MULTIPLE SCLEROSIS RESEARCH CENTER OF NEW YORK

Patent Trials and Appeals BoardJul 31, 2020

2019006719 (P.T.A.B. Jul. 31, 2020)

UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 14/525,903 10/28/2014 Saud A. SADIQ 22484ZY 3308 23389 7590 07/31/2020 SCULLY SCOTT MURPHY & PRESSER, PC 400 GARDEN CITY PLAZA SUITE 300 GARDEN CITY, NY 11530 EXAMINER MACFARLANE, STACEY NEE ART UNIT PAPER NUMBER 1649 NOTIFICATION DATE DELIVERY MODE 07/31/2020 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): Docket@SSMP.COM PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte SAUD A. SADIQ and VIOLAINE K. HARRIS1 ____________ Appeal 2019-006719 Application 14/525,903 Technology Center 1600 ____________ Before JEFFREY N. FREDMAN, DEBORAH KATZ, and JOHN G. NEW, Administrative Patent Judges. NEW, Administrative Patent Judge. DECISION ON APPEAL 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies Multiple Sclerosis Research Center of New York as the real party-in-interest. App. Br. ii. Appeal 2019-006719 Application 14/525,903 2 SUMMARY Appellant files this appeal under 35 U.S.C. § 134(a) from the Examiner’s Final Rejection of claims 16–25 as unpatentable under 35 U.S.C. § 101 as being directed to nonstatutory subject matter. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. NATURE OF THE CLAIMED INVENTION Appellant’s invention is directed to mesenchymal stem cell-derived neural precursor cells. Spec. p. 6, ll. 1–4. REPRESENTATIVE CLAIM Claim 16 is representative of the claims on appeal and recites: 16. Isolated neural precursor cells, prepared by a process comprising the steps of: (a) expanding mesenchymal stem cells isolated from a human subject, (b) culturing a portion of the expanded mesenchymal stem cells obtained in step (a) in a neural progenitor basal medium (NPBM) supplemented with epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and neural cell survival factor-1 (NSF-1), (c) collecting floating cell clusters from the culture of step (b), (d) measuring, in a test portion of the collected cells, expression of nestin, glial fibrillary acidic protein (GFAP), neurofilament-M (NF-M), and alpha smooth muscle (αSM) actin, and Vimentin, relative to expression of nestin, GFAP, NF- Appeal 2019-006719 Application 14/525,903 3 M, and αSM actin and Vimentin in a test portion of the expanded mesenchymal stem cells obtained from step (a), and (e) selecting the remaining portion of the collected cells as neural precursors based on increased expression of nestin, GFAP, and NF-M, decreased expression of Vimentin and decreased expression of αSM actin in said test portion of the collected cells, relative to the expression of nestin, GFAP, NF- M, and αSM actin in said test portion of the expanded mesenchymal stem cells, wherein the selected neural precursors exhibit 2–4 fold increase in the amount of nestin, 5–15 fold increase in the amount of NF-M, 7–10 fold increase in the amount of GFAP, and 0.4–0.7 fold decrease in Vimentin. App. Br. xvi. ISSUES AND ANALYSIS We agree with, and expressly adopt, the Examiner’s findings, reasoning, and conclusion that the claims are directed to nonstatutory subject matter. We address below the arguments raised by Appellant. Issue Appellant argues the claims recite mesenchymal stem cell-derived neural progenitor cells produced by an artificial culturing process that are markedly different from mesenchymal stem cells or neural precursor cells found in vivo. See App. Br. iv–v. Analysis The Examiner concludes that claim 16 is directed to a judicial exception, without reciting significantly more. Ans. 3. The Examiner finds the claims recite a product of nature or natural phenomenon, “specifically, a Appeal 2019-006719 Application 14/525,903 4 product-by-process isolated neural precursor cell.” Id. The Examiner finds that the claimed isolated neural precursor cells are not markedly different from mesenchymal stem cells or neural precursor cells found in nature. See id. Appellant argues that the claimed product is isolated mesenchymal cell-derived neural progenitor cells (“MSC-NPCs”) that do not exist in nature. See App. Br. iv. Appellant argues that “the MSC-NPCs have been derived artificially by driving MSC differentiation toward neural progenitors in a non-natural, ex vivo environment that induces increased expression of nestin, GFAP and NF-M and decreased expression of αSM actin.” Id. at v. In performing an analysis of patentability under Section 101, we follow the framework set forth by the Supreme Court in Mayo Collaborative Servc’s v. Prometheus Labs., Inc., 566 U.S. 66 (2012). We are also mindful of, and guided by, the United States Patent and Trademark Office’s 2019 Revised Patent Subject Matter Eligibility Guidance, 84(4) Fed. Reg. 50–57 (January 7, 2019) (the “Guidance”). Following the first step of the Mayo framework, we find that claim 16 recites a composition of matter and therefore falls into one of the broad statutory categories of patent-eligible subject matter under 35 U.S.C. § 