. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 We use the word Appellant to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the real party in interest as Exosomics S.P.A. (Appeal Br. 3.) Appeal 2021-001628 Application 15/316,188 2 STATEMENT OF THE CASE Appellant’s Specification states: Exosomes are natural lipidic extra cellular nanovescicles produced and released by virtually all cell types in a finely regulated and functionally relevant manner so that the protein and mRNA composition reflects the type and condition of a parent cell. (Spec. 3.) Appellant’s Specification further notes that “exosomes originated from different tissues can be found in easily accessible biological fluids such as blood.” (Id.) In addition it is stated that “[g]iven their biological roles and features, exosomes are considered early sentinels of alterations in cell and tissue homeostasis and metabolism.” (Id.) The Specification states that there is “a need for extracellular vesicle biomarkers that are able to determine the presence of a tumour (be it benign, malignant and metastatic) or the transformation status of a tumour (benign to malignant and non- metastatic to metastatic).” (Id.) Appellant’s inventions are directed at isolating exosomes from a patient sample and analyzing them for the presence of certain compounds. Claims 1 and 28, reproduced below, are illustrative of the claimed subject matter: 1. A method for determining in vitro the presence of a tumour in a subject, such method comprising: a) providing a biological sample obtained from the subject, b) isolating extracellular vesicles from said sample, wherein this step of isolating extracellular vesicles comprises isolating TM9SF4-positive extracellular vesicles, Appeal 2021-001628 Application 15/316,188 3 c) determining from the extracellular vesicles isolated in step b), a level or a presence of a biomarker selected from a group consisting of CD9 protein and d) detecting by Sandwich ELISA, whether the biomarker determined in step c) is over-expressed in the biological sample relative to the biomarker level in healthy donors, wherein said detecting of the biomarker level of the CD9 protein determined in step c) by at least an approximate 7-fold increase in the subject compared to the level of the CD9 protein in the healthy donors determines the presence of the tumour in the subject. (Appeal Br.2 25). Independent claim 21 differs from claim 1 in the biomarker being detected, i.e., miR-21 rather than CD9, and the manner by which miR-21 is detected, i.e., PCR, and the fold increase that “determines the presence of the tumour in the subject,” i.e., 2-fold. (Id. at 28-29.) 28. A method for detecting and quantifying TM9SF4 and CD9 positive exosomes in a subject, such method comprising: a) providing a biological sample obtained from the subject, b) isolating extracellular vesicles from said sample, wherein this step of isolating extracellular vesicles comprises isolating TM9SF4-positive extracellular vesicles, and c) determining, from the extracellular vesicles isolated in step b), a level or a presence of a biomarker selected from a group consisting of CD9 protein. (Appeal Br. 29-30.) Independent claim 29 differs from claim 28 by reciting that the biomarker is “selected from a group consisting of miR-21.” (Id. at 30.) 2 Appellant filed a “revised” Appeal Brief on September 14, 2020 in response to a Notice of Non-Compliant Appeal Brief. This is the Appeal Brief to which we refer. Appeal 2021-001628 Application 15/316,188 4 The prior art relied upon by the Examiner is: Name Reference Date Klass et al. US 2010/0184046 A1 July 22, 2010 Lozupone et al. US 2012/0058492 A1 Mar. 8, 2012 The following grounds of rejection by the Examiner are before us on review: Claims 1-4, 21, and 25-27 are rejected under 35 U.S.C. § 101 because the claimed inventions are directed to non-statutory subject matter.3 Claims 28 and 29 under 35 U.S.C. § 103 as unpatentable over Klass and Lozupone. DISCUSSION Patent-Ineligible Subject Matter The Dispute The Examiner found that claims 1 and 21 recite a natural phenomenon “the level of CD9, miR-21, . . . on TM9SF4-positivie exosomes in a biological sample from a subject with a tumor.” (Final Action 2-3; Ans. 4.) In addition, the Examiner found that detecting “whether the biomarker determined in step c) is overexpressed in the biological sample relative