Ex Parte Laughlin et alDownload PDFPatent Trial and Appeal BoardMay 26, 201610730549 (P.T.A.B. May. 26, 2016) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE FIRST NAMED INVENTOR 10/730,549 12/05/2003 Mary J. Laughlin 68705 7590 05/31/2016 TAROLLI, SUNDHEIM, COVELL & TUMMINO, LLP 1300 EAST NINTH STREET SUITE 1700 CLEVELAND, OH 44114 UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www .uspto.gov ATTORNEY DOCKET NO. CONFIRMATION NO. CWR-019292US ORD 1488 EXAMINER LANDAU, SHARMILA GOLLAMUDI ART UNIT PAPER NUMBER 1653 NOTIFICATION DATE DELIVERY MODE 05/31/2016 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): rkline@tarolli.com docketing@tarolli.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte MARY J. LAUGHLIN, STEPHEN HAYNESWORTH, and VINCENT POMPILI1 Appeal2014-001768 Application 10/730,549 Technology Center 1600 Before JEFFREY N. FREDMAN, JACQUELINE T. HARLOW, and RICHARD J. SMITH, Administrative Patent Judges. SMITH, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to a method for treating an ischemic tissue that have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. 1 According to Appellants, the real party in interest is Case W estem Reserve University. (Br. 2.) Appeal2014-001768 Application 10/730,549 STATEMENT OF THE CASE Background "[T]he invention provides a method for improving blood flow to an ischemic myocardium ... comprising administering ... enriched cn133+;cn34+ endothelial precursor2 cells isolated from umbilical cord blood . . . . [O]ne embodiment of this method further comprises administering ... human mesenchymal stem cells." (Spec. 4, 11. 6-16.) Claims on Appeal Claims 1, 2, 4, 10-12, 21, 23-27, 29-36, 40-43, 54, 57, and 67----69 are on appeal. (Claims Appendix, Br. 36-45.) Independent claim 1 is illustrative and reads as follows: 1. A method for treating an ischemic tissue in a subject in need thereof, comprising administering to said subject therapeutically effective amounts of human cn133+;cn34+ endothelial progenitor cells at least 75% pure isolated from umbilical cord blood and human mesenchymal stem cells at least 99% pure isolated from bone marrow, wherein the human CD133+/CD34+endothelial progenitor cells and the human mesenchymal stem cells are administered to the subject in a human cn133+;cn34+ endothelial progenitor cell:human mesenchymal stem cell ratio of about 5: 1 to about 1: 5. (Id. at 36.) 2 The record reflects that the term "precursor" is used interchangeably with "progenitor." Endothelial precursor cells are referred to as EPCs. (Spec. 2, 1. 24.) 2 Appeal2014-001768 Application 10/730,549 Examiner's Rejection3 Claims 1, 2, 4, 10-12, 21, 23-27, 29-36, 40-43, 54, 57, and 67----69 stand rejected under 35 U.S.C. § 103(a) as unpatentable over Strauer,4 Shake,5 Ueno,6 Kawamoto,7 Itescu,8 and Peichev. 9 (Ans. 2.) FINDINGS OF FACT We adopt as our own the Examiner's findings and analysis concerning the scope and content of the prior art. The following findings are included for emphasis and reference convenience. FF 1. The Specification states that "[b ]one marrow, peripheral blood or umbilical cord blood (UCB) are potential sources of CD133+ cells that can generate EPCs. Accordingly, the EPCs used in the methods described herein may be isolated from any of these three sources." (Spec. 15, 11. 16-18.) 1. rT""l1 ' 1 • ' 1 1 1 ' ' • • ' • • ' 1 ,,........,. .. ..,. ... ' • J l ne two oov10usness-type aouo1e patenung reJecuons m me urnce Acnon dated June 25, 2012, were obviated by Appellants' submission of a terminal disclaimer with the Amendment After Notice of Appeal filed May 28, 2013. 4 Strauer et al., Repair of Infarcted Myocardium by Autologous Intracoronary Mononuclear Bone Marrow Cell Transplantation in Humans, 106 Circulation, 1913-18 (Oct. 8, 2002) ("Strauer"). 5 Shake et al., Mesenchymal Stem Cell Implantation in a Swine Myocardial Infarct Model: Engraftment and Functional Effects, ANN. THORAC. SURG. 73, 1919-26 (2002) ("Shake"). 6 Ueno et al., US 2002/0037278 Al, published Mar. 28, 2002 ("Ueno"). 7 Kawamoto et al., Therapeutic Potential of Ex Vivo Expanded Endothelial Progenitor Cells for Myocardial Ischemia, 103 Circulation, 634--37 (Feb. 6, 2001) ("Kawamoto"). 8 Itescu, US 2003/0199464 Al, published Oct. 23, 2003 ("Itescu"). 9 Peichev et al., Expression of VEGFR-2 and ACJ 33 by circulating human CD34+ cells identifies a population of functional endothelial precursors, 95 BLOOD 3, 952-58 (2000) ("Peichev"). 