Takara Bio USA, Inc.Download PDFPatent Trials and Appeals BoardMay 26, 202015415754 - (D) (P.T.A.B. May. 26, 2020) 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. 15/415,754 01/25/2017 Michael Haugwitz CLON-125DIV 4313 93726 7590 05/26/2020 EPA - BOZICEVIC FIELD & FRANCIS LLP BOZICEVIC, FIELD & FRANCIS 201 REDWOOD SHORES PARKWAY SUITE 200 REDWOOD CITY, CA 94065 EXAMINER PROUTY, REBECCA E ART UNIT PAPER NUMBER 1652 NOTIFICATION DATE DELIVERY MODE 05/26/2020 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): docket@bozpat.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte MICHAEL HAUGWITZ, THOMAS PATRICK QUINN, ANDREW ALAN FARMER, and MONTSERRAT MORELL FERNÁNDEZ __________ Appeal 2019-005227 Application 15/415,754 Technology Center 1600 __________ Before FRANCISCO C. PRATS, TAWEN CHANG, and DAVID COTTA, Administrative Patent Judges. PRATS, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to finally reject claims 35, 37–47, and 63–66. We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the real party in interest as Takara Bio USA, Inc. Appeal Br. 3. Appeal 2019-005227 Application 15/415,754 2 STATEMENT OF THE CASE The following rejections are before us for review: (1) Claims 35, 37–39, 43–47, 63, and 66, under 35 U.S.C. § 103(a) as being unpatentable over Gho,2 Thaa,3 and Clontech4 (Ans. 3–6); (2) Claims 40–42, under 35 U.S.C. § 103(a) as being unpatentable over Gho, Thaa, Clontech, and Mangeot5 (Ans. 6–7); and (3) Claims 64 and 65, under 35 U.S.C. § 103(a) as being unpatentable over Gho, Thaa, Clontech, and Warming6 (Ans. 7–8). Claim 35, the sole independent claim on appeal, is illustrative and reads as follows: 35. A micro-vesicle comprising: a membrane-associated chimeric protein comprising a first dimerization domain; and a target chimeric protein that is not membrane-associated comprising a second dimerization domain, wherein the first and second dimerization domains are specifically bound to each other in a dimerized complex or the first and second dimerization domains are bound to each other by a single dimerization mediator. Appeal Br. 29. 2 WO 2011/002239 A2 (published Jan. 6, 2011). US 2012/0177574 A1 (published July 12, 2012) is the undisputed English equivalent of Gho cited by the Examiner, which we also cite herein. 3 Bastian Thaa et al., Viruses as vesicular carriers of the viral genome: A functional module perspective, 1803 BIOCHIM. BIOPHYS. ACTA 507–519 (2010). 4 Clontech, Switch on Protein-Protein Interactions, pp. 1–5 (2013) (date provided by Information Disclosure Statement filed Jan. 25, 2017). 5 WO 2011/058052 A1 (published May 19, 2011). 6 WO 2013/188522 A2 (published Dec. 19, 2013). Appeal 2019-005227 Application 15/415,754 3 DISCUSSION The Examiner’s Prima Facie Case In rejecting claims 35, 37–39, 43–47, 63, and 66, the Examiner cited Gho as describing microvesicles that include therapeutic or diagnostic substances contained within the vesicle itself or embedded in the vesicle’s membrane. Ans. 3. The Examiner cited Gho as disclosing that the vesicles may be naturally shed from nucleated cells that recombinantly express the diagnostic/therapeutic substances, and the substances may be proteins such as growth factors, cytokines, or antibodies. Id. at 3–4. The Examiner noted in particular Gho’s teaching that “the cells from which the microvesicles are derived can be transformed to express plasma membrane proteins which have been fused to heterologous domains [0146] [0157]” as well as Gho’s teaching that “it is known that the activity of proteins or peptides displayed on plasma membranes is higher when they are expressed within cells as a result of higher local concentration [0162].” Ans. 4. The Examiner found that Gho differs from the rejected claims in that Gho “do[es] not explicitly teach that when the therapeutic substance is a protein, that the therapeutic protein be engineered to comprise a domain which will bind directly or indirectly to a domain of a membrane associated protein.” Ans. 4. The Examiner cited Thaa as teaching that “enveloped viruses and cellular vesicles share obvious morphological and functional properties (abstract) and discuss[ing] the many similarities in the production and effects of enveloped viruses and cellular vesicles.” Ans. 4. The Examiner noted in particular Thaa’s teaching that “to create a functional transport Appeal 2019-005227 Application 15/415,754 4 vesicle or virus, the cargo and components of the vesicle must be specifically transported to the budding site and that viral assembly is the means of doing so for viruses (page 510).” Id. The Examiner cited Thaa as disclosing that several of the proteins present in influenza virus vesicles were bound to each other, in a manner encompassed by the rejected claims: Thaa et al. teach influenza virus particles comprise a transmembrane protein (HA) which binds to a target protein (NP) through a dimerization mediator (M) (see Fig. 3). Alternatively, one could characterize both the NP and M proteins as target proteins and thus Thaa et al. teach a complex comprising two target proteins that each comprise a dimerization domain. Thaa et al. teach that the HA protein is required for viral budding (page 513) and is also a viral membrane fusion protein (page 516). Ans. 4–5. The Examiner cited Clontech as describing a