THE CORPORATION OF MERCER UNIVERSITY

Patent Trials and Appeals Board

Feb 14, 2022

2021000831 (P.T.A.B. Feb. 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. 15/304,626 10/17/2016 Chalet Tan 10021.0020USWO 1055 44305 7590 02/14/2022 WITHERS & KEYS, LLC P. O. BOX 2049 MCDONOUGH, GA 30253 EXAMINER SCHLIENTZ, NATHAN W ART UNIT PAPER NUMBER 1616 MAIL DATE DELIVERY MODE 02/14/2022 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 CHALET TAN and WEI FAN ____________ Appeal 2021-000831 Application 15/304,626 Technology Center 1600 ____________ Before DONALD E. ADAMS, ULRIKE W. JENKS, and JAMIE T. WISZ, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s decision to reject claims 1, 2, 5, 7, 9, 11, 13, 15, 17, 20, 25, 28, 32, 34-36, 58, 62 and 87-92 (Appeal Br. 3). 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 “The Corporation of Mercer University” (Appellant’s August 3, 2020, Appeal Brief (Appeal Br.) 3). Appeal 2021-000831 Application 15/304,626 2 STATEMENT OF THE CASE Appellant’s disclosure “relates to vitamin E-based amphiphilic copolymers and compositions containing vitamin E-based amphiphilic copolymers and nanocarriers” and “to methods of making vitamin E-based amphiphilic copolymers and nanocarriers, and methods of using vitamin E- based amphiphilic copolymers and nanocarriers, for example, as a drug delivery device” (Spec.2 1). Claims 1, 2, 7, 9, 11, 13, 15, 20, and 88 are reproduced below: 1. An amphiphilic copolymer comprising a reaction product of: polyethylene glycol, and three or more vitamin E units, the three or more vitamin E units being bonded to the polyethylene glycol via one or more divalent linkages. (Appeal Br. 35.) 2. The amphiphilic copolymer of claim 1, wherein said amphiphilic copolymer comprises from four to eight vitamin E units bonded to the polyethylene glycol. (Id.) 7. The amphiphilic copolymer of claim 1, said amphiphilic copolymer having a structure: wherein PEG represents said polyethylene glycol or H3CO- (CH2CH2O)z-CH2CH2NH- with z ranging from about 25 to 12,500, V represents a given vitamin E unit, K represents a first 2 Appellant’s October 17, 2016, Specification. Appeal 2021-000831 Application 15/304,626 3 divalent linkage, and independently each n = 0 to 5 and a sum of both n’s is from 2 to 10. (Id.) 9. The amphiphilic copolymer of claim 1, said amphiphilic copolymer having a structure: wherein PEG represents said polyethylene glycol or H3CO- (CH2CH2O)z-CH2CH2NH- with z ranging from about 25 to 12,500, V represents a given vitamin E unit, K represents a first divalent linkage, R represents a crosslinking or cationic moiety, independently each m = 0 to 5 and a sum of both m’s is from 2 to 10, and independently each n = 0 to 20. (Id. a 36.) 11. The amphiphilic copolymer of claim 1, said amphiphilic copolymer having a structure: wherein PEG represents said polyethylene glycol or H3CO-(CH2CH2O)z-CH2CH2NH- with z ranging from about 25 to 12,500, V represents a given vitamin E unit, K represents a Appeal 2021-000831 Application 15/304,626 4 first divalent linkage, A represents a second divalent linkage, R represents a crosslinking or cationic moiety, independently each m = 0 to 5 and a sum of both m’s is from 2 to 10, and independently each n = 0 to 20. (Id.) 13. The amphiphilic copolymer of claim 1, said amphiphilic copolymer having a structure: wherein PEG represents said polyethylene glycol or H3CO- (CH2CH2O)z-CH2CH2NH- with z ranging from about 25 to 12,500, V represents a given vitamin E unit, K represents a first divalent linkage, independently each m = 0 to 5 and a sum of both m’s is from 2 to 10, and independently each n = 0 to 20. (Id. at 37.) 15. The amphiphilic copolymer of claim 1, said amphiphilic copolymer having a structure: Appeal 2021-000831 Application 15/304,626 5 wherein PEG represents said polyethylene glycol or H3CO- (CH2CH2O)z-CH2CH2NH- with z ranging from about 25 to 12,500, V represents a given vitamin E unit, K represents a first divalent linkage, A represents a second divalent linkage, PEI represents a polyethylenimine unit, and independently each m = 0 to 5 and a sum of both m’s is from 2 to 10. (Id. at 37-38.) 20. The amphiphilic copolymer of claim 11, wherein each A comprises aspartic acid or β-benzyl-L-aspartate N-carboxy anhydride. (Id. at 38.) 88. The amphiphilic copolymer of claim 13, wherein said amphiphilic copolymer has a structure: (Id. at 40.) Appeal 2021-000831 Application 15/304,626 6 Grounds of rejection before this Panel for review: I. Claims 1, 2, 5, 7, 9, 11, 13, 17, 28, 32, 34-36, 58, 62, and 87- 92 stand rejected under 35 U.S.C. § 103 as unpatentable over the combination of Lu,3 Luo,4 and Zhang.5 II. Claim 15 stands rejected under 35 U.S.C. § 103 as unpatentable over the combination of Lu, Luo, Zhang, and Gaucher.6 III. Claims 20 and 25 stand rejected under 35 U.S.C. § 103 as unpatentable over the combination of Lu, Luo, Zhang, and Li.7 ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? FACTUAL FINDINGS (FF) FF 1. Lu discloses the “Design and Characterization of PEG-Derivatized Vitamin E as a Nanomicellar Formulation for Delivery of Paclitaxel” (Lu, Title; id. at 3 (Lu discloses the use of a lysine linker to conjugate Vitamin E 3 Lu et al., Design and Characterization of PEG-Derivatized Vitamin E as a Nanomicellar Formulation for Delivery of Paclitaxel, 10 Mol. Pharm. 