Ex Parte Herrera Sanchez et al

Patent Trials and Appeals BoardMar 15, 2019

12737143 - (D) (P.T.A.B. Mar. 15, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 12/737,143 12/13/2010 136 7590 03/19/2019 JACOBSON HOLMAN PLLC 400 Seventh Street N.W. Suite 700 Washington, DC 20004-2218 FIRST NAMED INVENTOR Maria Beatriz Herrera Sanchez 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. P73804USO 2744 EXAMINER DA VIS, RUTH A ART UNIT PAPER NUMBER 1651 NOTIFICATION DATE DELIVERY MODE 03/19/2019 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): patent@jhip.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte MARIA BEATRIZ HERRERA SANCHEZ, VALENTINA FONSATO, TETTA CIRO, and CAMUSSI GIOVANNI Appeal2017-008616 Application 12/737, 143 1 Technology Center 1600 Before DONALD E. ADAMS, RYAN H. FLAX, and RACHEL H. TOWNSEND, Administrative Patent Judges. TOWNSEND, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. Â§ 134 involving claims to a cell free pharmaceutical composition, which have been rejected as obvious. Oral Argument was heard on March 5, 2019. We have jurisdiction under 35 U.S.C. Â§ 6(b). We reverse. STATEMENT OF THE CASE The Specification states: "[ s ]tern cell preparations were shown to exert a regenerative effect on human or animal tissues." (Spec. 1.) 1 Appellants identify the real party in interest as Fresenius Medical Care Deutschland GmbH. (Appeal Br. 4.) Appeal2017-008616 Application 12/737, 143 "However, stem cell preparations have the major disadvantage of causing immune reactions when administered. Some stem cell preparations even have the potential to cause cancer." (Id. at 2.) "[T]he object of the present invention is to provide a preparation which is effective as a pharmaceutical composition in the field of regenerative medicine but which does not contain cells." (Id.) Claims 32 and 34--37 are on appeal. Claim 32 is representative and reads as follows: 32. A cell free pharmaceutical composition comprising a pharmaceutically effective amount of a mixture comprising hepatocyte growth factor (HGF), interleukin 6 (IL-6), interleukin (IL-8), macrophage stimulating protein (MSP), and vascular endothelial growth factor (VEGF) in a pharmaceutically acceptable diluents, wherein the VEGF is present at a concentration ranging from 10 to 400 ng/mL. (Appeal Br. 37 .) The following ground of rejection by the Examiner is before us on review: Claims 32 and 34--37 under 35 U.S.C. Â§ I03(a) as unpatentable over Mansbridge2 and Srivastava. 3 DISCUSSION The Examiner finds that Mansbridge teaches a dermatological composition that is a conditioned media. (Final Action 3; Ans. 5, 6.) The Examiner explains that this conditioned media comprises an effective amount ofHGF, IL-6, IL-8, and VEGF in combination with a 2 Mansbridge, US 2004/0142861 Al, published July 22, 2004. 3 Srivastava et al., US 6,475,490 Bl, issued Nov. 5, 2002. 2 Appeal2017-008616 Application 12/737, 143 pharmaceutical carrier. (Id.) The Examiner further finds that Mansbridge teaches filtering the composition "to remove large particulate cell debris ( or cells)." (Final Action 3.) In addition, the Examiner finds that the conditioned media having the growth factors therein is "used to treat damaged skin (examples 12-14)." (Ans. 6.) The Examiner recognizes that Mansbridge does not teach including MSP in the composition, but that Mansbridge does teach that additional growth factors, "which affect it or other cells included in the compositions (0021 )," can be included. (Final Action 3--4; Ans. 4.) The Examiner notes that "Mansbridge specifically defines 'growth factors' to include proteins, polypeptides, complexes of polypeptides, cytokines, and factors that affect growth and/or differentiation of specific cells developmentally or in response to physiological or environmental stimuli (0021 )." (Final Action 5; Ans. 5.) The Examiner finds that Srivastava teaches compositions for dermatological use (promoting skin repair) that include IL-6, VEGF, and MSP. (Ans. 5 and 6; Final Action 4.) The Examiner finds further that