Georgia State University Research of Foundation, Inc.Download PDFPatent Trials and Appeals BoardApr 14, 20212020005199 (P.T.A.B. Apr. 14, 2021) 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. 14/400,846 11/13/2014 Gangli Wang GSURF 2012-11 8469 23579 7590 04/14/2021 PABST PATENT GROUP LLP 1545 PEACHTREE STREET NE SUITE 320 ATLANTA, GA 30309 EXAMINER LAMBERSKI, JENNIFER A ART UNIT PAPER NUMBER 1618 NOTIFICATION DATE DELIVERY MODE 04/14/2021 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): docketing@pabstpatent.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte GANGLI WANG, ZHENGHUA TANG, CECIL CONROY, and TARUSHEE AHUJA Appeal 2020-005199 Application 14/400,846 Technology Center 1600 ____________ Before ERIC B. GRIMES, RICHARD M. LEBOVITZ, and FRANCISCO C. PRATS, Administrative Patent Judges. LEBOVITZ, Administrative Patent Judge. DECISION ON APPEAL The Examiner rejected claims 1–16, 18–20, and 32–35 under 35 U.S.C. § 103 as obvious. Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject the claims. We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. 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 Georgia State University Research Foundation, Inc. Appeal Br. 2. Appeal 2020-005199 Application 14/400,846 2 STATEMENT OF THE CASE The Examiner rejected claims 1–16, 18–20, and 32–35 in the Final Office Action as follows: 1. Claims 1–4, 6–8, 12, 13, 16, and 32–34 under 35 U.S.C. § 103(a) as obvious in view of Wang et al., J. Phys. Chem. B, 2006, 110, 20282–20289 (“Wang–1”). Final Act. 5.2 2. Claims 1–8, 11–13, 16, and 32–35 under 35 U.S.C. § 103(a) as obvious over Wang–1, Lim et al., Nanotechnology, 20:405701, 2009 (“Lim”), and Liu et al., Sci. China Chem., 54: 1157–1176, 2011 (“Liu”). Final Act. 8. 3. Claims 1–4, 6–10, 12, 13, 16, and 32–35 under 35 U.S.C. § 103(a) as obvious in view of Wang–1 and Hostetler et al., J. Am. Chem. Soc., 120:9396–9397, 1998 (“Hostetler”). Final Act. 9. 4. Claims 1–4, 6–8, 12–16, and 32–35 under 35 U.S.C. § 103(a) as obvious in view of Wang-1, Jupally et al., J. Am. Chem. Soc., 133:20258– 20266, 2011 (“Jupally”), and U.S. Published Application No. US 2006/0286305 Al to Thies et al., published Dec. 21, 2006, (“Thies”). Final Act. 10. 5. Claims 1–4, 6–8, 12, 13, 16, 18, 19, and 32–34 under 35 U.S.C. § 103(a) as obvious in view of Wang-1 and de la Fuente, et al., Langmuir, 22:3286–3293, 2006 (“Fuente”). Final Act. 10. 6. Claims 1–4, 6–8, 12, 13, 16, 20, and 32–34 under 35 U.S.C. § 103(a) as obvious in view of Wang-1 and Zhang et al., Bioorg. Med. Chem., 18:5528–5534, 2010 (“Zhang”). Final Act. 11. 2 The alternative ground of this rejection under 35 U.S.C. § 102(b) was withdrawn by the Examiner. Ans. 9. Appeal 2020-005199 Application 14/400,846 3 Claim 1, the only independent claim on appeal, is reproduced below: 1. Monolayer protected nanoclusters comprising clusters and a monolayer comprising a plurality of ligands bound to the clusters, wherein the plurality of ligands comprises one or more ligands selected from the group consisting of mercaptosuccinic acid, tiopronin, dithiols, and combinations thereof, and wherein the monolayer protected nanoclusters display near-IR luminescence with a quantum efficiency that is greater than 1%. Appeal Br. 35 (Claims App.). An oral hearing was held in this appeal on March 2, 2021. A transcript of the hearing has been entered into the record. REJECTIONS Claim 1 is directed to a monolayer protected nanocluster, referred to as an “MPC” throughout this decision and in the cited publications. The claimed MPC comprises “clusters” and a “monolayer” of ligands bound to the clusters. The claim requires the ligands to be one of three choices, mercaptosuccinic acid (“MSA”), tiopronin, dithiols, and combinations thereof. Each of these ligands comprises sulfur. The MPCs display near-IR luminescence with a quantum efficiency (“QE”) that is greater than 1%. The claim does not limit the type of “clusters” comprising the MPC with the recited QE property, but dependent claim 3 lists the clusters as comprising “metal atoms or