Ex Parte Gleave et al

Patent Trial and Appeal BoardAug 4, 2017

12886027 (P.T.A.B. Aug. 4, 2017)

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. 12/886,027 09/20/2010 Martin Gleave UBC.P-039-2 9847 57381 7590 Larson & Anderson, LLC P.O. BOX 4928 DILLON, CO 80435 EXAMINER SHIN, DANA H ART UNIT PAPER NUMBER 1674 MAIL DATE DELIVERY MODE 08/07/2017 PAPER 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. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte MARTIN GLEAVE and GABRIELLA ZUPI1 Appeal 2015-007240 Application 12/886,027 Technology Center 1600 Before ERIC B. GRIMES, RICHARD J. SMITH, and JOHN E. SCHNEIDER, Administrative Patent Judges. GRIMES, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35U.S.C. § 134 involving claims to a method of treating breast cancer, which have been rejected for obviousness and obviousness-type double patenting. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. STATEMENT OF THE CASE The Specification discloses “a method for treating cancer in a mammalian subject using a combination of therapeutic agents, one of which 1 Appellants identify the Real Party in Interest as The University of British Columbia. (Appeal Br. 1.) Appeal 2015-007240 Application 12/886,027 is an oligonucleotide effective to reduce the amount of clusterin.” (Spec. 11.) “Clusterin or ‘TRPM-2’ is a ubiquitous protein, with a diverse range of proposed activities.” (Id. 17.) “HER-2, also known as ERBB2, or human epidermal growth factor receptor 2, helps control how cells grow, divide, and repair themselves. . . . HER-2 is overexpressed in about a third of all breast cancers and is the target of trastuzumab.” (Id. 135.) “Trastuzumab, sold under the brand name Herceptin™, is a recombinant monoclonal antibody administered intravenously to treat breast cancer.” (Id. 136.) Claims 25, 28—33, 35—41, 43, and 44 are on appeal. Claim 25 is the only independent claim and reads as follows: 25. A combination for treating breast cancer in a mammalian subject, consisting of (i) an agent that is effective for treating breast cancer in the mammalian subject and perturbs the HER-2 cell signaling pathway but increases the expression level of clusterin, the agent being a monoclonal antibody specific for HER-2, and (ii) one antisense oligonucleotide or one RNA interference inducing molecule, said antisense oligonucleotide or RNA interference inducing molecule that targets clusterin mRNA comprising nucleotides in a sequence that is complementery [sic] to clusterin mRNA and being effective to reduce the effective amount of clusterin in a breast cancer cell. (Amendment filed March 4, 2014, page 3.2) 2 The Claims Appendix to the Appeal Brief contains typographical errors in claim 25. The claim as reproduced above is as it was submitted in the cited amendment. 2 Appeal 2015-007240 Application 12/886,027 The claims stand rejected as follows: Claims 25, 28—33, 35—41, 43, and 44 under 35 U.S.C. § 103(a) as obvious based on Milella,3 Biroccio,4 Gleave ’591,5 and Redondo6 (Non- Final Action7 4); Claims 25, 28—33, 35—41, 43, and 44 for obviousness-type double patenting based on claims 1—8 of U.S. Patent 7,368,436 B2 in light of Milella, Biroccio, Gleave ’591, and Redondo (Non-Final Action 8); and Claims 25, 28—33, 35—41, 43, and 44 for obviousness-type double patenting based on claims 1—5 of U.S. Patent 7,732,422 B2 in light of Milella, Biroccio, Gleave ’591, and Redondo (Non-Final Action 10). I The Examiner has rejected all of the claims on appeal as obvious based on Milella, Biroccio, Gleave ’591, and Redondo. The Examiner finds that Milella teaches that “a combination comprising trastuzumab and bcl2/bcl-XL bispecific antisense oligonucleotide is useful for treating breast cancer.” (Non-Final Action 5.) The Examiner finds that Biroccio teaches “an anti-clusterin antisense oligonucleotide has been tested to be effective 3 Milella et al., Trastuzumab Down-Regulates Bcl-2 Expression and Potentiates Apoptosis Induction by BcI-2/BcI-Xl Bispecific Antisense Oligonucleotides in HER-2 Gene-Amplified Breast Cancer Cells, 10 Clinical Cancer Research 7747-56 (2004). 