BSN medical GmbH

Patent Trials and Appeals Board

Apr 1, 2022

2020006791 (P.T.A.B. Apr. 1, 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. 15/569,320 10/25/2017 Karsten HEMMRICH FAR-43271 9281 75628 7590 04/01/2022 RANKIN, HILL & CLARK LLP P.O. Box 1150 BONITA SPRINGS, FL 34133-1150 EXAMINER PEEBLES, KATHERINE ART UNIT PAPER NUMBER 1617 NOTIFICATION DATE DELIVERY MODE 04/01/2022 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): 75628@rankinhill.com digges@rankinhill.com shea@rankinhill.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte KARSTEN HEMMRICH, ANNAHIT ARSHI, and CHRISTIAN SCHULZE Appeal 2020-006791 Application 15/569,320 Technology Center 1600 Before ULRIKE W. JENKS, TAWEN CHANG, and RACHEL H. TOWNSEND, Administrative Patent Judges. JENKS, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s decision to reject the claims 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(a). Appellant identifies the real party in interest as BSN medical GmbH. Appeal Br. 3. Appeal 2020-006791 Application 15/569,320 2 CLAIMED SUBJECT MATTER The claims are directed to the production of nitrogen monoxide (“NO”). Claims 1, 3-16, and 18-202 are on appeal, and can be found in the Claims Appendix of the Appeal Brief.3 Claim 1, reproduced below, is illustrative of the claimed subject matter: Claim 1: A process for the production of nitrogen monoxide (NO), comprising steps: (a) providing a carrier medium, said carrier medium being an aqueous liquid comprising at least one pH-labile NO donor; (b) adjusting the pH value of the aqueous liquid from step (a) to a pH value that induces degradation of the at least one pH-labile NO donor while producing NO; (c) maintaining the pH value that induces the production of NO in step (b) for a period of time from 15 seconds to 60 minutes to permit production of an amount of 0.01 to 2 mM of NO; and (d) increasing the pH value of the aqueous liquid by at least one pH level following step (c) to maintain a steady-state of NO; wherein a first antioxidant is present in the aqueous liquid in step (a) or is added to the aqueous liquid in step (b), and wherein at least a second antioxidant that is different than the first antioxidant is added to the aqueous liquid in step (d) or after step (d). Appeal Br. 25 (Claims App.). 2 Claim 17 is withdrawn from consideration as being directed to a non- elected invention. Final Act. 2. Claim 2 has been canceled. Id. 3 Herein we refer to the Final Office Action mailed December 2, 2019 (“Final Act.”); Appeal Brief filed May 29, 2020 (“Appeal Br.”); Examiner’s Answer mailed August 3, 2020 (“Ans.”); and Reply Brief field September 29, 2020 (Reply Br.”). Appeal 2020-006791 Application 15/569,320 3 REJECTIONS Grounds of rejection before this Panel for review: I. Claims 1, 3-5, 8-14, and 16 under 35 U.S.C. § 103 as unpatentable over Balaban4 in view of Stasko5 and further in view of WebMD;6 II. Claim 6 under 35 U.S.C. § 103 as unpatentable over Balaban, Stasko, and WebMD, and further in view of Schor;7 III. Claims 7 and 18-20 under 35 U.S.C. § 103 as unpatentable over Balaban, Stasko, and WebMD, and further in view of Naguib;8 and IV. Claim 15 under 35 U.S.C. § 103 as unpatentable over Balaban, Stasko, and WebMD, and further in view of Sikorski.9 OPINION I. Obviousness over Balaban, Stasko, and WebMD The issue is whether the preponderance of evidence of record supports Examiner’s conclusion that the claims directed to the production of nitrogen monoxide (“NO”) are obvious over Balaban, Stasko, and WebMD. A. Findings of Fact FF1. Balaban teaches a system for producing nitric oxide (“NO”). [B]iocompatible two-component system and procedure for generating nitric oxide (NO) is described. One 4 Balaban et al., US 2013/0330244 A1 published Dec. 12, 2013 (“Balaban”). 5 Stasko et al., WO 2013/063354 A1, published May 2, 2013 (“Stasko”). 6 Beauty and Skin Care: Vitamins and Antioxidants, 1-14 (2019), https://www.webmd.com/beauty/features/beauty-skin-care-vitamins- antioxidants#1, last accessed June 8, 2019 (“WebMD”). 7 Schor, US 4,357,469, issued Nov. 2, 1982 (“Schor”). 8 Naguib, US 6,060,324, issued May 9, 2000 (“Naguib”). 