system in which two proteins could be configured to bind together through a dimerization mediator in a manner encompassed by the rejected claims: Clontech Switch On Protein Interactions teach a system wherein two proteins can be engineered to inducibly dimerize by fusing each with a dimerization domain (Dmr) wherein the domains dimerize directly (DmrD domains) or in the presence of a small organic molecule (DmrB domains in the presence of the B-B homodimerizer or DmrA and DmrC domains in the presence of the A/C heterodimerizer). Ans. 5. Based on the cited references’ combined teachings, the Examiner reasoned that a skilled artisan would have considered it obvious to prepare a microvesicle encompassed by the rejected claims: Appeal 2019-005227 Application 15/415,754 5 [A]s Gho et al. teach the therapeutic or diagnostic substance can be a protein present within the microvesicles or embedded in the membrane of the vesicles, and Thaa et al. teach that the influenza viral NP protein is incorporated in the viral envelope by binding to the viral M protein which is bound to the cytoplasmic portion of the transmembrane HA protein and teach that enveloped viruses and cellular vesicles share obvious morphological and functional properties, it would have been obvious to target a therapeutic protein of Gho et al. to the cell membrane of the cell from which the microvesicles are prepared by an analogous process wherein the therapeutic protein is fused to a domain which binds to a domain engineered into to a transmembrane protein that localizes in the microvesicles. One of ordinary skill in the art would have found it obvious to use the Clontech system to engineer [the] Clontech Dmr binding domain into the therapeutic protein and a transmembrane protein that localizes in the microvesicles. Ans. 5–6. Analysis In proceedings before the Patent and Trademark Office, the Examiner bears the burden of establishing a prima facie case of obviousness based upon the prior art. “[The Examiner] can satisfy this burden only by showing some objective teaching in the prior art or that knowledge generally available to one of ordinary skill in the art would lead that individual to combine the relevant teachings of the references.” In re Fritch, 972 F.2d 1260, 1265 (Fed. Cir. 1992) (citations omitted, bracketed material in original). In KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007), although the Supreme Court emphasized “an expansive and flexible approach” when evaluating claims for obviousness, id. at 415, the Court nonetheless also reaffirmed the importance of determining “whether there was an apparent Appeal 2019-005227 Application 15/415,754 6 reason to combine the known elements in the fashion claimed by the patent at issue.” Id. at 418 (emphasis added). Ultimately, therefore, as our reviewing court has stated, “[i]n determining whether obviousness is established by combining the teachings of the prior art, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art.” In re GPAC Inc., 57 F.3d 1573, 1581 (Fed. Cir. 1995) (internal quotations omitted). In the present case, having carefully considered the evidence and arguments presented by Appellant and the Examiner, Appellant persuades us that the Examiner has not shown that the vesicles of Appellant’s claim 35 would have been obvious in view of Gho, Thaa, and Clontech. In particular, we are not persuaded that the Examiner has explained with sufficient specificity why the teachings in Thaa and Clontech would have prompted a skilled artisan to configure Gho’s vesicles to include two chimeric proteins having the arrangement required by Appellant’s claim 35. As seen above, claim 35 recites a “micro-vesicle” that contains two chimeric proteins, one protein being membrane-associated, and the other “target” protein not being membrane-associated. Appeal Br. 29. Claim 35 recites that the two proteins are specifically bound to each other by dimerization domains present on each of the proteins, with the specific binding being either direct binding in the form of a “dimerized complex” between the dimerization domains, or through a dimerization mediator that binds to the two dimerization domains. See id. As the Examiner found, Gho discloses microvesicles that may be derived from cells, the microvesicles capable of delivering therapeutic or diagnostic substances to target tissues or cells. See Gho, abstract; id. ¶ 158. Appeal 2019-005227 Application 15/415,754 7 In particular, as the Examiner found, Gho discloses that membrane- bound proteins, such as antibodies on the surface of the vesicles, can be used to target the vesicles to specific cells, such as cancer cells, and deliver a drug such as doxorubicin to the cancerous cells. Gho ¶¶ 146–150. Gho further explains that the therapeutic/diagnostic substances to be delivered may be present inside the vesicles, or on the vesicles’ surfaces. Id. ¶ 151. As the Examiner found, Gho explains that one or more binding and/or therapeutic/diagnostic proteins may be recombinantly expressed in cells, and in the vesicles subsequently formed, by causing the cells to naturally shed the vesicles containing the recombinantly produced proteins. See Gho ¶¶ 157–158. In particular, Gho explains: It is known that the activity of proteins or peptides displayed on plasma membranes is higher