Wisconsin Alumni Research FoundationDownload PDFPatent Trials and Appeals BoardDec 16, 20212021000625 (P.T.A.B. Dec. 16, 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. 15/850,416 12/21/2017 Runhui Liu 09824014-P170021US02 5814 60961 7590 12/16/2021 Intellectual Property Dept./DeWitt LLP Wisconsin Alumni Research Foundation 2 East Mifflin Street, Suite #600 Madison, WI 53703-2865 EXAMINER VANHORN, ABIGAIL LOUISE ART UNIT PAPER NUMBER 1616 NOTIFICATION DATE DELIVERY MODE 12/16/2021 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): IP-DOCKET@dewittllp.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte RUNHUI LIU, BERNARD WEISBLUM, SAMUEL GELLMAN, FANG YUN LIM, LESLIE ANNE RANK, NANCY P. KELLER, JIN WOO BOK, CHRISTINA M. HULL, NAOMI MARIE WALSH, and MINGWEI HUANG Appeal 2021-000625 Application 15/850,416 Technology Center 1600 Before ERIC B. GRIMES, TAWEN CHANG, 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 an antifungal pharmaceutical composition of nylon-3 polymers as 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 Wisconsin Alumni Research Foundation. (Appeal Br. 2.) Appeal 2021-000625 Application 15/850,416 2 STATEMENT OF THE CASE Appellant’s Specification states that “[n]aturally occurring host- defense peptides (HDPs) represent one of the first forms of chemical defense by eukaryotic cells against bacteria, fungi, viruses, and protozoa.” (Spec. 4.) “[T]hese peptides are usually cationic, amphipathic molecules.” (Id.) “The targets of most HDPs remain unclear, though some mechanisms of antifungal HDPs have been reported.” (Id.) “A variety of synthetic, cationic polymers resembling HDPs have been developed with antibacterial activity and relatively low toxicity towards eukaryotic cells (human red blood cells).” (Id.) According to Appellant’s Specification, “[f]ar fewer examples of synthetic polymers with selective activity against fungi and minimum cytotoxicity towards mammalian cells exist.” (Id. at 5.) Appellant’s invention is directed to nylon-3 polymers present in an amount to inhibit fungal growth. (Id. at 1.) Claim 19, reproduced below, is illustrative of the claimed subject matter: 19. A pharmaceutical composition comprising: a fungal growth-inhibiting amount of a nylon-3 copolymer having a formula: Appeal 2021-000625 Application 15/850,416 3 or a pharmaceutically suitable salt thereof, wherein: R1, R3, R4, R5, and R6 are each independently selected from the group consisting of hydrogen or substituted or unsubstituted C1-C6- alkyl; R2 is C1-C6-alkylene; “A” is hydrogen or an amino-protecting group; “B” is hydroxyl or a carboxy-protecting group; and “X,” “Y,” and “Z” are positive numbers; in combination with a pharmaceutically suitable carrier. (Appeal Br. Claims Appendix 4–5.) The prior art relied upon by the Examiner is: Name Reference Date R. Liu et al. Tuning the Biological Activity Profile of Antibacterial Polymers via Subunit Substitution Pattern, 136 J. Am. Chem. Soc. 4410–18 2014 B. Mowery et al. Structure–activity Relationships among Random Nylon-3 Copolymers That Mimic Antibacterial Host-Defense Peptides, 131 J. Am. Chem. Soc. 9735–45 2009 Kasher et al. US 2014/0238939 A1 Aug. 28, 2014 The following ground of rejection by the Examiner is before us on review: Claims 19–26 under 35 U.S.C. § 103 as unpatentable over Liu, Mowery, and Kasher. Appeal 2021-000625 Application 15/850,416 4 DISCUSSION Appellant does not address the claims separately. We select claim 19 as representative. The Examiner found that Liu teaches an antimicrobial nylon-3 copolymer made from dimethyl (DM) β-lactam and tetramethyl (TM) β- lactam in a 1:1 ratio having the following formula (Final Action 4–5.) The Examiner also found that Liu teaches in Figure 1a that seven β-lactams were used in the study, including not only DM, but MM with the following structure (Id. at 5; Advisory Action continuation sheet; Ans. 4.) The Examiner further found that Liu teaches that antimicrobial nylon- 3 copolymers with a cylochexyl-based β-lactam, CHβ, had been previously prepared, namely CHβ with MM and CHβ with DM. (Final Action 5; Ans. 4.) The Examiner found that Liu teaches that the previous exploration of MM and DM CHβ polymers demonstrated that both “proved to be optimal” with respect to their antibacterial activity. (Final Action 5 (citing Liu 4411, left column, experimental design).) The Examiner noted, however, that Liu Appeal 2021-000625 Application 15/850,416 5 teaches that in the present study the CH subunit copolymers were determined to be toxic to bacteria as well as to hRBC and fibroblasts, whereas the TM subunit was only toxic to bacteria. (Final Action 5.) The Examiner noted that Liu teaches that the DM:TM polymer “is only very weakly hemolytic at high concentrations whereas the other polymers had significantly higher hemolytic activity.” (Ans. 5 (citing