9 Sikorski et al., US 5,834,445, issued Nov. 10, 1998 (“Sikorski”). Appeal 2020-006791 Application 15/569,320 4 component comprises sodium nitrite or other nitrite source, and the other component comprises a reductant, an acid and a base. . . . When these two components are mixed directly at a local site of administration or immediately prior to application . . . the mixture generates nitric oxide (NO) for topical application. Balaban Abstr. (emphasis added). FF2. Balaban Figure 4A, reproduced below, shows a two-component nitric oxide (NO) delivery system. Figure 4A, reproduced above, shows a NO generating system that utilizes a double-barreled mixing syringe and a static mixer nozzle. Id. ¶ 45. The gels containing nitrite (i.e., nitric oxide donor composition) and acid (i.e., nitric oxide activation composition) are mixed individually and maintained separately until use. Id. ¶ 68. To form the nitric oxide donor gel, sodium nitrite is added to deionized water before adding hydroxyethylcellulose (“HEC”) to form the gel. Id. To prepare the acid gel, citric acid, ascorbic acid (vitamin C) and, optionally, a measured amount of sodium citrate is added to deionized water before mixing in hydroxyethylcellulose (“HEC”) to form the gel. Id. ¶ 69. Appeal 2020-006791 Application 15/569,320 5 FF3. Balaban teaches that the purpose of adding a reductant such as “ascorbic acid and its derivatives, ascorbate salts, tocopherols (including particularly alpha tocopherol), erythrobates, carotenoids, tocotrienols and thiols” is for “preventing or slowing the oxidation of nitric oxide (NO) to nitrogen dioxide (NO2).” Id. ¶ 29. Balaban teaches using [a] reductant to help retain the nitric oxide in bioactive form [and the reductant] is included in the first or second gel. Where ascorbic acid alone is used, the ascorbic acid can function as both the acid and the reducing agent. However, if an acid such as ascorbic acid is the reductant, it is included in the second gel to avoid initiating production of NO2. Id. ¶ 32. FF4. Balaban teaches the inclusion of sodium citrate to the acid gel and explains that this “shifts the acid dissociation equilibrium so that the H+ concentration is reduced, increasing the pH of the acid gel.” Id. ¶ 78. Thus, Balaban recognizes that increasing the pH reduces the amount of NO produced (id.), and concludes that “[t]his provides a significant improvement to the suitability of acidified NO producing admixtures for therapeutic indications.” Id. ¶ 73. FF5. Stasko teaching using NO to treat a variety of ailments including skin conditions. Stasko ¶ 92. Stasko teaches that delivering NO “in the range from about 1 μmol NO/L up to about 2.5 mol NO/L” is beneficial. Stasko ¶ 65. FF6. Stasko teaches using NO producing bath compositions: [T]he bath composition may controllably release nitric oxide when contacted with an aqueous solution and/or when one or more components of the bath composition are Appeal 2020-006791 Application 15/569,320 6 combined and contacted with an aqueous solution. The release of nitric oxide may be immediate upon contact with an aqueous solution and/or may begin after a certain duration of time. Nitric oxide may be released from the bath continuously and/or intermittently, for example, by exposure to repeated light/dark cycles. The release kinetics of the nitric oxide may be varied and/or tuned by changing the temperature and/or pH of the aqueous solution and/or bath. To decrease the release rate of nitric oxide, the temperature of the aqueous solution and/or bath may be decreased and/or the pH of the aqueous solution and/or bath may be increased. To increase the release rate of nitric oxide, the temperature of the aqueous solution and/or bath may be increased and/or the pH of the aqueous solution and/or bath may be decreased. In some embodiments of the present invention, the amount of nitric oxide released may be controlled by the concentration of NO-releasing compounds in the bath composition and/or by the amount of bath composition contacted with the aqueous solution and/or bath. For example, a high concentration of NO-releasing compounds in the bath composition and/or contacting a greater amount of the bath composition with the aqueous solution, may result in more nitric oxide released in the bath or soak. Stasko ¶ 79 (emphasis added). FF7. WebMD teaches that the application of multiple antioxidants is beneficial to protect the skin. WebMD 2 (“vitamins C[10] and E,[11] as well as selenium, can help protect the skin against sun damage.”), see id. at 3 (“Coenzyme Q10 is a natural antioxidant in 10 Vitamin C is also known as ascorbic acid, l-ascorbic acid, and ascorbate. Nat’l Library of Med., Compound Summary: Ascorbic acid, https://pubchem .ncbi.nlm.nih.gov/compound/54670067, last accessed March 15, 2022. 