mixtures of metal atoms, metal oxides, metal atoms bridged by non-metallic elements, and combinations thereof” and dependent claim 4 lists the metal as selected from “aluminum, tin, Appeal 2020-005199 Application 14/400,846 4 magnesium, gold, copper, nickel, iron, cobalt, magnesium, platinum, palladium, iridium, vanadium, silver, rhodium, ruthenium, and combinations thereof.” The Specification does not provide a definition of quantum efficiency. However, based on disclosure in the Specification, the prior art cited in this appeal, and the Zheng Declaration,3 we understand that a high quantum efficiency is desirable because it bears a relationship to the light emission intensity of the MPC, and a high light emission intensity is a desirable property of an MPC. Spec. 18:1, 34: 21–22; Wang-1, 20284 (right col., 1st full para.), Zheng Decl. ¶ 8. The claimed MPCs are required by the claim to display Near-infra red (“Near-IR”) luminescence which is defined in the Specification as follows: “Near-infra red” and “Near-IR” are used interchangeabl[y] and refer to electromagnetic radiation having a wavelength from about 650 nm to about 1400 nm, preferably about 700 nm to about 1400 nm. In some embodiments, “near-IR” luminescence refers to the emission maximum at a wavelength of about 700 nm or greater or a the [sic] total emission at greater than 50% is at a wavelength of about 700 nm or greater. Spec. 25:21–26. The Specification explains that MPCs with these optical properties “are highly favorable for biomedical applications because tissues are most transparent within the spectrum range of about 650 to about 900 nm.” Spec. 1:13–15. The Specification discloses that MPCs with these properties can be used in imaging and hyperthermia therapeutics. Spec. 1:15–17. Thus, the recited nanoclusters with the recited “near-IR luminescence with a quantum 3 Appellant provided a declaration by Jie Zheng, Ph.D. (executed July 13, 2017) which is also referred to as the “Zheng Declaration” or “Zheng Decl.” Appeal 2020-005199 Application 14/400,846 5 efficiency that is greater than 1%” are useful in biomedical applications because of their spectrum range and light emission intensity associated with the quantum efficiency. The Examiner rejected all the claims over Wang-1 alone, or in combination with additional publications, depending on the type of cluster in the MPC. Wang-1, which describes MPCs comprising gold (“Au”) clusters, was cited by the Examiner for making it obvious to obtain MPCs that “display near-IR luminescence with a quantum efficiency that is greater than 1%” as recited in claim 1. Ans. 3–4. The Examiner acknowledged that Wang does not teach a QE greater than 1% as in claim, but found it would have been obvious to have optimized Wang-1 to achieve a QE within the claimed range. Ans. 4. The Examiner did not rely on the additionally cited publications in Rejections 2–6 as evidence of the obviousness of achieving a QE within the claim scope, but focused solely on Wang-1. Appellant disagrees that such optimization would have been obvious to one of ordinary skill in the art at the time the invention was filed. Appeal Br. 20. DISCUSSION The Examiner found that it would have been obvious to a person of ordinary skill in the art at the time the invention was made “to optimize the QE of the gold MPCs of Wang to within known amounts, e.g., 0.1–10%” to achieve a QE within the claimed range. Ans. 4. The Examiner found that “QE is clearly a results effective parameter that a person of ordinary skill in the art would routinely optimize.” Id. The Examiner explained: Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to Appeal 2020-005199 Application 14/400,846 6 determine the optimal QE needed to achieve the desired results. As noted in Wang, the PL [luminescence emission intensity] and QE are influenced by the nature of the surface ligand, the number of ligands attached to the gold MPCs, and the size of the gold MPCs, and QEs greater than 10% are quite impressive. Thus one of ordinary skill would optimize the QE by adjusting the