KYOWA HAKKO BIO CO., LTD.

Patent Trials and Appeals Board

Mar 14, 2022

2020004794 (P.T.A.B. Mar. 14, 2022)

UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 15/334,600 10/26/2016 Masahiko Morita 137466.00005 8876 29880 7590 03/14/2022 Fox Rothschild LLP 997 Lenox Drive Lawrenceville, NJ 08648 EXAMINER DABKOWSKI, ERINNE R ART UNIT PAPER NUMBER 1654 NOTIFICATION DATE DELIVERY MODE 03/14/2022 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): ipdocket@foxrothschild.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte MASAHIKO MORITA, MIHO KOMATSU, and TAKAHIRO HARA1 Appeal 2020-004794 Application 15/334,600 Technology Center 1600 Before ERIC B. GRIMES, ULRIKE W. JENKS, and RACHEL H. TOWNSEND, Administrative Patent Judges. GRIMES, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134(a) involving claims to a method of enhancing nitric oxide (NO) production in a subject, which have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 Appellant identifies the real party in interest as KYOWA HAKKO BIO CO., LTD. Appeal Br. 3. “Appellant” refers to “applicant” as defined in 37 C.F.R. § 1.42. Appeal 2020-004794 Application 15/334,600 2 STATEMENT OF THE CASE “The present invention relates to an agent for preventing or ameliorating vascular endothelial malfunction having an improved effect of enhancing nitrogen monoxide (NO) production.” Spec. ¶ 1.2 “NO produced by vascular endothelial cells exhibits a wide range of physiological activities for maintaining normal blood vessel functions.” Id. ¶ 3. The Specification discloses “an agent for preventing or ameliorating vascular endothelial malfunction which is safe, effective, and has an improved enhancing effect on NO production, and comprises citrulline or a salt thereof and glutathione or a salt thereof as active ingredients.” Id. ¶ 11. “Citrulline is a type of amino acid . . . [that] plays important roles in the body, serving as an arginine precursor in arginine biosynthesis.” Id. ¶ 2. “Glutathione is a tripeptide . . . and plays central roles in the mechanism of removing reactive oxygen species in vivo.” Id. ¶ 4. Claims 4-6 are on appeal. Claim 4, reproduced below, is illustrative: 4. A method for long-lasting enhancement of NO production comprising administering an agent comprising citrulline or a salt thereof and glutathione or a salt thereof to a subject in need thereof, wherein a ratio of citrulline to glutathione found in the agent range from 20:1 to 1:1 and amount of citrulline or a salt thereof in one dose of the agent range from 1 to 2 g and amount of glutathione or salt thereof in one dose of the agent range from 200 mg to 1 g. 2 NO is also called nitric oxide. See, e.g., Guilford (footnote 3, infra) at 3:2. Appeal 2020-004794 Application 15/334,600 3 OPINION Claims 4-6 stand rejected under 35 U.S.C. § 103(a) as obvious based on Guilford,3 Schwedhelm,4 and Engleman.5 Non-Final Action6 5. The Examiner finds that Guilford teaches a composition comprising glutathione and arginine for treating patients having vascular disease, and therefore “in need for enhancement of NO production.” Id. at 5-6. The Examiner also finds that Guilford suggests that citrulline can be substituted for the arginine in its composition. Id. at 6. The Examiner finds that Guilford teaches “several different doses of glutathione and L-arginine,” including 2.5 g glutathione plus 3.0 g arginine, and 800 mg glutathione plus 950 mg arginine, but does not teach a citrulline dose of 1-2 grams or the citrulline:glutathione ratio recited in claim 4. Id. The Examiner finds, however, that Schwedhelm teaches that “oral L-citrulline supplementation raises plasma L-arginine concentration and augments NO-dependent signaling, and that “use of citrulline at a dosage of . . . 1500 [mg] increased plasma L-arginine.” Id. The Examiner also finds that “Engleman teaches treatment of vascular diseases comprising administering doses of citrulline less than 1.7 grams per day,” including “1000 or 1600 mg of citrulline.” Id. 3 Guilford, WO 2007/115131 A2, published Oct. 11, 2007. 4 Schwedhelm, “Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism,” Br. J. Clin. Pharmacol. 65(1):51-59 (2007). 