2880- 90 (2013). 4 Luo et al., Well-defined, size-unable, multi-functional micelles for efficient paclitaxel delivery for cancer treatment, 21 Bioconjug. Chem. 1216-24 (2010). 5 Zhang et al., PEG-Farnesyl Thiosalicyclic Acid Telodendrimer Micelles as an Improved Formulation for Targeted Delivery of Paclitaxel, 11 Mol. Pharmaceutics 2807-14 (2014). 6 Gaucher et al., Block copolymer micelles: preparation, characterization and application in drug delivery, 109 Journal of Controlled Release 169-188 (2005). 7 Li et al., Well-defined, reversible disulfide cross-linked micelles for on- demand paclitaxel delivery, 32 Biomaterials 6633-45 (2011). Appeal 2021-000831 Application 15/304,626 7 to PEG, wherein vitamin E is attached to the amino group of lysine); id. at 6; Final Act.8 4 (citing Lu 3-4, 6) (Examiner finds that Lu discloses that PEG- Vitamin E (PEG-VE) “conjugates form micelles that act as carriers for drugs, such as” paclitaxel (PTX)); Final Act. 3 (citing Lu 3; Lu, Fig. 1) (Examiner finds that Lu discloses “amphiphilic copolymers comprising two vitamin E units bonded to PEG” through a single lysine molecule)). FF 2. Lu systematically compared the biophysical property and in vitro and in vivo efficiency of PTX delivery of four PEG-Vitamin E conjugates that differ in the size of PEG motif ([2,000 Dalton PEG (PEG2K) vs 5,000 Dalton PEG (PEG5K)]) and the molar ratio of PEG/Vitamin E (1/1 vs 1/2) in the conjugates. (Lu 9; see also Final Act. 3-4 (citing Lu 2) (Examiner finds that Lu discloses “four PEG-Vitamin E (PEG-VE) conjugates that vary in the molecular weight of PEG (PEG2K vs PEG5K) and the molar ratio of PEG/Vitamin E (1/1 vs 1/2) in the conjugates”); Lu 3 (Lu discloses the synthesis of four PEG-VE conjugates, specifically PEG2K-VE, PEG2K-VE2, PEG5K-VE, and PEG5K-VE2).) FF 3. Lu discloses that “conjugates with two Vitamin E molecules . . . worked better than the conjugates with one molecule of Vitamin E, particularly for the PEG2K-system” (Lu 2; see also Final Act. 4 (citing Lu 2)). FF 4. Lu discloses that “[a]s a hydrophilic motif of amphiphilic molecules, the size of PEG also critically affects the performance of the micelles” and In this regard, PEGs of higher MW are expected to be more effective than those of lower MW. However, the size of PEG also affects the [critical micelle concentration (CMC)] which in 8 Examiner’s February 4, 2020, Final Office Action. Appeal 2021-000831 Application 15/304,626 8 turn significantly affects the performance of the micelles, particularly in vivo. Different micellar systems appear to be differentially affected by the size of PEG. In a systematic study [of] . . . PEG-cholic acid cluster-based micellar system, PEG2K was shown to be the optimal hydrophilic motif. Our data clearly showed that PEG5K-conjugates (with either one or two Vitamin E molecules) were more active than PEG2K-conjugates in forming stable mixed micelles with [paclitaxel (PTX)]. (Lu 9 (endnotes omitted); see also Final Act. 4 (citing Lu 2, 9).) FF 5. Lu discloses: Vitamin E has a benzene ring and a long alkyl chain. In addition to hydrophobic interaction with PTX, the hydrogen bonding and the π-π stacking may . . . contribute to the overall carrier/PTX interaction. The close proximity of two Vitamin E molecules in PEG-VE2 conjugates is likely to facilitate the formation of a binding pocket that enhances the interaction between the carriers and PTX. . . . In an independent study with . . . [a] similar delivery system[] based on . . . PEG-farnesylthiosalicylic acid (FTS) conjugates, we also showed that conjugates with two . . . FTS molecules were more effective than conjugates with one . . . FTS molecule regardless whether PEG3.5K or PEG5K was used. (Lu 9 (endnotes omitted); see also Final Act. 4 (citing Lu 9).) FF 6. Examiner finds that Lu does “not explicitly disclose three or more vitamin E units bonded to PEG” (Final Act. 4; see also Appeal Br. 9 (citing Final Act. 3-7); Final Act. 11 (Examiner finds that Lu “does not explicitly disclose PEG-VE conjugates comprising a divalent linkage and . . . [polyethylenimine (PEI) unit] attached between the PEG and the vitamin E units”); see also id. at 14 (Examiner finds that Lu “does not explicitly disclose PEG-VE conjugates comprising a divalent linkage (A) and a crosslinking or cationic moiety attached between the PEG and the vitamin E units”)). Appeal 2021-000831 Application 15/304,626 9 FF 7. Luo developed a well-defined and biocompatible amphiphilic telodendrimer system (PEG-b-dendritic oligo-cholic acid) which can self-assemble into multifunctional micelles in aqueous solution for efficient delivery of hydrophobic drugs such as paclitaxel. In this telodendrimer system, cholic acid is essential for the formation of stable micelles with high drug loading capacity, owing to its facial amphiphilicity. (Luo Abstr.; see also id. (Luo discloses the synthesis of a “series of telodendrimers with variable length of PEG chain and number of cholic acid in the dendritic blocks”); id. at 9 (Luo discloses the design and synthesis of “a new linear-dendritic block copolymer (named as telodendrimer) using three biocompatible building blocks: polyethylene glycol (PEG), L-lysine, and cholic acid (CA)”); id. at 3-4 (Luo discloses the use of polylysine on one end of PEG onto which cholic acid is attached); id. 14:Figure 1 (Luo