Liu table 1).) Thus, explained the Examiner, Liu teaches the advantages of the TM monomer over the CHβ monomer in a nylon-3 copolymer with a cationic-hydrophobic copolymer structure. (Ans. 4; Final Action 8 (“Page 4411, right column, last sentence of the first paragraph states that the authors were surprised to discover that polymers containing the TM subunit displayed superior properties.”); Advisory Action continuation sheet.) In addition, the Examiner found that the “desire of Liu . . . is to provide polymers with lower hemolytic (red blood cell lysis) activity.” (Ans. 5.) The Examiner concluded from all of the foregoing teachings that “Liu suggests MM as a cationic subunit,” for use in a nylon-3 copolymer, although it “does not exemplify nylon-3 copolymers made from MM and TM.” (Final Action 5; Ans. 4–5.) Beyond the foregoing, however, the Examiner found that Mowery provides a further reason that one of ordinary skill in the art would have found it obvious to substitute MM for DM in a nylon-3 copolymer that includes TM. In particular, the Examiner found that Mowery teaches structure-activity relationships of nylon-3 random copolymers that mimic antibacterial host-defense peptides where polymers that were prepared included MM subunits or DM subunits. (Final Action 6 (citing Mowery Figure 7).) The Examiner noted that Mowery teaches when MM was Appeal 2021-000625 Application 15/850,416 6 replaced with DM, the net lipophilicity of the polymer was altered. (Id.) The Examiner found that Mowery teaches that “[t]rends suggest that increasing the overall lipophilicity of the polymer enhances hemolytic activity (page 9741, left column).” (Id.) In addition, the Examiner found that Mowery teaches that the DM homopolymer is more hemolytic than the MM homopolymer. (Id. (citing Mowery Table 1).) In light of the foregoing, the Examiner found that “the art as a whole . . . suggest[s] the advantages of replacing DM with MM” in Liu. (Ans. 5; Final Action 6.) The Examiner also found that there would have been a reasonable expectation of success in substituting MM for DM in a copolymer with TM. In particular, the Examiner determined that because the prior art demonstrated DM was used with TM to make antibacterial polymers and it is known that MM and DM are homologs differing only by a methyl group, and because MM and DM were successfully used with CHβ to make antibacterial polymers, that one of ordinary skill in the art would have reasonably expected to be able to substitute MM for DM in a nylon-3 copolymer including TM. (Final Action 6; Ans. 6–7.) Regarding the claim requirement of a carrier and the amount of the nylon-3 copolymer being a fungal growth-inhibiting amount, the Examiner found that Liu’s teachings render these limitations obvious for an MM/TM copolymer. In particular, the Examiner found that Liu “teach[es] solutions of the polymer[s]” that were made, which “necessarily indicates a carrier is present.” (Final Action 7.) In addition, the Examiner found that Liu “teaches [minimum inhibitory] concentrations overlapping with those exemplified in the instant specification” as being antifungal. (Id.; Ans. 7.) The Examiner further found that Kasher teaches nylon-3 copolymers Appeal 2021-000625 Application 15/850,416 7 comprising MM are antimicrobial and have the ability “to prevent, inhibit, reduce or destroy biofilm-forming microorganisms including bacteria, fungi, alga[e] or protozoa (paragraphs 0029, 0030 and paragraph 0070).” (Final Action 7.) Consequently, the Examiner concluded that it would be expected that the copolymer of MM and TM suggested by Liu and Mowery would have fungal growth inhibiting properties and one of ordinary skill in the art would have had “a reasonable expectation of success in forming a composition comprising a fungal growth-inhibiting amount of the instantly claimed nylon-3 copolymer.” (Ans. 7; Final Action 7, 9–10.) We agree with the Examiner’s finding of facts regarding the Liu and Mowery references as described above and the conclusion of obviousness. Appellant argues that Liu “literally teaches away from the claims by explicitly teaching that the cyclohexyl-based monomers are required for optimal performance.” (Appeal Br. 6.) Appellant contends that the description of using the MM co-monomer in Liu is restricted to the use in conjunction with a cyclically constrained co-monomer at 4411 and that Liu’s DM copolymer structures all include a co-monomer “incorporated into a ring system” which is a structure that is “outside the scope of the present claims.” (Appeal Br. 5–6.) We do not find Appellant’s arguments persuasive. We do not agree with Appellant that Liu teaches that cyclohexyl- based monomers are required for optimal performance or that all the DM copolymer structures explicitly described in Liu included a co-monomer incorporated into a ring