Philip J. Weintraub

Patent Trials and Appeals BoardSep 9, 2019

14561193 - (D) (P.T.A.B. Sep. 9, 2019)

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. 14/561,193 12/04/2014 Philip J. Weintraub 6339.PWEI.NP 1692 27472 7590 09/09/2019 Durham Jones & Pinegar P.O. Box 4050 SALT LAKE CITY, UT 84110 EXAMINER CLARKE, TRENT R ART UNIT PAPER NUMBER 1651 NOTIFICATION DATE DELIVERY MODE 09/09/2019 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): ipmail@djplaw.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte PHILIP J. WEINTRAUB1 ____________ Appeal 2019-001734 Application 14/561,193 Technology Center 1600 ____________ Before TONI R. SCHEINER, RICHARD M. LEBOVITZ, and DEBORAH KATZ, Administrative Patent Judges. LEBOVITZ, Administrative Patent Judge. DECISION ON APPEAL The claims in this appeal are directed to methods of identifying expansion and regression in areas of first and second malignant cancer cell colonies. The Examiner finally rejected the claims under 35 U.S.C. § 101 as reciting a judicial exception to patent eligibility, under 35 U.S.C. § 112 as lacking a written description, and under 35 U.S.C. § 103 as obvious. Pursuant to 35 U.S.C. § 134, Appellant appeals the Examiner’s determination that the claims are unpatentable. We have jurisdiction for the appeal under 35 U.S.C. § 6(b). The Examiner’s decision is reversed. A new ground of rejection is set forth pursuant to 37 C.F.R § 41.50(b). 1 The Appeal Brief (“Appeal Br.” entered June 7, 2018) lists Philip Weintraub as the real party in interest. Appeal Br. 2. Appeal 2019-001734 Application 14/561,193 2 STATEMENT OF THE CASE The Examiner rejected claims 1–9, 15, and 20 as follows: 1. Claims 1–9, 15, and 20 under 35 U.S.C. § 101 because the claimed invention is directed to an abstract idea which is a judicial exception to patent eligibility. Ans. 4. 2. Claims 1–9, 15, and 20 under 35 U.S.C. § 112(a) or 35 U.S.C. § 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. Ans. 3. 3. Claims 1–9, 15, and 20 under 35 U.S.C. § 103 as obvious in view of Kirsten Hattermann et al., The Chemokine CXCL16 Induces Migration and Invasion of Glial Precursor Cells via its Receptor CXCR6, 39 MOL. CELL. NEUROSCI., 133–41 (2008) (“Hattermann 2008”), N. G. Rainov et al., Characterization of a Canine Glioma Cell Line As Related to Established Experimental Brain Tumor Models, 59(7) J. NEUROPATH. EXP. NEUROL., 607–13 (2000) (“Rainov”), and Douglas Hanahan & Robert A. Weinberg, The Hallmarks of Cancer, 100 CELL, 57–70 (2000) (“Hanahan”). Ans. 8. Claim 1, the only independent claim on appeal, is reproduced below: 1. A method for identifying expansion in area of a colony of first malignant cancer cells with commensurate regression in area of a different colony of second malignant cancer cells in the same area as the expansion of the colony of first malignant cancer cells in an adjacent confrontation, comprising: plating on a culture plate in a growth medium a colony of first malignant cancer cells and a colony of second malignant cancer cells on directly opposite sides of a midline adjacent one another, wherein the colony of first malignant cancer cells and the colony of second malignant cancer cells are of different cancer types; Appeal 2019-001734 Application 14/561,193 3 culturing the colony of first malignant cancer cells and the colony of second malignant cancer cells under conditions sufficient to promote growth of the cancer cells; measuring the area of expansion of the colony of first malignant cancer cells across the midline into the area of the colony of second malignant cancer cells that is accompanied by regression of the second colony of malignant cancer cells from the midline commensurate with the area of expansion of the colony of malignant cancer cells. 1. REJECTION BASED ON 101 The Examiner found that the claims are directed to “abstract ideas” which are judicial exceptions to patent eligibility under 35 U.S.C. § 101. Ans. 4. Under 35 U.S.C. § 101, an invention is patent-eligible if it claims a “new and useful process, machine, manufacture, or composition of matter.” However, not every discovery is eligible for patent protection. Diamond v. Diehr, 450 U.S. 175, 185 (1981). “Excluded from such patent protection are laws of nature, natural phenomena, and abstract ideas.” Id. The Supreme Court articulated a two-step analysis to determine whether a claim falls within an excluded category of invention. Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 573 U.S. 208, 216 (2014); Mayo Collaborative Servs. v. Prometheus Labs, Inc., 566 U.S. 66, 75–77 (2012). In the first step, it is determined “whether the claims at issue are directed to one of those patent-ineligible concepts.” Alice, 573 U.S. at 217. If it is determined that the claims are directed to an ineligible concept, then the second step of the two-part analysis is applied in which it is asked “‘[w]hat else is there in the claims before us?’” Id. The Court explained that this step involves Appeal 2019-001734 Application 14/561,193 4 a search for 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.” Alice, 573 U.S. at 217–18 (citing from Mayo, 566 U.S. at 75–77). Alice, relying on the analysis in Mayo of a claim directed to a law of nature, stated that in the second part of the analysis “the elements of each claim both individually and ‘as an ordered combination’” must be considered “to determine whether the additional elements ‘transform the nature of the claim’ into a patent-eligible application.” Alice, 573 U.S. at 217. The PTO recently published revised guidance on the application of § 101. USPTO’s January 7, 2019 Memorandum, 2019 Revised Patent Subject Matter Eligibility Guidance, 84 Fed. Reg. 50, 51–57 (Jan. 7, 2019) (“2019 Guidelines”). This guidance provides direction on how to implement the two-part analysis of Mayo and Alice. The 2019 Guidelines implements the first step of the Alice/Mayo test as Step 2A. 84 Fed. Reg. at 51 (col. 1). Step 2A, Prong One, of the 2019 Guidelines, looks at the specific limitations in the claim to determine whether the claim recites a judicial exception to patent eligibility. 84 Fed. Reg. at 54 (“1. Prong One”). In Step 2A, Prong Two, the claims are examined to identify whether there are additional elements in the claims that integrate the exception in a practical application, namely, is there a “meaningful limit on the judicial exception, such that the claim is more than a drafting effort designed to monopolize the judicial exception.” 84 Fed. Reg. at 54 (“2. Prong Two”). Appeal 2019-001734 Application 14/561,193 5 If the exception is not integrated into a practical application, then as in the Alice/Mayo framework, Step 2B of the 2019 Guidelines asks whether there is an inventive concept to ensure that the patent is significantly more than a patent on the ineligible concept, itself. 84 Fed. Reg. 56. In making this determination, it must be considered whether specific limitations or elements recited in the claim “that are not well-understood, routine, conventional activity in the field, which is indicative that an inventive concept may be present” or whether the claim “simply appends well- understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, indicative that an inventive concept may not be present.” 84 Fed. Reg. at 56. With these guiding principles, we proceed to determine whether the claimed subject matter in this appeal is eligible for patent protection under 35 U.S.C. § 101. As explained below, we agree with the Examiner that claim 1 recites an abstract idea, but we disagree with the Examiner’s analysis that the claim as a whole is directed to an abstract idea. Step 2A, Prong One In Step 2A, Prong One, of the 2019 Guidelines, the specific limitations in the claim are examined to determine whether the claim recites a judicial exception to patent eligibility, i.e., whether the claim is an abstract idea, law of nature, or natural phenomenon. The Examiner found that the claim recites an abstract idea and therefore is ineligible for a patent.2 Ans. 5. 22 It does not appear that the Examiner considered whether the claims recite a law of nature, e.g., under Funk Brothers Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130 (1948). Appeal 2019-001734 Application 14/561,193 6 We first address whether the claim recites an abstract idea. The 2019 Eligibility Guidance identifies three groupings identified as abstract ideas. 