nature of the surface ligand, the number of ligands attached to the gold MPCs, and the size of the gold MPCs in order to achieve the desired QE. Ans. 4. The dispute in this appeal is whether it would have been obvious to one of ordinary skill in the art at the time the application was filed to have optimized Wang-1 to have achieved MPCs which “display near-IR luminescence with a quantum efficiency that is greater than 1%.” We begin the analysis with Wang-1. MPCs comprise a cluster of atoms and a monolayer of ligands bound to the cluster. Wang-1 describes monolayer-protected Au38 and Au140 clusters comprising different ligands. Wang-1 Abstract. The monolayer- protected Au clusters in Wang-1 are MPCs. Id. The values of 38 and 140 are the number of Au atoms in the MPC core cluster. Wang-1 20282. Wang-1 discloses various sulfur containing ligands in the monolayer bound to the Au clusters, including tiopronin (Wang-1 20283 (Table 1)), which is one of three ligands recited in rejected claim 1. The experiments described in Wang-1 involve the exchange, or replacement, of one ligand for another ligand on an MPC comprising Au clusters. Wang-1 20284 (right col.). Using this technique, Wang-1’s experiments demonstrated that “near-infrared photoluminescence of monolayer-protected Au38 and Au140 clusters (MPCs) is intensified with the exchange of nonpolar ligands by more polar thiolate ligands,” the latter of Appeal 2020-005199 Application 14/400,846 7 which are sulfur-containing ligands, including the claimed tiopronin ligand. Wang-1 Abstract. Wang-1 describes the synthesis of the MPC, Au38(SC2Ph)24 which served as the exchange MPC in Wang-1’s experiments. Wang-1 20283– 20284. This MPC was mixed with the thiols listed in Wang-1’s Table 1 and measurements were made as the thiol ligands replaced the ligands on the Au38(SC2Ph)24 MPC. Wang-1 20284, 20285. This process is referred to by Wang-1 as “ligand exchange.” Wang-1 20283. Wang-1 reported QE enhancement as a result of the ligand exchange “assuming that quantum efficiency is proportional to emission intensity” (Wang-1 20284, 2nd col.) and recorded it in Table 1 as “emission QE enhancement” (Wang-1 20283 (Table 1)). While the reported values in Table 1 are QE enhancement, the measurements in Wang-1 are of luminescence intensity (“PL”). See Wang-1 Figs. 1–3; Table 1 (footnote a). Based on this disclosure in Wang-1 the Examiner found that “QE is optimizable based on the size of the MPCs, nature of the surface ligand, the number of ligands attached to the MPCs.” Ans. 10. The Examiner cited the following disclosures from Wang-1 to support her position (numbered herein as W1–W4, where “W” is shorthand for Wang-1). W1. Quantum confinement effects become significant when the dimensions of the metal object are greatly decreased, and among other changed properties, luminescence becomes more likely. Wang-1 20282 (right col.). W2. The reason(s) for the discord among ligand types in the nanoparticle size dependency of the Au MPC luminescence Appeal 2020-005199 Application 14/400,846 8 energy is unclear. Variations in Au nanoparticle luminescence intensities are, on the other hand, more consistent; emission intensities of both PAMAM- and thiolate-protected nanoparticles increase with decreasing size, and at the smallest sizes, attain quite impressive (>10%) quantum efficiencies. Wang-1 20283 (left col.). W3. Figure 3 amplifies the linear correlation between exchanged ligand number and emission intensity of Au38(SC2Ph)24 MPCs for the thiophenolate series I-V by plotting them directly against one another. These linear changes of luminescence intensity with nanoparticle ligand count are remarkable and, as far as we know, unprecedented among nanoparticle spectral observations. Wang-1 20286 (spanning left and right cols.). W4. Ligand exchange to the extent of ca. seven TMA ligands (after product cleanup and NMR analysis) increases the QE to ~2 x 10-4, a roughly 10-fold increase. Exhaustive exchange of all of the Au140 MPC thiolate ligands has not been achieved, but extrapolation