Ex Parte WuDownload PDFBoard of Patent Appeals and InterferencesJun 6, 201110176971 (B.P.A.I. Jun. 6, 2011) Copy Citation MOD PTOL-90A (Rev.06/08) APPLICATION NO./ CONTROL NO. FILING DATE FIRST NAMED INVENTOR / PATENT IN REEXAMINATION ATTORNEY DOCKET NO. 10/176,971 06/19/2002 Ping Wu EXAMINER MUETING, RAASCH & GEBHARDT, P.A. P.O. BOX 581336 MINNEAPOLIS MN 55458-1336 KOLKER, DANIEL ART UNIT PAPER NUMBER 1649 MAIL DATE DELIVERY MODE 06/06/2011 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. UNITED STATES DEPARTMENT OF COMMERCE U.S. Patent and Trademark Office Address : COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov UNITED STATES PATENT AND TRADEMARK OFFICE _____________________________________________________________________________________ UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES __________ Ex parte PING WU __________ Appeal 2011-001750 Application 10/176,971 Technology Center 1600 __________ Before ERIC GRIMES, JEFFREY N. FREDMAN, and STEPHEN WALSH, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to producing cholinergic neurons. The Examiner rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. Appeal 2011-001750 Application 10/176,971 2 Statement of the Case Background The Specification teaches a method of “producing neurons by adhesively culturing neural stem cells and/or progeny thereof in vitro with a mixture including a mitogenic growth factor, a heparin-like agent and an extracellular matrix component, and implanting the cultured stem cells and/or progeny thereof into the mammalian spinal cord or brain, where they differentiate into neurons” (Spec. 4, ll. 1-6). The Claims Claims 5, 7, 9, 11-16, 23, 28, 33, 35, 46-47, 51-58, and 61-69 are on appeal. 1 Claim 46 is representative and reads as follows: 46. A method of producing cholinergic neurons, the method comprising: expanding human neural stem cells and/or progeny thereof by suspension culture as neurospheres in a serum- free mixture comprising epidermal growth factor, basic fibroblast growth factor and leukemia inhibitory factor (LIF); adhesively culturing the expanded human neural stem cells and/or progeny thereof in vitro with a serum-free mixture comprising basic fibroblast growth factor, heparin, and an extracellular matrix component; and implanting the adhesively cultured human neural stem cells and/or progeny thereof into the mammalian spinal cord or brain; wherein the implanted adhesively cultured human neural stem cells and/or progeny thereof differentiate into cholinergic neurons. 1 The Examiner withdrew the obviousness rejection over Kalyani, so claims 17, 18, 59, 60, 70, and 71 are not subject to any rejection (see Ans. 8). Appeal 2011-001750 Application 10/176,971 3 The issue The Examiner rejected claims 5, 7, 9, 11-16, 23, 28, 33, 35, 46-47, 51- 58, and 61-69 under 35 U.S.C. § 103(a) as obvious over Weiss2 and Carpenter3 (Ans. 3-8). The Examiner finds that “Weiss teaches methods of proliferating, or expanding, human neural stem cells, followed by culturing the neural stem cells as an adhesive culture, and finally implanting the cells or progeny thereof into the central nervous system of subjects” (Ans. 3). The Examiner finds “Weiss also discloses that following implantation the cells differentiate into neurons, including cholinergic neurons” (id. at 3-4). The Examiner finds that “Carpenter teaches defined, serum-free medium for use in the proliferation stage, containing EGF and bFGF . . . Carpenter teaches that inclusion of LIF increases the rate of proliferation” (id. at 5). The Examiner finds that Carpenter includes heparin in the medium used to culture adherent cells (id.). The Examiner finds it obvious “to add LIF, taught by Carpenter to be effective in increasing the proliferation of neural stem cells, to the defined medium taught by Weiss” (id. at 6). The Examiner also finds that “Carpenter teaches that inclusion of heparin is preferred in the differentiation medium . . . Therefore the step of ‘adhesively culturing’ would have been obvious to one of ordinary skill in the art” (id.). Appellant contends that it is the “sequential exposure of neural stem cells to the appropriate growth factors under the specific culture conditions 2 Weiss et al., US 5,750,376, issued May 12, 1998. 3 Carpenter, US 5,968,829, issued Oct. 19, 1999. Appeal 2011-001750 Application 10/176,971 4 of the claimed method that is critical for generating a specific neuron subtype, cholinergic neurons” (App. Br. 11). Appellant contends “neither of Weiss or Carpenter ever provides a demonstration of a method of the differentiation of implanted human neural stem cells and/or progeny thereof into cholinergic neurons” (id.). Appellant “submits that one of ordinary skill in the art would not have a reasonable expectation of success in combining the teachings of Weiss et al. and Carpenter to obtain the claimed methods” (id. at 14). Appellant “submits that the Examiner is using improper hindsight, using the present specification to pick and choose elements from the cited references. ‘Obviousness cannot be predicated on what is not known at the time an invention is made, even if the