Laura Brown et al.Download PDFPatent Trials and Appeals BoardMay 5, 20212020004486 (P.T.A.B. May. 5, 2021) Copy Citation 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. 11/315,969 12/22/2005 Laura Brown JNJ-0207C1US (001705.0012 4989 93358 7590 05/05/2021 BakerHostetler/ Johnson & Johnson Washington Square, Suite 1100 1050 Connecticut Avenue, NW Washington, DC 20036-5304 EXAMINER WILSON, MICHAEL C ART UNIT PAPER NUMBER 1632 NOTIFICATION DATE DELIVERY MODE 05/05/2021 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): eofficemonitor@bakerlaw.com jnjuspatent@corus.jnj.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________________ Ex parte LAURA BROWN, SRIDEVI DHANARAJ, and AGNIESZKA SEYDA1 ____________________ Appeal 2020-004486 Application 11/315,969 Technology Center 1600 ____________________ Before ERIC B. GRIMES, RICHARD M. LEBOVITZ, and ROBERT A. POLLOCK, Administrative Patent Judges. POLLOCK, Administrative Patent Judge. DECISION ON APPEAL This appeal under 35 U.S.C. § 134(a) involves claims to in vitro methods of inducing chondrogenic differentiation in a homogeneous cell population. Appellant seeks our review of the Examiner’s decision to reject claims 2, 3, and 63–66 for obviousness-type double patenting, and as obvious in view of the prior art. We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. 1 Appellant identifies, via an extensive chain of title, DePuy Synthes Products, Inc. as the real party in interest. Appeal Br. 3. We use the word Appellant to refer to “applicant” as defined in 37 C.F.R. § 1.42(a). Appeal 2020-004486 Application 11/315,969 2 Statement of the Case Appellant describes the invention as “directed to in vitro methods of inducing differentiation of an isolated homogeneous population of umbilical cord tissue-derived cells (having defined characteristics) into a chondrogenic phenotype.” App. Br. 4; see Spec. ¶ 10 (reciting extensive list of defined characteristics). On appeal are claims 2, 3, and 63–66, of which, only claim 2 is independent: 2. An in vitro method of inducing differentiation of a population of cells to a chondrogenic phenotype comprising: i) obtaining an isolated homogeneous population of umbilical cord tissue-derived cells, wherein said isolated cell population is obtained from human umbilical cord tissue substantially free of blood, can undergo at least 40 doublings in culture, maintains a normal karyotype upon passaging, expresses each of CD10, CD13, CD44, CD73, CD90, PDGFr-alpha, PD-L2, and HLA-A,B,C; and does not express any of CD31, CD34, CD45, CD80, CD86, CD117, CD141, CD178, B7-H2, HLA-G, or HLA- DR,DP,DQ, exhibits increased expression of a gene encoding interleukin 8 relative to expression of an endogenous gene encoding interleukin 8 by a human cell that is a fibroblast, a mesenchymal stem cell, or an iliac crest bone marrow cell, and exhibits increased expression of a gene encoding reticulon l relative to expression of an endogenous gene encoding reticulon 1 by a human cell that is a fibroblast, a mesenchymal stem cell, or an iliac crest bone marrow cell; ii) culturing said isolated cell population in chondrogenic induction medium, wherein the induction medium comprises modified essential medium comprising L-glutamine, sodium Appeal 2020-004486 Application 11/315,969 3 pyruvate, L-proline, L-ascorbic acid, insulin, transferrin, and selenium; and iii) exposing the isolated homogeneous population of cells in culture to one or more chondrogenic differentiation-inducing agents, wherein said exposing induces differentiation of said isolated cell population to a chondrogenic phenotype. See App. Br. 29 (claims appendix, paragraphing added). Obviousness-Type Double Patenting In the Final Action, the Examiner withdrew obviousness-type double patenting rejections over claims of US Pat. Nos. 7,510,873, 8,318,483, and 8,815,587, as well as a number of provisional obviousness-type double patenting rejections, in view of Appellant’s filing of terminal disclaimers. Final Act. 24–25. Presently before us is a similar rejection of claims 2, 3, and 63–66 on the grounds of nonstatutory double patenting over the claims of US Pat. No. 9,579,351 (“the ’351 Patent”). The doctrine of obviousness-type double patenting is intended to “prevent the extension of the term of a