to the biomarker level in healthy donors” is abstract in that it requires a comparison that “could be done by merely reviewing the data mentally and mentally comparing the levels of the biomarker.” (Id.) 3 The Examiner withdrew that rejection of claims 28 and 29 under this ground in the Answer. (Ans. 3.) Appeal 2021-001628 Application 15/316,188 5 The Examiner also found that the limitations “encompass[] mathematical equations or graphs which could be used to compare the levels of the biomarker[s].” (Final Action 3; Ans. 4.) The Examiner also provides an extensive discussion about the wherein clause involving mathematical equations. (Final Action 7-8; Ans. 7-8.) The Examiner next stated that the claims fail to integrate the judicial exception into a practical application. (Final Action 4.) In particular, the Examiner notes that the wherein clause which provides for the determination of the presence of a tumor by having determined that the level of the CD9 protein is at least an approximate 7-fold increase compared to that of healthy donors is not an integration of the exception but simply is a recitation of observing a value that denotes the presence of a tumor, which is the natural phenomenon. (Final Action 8; Ans. 7.)4 The Examiner explained that the active method steps of isolating TM9SF4-positive extracellular vesicles, and determining the presence of CD9 is well-understood, routine, and conventional activity engaged in by scientists to achieve the goals of the invention. (Final Action 9; Ans. 9.) Appellant contends that the claims “can certainly not be an abstract idea, a law of nature that only uses a natural correlation, and indeed does transform the method into a practical application.” (Appeal Br. 11.) According to Appellant that is because there are “specific claim elements essentially limiting the use of the judicial exception.” (Id.) Appellant urges 4 The Examiner provided an extensive discussion about the wherein clause involving mathematical equations. (Final Action 7-8.) We need not and do not rely on this in affirming the Examiner’s rejection. Appeal 2021-001628 Application 15/316,188 6 that capturing the TM9FS4 positive-carrying exosomes, quantifying them, and then determining the presence of a tumor in the investigated subject because a particular fold increase of the biomarker serve to limit the use of the exception. (Id.) Moreover, Appellant urges that these steps provide a practical utility because “thanks to the claimed biochemical assay methods, they solve inter alia the issue of potentially avoiding obtaining false positive cancer diagnostic outcomes.” (Id.) We address claims 1 and 21 below as Appellant’s arguments are only addressed to these independent claims on appeal. The Analysis The Supreme Court has established a two-step framework for “distinguishing patents that claim laws of nature, natural phenomena, and abstract ideas from those that claim patent-eligible applications of those concepts.” Alice Corp. v. CLS Bank Int’l, 573 U.S. 208, 217 (2014). “First, we determine whether the claims at issue are directed to” a patent-ineligible concept. Id. If so, “we consider the elements of each claim both individually and ‘as an ordered combination’ to determine whether the additional elements ‘transform the nature of the claim’ into a patent-eligible application.” Id. (quoting Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 78-79 (2012)). Applying the 2019 Revised Patent Subject Matter Eligibility Guidance (“Revised Guidance”), 84 Fed. Reg. 50-57 (January 7, 2019), we agree with the Examiner’s conclusion that the claims are addressed to ineligible subject matter. Under the Revised Guidance, we first determine whether the claim recites: Appeal 2021-001628 Application 15/316,188 7 (1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts; certain methods of organizing human activity such as a fundamental economic practice; or mental processes), a law of nature, or a natural phenomenon; and (2) additional elements that integrate the judicial exception into a practical application (see MPEP §§ 2106.05(a)-(c), (e)-(h)). See Revised Guidance, 84 Fed. Reg. at 52-55. Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then determine whether the claim: (3) adds a specific limitation beyond the judicial exception that is not a “well-understood, routine, conventional activity” in the field (see MPEP § 2106.05(d)); or (4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception. See Revised Guidance, 84 Fed. Reg. at 56. Revised Guidance Step 2(A), Prong 1 Under the Revised Guidance, in determining what concept a claim is “directed to” in step one of the Supreme Court’s two-step framework, we first look to whether the claim recites any judicial exceptions. We agree with the Examiner that claims 1 and 21 recite a natural phenomenon. The Revised Guidance identifies “a law of nature, or a natural phenomenon” as being among the judicial exceptions to patentability. 84 Fed. Reg. at 54. Appellant does not address the Examiner’s position that the claims recite a natural phenomenon. Instead, Appellant focuses only on the Examiner’s assertion that the claims recite a mathematical concept. (Appeal Br. 13-14.) We agree with Appellant that claims 1 and 21 do not recite a mathematical concept, but that does not end our assessment of whether the Appeal 2021-001628 Application 15/316,188 8 claims are directed to patent ineligible subject matter. That is because the claims, as the Examiner found, are directed to a natural phenomenon. Indeed, we find claims 1 and 21 analogous to those found ineligible in Athena Diagnostics, Inc. v. Mayo Collaborative Servs., LLC, 915 F.3d 743 (Fed. Cir. 2019) and in Cleveland Clinic Foundation v. True Health Diagnostics LLC, 859 F.3d 1352 (Fed. Cir. 2017). In particular, at issue in Athena was a method for diagnosing neurotransmission or developmental disorders related to MuSK in a mammal, the method “comprising the step of detecting in a bodily fluid of said mammal autoantibodies to an epitope of [MuSK]” (Claim 1) which involved contacting MuSK or an epitope or antigenic determinant thereof having a suitable label thereon, with said bodily fluid, immunoprecipitating any antibody/MuSK complex or antibody/MuSK epitope or antigenic determinant complex from said bodily fluid and monitoring for said label on any of said antibody/MuSK complex or antibody/MuSK epitope or antigen determinant complex, wherein the presence of said label is indicative [that] said mammal is suffering from said neurotransmission or developmental disorder related to [MuSK]. 915 F.3d at 747 (Claim 7). In Athena, the law of nature was the “correlation between the presence of naturally-occurring MuSK autoantibodies in bodily fluid and MuSK related neurological diseases like MG.” Id. at 750. The Federal Circuit explained that “[t]his correlation exists in nature apart from any human action.” Id. Appeal 2021-001628 Application 15/316,188 9 At issue in Cleveland Clinic was a claim for assessing a test subject’s risk of having a disease. The claim read: 11. A method of assessing a test subject’s risk of having atherosclerotic cardiovascular disease, comprising comparing levels of myeloperoxidase in a bodily sample from the test subject with levels of myeloperoxidase in comparable bodily samples from control subjects diagnosed as not having the disease, said bodily sample being blood, serum, plasma, blood leukocytes selected from the group consisting of neutrophils, monocytes, sub-populations of neutrophils, and sub-populations of monocytes, or any combination thereo[f]; wherein the levels of myeloperoxidase in the bodily from the test subject relative to the levels of [m]yeloperoxidase in the comparable bodily samples from control subjects is indicative of the extent of the test subject’s risk of having atherosclerotic cardiovascular disease. 859 F.3d at 1356. The Court in Cleveland Clinic explained: the testing patents purport to detect MPO and other MPO- related products, which are naturally occurring in bodily samples. The method then employs the natural relationship between those MPO values and predetermined or control values to predict a patient’s risk of developing or having cardiovascular disease. Thus, just like Ariosa, the method starts and ends with naturally occurring phenomena with no meaningful non-routine steps in between-the presence of MPO in a bodily sample is correlated to its relationship to cardiovascular disease. Id. at 1361. As such, the Court found the claims to be directed to a natural law. Id. Similarly, here, the correlation between the level of CD9 (claim 1), or the over-expression of miR-21 (claim 21), and the presence of a tumor in the subject exists apart from any human action. These claims recite