84 Fed. Reg. at 52. The Examiner found that the subject matter of the claim fits into grouping “(c) Mental process—concepts performed in the human mind[] (including an observation, evaluation, judgment, opinion). The Examiner found: Specifically, the [claimed] method is drawn to identifying expansion in area of a colony of cells, a mental step, and comprises comparing the area of the first malignant cell colony with the area of a second malignant cell colony to see if their expansion and regression, respectively, are commensurate – also a mental step. Ans. 5. The first step of claim 1 comprises “plating” malignant cells on a culture plate. The second step of the claim comprises “culturing” the cells on the plate under conditions to promote their growth. Both of these steps involve physical, concrete manipulations to the cells. The third and last step of the claim comprises “measuring the area of expansion” of the malignant cells. We agree with the Examiner that such a step can be considered to be a mental process because it involves a mental observation about how much area on the plate the malignant cells have expanded by their growth. Thus, as found by the Examiner, the claim recites an abstract idea. Step 2A, Prong Two Prong Two of Step 2A under the 2019 Guidance asks whether there are additional elements that integrate the exception into a practical application. The claim recites “plating” and “culturing” steps, which are concrete manipulations carried out on cells for the purpose of performing a Appeal 2019-001734 Application 14/561,193 7 confrontation assay where two cell types are faced off on a culture dish to determine their relative growth properties. See, e.g., Hattermann 2008, Hattermann 2011, and Nygaard (full citations below). Once the plating and culturing steps are accomplished, and the confrontation assay is completed, the claim further requires the mental step of observing the result of the recited manipulative steps. The mental step is therefore integrated into a practical application because it is merely an observation performed after the manipulative steps of the confrontation assay and unnecessary to carry the assay out. The Examiner did not explain how the recitation of a single step in the claim in which an observation is made about the growth of cells plated on a culture plate transforms the claim as a whole into a patent-ineligible abstract idea. The Examiner dismissed the plating and culturing steps as “well- understood, routine and conventional steps” (Ans. 5), but the steps of plating and culturing cells constitute the core of the claim and a practical application into which the mental process is integrated. In the Examiner’s analysis, any method involving physical, manipulative steps would be an “abstract idea” if an observation was made about the outcome of performing such steps. For the foregoing reasons, we reverse the Examiner’s determination that the claims are directed to patent ineligible subject matter under 35 U.S.C. § 101. 2. WRITTEN DESCRIPTION REJECTION The Examiner found that the Specification as originally filed does not describe the limitation of claim 1: Appeal 2019-001734 Application 14/561,193 8 measuring the area of expansion of the colony of first malignant cancer cells across the midline into the area of the colony of second malignant cancer cells that is accompanied by regression of the second colony of malignant cancer cells from the midline commensurate with the area of expansion of the colony of malignant cancer cells. Ans. 4. The Examiner states that the Specification describes both the expansion and regression of cells as “possible offensive and defensive behaviors cells may show,” but not where the expansion of the first colony of cells is accompanied by regression of the second colony of cells as recited in the last clause of claim 1. Ans. 19. The Examiner’s position is not supported by a preponderance of the evidence. To satisfy the written description requirement of 35 U.S.C. § 112, the inventor must “convey with reasonable clarity to those skilled in the art that, as of the filing date sought” they were “in possession of the invention.” Vas- Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563–64 (Fed. Cir. 1991) (emphasis omitted). “One shows that one is ‘in possession’ of the invention by describing the invention, with all its claimed limitations . . . .” Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997) (emphasis and internal citation omitted). In describing the claimed invention, there is no requirement that the wording be identical to that used in the specification as long as there is sufficient disclosure to show one of skill in the art that the inventor “invented what is claimed.” Union Oil Co. v. Atlantic Richfield Co., 208 F.3d 989, 997 (Fed. Cir. 2000) (internal quotations and citation omitted). The written description “need not recite the claimed invention in haec verba but [it] must do more than merely disclose that which would Appeal 2019-001734 Application 14/561,193 9 render the claimed invention obvious.” ICU Med., Inc. v. Alaris Med. Sys., Inc., 558 F.3d 1368, 1377 (Fed. Cir. 2009). Thus, as long as a person “of ordinary skill in the art would have understood the inventor to have been in possession of the claimed invention at the time of filing, even if every nuance of the claims is not explicitly described in the specification, then the adequate written description requirement is met.” In re Alton, 76 F.3d 1168, 1175 (Fed. Cir. 1996). In this case, Appellant provided adequate evidence that the Specification discloses the claimed limitation, namely, “measuring the area of expansion of the colony of first malignant cancer cells . . . into the area of the colony of second malignant cancer cells that is accompanied by regression of the second colony of malignant cancer cells . . . commensurate with the area of expansion of the colony of malignant cancer cells.” For example, Appellant cited the following written descriptive support from the Specification for this limitation: In another aspect of the invention, the area over which the first and second colony of malignant cancer cells is plated is selected such that the relative differences in growth over the course of culturing can be readily ascertained. For example, in some embodiments, the colony of first malignant cancer cells and the colony of second malignant cancer cells plated each cover an area that is substantially equal. Plating about an equal number of cells, plated over about an equal area, generally simplifies the comparison of territorial expansion or regression, without the need to normalize the data for purposes of determining which cell line is expanding or regressing. Spec. ¶ 44 (emphasis added). In another aspect, the present invention may further include means for quantitating the extent or degree of dominant behavior associated with territorial expansion of a dominant cell Appeal 2019-001734 Application 14/561,193 10 type. For example, in one embodiment the culture plate may comprise unit markers for scoring the area of expansion of the dominant malignant cancer cells. Such unit markers may be in either standard U.S. measurement units (such as inches) or metric units (cm). The unit markers may comprise vertical and/or horizontal line markers, marked to enable visibility and measurement of the area of expansion of a dominant cell type (or area of regression of a submissive cell type). Spec. ¶ 46 (emphasis added). As indicated in the passages reproduced above, the Specification expressly teaches plating cells so “relative differences in growth” can be observed, indicating that the behavior of both cells on the plate are observed. Spec. ¶ 44. In this same paragraph, it is disclosed that the plating procedure “simplifies the comparison of territorial expansion or regression,” indicating that both expansion and regression can be accomplished at the same time. Id. The plates are marked to enable measurement of these behaviors. Spec. ¶ 46. The Specification, thus, demonstrates that the inventor had possession of the concept of measuring expansion of cells and the accompanying regression of cells. Figure 5, reproduced below, provides written descriptive support for the concept that the regression is commensurate with expansion as required by the claim. Appeal 2019-001734 Application 14/561,193 11 FIG. 5 shows a culture dish, illustrating various offensive behaviors of a dominant cancer cell line (diagonal hatched lines region) expanding into another cancer cell line territory (dotted region), and also illustrating a defensive behavior of a cancer cell line (dotted region) partially retreating behind a backline. Spec. ¶ 19. Figure 5 shows that one cell type (hatched lines) has expanded across a midline into the region of another cell type (dotted region) which regresses in response, providing support for the limitation “regression of the second colony of malignant cancer cells from the midline commensurate with the area of expansion of the colony of malignant cancer cells.” In sum, one of ordinary skill in the art would understand that when the cells of one type cross the midline and invade cells of a second type, the first cell type has expanded and the second cell type has regressed. This is illustrated in Figure 5 reproduced above. The Specification describes measuring both expansion and regression of the cell colonies. Spec. ¶¶ 44, 46. Consequently, we conclude that the inventor had possession of the claimed subject matter at the time of the invention. Appeal 2019-001734 Application 14/561,193 12 The written description rejection of claim 1, and dependent claims 2–9, 15, and 20 is reversed. 