patent . . . by prohibiting the issuance of the claims in a second patent not patentably distinct from the claims of the first patent.” In re Longi, 759 F.2d 887, 892 (Fed. Cir. 1985). “A later patent claim is not patentably distinct from an earlier claim if the later claim is obvious over, or anticipated by, the earlier claim.” Eli Lilly & Co. v. Barr Labs., Inc., 251 F.3d 955, 968 (Fed. Cir. 2001). Accordingly, we focus first on the patent claims. As indicated above, the claims before us relate to a “method of inducing differentiation of a population of cells to a chondrogenic phenotype” using “an isolated homogeneous population of umbilical cord tissue-derived cells.” The claims of the ’351 patent, in contrast, relate to “an Appeal 2020-004486 Application 11/315,969 4 isolated homogeneous cell population . . . obtained from human postpartum placenta.” See e.g., ’351 Patent, 127:18–37 (claim 1). In arguing that the two sets of claims are not patentably distinct, the Examiner contends that “the cells obtained from the placenta in ’351 and used [in] the method of claim 2 in the instant application are linked as methods of using the same product” such that “the method of using the cells in claim 2 of the instant application is an obvious process for using the cells . . . disclosed in ’351.” Ans. 21. More specifically, the Examiner contends that, although “[t]he cell culture claims of ’351 are obtained from human postpartum placenta while the cells in the method of differentiating cells into chondrogenic cells in the instant application are from umbilical cord. . . the cells used in ’351 and in claim 2 are related as processes of using the same product.” Ans. 18. In support, the Examiner points to Example 29 of the ’351 Patent’s specification (see col. 115:12–119:24) as teaching “administering matrix and a homogenous population of undifferentiated placenta- or umbilical cord-derived cells free of blood to create cartilage in patients.” Id. The Examiner further finds that the instant Specification and the ’351 Patent teach that “both placenta-derived and umbilical derived cells have the same markers expressed . . . and are both capable of differentiating into cartilage and chondrogenic phenotypes.” Id. at 29–30; see Final Action, 28 (“The cells are the same because they have the same marker pattern; the location from which they are taken does not alter the structure of the cells.”). Appellant responds that the “the Examiner errs by incorrectly equating different cell populations” and, thus, has not established that the cells claimed in the ’351 Patent are patentably indistinct from those used in the method claims on appeal. App. Br. 6. According to Appellant, the two Appeal 2020-004486 Application 11/315,969 5 cell populations “are from different sources and have a different marker profile.” Id. at 8; see id. at 9 (table illustrating different marker profiles for the two cell populations). Considering the record before us, Appellant has the better position. We find particularly compelling Appellant’s comparison of cellular markers based on Examples 7 and 12 of the instant application and Examples 8 and 12 of the ’351 patent. In this respect, the record shows that placenta-derived cells of the ’351 patent show increased expression of oxidized low density lipoprotein and renin (Spec. Table 7-4; ’351 patent, Table 8-3) as compared to other cell types, whereas umbilical cord-derived cells have increased expression of interleukin 8 and reticulon 1 not seen with those claimed in the ’351 patent (Spec. Table 7-4; ’351 patent, Table 8-4). The record similarly shows that levels of various secretory factors differ markedly between the two lines. See Spec. ¶ 365, Tab. 12–1, 12–2, 12–3 (head-to-head comparisons showing, e.g., non-detectable levels of FGF and MIF1a in placenta-derived but not umbilical-derived cells, and non- detectable levels of I309 antigen and MDC in umbilical-derived cells but not in those derived from placenta). As summarized in the Specification: The amount of HGF, FGF, and BDNF secreted from umbilicus-derived cells were noticeably higher than fibroblasts and placenta-derived cells (Tables 12-2 and 12-3). Similarly, TIMP1, TPO, HBEGF, MCP-1, TARC, and IL-8 were higher in umbilicus-derived cells than [fibroblasts and