illustrates a PEG5k-CA8 conjugate, wherein polylysine is used to conjugate cholic acid to PEG); Final Act. 4.) FF 8. Luo discloses that its telodendrimer system is easily engineered with well-defined structures that provide the advantage of providing “tunable properties,” specifically, Luo discloses that “[b]y varying the PEG chain length and the number of cholic acid in the dendritic core, . . . [it was] able to prepare a series of stable micelle systems with tunable particle sizes that have superior PTX loading capacities” (Luo 2-3; see id. at 7 (Luo discloses that “[t]hrough adjusting the PEG chain length and the number of CA subunits in the telodendrimers, the particle sizes of the PTX loaded micelles can be tuned ranging from 15 nm to 141 nm.”); see also Final Act. 4-5 (citing Luo 2-3, 6, Table 1) (Examiner finds that Luo’s telodendrimer Appeal 2021-000831 Application 15/304,626 10 system “results in a well-defined structure that is easily engineered, has “tunable properties” and “superior PTX loading capacities”)). FF 9. Examiner finds that although Luo discloses “multifunctional telodendrimers wherein a divalent linkage, (Fmoc)Lys(Boc)-OH, is attached between PEG and cholic acid in order to allow conjugation of further molecules to the polymer at precise locations in the polymer,” Luo does “not explicitly disclose attaching PEI to the divalent linkages” (Final Act. 11-12 (citing Luo 3-6); see also Final Act. 14 (Examiner finds that Luo does “not explicitly disclose attaching thioctic acid, cysteine, diethylenetriamine, triethylenetetramine, tris(2-aminoethyl)amine or N,N-diisopropylethylene- diamine to the divalent linkages”)). FF 10. Zhang discloses “PEG-Farnesyl Thiosalicylic Acid Telodendrimer Micelles as an Improved Formulation for Targeted Delivery of Paclitaxel,” wherein “conjugates with PEG5K were more effective than the counterparts with PEG2K in forming stable mixed micelles” and “PTX formulated in PEG5K-FTS2 micelles as the most effective formulation in inhibiting the tumor growth in vivo” (Zhang Abstract; see also Final Act. 5 (citing Zhang, Abstract, 2807-08, 2812) (Examiner finds that Zhang discloses “conjugates of PEG and FTS with varying molecular weights of PEG (PEG2K vs PEG5K) and the molar ratio of PEG/FTS (1/2 vs 1/4),” wherein “conjugates with four FTS molecules were more effective than the conjugates with two molecules of FTS” and “PTX formulated in PEG5K-FTS4 micelles was the most effective formulation in inhibiting the tumor growth in vivo”)). FF 11. Examiner finds that Zhang discloses that FTS “has a lipid chain and benzene ring structure, wherein the lipid chain contributes to the loading of hydrophobic drug through hydrophobic interaction, and the benzene ring is Appeal 2021-000831 Application 15/304,626 11 capable of forming π-π interaction with drug carrying aromatic ring structure” (Final Act. 5-6 (citing Zhang 2812-2813); see also id. at 5-6 (citing Zhang 1812) (Examiner finds that Zhang discloses that “[t]he π-π stacking and hydrophobic interaction are likely to work cooperatively to promote both drug/carrier and carrier/carrier interactions, and are also expected to be further enhanced with an increase in the number FTS molecules in the PEG-FTS conjugates”)). FF 12. Zhang discloses that “[r]ecent studies . . . [established that] Vitamin E-based micellar systems could be significantly improved via modulating the PEG motifs and the molar ratio of PEG/Vitamin E” and that these studies and others “prompted . . . [Zhang] to carry out a similar study with [the] PEG-FTS system” (Zhang 2807). FF 13. Examiner finds that Gaucher discloses “that PEI is a good candidate for the preparation of polyion complex micelles” and “that the neutral nature of the PEG corona in micelles could effectively shield the cationic PEI and prevent nonspecific interactions with negatively charged plasma proteins in the biological environment, thereby ensuring prolonged circulation times” (Final Act. 12 (Gaucher 171, 179-180); see generally Gaucher, Title (Gaucher discloses “[b]lock copolymer micelles: preparation, characterization and application in drug delivery”)). FF 14. Examiner finds that Li discloses that upon intravenous administration, conventional self-assembled polymeric micelles are susceptible to: Dilution below the CMC leading to dissociation of the polymeric micelle into unimers, interaction with blood cells, and adsorption by plasma proteins, all of which may lead to premature disintegration of the Appeal 2021-000831 Application 15/304,626 12 micelle resulting in release of a drug, from a drug containing micelle, prior to the micelle reaching its target (Final Act. 14 (citing Li 6633-6634)). FF 15. Examiner finds that Li discloses that the disadvantages associated with conventional self-assembled polymeric micelles can be overcome by utilizing a “cross-linking approach to improve the stability of polymeric micelles for drug delivery, including shell-cross-linking, core-cross-linking and cross-linking at the core-shell interface,” wherein “[c]ross-linking not only can improve the structural stability of micelles, but also can control the release rate of the entrapped drugs” (Final Act. 15 (citing Li 6634)). FF 16. Examiner finds that Li discloses amphiphilic PEGylated oligomer of cholic acids synthesized via peptide chemistry wherein the modular