3 Appeal2014-001768 Application 10/730,549 FF 2. The Examiner finds that Strauer teaches isolating bone marrow mononuclear cells (BM-MNCs) and administering the BM-MNCs to ischemic tissue in a subject in need thereof. (Ans. 2.; cf Strauer 1914, col. 1-2) FF 3. The Examiner finds that Strauer teaches that 0.65% ofBM-MNCs are AC133+ (CD133+) and 2.1 % are CD34+. (Id.; cf Strauer 1914, col. 2) FF 4. Strauer teaches that "mononuclear BMCs10 contain [mesenchymal stem cells] and progenitor cells ... [for example] endothelial progenitor cells." (Strauer 1916, right col.) FF 5. The Examiner finds that Shake teaches isolating MS Cs 11 from bone marrow and culturing them to yield a purified MSC culture. (Ans. 3.; cf Shake 1919, col. 2 to 1920, col. 1) FF 6. The Examiner finds that Shake teaches administering the MSCs to an infarcted region of heart tissue, resulting in a beneficial impact on cardiac remodeling after myocardial infarction. (Id.; cf Shake 1923, col. 1) FF 7. The Examiner finds that Ueno teaches methods for treating ischemic tissues by administering BM-MNCs, and that the number of cells administered is optimizable. (Id. at 3--4.; cf Ueno i-f 34) FF 8. The Examiner finds that Kawamoto teaches administering expanded EPCs, and that EPCs so administered promote neovascularization in rats with myocardial ischemia. (Id. at 4.; cf Kawamoto 635---636) FF 9. The Examiner finds that Itescu teaches methods for regenerating myocardial tissue after ischemic damage by injection of EPCs, that the EPCs 10 BMCs stands for bone marrow cells. (Strauer Abstract.) 11 MSCs stands for mesenchymal stem cells. (Shake Abstract.) 4 Appeal2014-001768 Application 10/730,549 are found in bone marrow and express CD34 and CD133. (Id.; cf ltescu iii! 55-56) FF 10. Itescu teaches that "[i]n one embodiment the agent is human endothelial progenitor cells. In one embodiment the endothelial progenitor cells are bone marrow-derived. In another they are derived from cord blood, or embryonic or fetal sources." (Itescu if 56.) Itescu also teaches that the number of EPCs administered may vary. (Id.) FF 11. The Examiner finds that Peichev teaches methods for purifying CD34+ and CD133+ cells using fluorescence sorting, and that EPCs express CD34+ and CD133+. (Ans. 4.; cf Peichev 955-956) ISSUE Whether a preponderance of evidence of record supports the Examiner's conclusion of obviousness under 35 U.S.C. § 103(a). ANALYSIS The Examiner found that the claim limitation that the EPCs be isolated from umbilical cord blood is a product-by-process limitation, and that the burden shifts to Appellants to show that the manner in which the EPCs were isolated affects the EPCs' material properties. (Ans. 4--5.) The Examiner concluded that the co-administration of the EPCs of Strauer with the purified MSCs of Shake was prima facie obvious since the prior art teaches that both types of cells promote healing after myocardial infarction. (Id. at 5.) The Examiner also concluded that it would have been obvious to a person of ordinary skill in the art to enrich the CD34+cn133+ endothelial precursor cells (EPCs) from the BM-MNCs of Strauer, using the methods of Peichev, and administering such EPCs with the purified mesenchymal stem cells of Shake. (Id. at 7.) The Examiner further concluded that it would 5 Appeal2014-001768 Application 10/730,549 have been obvious to vary the numbers of each type of cell because Strauer, Ueno, and Itescu teach that this is an optimizable variable. (Id. at 8.) We find that the Examiner has satisfied the burden of showing "some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness." KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007). Moreover, the Examiner has established a prima facie case of obviousness and, as discussed below, Appellants have not overcome or rebutted that prima facie case. Prima F acie Case Claims 1 and 57 Appellants argue that the cited references do not teach or suggest all the limitations of claims 1 and 57, 12 that the Examiner has failed to provide a reasonable rationale to combine the cited references, and that one of ordinary skill in the art "would not find it predictable and/or have a reasonable expectation of success." (Br. 12-13.) In support of those arguments, Appellants focus on the source of EPCs (umbilical cord blood), the purity of the cells, and the ratio of the cells. (Br. 12-30.) We address each argument below. At the outset, we agree with the Examiner that the co-administration of the EPCs of Strauer with the purified MS Cs of Shake was prima facie obvious since the prior art teaches that both types of cells promote healing 12 Claim 57 differs from claim 1 by the preamble recitation of "A method for inducing the formation of blood vessels in an ischemic tissue" and the recitation of "hemangioblast cells" rather than "endothelial progenitor cells." (Br. 36, 43--44.) 