of the data predicts that a completely TMA- ligated Au140 MPC should exhibit a quantum efficiency of ca. 10-3, or 0.1%. Wang-1 20287 (left col.) (footnotes omitted). The disclosures in Wang-1 cited by the Examiner establish that emission intensity increases with decreasing size of the cluster (W2), that ligand exchange with the thiolate ligands increased PL luminescence linearly (W3), and that this ligand exchange also increased QE (W4). While this data establishes that increasing the content of the thiolate ligands, including the claimed ligand tiopronin, in MPCs also increases PL and QE, the question in this appeal is narrower. Specifically, the question is whether Wang-1 describes the conditions necessary to optimize the production of an MPC Appeal 2020-005199 Application 14/400,846 9 having “near-IR luminescence with a quantum efficiency that is greater than 1%” with a reasonable expectation of success. The Examiner found that the size of the cluster is one of the optimizable parameters, namely decreasing the cluster atom size results in increased PL and QE. Ans. 4, 10 (citing W1 at 20282 above). While it is correct that Wang-1 describes a relationship between cluster size and luminescence, the full passage on page 20282 of Wang-1 – not quoted by the Examiner – gives a more complete understanding of its teachings: Quantum confinement effects become significant when the dimensions of the metal object are greatly decreased, and among other changed properties, luminescence becomes more likely. Luminescence of a variety of Au nanoparticles, nearly all <5 nm diameter and with capping ligands ranging from citrate to PAMAM dendrimer to thiolate, has been reported. PAMAM Au nanoparticle luminescence energies are reported to vary strongly with their size, from 3.2 to 1.4 eV for Au5 to Au31. In contrast, thiolate-protected Au nanoparticle luminescence energies vary more modestly with size, for example that from glutathione-protected MPCs ranging in size from Au10 to Au39 lies in the 1.4-1.7 eV range. The broad 1.1- 1.3 eV NIR [Near-IR] emission in a collection of Au13, Au38, and Au140 MPCs having a variety of different thiolate monolayers also varied scarcely at all. The reason(s) for the discord among ligand types in the nanoparticle size dependency of the Au MPC luminescence energy is unclear. Variations in Au nanoparticle luminescence intensities are, on the other hand, more consistent; emission intensities of both PAMAM- and thiolate-protected nanoparticles increase with decreasing size, and at the smallest sizes, attain quite impressive (>10%) quantum efficiencies. Wang-1 20282–20283 (underlining added, footnotes omitted). The Examiner only cited the first sentence of this paragraph. The remaining paragraph indicates that both ligand type and cluster size are Appeal 2020-005199 Application 14/400,846 10 factors in determining the luminescence of MPCs. As to the ligand type, Wang-1 discloses that NIR emissions varied “scarcely at all” for different thiolate ligands in a collection of Au MPCs for reasons that are “unclear.” Thiolate ligands contain a sulfur atom. Spec. 3: 16–17. Therefore, based on this disclosure from Wang-1 about the effect of ligands on MPCs, it cannot be concluded that one of ordinary skill in the art on the application filing date could have predicted the effect of one of three different ligands recited in claim 1 on the near-IR luminescence of an MPC. The same passage copied also, in describing the background to the experiments in Wang-1, states that decreasing size of the cluster leads to increased emissions intensities and quantum efficiencies. Wang-1 referenced two publications, footnotes 3 and 32, respectively, to support this statement. Footnote 3 is to the Zheng publication,4 a publication listing Dr. Zheng as first author, the same Dr. Zheng who authored the Zheng Declaration. Footnote is to 32 is to another Wang publication, Wang-2.5 In his declaration, Dr. Zheng states, with respect to his scientific expertise, that he has “been working in the field of nanotechnology, single molecule spectroscopy, and bioimaging for more than 15 years” and that he has “performed research on the in vivo and in vitro luminescent properties of metal nanoclusters that are encapsulated in organic molecules, such as polymers.” Zheng Decl. ¶ 1. Dr. Zheng explains in his declaration that the results in the Zheng publication are not applicable to gold MPCs. Dr. Zheng explains: [T]he statement of Wang-1 on page 20283 to the effect that emission intensities of gold MPCs increase with decreasing size 4 Zheng et al., Phys. Review Lett., 93(7): 077402-1–077402-4, 2004. 