inherency of a certain feature is later established. (MPEP 2141.02(V). . .)’” (id.). Appellant “submits that in applying the teachings of Weiss et al., the Examiner appears to be picking and choosing various steps and conditions from the multitude of different methods taught by Weiss” (id. at 15). Appellant contend that combining “the teachings of Weiss et al. and Carpenter will at most result in the increased in vitro yield of undifferentiated neuronal stem cells. There is no common sense reason to combine the cited teachings to obtain the claimed methods” (id. at 16). The issue with respect to this rejection is: Does the evidence of record support the Examiner’s conclusion that Weiss and Carpenter render obvious the method of claim 46? Findings of Fact Appeal 2011-001750 Application 10/176,971 5 The following findings of fact (“FF”) are supported by a preponderance of the evidence of record. 1. The Specification teaches that transplanted cells differentiate by acquiring cholinergic, glutamatergic and/or GABAergic phenotypes in a region- specific manner. For example, when transplanted into medial septum or spinal cord, they preferentially differentiate into cholinergic neurons; when transplanted into frontal cortex they preferentially differentiate into glutamatergic neurons; and when transplanted into hippocampus they preferentially differentiate into GABAergic neurons. (Spec. 15, ll. 19-24.) 2. Weiss teaches that “a preferred embodiment for proliferation of neural stem cells is to use a defined, serum-free culture medium, as serum tends to induce differentiation and contains unknown components” (Weiss, col. 16, ll. 35-38). 3. Weiss teaches that a “particularly preferable culture medium is a defined culture medium comprising a mixture of DMEM, F12, and a defined hormone and salt mixture” (Weiss, col. 16, ll. 40-42). 4. Weiss teaches that “culture medium is supplemented with at least one proliferation-inducing growth factor. . . . Preferred proliferation- inducing growth factors include EGF . . . [and] basic fibroblast growth factor (bFGF or FGF-2)” (Weiss, col. 16, ll. 53-65). 5. Weiss teaches that “[w]ithin 3-4 days in the presence of a proliferation-inducing growth factor, a multipotent neural stem cell begins to divide giving rise to a cluster of undifferentiated cells referred to herein as a ‘neurosphere’” (Weiss, col. 17, ll. 17-20). Appeal 2011-001750 Application 10/176,971 6 6. Weiss teaches that the “neurospheres of the suspension culture can be easily passaged to reinitiate proliferation” (Weiss, col. 17, ll. 51-52). 7. Weiss teaches that “[d]ifferentiation can also be induced by plating the cells on a fixed substrate such as flasks, plates, or coverslips coated with an ionically charged surface such as poly-L-lysine” (Weiss, col. 18, ll. 51-55). 8. Weiss teaches that other “substrates may be used to induce differentiation such as . . . laminin” (Weiss, col. 18, ll. 56-57). 9. Weiss teaches that among “the growth factors and other molecules that can be used to influence the differentiation of precursor cells in vitro are . . . FGF-2” (Weiss, col. 20, ll. 45-47). 10. Weiss teaches that the progeny of multipotent neural stem cells obtainable from embryonic or adult CNS tissue, which are able to divide indefinitely when maintained in vitro using the culture conditions described herein, meet all of the desirable requirements of cells suitable for neural transplantation purposes and are a particularly suitable cell line as the cells have not been immortalized and are not of tumorigenic origin. The use of multipotent neural stem cells in the treatment of neurological disorders and CNS damage can be demonstrated by the use of animal models. (Weiss, col. 23, ll. 27-36.) 11. Weiss teaches that “[s]tandard stereotactic neurosurgical methods are used to inject cell suspensions both into the brain and spinal cord” (Weiss, col. 25, ll. 58-60). 12. Carpenter teaches that “neural stem cells have been cultured in serum-free media containing epidermal growth factor (‘EGF’) . . . as the Appeal 2011-001750 Application 10/176,971 7 mitogen for proliferation. . . . Further, basic fibroblast growth factor (‘bFGF’) has been used, either alone, or in combination with EGF, to enhance long term neural stem cell survival” (Carpenter, col. 2, ll. 60-67). 13. Carpenter teaches that the “improved medium according to this invention, which contains leukemia inhibitory factor (‘LIF’), markedly and unexpectedly increases the rate of proliferation of neural stem cells, particularly human neural stem cells” (Carpenter, col. 3, ll. 1-4). 14. Carpenter teaches that it “is also advantageous to provide heparin in the culture medium” (Carpenter, col. 3, ll. 38-39). 15. Carpenter teaches that “this invention provides a differentiated cell culture containing previously unobtainable large numbers of neurons . . . we have routinely achieved neuron concentrations of between 20% and 35% (and much higher in other cases) in differentiated human forebrain-derived neural stem cell cultures” (Carpenter, col. 4, ll. 18-27). 