11 Vitamin E is also known as alpha-tocopherol or D-alpha-tocopherol. Nat’l Library of Med., Compound Summary: Vitamin E, https://pubchem.ncbi. nlm.nih.gov/compound/14985, last accessed March 15, 2022. Appeal 2020-006791 Application 15/569,320 7 the body that helps the cells grow and protects them from the ravages of cancer.”), id. at 5 (“Retinoic acid is the active form of vitamin A in the skin and the ‘gold standard’ in anti-ageing skin care.”). B. Analysis Claim 1 Examiner finds that Balaban discloses a method for producing nitric oxide (i.e., nitrogen monoxide or NO; abstract). Ans. 4. Balaban teaches mixing a nitric oxide donor composition (sodium nitrate) with a nitic oxide activation composition (acid) that can also contain an anti-oxidant. FF2- FF3; Ans. 4. Examiner finds that Balaban teaches that the NO is produced over a period time ranging from 10-20 minutes. Ans. 5 (citing Balaban Figs. 1A and 1B, drawing sheet 1 and ¶ 72, ll. 13-16). Examiner finds that “liquid” is not defined in the Specification, and therefore Balaban’s aqueous gel carrier medium reads on the claimed aqueous liquid.12 Ans. 5 (citing Balaban ¶ 68); FF2. Examiner notes that Balaban contemplates other applications, thereby rendering a liquid form obvious. Ans. 5 (citing Balaban ¶ 57); Balaban ¶ 57 (“Other mechanisms of application (other than topical) are possible. This technology might be used as sprays. . . or even injectable form . . . [or] be dispensed in dropper [form].”). Examiner acknowledges that “Balaban is silent with respect to how much NO is produced in mM units and is also silent with respect to actively raising the pH after initially decreasing the pH to initiate NO production.” Ans. 5-6. Examiner looks to Stasko for these teachings. Ans. 6; FF5-FF6. Examiner finds that “[t]he relationship between pH and extent of NO 12 We note that Appellant does not dispute this interpretation. Appeal 2020-006791 Application 15/569,320 8 production was known at the time the instant invention was filed,” and therefore adjusting “the pH in order to fine tune the [NO] release rate of the composition to be a matter of routine optimization for one of ordinary skill in the art.” Ans. 6; FF6. Examiner cites Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959), In re Burhans, 154 F.2d 690 (CCPA 1946), and In re Gibson, 39 F.2d 975 (CCPA 1930) to support the position that mixing the components in any order to arrive at the final NO containing product is obvious. See Ans. 17. Examiner finds that Balaban already teaches that “the reductant (i.e. antioxidant) helps to maintain the nitric oxide in bioactive form,” and that the inclusion of a second antioxidant “would provide further benefit in terms of preserving the NO in the medium for a longer period of time.” Ans 7 (citing Balaban ¶ 32); FF3. Examiner looks to WebMD as further supporting that the addition of other antioxidants is obvious because WebMD suggests that “combinations of antioxidants may be more effective than single agents.” Ans. 7; FF7. We agree with Examiner that based on the combined teachings of Balaban, Stasko, and WebMD, the claimed NO production, and subsequent maintenance of NO in the product is obvious. Therefore, we adopt the findings concerning the scope and content of the prior art as well as the conclusion as set forth in Examiner’s Answer and the Final Office Action. The findings of fact reproduced above are referenced to highlight certain pertinent evidence. Appellant contends that “[t]he Examiner provides no explanation how one would possibly effectuate carrying out a step of increasing the pH of a composition according to Balaban et al. after it has been applied to the skin.” Appeal Br. 12 (emphasis added); see also id. at 13-14 (“After that Appeal 2020-006791 Application 15/569,320 