design enables them to assemble different components in a step-wise fashion with high flexibility, such that nontoxic building blocks and amino acids may be easily introduced into the telodendrimers at the desired position and at the optimal numbers, wherein cysteine residues are introduced into the telodendrimers to develop “a self-assembling disulfide-crosslinking system so that micelles can be further stabilized to avoid premature release of the loaded drugs during circulation” (Final Act. 15 (citing 6634); see also Final Act. 15 (citing Li 6644) (Examiner finds that Li discloses that its “cysteine-containing telodendrimers [have] the characteristics of superior drug loading capacity, enhanced micellar stability, lack of hemolytic activity, prolonged in vivo circulation time and preferential tumor targeting”).) Appeal 2021-000831 Application 15/304,626 13 ANALYSIS Rejection I: Lu, Luo, and Zhang each disclose PEG-based micellar systems for the delivery of hydrophobic drugs such as paclitaxel (see FF 1-12). The evidence of record establishes that those of ordinary skill in this art looked to studies related to PEG-VE, PEG-cholic acid, and PEG-FTS micellar systems and applied improvements discovered in one system to further improve a related system (see e.g., FF 4 (PEG size affects CMC, which “significantly affects the performance of the micelles, particularly, in vivo”); FF 12 (Zhang discloses the application of improvements in the PEG-VE micellar system to the PEG-FTS micellar system); (FF 4; cf. FF 7) (Lu compares its PEG-VE micellar systems to PEG-cholic acid micellar systems, such as those disclosed by Luo.); Ans.9 4-5 (Examiner finds that the combination of Lu, Luo, and Zhang makes obvious “tunable” micellar systems for hydrophobic drug delivery)). See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007) (“[I]f a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill.”). Taken as a whole, the evidence on this record supports a conclusion that although PEG2K was the optimal hydrophilic motif in PEG-cholic acid micellar systems, “PEG5K-conjugates (with either one or two Vitamin E molecules) were more active than PEG2K-conjugates in forming stable mixed micelles with PTX” (FF 4). The evidence on this record, further 9 Examiner’s September 16, 2020, Answer. Appeal 2021-000831 Application 15/304,626 14 makes clear that those of ordinary skill in this art would apply improvements in a related system, i.e., PEG-FTS micellar systems, to improve Vitamin E- based micellar systems (see FF 12 (Zhang makes clear “that the Vitamin E- based micellar system could be significantly improved via modulating the PEG motifs and the molar ratio of PEG/Vitamin E”); see also FF 10). In sum, the combination of Lu, Luo, and Zhang establishes that PEG- VE, PEG-FTS, and PEG-cholic acid are similar micellar delivery systems for hydrophobic drugs, such as paclitaxel, that can be compared and contrasted in order to “improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill.” KSR, 550 U.S. at 417. Based on the combination of Lu, Luo, and Zhang, Examiner concludes that, before the effective filing date of Appellant’s claimed invention, it would have been prima facie obvious to prepare “PEG-VE conjugates according to Lu . . . wherein the length of the PEG chain is varied and the number of vitamin E units is varied in order to prepare micelle systems with tunable particle sizes and drug loading capacities, as reasonably suggested by Luo” (Final Act. 6; see FF 1-9). Examiner further concludes that, before the effective filing date of Appellant’s claimed invention, it would have been prima facie obvious to adjust the PEG length and the number of vitamin E units in a PEG-VE, because Zhang discloses “that micelles formed with PEG5K and an increasing hydrophobic/ hydrophilic block ratio (PEG5K-FTS4) increased drug loading capacity, enhanced formulation stability, and increased in vivo efficacy” (Final Act. 6; see FF 10-12). Appeal 2021-000831 Application 15/304,626 15 In support of the foregoing conclusion, Examiner reasons that “[a] person having ordinary skill in the art would have been motivated to determine the PEG chain length and the number of vitamin E units that would provide the greatest efficacy, lowest CMC, enhanced stability and increased drug loading capacity” (Final Act. 6; see also Ans. 5-6). See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007) (“[I]f a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill.”). Examiner further reasons that, based on the combination of Lu, Luo, and Zhang, “a person having ordinary skill in the art would reasonably expect the longer PEG chains, such as PEG5K, and a higher hydrophobic/hydrophilic block ratio, such as four VE units, would result in increased drug loading capacity, enhanced formulation stability, and increased in vivo efficacy” for the reasons disclosed by Lu and Zhang, including hydrophobic interaction with PTX, hydrogen bonding, and π-π stacking (see Final Act. 6-7; see also FF 1-12; Final Act. 7 (Examiner reasons that a copolymer made obvious by the combination of Lu, Luo, and Zhang will necessarily “comprise unreacted NH2 groups if the additional lysine coupling reactions and the reaction with vitamin E succinate are not complete”)). Appeal 2021-000831 Application 15/304,626 16 Claim 1: Appellant’s claim 1 is reproduced