City of HopeDownload PDFPatent Trials and Appeals BoardMar 18, 20212021002450 (P.T.A.B. Mar. 18, 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. 14/978,590 12/22/2015 Don J. Diamond 048440-532N01US 7205 64046 7590 03/18/2021 Mintz Levin/San Diego Office One Financial Center Boston, MA 02111 EXAMINER PAPCIAK, SHARON M ART UNIT PAPER NUMBER 1651 NOTIFICATION DATE DELIVERY MODE 03/18/2021 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): IPDocketingBOS@mintz.com IPFileroombos@mintz.com mintzdocketing@cpaglobal.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte DON J. DIAMOND and EDWIN MANUEL1 Appeal 2021-002450 Application 14/978,590 Technology Center 1600 Before ERIC B. GRIMES, ROBERT A. POLLOCK, and TAWEN CHANG, Administrative Patent Judges. GRIMES, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134(a) involving claims to a method of treating cancer or stimulating the immune system in a subject, which have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. 1 Appellant identifies the real party in interest as City of Hope. Appeal Br. 2. We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appeal 2021-002450 Application 14/978,590 2 STATEMENT OF THE CASE The Specification states that “[o]verexpression of indoleamine 2,3- dioxygenase (IDO) in PDAC [pancreatic ductal adenocarcinoma] plays a major role in accelerating disease progression by suppressing antitumor immunity.” Spec. ¶ 2. The Specification also states that “[s]hIDO-ST is a Salmonella typhimurium (ST) cell that expresses a small hairpin (sh)RNA to specifically silence indoleamine-pyrrole 2,3-dioxygenase (IDO) with decreased toxicity.” Id. ¶ 55. The Specification states that “the term ‘tumor penetrating agent’ refers to an agent that is capable of penetrating a tumor and/or a tumor cell. . . . By way of example, a tumor penetrating agent penetrates a tumor by breaking down or degrading the extracellular matrix surrounding tumor cells.” Id. ¶ 25. Hyaluronidase polypeptides are an example of tumor penetrating agents. Id. The Specification states that “the combination of pegylated recombinant human hyaluronidase PH20 . . . and shIDO-ST resulted in effective control of and, in some cases, complete elimination of established pancreatic tumors in autochthonous and orthotopic models.” Id. ¶ 55. Claims 1–5, 8, 9, 11, 12, 14, 15, 18, 42, and 43 are on appeal. Claims 1 and 3, the independent claims, are illustrative and are reproduced below: 1. A method of treating cancer in a subject comprising administering to the subject a combined effective amount of a bacterial cell and a tumor penetrating agent, wherein administration treats the cancer in the subject, wherein the tumor penetrating agent is a hyaluronidase polypeptide, wherein the combined effective amount is effective to increase Appeal 2021-002450 Application 14/978,590 3 tumor penetration by the bacterial cell relative to absence of the tumor penetrating agent, and wherein said tumor penetrating agent is not expressed by said bacterial cell, wherein the tumor penetrating agent is formulated in combination with a pharmaceutically acceptable carrier. 3. A method of stimulating an immune system in a subject comprising administering to the subject a combined effective amount of a bacterial cell and a tumor penetrating agent, wherein administration of the bacterial cell and the tumor penetrating agent stimulates the immune system of the subject, wherein the tumor penetrating agent is a hyaluronidase polypeptide, and wherein the combined effective amount is effective to increase tumor penetration by the bacterial cell relative to absence of the tumor penetrating agent, wherein said tumor penetrating agent is not expressed by said bacterial cell, wherein the tumor penetrating agent is formulated in combination with a pharmaceutically acceptable carrier. Appeal Br. 15 (Claims Appendix). OPINION Claims 1–5, 8, 9, 11, 12, 14, 15, 18, 42, and 43 stand rejected under 35 U.S.C. § 103 as obvious based on Xu,2 Frost,3 and Bookbinder.4 Ans. 5.5 The Examiner finds that Xu discloses a method “for inhibiting growth or reducing the volume of a solid tumor cancer comprising administering an effective amount of an attenuated Salmonella sp. . . . expressing a short 2 Xu et al. (US 2009/0208534 A1, published August 20, 2009). 3 Frost et al. (WO 2009/128917 A2, published October 22, 2009). 4 Bookbinder et al. (US 2009/0123367 A1, published May 14, 2009). 