than when they are expressed within cells as a result of the higher local concentration. Proteins or peptides on plasma membranes may act as ligands to trigger signaling or as antagonists to inhibit the function of various ligands. Id. ¶ 162. Turning to the second reference cited by the Examiner, Thaa is a review article that discusses the common features involved in the formation of enveloped viruses and cellular transport vesicles. See Thaa 507 (“Enveloped viruses and cellular transport vesicles share obvious morphological and functional properties. Both are composed of a closed membrane, which is lined with coat proteins and encases cargo. Transmembrane proteins inserted into the membrane define the target membrane area with which the vesicle or virus is destined to fuse.” (Abstract)). Thaa includes a discussion of the various proteins, including membrane-bound proteins, involved in the budding of influenza virus Appeal 2019-005227 Application 15/415,754 8 vesicles from cells, as well as the fusion of the viral vesicles to target cells. See id. at 510–511, 513, 516. Turning to the third reference cited by the Examiner, Clontech discloses a commercialized system that induces two proteins of interest to be bound together in cells, thereby activating a desired cellular pathway. See Clontech 2. As recited in Appellant’s claim 35, Clontech discloses that each of the two proteins that are desired to be brought together in cells are modified with dimerizing domains, designated DmrA and DmrC. See id. Once expressed in cells, the modified (chimeric) proteins are induced to bind together by a small molecule (the A/C Heterodimerizer) that binds to the dimerizing domains of the two modified proteins. See id. Clontech discloses in particular that a membrane-bound protein and a non-membrane-bound protein in a cell can be induced to bind together, resulting in activation of a signal transduction pathway. See Clontech 3 (figure in upper right corner showing A/C Heterodimerizer-mediated binding of DmrA and Dmr C modified proteins). Indeed, we note that Appellant’s examples use the Clontech technology. See Spec. 34–36. Thus, to summarize, as the Examiner found, Gho describes microvesicles that can deliver therapeutic proteins in a targeted fashion using membrane-bound proteins, Thaa discloses that influenza viral vesicle budding and cell fusion involves specific interactions between viral proteins including membrane-bound proteins, and Clontech discloses that a dimerization mediator may be used in intact cells to induce a chimeric membrane-bound protein to bind with another chimeric protein, in turn activating a desired cellular pathway. Appeal 2019-005227 Application 15/415,754 9 We are not persuaded that the Examiner has explained with sufficient specificity which particular elements of Gho, Thaa, and Clontech a skilled art would have combined to arrive at the vesicles recited in Appellant’s claim 35, and how those prior art elements correspond to the features recited in claim 35. The Examiner appears to posit that a skilled artisan would have been motivated to express, in Gho’s cells, the proteins involved in influenza virus budding and viral vesicle fusion described in Thaa, thereby promoting Gho’s cells to form vesicles that are predisposed to fuse with target cells. See Ans. 5–6 (determining that it would have been obvious to target Gho’s therapeutic protein “to the cell membrane of the cell from which the microvesicles are prepared by an analogous process wherein the therapeutic protein is fused to a domain which binds to a domain engineered into to a transmembrane protein that localizes in the microvesicles”). The Examiner does not explain sufficiently clearly, however, which elements of the posited Gho/Thaa combination correspond to which specific features of the vesicles of Appellant’s claim 35, or whether Clontech is also required to arrive at all of the features of claim 35. Moreover, the Examiner points to no specific teachings in any of the references suggesting that it would be desirable, suitable, or even useful, to recombinantly express the viral proteins described in Thaa when preparing a vesicle containing therapeutic/diagnostic substances, as described in Gho. We acknowledge Thaa’s teaching that formation of viral vesicles and cellular transport vesicles are similar processes. Thaa 507 (Abstract); see also Ans. 6 (suggesting the obviousness of using “an analogous process” to form Gho’s vesicles); Ans. 12 (asserting that a skilled artisan had motivation “to use the means of specifically transporting and incorporating the cargo of Appeal 2019-005227 Application 15/415,754 10 enveloped viruses (i.e., the vRNP) into the virus for the analogous process of specifically transporting and incorporating the cargo of a transport vesicle as disclosed by Gho et al. into the transport vesicle”). However, absent some specific teaching in the prior art, or identification of knowledge available to a skilled artisan suggesting the use of Thaa’s influenza virus proteins in drug-delivering vesicles like those described in Gho, we are not persuaded that the similarity between viral vesicle formation and cellular transport vesicle formation would have been sufficient to prompt a skilled artisan to express Thaa’s influenza virus proteins in Gho’s