101. In the next step of the Mayo analysis, we determine whether the claim at issue is directed to a nonstatutory, patent-ineligible concept, i.e., a law of nature, a phenomenon of nature, or an abstract idea. Mayo, 566 U.S. at 70– 71; Guidance 54 (step 2A, Prong 1). If we determine that the claim recites a judicial exception, we then determine whether the limitations of the claim reciting the judicial exception are integrated into a practical application. Id. (Step 2A, Prong 2). Finally, if we determine that the claim is directed to a Appeal 2019-006719 Application 14/525,903 5 judicially-created exception to Section 101, we evaluate the claims under the next step of the Mayo analysis, considering the elements of each claim both individually and “as an ordered combination” to determine whether additional elements “transform the nature of the claim” into a patent-eligible application. Mayo, 566 U.S. at 78–79; 2019 Guidance at 56 (Step 2B). Appellant’s claim 16 recites: “[i]solated neural precursor cells, prepared by a process.” App. Br. xvi. The claim further includes product- by-process limitations, viz., steps of expanding, culturing, collecting, measuring, and selecting. Id. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself.” In re Thorpe, 777 F.2d 695, 697 (Fed. Cir. 1985). Accordingly, we evaluate the patentability of the claim, including under Section 101, based on the product. Appellant argues the claimed process steps are limiting on the claimed product. See Reply Br. 3–4. For example, Appellant argues that “the claimed NPCs are collected from ‘floating neural precursor clusters’ after MSCs have been induced to differentiate, and have a spherical morphology.” Id. (citing Spec. p. 19, ll. 11–22)(emphasis omitted). However, the claims do not recite any specific morphology, and “limitations are not to be read into the claims from the specification.” In re Van Geuns, 988 F.2d 1181, 1184 (Fed. Cir. 1993). Appellant also argues that the claimed “expression pattern” in the selecting step “is defined by relative changes of a combination of markers as compared to the starting MSCs.” Id. at 5 (emphasis omitted). However, selecting neural precursor cells from a mixed population of cells based on an expression pattern merely exploits the natural characteristic of the cells in response to extraneous stimuli used to Appeal 2019-006719 Application 14/525,903 6 isolate the natural product. In other words, the cells are doing what they would naturally do under the circumstances to which they are subjected to by Appellant. Because the process steps themselves are not limiting on the claim, claim 16 recites an isolated natural product, i.e., isolated neural precursor cells. Isolating a natural product and thereby creating a non-naturally occurring material does not necessarily result in patent-eligible subject matter. See Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 593 (2013). In Myriad, the Supreme Court held claims directed to isolated DNA were not “saved by the fact that isolating DNA from the human genome severs chemical bonds and thereby creates a nonnaturally occurring molecule.” 569 U.S. at 593. Rather, to be patent eligible, a “nonnaturally occurring manufacture or composition of matter” must possess “markedly different characteristics from any found in nature.” Id. at 590–591 (citing Diamond v. Chakrabarty, 447 U.S. 303, 309 (1980)). Appellant argues that the claimed cells are markedly different from naturally-occurring neural progenitor cells because: (1) “[t]he claimed MSC- NPCs are produced by an artificial culturing process,” (2) “[t]he claimed MSC-NPCs behave differently from naturally-occurring neural precursors,” and (3) “[t]he claimed MSC-NPCs demonstrate specific expression marker characteristics as recited.” App. Br. v, vi, ix (emphasis omitted). We do not find these arguments persuasive for the reasons set forth below. Appellant first argues that the claimed cells are markedly different from naturally-occurring cells because the claimed cells are produced by an artificial culturing process. App. Br. v. Appellant argues that different artificial culture conditions generate neural precursor cells with different Appeal 2019-006719 Application 14/525,903 7 phenotypes. See id. Appellant cites C. S. Padovan et al., Expression of Neuronal Markers in Differentiated Marrow Stromal Cells and CD133+ Stem-Like Cells, 12 CELL TRANSPLANTATION 839–848 (2003) (“Padovan”), as evidence that culturing mesenchymal stem cells using different known protocols results in different cells. See id. Padovan teaches that mesenchymal stem cells “are capable of differentiating into cells that express the neural stem cell marker nestin as well as neuronal proteins resembling immature neurons when cultured in conditions appropriate for neural stem cells.” Padovan 845. Rather than support Appellant’s argument, Padovan supports the conclusion that mesenchymal stem cells have the natural ability to differentiate toward neural precursor cells when cultured in the appropriate conditions. See id. In other words, the cells are performing their natural function depending upon the artificial environment in which they are cultured. We can distinguish these claims from those in Chakrabarty. In Chakrabarty, the Supreme Court held that claims directed to a genetically altered Pseudomonas bacterium, which was thereby rendered capable of digesting crude oil, were directed to patentable subject matter. 