system. Two of the four hydrophobic monomers used with the cationic subunit DM in the Liu “present study” were not cyclohexyl based. In particular, diethyl (βDEβ) and tretramethyl (TMβ) β Appeal 2021-000625 Application 15/850,416 8 lactam monomers were combined with DM. (See Liu 4411.) The structures of βDEβ and TMβ are set forth below. Furthermore, it was noted that these hydrophobic β-lactams “should be comparable in terms of hydrophobicity” to CH-DM and β-cyclopentyl (βCPβ)-DM nylon-3 polymers “because each contains four side chain carbon atoms.” (Id.) Liu then notes that “one might have predicted that all of the new copolymers would have less desirable activity profiles relative to 1:1 DM:CH, because none of the new hydrophobic subunits has a cyclic constraint on the backbone Cα-Cβ bond” and the Liu authors had “[r]ecently . . . showed that removing the six-membered ring constraint . . . led to a substantial (and unfavorable) increase in hemolytic activity along with a small diminution in antibacterial activity.” (Id.) However, as the Examiner noted, Liu states that they “were surprised . . . to discover that [the nylon-3] polymers containing the TM subunit display superior properties” compared to the DM:CH polymer and that 1:1 DM:TM was the best copolymer. (Id. 4411 and 4414.) In particular, Liu notes that 1:1 DM:TM had similar antibacterial activities to 1:1 DM:CH, and both were “potent bactericidal agents,” but 1:1 DM:TM was “only very weakly hemolytic at high concentrations” and that “the prokaryote-selective biological activity profile of 1:1 DM:TM is the most favorable among the four copolymers compared here and among all nylon-3 polymers we have examined.” (Id. at 4411– Appeal 2021-000625 Application 15/850,416 9 4412, 4414, Tables 1 and 2, and Figure 6.) It was also determined that it was “difficult for bacteria to develop resistance to” 1:1 DM:TM. (Id. at 4414.) Liu further notes that data from their study “suggests that polymers containing a hydrophobic subunit that is expected to be more flexible (βDE) are more strongly hemolytic than polymers containing isomeric but more conformationally constrained hydrophobic subunits (TM). (Id. at 4412–13.) Additionally, Liu notes that their studies with DM:CH and DM:TM lead to the conclusion “that the superior prokaryote vs eukaryote selectivity of the DM:TM copolymer arises from the intrinsic properties of the hydrophobic TM subunit, relative to CH, rather than from variations in subunit distribution along the polymer chains.” (Id. at 4413.) In short, Liu teaches that a noncyclohexyl based monomer, TM, was superior in selectivity to cyclohexyl based monomers while still providing bactericidal activity. Thus, we do not find persuasive of error Appellant’s argument that “the two-way combination of Liu et al. with Mowery et al. describes compounds that are outside the scope of the claims” (Appeal Br. 8). Furthermore, we agree with the Examiner that the teachings of Liu and Mowery would have suggested substitution of MM for DM to one of ordinary skill in the art in a nylon 3 copolymer using the hydrophobic TM co-monomer. Mowery teaches preparation of nylon-3 polymers using MM or DM cationic subunits in combination with different cyclic lipophilic/hydrophobic subunits and studying their activity as compared to host-defense peptides “and established that membrane lysis is one Appeal 2021-000625 Application 15/850,416 10 mechanism by which they are likely to act.” (Mowery 9737.) Mowery states: In the present study we evaluate the impact of structural parameters such as lipophilic subunit identity, cationic subunit identity, lipophilic:cationic proportion, length, and end group on the antibacterial and hemolytic activities of nylon-3 copolymers. (Id.) Mowery teaches that homopolymers of DM and MM “are generally comparable in antibacterial activity” but the “DM homopolymer is more hemolytic.” (Id. at 9742.) Mowery “evaluated the impact of varying the subunits [of copolymers] . . . on biological activity by replacing either MM or CHx with an analogous β-lactam in the ROP[2] process.” (Id. at 9740.) “MM was replaced with DM, which bears an additional methyl substituent.” (Id.) Mowery explains that all of the changes made to both the cationic and lipophilic/hydrophobic subunits “alter the net lipophilicity of the resulting polymers, since the analogous β-lactams differ from one another in the number of methylene units they contain.” (Id.) Mowery teaches that its study trends “suggest that increasing the overall lipophilicity of the polymer enhances hemolytic activity.” (Id. at 9741.) We note that the additional methyl group of DM compared to MM renders the DM group more lipophilic than the MM group. Given the teaching of Mowery that increasing the lipophilicity enhances hemolytic activity, one of ordinary skill in the art would