3. REJECTION BASED ON HATTERMANN 2008 Claim 1 comprises “plating” two populations of malignant cancer cells on opposite sides of a midline on a culture plate. The claim further recites “culturing” the cells under conditions to promote growth. The last step of the claim comprises “measuring the area of expansion of the colony of first malignant cancer cells across the midline into the area of the colony of second malignant cancer cells.” The expansion is recited in the claim to be “accompanied by regression of the second colony of malignant cancer cells from the midline commensurate with the area of expansion of the colony of malignant cancer cells.” The Examiner found that Hattermann 2008 describes a “confrontation assay,” the same type of assay as claimed in which two different cell populations are plated on a culture plate adjacent and opposite from each other along a midline. Ans. 9–10. The Examiner found that, in its confrontation assay, Hattermann 2008 uses “U343 glioma cells which are a malignant cancer cell line and GPC cells which are invasive immortalized cells.” Ans. 10. Appellant disputed the Examiner’s finding that the cells are malignant cancer cells as required by claim 1. Appeal Br. 13–14. In response, the Examiner further cited Rainov and Hanahan as evidence that the cells used by Hattermann meet the definition of malignant cells, designating it as a new ground of rejection. Ans. 10. Appeal 2019-001734 Application 14/561,193 13 Appellant responded to the new ground of rejection in the Reply Brief, but did not challenge the Examiner’s determination that the cells plated in Hattermann 2008 meet the claimed limitation of “malignant cancer cells.” See Reply Br. 8. We, therefore, consider this argument to be waived. See MANUAL OF PATENT EXAMINING PROCEDURE (“MPEP”) § 1205.02 (9th Ed., Rev. 08.2017, Jan. 2018) (“If a ground of rejection stated by the examiner is not addressed in the appellant’s brief, appellant has waived any challenge to that ground of rejection and the Board may summarily sustain it.”); see also In re Berger, 279 F.3d 975, 984 (Fed. Cir. 2002) (in which the Board affirmed an uncontested rejection of claims under 35 U.S.C. § 112, second paragraph, and on appeal the Federal Circuit affirmed the Board’s decision and found that the appellant had waived his right to contest the indefiniteness rejection by not presenting arguments as to error in the rejection on appeal to the Board). In the Reply Brief, Appellant argues that the rejection is “clearly erroneous” because the cited prior art references do not describe the claim limitation of measuring the area of expansion of the colony of first malignant cancer cells across the midline into the area of the colony of second malignant cancer cells that is accompanied by regression of the second colony of malignant cancer cells from the midline commensurate with the area of expansion of the colony of malignant cancer cells. Reply Br. 8–9. We agree with Appellant that the Examiner did not establish that Hattermann 2008 describes the recited limitation. Hattermann 2008 discloses a spheroid confrontation model using U343 glioma cells and an immortalized glial precursor cell line (“GPC”) (Hattermann 2008, 139 (in Appeal 2019-001734 Application 14/561,193 14 section titled “Tissue samples and cell cultures”); 140 (in section titled “Spheroid confrontation model”)). Hattermann 2008 reported that soluble chemokine CXCL16, produced by U343 glioma cells, induced the migration of the GPC cells into the glioma cells. Hattermann 2008, 137. To differentiate between the cell types, Hattermann 2008 labels the GPC cells with a green fluorescent dye and the U343 glioma cells with a red dye. Hattermann 2008, 137 (right col.) Hattermann 2008 found: After 24 h of co-incubation green-labeled CXCR6-GPC were detected as single cells or in small groups within the red- labeled spheroid of glioma cells producing soluble CXCL16. Hattermann 2008, 137 (right col.) Based on this observation, Hattermann 2008 concluded that “CXCR6 mediates