above. Appellant “agree[s] that one skilled in the art could have made the above modifications to the disclosed PEG-Vitamin E conjugates of Lu” (Appeal Br. 13; see also id. at n.1 (Appellant “note[s] that one skilled in the art could have also considered possible substitutes for vitamin E such as the moiety farnesylthiosalicylate (FTS) as shown in the actual teaching of Zhang”)). Appellant contends, however, that “the separate teachings of Lu, Luo and Zhang guides one skilled in the art to form specifically designed, unique drug delivery devices as described in each of the separate teachings of Lu, Luo and Zhang” and, thus, one skilled in the art . . . would not have been guided to (1) seek out (i) the teaching of Luo directed to specific biocompatible amphiphilic telodendrimer systems consisting of PEG-b- dentritic oligo-cholic acid with up to 16 cholic acid units, and (ii) the teaching of Zhang directed to specific polyethylene glycol (PEG)-derivatized famesylthiosalicylate (FTS) conjugates having up to 4 FTS units, and (2) subsequently decide to form PEG-vitamin E conjugates having 3 or more vitamin E units. (Appeal Br. 11; see also id. at 11-12 (Appellant contends that “it is difficult for Appellant[] to understand how or why one skilled in the art” would combine Lu, Luo, and Zhang as proposed by Examiner.); (Appeal Br. 13 (Appellant contends, “given the teaching of Zhang, or the proposed combination of the teachings of Lu and Zhang,” a person of ordinary skill in this art would have been “guided to utilize the proven, improved formulation for targeted delivery of paclitaxel as disclosed in Zhang, not some unknown, unproven, modified version of Lu's PEG-Vitamin E conjugate formulation for targeted delivery of paclitaxel as suggested [by Examiner]”)). Appeal 2021-000831 Application 15/304,626 17 Stated differently, Appellant contends that “the proposed combination of the teachings of Lu, Luo and Zhang, fails to suggest ‘the desirability of the combination’ of claim features recited in [Appellant’s] independent claim 1” (Appeal Br. 13-14; see also id. at 14, n.2 (Appellant contends that although “Luo discloses improvements with micelle stability and drug delivery capacity by increasing the number of cholic acid units within Luo’s disclosed telodendrimer system,” “Luo does not teach or suggest a similar outcome if a number of vitamin E units were increased in a conjugate system” and “[t]he same can be said for the improved formulation for targeted delivery of paclitaxel namely, PEG-FTS conjugates, described in the teaching of Zhang.”)). We are not persuaded. As discussed above, those of ordinary skill in this art would have reasonably looked to other micellar systems, such as Luo’s PEG-cholic acid and Zhang’s PEG-FTS systems, and applied improvements discovered in those systems to further improve a related micellar system, such as PEG-VE. We are not persuaded by Appellant’s contention that “increasing the number of vitamin E units in Lu’s disclosed PEG-Vitamin E conjugates would ‘improve upon the teachings of Lu’,” which fails to account for Zhang’s disclosure that “[r]ecent studies . . . [established that] Vitamin E- based micellar systems could be significantly improved via modulating the PEG motifs and the molar ratio of PEG/Vitamin E,” which prompted Zhang to observe that in the related PEG-FTS system, “conjugates with four FTS molecules were more effective than . . . conjugates with two molecules of Appeal 2021-000831 Application 15/304,626 18 FTS” (Reply Br. 310; see also id. at 4 (Appellant makes similar contentions with regard to Luo’s PEG-cholic acid system); cf. FF 10, 12; Ans. 5). For the foregoing reasons, we are not persuaded by Appellant’s contention that any increased performance of Zhang’s disclosed PEG- FTS conjugates by increasing the number of famesylthiosalicylate units is specific to the use of famesylthiosalicylate, and does not necessarily mean that an increase in the number of vitamin E units in Lu’s disclosed PEG-Vitamin E conjugates would result in similar increased performance. (Reply Br. 3; see id. (Appellant contends that the combination of Lu, Luo, and Zhang “would most likely lead one skilled in the art . . . to follow the teachings of Zhang using famesylthiosalicylate units instead of vitamin E units, or the teaching of Luo using cholic acid units instead of vitamin E units.”); id. at 3-4 (Appellant contends that Zhang directs those of ordinary skill in this art to “specific . . . [PEG- FTS] conjugates having up to 4 FTS units).) For the foregoing reasons, we are not persuaded by Appellant’s contention that because of “the structural differences between vitamin E and farnesyl thiosalicylic acid,” “a person having ordinary skill in the art would not [have] reasonably expect[ed] ‘a conjugate with four vitamin E units [to] have increased hydrophobic interactions with [a] hydrophobic drug as well as π-π stacking, which would yield enhanced formulation stability and increased in vivo efficacy’” (Reply Br. 4; see also id. at 5; cf. FF 5, 10-12; Ans. 5 (Examiner finds that the evidence on this record establishs that “increasing the ratio of hydrophobic/hydrophilic blocks is associated with 10 Appellant’s November 16, 2020, Reply Brief. Appeal 2021-000831 Application 15/304,626 19 increased drug loading capacity and enhanced formulation