5 G. Wang et al., J. Am. Chem. Soc., 127, 812–813, 2005. Appeal 2020-005199 Application 14/400,846 11 is not predictive of changes in emission intensities of the MPCs described in the amended claim because the statement is based on unrelated ligands with confounding features. Based on my experience, those in the field of bioimaging involving MPCs would not have any reason to expect that substituting the PAMAM dendrimers in the MPCs of Zheng with the thiolate- containing ligands described in the amended claims would result in MPCs with a QE greater than 1%, at least because they would have different relaxed midgap energy states. Zheng ¶ 14. Dr. Zheng’s statement about lack of predictability is also consistent with Wang-1’s disclosure discussed above that NIR emissions varied “scarcely at all” for different thiolate ligands in a collection of Au MPCs for reasons that are “unclear.” Wang-2, cited in Wang-1 for showing that the emission-intensity of thiolate-protected nanoparticles increases with decreasing size of the cluster, also shows in Figure 2B that the intensity increased as the number of Au atoms in an Ag/Au-tiopronin MPC increased: A similar quantitative dependence (Figure 2B) was observed in core metal galvanic exchange reactions of tiopronin-coated Ag MPCs with Au(I)[p-SCH2(C6H4)C(CH3)3, at various mole ratios of the two . . . The final Au MPC-like emission increases linearly with the reactant ratio of Au(I)[p-SCH2(C6H4)C(CH3)3] to silver MPCs; analysis of the products reveals that the increase is linear with the number of incorporated gold atoms per MPC core. Wang-2 812–813 (emphasis added). Thus, it is not immediately predictable from this disclosure that reducing the size of the Au cluster would increase emission intensity as asserted by Wang-1 and the Examiner, because in the exchange experiment Appeal 2020-005199 Application 14/400,846 12 performed by Wang-2, the intensity increased in proportion to the number of Au atoms. The Examiner cited Wang-1 (W4) as showing it was obvious to optimize the QE to the amount of greater than 1% as recited in claim 1. Ans. 4, 11. However, this disclosure in Wang-1 acknowledges that exhaustive exchange of the thiolate ligand had not been achieved and that extrapolation of the data in Wang-2 (footnote 32) would result in a QE of 0.1% for the TMA ligand. This value is 10-fold below the claimed value of greater than 1%, indicating the opposite of what the Examiner asserts, namely, that if the method of making the MPC is optimized to get full ligand exchange, a QE of only about 0.1% would be achieved. The Examiner also found that there is a relationship between luminescence and quantum efficiency and that therefore increasing luminescence would necessarily increase QE. However, while the disclosure in Wang-1 may have led the Examiner to make such a statement, Appellant provided additional evidence, a publication by Muhammed,6 that is inconsistent with a strict relationship between the two. Muhammed, as explained by Appellant in reference to Figure 4 of Muhammed, “demonstrates that luminescence emission intensities are not correlated with quantum efficiencies of MCPs.” Appeal Br. 17. Figure 4 of Muhammed shows that “Au8 (Traces I and II) and Au25 (Traces III and IV) both display very similar maximum PL [luminescence intensity] values of about 160, but the observed quantum efficiencies of Au8 and Au25 were different, 15% and 0.19%.” Appeal Br. 17. Figure 4 of Muhammed is reproduced below: 