migration and invasion of GPC into a three-dimensional network of CXCL16-producing cells.” Hattermann 2008, 137 (right col.). Figure 4 of Hattermann 2008 shows the migration of GPC into the glioma cells. In the legend to Figure 4, Hattermann 2008 states that “[a]fter 24 h in 10% fetal calf serum, green CXCR6-cells invaded the red CXCL16- producing spheroids.” Hattermann 2008, 137. Hattermann 2008 further describes the “proliferation, migration and invasion of GPC . . . induced by soluble CXCL16.” Id. at 138 (right col.). However, none of these disclosures show cellular regression accompanying expansion as required by all the rejected claims. The Examiner cited Figure 4 on page 137, the section titled “Tissue samples and cell cultures” on page 139, and the section titled “Spheroid confrontation model”) on page 140 as describing “regression of the second colony of malignant cancer cells from the midline commensurate with the area of expansion of the colony of malignant cancer cells.” Ans. 9. The Appeal 2019-001734 Application 14/561,193 15 Examiner did not point to specific disclosure where Hattermann 2008 describes cellular regression accompanying expansion. We have reviewed these sections, and are in agreement with Appellant, that there is no express disclosure that Hattermann 2008 measured “expansion” of the GPC cells “accompanied by regression” of the U343 glioma cells as required by the claim. Because the Examiner did not meet the burden3 of establishing that each limitation of the claim is disclosed or suggested by Hattermann, Rainov, and Hanahan, the obviousness rejection of claim 1, and dependent claims 2–9, 15, and 20 is reversed. NEW GROUND OF REJECTION In the rejection based on 35 U.S.C. § 101, the Examiner identified six publications (Golembieski, Nygaard, Wartenberg, Hattermann 2011, Vinci, and Dolznig) for their disclosure of confrontation assays between two cell types. Ans. 5–7. The Examiner cited these publications to establish that the claimed steps of “plating colonies adjacent to each other (i.e. on directly opposite sides of a midline), culturing and measuring the areas of expansion and regression are well-understood, routine and conventional steps.” Ans. 7. Nygaard4 describes co-culture of glioblastoma multiforme (“GBM”) and fetal rat brain cell aggregates (“BCAs”). Nygaard, Abstract. Nygaard 3 An examiner bears the initial burden of presenting a prima facie case of obviousness. In re Huai-Hung Kao, 639 F.3d 1057, 1066 (Fed. Cir. 2011). 4 Svein J.T. Nygaard et al., Dynamic Determination of Human Glioma Invasion In Vitro, 89 J. NEUROSURG., 441–47 (1998). Appeal 2019-001734 Application 14/561,193 16 discloses that the GBM cells infiltrated the BCAs cells and progressively destroyed them: We scored the aggressiveness of the tumors by measuring the remaining BCA volume. Using this as a parameter, it was shown that the tumor spheroids progressively destroyed the BCAs in a linear fashion and, from the results provided, it is most likely that the disintegration of normal brain tissue is complete after approximately 200 hours of coculture. Nygaard 444–45 (“Discussion”). Nygaard also discloses variation in the different tumors studied: As indicated in Fig. 2 and Table 2, considerable variation in BCA destruction was observed between the different tumor specimens. The tumor spheroid grown from Case 14 destroyed BCA at the highest rate and those grown from Cases 8 and 13 to the least extent (Table 2). Nygaard 444 (left col.). Nygaard explains that the destruction of the BCA cells by the GBM tumor cells is likely a result of destructive proteinases produced by the tumor cells. Nygaard 445. Nygaard also discloses that the overall destruction “likely . . . represents a reflection of an imbalance between several proteases and their inhibitors.” Id. Hattermann 20115 discloses that spheroid confrontation assays can be performed using different cell types and for the purpose of determining the influence of proteases: Therefore, we developed an easy three-dimensional migration model using spheroids of different (or also the same) cell types. For this purpose, cells are differentially fluorescently labelled, 5 Kirsten Hattermann et al., Spheroid Confrontation Assay: A Simple Method to Monitor the Three-Dimensional Migration of Different Cell Types In Vitro, 193 ANNALS OF ANAT., 181–84 (2011). Appeal 2019-001734 Application 14/561,193 17 spheroids of one or both cell