stability. It is clear that adjusting the PEG chain length and the ratio of hydrophobic/ hydrophilic blocks is a result effective variable that effects the stability of the micelles and their drug loading capacity.”); Ans. 7 (Examiner finds that “[a] person having ordinary skill in the art would reasonably expect a conjugate with four vitamin E units would have increased hydrophobic interactions with the hydrophobic drug as well as π-π stacking, which would yield enhanced formulation stability and increased in vivo efficacy.”)). For the foregoing reasons, we are not persuaded by Appellant’s contention that “the proposed combination . . . [of Lu, Luo, and Zhang] fails to provide any reason that would have lead one skilled in the art . . . to reproduce [Appellant’s] claimed amphiphilic copolymers” and “the only motivation and guidance for combining elements of the prior art . . . has been [improperly] gleaned [in hindsight] from [Appellant’s] original specification, not the art” (Appeal Br. 15). Claim 2: Appellant’s claim 2 is reproduced above. As Appellant makes clear, its claim 2 “require[s] from four to eight vitamin E units bonded to the polyethylene glycol” (Appeal Br. 17). For the reasons discussed above, we are not persuaded by Appellant’s contention that “the state of the art appears to guide one skilled in the art towards” Zhang’s PEG-FTS “conjugates having up to 4 FTS units in the teaching of Zhang having known, proven, drug delivery advantages” and not to modifying “Lu’s PEG-Vitamin E conjugates to form unknown, unproven, modified versions of Lu’s PEG-Vitamin E conjugates as suggested” by Appeal 2021-000831 Application 15/304,626 20 Examiner (id.). Specifically, we find that the combination of Lu, Luo, and Zhang makes obvious the optimization and/or improvement of the PEG-VE micellar delivery system based on optimizations and/or improvements in similar systems (see e.g., FF 12 (Zhang discloses that “[r]ecent studies . . . [established that] Vitamin E-based micellar systems could be significantly improved via modulating the PEG motifs and the molar ratio of PEG/Vitamin E” and that these studies and others “prompted . . . [Zhang] to carry out a similar study with [the] PEG-FTS system”); FF 10 (Zhang found that PEG “conjugates with four FTS molecules were more effective than the conjugates with two molecules of FTS”)). For the foregoing reasons, we are not persuaded by Appellant’s contention that Examiner’s conclusion of obviousness, is based on improper hindsight (id.). Claim 7: Appellant’s claim 7 is reproduced above and requires that the amphiphilic copolymer of Appellant’s claim 1 has the structure: wherein PEG represents, inter alia, polyethylene glycol, V represents a given vitamin E unit, K represents a first divalent linkage, and independently each n = 0 to 5 and a sum of both n’s is from 2 to 10. The combination of Lu, Luo, and Zhang makes obvious an amphiphilic copolymer that utilized polylysine as a linker to conjugate PEG Appeal 2021-000831 Application 15/304,626 21 conjugated to more than three VE units (FF 1-12; see Final Act. 6 (Examiner finds that Lu discloses vitamin E coupled to PEG through the free amine of a lysine linker and Luo discloses the use of polylysine as a linker to conjugate PEG to other molecules, i.e. cholic acid); see also Ans. 8-9; FF 1, 5, 7, 10-12). Thus, we find no error in Examiner’s rationale: A person having ordinary skill in the art would have been able to vary the PEG chain length and the number of vitamin E units by preparing the copolymers with a method similar to Lu et al. and Luo et al. wherein multiple repeat couplings of protected lysine is carried out to generate several generations of dendritic polylysine on one end of PEG (see Luo et al., pg. 3, paragraph 3), and then vitamin E succinate is reacted with the free amine of lysine to prepare PEG-VEn, wherein n depends on the number of lysine couplings. (Ans. 8) For the foregoing reasons, we are not persuaded by Appellant’s contention that “Lu fails to teach or suggest PEG-Vitamin E conjugates having (1) at least three first divalent linkages K in series with and bonded to one another, and (2) at least three vitamin E units bonded to PEG via the at least three first divalent linkages K” (Appeal Br. 19; see id. (Appellant contends that “Lu guides one skilled in the art to utilize PEG, a single lysine unit, and succinate-substituted vitamin E to form Lu’s disclosed PEG- Vitamin E conjugates.”). In sum, we find that the combination of Lu, Luo, and Zhang makes obvious the use of polylysine to conjugate VE to PEG, wherein the number of lysine residues in the polylysine is optimized through routine experimentation. In re Aller, 220 F.2d 454, 456 (CCPA 1955) (“[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.”). Appeal 2021-000831 Application 15/304,626 22 For the foregoing reasons, we are not persuaded by Appellant’s contention that Examiner’s conclusion of obviousness, is based on improper hindsight (id.). Claim 9: Appellant’s claim 9 is reproduced above and requires that the amphiphilic copolymer of Appellant’s claim 1 has the structure: wherein PEG represents, inter alia, polyethylene glycol, V represents a given vitamin E unit, K represents a first divalent linkage, R represents a crosslinking or cationic moiety, independently each m = 0 to 5 and a sum of