placenta-derived cell] populations (Table 12-3). Spec. ¶ 365. In light of the above differences in expression, we are not persuaded that the Examiner had sufficient evidence to conclude that the placenta- derived cells claimed in the ’351 patent are “the same product” as the Appeal 2020-004486 Application 11/315,969 6 umbilicus-derived cells used in the method claims on appeal. See Ans. 18. The Examiner has, therefore, not established that the appealed claims are patentably indistinct from those of the ’351 patent. Accordingly, we reverse the obviousness-type double patenting rejection. Obviousness The obviousness rejections rely on the following prior art references: US Pat. No. 5,962,325, issued October 5, 1999 (“Naughton”); Pittenger et al., “Human Mesenchymal Stem Cells: Progenitor Cells for Cartilage, Bone, Fat and Stroma,” Lymphoid Organogenesis, 3–11, F. Melchers (ed.), Springer-Verlag Berlin Heidelberg 2000 (“Pittenger”); Ciavarella et al, “Umbilical Cord Mesenchymal Stem Cells: Role of Regulatory Genes in Their Differentiation to Osteoblasts,” 18(8) Stem Cells and Development 1211– 1220 (2009) (“Ciavarella”); US Pat. No. 6,291,240, issued Sept. 18, 2001 (“Mansbridge”); US Pat. No. 5,308,763, issued May 3, 1994 (“Ronnett”). Liddiard et al., “An Improved Method for the Preparation of Human Fetal and Adult Hepatocytes,” 44 Arch. Toxicol 107–112 (1980) (“Liddiard”); and The Examiner rejects claims 2, 3, 63, 64, and 66 under 35 U.S.C. § 103(a) as obvious in view of Naughton and Pittenger, as supported by Ciavarella. Final Act. 2, 9. The Examiner also rejects claim 65 in view of Naughton, Pittenger, and Ciavarella as applied to claims 2, 3, 63, 64, and 66, and further in view of Mansbridge, Ronnett, and Liddiard. Id. at 13. For the purposes of this appeal, we focus on the rejection of claim 2 as obvious in view of Naughton and Pittenger, as supported by Ciavarella. Appeal 2020-004486 Application 11/315,969 7 Findings of Fact FF1. Naughton “relates to growing stromal cells, such as chondrocytes, progenitor-chondrocytes, fibroblasts and/or fibroblast-like cells on a three-dimensional scaffold or framework in vitro under conditions which enhance the formation of cartilage in culture.” Naughton, 2:10–14. In particular, “stromal cells, including, but not limited to, chondrocytes, chondrocyte- progenitors, fibroblasts, fibroblast-like cells, umbilical cord cells or bone marrow cells from umbilical cord blood are inoculated and grown on a three-dimensional framework in the presence of TGF- β.” Id. at Abstract; see also id. at 6:11–32, 11:35–41. “[T]he stromal cells are stimulated to produce cartilage using exogenously added growth factors, e.g., TGF-β with or without ascorbate, in culture.” Id. at 6:41–43. FF2. Naughton discloses that fibroblasts may be readily isolated from mechanically and/or enzymatically disaggregated human umbilical cord tissue using techniques known to those skilled in the art. Id. at 12:4–47. For example, “[e]nzymatic dissociation can be accomplished by mincing the tissue and treating the minced tissue with any of a number of digestive enzymes either alone or in combination. These include but are not limited to trypsin, chymotrypsin, collagenase, elastase, and/or hyaluronidase, Dnase, pronase, etc.” Id. at 12:12–16. FF3. According to Naughton, chondrocytes, chondrocyte- progenitors, fibroblasts or fibroblast-like cells may be isolated from minced tissue incubated “in a freshly prepared solution of a Appeal 2020-004486 Application 11/315,969 8 dissociating enzyme such as trypsin. After such incubation, the dissociated cells are suspended, pelleted by centrifugation and plated onto culture dishes. All fibroblasts will attach before other cells, therefore, appropriate stromal cells can be selectively isolated and grown.” Id. at 12:48–59. Naughton discloses that other types of “stromal cells may readily be derived from . . . umbilical cord or placenta . . . using methods known in the art such as those discussed above.” Id. at 13:7–10 FF4. Naughton discloses an Example in which chondrocyte cultures were isolated from adult cow or rabbit cartilage by collagenase digestion. Id. at 21:5–16. FF5. Pittenger investigates culture conditions for the differentiation of bone marrow derived human mesenchymal stem cells (hMSCs) into adipogenic, osteogenic, and chondrogenic cell lineages. See, generally, Pittenger, 5–7. Pittenger discloses, for example, that culturing hMSCs in serum-free DMEM comprising TGF-β3, ascorbic acid, sodium pyruvate, proline, and a commercially available insulin-transferrin-selenium solution induces chondrogenic differentiation as indicated by gross phenotype and chondrogenic marker expression. FF6. In support of inherency, the Examiner points to Ciavarella as post-filing evidence that umbilical-derived mesenchymal cells have at least a subset of the cell marker characteristics recited in claims 2, 63, and 64. Ans. 9. Ciavarella states that “[f]ibroblast-like cells from the Warthon’s Jelly [a component of human umbilical cord] were cultured with dedicated Appeal 2020-004486 Application 11/315,969 9 media to obtain osteogenic-, adipogenic-, and chondrogenic- differentiated cells.” Ciavarella, Abstract. Analysis According to the Examiner, “the starting material, disaggregation techniques/enzymes, and culture methods used to obtain a cell population from human umbilical cord described by Naughton must inherently result in a ‘homogeneous population of umbilical cord tissue-derived’ cells as required in . . . claim 2,” and its dependent claims. Ans. 6. The Examiner relies on Pittenger as teaching a serum-free media that supports chondrocyte differentiation. Id. at 8. Appellant argues, inter alia, that Naughton’s isolation protocols “are insufficient to establish Naughton inherently discloses the claimed cells.” Reply Br. 10. As an initial matter, the record before us supports the Examiner’s finding that at the time the claimed invention was made, it was within the routine skill level of the ordinary artisan to culture human stem cells in chondrogenic medium comprising TGF-beta3 and L- glutamine, sodium pyruvate, L-proline, L-ascorbic acid, insulin, transferrin and selenium as required in lines 19-20 of claim 2, as demonstrated by Pittenger, who used serum-free DMEM comprising TGF-beta3, ascorbic acid, sodium pyruvate, proline, and a commercially available insulin-transferrin-selenium solution, for chondrogenic differentiation of human mesenchymal stem cells (pg 6, para. 1). Therefore, it would have been prima facie obvious to a person of ordinary skill in the art to differentiate stromal cells into chondrogenic cell types using TGFbeta3 and proline as described by Naughton using the chondrogenic medium comprising L-glutamine, sodium pyruvate, L-proline, L- ascorbic acid, insulin, transferrin and selenium disclosed by Pittenger. Those of ordinary skill in the art at the time the Appeal 2020-004486 Application 11/315,969 10 invention was made would have been motivated to use the chondrogenic medium of Pittenger in the method of Naughton because Pittenger showed the chondrogenic medium successfully differentiated stromal cells into chondrogenic phenotypes under serum-free conditions and for the obvious advantage of reducing animal protein contamination. Those of ordinary skill in the art at the time of filing would have had a reasonable expectation of using the chondrogenic medium comprising insulin, transferrin and selenium of Pittenger instead of the medium described by Naughton because Pittenger showed the chondrogenic medium successfully differentiated stromal cells into chondrogenic phenotypes under serum-free conditions. Ans. 8. This does not end our analysis because, as Appellant points out, claim 2 and its dependent claims are directed to a “homogeneous population of umbilical cord tissue-derived cells” having defined characteristics. See, e.g., Reply Br. 10 (“Naughton does not disclose or suggest that these cells are a homogenous cell population having the same markers as claimed.”). In the context of the instant specification and the relevant claim language, we construe “homogeneous population” to mean that each cell in the referenced population has the pattern of expression recited in claim 2. According to the Examiner, Appellant has failed to establish that “Naughton . . . cannot result in cells having the [claimed] characteristics.” Ans. 26. However, this is not the appropriate standard for inherency, which requires that “the allegedly inherent characteristic necessarily flows from the teachings of the applied