types are formed and confronted to each other. This spheroid-confrontation assay has the following advantages: it is easy to perform, inexpensive, monitors the chemotactic gradient as well as the influence of matrix proteins and cell-cell-adhesion. Neutralizing antibodies or inhibitors can be used to determine the specificity of chemotactic factors/receptors, the influence of proteases, and the effects of cell adhesion molecules. Id. at 181 (right col.) (emphasis added). Hattermann 2011 used glioma cells in some assays, but reasonably suggests to one of ordinary skill in the art performing other types of cell studies using other cell types: Typical results of spheroid formation and confrontation are depicted in Fig. 1. Either single cell suspensions (here glioma-invading macrophages/microglial cells) or spheroids of a different cell type (here glial precursor cells) can be confronted to the “homing” spheroids (here glioma cells). Although this approach with fluorescent-labelled cells has been mostly used to study the migration/invasion into tumour spheroids (Golembieski et al., 1999; Mohanam et al., 2002; Oxmann et al., 2008; Held-Feindt et al., 2010), it can also be applied for other types of studies, e.g. invasion of inflammatory cells or developmental studies (Hattermann et al., 2008). Id. at 183 (right col.) (emphasis added). It would have been obvious to one of ordinary skill in the art to use two different GBM or malignant cell types in a confrontation assay to determine the relative “influence of proteases.” Hattermann 2011. Nygaard specifically teaches that tumors vary in their destructive ability. Nygaard 444 (left col.). Nygaard also teaches that the balance of proteases and inhibitors produced by one cell type is a factor in its destructive ability. Nygaard 445. Hattermann 2008, as discussed above, used two malignant cell types in a confrontation assay, but did not measure their relative Appeal 2019-001734 Application 14/561,193 18 destructive abilities. One of ordinary skill in the art would have had reason to perform the confrontation assay using two different GBM tumors and/or malignant cell types to determine the relative destructive ability of each. The following new ground of rejection pursuant to 37 C.F.R. § 41.50(b) is set forth. Claim 1 is rejected under 35 U.S.C. § 103 as obvious in view of Nygaard, Hattermann 2011, and Hattermann 2008. We leave it to the Examiner to determine the obviousness of dependent claims 2–9, 15, and 20 based on Nygaard, Hattermann 2011, and Hattermann 2008, and any other additional prior art publications, including those cited by the Examiner in the 35 U.S.C. § 101 rejection. TIME PERIOD FOR RESPONSE This decision contains a new ground of rejection pursuant to 37 C.F.R. § 41.50(b). Section 41.50(b) provides “[a] new ground of rejection pursuant to this paragraph shall not be considered final for judicial review.” Section 41.50(b) also provides: When the Board enters such a non-final decision, the appellant, within two months from the date of the decision, must exercise one of the following two options with respect to the new ground of rejection to avoid termination of the appeal as to the rejected claims: (1) Reopen prosecution. Submit an appropriate amendment of the claims so rejected or new Evidence relating to the claims so rejected, or both, and have the matter reconsidered by the examiner, in which event the prosecution will be remanded to the examiner. The new ground of rejection is binding upon the examiner unless an amendment or new Evidence not previously of Record is made which, in the opinion of the examiner, overcomes the new ground of rejection Appeal 2019-001734 Application 14/561,193 19 designated in the decision. Should the examiner reject the claims, appellant may again appeal to the Board pursuant to this subpart. (2) Request rehearing. Request that the proceeding be reheard under §41.52 by the Board upon the same Record. The request for rehearing must address any new ground of rejection and state with particularity the points believed to have been misapprehended or overlooked in entering the new ground of rejection and also state all other grounds upon which rehearing is sought. Further guidance on responding to a new ground of rejection can be found in the MPEP § 1214.01. 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). See 37 C.F.R. §§ 41.50(f), 41.52(b). REVERSED; 37 C.F.R. § 41.50(b)