16. Carpenter teaches that “we have achieved differentiated neural stem cell cultures that are highly enriched in GABA-ergic neurons. Such GABA-ergic neuron enriched cell cultures are particularly advantageous in the potential therapy of excitotoxic neurodegenerative disorders” (Carpenter, col. 4, ll. 31-36). 17. Carpenter teaches that “[c]holinergic neurons may be identified by their production of choline acetyltransferase (‘ChAT’)” (Carpenter, col. 5, ll. 2-4). 18. Carpenter teaches methods for differentiating neural stem cells to yield cell cultures enriched with neurons to a degree previously unobtainable. According to one protocol, the proliferating Appeal 2011-001750 Application 10/176,971 8 neurospheres are induced to differentiate by removal of the growth factor mitogens and LIF, and provision of 1% serum, a substrate and a source of ionic charges (e.g., glass cover slip covered with poly-ornithine or extracellular matrix components). The preferred base medium for this differentiation protocol, excepting the growth factor mitogens and LIF, is otherwise the same as the proliferation medium. This differentiation protocol produces a cell culture enriched in neurons. According to this protocol, we have routinely achieved neuron concentrations of between 20% and 35% in differentiated human forebrain-derived neural stem cell cultures. (Carpenter, col. 5, ll. 49-63.) 19. Carpenter teaches that “[w]e also contemplate use of the cells of this invention in the treatment of various acute and chronic pains, as well as for certain nerve regeneration applications (such as spinal cord injury)” (Carpenter, col. 7, ll. 48-51). 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). Analysis Weiss teaches a method of expanding human neural stem cells in suspension culture as neurospheres in serum free medium with epidermal growth factor and basic fibroblast growth factor (FF 2-6). Weiss teaches that the expanded cells can be cultured on a solid support with basic fibroblast growth factor and the extracellular matrix component, laminin (FF 7-9). Weiss teaches implanting the cultured cells into brain and spinal cord (FF 10-11). Appeal 2011-001750 Application 10/176,971 9 The Examiner acknowledges that Weiss does not teach inclusion of LIF in the proliferation medium or heparin in the differentiation medium (Ans. 5). Carpenter also teaches culture of neural stem cells (FF 12). Carpenter specifically teaches that the “improved medium according to this invention, which contains leukemia inhibitory factor (‘LIF’), markedly and unexpectedly increases the rate of proliferation of neural stem cells, particularly human neural stem cells” (Carpenter, col. 3, ll. 1-4; FF 13). Carpenter teaches that for the differentiation medium, it “is also advantageous to provide heparin in the culture medium” (Carpenter, col. 3, ll. 38-39; FF 14). Carpenter teaches that the use of LIF in the proliferation medium followed by heparin in the differentiation medium results in large numbers of neurons (FF 18), which Carpenter teaches may be applied to spinal cord injury (FF 19). Applying the KSR standard of obviousness to the findings of fact, we conclude that an ordinary artisan would have reasonably found it obvious to incorporate LIF into the proliferation medium of Weiss since Carpenter teaches this increases the rate of proliferation of stem cells (FF 13). We also find that the ordinary artisan would have incorporated heparin into the differentiation medium of Weiss since Carpenter teaches that this is advantageous (FF 14). Such a combination is merely a “predictable use of prior art elements according to their established functions.” KSR, 550 U.S. at 417. Appellant contends that it is the “sequential exposure of neural stem cells to the appropriate growth factors under the specific culture conditions Appeal 2011-001750 Application 10/176,971 10 of the claimed method that is critical for generating a specific neuron subtype, cholinergic neurons” (App. Br. 11). Appellant contends “neither of Weiss or Carpenter ever provides a demonstration of a method of the differentiation of implanted human neural stem cells and/or progeny thereof into cholinergic neurons” (id.). We are not persuaded on this point for several reasons. It is solely attorney argument that sequential exposure is “critical.” In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974). The Wu Declaration4 states that adhesively culturing human neural stem cells and/or progeny thereof in vitro with a mixture comprising a mitogenic growth factor, a heparin-like agent, and an extracellular matrix component, all at defined concentrations, and implanting neural stem cells and/or progeny thereof primed in such a fashion into the mammalian spinal cord or brain effectively results in the differentiation of cholinergic neurons. (Wu Dec. 5 ¶ 15.) Thus, Dr. Wu does not indicate that particular growth factors, heparin-like agents or matrix components are critical for priming. This lack of criticality is also consistent with Appellant’s Specification, which states that transplanted cells differentiate by acquiring cholinergic, glutamatergic and/or GABAergic phenotypes in a region- specific manner. For example, when