9 single step [disclosed in Balaban], the two gel components have been mixed together and topically applied to the skin. . . . In other words, there simply is no further way to add a further pH adjusting agent and antioxidant to Balaban et al. because the process according to Balaban et al. has been concluded once the two gel compositions are mixed together and applied topically to skin.”). Appellant contends that “[o]ne simply cannot change the sequence of a single step in such a way as to arrive at two different steps.” Id. at 15. The Examiner merely imagines a second step of adding a pH adjusting material to an ointment that has been mixed but not yet applied to the skin, and also imagines that if there is a combination of antioxidants, one of them can be added with or after the pH adjusting material in the imagined second step. Reply Br. 5. In other words, Appellant contends that the art cited by Examiner does not contain two-steps, therefore, there is no order that can be changed. See id. We do not find Appellant’s argument persuasive. We note that Appellant’s arguments attacking the Balaban reference individually (see, e.g., Reply Br. 5), where the rejection is based on a combination of Balaban, Stasko, and WebMD, is improper. In re Keller, 642 F.2d 413, 426 (CCPA 1981); see Soft Gel Techs., Inc. v. Jarrow Formulas, Inc., 864 F.3d 1334, 1341 (Fed. Cir. 2017) (“[N]on-obviousness cannot be established by attacking references individually where the rejection is based on the teachings of a combination of references.”) (citations omitted); see also Ans. 14 (“Appellant’s assertions regarding a one or two step process being wholly unmodifiable ignore the teachings of the Stasko disclosure.”). We are also not persuaded by Appellant’s contention that “Examiner merely imagines a second step of adding a pH adjusting material to an Appeal 2020-006791 Application 15/569,320 10 ointment that has been mixed but not yet applied to the skin, and also imagines that if there is a combination of antioxidants, one of them can be added with or after the pH adjusting material in the imagined second step.” Reply Br. 5; see also Appeal Br. 12-15 (focusing on Balaban’s single step skin application). We find that Appellant is reading the Balaban reference too narrowly. Balaban teaches two different applications using their double barrel syringe. Specifically, Balaban teaches that the two components can be “mixed directly at a local site of administration or immediately prior to application and the mixture generates nitric oxide (NO) for topical application.” FF1 (emphasis added); Ans. 14 (“[E]xaminer considers it obvious to add a step of adjusting pH to Balaban’s composition prior to applying the composition to the skin, not after adding the composition to the skin.”). We find no error with Examiner’s reliance on further manipulating Balaban’s product after extruding the components from the syringe and before applying the product to the skin. See Ans. 15. Examiner acknowledges that Balaban does not teach the amount of NO produced or increasing the pH after initiating NO production and, therefore, Examiner relies on the teaching of Stasko and WebMD for these limitations. See Ans. 5-6, see also id. at 15 (“Stasko discloses that nitric oxide release kinetics may be varied or tuned by adjusting pH.”). We are not persuaded by Appellant’s contention that Stasko “expressly teaches away from Applicant’s method in that it teaches that NO production should be modified by adjusting pH or temperature or the concentration of the NO-releasing compounds.” Appeal Br. 16. We have reviewed Stasko’s disclosure but find no teachings in Stasko that suggests that the inclusion of an antioxidant, to support the stability of Appeal 2020-006791 Application 15/569,320 11 NO as taught by Balaban (FF3), is in any way detrimental to Stasko’s NO containing bath. We note that Stasko also does not teach that the inclusion of an antioxidant would render the NO in Stasko’s bath inoperable. Examiner relies on Stasko’s teaching that the rate of NO production in an aqueous solution can be adjusted. Specifically, relying on the teaching that the NO liberation from the NO-donor can be controlled by “adjusting the pH of the composition.” Ans. 