a method in Appeal 2021-001628 Application 15/316,188 10 which a law of nature is observed, the presence of an elevated level of expression of a biomarker that is correlated to whether there is a tumor present in the subject. The steps to assess the presence and amount of the CD9 (or miR-21), of course, require human action, just as they did in Athena. However, as we discuss below, the presence of these steps that require human action do not overcome the fact that a natural law is stated by the claim, just as they did not in Athena. Revised Guidance Step 2(A), Prong 2 Having made the determination that claims 1 and 21 recite a natural law (i.e., a natural correlation/natural phenomenon), following the Revised Guidance, we next consider whether “the claim as a whole integrates the recited judicial exception into a practical application of the exception”; i.e., whether the claim “appl[ies], rel[ies] on, or use[s] the judicial exception in a manner that imposes a meaningful limit on the judicial exception.” Revised Guidance, 84 Fed. Reg. at 54. This analysis includes “[i]dentifying whether there are any additional elements recited in the claim beyond the judicial exception(s)” and “evaluating those additional elements individually and in combination to determine whether they integrate the exception into a practical application.” Id. at 54-55 (emphasis added). Here, the additional limitations of claim 1 are merely necessary steps undertaken to collect the biological sample and determine the presence and level of the biomarkers. Contrary to Appellant’s argument (Appeal Br. 11), this activity is not a practical application of the judicial exception. Rather it Appeal 2021-001628 Application 15/316,188 11 is pre-solution activity in that it is a data gathering step and that activity does not integrate the exception. The method begins with having a biological sample and ends with detecting that which is indicative of the presence of a tumor. The method does not require that any action be taken when the level of biomarker indicative of a tumor is detected. Like the claims in Athena and Cleveland Clinic, the method begins and ends with the natural correlation/natural phenomenon. Athena, 915 F.3d at 752 (“The claims here are directed to a natural law because they recite only the natural law together with standard techniques for observing it. That the routine steps are set forth with some specificity is not enough to change that conclusion.”); Cleveland Clinic, 859 F.3d at 1361 (“Cleveland Clinic’s invention thus involves ‘seeing’ MPO already present in a bodily sample and correlating that to cardiovascular disease. . . method then employs the natural relationship between those MPO values and predetermined or control values to predict a patient’s risk of developing or having cardiovascular disease. Thus. . . the method starts and ends with naturally occurring phenomena with no meaningful non-routine steps in between”); see also Mayo, 566 U.S. at 79-80 (claims ineligible where they “simply tell doctors to gather data from which they may draw an inference in light of the correlations”). While a concrete step is undertaken in the method, it is only effected so as to observe the operation of the natural correlation/natural phenomenon. See Athena, 915 F.3d at 751. The correlation between the presence of the biomarkers and the relationship with respect to relative amounts compared to healthy individuals as indicative of cancer is a law of nature, and cannot impart patentability to Appeal 2021-001628 Application 15/316,188 12 the claims even if it was previously unknown. Athena, 915 F.3d at 754. The process itself, not merely the recognition of the law of nature, must be new and useful. See Parker v. Flook, 437 U.S. 584, 591-95 (1978) (“[R]espondent’s claim is, in effect, comparable to a claim that the formula 2πr can be usefully applied in determining the circumference of a wheel.[] As the Court of Customs and Patent Appeals has explained, ‘if a claim is directed essentially to a method of calculating, using a mathematical formula, even if the solution is for a specific purpose, the claimed method is nonstatutory.’ In re Richman, 563 F.2d 1026, 1030 (1977).”). That is “to supply an inventive concept the sequence of claimed steps must do more than adapt a conventional assay to a newly discovered natural law; it must represent an inventive application beyond the discovery of the natural law itself.” Athena, 915 F.3d at 754. That the observation of the natural law “solve[s] the issue of potentially avoiding obtaining false positive cancer diagnostic outcomes” (Appeal Br. 11), is not an integration of the judicial exception in a manner that imposes a meaningful limit on the judicial exception. Essentially the claim merely tells those “interested in the subject about the correlations that the researchers discovered.” Mayo, 566 U.S. at 78. Accordingly, we conclude that neither claim 1 nor claim 21 integrate the natural law into a practical application. Revised Guidance Step 2(B) Finally, the Revised Guidance directs us to consider whether claim 1 includes “additional elements . . . [that] provide[] ‘significantly more’ than the recited judicial exception.” Revised Guidance, 84 Fed. Reg. at 56. The Appeal 2021-001628 Application 15/316,188 13 Revised Guidance states that an additional element that “simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, . . . is indicative that an inventive concept may not be present.” Id. Appellant does not contest the Examiner’s assertion that isolation of TM9SF4-positive extracellular vesicles and determining the presence of CD9 (or miR-21) involves well-understood, routine, and conventional activity engaged in by scientists. Appellant’s Specification corroborates the Examiner’s position that the detection and quantification methods are conventional activity. (Spec. 18-23 (describing standard methods of isolation by immunocapture, protein marker detection by standard sandwich ELISA assay, and quantification using PCR).) Thus, the only steps that are not part of the abstract idea recited in the claim are admittedly well-understood and conventional; patent eligibility cannot reside in those steps. See Cleveland Clinic, 859 F.3d at 1362. Even considering the steps of the claim as an ordered combination, we conclude that claim 1 (and claim 21) is directed to ineligible subject matter under 35 U.S.C. § 101. See, id. (“The claims, whether considered limitation-by- limitation or as a whole, do not sufficiently transform the natural existence of MPO in a bodily sample and its correlation to cardiovascular risk into a patentable invention.”). We consequently affirm the Examiner’s rejection that claim 1 and claim 21 are directed to patent-ineligible subject matter. Appellant does not argue claims 2-4 or 25-27 separately. Thus, those claims fall with claims 1 and 21. 37 C.F.R. § 41.37(c)(1)(iv). Appeal 2021-001628 Application 15/316,188 14 Obviousness The Examiner found that Klass teaches isolating exosomes from a biological sample with a capture antibody and detecting biomarkers on the exosomes, including CD9 and miR-21. (Final Action 7.) The Examiner recognized that Klass does not disclose isolating exosomes expressing TM9SF4 but determined that it would have been obvious to do so in light of Lozupone teaching isolating exosomes using antibodies to exosome proteins TM9SF4 as capture antibodies. (Id.) The Examiner explained that “both Klass and Lozupone 492 disclose detecting biomarkers such as CD9 on isolated exosomes” and it would have been obvious to “substitute Lozupone 492 ant[i]-TM9S4 capture antibody for Klass’s primary binding agent.” (Id. at 7-8.) We agree with the Examiner’s findings and conclusion of obviousness. Appellant’s claims 28 and 29 are directed to a method for isolating TM9SF4-positive exosomes and then determining a level or presence of a biomarker that is CD9 (claim 28) or miR-21 (claim 29). We note that these claims do not require determining a particular tumor type is present in the biological sample. The claims are also not restricted to a method in which only the specifically identified biomarkers, CD9 and miR- 21, are determined. These method claims use the transition phrase comprising. “The transition ‘comprising’ in a method claim indicates that the claim is open-ended and allows for additional steps.” Invitrogen Corp. v. Biocrest Mfg., L.P., 327 F.3d 1364, 1368 (Fed. Cir. 2003). Thus, even though the claims recite, in step c), that a particular biomarker “selected from a group consisting of” one particular compound is determined, the Appeal 2021-001628 Application 15/316,188 15 methods are not restricted to only detection of those compounds because there is nothing in the claim that