transplanted into medial septum or spinal cord, they preferentially differentiate into cholinergic neurons; when transplanted into frontal cortex they preferentially differentiate into glutamatergic neurons; and when transplanted into 4 Declaration of Dr. Ping Wu, filed May 8, 2006. Appeal 2011-001750 Application 10/176,971 11 hippocampus they preferentially differentiate into GABAergic neurons. (Spec. 15, ll. 19-24; FF 1.) Thus, the Specification disputes Appellant’s “critical” sequential exposure argument, by indicating that neural cells transplanted into spinal cord preferentially differentiate into cholinergic neurons (FF 1). We therefore agree with the Examiner that “once the cells are cultured in the two different media and implanted, they will necessarily differentiate into cholinergic neurons” (Ans. 9). See In re Best, 562 F.2d 1252, 1255 (CCPA 1977) (“Where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product.”). Appellant “submits that one of ordinary skill in the art would not have a reasonable expectation of success in combining the teachings of Weiss et al. and Carpenter to obtain the claimed methods” (App. Br. 14). Appellant “submits that the Examiner is using improper hindsight, using the present specification to pick and choose elements from the cited references. ‘Obviousness cannot be predicated on what is not known at the time an invention is made, even if the inherency of a certain feature is later established. (MPEP 2141.02(V) . . .)’” (id.). Appellant “submits that in applying the teachings of Weiss et al., the Examiner appears to be picking and choosing various steps and conditions from the multitude of different methods taught by Weiss” (id. at 15). Appeal 2011-001750 Application 10/176,971 12 We are not persuaded. The use of LIF and heparin do not result from “picking and choosing” but rather from the direct suggestion and teaching of Carpenter. That is, Carpenter teaches that LIF “markedly and unexpectedly increases the rate of proliferation of neural stem cells, particularly human neural stem cells” (Carpenter, col. 3, ll. 1-4; FF 13). Carpenter also teaches, for the adherent medium, that it “is also advantageous to provide heparin in the culture medium” (Carpenter, col. 3, ll. 38-39; FF 14). The express suggestion of Carpenter not only provides reasons to incorporate LIF and heparin into the protocol of Weiss, but provides a reasonable expectation of success, since Carpenter teaches that the addition of LIF enhances the proliferation rate of neural stem cells (FF 13). Kubin stated that “[R]esponding to concerns about uncertainty in the prior art influencing the purported success of the claimed combination, this court [in O’Farrell] stated: ‘[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) (citing In re O’Farrell, 853 F.2d 894, 903- 904 (Fed. Cir. 1988)). Appellant has provided no evidence to rebut the very reasonable expectation of success that would be expected based upon the teachings of Carpenter (FF 13-18). Appellant contends that combining “the teachings of Weiss et al. and Carpenter will at most result in the increased in vitro yield of undifferentiated neuronal stem cells. There is no common sense reason to combine the cited teachings to obtain the claimed methods” (App. Br. 16). We are not persuaded. Both Weiss and Carpenter teach and suggest the transplantation of the neural stem cells into the brain and spinal cord (FF Appeal 2011-001750 Application 10/176,971 13 11, 19). Carpenter specifically teaches identification of cholinergic cells (FF 17). Upon combining the methods, and treating brain or spinal cord with the neural stem cells suggested by Weiss and Carpenter, the Examiner reasonably concludes that some neural stem cells will necessarily differentiate into cholinergic neural cells (Ans. 6). Not only has Appellant not shown otherwise (Best, 562 F.2d at 1255), but the Wu Declaration taught that even in the unprimed graft group “only a few differentiated into cholinergic neurons” (Wu 4 ¶ 11). However, these few cells would reasonably satisfy the requirements of claim 46, which simply requires that some of the implanted human neural stem cells differentiate into cholinergic neurons (see Claim 46). Thus, it is reasonable to conclude that neural stem cells primed as taught and suggested by Weiss and Carpenter (FF 2-19), implanted into brain or spinal cord environments which necessarily result in differentiation into cholinergic neurons (FF 1), would inherently differentiate into cholinergic neurons. Conclusion of Law The evidence of record supports the Examiner’s conclusion that Weiss and Carpenter render obvious the method of claim 46. SUMMARY In summary, we affirm the rejection of claim 46 under 35 U.S.C. § 103(a) as obvious over Weiss and Carpenter. Pursuant to 37 C.F.R. § 41.37(c)(1)(vii)(2006), we also affirm the rejection of claims 5, 7, 9, 11-16, 23, 28, 33, 35, 47, 51-58, and 61-69, as these claims were not argued separately. Appeal 2011-001750 Application 10/176,971 14 No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a)(1). AFFIRMED JNF SW EG cdc Copy with citationCopy as parenthetical citation