5 The Examiner also cites evidence provided by a BLAST sequence alignment, but this evidence is only relevant to the SEQ ID Nos recited in claim 18. Ans. 5, 7. Appeal 2021-002450 Application 14/978,590 4 hairpin (sh) RNA [that] is capable of inhibiting the growth or reducing the volume of the solid tumor cancer (shRNA-Stat3).” Id. The Examiner acknowledges that Xu does not disclose hyaluronidase as a tumor penetrating agent or increased anti-cancer or immune-stimulation activity by the combination of a bacterial cell and hyaluronidase. Id. at 7–8. However, the Examiner finds that Frost discloses that “the introduction of soluble hyaluronidases to tumor interstitia would enhance delivery of locally and systemically delivered anti-cancer agents which can more readily penetrate the tumor.” Id. at 8. The Examiner also finds that Frost discloses that “[t]he co-administration of pegylated rHuPH20 [hyaluronidase PH20] with a chemotherapeutic agent can increase the anti-tumor activity of the therapeutic agent compared to when the therapeutic agent is administered alone.” Id. at 9. The Examiner finds that Bookbinder teaches “soluble enzymes that are members of the hyaluronidase glycoprotein family (sHASEGPs).” Id. The Examiner finds that Bookbinder teaches that sHASEGPs “would enhance delivery of anti-cancer agents which can more readily penetrate the tumor when . . . diffusion and/or convective transport [is] increased.” Id. “[T]he effects of diffusion were greatest with particles less than about 500nm in diameter.” Id. at 10. The Examiner finds, however, that Bookbinder also teaches that when “larger pores or channels are desired, sHASEGP . . . can be combined with relatively pure forms of other matrix- degrading enzymes to facilitate further spreading of larger size macromolecular complexes or cells.” Id. Appeal 2021-002450 Application 14/978,590 5 The Examiner concludes that it would have been obvious to modify Xu’s method of treating cancer “by administering to the subject an effective amount of the bacterial cell Salmonella expressing an antisense nucleic acid . . . by adding a tumor penetrating agent such as hyaluronidase . . . as shown by Frost.” Id. The Examiner reasons that Frost shows that hyaluronidase “increas[es] tissue permeability,” and therefore “contacting tumor tissue with exogenous hyaluronidase and an anti-tumor agent . . . would increase the permeability of the ECM [extracellular matrix] to said anti-tumor agent.” Id. at 11. The Examiner also notes that Bookbinder “shows a method for reducing and/or treating tumors using hyaluronidase polypeptides and a variety of other anti-cancer agents.” Id. The Examiner finds that “Bookbinder et al. teaches that there is an expectation that particles which are greater than 500nm in diameter, such as (bacterial) cells, could readily penetrate tumor tissue if other (EC)matrix-degrading enzymes were combined with the specific form of hyaluronidase (i.e., sHASEGP) shown in Bookbinder et al.” Id. Appellant argues that Xu does not teach any tumor penetrating agents, while Frost only teaches combining hyaluronidase with small molecule drugs, and “fails to provide a reasonable expectation that any enhancement would be achieved for much larger agents, such as a bacterial cell.” Reply Br. 4–5.6 6 In the Answer, the Examiner withdrew the pending rejections and entered a new ground of rejection. Ans. 3–4. Appellant responded to the new ground of rejection in the Reply Brief. Appeal 2021-002450 Application 14/978,590 6 Appellant also argues that “Bookbinder repeatedly emphasizes what was believed to be an ‘upper limit’ to the size of molecules whose diffusion could be enhanced by hyaluronidase, and repeatedly refers to 500 nm as that upper limit. Bookbinder also expressly states that the ‘pores’ opened by hyaluronidase are not large enough to promote movement of cells.” Id. at 6. Appellant argues that, “[a]s such, a person of ordinary skill in the art would have had no reason to combine a hyaluronidase polypeptide with a bacterial cell in general, or the Salmonella cells of Xu et al. in particular. Moreover, one of ordinary skill in the art would have had no reasonable expectation of success.” Id. Finally, Appellant cites the Diamond Declaration7 as evidence showing skepticism by an expert regarding the claimed invention. Reply Br. 9–10. “Specifically, an expert reviewing a grant application proposing experiments to test the effect of a hyaluronidase polypeptide (PEGPH20) on anti-cancer activity of a Salmonella typhimurium (ST) bacteria expressly doubted whether hyaluronidase would have any beneficial effect on delivery due to the size of bacteria.” Id. at 10. We agree with Appellant that a preponderance of the evidence of record does not show that a skilled artisan would have reasonably expected administration of Xu’s bacterial cell together with a hyaluronidase to result in “the combined effective amount [being] effective to increase tumor penetration by the bacterial cell relative to absence of the” hyaluronidase, as required by the claims. 