Srivastava discloses that MSP is a chemoattractant for macrophages, and has been shown to induce "proliferation ( or growth of), migration and differentiation of keratinocytes and identifies this as important for normal skin function and tissue repair (col. 1 line 55-65)." (Final Action 5; see also id. at 4.) Thus, the Examiner concludes that "Srivastava specifically identifies MSP as a growth factor as defined and required by Mansbridge." (Id. at 5.) In light of the teachings of these references, the Examiner concludes that it would have been obvious to one of ordinary skill in the art to include 3 Appeal2017-008616 Application 12/737, 143 MSP, "a known growth factor known to effect other cells, as evidenced by Srivastava," in the composition of Mansbridge, "as suggested by Mansbridge." (Id. at 4.) That is, "[t]hese combined teachings suggest that at the time of the claimed invention one of ordinary skill in the art would have been motivated to combine claimed combination of growth factors together with a reasonable expectation for successfully obtaining an effective dermatological composition." (Ans. 5.) The Examiner also finds that, while neither Mansbridge nor Srivastava disclose the claimed amounts of ingredients, these references, nevertheless, teach the components as active, and one of ordinary skill in the art would have found it obvious to optimize the amount of the ingredients to achieve "a therapeutic effect (Mansbridge 0021, 0029, Table 3; Srivastava)." (Ans. 3; see also Final Action 4.) The Examiner finds that one of ordinary skill in the art would have had "a reasonable expectation for successfully obtaining an effective pharmaceutical composition." (Id.) Regarding the claimed amount of VEGF, in particular, the Examiner notes that Mansbridge "teaches the compositions contain VEGF as an active extract ( claims, 0021, 0026) where the optimal amount can be varied according to desired therapeutic effect (0029, examples 10-14)." (Ans. 5.) The Examiner further points out that "Mansbridge clearly teaches enhancing VEGF production (examples), further suggesting that the growth factor is a result effective variable" in the composition. (Id.) Prima Facie Case of Obviousness We agree with the Examiner's factual findings and, based thereon, conclude that a prima facie case of obviousness has been established. 4 Appeal2017-008616 Application 12/737, 143 Appellants present several arguments for non-obviousness, which we address below. Appellants' argument that "no quantitative amount of VEGF is taught or suggested in the cited references for use in accordance with the teachings of either reference" (Appeal Br. 10; see also Appeal Br. 11-14) is not persuasive. As the Examiner explained, Mansbridge teaches a conditioned media composition that includes a particular amount of VEGF in it (Ans. 2 (citing Table 3) and that the amount can be varied (id. at 5 (citing examples 10-14)). The amount ofVEGF in the conditioned media of Example 2, that also included IL-6, IL-8, and other growth factors, is 3 .2 ng/ml. (Mansbridge ,r 72, Table 3.) Furthermore, Mansbridge discloses in Example 10 that VEGF amounts can be enhanced in a conditioned media by increasing the quantity of PDGF. (Id. ,r 98 and Figure 6 (depicting VEGF increasing up to above 6 ng/ml with increasing amounts of PDGF).) Mansbridge discloses other conditions that can be altered to increase the amount ofVEGF in a conditioned media. (Id. ff 99-101 (Example 11).) As Mansbridge further explains, the conditioned media is filtered to remove cell debris, which is referred to as "Ix conditioned media," and that Ix conditioned media can be concentrated by ultrafiltration to a "nutrient solution" that is called a "I Ox conditioned media." (Id. ,r 75.) Consequently, we find that Mansbridge teaches a conditioned media composition with a specified amount of VEGF, and that such can be purified to be cell-free. Mansbridge further teaches that the "cosmeceutical effect of nutrient solution" on photodamaged skin was assessed and it was found that there was an increase in epidermal thickness and that dermal fibroblast increased. 