indicates no other biomarker determination step is permitted. See Amgen, Inc. v. Amneal Pharms. LLC, 945 F.3d 1368, 1378-79 (Fed. Cir. 2020). Lozupone teaches that exosomes are microvesicles that are “actively secreted through an exocytosis pathway normally used for receptor discharge and intercellular cross-talk” and that several cell types “are known to be capable of releasing exosomes.” (Lozupone ¶¶ 5, 6.) Lozupone explains, though, that increased amount of exosome “in the peripheral circulation appears to be unique to pregnancy and to cancer.” (Id. ¶ 6.) Lozupone teaches that TM9SF4-protein (also called TUCAP1) is a specific marker of tumor derived exosomes from the plasma/serum of tumor patients. (Lozupone ¶ 18; see also id. ¶¶ 83, 86, 87, 88.) Lozupone also states that an object of the invention is to provide a method and a tool for detection of TM9SF4 bearing tumor exosomes in the plasma/serum of human patients for diagnosis of human tumor malignancies and patients’ follow up. (Id. ¶ 19.) And, Lozupone teaches the use of anti TM9SF4 antibodies as capture antibodies for tumor-specific exosomes. (See Lozupone ¶ 82; see also id. at claim 6.) Consequently, we do not find Appellant’s argument that Lozupone does not teach capture with an anti TM9SF antibody, and instead teaches detecting with such antibody (Appeal Br. 19) persuasive. Lozupone further teaches that after capture, “[q]uantification and characterization of exosomal proteins is subsequently performed by using appropriate detection antibodies against exosome associated antigens that Appeal 2021-001628 Application 15/316,188 16 can be either common for all exosomes or cell type- or cell condition specific.” (Lozupone ¶ 76.) Klass teaches a method in which exosomes from a sample are isolated by employing one or more binding agents where the binding agents “can be selected based on their specificity for a target antigen(s) that is specific to a cell-of-origin, tumor or disease.” (Klass ¶¶ 172, 174.) Klass teaches that “[c]irculating tumor-derived exosomes (CTEs) . . . are exosomes that are shed into circulation or bodily fluids from tumor cells.” (Id. ¶ 112.) Klass further notes that “CTEs as with cell-of-origin specific exosomes, typically have unique biomarkers that permit their isolation from bodily fluids in a highly specific manner.” (Id.) Klass further teaches that “[a]n enriched population of exosomes can be obtained from a biological sample. . . [including by] immunoabsorbent capture.” (Id. ¶ 116.) Klass teaches that the binding agent to isolate exosomes can be any known binding agent, such as one “that binds to exosomes derived from specific cell types, such as tumor cells . . . or specific cell-of-origins.” (Id. ¶ 129.) Klass further teaches that after isolation “[t]he method can include determining a bio-signature of an exosome in a biological sample . . . and characterizing a phenotype . . . based on the bio-signature.” (Id. ¶¶ 7-8; see also id. ¶¶ 681-684.) Klass explains further that there are a number of biomarkers that may be useful in determining a bio-signature, including CD9. (See e.g., id. ¶¶ 684, 779.) Klass also teaches that the biomarker can be an miRNA, such as miR-21 (Id. ¶¶ 325, 343, 349, 356, 412, 788). In light of the foregoing teachings of Klass and Lozupone, we agree with the Examiner that it would have been obvious to use anti TM9SF4 antibodies as tumor Appeal 2021-001628 Application 15/316,188 17 exosome capture antibodies as taught by Lozupone and to further analyze the exosomes for biosignature purposes as taught by Klass, including detecting the presence of CD9 or miR-21. See Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 335 (1945) (“Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put into the last opening in a jig-saw puzzle. It is not invention.”); see also Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (That a reference “discloses a multitude of effective combinations does not render any particular formulation less obvious.”). Appellant argues: A skilled artisan in cancer diagnostics would not have had the required motivation nor the impetus extracted from Klass’ and Lozupone’s disclosures with a reasonable expectation of success to specifically use (i) anti-CD9 antibodies as unequivocally the isolation antibody and (ii) subsequently use anti-TMSF4 antibodies as particularly the detection antibody. They