both m’s is from 2 to 10, and independently each n = 0 to 20. Appellant contends that “Lu fails to teach or suggest PEG-Vitamin E conjugates having (1) at least five first divalent linkages K bonded to one another, and (2) at least three vitamin E units bonded to PEG via the at least five first divalent linkages K,” but instead “guides one skilled in the art to utilize PEG, a single lysine unit, and succinate-substituted vitamin E to form Lu’s disclosed PEG-Vitamin E conjugates” (Appeal Br. 22). Therefore, Appellant contends, in order to arrive at Appellant’s claimed invention, one skilled in the art would need to (1) ignore the teaching of Lu which guides one skilled in the art to utilize a single lysine unit and vitamin E succinate when forming Lu’s disclosed PEG- Appeal 2021-000831 Application 15/304,626 23 Vitamin E conjugates, and (2) substitute therefor at least five divalent linkages K and at least three vitamin E units without the succinate moiety. The art fails to make such a suggestion or provide such guidance. (Id.) We are not persuaded for the reasons set forth above, we respect to Appellant’s separate argument of claim 7. As Examiner explains: A person having ordinary skill in the art would have been able to vary the PEG chain length and the number of vitamin E units by preparing the copolymers with a method similar to Lu et al. wherein multiple repeat couplings of protected lysine is carried out to generate several generations of dendritic polylysine[s] on one end of PEG (see Luo et al., pg. 3, paragraph 3), and then vitamin E succinate is reacted with the free amine of lysine to prepare PEG-VEn, wherein n depends on the number of lysine couplings. (Ans. 10.) For the foregoing reasons, we are not persuaded by Appellant’s contention that Examiner’s conclusion of obviousness, is based on improper hindsight (id.). Claim 88: Appellant’s claim 88 is reproduced above and require the amphiphilic copolymer to have the following structure: Appeal 2021-000831 Application 15/304,626 24 Appellant contends that “Lu fails to teach or suggest PEG-Vitamin E conjugates having (1) eleven first divalent linkages K bonded to one another, and (2) four vitamin E units bonded to PEG via seven of the eleven first divalent linkages K” but instead “guides one skilled in the art to utilize PEG, a single lysine unit, and succinate-substituted vitamin E to form Lu’s disclosed PEG-Vitamin E conjugates” (Appeal Br. 24). Therefore, Appellant contends, in order to arrive at Appellant’s claimed invention, one skilled in the art would need to (1) ignore the teaching of Lu which guides one skilled in the art to utilize a single lysine unit and vitamin E succinate when forming Lu’s disclosed PEG- Vitamin E conjugates, and (2) substitute therefor eleven divalent Appeal 2021-000831 Application 15/304,626 25 linkages K and four vitamin E units without the succinate moiety. The art fails to make such a suggestion or provide such guidance. (Id.) We are not persuaded for the reasons set forth above, with regard to Appellant’s separate argument with respect to claims 7 and 9 (see e.g., Luo Fig. 1 (illustrating “[t]he chemical structure of PEG5k-CA8 with multiple functional groups . . . [and] functionalized micelles formed by telodendrimers”). In sum, we find that the combination of Lu, Luo, and Zhang makes obvious the use of polylysine to conjugate VE to PEG, wherein the number of lysine residues in the polylysine is optimized through routine experimentation. In re Aller, 220 F.2d 454, 456 (CCPA 1955) (“[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.”). For the foregoing reasons, we are not persuaded by Appellant’s contention that Examiner’s conclusion of obviousness, is based on improper hindsight (id.). Rejection II: Appellant’s claim 15 is reproduced above and requires that the amphiphilic copolymer of Appellant’s claim 1 has the structure: wherein PEG represents, inter alia, polyethylene glycol, V represents a given vitamin E unit, K represents a first divalent linkage, A represents a Appeal 2021-000831 Application 15/304,626 26 second divalent linkage, PEI represents a polyethylenimine unit, and independently each m = 0 to 5 and a sum of both m’s is from 2 to 10. Based on the combination of Lu, Luo, Zhang, and Gaucher, Examiner concludes that, before the effective filing date of Appellant’s claimed invention, it would have been prima facie obvious “to prepare PEG-VE conjugates according to” the combination of Lu, Luo, and Zhang, “wherein the conjugates are functionalized to contain PEI . . . because Gaucher [discloses] . . . that micelles containing PEI are suitable for incorporating polyanionic molecules” (Final Act. 12; see FF 1-13). Examiner reasons that a person having ordinary skill in the art would have been motivated to conjugate the PEI between the PEG and vitamin E units of Lu . . . via a divalent linkage in order to controllably attach the PEI to the polymer at a specific site, as reasonably suggested by Luo [and Gaucher]. (Final Act. 12; see also FF 13 (Gaucher, like Lu, Luo, and Zhang relates to the preparation, characterization, and application of copolymer micelles for drug delivery)). Thus, we are not persuaded by Appellant’s contention that “given the teaching of Lu, [a person of ordinary skill in this art] would not have even considered or thought of the need to