5 Cha et al., WO 2006/002096 A2, published Jan. 5, 2006. The Examiner and Appellant refer to this reference as “Engleman,” so we do as well. 6 Office Action mailed March 20, 2019. Appeal 2020-004794 Application 15/334,600 4 The Examiner concludes that it would have been obvious “to use 1500 mg of citrulline as taught by Schwedhelm and Engleman in combination with [Guilford’s] 800 mg (resulting in a ratio of 1.875/1) of glutathione to enhance nitric oxide production which is beneficial for improving endothelial function and treatment of vascular disease.” Id. The Examiner also reasons that “the dosages and ratios of glutathione and citrulline are considered result effective variables. . . . Therefore, it would have been obvious to optimize dosages and ratios of glutathione and citrulline to achieve optimal activity and therapeutic effectiveness of the composition in patients.” Id. at 7. We agree with the Examiner that the method of claim 4 would have been obvious to a person of ordinary skill in the art based on the cited references. Guilford discloses “us[ing] the combination of liposomal reduced glutathione and l-arginine to increase the ability weight loss in individuals with excess weight.” Guilford, abstract. Guilford discloses that its “invention is useful for the management of the metabolic syndrome. The metabolic syndrome is actually a group of metabolic factors associated with an increased risk of vascular disease problems.” Id. at 2:10-12. In one example, Guilford describes a patient with “elevated blood pressure and excess weight.” Id. at 36:27-28. The patient “us[ed] doses of liposomal glutathione 800 mg morning and l-arginine 950 mg, with each of these ingested together twice a day.” Id. at 37:4-6. Guilford also discloses using a combination of “[l]iposomal glutathione 1200 mg + arginine 1500 mg plus colloidal silver 32 ppm of silver nano particles 10 cc to be used three times a day for the treatment of acute malarial disease.” Id. at 34:17- Appeal 2020-004794 Application 15/334,600 5 19. Guilford discloses using the same combination for treating lyme disease. Id. at 34:24-26. Guilford states that “[a]lternative biochemicals may be substituted for arginine in the formation of nitric oxide. . . . Citrulline will also become incorporated in the pathways forming arginine and may be considered a substitute for arginine.” Id. at 32:8-11. Schwedhelm discloses that “[a]fter oral administration, L-arginine is subject to extensive presystemic and systemic elimination. . . . L-citrulline is not subject to presystemic elimination but to systemic metabolism. L-Citrulline is converted to . . . L-arginine. . . . It may therefore serve as an L-arginine precursor.” Schwedhelm 52, left col. Schwedhelm states that its data showed that “[t]he peak plasma arginine concentration was significantly increased for L-citrulline administration at a dose of 1.5 g twice daily compared with L-arginine SR [sustained release].” Id. at 54, right col. to 55, left col. Schwedhelm concludes that “that oral administration of L-citrulline efficiently increases L-arginine plasma concentrations in healthy human,” and that its “findings strongly suggest that oral L-citrulline is at least as efficient in improving plasma L-arginine concentrations in man as is oral administration of L-arginine.” Id. at 55, left col. Engleman discloses that “low doses (<1.7 g per day) of L-citrulline are efficacious for treating sexual dysfunction, vascular diseases, infertility; and improving health.” Engleman 4:16-17. “A therapeutically effective dose of L-citrulline often elevates L-arginine level in a target organ and/or plasma or serum.” Id. at 4:19-21. Engleman states that “[l]ow doses of L-citrulline Appeal 2020-004794 Application 15/334,600 6 are beneficial in treating vascular disease, which includes but is not limited to peripheral arterial disease, nitrate tolerance, sickle cell disease, pulmonary hypertension, coronary artery disease, cerebrovascular disease, and migraine headache.” Id. at 4:30-33. Engleman also states that “low doses of L-citrulline improve blood flow, which leads to improved vascular compliance and exercise tolerance in subjects that are in good health as well as subjects affected by vascular diseases.” Id. at 6:33 to 7:2. Engleman teaches that [t]he amount of active compound (L-citrulline) administered depends on the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician. The effective dose of the present invention is less than 1.7 g/day. In one embodiment, an effective dosage of L-citrulline is in the range of 250 to 1600 mg/day. In another embodiment, an