CHUGAI SEIYAKU KABUSHIKI KAISHA

Patent Trials and Appeals Board

Mar 22, 2022

2021002365 (P.T.A.B. Mar. 22, 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. 14/426,485 03/06/2015 Takashi Nakai NAKAI3 7325 1444 7590 03/22/2022 Browdy and Neimark, PLLC 1625 K Street, N.W. Suite 550 Washington, DC 20006 EXAMINER MAIER, LEIGH C ART UNIT PAPER NUMBER 1623 MAIL DATE DELIVERY MODE 03/22/2022 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 TAKASHI NAKAI, TOMOKO YASUGI, YOSHIHIRO TAMPO, KENJI YASUGI, and TSUYOSHI SHIMOBOJI __________ Appeal 2021-002365 Application 14/426,485 Technology Center 1600 __________ Before JEFFREY N. FREDMAN, TAWEN CHANG, and RACHEL H. TOWNSEND, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1 under 35 U.S.C. § 134 involving claims to a hyaluronic acid derivative, which is biodegradable and comprises a repeating unit. The Examiner rejected the claims under 35 U.S.C. § 103 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 Chugai Seiyaku Kabushiki Kaisha (see Appeal Br. 1). We have considered the Specification filed Mar. 6, 2015 (“Spec.”); Final Rejection of Jan. 28, 2020 (“Final Act.”); Appeal Brief filed Oct. 27, 2020 (“Appeal Br.”); Examiner’s Answer filed Dec. 18, 2020 (“Ans.”); and Reply Brief filed Feb. 18, 2021 (“Reply Br.”). Appeal 2021-002365 Application 14/426,485 2 Statement of the Case Background “There is a demand for a drug delivery system (DDS) matrix having a sustained release or targeting function for encapsulating a protein or a peptide without impairing its pharmacological activity” (Spec. ¶ 2). “Use of polysaccharides as matrices for pharmaceutical carriers has been recently reported. One of them, hyaluronic acid (HA)[,] is a biomaterial . . .[,] and it has been known for a long time as a main component of the extracellular matrix” (id. ¶ 6). “Conjugation of drug with hyaluronic acid has been reported to be successfully used in the drug targeting to cancerous tissue . . . the targeting to liver . . . and the reduction of [antigenicity]” (id. ¶ 7). “An object of the invention is to provide a hyaluronic acid derivative having properties of both biodegradability and retention in the blood” (id. ¶ 15). The Claims Claims 1, 2, 5, and 8-12 are on appeal. Claim 1 is independent, representative, and reproduced below: 1. A hyaluronic acid derivative, which is biodegradable and comprises a repeating unit represented by formula (I): Appeal 2021-002365 Application 14/426,485 3 where R1, R2, R3, and R4 are independently selected from a hydrogen atom, C1-6 alkyl, formyl, and C1-6 alkylcarbonyl; R5 is a hydrogen atom, formyl, or C1-6 alkylcarbonyl; X1 is hydroxy, -O-Q+, C1-6 alkoxy, -NR7R8, or -NH-Z1-Z2; Q+ represents a counter cation; R6, R7, and R8 are independently selected from a hydrogen atom and C1-6 alkyl; Ra is a hydrogen atom or C1-6 alkyl, where the alkyl may be independently substituted by one or more groups selected from hydroxy, carboxy, carbamoyl, C1-6 alkylthio, aryl, and heteroaryl, where the aryl may be substituted with one or more hydroxy groups; wherein when X1 is -NH-Z1-Z2, the group -CHRa-CONH-Z1-Z2 is represented by any one of the following formulae: Z1 is a C2-30 alkylene or -(CH2CH2O)m-CH2CH2-, where into the alkylene 1 to 5 groups independently selected from -O-, and -NRg- may be inserted, and m is an integer selected from 1 to 100; Z2 is selected from groups represented by the following formulas: -NRb-Z3, -NRb-COO-Z3, -NRb-CO-Z3, -NRb-CO-NRc-Z3, Appeal 2021-002365 Application 14/426,485 4 -CO-NRc-Z3, -S-Z3, -CO-Za-S-Z3, and -NRb-CO-Zb-S-Z3, Rb and Rc are independently selected from a hydrogen atom, C1- 20 alkyl, amino C2-20 alkyl, and hydroxy C2-20 alkyl, where into the alkyl moieties of the groups 1 to 3 groups independently selected from -O- and -NRf- may be inserted; Rf is independently selected from a hydrogen atom, C1-12 alkyl, amino C2-12 alkyl, and hydroxy C2-12 alkyl, and into the alkyl moieties of the groups 1 to 2 groups independently selected from -O- and -NH- may be inserted; Rg is independently selected from a hydrogen atom, C1-20 alkyl, amino C2-20 alkyl, or hydroxy C2-20 alkyl, and into the alkyl moieties of the groups 1 to 3 groups independently selected from -O- and -NH- may be inserted; Z3 is cholesteryl, stigmasteryl, lanosteryl, ergosteryl, cholanoyl, or choloyl; Za is C1-5 alkylene; and Zb is C2-8 alkylene or C2-8 alkenylene, wherein the hyaluronic acid derivative comprises at least one repeating unit represented by formula (I) in which X1 is NH-Z1-Z2, and wherein a percentage of the repeating unit represented by formula (I) is 95 to 100%. Appeal 2021-002365 Application 14/426,485 5 The Rejection The Examiner rejected claims 1, 2, 5, and 8-12 under 35 U.S.C. § 103(a) as obvious over Akiyoshi,2 Schante,3 and Yasugi4 (Final Act. 2- 10). The issue with respect to this rejection are: Does a preponderance of the evidence of record support the Examiner’s conclusion that the prior art renders the rejected claims obvious? Findings of Fact 1. Akiyoshi teaches that hyaluronic acid (HA) is “one of the safest medical biomaterials in terms of immunity and toxicity. Recent years have enabled microbial mass production of high-molecular-weight HA and also have allowed practical use of HA in the fields of therapeutic agents for degenerated cartilage, cosmetics” (Akiyoshi ¶ 7). 