are simply entirely silent in this regard. (Appeal Br. 20.) Appellant states: According to the pioneering features of the presently claimed embodiments of the invention is that the i) capturing must be conducted using anti-CD9 antibodies and ii) detection must be done using anti-TMSF4 antibodies as specifically shown in Figure 5. (Appeal Br. 19.) Appellant further points to the Declaration of Mr. Zocco in support of the foregoing. (Appeal Br. 20-21 (citing Declaration Under 37 C.F.R. § 1.132 signed by Mr. Zocco April 24, 2019).) We do not find the foregoing arguments persuasive as claims 28 and 29 are not directed to the Appeal 2021-001628 Application 15/316,188 18 use of anti-CD9 antibodies as isolation antibodies or using anti-TMSF4 antibodies for detection antibodies.5 Despite the foregoing, Appellant does also argue, consistent with what is required as an isolating antibody by claims 28 and 29, that one of ordinary skill in the art in cancer diagnostic development would have had no assurance that he/she could have arrived at the invention, as claimed, by modifying Klass’ method for isolating exosomes by using the antibody capturing system as disclosed by Lozupone and subsequently assessing the expression of CD9 and mIR-21 on TMSF4 positive exosomes with a reasonable expectation of success. (Appeal Br. 21.) Appellant contends that the Examiner has improperly relied on hindsight. (Id. at 21-22.) Appellant states that Klass does not provide the requisite motivation “to look for exactly the concept of employing TMSF-4 plus CD9 positive exosomes and TM9SF4 plus mIR-21 positive exosomes in Lozupone’s disclosure.” (Id.; see also Appeal Br. 24.) We do not find Appellant’s arguments persuasive. 5 We do see that in Mr. Zocco’s Declaration at page 3, paragraph 7, similar to the argument made by Appellant, Mr. Zocco states: Hence the essence of the present invention is that the i) isolation MUST BE done using anti-CD9 antibodies and ii) detection MUST BE done using anti-TMSF4 antibodies as disclosed specifically in paragraph [0149] and shown in FIG. 5. If the reverse is done, as disclosed particularly in paragraph [0160] and depicted in FIG. 16, the invention does not work according to its main principles. In other words, Mr. Zocco’s statement does not comport with the requirement of claim 28 that isolation is with anti-TM9SF4 antibodies and detection is effected thereafter with anti-CD9 antibodies. Appeal 2021-001628 Application 15/316,188 19 As already explained, Lozupone specifically teaches culling tumor- secreted exosomes from a biological sample by using anti-TM9SF4 antibodies. And Klass teaches a method for isolating specific exosome populations, be they cell-of-origin specific or tumor specific (Klass ¶ 129), and further analyzing those for biomarkers or bio-signature. Thus one of ordinary skill in the art would have been motivated explicitly from Lozupone’s teachings to isolate tumor-secreted exosomes from a biological sample with an anti-TM9SF4 antibody, and would have had a reasonable expectation of success in doing so. And, Klass teaches CD9 and miR-21 can serve as biomarkers on an exosome in different cancers. (See, e.g., Klass ¶¶ 683, 684, 703, 779 (CD9 prostate cancer)) and miR-21 (id. ¶ 337 (miR-21 breast cancer), ¶ 343 (miR-21 ovarian cancer), ¶ 349 (miR-21 lung cancer) ¶ 356 (miR-21 colon cancer).) One of ordinary skill in the art would have had a reasonable expectation that those same elements would serve as biomarkers of the tumor-secreted exosome population isolated by anti- TM9SF4 to the extent the population included a particular cancer in which those biomarkers may be found. Appellant does not provide any scientific basis for why this would not be the case. “Obviousness does not require absolute predictability of success. . . . For obviousness under § 103, all that is required is a reasonable expectation of success.” In re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988).6 6 Appellant raises arguments with respect to three references that the Examiner does not rely on in rejecting claims 28 and 29 in the Final Office Action or in the Answer. (Appeal Br. 22-23.) We note also that regarding the “species” election of colorectal cancer argument (id.), such is not applicable to claims 28 and 29, which are not directed to determining a Appeal 2021-001628 Application 15/316,188 20 Appellant’s argument