447 U.S. at 305. The Court held that genetically modifying the bacterium rendered it: “a nonnaturally occurring manufacture or composition of matter-a product of human ingenuity ‘having a distinctive name, character [and] use.’” Id. at 310 (quoting Hartranft v. Wiegmann, 121 U.S. 609, 615 (1887)). In this instance, the cells are not genetically altered, but merely subjected to a regime that causes them to respond in a manner that is consonant with no more than their natural capabilities. Appeal 2019-006719 Application 14/525,903 8 Second, Appellant submits evidence to support their argument “that neural progenitors derived from MSCs, prepared using the same methods described in the present application, are markedly different from neural precursors that exist in vivo.” App. Br. vi. Appellant cites V. K. Harris et al., Clinical and pathological effects of intrathecal injection of mesenchymal stem cell-derived neural progenitors in an experimental model of multiple sclerosis, 313 J. NEUROLOGICAL SCI. 167–177 (2012) (“Harris”),2 to demonstrate the properties of the claimed cells in an experimental autoimmune encephalomyelitis (“EAE”) model. See Harris at *1. Appellant argues that Harris teaches that “MSC-NPCs initially display higher nestin expression as compared to the MSCs they were derived from,” but “lose nestin expression as early as 2 weeks after engraftment.” App. Br. vi. Appellant contrasts endogenous neural progenitor cells, which do not lose nestin positivity. Id. Appellant further argues that Harris demonstrates “MSC-NPCs locate to the inflammatory foci and act to regulate immune responses by reducing T-cell infiltration” and “increase the association of endogenous progenitor cells in vivo.” Id. (emphasis omitted). In response to Appellant’s argument, the Examiner cites A. M. Parr et al., Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury, 40 BONE MARROW TRANSPLANTATION 609– 619 (2007) (“Parr”), which summarizes the art regarding transplantation of MSCs in vivo. Ans. 12. Parr teaches “[m]uch of the interest surrounding the use of stromal cells in [central nervous system] injury began with the 2 We cite to Appellant’s submitted “article in press” version of Harris. Appeal 2019-006719 Application 14/525,903 9 discovery that MSCs from both rats and humans give rise to cells with neuronal morphology in vitro, and may also express neuronal or astrocytic markers in vitro.” Parr 609. Parr teaches that “it has also been shown that continued expression of neuronal markers … may depend on the continuation of specific, nonphysiological environmental conditions in vitro.” Id. at 609–610. With respect to the behavior of the cells after administration, Parr teaches that, “human MSCs can improve neurological functional recovery in mice with experimental autoimmune encephalitis (EAE), possibly via reduction of inflammatory infiltrates and areas of demyelination, stimulation of oligodendrogenesis and by elevating [brain- derived neurotrophic factor] expression.” Id. at 613. Although Parr does not specifically describe neural precursor cells as claimed, Parr teaches that MSCs may express neuronal markers in vitro, stop expressing neuronal markers absent artificial conditions, and act to regulate the immune response in EAE. Accordingly, the claimed neural precursor cells do not appear to behave markedly differently from similar cells administered for similar conditions. Appellant also submits two Declarations by Dr. Harris. App. Br. vii. Appellant argues that the Harris Declaration submitted October 16, 2017 (“Harris Declaration 1”) establishes that “mouse MSC-derived neural precursors actually did not fully differentiate into neural cells types in the brain” and thus are different from naturally-occurring neural precursor cells. Id. (emphasis in original). Appellant argues that the Harris Declaration submitted April 20, 2018 ( “Harris Declaration 2”) establishes that “unlike isolated human MSCs, the claimed MSC-NPCs do not proliferate and do not demonstrate self-renewal properties in vitro.” Id. (emphasis omitted). Appeal 2019-006719 Application 14/525,903 10 We agree with the Examiner that the Declarations are not persuasive evidence of markedly different characteristics of the isolated neural precursor cells as compared to their naturally-occurring counterparts. See Ans. 11–13. The Declarations state that isolated neural precursors cells may not share the identical characteristics of naturally-occurring cells in particular situations, e.g., endogenous neural precursors cells in vivo or MSCs in vitro. Harris Decl. 1 ¶¶ 8–11; Harris Decl. 2 ¶¶ 5–6. However, neither Declaration presents evidence of the behavior of naturally-occurring isolated neural precursors cells or isolated MSCs administered in an EAE model. See generally, Harris Decls. 1, 2. Given the Examiner’s findings in Parr that MSCs share similar characteristics to the claimed isolated neural precursor cells, the burden shifts to the Appellant to show a difference between the naturally-occurring cells and the claimed cells. The PTO lacks the resources to do comparisons. See in re Best, 562 F.2d 1252, 1254–1255 (C.C.P.A. 1977). Third, Appellant argues that “[t]he claimed MSC-NPCs display specific fold differences of the expression of the recited markers as a result of an artificial culturing process.” App. Br. ix. Appellant argues that the references cited by the Examiner do not represent naturally-occurring cells, but rather cells that have been manipulated in cell culture. Id. at x. We agree with the Examiner that “[t]here is no evidence that alterations in the relative levels of marker proteins constitutes a marked difference — either structurally or functionally — over naturally-occurring counterparts.” Ans. 10. The references cited by the Examiner indicate that naturally-occurring neuronal precursor cells will express different markers, e.g., nestin, GFAP, NF-M, Vimentin, and αSM, at different levels when Appeal 2019-006719 Application 14/525,903 11 exposed to artificial culture conditions. See id. at 15–17. As discussed supra, the claimed cells naturally function to express different phenotypes due to environmental conditions. Appellant’s manipulation of the environmental conditions does not alter the cells from performing their natural function, and thus the claimed isolated neural precursor cells are not markedly different from their naturally-occurring counterparts. Consequently, we find that the claims recite a judicial exception, i.e., a product of nature. We next determine whether the judicial exception is integrated into a practical application. See 2019 Guidance at 55 (Step 2A, Prong 2). For example, integration may include using the natural product in a particular treatment or prophylaxis for a medical condition or a particular manufacture that is integral to the claims. Id. As discussed supra, the claims recite a product-by-process including steps for preparing the claimed product. The claims do not include any particular treatment or prophylaxis for a medical condition. Because the patentability of product-by-process claims centers on the product itself, we are not presented with the question whether the method of culturing and selecting neural precursor cells is patentable. See Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130 (1948). Accordingly, we determine that the recited natural product is not integrated into a practical application, and claim 16 is directed to a judicial exception. Finally, we evaluate whether additional elements in the claims recite “an inventive concept —i.e., an element or combination of elements that is sufficient to ensure that the patent in practice amounts to significantly more than a patent upon the [ineligible concept] itself.” Ariosa Diagnostics, Inc. Appeal 2019-006719 Application 14/525,903 12 v. Sequenom, Inc., 788 F.3d 1371, 1375 (Fed. Cir. 2015). Particularly, we evaluate whether the claims include specific limitations that are not “well- understood, routine, conventional activity previously engaged in by scientists who work in the field.” Mayo, 566 U.S. at 79. Apart from the process limitations, which are not considered for patentability, the claims include isolated MSCs and an artificial culture including NPBM, EGF, bFGF, and NSF-1. See App. Br. xvi. MSCs are naturally occurring materials. The Specification describes the artificial culture medium as Neural Progenitor Maintenance Medium (NPMM) commercially sold by Lonza. Spec. p. 15, ll. 28–33. There is no evidence of record that the claim includes other, unconventional elements, either alone or in combination. See In re Marco Guldenaar Holding B.V., 911 F.3d 1157, 1161 (Fed. Cir. 2018). We therefore conclude that claim 16 recites no additional elements that amount to significantly more than a patent on the ineligible concept itself. See Ariosa, 788 F.3d at 1378. Because the claim is directed to a judicial exception and the additional recited elements do not transform the judicial exception into a patent-eligible invention, we sustain the Examiner’s rejection upon this ground. Appellant does not argue present separate arguments with respect to the dependent claims. Accordingly, we sustain the Examiner’s rejection of claims 16–25. Appeal 2019-006719 Application 14/525,903 13 CONCLUSION The rejection of claims 16–25 as unpatentable under 35 U.S.C. § 101 is affirmed. 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 Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 16–25 101 Eligibility 16–25