cells, as a way ultimately to form Gho’s microvesicles. And again, absent some identification of which specific elements from Gho and Thaa correspond to which specific features recited in Appellant’s claim 35, we are not persuaded that the Examiner has explained adequately why claim 35 would have been prima facie obvious in view of the cited references. We are not persuaded, moreover, that the Examiner has explained sufficiently why a skilled artisan would have configured the proteins of Gho’s microvesicles to have the dimerizing features described in Clontech. In setting forth the prima facie case, the Examiner states as to Clontech that “[o]ne of ordinary skill in the art would have found it obvious to use the Clontech system to engineer Clontech Dmr binding domain into the therapeutic protein and a transmembrane protein that localizes in the microvesicles.” Ans. 6. In setting forth the prima facie case, however, the Examiner does not explain clearly why a skilled artisan would have configured Gho’s therapeutic and transmembrane proteins to have Clontech’s dimerizing domains. Appeal 2019-005227 Application 15/415,754 11 In responding to Appellant’s arguments, the Examiner expands on the rationale for applying Clontech’s dimerizing domains to Gho’s proteins: Thaa et al. makes clear that the “selection and enrichment of a desired cargo” is provided by the presence of a binding site specific for a desired cargo within the transmembrane protein(s) of the virus. Thus to provide such a system to the shedding microvesicles a skilled artisan would understand that one would need to provide a binding site specific for a desired cargo to a transmembrane protein of the shedding microvesicle. As Clontech specifically discloses a system for providing a rapid and specific binding interaction of two proteins of interest a skilled artisan would have been motivated to select this system to engineer the transmembrane protein and desired cargo protein of Gho et al. to provide a specific binding interaction of the two that would select and enrich the cargo protein in the microvesicle of Gho et al. . . . Ans. 14–15. Thus, as we understand it, the Examiner’s position is that, because Thaa teaches that influenza viral vesicle formation involves binding of certain cargo proteins to transmembrane proteins, a skilled artisan would have modified Gho such that Gho’s therapeutic/diagnostic protein would bind to a vesicle-inducing viral transmembrane protein, and the skilled artisan would have used Clontech’s dimerizing domains to accomplish that binding. We are not persuaded. In particular, as discussed above, we are not persuaded that the Examiner has as identified specific teachings in any of the references suggesting that it would be desirable, suitable, or even useful, to recombinantly express the viral proteins described in Thaa when preparing a vesicle containing therapeutic/diagnostic substances, as described in Gho. We are not persuaded, therefore, that the Examiner has explained Appeal 2019-005227 Application 15/415,754 12 sufficiently why Thaa would have motivated a skilled artisan to use Clontech’s dimerizing domains to cause binding between a transmembrane vesicle-inducing protein, and a therapeutic/diagnostic protein in Gho’s vesicles. In sum, for the reasons discussed, having carefully considered all of the arguments and evidence advanced by both the Examiner and Appellant, we find that the Examiner has not shown by a preponderance of the evidence that the vesicles of Appellant’s claim 35 would have been obvious in view of Gho, Thaa, and Clontech. We therefore reverse the Examiner’s rejection of claim 35, and its dependent claims 37–39, 43–47, 63, and 66, over Gho, Thaa, and Clontech. In rejecting claims 40–42, all of which depend directly or ultimately from claim 35, the Examiner cited Gho, Thaa, and Clontech for the teachings discussed above, and cited Mangeot as evidence that the additional features recited in claims 40–42 would have been obvious features of the vesicles suggested by Gho, Thaa, and Clontech. See Ans. 6–7. Because the Examiner did not identify any teachings in Mangeot that remedy the deficiencies discussed above of Gho, Thaa, and Clontech in relation to claim 35, we also reverse the Examiner’s rejection of claims 40–42 over Gho, Thaa, Clontech, and Mangeot. In rejecting claims 64 and 65, both of which depend ultimately from claim 35, the Examiner cited Gho, Thaa, and Clontech for the teachings discussed above, and cited Warming as evidence that the additional features recited in claims 64 and 65 would have been obvious features of the vesicles suggested by Gho, Thaa, and Clontech. See Ans. 7–8. Because the Examiner did not identify any teachings in Warming that remedy the Appeal 2019-005227 Application 15/415,754 13 deficiencies discussed above of Gho, Thaa, and Clontech in relation to claim 35, we also reverse the Examiner’s rejection of claims 64 and 65 over Gho, Thaa, Clontech, and Warming. CONCLUSION In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 35, 37–39, 43–47, 63, 66 103(a) Gho, Thaa, Clontech 35, 37–39, 43– 47, 63, 66 40–42 103(a) Gho, Thaa, Clontech, Mangeot 40–42 64, 65 103(a) Gho, Thaa, Clontech, Warming 64, 65 Overall Outcome 35, 37–47, 63– 66 REVERSED Copy with citationCopy as parenthetical citation