effective dosage is in the range of 500, 750, or 1000 to 1600 mg/day. In another embodiment, an effective dosage is in the range of 500, 750, or 1000 to 1500 mg/day. These doses may be administered all at a time or in divided doses. The dosage of these compounds may vary in accordance with the administration route, the age of the patient and the degree of the therapeutic effect desired. Id. at 8:17-25. Based on these teachings, it would have been obvious to administer a combination of glutathione and citrulline to a subject in need of long-lasting enhancement of NO production, such as a subject suffering from or at risk of vascular disease, because Guilford suggests that the combination of glutathione and arginine is useful for management of metabolic syndrome, which is associated with increased risk of vascular disease (Guilford 2:10- 12), Guilford suggests substituting citrulline for arginine (id. at 32:10-11), Appeal 2020-004794 Application 15/334,600 7 and Engleman teaches that citrulline is effective in treating vascular diseases (Engleman 4:16-17). In addition, the amounts and ratio of glutathione and citrulline recited in claim 4 would have been obvious based on the cited references. Guilford suggests doses of glutathione that are between 200 mg and one gram; e.g., “doses of liposomal glutathione 800 mg” (Guilford 37:4-5), “liposomal glutathione drink 420 mg per teaspoon” (id. at 37:20-21); and “one gram capsule contains 450 mg reduced glutathione” (id. at 40:4-5). Guilford also suggests an arginine:glutathione ratio between 20:1 and 1:1; e.g., 3000 mg arginine per ounce plus 2500 mg glutathione per ounce (a 1.2:1 ratio, Guilford 32:15-16), 1500 mg arginine plus 1200 mg liposomal glutathione (a 1.25:1 ratio, id. at 34:17), and 950 mg arginine plus 800 mg liposomal glutathione (a 1.19:1 ratio; id. at 37:4-5). In addition, Guilford suggests arginine doses of one to two grams. See Guilford 34:17 (“l-arginine 1000 mg”), 37:20 (“l-Arginine 1000 mg to 3000 mg is ingested orally”). Similarly, Schwedhelm and Engleman disclose doses of citrulline between one and two grams. See Schwedhelm 55, left col. (“L-citrulline administration at a dose of 1.5 g twice daily”), Engleman 4:14 (“low doses (<1. 7 g per day) of L-citrulline are efficacious”). Finally, Engleman expressly states that the dose of citrulline is a result-effective variable: The amount of active compound (L-citrulline) administered depends on the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician. . . . In another embodiment, an effective dosage is in the range of . . . 1000 to 1500 mg/day. These doses may be administered all at a time or in divided Appeal 2020-004794 Application 15/334,600 8 doses. The dosage of these compounds may vary in accordance with the administration route, the age of the patient and the degree of the therapeutic effect desired. Engleman 8:17-25. “It has long been established law that ‘where 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.’” ModernaTx, Inc. v. Arbutus Biopharma Corp., 18 F.4th 1364, 1375 (Fed. Cir. 2021) (quoting In re Aller, 220 F.2d 454, 456 (CCPA 1955)). See also In re Boesch, 617 F.2d 272, 276 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”). Here, the doses of glutathione and citrulline recited in claim 4, as well as the range of citrulline:glutathione ratios, encompass the amounts and ratios described in the prior art, and the prior art states that the dose of citrulline is a result-effective variable. We therefore agree with the Examiner that a person of ordinary skill in the art would have been led to doses of citrulline and glutathione, and a citrulline:glutathione ratio, within the ranges recited in claim 4 through routine optimization Appellant argues that “Guilford . . . contains only one mention of potentially substituting citrulline for arginine (page 32, lines 10-11) - being silent to the dosage of citrulline.” Appeal Br. 11. Appellant argues that “there is no motivation for one of skill in the art to combine the teachings of Scwedhelm [sic] or Engleman, which are directed to citrulline, with those of Guilford because neither Schwedhelm nor Engleman even mentions glutathione.” Id. Appellant argues that, “[i]n fact, Schwedhelm actually Appeal 2020-004794 Application 15/334,600 9 discloses the effectiveness of using citrulline by itself, teaching that it is at least as if not more