that one of ordinary skill in the art would not have had a reasonable expectation of success in subsequently determining the level or presence of CD9 or mi-R21 in the isolated exosomes as claimed because Klass does not teach this “exact[ ] concept” (Appeal Br. 21) is not persuasive of non-obviousness. “Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references. . . . [The reference] must be read, not in isolation, but for what it fairly teaches in combination with the prior art as a whole.” In re Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986). In addition to the foregoing, Appellant suggests that the testimony of Mr. Zocco supports a finding of unexpected results over the prior art. (Appeal Br. 20). Aside from the apparent misstatement regarding the invention in the Zocco Declaration that we note in footnote 5 above, Mr. Zocco asserts “these [results in Figure 5 and Figure 16 of the Specification] are highly unexpected and surprising results over both Klass . . . and Lozupone . . . which respectively teach that an anti-CD9 antibody . . . and an anti-TM9SF4 antibody . . . can be used effectively BOTH for the capture and for the detection of exosomes.” (Zocco Decl. ¶ 7.) Mr. Zocco’s statement is conclusory and is insufficient to establish unexpected results regarding the claimed invention for the reasons we discuss below. “An expert opinion is no better than the soundness of the reasons supporting it.” tumor, but rather are directed to collecting a particular cohort of exosomes and determining whether that cohort includes exosomes where CD9 protein is present (claim 28) or miR-21 is present (claim 29). Appeal 2021-001628 Application 15/316,188 21 Perreira v. Sec’y of the Dept. of HHS, 33 F.3d 1375, 1377 n.6 (Fed. Cir. 1994); see also In re Beattie, 974 F.2d 1309, 1313 (Fed. Cir. 1992) (opinion evidence in declarations has little value without factual support); In re Buchner, 929 F.2d 660, 661 (Fed. Cir. 1991) (“[A]n expert’s opinion on the ultimate legal issue must be supported by something more than a conclusory statement.”). Mr. Zocco does not describe the experiments leading to the results depicted in Figures 5 or 16. The Specification also does not specifically describe the experiments leading to the results depicted in Figures 5 or 16. Indeed, there is only a generic description of ELISA assays for biological fluids in which TM9SF4 is coated on a plate and CD9 is used as a detection antibody in the Specification. (Spec. 21.) And, there is no description in the Specification of the method used that resulted in what is depicted in Figure 16. Moreover, we note that the populations tested of healthy individuals (HD) and of those with colorectal cancer (CRC) are vastly different in the two tests identified by Figures 5 and 16. Figure 5 reports N=200 for HD and N=103 for CRC whereas in Figure 16 the N for HD is 13 and the N for CRC is 9. In addition, Figure 5 reports, on the vertical axis, the Ratio to Background (i.e., dividing samples adsorbance values for the background value (Spec. 15)), whereas Figure 16 reports adsorbance values directly. “The Board has broad discretion as to the weight to give to declarations offered in the course of prosecution. See Velander v. Garner, 348 F.3d 1359, 1371 (Fed. Cir. 2003) (‘[A]ccord[ing] little weight to broad conclusory statements [in expert testimony before the Board] that it Appeal 2021-001628 Application 15/316,188 22 determined were unsupported by corroborating references [was] within the discretion of the trier of fact to give each item of evidence such weight as it feels appropriate.’).” In re Am. Acad. of Sci. Tech Ctr., 367 F.3d 1359, 1368 (Fed. Cir. 2004) (alterations in original). In light of the foregoing, and the lack of factual discussion by Mr. Zocco in his declaration regarding the experiments that resulted in the Figure 5 and Figure 16 reported results, we give Mr. Zocco’s Declaration very little weight on the issue of alleged unexpected results. For the reasons discussed, we affirm the Examiner’s rejection of claims 28 and 29 as being obvious from Klass and Lozupone. DECISION SUMMARY In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1-4, 21, 25- 27 101 Eligibility 1-4, 21, 25- 27 28, 29 103 Klass, Lozupone 28, 29 Overall Outcome 1-4, 21, 25- 29 TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R. § 1.136(a)(1)(iv) (2020). AFFIRMED