7 Declaration under 37 C.F.R. § 1.132 of Don J. Diamond, filed March 7, 2019. Appeal 2021-002450 Application 14/978,590 7 Xu discloses “a method of inhibiting the growth . . . of a solid tumor cancer comprising administering an effective amount of an attenuated Salmonella sp. to a patient . . . , wherein said attenuated Salmonella sp. is a tumor targeting attenuated Salmonella sp. expressing a short hairpin (sh) RNA.” Xu ¶ 5. Although, as the Examiner points out (Ans. 6), Xu discloses that “Salmonella specifically home to the tumor” (Xu ¶ 34), Xu does not disclose any tumor penetration agents for use with its therapeutic bacterial cell. Frost discloses “methods for treating hyaluronan-associated diseases or conditions . . . [by] administering a hyaluronan degrading enzyme, such as a hyaluronidase.” Frost 2:20–22. Hyaluronan-associated diseases include hyaluronan-rich cancers such as solid tumors. Id. at 133:7–15. Frost suggests “administration of the hyaluronan degrading enzyme in combination with . . . a chemotherapeutic or other anti-cancer agent or treatment.” Id. at 147:30 to 148:1. Frost suggests numerous anti-cancer agents that can be administered with a hyaluronan degrading enzyme, see id. at 148:16 to 152:28, but the Examiner has not identified any therapeutic cells in the list of suggested agents. Bookbinder discloses “members of the soluble neutral-active Hyaluronidase Glycoprotein family (also referred to [t]herein as sHASEGPs) . . . , particularly the human soluble PH-20 Hyaluronidase Glycoproteins (also referred to [t]herein as rHuPH20s).” Bookbinder ¶ 20. Bookbinder states that sHASEGPs open channels in the interstitial space through degradation of glycosaminoglycans that generally permit the diffusion of molecules less than about 500 nm in size. . . . Such Appeal 2021-002450 Application 14/978,590 8 channels can be used to facilitate the diffusion of exogenously added molecules such as fluids, small molecules, proteins, nucleic acids and gene therapy vectors and other molecules less than about 500 nm in size. Id. ¶ 51. “The introduction of sHASEGPs to tumor interstitia would thus tend to enhance the delivery of . . . anti-cancer agents which can more readily penetrate the tumor when interstitial oncotic pressure is reduced and diffusion and/or convective transport increased.” Id. ¶ 78. In summary, Xu does not disclose any tumor penetrating agents that would be suitable for use with its Salmonella bacteria and Frost suggests combining a hyaluronidase with any of a variety of anti-cancer agents, but does not suggest combining it with a therapeutic bacterial cell. Bookbinder expressly suggests using a hyaluronidase (“sHASEGPs”) to enhance delivery of anti-cancer agents to tumors. See Bookbinder ¶ 78. As Appellant has pointed out (Reply Br. 5–6), however, Bookbinder consistently emphasizes that hyaluronidase’s effect of enhancing delivery of anti-cancer agents to tumors is limited to agents less than 500 nm in size. See Bookbinder ¶ 51 (“molecules less than about 500 nm in size”), ¶ 533 (“These pores generally do not enhance the diffusion of substances greater than about 200–500 nm in diameter.”); and ¶ 576 (“molecules and macromolecular complexes ranging from less than about 10 nm to around 500 nm in diameter”). With regard to therapeutic bacterial cells, Bookbinder states that “sHASEGPs generally act to open channels that are substantially large enough to permit the movement of most therapeutic and other pharmacological agents of interest . . . and yet are generally not so large as to promote the dislocation and movement of cells.” Bookbinder ¶ 533. Appeal 2021-002450 Application 14/978,590 9 Bookbinder teaches that a hyaluronidase “can be combined with . . . other matrix-degrading enzymes such as collagenases to facilitate further spreading of larger size macromolecular complexes or cells.” Id. ¶ 578. However, as Appellant has pointed out (Reply Br. 8), both of the independent claims require a combined amount of hyaluronidase and bacterial cell that is “effective to increase