have expected a DM copolymer as compared to an MM copolymer having the same lipophilic subunits to be comparatively more hemolytic. Consequently, we agree with 2 ROP stands for ring-opening polymerization. (Id. at 9737.) Appeal 2021-000625 Application 15/850,416 11 the Examiner that such a teaching in combination with Liu’s teachings of a DM:TM copolymer where it was determined that of the DM copolymers made, the copolymer with the TM subunit had the most favorable prokaryote-selective biological activity profile, would have suggested to one of ordinary skill in the art that replacing the DM subunit with an MM subunit would result in an even less hemolytic copolymer. Furthermore, as discussed, Liu describes making nylon-3 copolymers having cationic subunits and hydrophobic subunits and provides a list of seven β-Lactams “used in this study” in Figure 1a, only two of which are cationic monomers, i.e., DM and MM. Moreover, as the Examiner noted Liu teaches that it had previously studied antibacterial properties of MM:CH and DM:CH nylon-3 polymers. We conclude that the foregoing teachings would have motivated one of ordinary skill in the art to substitute MM for DM in the Liu DM:TM polymer in order to provide an even less hemolytic copolymer and still have comparable antibacterial activity to the DM:TM copolymer. And we conclude that the teachings of the prior art that MM and DM copolymers are able to be made with a number of different lipophilic monomers and both exhibited antibacterial activity (see, e.g., Mowery Figure 8, Liu Tables 1 and 2) would also have given one of ordinary skill in the art a reasonable expectation of being able to make the MM:TM polymer. For the foregoing reasons, we do not find persuasive of error Appellant’s argument that Mowery does not disclose MM:TM polymers or that Mowery does not “disclose or even remotely suggest a co-polymer which lacks a cyclically constrained co-monomer” (Appeal Br. 7). The Examiner’s rejection was not based on the teachings of Mowery alone, but Appeal 2021-000625 Application 15/850,416 12 rather the combination of Liu and Mowery. “In determining whether obviousness is established by combining the teachings of the prior art, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art.” In re GPAC Inc., 57 F.3d 1573, 1581 (Fed. Cir. 1995) (internal quotations omitted); In re Gorman, 933 F.2d 982, 986 (Fed. Cir. 1991) (The test of obviousness is “whether the teachings of the prior art, taken as a whole, would have made obvious the claimed invention.”). We now turn to the claim requirement of the nylon-3 copolymer being present in “a fungal growth-inhibiting amount.” We agree with the Examiner that Liu teaches MIC concentrations of DM:TM copolymers that overlap with MIC for MM:TM against certain Candida fungi. (Compare Spec. Table 8, with Liu Tables 1 and 2 and 4414 (“Further Antibacterial Studies with 1:1 DM:TM”).) Consequently, we conclude that it would have been obvious to one of ordinary skill in to arrive at an MM:TM composition by the substitution of MM for DM in the amounts taught by Liu which would inherently include a fungal inhibiting amount of the nylon-3 copolymer. Inherency may supply a missing claim limitation in an obviousness analysis. See, e.g., Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012); Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir. 2012); In re Kao, 639 F.3d 1057, 1070 (Fed. Cir. 2011); In re Kubin, 561 F.3d 1351, 1357 (Fed. Cir. 2009). “The fact that [A]ppellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” Ex parte Obiaya, 227 USPQ 58, 60 (BPAI 1985). Appeal 2021-000625 Application 15/850,416 13 Although it may be the case that one of ordinary skill in the art would not have recognized the amount was anti-fungal, such recognition is not necessary to establish the property was inherent to the composition. “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999); see also Abbott Labs. v. Baxter Pharm. Products, Inc., 471 F.3d 1363, 1367 (Fed. Cir. 2006) (“[A] reference may anticipate even when the relevant properties of the thing disclosed were not appreciated at the time.”). Thus, we affirm the Examiner’s rejection of claim 19 as being obvious from the teachings of Liu and Mowery. That we do not rely on Kasher to affirm the Examiner does not require we designate the affirmance as a new ground of rejection. In re Bush, 296 F.2d 491, 496 (CCPA 1961). Moreover, the Examiner noted the inherency aspect that we rely on. (Final Action 7; Ans. 7.) Claims 20–26, which have not been argued separately, fall with claim 19. 37 C.F.R. § 41.37(c)(1)(iv). DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 19–26 103 Liu, Mowery, Kasher 19–26 Appeal 2021-000625 Application 15/850,416 14 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 Copy with citationCopy as parenthetical citation