6 Appeal2014-001768 Application 10/730,549 after myocardial infarction. See Jn re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980) (citing cases) ("It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose."). See also KSR, 550 U.S. at 417 ("[W]hen a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious.") Source of EPCs The Examiner found that Appellants' recitation that the EPCs are "isolated from umbilical cord blood" was a product-by-process limitation, and that "[t]he patentability of a product [EPCs] does not depend on its method of production [isolated from umbilical cord blood]." (Ans. 4.) Indeed, it is well settled that "[t]he patentability of a product does not depend on its method of production. If the product in a product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 697 (Fed. Cir. 1985) (citations omitted). Appellants argue that CD133+/CD34+ EPCs from UCB are different in kind and provide a different result than CD133+/CD34+ EPCs isolated from bone marrow. (Br. 20.) Appellants support this argument by citing a Cardiovascular Research paper13 for the proposition that "an enriched 13 Ma et al., Intramyocardial delivery of human CDJ 33+ cells in a SCID mound cryoinjury model: Bone marrow vs. cord blood-derived cells, CARDIOVASCULAR RESEARCH 71, 15 8---69 (2006). 7 Appeal2014-001768 Application 10/730,549 population of bone marrow CD133 cells has a different surface expression phenotype than an enriched population of [umbilical] cord blood derived CD133 cells." (Id. at 19.) Appellants also cite the Finney Article 14 for the proposition that EPCs isolated from umbilical cord "provided improved capillary density, decreased necrosis, and improved engraftment" compared with bone marrow CD133+ cells and BM MNCs in response to ischemia. (Id. at 20.) We find that the Examiner has the better argument. At the time of the invention, EPCs from bone marrow and umbilical cord blood were viewed as substantial equivalents. (FF 10.) In fact, Appellants' Specification acknowledges that the EPCs in the claimed methods could be isolated from bone marrow or umbilical cord blood. (FF 1.) Accordingly, for purposes of patentability, we find the claimed EPCs from UCB to be "the same as or obvious from" the prior art EPCs derived from bone marrow. See Thorpe, 777 F .2d at 697. Purity of Cells Appellants argue that none of the cited references teach or suggest that the EPCs are "at least 7 5% pure" and that the MS Cs are "at least 99% pure." (Br. 12-30.) For example, Appellants point to Strauer's statement that "we decided to use all mononuclear cells from the bone marrow aspirate as a whole, rather than a subpopulation." (Br. 23, citing Strauer 1917, col. 1, 11. 6-9.) Appellants conclude from that statement that it would not be obvious to modify Strauer to use a subpopulation of EPCs "let alone human 14 Finney et al., Umbilical cord blood-selected CDJ 33+ cells exhibit vasculogenicfunctionality in vitro and in vivo, CYTOTHERAPY 12, 67-78 (2010) ("Finney Article"). 8 Appeal2014-001768 Application 10/730,549 cn133+;cn34+ endothelial progenitor cells at least 75% pure isolated from umbilical cord blood." (Br. 23-24.) We are not persuaded. We note at the outset the Examiner's position that a co-administered composition of two agents cannot have one of the agents at 75% purity and the other at 99% purity unless one is referring to each agent individually. (Ans. 9-11.) That is, "[i]f the administered composition is 99% pure in MS Cs, it cannot be simultaneously 7 5% pure in EPCs." (Id. at 10.) Moreover, as pointed out by the Examiner, "Appellants' argument as it regards a single administered composition is persuasive only if the EPCs physically remain in their '75% pure' fraction once mixed with the MSCs, which likewise remain in their '99% pure' fraction." 15 (Id.) Under this interpretation, any composition that contains EPCs and MSCs necessarily comprises EPCs that are 100% pure and MSCs that are 100% pure. (Id.) Accordingly, Strauer's overall composition contains EPCs that "are 100% pure with respect to themselves" and MSCs "which are 100% pure with respect to themselves." (Id. at 10-11.) Thus, under this interpretation, the cell purity claim limitations are satisfied. (Id. at 10.) In addition, reading the claims in a more ordinary way, the prior art suggests purifying these components. Appellants acknowledge that Shake teaches "a purified MSC culture." (Br. 14.) Peichev teaches methods for purifying CD34+ and CD133+ cells. (FF 11.) Appellants also acknowledge that Itsecu teaches that "a population of CD34+ cells of98% purity ... can be administered to a subject." (Br. 15.) See Aventis Pharma Deutschland 15 Appellants state that the claims are not limited to separate administration of the cell types or phenotypes. (Br. 11.) 