6; FF6. We agree with Examiner that Stasko’s teaching of using temperature and pH as a means to control the NO release rate in a product is not the only means to control the stability of NO in a product. See Ans. 21; see FF3 (using a “reductant to help retain the nitric oxide in bioactive form.”). We, therefore, agree with Examiner that providing an alternative means for maintaining NO levels is not teaching away. Ans. 21. Appellant contends that no reference of record teaches adding at least a second antioxidant that is different than the first antioxidant to the aqueous liquid in step (d) or after step (d). Appellant acknowledges that Balaban teaches “the presence of a compound that could fairly be characterized as an antioxidant. . . . But including a combination of different antioxidants in one or both of the two components of the topical ointment of Balaban et al. would not read on the subject matter claimed in claim 1.” Reply Br. 4. We are not persuaded, and agree with Examiner that “if it is obvious to add a substance, then . . . the step of adding the substance is obvious.” Ans. 22. “[E]xaminer considers it obvious to either add the antioxidants at the same time, or to add them at different times, absent evidence that the order of steps is critical.” Id. Here, Balaban provides a list of suitable reductants (i.e., antioxidants) and explains that they are used for “preventing or slowing the oxidation of nitric oxide (NO) to nitrogen dioxide (NO2)” in the product. FF3. Balaban suggests the use of “[a] reductant to help retain Appeal 2020-006791 Application 15/569,320 12 the nitric oxide in bioactive form is included in the first or second gel.” FF3. Balaban therefore provides a reason to add an antioxidant. Balaban also provides a list of suitable antioxidants and explains that the only limitation is that an acid antioxidant, for example vitamin C (ascorbic acid) should not be included in gel a containing the NO-donor. FF3. Examiner relies on WebMD to establish that “one of ordinary skill in the art would be motivated to find a combination of antioxidants that shows greater efficacy than each agent alone in view of WebMD’s disclosure that this is frequently observed.” Ans. 23, see also id. at 8 (citing In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980)), 17 (“WebMD provides further motivation to try a combination of antioxidants with the expectation that combinations of antioxidants are often more effective than the single antioxidants alone.”); FF7. Here, WebMD suggests that the inclusion of compounds such as vitamin C, vitamin E, and selenium in combination would be beneficial for the application to the skin. FF7. Based on the teachings in WebMD, we agree with Examiner that adding an additional antioxidant after completing step (d) but before applying the composition to the skin is obvious. Here, Balaban already suggests the use of reductants (i.e., antioxidants) and even lists vitamin C (i.e., ascorbic acid) and vitamin E (i.e., alpha tocopherol) as suitable candidates. FF3. We note that Balaban does not limit the number of antioxidants that can be included in the product, the only limit being that an acid, such as ascorbic acid (vitamin C) should not be included in the gel that contains the NO-donor. FF3. Based on the combined teachings relied on by Examiner, we find that Examiner has directed us to sufficient evidence in the record from which to conclude that the process and resulting product as recited in claim 1 is obvious. Appeal 2020-006791 Application 15/569,320 13 For the foregoing reasons we affirm the Examiner’s obviousness rejection of claim 1. For any points made by Appellant and not specifically addressed above we adopt Examiner’s responses as our own. Claims 12 and 14 Appellant contends that Examiner has not provided a sufficient rationale to arrive at the limitations of claims 12 and 14. The claims depend on claim 1 and therefore recite all the limitations of that claim in addition to further specifying that in step (d) the pH increase “is an increase of the pH value to pH 7 or more” or “to a pH that is between 7.0 and 12.0.” Appeal Br. 16. Specifically, Appellant contends that Examiner has not directed us to any teaching that suggests raising the