effective than arginine.” Id. This argument is not persuasive. Guilford states that “[c]itrulline . . . may be considered a substitute for arginine” (Guilford 32:10-11), and thus expressly suggests substituting citrulline for the arginine in its composition. Schwedhelm confirms that citrulline is an effective substitute for arginine, stating that “oral L-citrulline is at least as efficient in improving plasma L- arginine concentrations in man as is oral administration of L-arginine” (Schwedhelm 55, left col.). Finally, Engleman states that “a therapeutically effective amount of L-citrulline of up to 1.7 grams per day . . . often elevates L-arginine in a target organ and/or plasma” (Engleman 4:18-20). The cited references thus provide ample reason to substitute citrulline for the arginine in Guilford’s composition. Appellant also argues that the claimed “methods provide a synergistic effect that is unexpected in view of the prior art. Specifically, as shown in Figures 1 and 2 and described in Test Examples 1 and 2, the combined use of citrulline and glutathione at the concentrations claimed in vivo synergistically promoted NO production.” Appeal Br. 12. We have considered the data in the cited examples but are not persuaded that it shows that the claimed method results in unexpected synergy. Test Example 1 describes an experiment using “[a] normal human umbilical vein endothelial cell (HUVEC) line.” Spec. ¶ 44. Test Example 1 is therefore an in vitro experiment, not a “method . . . comprising administering an agent comprising citrulline or a salt thereof and glutathione Appeal 2020-004794 Application 15/334,600 10 or a salt thereof to a subject in need thereof,” as claimed, and cannot show unexpected results for the claimed method. Test Example 2 is an experiment in which “ rats . . . received either purified water . . . , L-citrulline (500 mg/kg/day) (n = 8), or a combination of L-citrulline (500 mg/kg/day) plus reduced glutathione (50 mg/kg/day) (n = 8).” Spec. ¶ 48. The Specification states that the “results demonstrated that an enhancing effect of NO production of L-citrulline + reduced glutathione group was significantly greater than those of control group and L-citrulline group.” Id. ¶ 49. The Specification also states that “[t]hese results show that the combination use of citrulline and glutathione. . . enhances NO production synergistically.” Id. ¶ 50. The data, however, do not support the Specification’s conclusion that Test Example 2 demonstrates synergy between citrulline and glutathione. “Synergism” occurs when a combination’s effect is greater than would be expected based on the effect of each component of the combination, by itself. See Richardson-Vicks Inc. v. Upjohn Co., 122 F.3d 1476, 1481 (Fed. Cir. 1997) (“The combination dosage of a ratio of ibuprofen to pseudoephedrine of 7:1 . . . demonstrated that the combination produced greater pain relief than that dictated by the pain relief properties of the two drugs individually. In other words, the two drugs produced a ‘synergistic’ effect.”). Here, as the Examiner has pointed out, “[t]o determine synergism, Appellants would need to show administering glutathione, glutathione + citrulline and citrulline to subjects and then measuring nitric oxide production.” Ans. 10. But “there is no GSH [glutathione] alone group” in Appeal 2020-004794 Application 15/334,600 11 Test Example 2 or Figure 2. Id. at 11. In other words, the data do not show what effect glutathione has by itself in enhancing effect of NO production. And, because the effect of glutathione alone is unknown, it cannot be determined whether the effect of glutathione plus citrulline is greater than would be expected based on the effect of glutathione alone and the effect of citrulline alone. The data do not show synergy for the claimed combination. As further evidence of unexpected results, Appellant points to the Morita Declaration7 and the McKinley-Barnard reference8 cited therein. Dr. Morita states that McKinley-Barnard states that the effect of “‘L-citrulline + GSH was significantly greater than placebo at 30 min post-exercise’ for NOx (Fig. 8).” Morita Decl. ¶ 5. Dr. Morita declares that this experimental result shows the synergic [sic] effect of the combination of citrulline and glutathione, and that this synergistic effect was unexpected. In Fig. 8, at 30 Post-Ex, Δ Plasma NOx was zero both in CIT alone and GSH alone. The combination of no effects (i.e., Δ Plasma NOx = zero) is considered to be no effect, but the high Δ Plasma NOx was observed in CIT + GSH. Therefore, the effect of the combination of citrulline and glutathione is unexpected. The claimed invention unexpectedly provided long-lasting enhancement of nitrogen monoxide NO production without affecting the survival rate and proliferative ability of vascular endothelial cells. Morita Decl. ¶ 5. 