9 Appeal2014-001768 Application 10/730,549 GmbH v. Lupin Ltd., 499 F.3d 1293, 1301 (Fed. Cir. 2007) ("[l]f it is known that some desirable property of a mixture derives in whole or in part from a particular one of its components, or if the prior art would provide a person of ordinary skill in the art with reason to believe that this is so, the purified compound is prima facie obvious over the mixture even without an explicit teaching that the ingredient should be concentrated or purified.") The obviousness analysis "can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR, 550 U.S. at 418. Furthermore, "[a] person of ordinary skill is also a person of ordinary creativity, not an automaton." Id. at 421. We find that Appellants' claim limitations of "at least" 7 5% and "at least" 99% reflect a desire to maximize the purity of the cells to be administered. Accordingly, in light of the prior art, we find that a person of ordinary skill would seek to obtain a maximum degree of purity for both the EPCs and MS Cs to be administered. Ratio of Cells Appellants argue that Strauer does not teach administering the claimed EPCs and MSCs at a ratio of about 5: 1 to about 1 :5, and that the other cited references do not overcome the deficiencies of Strauer. (Br. 14.) We are not persuaded. The prior art teaches that the number of cells administered to ischemic tissue is optimizable. (Ans. 12; FF 7, 10.) Where the general conditions of a claim are disclosed in the prior art (e.g., optimization or variation of number of cells), it is not inventive to discover the optimum or workable ranges (e.g., about 5: 1 to about 1 :5) by routine experimentation. See In re Aller, 220 F.2d 454, 456 (CCPA 1955). 10 Appeal2014-001768 Application 10/730,549 Unexpected Results Appellants argue that "the subject matter of claims 1 and 57 exhibit unexpected results." (Br. 30-34.) In support of that argument, Appellants rely on the Laughlin Declaration, 16 which discusses several tests related to human umbilical cord cells. (Deel. 2--4.) For the reasons set forth below, we do not find the evidence of unexpected results sufficiently persuasive to rebut the prima facie case of obviousness. We note at the outset that the prior art teaches that both EPCs and MSCs promote increased blood flow in ischemic tissue. (FF 2, 6-9.) Furthermore, Appellants' test results generally compare the combination of umbilical cord EPCs and bone marrow MSCs to either agent alone. (Deel. 2--4.) Moreover, it would have been expected that the EPC/MSC combination would treat ischemic tissue more effectively than either agent alone. See Merck & Co., Inc. v. Biocraft Labs, Inc., 874 F.2d 804, 808 (Fed. Cir. 1989). The expectation that two compounds (having the same property) would act in concert, was supported in Merck by the following citation to In re Crocket, 279 F.2d 274, 276 (CCPA 1960): the "joint use [of magnesium oxide and calcium carbide] is not patentable" where the prior art teaches "that both magnesium oxide and calcium carbide, individually, promote the formation of a nodular structure in cast iron, and it would be natural to suppose that, in combination, they would produce the same effect and would supplement each other" Merck, 874 F.2d at 808---09. We also acknowledge Appellants' reference to "synergy." (Br. 32- 16 Declaration under 37 CPR§ 1.132 of Mary Laughlin M.D. dated May 3, 2011 ("Laughlin Declaration"). 11 Appeal2014-001768 Application 10/730,549 33.) However, even if we agreed that the claimed method provided synergistic results, more would be required to show nonobviousness since synergism per se may be expected or unexpected. See In re Diamond, 360 F.2d 214, 218 (CCPA 1966). Appellants' test results are discussed below. Example 11 Appellants refer to Example 11 in the Specification which showed increased blood flow in mice receiving both CD133+ cells (lxl06) isolated from UCB and human MSCs (lxl06) isolated from bone marrow compared to mice infused with CD133+ cells or human MSCs alone. (Spec. 43 and Figure 17; Br. 31; Deel. 2-3.) These results were apparently time dependent, with mice receiving both agents showing an increased blood flow at an earlier time point (day 7) rather than later. (Spec. 43 and Figure 17; Br. 31.) Lab Experiments Appellants argue the results of certain lab experiments performed by Dr. Laughlin (Declarant) on mice in which human bone marrow (BM)- derived mesenchymal stem cells were injected alone and in combination with UCB-derived CD133+ HSCs. 17 (Br. 31-32; Deel. 3--4.) Group 1 (control) was injected with 0.02 ml of media, Group 2 received human MSC (lxl06 in 0.02 ml), and Group 3 received both UCB CD133+ HSCs and MSCs at an equivalent total cell dose (0.5xl06 + 0.5xl06 in 0.02 ml with a total combined cell dose of lxl06 in 0.04 ml). (Id.) Appellants argue "significantly higher blood flow measured in animals injected with both 17 We understand HS Cs to stand for human stem cells. 