pH to adjust NO production and, therefore, Examiner cannot rely on reaching this limitation based on this being a “result-effective variable.” See Appeal Br. 17. We are not persuaded by Appellant’s contention that the Examiner has not identified a teaching in the record that supports the position that pH is a result effective variable with respect to NO production. Specifically, Stasko teaches that [t]he release kinetics of the nitric oxide may be varied and/or tuned by changing the temperature and/or pH of the aqueous solution and/or bath. To decrease the release rate of nitric oxide, the temperature of the aqueous solution and/or bath may be decreased and/or the pH of the aqueous solution and/or bath may be increased. FF6 (emphasis added). Thus, Stasko teaches that increasing the pH of a NO containing composition will decrease the rate of NO release from the NO- donor. We, therefore, agree with Examiner’s position, that these teachings in Stasko support the conclusion that “arriving at an optimal pH value to Appeal 2020-006791 Application 15/569,320 14 produce NO is merely a matter of routine testing for one having ordinary skill in the art.” Ans. 25. Claim 13 Appellant contends that claim 13 further recites that the pH is increased with the use of a buffer from a list. Appeal Br. 17-18. Specifically, Appellant contends that “there is no teaching in any prior art reference of record regarding how one could apply NaOH to the two-component gel composition of Balaban et al. after it has been applied to skin.” Appeal Br. 18. We are not persuaded. As discussed above (see claim 1), we find that Appellant is reading the Balaban reference too narrowly. Balaban teaches two different applications for using their double barrel syringe. FF1. One application allows for the product to be mixed while simultaneously applying the product to the skin by extruding the gels through the tip of the syringe. Id. The second application allows for the product to be mixed before it is applied to the skin. Id. It is the product from the second application that Examiner relies on in formulating the rejection and we discern no error with Examiner’s position. See Ans. 14 (“[E]xaminer considers it obvious to add a step of adjusting pH to Balaban’s composition prior to applying the composition to the skin, not after adding the composition to the skin.”). Claim 16 Claim 16 further recites that “the aqueous liquid [of claim 1] is irradiated with light for photolytic degradation of the NO and simultaneous production of NO after step (d) or after addition of the second antioxidant.” Appeal 2020-006791 Application 15/569,320 15 Appellant contends that Examiner has not explained how one would “carry out this process on a gel composition after it has been applied to skin as would be the case in Balaban.” Appeal Br. 18-19. We are not persuaded. Stasko teaches that “[n]itric oxide may be released from the bath continuously and/or intermittently, for example, by exposure to repeated light/dark cycles.” FF6. We agree with Examiner that Stasko, therefore, teaches the use of light to release NO from a NO-donor. See Ans. 9 (“Stasko discloses further that NO may be produced by light induced cleavage of an NO-donor.”). Based on this teaching in Stasko, Examiner concludes that [i]t would have been prima facie obvious to add a light sensitive NO-donor to the composition disclosed by Balaban and to release the NO from this source by exposure to light because these two methods of generating NO were known for the same purpose at the time of the instant invention. . . . One of ordinary skill in the art would have recognized that successive administration could be achieved by acid-induced NO release followed by light-induced NO release. Ans. 9. We find no error with Examiner’s position that the inclusion of a light sensitive NO-donor, as suggested by Stasko, would allow for NO- production after exposure of the composition to light. We see no reason why light cannot be used to induce NO production in product that contains a light sensitive NO-donor after either being applied directly to the skin or after extrusion of the product from the syringe but before the application to the skin. C. Conclusion For the reasons discussed above, we determine that the preponderance of the evidence supports Examiner’s conclusion that claims 1, 12-14, and 16 Appeal 2020-006791 Application 15/569,320 16 are obvious. Claims 3-5 and 8-11 were not separately argued and fall with claim 1. 