tumor penetration by the bacterial cell relative to absence of the tumor penetrating agent [hyaluronidase].” The claim language therefore requires an amount of hyaluronidase, not some other matrix-degrading enzyme, that is effective to increase tumor penetration of the bacterial cell. In short, none of the references cited by the Examiner would have provided a skilled artisan with a reasonable expectation that administering a combination of Xu’s bacterial cell and a hyaluronidase would provide increased tumor penetration of the bacterial cell, relative to administration of the bacterial cell by itself. Thus, the cited references do not provide a reasonable expectation of success in practicing the claimed methods. As further evidence that those of skill in the art would not have had a reasonable expectation of success, Appellant cites the Diamond Declaration. Dr. Diamond states that he applied for a grant from the National Institutes of Health, “propos[ing] experiments including testing the effect of a hyaluronidase polypeptide (PEGPH20) on anti-cancer activity of Salmonella typhimurium (ST) bacteria.” Diamond Decl. ¶ 3. Dr. Diamond states that the “Summary Statement released . . . [by] a review panel of over 20 experts” included a critique from a member of the panel expressing “concern [that] the effect of PEGPH20 on a large particle like ST is not well elucidated” and Appeal 2021-002450 Application 14/978,590 10 “stat[ing] that ‘it is questionable if PEGPH20 enhances the delivery of ST.’” Id. ¶¶ 4–5; see also Decl., Exh. A. The evidence provided by the Diamond Declaration supports the disclosure in Bookbinder that hyaluronidase, by itself, would not have reasonably been expected to increase tumor penetration of a Salmonella bacterial cell. While the Declaration does not identify the individual who provided the quoted critique, that person was asked to evaluate an NIH grant application and therefore it is reasonable to conclude that this person’s opinion is at least probative of the level of ordinary skill in the art. And the critique expresses doubt regarding whether a hyaluronidase (“PEGPH20”) would enhance delivery of therapeutic Salmonella bacteria (although the reviewer noted that it might not matter, “since shIDO-ST is working in prelim data without PH20”). In summary, a preponderance of the evidence of record does not support a reasonable expectation of successfully combining Xu’s Salmonella bacteria with a hyaluronidase, and producing a “combined effective amount [that] is effective to increase tumor penetration by the bacterial cell relative to absence of the tumor penetrating agent [hyaluronidase],” as required by the claims. The Examiner reasoned that, because Bookbinder et al. teaches that there is an expectation that particles which are greater than 500nm in diameter, such as (bacterial) cells, could readily penetrate tumor tissue if other (EC)matrix-degrading enzymes were combined with the specific form of hyaluronidase (i.e., sHASEGP) shown in Bookbinder et al. . . . one of ordinary skill in the art of enzyme biochemistry would understand that by increasing the concentration of the hyaluronidase enzyme or by increasing the Appeal 2021-002450 Application 14/978,590 11 stability of the hyaluronidase enzyme there is a reasonable expectation of success that pores could be introduced into the tumor matrix that would allow the penetration of bacteria-sized cells, in view of the teachings of Bookbinder et al. Ans. 11–12 (emphasis added). As Appellant has pointed out (Reply Br. 8), however, the Examiner has not cited evidence supporting the position that a skilled artisan would have expected that increasing the concentration or stability of hyaluronidase in Bookbinder’s method would increase tumor penetration by Xu’s bacterial cells. As the Examiner herself noted, Bookbinder expressly suggests combining another matrix-degrading enzyme with hyaluronidase, not increasing the hyaluronidase’s concentration or stability, in applications where larger pores are desired. Ans. 11; Bookbinder ¶ 578. Because the above-quoted rationale is unsupported by evidence, it does not show that those skilled in the art would have had a reasonable expectation of successfully practicing the claimed methods based on the cited references. DECISION SUMMARY In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1–5, 8, 9, 11, 12, 14, 15, 18, 42, 43 Xu, Frost, Bookbinder 1–5, 8, 9, 11, 12, 14, 15, 18, 42, 43 REVERSED Copy with citationCopy as parenthetical citation