5 Appeal2017-008616 Application 12/737, 143 (Id. ,r 104.) Thus, we also find that Mansbridge discloses its conditioned media composition that is cell-free and contains VEGF is useful in pharmaceutical applications on the skin. In light of the foregoing, we disagree with Appellants' argument that the Examiner has improperly applied a "per se" obvious to optimize rejection where Mansbridge "mentions nothing about amounts" of VEGF. (Appeal Br. 10-11.) Appellants' additional argument that there is no motivation to combine Srivastava with Mansbridge because Srivastava does not teach MSP is a growth factor (Appeal Br. 23-27), is not persuasive. Srivastava identifies MSP as being within a class of compounds that it denotes "additional wound healing factors." (Srivastava 6:4--11) It is true that "MSP" does not include the term growth factor in its name as is the case, for example, for EGF ("epidermal growth factor") and FGF ("fibroblast growth factor"),----each growth factors that Srivastava also indicates are within the class of compounds it denotes as "additional wound healing factors." (Id.) However, growth factor, as defined by Mansbridge, does not require the compound name to include the phrase "growth factor" in order for it to be so designated and considered as such, nor does it exclude a compound that may be a wound healing factor. As to the first point, Mansbridge provides a list of"[ e ]xemplary growth factors" and within that list are the hormone insulin and interleukin-6 (IL-6), neither of which include "growth factor" as part of their name. As to the second point, Mansbridge, as the Examiner noted (Final Action 5), defines a growth factor that can be used in its compositions as "a protein, a polypeptide, or a complex of polypeptides, including cytokines, 6 Appeal2017-008616 Application 12/737, 143 that are produced by a cell and which can effect itself and/or a variety of other neighboring or distant cells." (Mansbridge ,r 21.) That definition certainly includes, as Mansbridge explains, compounds that "affect the growth and/or differentiation of specific types of cells, either developmentally or in response to a multitude of physiological or environmental stimuli." (Id.) However, as Mansbridge also indicates those functions are what one "[t]ypically" considers to be functions that a growth factor has, not that those are functional requirements to be a "growth factor" as Mansbridge has defined that term. (Id.) Thus, even if we were to agree with Appellants that Srivastava does not teach that MSP induces differentiation of keratinocytes and that the proliferation of keratinocytes is not the same as growth ofkeratinocytes (Appeal Br. 26), and that MSP is a wound healing factor, such is not dispositive as to whether MSP is a Mansbridge "growth factor." Mansbridge' s definition that a growth factor is a compound produced by a cell that "effect[ s ]" itself or a variety of other neighboring or distant cells, indicates that a compound that induces proliferation and migration of keratinocytes, which is not disputed by Appellants to be a function of MSP (Appeal Br. 26H even if it may function differently in other cells (see Appeal Br. 27 and Ans. 8), 4-is a growth factor as Mansbridge defines the term. 4 Appellants and the Examiner refer, here, to Broxmeyer et al., Macrophage-stimulating protein, a ligand for the RON receptor protein tyrosine kinase, suppresses myeloid progenitor cell proliferation and synergizes with vascular endothelial cell growth factor and members of the chemokinefamily, 73 Ann Hematol., abstract, (1996); available at http://www.ncbi.nlm.nih.gov/pubmed/8695717. 