37 C.F.R. § 41.37 (c)(1)(iv). II. Obviousness over Balaban, Stasko, WebMD, and Schor Claim 6 Appellant contends that Examiner’s reliance on Schor for teaching the reducing agents ascorbyl stearate, ascorbyl palmitate, and sodium metabisulfite is improper because Schor “has absolutely nothing to do with the production of NO as claimed in the present application.” Appeal Br. 20. We are not persuaded. Examiner relies on Schor for teaching “that the ascorbate derivatives ascorbyl stearate and ascorbyl palmitate were known to function as antioxidants in biomedical compositions.” Ans. 10 (citing Schor claim 3). Examiner explains that “Balaban discloses the genus of ascorbate- based antioxidants (or reductants) and Schor establishes that the substances recited in the instant claims were known members of the genus disclosed by Balaban.” Ans. 28. Accordingly, we find no error in Examiner’s reliance on Schor for establishing that ascorbyl stearate and ascorbyl palmitate are known antioxidants. III. Obviousness over Balaban, Stasko, WebMD, and Naguib Claims 7, 18, and 19 Claim 7 depends on claim 1 and further recites “the presence of (RS)- 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, also specifies the relative molar ratio of nitrite, ascorbate, and (RS)-6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxylic acid to be 1 : 2-20: 4-100, and also that the molar ratio: is nitrite < ascorbate < (RS)-6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxylic acid.” Appeal Br. 21. Appellant contends that Examiner’s rejection is in error because it relies on routine optimization Appeal 2020-006791 Application 15/569,320 17 without establishing that there is a reason in the prior art to optimize these particular ingredients. See Appeal Br. 21-22. We are not persuaded. Examiner relies on the rationale that [i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. . . . [T]he idea of combining them flows logically from their having been individually taught in the prior art. Kerkhoven, 626 F.2d at 850 (citations omitted); see Ans. 11, 12 (“it is prima facie obvious to add a combination of different antioxidants, known for the same purpose” before application to the skin). Examiner’s position is that Balaban already discloses that reductants (i.e., antioxidants) can be added to either the first or second composition and are used for the purpose of retaining NO in its bioactive form. Ans. 11. Examiner looks to Naguib for teaching “that Trolox is comparatively stable relative to its analogue, α- tocopherol.” Id. We find no error with Examiner’s reason that it would have been obvious to use the more stable Trolox in place of Balaban’s alpha- tocopherol in order to maintain the NO in the bioactive form. See Ans. 11 (“The skilled Artisan would have been motivated to do so because this compound has greater stability and therefore would provide anti-oxidant effect for a longer period.”). We are not persuaded by Appellant’s contention that Examiner has not established a “known existing relationship between the materials in a particular context, and known result-effective changes that can be routinely optimized.” Appeal Br. 22. Examiner directs our attention to the examples disclosed in Balaban for teaching that the molar ratio of NO-donor to antioxidant, such as Appeal 2020-006791 Application 15/569,320 18 ascorbic acid is 1:1. Ans. 11 (citing Table 1, ¶¶ 72, 82). Thus, Balaban provides a starting ratio for further optimization. “[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.” In re Aller, 220 F.2d 454, 456 (CCPA 1955). The art already teaches that NO production is known to be dependent on several variables (see generally Stasko) and that any NO produced can be stabilized with the addition of an antioxidant (see generally Balaban). The concentration of NO-donor determines the maximum NO that can be liberated and by either adjusting the pH or temperature the rate of NO production is tuned. See FF5, FF6; Balaban ¶ 11. Once NO is produced, the application of an antioxidant helps maintain the NO in its bioactive form. FF3; see also Ans. 12 (“determin[ing] the amount of anti-oxidant necessary to maintain the nitric oxide in bioactive form [is a matter of optimization], as this would depend upon the strength of the antioxidant, the amount of NO generated, as well as the duration the NO was required to remain useful for treatment.”). Based on these disclosures we determine that Examiner has directed us to sufficient teachings to establish that these parameters were known result effective variable that may be optimized. Claim 20 Appellant contends that Examiner’s rejection is in error because it does not provide an articulated reasoning with some rational underpinning to arrive at that conclusion. See Appeal Br. 22 (“nothing in the prior art that would provide one having ordinary skill in the art with any roadmap or expectation regarding how to optimize the molar ratios.”). We are not persuaded. Examiner relies on the rationale that it is obvious to mix compositions that are taught to be used for the same purpose. Appeal 2020-006791 Application 15/569,320 19 See Kerkhoven, 626 F.2d at 850; Ans. 11. Examiner directs our attention to the examples disclosed in Balaban for teaching that the molar ration of NO- donor to antioxidant, such as ascorbic acid is 1:1. Ans. 11 (citing Table 1, ¶¶ 72, 82). Examiner views this as a reasonable starting point for further optimization. “Balaban discloses the purpose of the reductant is to maintain the NO in bioactive form (i.e. to prevent it’s degradation via oxidation to a different, non-bioactive substance; para 0032).” Ans. 18. IV. Obviousness over Balaban, Stasko, WebMD, and Sikorski Claim 15 Claim 15 depends from claim 1 and specifies a list of suitable second antioxidants. Appeal Br. 23. Appellant contends that there is nothing in Sikorski “that would lead one having ordinary skill in the art to add glutathione to the aqueous liquid in step (d) or after step (d).” Id. We are not persuaded by Appellant’s contention. Examiner explains that it would have been prima facie obvious to add “glutathione as the antioxidant in Balaban’s invention because Balaban discloses the thiol category of antioxidant to be suitable for the invention and glutathione is a species of the genus ‘thiol antioxidant’.” Ans. 31. Specifically, Examiner is relying on Balaban’s teaching that adding a reductant such as “ascorbic acid and its derivatives, ascorbate salts, tocopherols (including particularly alpha tocopherol), erythrobates, carotenoids, tocotrienols and thiols” is for “preventing or slowing the oxidation of nitric oxide (NO) to nitrogen dioxide (NO2).” FF3; Ans. 33. Examiner explains that Balaban already teaches that the use of a reductant such as ascorbic acid helps maintain the nitric oxide in bioactive form. Ans. 7; FF3. In addition, Examiner relies on WebMD to establish that it was known in the art to supply skin care compositions containing multiple antioxidants, for example a combination of vitamin C Appeal 2020-006791 Application 15/569,320 20 and vitamin E. Ans. 7; FF7. Here, Examiner is relying on Sikorski for teaching “that glutathione is a [known] thiol antioxidant,” and Balaban already explains that a thiol reductant is suitable for the application. Ans. 13 (citing Sikorski 14:38-39), see id. at 31 (“glutathione is a species of the genus ‘thiol antioxidant’.”); FF3. Based on the combined teachings Examiner concludes, and we agree, that it would have been obvious to include an additional antioxidant (i.e., reductant) in either step (a) or (b), or before applying the composition to the skin, in other words after step (d). Ans. 7, 13. CONCLUSION We conclude, considering the totality of the cited evidence and arguments, that the preponderance of the evidence supports Examiner’s conclusion of obviousness. Appeal 2020-006791 Application 15/569,320 21 DECISION SUMMARY In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 3-5, 8-14, 16 103 Balaban, Stasko, WebMD 1, 3-5, 8-14, 16 6 103 Balaban, Stasko, WebMD, Schor 6 7, 18-20 103 Balaban, Stasko, WebMD, Naguib 7, 18-20 15 103 Balaban, Stasko, WebMD, Sikorski 15 Overall Outcome 1, 3-16, 18-20 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) (2019). AFFIRMED