2. Akiyoshi teaches the “use of modified HA for the purpose to prolong residence time in blood . . . use of an alkyl chain-introduced HA derivative for the purpose to prolong residence time in the knee joint . . . use of in situ crosslinked HA gel for sustained release of a protein” (Akiyoshi ¶ 8). 2 Akiyoshi et al., US 2011/0212901 A1, published Sept. 1, 2011. 3 Schante et al., Synthesis of N-alanyl-hyaluronamide with high degree of substitution for enhanced resistance to hyaluronidase-mediated digestion, 86 Carbohydrate Polymers 747-52 (2011). 4 Yasugi et al., US 2009/0148534 A1, published June 11, 2009. Appeal 2021-002365 Application 14/426,485 6 3. The structure of Akiyoshi is compared to claim 1, in relevant parts, below: Claim 1 Formula I of Akiyoshi (¶ 60) where R1, R2, R3, and R4 are independently selected from a hydrogen atom, C1-6 alkyl, formyl, and C1-6 alkylcarbonyl Akiyoshi teaches R1, R2, R3, and R4 are each independently selected from a hydrogen atom, C1-6 alkyl, formyl, and C1-6 alkylcarbonyl (¶ 61) R5 is a hydrogen atom, formyl, or C1-6 alkylcarbonyl Akiyoshi teaches a C1 alkyl carbonyl group at the R5 position of claim 1 (¶ 60) X1 is attached to the hyaluronic acid by a linker comprising a single amino acid (-NR6-CHRa-C(O)-) Akiyoshi teaches that Y may be - (CH2CH2O)m- and linked to an X1 group (¶ 78) X1 itself may be hydroxy, -O-Q+, C1-6 alkoxy, -NR7R8, or -NH-Z1-Z2; where Q+ represents a counter cation; where R7, and R8 are Akiyoshi teaches that the X1 group may be hydroxy, NRb-R, among other overlapping disclosures (¶¶ 63-77, 92-110) Appeal 2021-002365 Application 14/426,485 7 independently selected from a hydrogen atom and C1-6 alkyl; and where Z1-Z2 may be alkylene or other groups. 4. The Examiner acknowledges that while Akiyoshi teaches “HA cholesteryl conjugates may be prepared starting with other HA derivatives and not limited to HA, per se[, Akiyoshi] is silent regarding the use of a starting derivative or a suggested linker configuration that would provide the instant product” (Final Act. 4). 5. Schante teaches we prepared Ala-HA using different chemical methods and showed that alanine can be condensed to carboxylic acid of HA at will and at degrees of substitution up to 100%. The various chemical processes did induce HA fragmentation but to still acceptable levels. Moreover, we also demonstrated that Ala- HAs present enhanced resistance towards enzymatic digestion while forming solutions with shear-thinning properties. These results suggest that Ala-HAs and similar aminoacid-HA derivatives may become interesting for viscosupplementation purposes. (Schante 752, col. 1). Appeal 2021-002365 Application 14/426,485 8 6. Schante teaches an hyaluronic acid conjugate with 100% substitution that differs from claim 1 only in the absence of an NH-Z1-Z2 group in a repeating unit as shown in Figure 1, partially reproduced below: “Fig. 1. Chemical structure of . . . N-alanyl-hyaluronamide with a degree of substitution of 100%” (Schante 748). 7. Figure 5 of Schante is reproduced below: “Fig. 5. Enzymatic degradation profiles for the various alanyl- hyaluronamide. Each polymer solution (2 mM) was incubated with hyaluronidase 4.106 IU/mL in PBS at 37 ºC. Fragmented HAs were detected by colorimetric dosage of NAG reducing ends” (Schante 751, col. 2). Appeal 2021-002365 Application 14/426,485 9 8. Yasugi teaches: In general, when a substituent is introduced into hyaluronic acid, the residence time in blood is elongated, and it is considered that the degree of such elongation correlates to the introduction rate of a substituent. A modified hyaluronic acid obtained by introducing substituents into various sites of hyaluronic acid has been reported. . . . Thus, it is considered that the modified hyaluronic acid is excellent in terms of the residence time in blood. (Yasugi ¶ 6). Principles of Law “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). “If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” Id. at 417. Analysis We adopt the Examiner’s findings of fact and