12 Appeal2014-001768 Application 10/730,549 MSCs and UCB 133+ HSCs compared with those animals treated with MSCs alone."18 (Br. 32.) Finney Article Appellants argue the test results from the Finney Article, which are identified as the results of experiments conducted in Dr. Laughlin's laboratory. (Br. 32-34; Deel. 4.) Based on those experiments and the Finney Article, Appellants argue that "the administration of a UCB CD133+ cells to ischemic tissue provides improved or enhanced vasculogenesis, improved capillary density, and reduced necrosis in the ischemic tissue compared to the administration of CD 13 3 + bone marrow cells, a heterogenous population of BM MN Cs, and a heterogenous population of UCB MNCs." (Br. 33.) Analysis Unexpected results must be shown to be unexpected compared with the closest prior art. In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (citing In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984)). In this case, the closest prior art is Strauer. (FF 2--4.) Test results comparing the claimed combination to the composition and method taught by Strauer appear to be absent on the record before us. Evidence of nonobviousness must also be commensurate in scope with the claims. In re Lindner, 457 F .2d 506, 508 (CCP A 1972). Here, neither claim 1 nor claim 57 is limited to an amount of endothelial progenitor cells or human MSCs or a ratio of 1: 1. However, Example 11 18 Blood flow ratio appears to increase from about 0.49 to about 0.60, an increase characterized by the Examiner as "modest." (See Laughlin Declaration, Exhibit B; Ans. 14.) 13 Appeal2014-001768 Application 10/730,549 indicates an amount of each type of cell and a ratio of 1: 1. (Br. 31.) The Lab Experiments also reflect amounts of the respective cells and a ratio of 1: 1. (Id. at 32.) The Finney Article reflects the administration of agents alone rather than the claimed combination. (Id. at 32-34.) Moreover, the evidence submitted by Appellants reflects a difference in degree of blood flow of UCB CD133+ alone or in combination with human MSCs, as compared to agents alone. However, "differences in degree" of a known and expected property are not as persuasive in rebutting obviousness as differences in "kind" (i.e., a new property dissimilar to the known property). Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014); see also In re Merck, 800 F.2d 1091, 1099 (Fed. Cir. 1986) (finding evidence that the new drug was a more potent sedative and had a stronger anticholinergic effect than the prior art was insufficient to outweigh the evidence of obviousness). On balance, we are not persuaded that the evidence of unexpected results is sufficient to overcome the evidence favoring obviousness. The rejection of claims 1 and 57 is affirmed. Dependent Claims Appellants refer to claims 2, 4, 10-12, 21, 23-27, 29-36, 40-43, 54, and 67----69, and argue that those claims are allowable based on their dependency on claims 1 or 57 and the specific limitations they recite. 19 (Br. 34.) However, because Appellants present no additional arguments with respect to the rejection of those claims, we affirm the rejection of claims 2, 19 Appellants also reference claim 28 but claim 28 is cancelled. (Br. 39.) 14 Appeal2014-001768 Application 10/730,549 4, 10-12, 21, 23-27, 29-36, 40-43, 54, and 67----69 as well. See 37 C.F.R. § 41.37(c)(l)(iv); Hyatt v. Dudas, 551F.3d1307, 1314 (Fed. Cir. 2008). CONCLUSION A preponderance of evidence of record supports the Examiner's conclusion that claims 1, 2, 4, 10-12, 21, 23-27, 29-36, 40-43, 54, 57, and 67----69 are obvious under 35 U.S.C. § 103(a). Furthermore, Appellants have not provided evidence of unexpected results that, when weighed with the evidence favoring obviousness, shows that the claims would have been nonobvious. SUMMARY We affirm the rejection of all claims on appeal. TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED 15 Copy with citationCopy as parenthetical citation