incorporate PEI or any other moiety within Lu’s specific PEG-vitamin E conjugates” and, given Luo’s disclosure that “cholic acid is essential for the formation of stable micelles with high drug loading capacity, owing to its facial amphiphilicity,” “one skilled in the art . . . would have been guided to utilize cholic acid, not PEI, in [a] copolymeric micelle,” which fails to account for the contribution of Luo, Zhang, and Gaucher to the rejection of Appellant’s claim 15 (Appeal Br. 28; see also id. at 27-28). For the reasons set forth above, we are not persuaded by Appellant’s contention that “Lu fails to guide one skilled in the art to Appeal 2021-000831 Application 15/304,626 27 seek out the teachings of Luo, Zhang, and Gaucher, and subsequently decide ‘to functionalize the micelles of Lu . . . in order to incorporate polyanionic molecules’” (Reply Br. 6). For the foregoing reasons, we are not persuaded by Appellant’s contention that Examiner’s conclusion of obviousness, is based on improper hindsight (Appeal Br. 28-29). Rejection III: Appellant’s claim 20 is reproduced above depends from Appellant’s dependent claim 11, reproduced above, and requires that the amphiphilic copolymer of Appellant’s claim 1 has the structure: wherein PEG represents, inter alia, polyethylene glycol, V represents a given vitamin E unit, K represents a first divalent linkage, A represents a second divalent linkage, R represents a crosslinking or cationic moiety, independently each m = 0 to 5 and a sum of both m’s is from 2 to 10, and independently each n = 0 to 20, wherein each A comprises aspartic acid or β-benzyl-L-aspartate N-carboxy anhydride. Appeal 2021-000831 Application 15/304,626 28 Based on the combination of Lu, Luo, Zhang, and Li, Examiner concludes that, before the effective filing date of Appellant’s claimed invention, it would have been prima facie obvious to prepare PEG-VE conjugates according to Lu . . . wherein the conjugates are functionalized to contain a cross-linking agent, such as cysteine, in the polymer between the PEG and the vitamin E units. Such would have been obvious because Luo . . . [discloses] functionalizing the telodendrimers to contain a divalent linkage between PEG and the hydrophobic core such that additional functional groups may be attached, and Li . . . [discloses] including cysteine in the telodendrimers in order to facilitate cross-linking of the micelles in order to yield superior drug loading capacity, enhanced micellar stability, lack of hemolytic activity, prolonged in vivo circulation time and preferential tumor targeting. A person having ordinary skill in the art would have chosen suitable divalent linkages such as amino acids with differing protecting groups, that can be selectively removed to add different functional groups to the telodendrimers (e.g., cysteine and vitamin E). (Final Act. 15-16; see FF 1-12 and 14-16.) For the foregoing reasons, we are not persuaded by Appellant’s contention that given Luo’s disclosure that “‘cholic acid is essential for the formation of stable micelles with high drug loading capacity, owing to its facial amphiphilicity,’” a person of ordinary skill in this art “would not have even considered or thought of the need to incorporate crosslinking moieties within Lu’s specific PEG-vitamin E conjugates,” which fails to account for the contribution of Lu, Zhang, and Li to the rejection of Appellant’s claim 20 (Appeal Br. 32; see id. (Appellant contends that “given the combination of Li and Luo, a person of ordinary skill in this art “would have been guided to form thiolated PEG-cholic acid telodendrimers, not PEG-vitamin E conjugates”); cf. FF 14-16; Ans. 11-12). For the reasons set forth above, we Appeal 2021-000831 Application 15/304,626 29 are not persuaded by Appellant’s contention that “Lu does not guide one skilled in the art to seek out the teachings of Luo, Zhang, and Li, and subsequently decide to modify Lu’s disclosed PEG-Vitamin E conjugates so as to result in the compound of [Appellant’s] claim 20” (Reply Br. 6). For the foregoing reasons, we are not persuaded by Appellant’s contention that Examiner’s conclusion of obviousness, is based on improper hindsight (Appeal Br. 32). CONCLUSION The preponderance of evidence relied upon by Examiner supports a conclusion of obviousness. Rejection I: The rejection of claims 1, 2, 7, 9, and 88 under 35 U.S.C. § 103 as unpatentable over the combination of Lu, Luo, and Zhang is affirmed. Claims 5, 11, 13, 17, 28, 32, 34-36, 58, 62, 87, and 89-92 are not separately argued and fall with claim 1. Rejection II: The rejection of claim 15 under 35 U.S.C. § 103 as unpatentable over the combination of Lu, Luo, Zhang, and Gaucher is affirmed. Rejection III: The rejection of claim 20 under 35 U.S.C. § 103 as unpatentable over the combination of Lu, Luo, Zhang, and Li is affirmed. Claim 25 is not separately argued and fall with claim 20. Appeal 2021-000831 Application 15/304,626 30 DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 2, 5, 7, 9, 11, 13, 17, 28, 32, 34-36, 58, 62, 87-92 103 Lu, Luo, Zhang 1, 2, 5, 7, 9, 11, 13, 17, 28, 32, 34-36, 58, 62, 87-92 15 103 Lu, Luo, Zhang, Gaucher 15 20, 25 103 Lu, Luo, Zhang, Li 20, 25 Overall Outcome 1, 2, 5, 7, 9, 11, 13, 15, 17, 20, 25, 28, 32, 34-36, 58, 62, 87-92 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). AFFIRMED