7 Declaration under 37 C.F.R. § 1.132 of Masahiko Morita, filed April 30, 2018. 8 McKinley-Barnard et al., “Combined L-citrulline and glutathione supplementation increases the concentration of markers indicative of nitric oxide synthesis,” J. Intl. Soc. Sports Nutrition 12:27 (2015). Our citations are to the copy of record, which is an Open Access article with pages numbered 1-8. Appeal 2020-004794 Application 15/334,600 12 Appellant argues that the Morita Declaration “show[s] that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage.” Appeal Br. 15. We have considered the Morita Declaration and the McKinley- Barnard reference but do not agree that the evidence shows nonobviousness for the claimed method. Dr. Morita declares that the results shown in McKinley-Barnard’s Figure 8 show that “the combination of citrulline and glutathione . . . [provides a] synergistic effect [that] was unexpected.” Morita Decl. ¶ 5. However, even assuming that the combination of citrulline and glutathione resulted in a greater-than-additive (i.e., synergistic) effect as compared to citrulline or glutathione alone, “[s]ynergism, in and of itself, is not conclusive of unobviousness in that synergism might be expected.” In re Kollman, 595 F.2d 48, 55 n.6 (CCPA 1979). What is required is evidence of unexpected results, and “evidence of unexpected results must establish that there is a difference between the results obtained and those of the closest prior art, and that the difference would not have been expected by one of ordinary skill in the art at the time of the invention.” Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014). Here, the closest prior art is Guilford’s disclosed combination of glutathione and arginine, and Appellant’s evidence provides no comparison of the claimed method of administering citrulline and glutathione with Guilford’s method of administering arginine and glutathione. Appeal 2020-004794 Application 15/334,600 13 In addition, “[e]vidence of secondary considerations must be reasonably commensurate with the scope of the claims.” In re Huai-Hung Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011). That is, “[i]f an applicant demonstrates that an embodiment has an unexpected result and provides an adequate basis to support the conclusion that other embodiments falling within the claim will behave in the same manner, this will generally establish that the evidence is commensurate with [the] scope of the claims.” Id. Here, claim 4 encompasses administration of an agent containing 1-2 grams of citrulline and 200 mg to 1 gram of glutathione, in a citrulline:glutathione ratio of 20:1 to 1:1. McKinley-Barnard discloses that its human testing involved a daily dose of placebo, citrulline alone (2 g/day), glutathione alone (1 g/day), or the combination of citrulline (2 g/day) and glutathione (200 mg/day). McKinley-Barnard 3, right col. Thus, the dose administered by McKinley-Barnard represents only the highest citrulline dose recited in claim 4 (2 g), combined with the lowest glutathione dose recited in claim 4 (200 mg), at a citrulline:glutathione ratio of 10:1. Appellant has not pointed to evidence showing the effect of other doses of citrulline and glutathione, at other ratios, and so has not “provide[d] an adequate basis to support the conclusion that other embodiments falling within the claim will behave in the same manner.” In re Huai-Hung Kao, 639 F.3d at 1068. Thus, even if Appellant’s evidence shows unexpected results, those results are not commensurate in scope with the claims. Appeal 2020-004794 Application 15/334,600 14 In summary, we affirm the rejection of claim 4 under 35 U.S.C. § 103(a) based on Guilford, Schwedhelm, and Engleman. Claims 5 and 6 fall with claim 4. 37 C.F.R. § 41.37(c)(1)(iv). DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 4-6 103(a) Guilford, Schwedhelm, Engleman 4-6 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