prior art.” Ex parte Levy, 17 USPQ2d 1461, 1464 (BPAI 1990). Thus, “[i]nherency . . . may not be established by probabilities or possibilities. The mere fact that a certain thing may result from a given set of circumstances is not sufficient.” In re Robertson, 169 F.3d 743, 745 (Fed. Appeal 2020-004486 Application 11/315,969 11 Cir. 1999) (citations and internal quotation marks omitted). For at least the reasons set forth below, we are not persuaded that one of ordinary skill in the art reading Naughton would have necessarily arrived at the homogeneous cell population set forth in claim 2. As noted by Appellant, Table 1-1 of the Specification discloses that the claimed population of chondrogenic precursor cells cannot be isolated from umbilical tissue using collagenase or hyaluronidase alone, whereas combinations of collagenase and hyaluronidase, with or without the further addition of dispase or thermolysin, were effective. Reply Br. 12; Spec. ¶¶ 224–225, Table 1-1. Naughton, by contrast, suggests the isolation of fibroblasts from umbilical cord tissue using any number of mechanical and/or enzymatic techniques known to those skilled in the art. FF2; see Reply Br. 10–11. As reasonably interpreted by Appellant, Naughton further suggests that these same “general protocols may also be used to isolate chondrocytes, chondrocyte-like cells, or fibroblast like cells, including fibroblast-like cells from umbilical cord tissue.” Reply Br. 11 (citing Naughton 12:4–65). Nowhere, however, does this teaching suggest the enzyme combinations set forth in the Specification, or provide guidance for other specific enzymes, enzyme combinations, or mechanical dissociation methods that would necessarily provide the homogeneous cell population set forth in claim 2. With respect to the isolation of chondrocyte-lineage cells in particular, Naughton suggests incubating “minced [umbilical] tissue . . . in a freshly prepared solution of a dissociating enzyme such as trypsin,” and selectively isolating non-fibroblast stromal cells based on the rapidity at which fibroblasts adhere to culture plates. FF3. The Examiner, however, fails to Appeal 2020-004486 Application 11/315,969 12 provide persuasive evidence that this would provide a homogeneous population of cells having the claimed characteristics. To the contrary, because this teaching merely seeks to eliminate fibroblasts from a mixed stromal population, the Examiner did not establish the likelihood that the remaining stromal cells consist of a homogeneous population as required by claim 2. See id. In this respect, we note Appellant’s citation to Yasumoto, which showed that trypsin digestion of umbilical tissue also releases myofibroblasts, which can be expanded and differentiated in appropriate media. App. Br. 13 (citing Yasumoto et al., US 6,916,655 B2 at 7:25–8:41). Naughton further exemplifies the isolation of chondrocytes by treating adult animal cartilage with collagenase. FF4. Again, the Examiner does not persuade us that this provides sufficient guidance for the isolation of the claimed homogeneous population, with all of its attendant markers, from umbilical tissue—particularly where the Specification teaches that treating umbilical tissue with collagenase alone is insufficient for this purpose. See Spec. Table 1-1. The Examiner does not explain sufficiently how the post- filing disclosure of Ciavarella establishes inherency. See FF6 (noting subset of claimed markers in cells derived from Wharthon’s Jelly). Accordingly, we reverse the rejection of claims 2, 3, 63, 64, and 66 as obvious in view of Naughton and Pittenger, as supported by Ciavarella. Because the Examiner relies on the same evidence of inherency in rejecting dependent claim 65 in view of Naughton, Pittenger, Ciavarella, Mansbridge, Ronnett, and Liddiard, we reverse the rejection of claim 65 for the same reasons. Appeal 2020-004486 Application 11/315,969 13 CONCLUSION Claims Rejected 35 U.S.C § Reference(s)/Basis Affirmed Reversed 2, 3, 63–66 Obviousness-Type Double Patenting 2, 3, 63–66 2, 3, 63, 64, 66 103(a) Naughton, Pittenger, Ciavarella. 2, 3, 63, 64, 66 65 103(a) Naughton, Pittenger, Ciavarella, Mansbridge, Ronnett, Liddiard, 65 Overall Outcome 2, 3, 63–66 REVERSED tkl Copy with citationCopy as parenthetical citation