7 Appeal2017-008616 Application 12/737, 143 The next question is whether one of ordinary skill in the art would have found it obvious to select MSP for use in the conditioned media of Mansbridge with a reasonable expectation of success given its undisputed function with respect to keratinocytes set forth in Srivastava. We conclude that there is sufficient evidence of record to support the Examiner's determination in the affirmative. As we noted above, Mansbridge teaches applying lOx conditioned media to photodamaged skin, i.e., Mansbridge teaches its composition includes being a dermatological composition that assists skin tissue repair. And Srivastava teaches, as the Examiner noted (Final Action 5), that it was known that MSP induces proliferation and migration of keratinocytes, and that proliferation of keratinocytes is important for normal skin functioning and wound healing/tissue repair, and that MSP "may have implications for tissue repair of cutaneous wounds." (Srivastava 1 :55---63.) Srivastava also teaches using wound healing factors, which MSP is considered to be (id. at 6:4--16), on tissue that has been disrupted by trauma, including bums (id. at 6:42--44, claim 24). Further, as the Examiner noted (Ans. 5), Srivastava teaches MSP may be combined with IL-6 and VEGF. (Id. 5:66-6:35.) Evidence of Unexpected Results We find that Appellants have provided evidence of unexpected results that, when considered with the factual findings concerning the prior art discussed above, establishes the claimed invention is not obvious over the cited prior art. It is well settled that Appellants have the burden of showing unexpected results. In re Freeman, 4 7 4 F .2d 1318, 13 24 ( CCP A 1973 ). The burden requires Appellants to proffer factual evidence that shows 8 Appeal2017-008616 Application 12/737, 143 unexpected results relative to the closest prior art. See In re Baxter Travenol Labs., 952 F.2d 388,392 (Fed. Cir. 1991). We disagree with the Examiner (Ans. 9) that Appellants' experimental evidence in the record does not include a comparison to the closest prior art for the reasons explained by Appellants (Appeal Br. 28-30) and discussed below. The Evidence According to Appellants, Figure 8 of the Specification, which graphically shows hepatocyte apoptosis inhibition in vitro, demonstrates the claimed invention in the fourth bar of the Figure (MIX 4 + MSP). (Id.) We reproduce Figure 8 from the Specification below and as annotated by Appellants further below. Fig. 8 C 9 T l li I I q :Â·. !.Â·Â· 1 I I I â€¢. 1. â€¢. I i â€¢ â€¢Â·1 . : .l: Appeal2017-008616 Application 12/737, 143 ~H>..~~ Â·3~~~ ~r: ~~~t-t {-~ :p ... :f ~,~~ {Â·~:~t\f't ~S(.~"'Â·Â·~ Figure 8 and Figure 8 Annotated- I graphically show hepatocyte apoptosis inhibition in vitro when human hepatocyte samples were cultured with various cytokine mixtures in the presence of D-Galactosamine ( a hepatotoxic agent). We note that while the y-axis of the figure is labeled "% of Apoptotic hepatocyte," the Specification indicates that what is measured is the time after co-culturing that apoptosis inhibition resulted. For example, the Specification states: "The use of MIX4 + MSP on GalN-treated hepatocytes resulted in apoptosis inhibition after 24 hours." (Spec. 15.) The annotations in Figure 8 by Appellants indicate which bars of the graph as presented in the Specification correspond to the prior art and the invention. 10 Appeal2017-008616 Application 12/737, 143 The Tested Mansbridge Composition According to Appellants, the third bar in Appellants' annotated Figure 8 is labeled "Mansbridge," "because according to the rejection ([F]inal Office Action, page 3) 'Mansbridge teaches pharmaceutical compositions .. . comprising effective amounts ofHGF, IL-6, IL-8, and VEGF'," which is MIX 4. 5 (Appeal Br. 29.) We note that Mansbridge does not exemplify a conditioned medium that, in fact, includes all these ingredients, but suggests such a composition. We determine that Appellants' Mansbridge comparison is, thus, closer to the claimed invention than what is exemplified in Mansbridge. In particular, Table 3 of Mansbridge exemplifies a conditioned media as follows: 1)\.BLE 3 Grmvth factor aud Cytokine Ccmcentratfons. in Conditioned l'l'kd:ia (tmckÂ£,wund subtracted~ Gmwfo foctm VEGF G-CSF n, ... 6 IL-8 Co11centrntion r:ig/ml .:.t2 11:g/ml 2.3 nglml 0.9 rig/ml ;t2 11g/ml TABLE 3-continued Gm1nib Factor an