6 M. A. H. Muhammed et al., Nano Res., 1: 333-340, 2008. Appeal 2020-005199 Application 14/400,846 13 Figure 4, copied above from Muhammed, shows a “Comparison of the photoluminescence profiles of the clusters with Au@MSA.” Muhammed 336. “Traces I and II are the excitation and emission spectra of Au8, respectively. Traces III and IV are the excitation and emission spectra of Au25.” Id. Appellant’s statement about Muhammed is consistent with the graph reproduced above, at least, that the emission intensity of Au8 and Au25 clusters with mercaptosuccinic acid (MSA), which is one of three claimed ligands, have about the same emission intensity value of 160 (y-axis) at their spectra peak (x-axis) (see traces II and IV). In this example, the emission intensity did not change as the Au cluster size varied from Au8 to Au25. Appellant also relied upon Muhammed as teaching MPCs that have the same components but do not have the same quantum efficiencies. Appeal Br. 15. As explained by Appellant, Muhammed shows that MSA Au25 exhibits near-IR luminescence,7 but its QE is 0.19%, while MSA Au8 has a 7 Near-IR has a wavelength “from about 650 nm to about 1400 nm, preferably about 700 nm to about 1400 nm.” See Spec. 25:21–26. Appeal 2020-005199 Application 14/400,846 14 quantum efficiency of 15%,8 but it does not show near-IR luminescence. See Muhammed, Figure 4, showing that II, associated with Au8, shows an emission peak below the Near-IR, while IV, the emission spectrum of Au25, has an emission peak in the near-IR. The claim requires that the cluster display near-IR luminescence. Therefore, it is not predictable from Muhammed that a MPC with Au and MSA would have near IR- luminescence and a QE within the scope of claim 1. Muhammed was originally cited by the Examiner in a § 103 rejection,9 but was withdrawn by the Examiner upon Appellant making the same argument above.10 We could not identify a response by the Examiner to this argument at that time, nor a response to it when the same argument was made in the Appeal Brief. Dr. Zheng states in the declaration that “it is not possible, as the Examiner suggested, to calculate or predict the QE of an MPC from only the maximum PL of the MPC or of another MPC.” Zheng Decl. ¶ 8. Dr. Zheng showed an equation describing “the standard relationship of QE to intensity (I), absorbance (A), and refractive index (ƞ),” explaining the QE cannot be directly predicted from intensity, as asserted by the Examiner, because absorbance and refractive indices are also factors affecting the QE of an MPC. Zheng Decl. ¶ 10. Dr. Zheng’s testimony is also consistent with Muhammad as discussed above. Dr. Zheng states in his declaration that the Examiner was not correct in concluding that “it is possible to optimize the QE of gold MPCs such as 8 “The quantum yields calculated for Au8 and Au25 were 0.15 and 1.9xl0-3, respectively, which are in agreement with the reported values.” Wang-2 336 (left col.). 9 Office Action (dated Mar. 22, 2016) 7. 10 Response to Office Action (dated Aug. 16, 2016) 10–11. Appeal 2020-005199 Application 14/400,846 15 those of Wang-I to a desired QE within the range 0.1-10%.” Zheng Decl. ¶ 14. Dr. Zheng explains that the Examiner is incorrect “because the relationship of the characteristics of MPCs and their QE were not sufficiently known, direct, or predictable to allow for directed optimization.” Id. Dr. Zheng, as explained above, explained why the results of MPCs with PAMAM dendrimers would not be predictive of MPCs with the ligands required by claim 1. Id. Appellant’s own data in the Specification shows variability in quantum efficiency. Table 1 contains entries for MSA-Au and tiopronin-Au MCPs, both ligands encompassed by claim 1. For MSA-Au MPC’s prepared with a 15x ligand:Au synthesis ratio, three MPCs had QE’s less than 1% (0.4, 0.8, 0.6) and one MPC had a QE greater than 1% (1.7). For tiopronin-Au MCPs prepared with a 3x ligand:Au synthesis ratio, one MPC was less than 1% (0.7) and the other was greater than 1% (1.8). Thus, despite having the same components and