conclusion of law (see Final Act. 2-10, FF 1-8) and agree that the combination of Akiyoshi, Schante, and Yasugi renders the claims obvious. In particular, we note that Schante teaches a hyaluronic derivative within the scope of claim 1, including a repeating unit between 95 and 100%, and that differs from claim 1 only in not having at least one repeating unit where X1 is NH-Z1-Z2 (FF 6). And Akiyoshi teaches a variety of hyaluronic derivatives that may include groups satisfying the claim requirement for an X1 that is NH-Z1-Z2 (FF 1-3). Yasugi provides reasons for modifying hyaluronic acids such as those of Schante with linkers and substituents as in Akiyoshi to improve blood residence time (FF 7). We address Appellant’s arguments below. Appeal 2021-002365 Application 14/426,485 10 Appellant contends that “the desired property of biodegradability, such as by susceptibility to enzymatic cleavage/digestion (e.g., with a peptidase), in Akiyoshi in the body of the patient to be treated in order to release the drug from being encapsulated by the HA derivative is the diametric opposite of the desired property of enhanced resistance to enzyme digestion in Schante” (Appeal Br. 6 (emphasis omitted)). We find this argument unpersuasive because Akiyoshi is not simply interested in biodegradability per se, but rather Akiyoshi teaches “[h]aving a degradable chemically crosslinked structure enables control of the biodegradation rate of a gel, which in turn also enables control of the drug release rate” (Akiyoshi ¶ 144). So Akiyoshi is interested in controlled biodegradation, not simply maximum biodegradation. This is consistent with Schante who teaches “[r]esults show alanine modification to diminish enzymatic degradation according to the grafting degree” (Schante 752, col. 1). That is, Akiyoshi teaches a desire for controlled biodegradation and Schante teaches that the use of alanine modifications allows such control of enzyme degradation. Therefore, rather than being inconsistent, both Akiyoshi and Schante teach hyaluronic acid derivatives that permit controlled biodegradation. Appellant contends the Nakai5 Declaration states that he, as a person of skill in the art, would consider such a difference between the spacers to bring a substantial change in the property of the resulting hyaluronic acid derivatives. A single amino acid is different from a peptide of two or more amino acid residues as there is no peptide bond available for enzymatic cleavage by peptidases in the body. There is no 5 Declaration of Takashi Nakai, dated Feb. 26, 2018. Appeal 2021-002365 Application 14/426,485 11 reasonable expectation of success in substituting a single amino acid for peptides with enzymatically cleavable peptide bonds. (Appeal Br. 8; citing Nakai Decl. 2). We find this argument unpersuasive because the actual data in Schante demonstrates enzymatic degradation of the alanyl-hyaluronamides on a time frame of 1 to 6 hours (FF 7).6 Moreover, neither Appellant nor the Declarant provides any evidence, as opposed to opinion statements, suggesting that the presence of a peptide bond would necessarily result in non-functional molecules. We note that the standard is that “[o]bviousness does not require absolute predictability of success . . . all that is required is a reasonable expectation of success.” In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009) (emphasis omitted) (citation omitted). There is a strong expectation of success in synthesis of the obvious product based on the teachings of the prior art and a reasonable expectation that the compounds rendered obvious would be useful in the methods of Akiyoshi, as Akiyoshi teaches the use of “a peptide linker comprising 2 to 30 arbitrary amino acid residues” (Akiyoshi ¶ 62). Akiyoshi is a published US patent application and as such, “is presumptively enabling barring any showing to the contrary by a patent applicant.” In re Antor Media Corp., 689 F.3d 1282, 1288 (Fed. Cir. 2012). No such persuasive showing has been made by Appellant. The Board is entitled to weigh declarations expressing opinions as to fact and conclude that the lack of factual corroboration warrants discounting the opinions expressed in the declarations. In re Am. Acad. of Sci. Tech. 6 We appreciate that peptidases and hyaluronidases are different enzymes, but the evidence in Schante demonstrates that enzyme degradation functions on these molecules, suggesting that steric hindrance is not a concern. Appeal 2021-002365 Application 14/426,485 12 Ctr., 367 F.3d 1359, 1368 (Fed. Cir. 2004). Moreover, a declaration by the named inventor is less persuasive than one made by a disinterested person. See In re Bulina, 362 F.2d 555, 559 (CCPA 1966). Therefore, while we consider the Nakai Declaration, we do not find it persuasive in overcoming the presumptively enabling disclosures in the prior art. Appellant contends that: the experimental results from the specification show that the HA derivative of Comparative Example 1-2 (paragraphs [0283]-[0285] of the specification), which is HA-EDOBEA- Ac/FL and which includes the following unit, with a direct amide bond . . . was found to be not metabolized (i.e., not biodegradable) in Fig. 2-2-26 (Appeal Br. 9). Appellant further contends: Based on the clear difference in biodegradability between the HA derivatives of the present invention and an HA derivative with an amide bond (but not a single amino acid as spacer), there is no reasonable expectation of success with a single amino acid as spacer since an amine derivatized HA with an amide bond (e.g., when Z in Akiyoshi is a direct bond with no amino acid present, as held by the examiner to be similar to the amide bond in a single amino acid) would be biodegradable. (id. at 10). We find these arguments unpersuasive as we agree with the Examiner’s statement that: It is not immediately clear how this is relevant as Akiyoshi clearly exemplifies amide-bonded derivatives with a hydrophobic moiety, as required by the claims, and expressly describes them as being biodegradable. Furthermore, Schante demonstrates that all the substituted products are biodegradable. Appellant contends that the fact that this comparison example (without the required hydrophobic moiety) is not biodegradable serves to demonstrate that there would be no reasonable Appeal 2021-002365 Application 14/426,485 13 expectation of success in making this modification. However, Appellant fails to address the fact that Akiyoshi’s amide- substituted products are biodegradable. (Ans. 9). Appellant contends “[t]here is no disclosure, teaching or suggestion in Schante regarding use of N-alanyl-hyaluronamide as a material for drug delivery, biodegradability and retention time in the blood” (Appeal Br. 11). Appellant notes that Schante cites Esposito7 and contends The HA derivatives described in this Esposito publication are entirely different from the N-alanyl-hyaluronamide (Ala-HA) disclosed in Schante, and one of ordinary skill in the art would not have considered the mere reference to Esposito in Schante as providing a teaching for use of N-alanyl-hyaluronamide described in Schante as an alternative in drug delivery. (id. at 12). We find this argument unpersuasive because Schante expressly teaches hyaluronic acid has many uses and identifies “applications include drug delivery and wound healing,” citing Esposito. Thus, the ordinary artisan would have recognized that Schante understood that one use of hyaluronic acid derivatives includes drug delivery as well as degenerated cartilage. Indeed, Akiyoshi also teaches the “use of HA in the fields of therapeutic agents for degenerated cartilage” (Akiyoshi ¶ 7) as well as using hyaluronic acid derivatives as “a matrix which can be used as a carrier for sustained release in blood and a targeting carrier excellent in residence time 7 Esposito et al., Hyaluronan-based microspheres as tools for drug delivery: a comparative study, 288 International J. of Pharmaceutics 35-49 (2005). Appeal 2021-002365 Application 14/426,485 14 in blood and is capable of serving as a local (e.g., in the subcutis) sustained- release carrier which enables sustained release of a drug” (Akiyoshi ¶ 57). Thus, the ordinarily skilled artisan certainly had reason to use hyaluronic acid derivatives as known compounds for enhancing drug delivery and as cartilage therapeutic agents and would have recognized that these modifications would “provide two variables for [drug delivery] optimization - (1) the degree of overall amidation and (2) the degree of incorporation of a hydrophobic steryl group” (Final Act. 5). The use of these modifications amounts “to applying a known technique to modify a product with predictable results” (Ans. 9-10). And Yasugi evidences a desire for such derivatives because “modified hyaluronic acid is excellent in terms of the residence time in blood” (FF 8). Therefore, the prior art provides reasons to select and modify hyaluronic acid as suggested by Schante and Akiyoshi in order to maximize treatment efficacy. Conclusion of Law A preponderance of the evidence of record support the Examiner’s conclusion that the prior art renders the rejected claims obvious. DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 2, 5, 8-12 103 Akiyoshi, Schante, Yasugi 1, 2, 5, 8-12 Appeal 2021-002365 Application 14/426,485 15 No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED