Ex Parte Ghoroghchian et alDownload PDFPatent Trial and Appeal BoardMar 29, 201813508271 (P.T.A.B. Mar. 29, 2018) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 13/508,271 12/20/2012 22208 7590 04/02/2018 The Marbury Law Group, PLLC 11800 SUNRISE VALLEY DRIVE 15THFLOOR RESTON, VA 20191 FIRST NAMED INVENTOR P. Peter Ghoroghchian 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 ATTORNEY DOCKET NO. CONFIRMATION NO. 1597-00lUS 1543 EXAMINER PURDY, KYLE A ART UNIT PAPER NUMBER 1611 NOTIFICATION DATE DELIVERY MODE 04/02/2018 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): ptonotices@marburylaw.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte P. PETER GHOROGHCHIAN, MARK W. DEWHIRST, and GREGORYM. PALMER Appeal2017-001943 Application 13/508,271 1 Technology Center 1600 Before FRANCISCO C. PRATS, RACHEL H. TOWNSEND, and DEVON ZASTROW NEWMAN, Administrative Patent Judges. NEWMAN, Administrative Patent Judge. DECISION ON APPEAL This appeal under 35 U.S.C. § 134 involves claims to a method of increasing efficacy of radiation or chemotherapy applied to a tumor in a subject. The Examiner entered final rejections for obviousness. We have jurisdiction under 35 U.S.C. § 6(b ). We AFFIRM. 1 Appellants identify the real party in interest as "Vindico Nanobio Technology, Inc. and Duke University." App. Br. 3. Appeal2017-001943 Application 13/508,271 STATEMENT OF THE CASE Background The Specification discloses that more than 50% of patients having solid tumor malignancies patients "undergo radiotherapy (XR T) as part of their treatment plan." Spec. i-f 3. The ability of XR T to eradicate malignant cells depends critically upon the intratumoral content of 0 2, a potent radiosensitizer involved in mediating DNA damage. The intratumoral 02 level is one of the most important determinants of response among tumors of the same type treated with a single fraction of ionizing radiation therapy. Id. (citations omitted). The Specification (i-f 2) discloses "methods for synthesis and delivery of high-affinity oxygen binding agents to tumors to increase intratumoral partial pressures of oxygen, mitigate the natural selection of tumor cells that demonstrate aggressive molecular behavior and metastatic potential, and potentiate the effects of radiation and chemotherapies." The Claims Claims 1-7, 13, 15, and 23-30 are on appeal. App. Br. 3. Claim 1, the only independent claim on appeal, is illustrative and reads as follows: 1. A method of increasing efficacy of radiation or chemotherapy applied to a tumor in a subject, comprising: delivering a high-oxygen affinity agent to the tumor by administering to the subject an oxygen carrier that incorporates the high-oxygen affinity agent, wherein: the high-oxygen affinity agent comprises a myoglobin composition; and the oxygen is released by the high-oxygen affinity agent at oxygen tensions less than 10 mmHg, wherein the released 2 Appeal2017-001943 Application 13/508,271 oxygen diffuses out of the oxygen carrier while the high- oxygen affinity agent remains within the oxygen carrier. App. Br. 17 (Claims Appendix). The Issues The following rejections are before us to review: Claims 1-7, 13, 15, 23-28, and 30 are rejected under pre-AIA 35 U.S.C. § 103(a) as being unpatentable over Winslow, 2 Galluzzo, 3 and Arifin. 4 Ans. 2. Claim 29 is rejected under pre-AIA 35 U.S.C. § 103(a) as being unpatentable over Winslow, Galluzzo, Arifin, and Awasthi. 5 Id. at 4. Because Appellants have waived arguments based on Awasthi (see Appeal Br. 16), the same issue is dispositive for both rejections. I The Examiner finds that Winslow teaches methods for delivering oxygen using a "hemoglobin-based oxygen carrier" that may be "unmodified hemoglobin or modified hemoglobin," "encapsulated in a vesicle, such as a synthetic particle, micro-balloon or liposome." Ans. 2. The Examiner finds that Winslow teaches "delivery of oxygen to hypoxic inner cores of a tumor mass increases sensitivity to radiotherapy and chemotherapy" but that 2 US 2003/0162693 Al, published August 28, 2003 ("Winslow"). 3 Maria Galluzzo et al., Prevention of hypoxia by myoglobin expression in human tumor cells promotes differentiation and inhibits metastasis, 119:4 THE J. OF CLINICAL INVESTIGATION 865-75 (2009) ("Galluzzo"). 4 Dian R. Arifin & Andre F. Palmer, Polymersome Encapsulated Hemoglobin: A Novel Type of Oxygen Carrier, 6 BIOMACROMOLECULES 2172-81 (2005) ("Arifin"). 5 US 2011/0059157 Al, published March 10, 2011 ("Awasthi"). 3 Appeal2017-001943 Application 13/508,271 because of the unique microvasculature of a tumor, "sensitization through increasing oxygen levels requires oxygen be unloaded within the hypoxic core." Id. The Examiner finds that Winslow teaches the "partial pressure[] of oxygen" or P50, which is the measurement of the pressure at which oxygen is released to the surrounding tissues, "should be low to prevent early unloading of oxygen, increasing the oxygen levels, to insure optimal sensitization of the tumor to subsequent radiation and chemotherapy treatments." Id. The Examiner finds that Winslow does not teach myoglobin as the high-oxygen affinity agent, but finds that "Galluzzo teaches that myoglobin prevents hypoxic response in vitro and delays tumor engraftment and reduces tumor growth following xenotransplantation into mice." Id. The Examiner further finds that Galluzzo teaches that when tumors were engineered to express [human] myoglobin, they displayed "reduced or no hypoxia, minimal HIP-la levels and a homogenously low vessel density." Id. at 2-3. The Examiner finds that Galluzzo teaches "myoglobin-mediated tumor oxygenation promoted differentiation of cancer cells and suppressed both local and distal metastatic spreading which were due primarily to reduced tumor hypoxia." Id. at 3. The Examiner finds that the skilled artisan would have found it obvious to "to modify Winslow such that the particles comprised myoglobin so as to provide oxygen to the tissues affected by hypoxia with a reasonable expectation for success." Id. The Examiner finds that Winslow and Galluzzo do not teach a particle that encapsulates the myoglobin as being a polymersome with a particle size of less than 100 nanometers. Id. However, the Examiner finds that Arifin 4 Appeal2017-001943 Application 13/508,271 teaches "polymersome encapsulated hemoglobin" and that "[t]he hemoglobin loaded polymersome[ s] were extruded through a filter having a pore size of 100 nm." Id. The Examiner concludes that, in light of "prior art and general skill in manipulating/understanding said art, any person skilled in the art would readily envisage reducing the particle size to a diameter of less than 100 with a reasonable expectation in that the particle would be useful for increasing radiation or chemotherapy efficacy." Id. The Examiner concludes the skilled artisan would have found it obvious to modify the method of Winslow to make therapeutic particles comprising myoglobin "contained within a polymersome particle having a size less than 100 nm, as taught by Arifin, with a reasonable expectation for success in arriving at a method of increasing efficacy of radiation or chemotherapy applied to a tumor." Id. at 3--4. Appellants contend that the cited references do not teach the claimed invention, and that even if a prima facie case existed, evidence provided in the declaration of Appellants' expert, Dr. Ghoroghchian, 6 is sufficient to rebut the prima facie case. App. Br., passim. The issue with respect to this rejection is whether a preponderance of the evidence supports the Examiner's conclusion that Winslow, Galluzzo, and Arifin suggest the claimed method of increasing efficacy of radiation or chemotherapy applied to a tumor in a subject. We select claim 1 as representative of the claims subject to this ground of rejection. 37 C.F.R. § 41.37(c)(l)(iv). 6 Declaration Pursuant to 37 C.F.R. § 1.132 of P. Peter Ghoroghchian, executed November 27, 2014 ("Ghoroghchian Deel."). The declarant is an inventor on the application. 5 Appeal2017-001943 Application 13/508,271 As stated in Jn re Oetiker, 977F.2d1443, 1445 (Fed. Cir. 1992): [T]he examiner bears the initial burden ... of presenting a prima facie case of unpatentability .... After evidence or argument is submitted by the applicant in response, patentability is determined on the totality of the record, by a preponderance of evidence with due consideration to persuasiveness of argument. Here, Appellants do not persuade us that a preponderance of the evidence fails to support the Examiner's conclusion that the claimed method of increasing efficacy of radiation or chemotherapy applied to a tumor in a subject would have been obvious to an ordinary artisan. Unless otherwise indicated herein, we adopt the Examiner's findings of fact, reasoning on scope and content of the claims and prior art, and conclusions set out in the Final Action and Answer. Final Act. 7 5-9; Ans. 2-5. Only those arguments made by Appellants in the Appeal Brief and properly presented in the Reply Brief have been considered in this Decision. Arguments not so presented in the Briefs are waived. See 37 C.F.R. § 41.37(c)(l)(iv) (2015); see also Ex parte Borden, 93 USPQ2d 1473, 1476 (BP AI 2010) (informative) ("Any bases for asserting error, whether factual or legal, that are not raised in the principal brief are waived."). We agree with the Examiner (see Final Act. 5-9; Ans. 2-5) that the skilled artisan would have found it obvious to combine the teachings of Winslow, Galluzzo, and Arifin to practice the claimed method of increasing efficacy of radiation or chemotherapy applied to a tumor in a subject. 8 As 7 Examiner's Final Act, mailed November 19, 2015 ("Final Act."). 8 As noted by the Appellants, (App. Br. 11-12) claim 1 does not require a particle size of less than 100 nm. However, claim 11 recites that "the nanoparticle is less than 100 nanometers in diameter." Id. at 19 (Claims 6 Appeal2017-001943 Application 13/508,271 found by the Examiner, Winslow teaches compositions comprising a modified or unmodified oxygenated hemoglobin and having a high affinity for oxygen that can be added in free form or encapsulated in a carrier such as a liposome. Winslow, Abstract, i-fi-174--75. The skilled artisan would have further learned by reading Winslow that when oxygen is delivered to the inner core of a cancerous mass, radiotherapy and chemotherapy are more effective against the mass, and that using a high-affinity oxygen carrier with a low P50 would assist delivery of oxygen to the mass by preventing "early unloading." Id. i-f 108. We further agree with the Examiner that the skilled artisan would have had a reasonable expectation of success in substituting myoglobin for hemoglobin in the method of Winslow, given that myoglobin is shown in Galluzzo to have a similar capability of enhancing oxygen use by hypoxic tissues. See, e.g., Galluzzo 867 ("t]hese results suggest that Mb attenuates the hypoxic response of cancer cells by enhancing their oxygenation during hypoxia and allowing them to 'hold their breath' for short periods of time."), 871-873 (Mb supplies oxygen during hypoxia). Indeed, Appellants' Specification acknowledges that myoglobin has a very low P50, as is taught by Winslow (i-f l 08) to be important for oxygen transfer in vivo. See Spec. i1 80 ("the oxygen dissociation curve of myoglobin is a rectangular hyperbola with a very low P50"). As a result, we agree with the Examiner (Ans. 3--4) that, upon reading Winslow, the artisan would have had reason to substitute myoglobin, based on its low P50, for Appendix). Accordingly, we adopt the Examiner's findings with regard to Arifin as they relate to claim 27 only. 7 Appeal2017-001943 Application 13/508,271 hemoglobin in the method of Winslow to allow myoglobin to deliver oxygen to combat tumor hypoxia, which was shown by Galluzzo to be an effective treatment for reducing tumor activity, such as angiogenesis and metastasis, (Galluzo 868, 869). It is obvious to those skilled in the art to substitute one known equivalent for another. See In re Omeprazole Pat. Litig., 483 F .3d 1364, 1374 (Fed. Cir. 2007) (This court finds "no error in [the] conclusion that it would have been obvious to one skilled in the art to substitute one ARC [alkaline reactive compound] for another."). We further agree that the skilled artisan would have learned from Arifin that polymersome oxygen carriers could be created by loading them with myoglobin, and extruding them through a filter having a pore size of 100 nm (Arifin, Abstract, 2173-2176) and we see no error in the Examiner's conclusion that the skilled artisan would have found doing so "useful for increasing radiation or chemotherapy efficacy" (Ans. 3--4). We conclude the combined teachings of the references as a whole would have suggested the claimed invention to the ordinarily skilled artisan. In re Keller, 642 F.2d 413, 425 (CCPA 1981) (The test for obviousness is what the combined teachings of the references, as a whole would have suggested to those of ordinary skill in the art); KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). We have considered Appellants' arguments but do not find them persuasive. Appellants argue that the skilled artisan "would not have modified the hemoglobin-based oxygen carriers taught in Winslow to provide a 'high- oxygen affinity agent [comprising] a myoglobin composition,"' as claimed based on Galluzzo' s disclosure because the proposed modification "would 8 Appeal2017-001943 Application 13/508,271 render the invention in Winslow improper for its intended purpose and/or change the principle of operation." App. Br. 6. According to Appellants, the Examiner's supposition that myoglobin can be substituted for hemoglobin is erroneous because "Winslow relies on the fact that hemoglobin is the most commonly used blood substitute" and related findings while "Galluzzo discloses genetically modifying tumors to express myoglobin, which is not useful for the improvements in blood substitutes to which Winslow is directed." Id. at 6-7, 11. Appellants argue the skilled artisan would not have been motivated to apply Galluzzo' s teachings on myoglobin expressed by genetically-modified tumors to the HBOC improvements disclosed in Winslow. Id. at 7. Appellants further argue the proposed modification "to provide oxygen carriers comprising myoglobin would frustrate the purpose of Winslow in creating effective, commercially viable hemoglobin-based oxygen carriers." App. Br. 7. We are not persuaded. That Winslow developed hemoglobin-based carriers does not show that myoglobin-based carriers would not be effective. Indeed, Winslow describes its goal as developing "blood substitutes and plasma expanders. A blood substitute is a blood product that is capable of carrying and supplying oxygen to the tissues." Winslow i-f 8. Galluzzo demonstrates that myoglobin would be expected to be an effective substitute for the delivery of oxygen, as discussed above. Appellants have not pointed us to nor do we find any teaching in Winslow that discourages or excludes any non-hemoglobin oxygen carrier for use with its methods. And even if the purpose of Winslow is different, "the mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230 (1976). Moreover, 9 Appeal2017-001943 Application 13/508,271 Appellants do not provide evidence or persuasive argument that the skilled artisan would have believed at the time of the invention that myoglobin was an unsuitable high-oxygen affinity agent for use in the method of Winslow. Attorney arguments and conclusory statements that are unsupported by factual evidence are entitled to little probative value. See In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997). Appellants instead argue that statements in the Ghoroghchian Declaration and the Specification support their argument that "myoglobin does not share the properties of hemoglobin that enable hemoglobin to maintain physiologic oxygen levels in all tissues within the body, and the use of myoglobin is incompatible with the blood substitutes disclosed by Winslow." App. Br. 7-8 (citing Spec.; Ghoroghchian Deel. i-fi-f 14--23); Reply Br. 5---6. According to Appellants, "the different biochemical pathways, mechanisms of action, and capabilities for binding and releasing oxygen that exist for hemoglobin and myoglobin sufficiently demonstrate that the proposed combination of Winslow and Galluzzo is improper." App. Br. 8. Appellants cite teachings of the Specification including Figure 3 of the Specification as evidence that the oxygen dissociation curves for hemoglobin and myoglobin differ. Figure 3 is reproduced below: 10 Appeal2017-001943 Application 13/508,271 _g -~ ~ 3j '§ S{?~ ::.~' tfi ~ ..... Figure 3 "is a graph illustrating the oxygen dissociation curves of hemoglobin and myoglobin." Spec. i-f 29. Appellants also cite the following disclosure of the Specification: FIG. 3 illustrates the oxygen dissociation curves of hemoglobin and myoglobin, a ubiquitous protein involved in regulating oxygen levels in muscle tissues. FIG. 3 shows that the oxygen dissociation curve of myoglobin is a rectangular hyperbola with a very low P50 that lies to the left of the sigmoid-shaped hemoglobin oxygen dissociation curve (i.e., myoglobin has a much higher affinity for oxygen than hemoglobin). That is, in contrast to the example agents (e.g., Agent A, Agent B) discussed above with reference to FIG. 2, myoglobin has an oxygen dissociation curve that is shifted to the left of the hemoglobin oxygen dissociation curve. App. Br. 7 (citing Spec. i-fi-177-78, 80). Appellants further argue that the "tetrameric structure" of hemoglobin is responsible for its ability "to effectively transport oxygen in circulation, as required by the invention disclosed in Winslow" and note that this structure is not present in myoglobin. App. Br. 8 (citing Ghoroghchian Deel. i-fi-1 15- 23), 14; Reply Br. 3--4. 11 Appeal2017-001943 Application 13/508,271 The Examiner responds: myoglobin P50 is about 130 pascals (Pa) while the P50 for hemoglobin is about 3500 Pa and so in terms of using an oxygen carrier for treating the hypoxic inner core of a tumor, myoglobin would be a better choice than that of hemoglobin given Winslow's admission that the oxygen carrier should have a very low P50. Ans. 6. We are not persuaded that the Examiner erred. With regard to the teachings of the cited art, we agree with the Examiner that Winslow teaches that a low P50 is required for oxygen delivery to the hypoxic tumor. Winslow i-f 108. Galluzzo teaches that "Mb functions as an oxygen supplier when environmental p02 is low." Galluzzo 867. The Specification acknowledges that myoglobin has a very low P50 (Spec. i-f 80) and Appellants have not pointed us to teachings in the art otherwise. Thus, the prior art disclosures and Appellants' Specification statements align with rather than contradict the reasoning that myoglobin would be an equally effective - if not better - high-affinity oxygen carrier for delivering oxygen to hypoxic tumors. In addition, Galluzzo teaches: Mb is a cytoplasmic heme protein that plays a well- characterized role in oxygen transport and free radical scavenging in skeletal and cardiac muscle cells (14, 15). Its oxygen-related functions are multiple and include at least 3 different activities. First, Mb acts as an oxygen reservoir, binding 0 2 in aerobic conditions and releasing it under hypoxia . . . . Third, Mb supplements simple 0 2 diffusion by working as a carrier in an activity known as facilitated 02 diffusion .... We reasoned that if cancer cells expressed a similar multifunctional oxygen transporter, the tumor as a whole would (a) capture more oxygen from blood vessels, (b) benefit from a more homogeneous oxygenation, and ( c) be less subject to cycles of hypoxia and reoxygenation. 12 Appeal2017-001943 Application 13/508,271 Galluzzo 865-866. These teachings reinforce that the skilled artisan would have recognized the suitability of myoglobin as an oxygen carrier and would have expressly chosen to use it given the characteristics of the method disclosed in Winslow. Appellants further argue that the skilled artisan would have understood "the known properties of myoglobin provide evidence that myoglobin is specifically more harniful in circulation in a patient compared to other heme-binding proteins." App. Br. 9. Appellants cite, for example, the following Specification teaching: While delivering high-oxygen affinity agents (e.g., myoglobin, other synthetic proteins having similar oxygen affinity as myoglobin, etc.) to solid tumors may improve the efficacy of radiation therapy, in order to achieve proper localization to the tumor, a large amount of the high-oxygen affinity agents must be injected into the blood stream. Injecting a large amount of such proteins into the bloodstream is dangerous, as the injected agent (e.g., myoglobin) may be nephrotoxic and/or cause hypertensive urgency or emergency (via sequestration of the vasodilator nitric oxide that normally controls blood vessel tone). Spec. i-f 83 (emphasis added). Appellants also cite the Ghoroghchian Declaration (i-fi-1 14--28 (e.g., "myoglobin does not share the properties of hemoglobin that enable hemoglobin to maintain physiologic oxygen levels in all tissues within the body, and the use of myoglobin is incompatible with the blood substitutes disclosed by Winslow" and "one knowledgeable in biochemistry would not expect myoglobin to be successful or safe for use in systemic oxygen transport or to be able to specifically deliver oxygen only to tumor tissues")). App. Br. 7-9. Appellants argue that the Ghoroghchian Declaration "provides solid evidence that one of ordinary skill in the art would not combine the teachings of Winslow and Galluzzo for a number of 13 Appeal2017-001943 Application 13/508,271 reasons," including the unpredictability of potential blood substitutes, unsuitability of myoglobin for use as a blood substitute, and the inability to express myoglobin in tumor tissue. Id. at 14--15. Appellants argue that the Examiner "fails to properly address the evidence set forth in the Declaration under 3 7 C.F .R. § 1.13 2 by Dr. Paiman Peter Ghoroghchian" and that the Examiner's failure to do so in favor of the Examiner's own personal opinion is error. Reply Br. 3--4. The Examiner responds: It is not and has not been the Examiner's position that myoglobin would maintain physiologic oxygen level in all tissues. Rather, the myoglobin is included to oxygenate the hypoxic tissues of a tumor due to its low P50. Second, the Examiner understands that tumors arise in various tissues throughout the body which is why the invention of Winslow is critical. Winslow teaches that their invention is capable of reaching and oxygenating the hypoxic regions of tumors via systemic administration that are otherwise unreachable. Whether the oxygen carrier of the Winslow's method is hemoglobin or myoglobin or both, the result would be alike in that oxygen would be provided to the hypoxic target tissue so as to sensitize the area to chemotherapy and radiation. Ans. 9. 9 The Examiner further responds that the several points raised by the Ghoroghchian Declaration are unpersuasive as the claim does not recite 9 We note the Examiner, in response to Appellants' assertion that certain differences between hemoglobin and myoglobin demonstrate the combination of Winslow and Galluzzo is improper, stated that the rejection "is not suggesting that the myoglobin carrier be provided in place of hemoglobin (whether of blood or synthetic carrier)." Ans. 6, 9. However, in context, we understand the Examiner to have been indicating that the rejection was not based on replacing hemoglobin as a blood substitute "to maintain physiologic [oxygen] levels" in all tissues. Id. at 9. Rather the myoglobin, is substituted "for the express purpose of oxygenating the 14 Appeal2017-001943 Application 13/508,271 systemic injection of myoglobin alone, the prior art suggests myoglobin as a carrier is predictable, and that if the claimed method were toxic, Appellants' own invention would be inoperable. Id. at 9-11. Appellants reply that the Examiner has not addressed "the problems with myoglobin administration" such as the disclosure in the Specification that myoglobin injected into the bloodstream can be dangerous and cause, e.g., "hypertensive urgency or emergency (via sequestration of the vasodilator nitric oxide that normally controls blood vessel tone)" and the conclusions stated in the Ghoroghchian Declaration that "one knowledgeable in biochemistry would not expect myoglobin to be successful or safe for use in systemic oxygen transport or to be able to specifically deliver oxygen only to tumor tissues". Reply Br. 4--5. We are not persuaded. The claims do not require, as Appellants argue, that the high-oxygen affinity agent "maintain physiologic oxygen levels in all tissues within the body", or injection into the bloodstream, but instead that "the oxygen is released by the high-oxygen affinity agent at oxygen tensions less than 10 mmHg." The record before us shows that myoglobin will release oxygen at tensions less than 10 mmHg, as discussed above. Moreover, the claims recite the use of an "oxygen carrier that incorporates the high-oxygen affinity agent." As found by the Examiner, Winslow teaches that "hemoglobin can be added to the blood product hypoxic region of tumor" (id.), which Winslow "teaches that their composition may be used for ... See [O 108]" (id. at 8). See also id. at 10 ("The myoglobin would be provided in an amount sufficient to provide oxygen to the hypoxic areas of a tumor mass and not replace the entirety of a subject['s] hemoglobin."). 15 Appeal2017-001943 Application 13/508,271 composition in free form, or it may be encapsulated in a vessicle, such as a synthetic particle, microballoon or liposome." Winslow i-f 75. The dangers cited by Appellants' declarant relating to myoglobin relate to injection of unencapsulated myoglobin into the bloodstream, not to use of myoglobin encapsulated in a carrier such as a synthetic particle, as posited by the Examiner. In that regard we note that the polymersomes used by Arifin to deliver its oxygen-carrying protein are described as having camouflaging ability. Arifin 2180. With regard to the remaining statements by Ghoroghchian, we agree with the Examiner that none pertain to requirements of the claims but rather speak to issues outside of the claims, such as the inability of myoglobin to be expressed in tumor tissue. Because Winslow teaches use of a carrier, as is required by the claims, we find that Appellants have not demonstrated that the skilled artisan would have believed the use of myoglobin would be dangerous to the patient and consequently been inclined not to use it. Appellants next argue that "Galluzzo expressly teaches away from a method of systemic oxygen delivery because of the vascular irregularities that by definition characterize the hypoxic tumors." App. Br. 10. Galluzzo' s statement at issue is "it is uncertain whether increasing p02 systemically will result in enhanced oxygenation of a tumor that presents manifest delivery flaws, due to the above discussed vascular abnormalities." Galluzzo 865. Under the proper legal standard, a reference will teach away when it suggests that the developments flowing from its disclosures are unlikely to produce the objective of the applicant's invention. A statement that a particular combination is not a preferred embodiment does not teach away absent clear discouragement of that combination. 16 Appeal2017-001943 Application 13/508,271 Syntex (US.A.) LLC v. Apotex, Inc., 407 F.3d 1371, 1380 (Fed. Cir. 2005) (citations omitted). We agree with the Examiner that Galluzzo's uncertainty does not discourage use of a method of systemic oxygen delivery, particularly because neither of the methods discussed by Galluzzo, hyperbaric oxygen and systemic erythropoietin treatment, use carriers to shield the oxygen from the system until it is in the region of the tumor, as disclosed by Winslow and as recited in the claims. Appellants next argue that Winslow does not teach or suggest "'the released oxygen diffuses out of the oxygen carrier while the high-oxygen affinity agent remains within the oxygen carrier,' as is recited in claim 1." App. Br. 11. The Examiner does not respond to this argument directly, but we do not find reason within Winslow to believe that the hemoglobin based oxygen carrier (see, e.g., i-f 53) would release its oxygen and also - separately- unbind itself from a carrier vehicle like a polymersome into the bloodstream. Appellants' Specification describes the process of the high- affinity oxygen agent inside a carrier releasing its oxygen as follows: high-affinity oxygen binding agents may be encapsulated in carrier vehicles having characteristics that allow for their accumulation around tumor regions and/or are capable of targeting tumors experiencing low oxygen tension. The carrier vehicle may also have characteristics such that oxygen will diffuse from within the vehicle to regions of low oxygen tension (as exist in the center of tumors) while the high-affinity oxygen binding agents remain encapsulated. The high-oxygen affinity agents may be delivered to tumors in a manner that allows the delivered agent to release oxygen at the oxygen tension required to increase the efficacy of radiation due to the oxygen partial pressure gradient characteristics of the agent. Spec. i-f 85. This description is essentially identical to that described in Winslow. See Winslow i-fi-175, 108. Appellants have not pointed to any 17 Appeal2017-001943 Application 13/508,271 teaching in Winslow suggesting the high affinity oxygen agent would also dissociate from the carrier and we see no reason to believe it would, simply because Winslow does not explicitly state that this event does not happen. Conclusion of Law For the reasons discussed above, we affirm the rejection of claim 1 under 35 U.S.C. § 103(a) based on Winslow, Galluzzo, and Arifin. Claims 2-7, 13, 15, 23-28, and 30 have not been argued separately and, therefore, fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv). II Claim 29 stands rejected under 35 U.S.C. § 103(a) based on Winslow, Galluzzo, Arifin, and Awasthi. Appellants have waived arguments based on Hickey. Appeal Br. 16. We, therefore, affirm the rejection of claim 29 for the reasons set out in the Examiner's Answer and as discussed above. See 37 C.F.R. § 41.37(c)(l)(iv) (Appeal Brief must contain "[t]he arguments of appellant with respect to each ground of rejection."); Hyatt v. Dudas, 551 F.3d 1307, 1314 (Fed. Cir. 2008) ("When the appellant fails to contest a ground of rejection to the Board, ... the Board may treat any argument with respect to that ground of rejection as waived."). SUMMARY We affirm the rejection of claims 1-7, 13, 15, 23-28, and 30 under pre-AIA 35 U.S.C. § 103(a) as being unpatentable over Winslow, Galluzzo, and Arifin. We affirm the rejection of claim 29 under pre-AIA 35 U.S.C. § 103(a) as being unpatentable over Winslow, Galluzzo, Arifin, and Awasthi. 18 Appeal2017-001943 Application 13/508,271 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). AFFIRMED 19 Copy with citationCopy as parenthetical citation