prepared under the same conditions, variability in QE was observed, consistent with Muhammed and Dr. Zheng’s declaration that QE could not be routinely optimized because the same conditions and components produce variable results. Appellant addressed this issue in the Specification by using a technique known as “etching” which increased all the MPCs in Table 1 to above 1%. Spec. 19:6–20:1.11 11 “It is believed that the annealing process enhances the optical and/or electrochemical properties of the nanoclusters by: (1) optimizing the ligand arrangement; (2) favoring formation of more stable nanoclusters, and/or (3) modifying less stable compositions and/or ligand attachments to improve stability.” Appeal 2020-005199 Application 14/400,846 16 The Examiner correctly recognized that “the nature of the surface ligand, the number of ligands attached to the gold MPCs, and the size of the gold MPCs” are factors to be considered when producing MPCs with the goal of increasing their luminescence and QE. Ans. 4. However, the Examiner’s conclusion that QE could be routinely optimized based on these factors is not supported by the evidence in this record. Specifically, as discussed above, it is unclear how the ligand type would affect luminescence (see Wang-1) and how the number of atoms in the MPC would affect luminescence and therefore QE (see Wang-2). While Wang-1 provides evidence that increasing ligand number also increases luminescence,12 there is a lack of expectation of success that increasing the luminescence intensity would predictably result in increased QE and Near-IR luminescence (see Muhammed). Wang-1 refers to achieving “[e]xhaustive exchange” of ligands to increase QE (Wang-1 20287, left col.), but the value cited by Wang-1 is far less than the required value in claim 1. Even using the same ligand, Muhammed shows that Near-IR luminescence is not always obtained. While it is admitted by the inventors that “QE . . . increases with the decrease of core size from about 2.2 nm” of an MPC,13 their own data, as discussed above, shows the unpredictability of achieving a QE within the scope of claim 1. 12 For tipronin, Wang-1 shows that as the number of exchanged ligands increased, the PL increased, as well. Wang-1 20285–20286 (see Fig. 2(B)). Wang-1 states that “All of the Au38(SC2Ph)24 MPC ligand exchanges using the latter three thiol groups enhance the NIR emission intensities.” Wang-1 20286 (right col., second full para.). 13 Spec. 2:2–3. Appeal 2020-005199 Application 14/400,846 17 To establish obviousness under 35 U.S.C. § 103, one of ordinary skill in the art must have a reasonable expectation that the prior art, when combined, would succeed in making the claimed invention. In re Merck & Co., Inc., 800 F.2d 1091 (Fed. Cir. 1986). Obviousness, however, does not require “absolute predictability of success.” In re O’Farrell, 853 F.2d 894, 903–04 (Fed. Cir. 1988). In some cases, however, “the evidentiary basis for an inference of reasonable expectation of success may be inadequate.” Accorda Therapeutics, Inc. v. Roxane Laboratories, Inc., 903 F.3d 1310, 1333–34 (Fed. Cir. 2018). Here, we find that there is insufficient evidence to establish a reasonable expectation of success. Accordingly, for the reasons discussed above, we reverse the obviousness rejections 1–6 of claim 1, and dependent claims 2–16, 18–20, and 32–35. Appeal 2020-005199 Application 14/400,846 18 CONCLUSION In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1–4, 6–8, 12, 13, 16, 32–34 103(a) Wang-1 1–4, 6–8, 12, 13, 16, 32–34 1–8, 11– 13, 16, 32– 35 103(a) Wang-1, Lim, Liu 1–8, 11– 13, 16, 32– 35 1–4, 6–10, 12, 13, 16, 32–54 103(a) Wang-1, Hostetler 1–4, 6–10, 12, 13, 16, 32–35 1–4, 6–8, 12–16, 32– 35 103(a) Wang-1, Jupally, Thies 1–4, 6–8, 12–16, 32– 35 1–4, 6–8, 12, 13, 16, 18, 19, 32– 34 103(a) Wang-1, de la Fuente 1–4, 6–8, 12, 13, 16, 18, 19, 32– 34 1–4, 6–8, 12, 13, 16, 20, 32–34 103(a) Wang-1, Zhang 1–4, 6–8, 12, 13, 16, 20, 32–34 Overall Outcome 1–16, 18– 20, 32–35 REVERSED Copy with citationCopy as parenthetical citation