4 Biroccio et al., The future of antisense therapy: combination with anticancer treatments, 22 Oncogene 6579—88 (2003). 5 US 2003/0166591 Al, published Sept. 4, 2003 6 Redondo et al., Overexpression of Clusterin in Human Breast Carcinoma, 157(2) American Journal of Pathology 393-99 (2000). 7 Office Action mailed Dec. 9, 2013. 3 Appeal 2015-007240 Application 12/886,027 when used in combination with conventional anticancer drugs” and that Gleave ’591 teaches that “an anti-clusterin (also known as TRPM-2) antisense oligonucleotide ISIS 112989 ... is useful for treatment of cancer cells expressing TRPM-2 including ‘some breast cancer cells.’” (Id.) The Examiner also finds that Redondo teaches that “clusterin is overexpressed in breast cancer cells and that clusterin expression may contribute to breast tumorigenesis.” (Id.) The Examiner concludes that it would have been obvious to replace the bispecific oligonucleotide [of Milella] with ISIS 112989 because inhibiting clusterin expression in breast cancer cells was suggested to be therapeutically useful for treating breast cancer expressing clusterin as taught by Gleave et al. (see paragraph 0022) and Redondo et al., and because antisense oligonucleotides including anti-clusterin oligonucleotide were known to provide “promising results” when combined with another anticancer drug as reported by Biroccio et al. (Id. at 6.) We agree with the Examiner that the cited references support a prima facie case of obviousness. Milella discloses treatment of breast cancer cells with “trastuzumab, alone or in combination with . . . Bcl-2/Bcl-XL bispecific antisense oligonucleotides (AS-4625).” (Milella 7747, abstract.) Milella reports that “trastuzumab only marginally increased the rate of apoptosis” while “the combination of AS-4625 followed by trastuzumab resulted in a significantly stronger induction of apoptosis.” (Id.) Milella concludes that “[djespite its lack of proapoptotic activity when used alone, trastuzumab significantly potentiates apoptosis induction by agents (either AS or small molecule antagonists) that interfere with Bcl-2 and/or Bcl-XL expression and 4 Appeal 2015-007240 Application 12/886,027 function, resulting in a proapoptotic synergism that could be exploited for therapeutic purposes.” {Id. at 7752, right col.) Biroccio states: In prostate cancer, experimental and clinical studies suggest that clusterin increases after therapeutic cell death signals, such as androgen ablation or chemotherapy, and has a protective role against apoptotic cell death. Therefore, clusterin PS ASOs [phosphorothioate antisense oligonucleotides] were designed to reduce mRNA and protein expression, thus delaying tumor progression and enhancing chemotherapy-induced apoptosis. (Biroccio 6582, right col.) Biroccio reports that, “although treatment with single-agent clusterin PS ASOs has no effect on prostate, renal and urothelial tumor growth, clusterin PS ASOs synergistically enhance the effect of cytotoxic chemotherapy.” {Id.) Gleave ’591 discloses “the antisense TRPM-2 oligonucleotide ISIS 112989.” (Gleave ’591122.) Gleave ’591 states that its “invention also relates to the use of ISIS 112989 compositions in the treatment of cancer. The invention can be applied in the treatment of cancers where the cancer cells express TRPM-2. Significant classes of cancer cells which express TRPM-2 include prostate cancer cells,. . . and some breast cancer cells.” {Id.) Gleave discloses that treatment with antisense TRPM-2 ODN in the presence of taxol or mitoxanthrone resulted in a reduced tumor volume as compared to the combination of taxol or mitoxanthrone with the mismatch (MM) ODN. Other agents likely to show synergistic activity include other cytotoxic agents (e.g. cyclophosphamide, topoisomerase inhibitors), angiogenesis inhibitors, differentia tion agents and signal transduction inhibitors. {Id. 132.) 5 Appeal 2015-007240 Application 12/886,027 Redondo states that “evidence has accumulated suggesting that clusterin expression is not enhanced, but rather down-regulated in the cells undergoing apoptosis, and that its expression in the apoptotic tissue is restricted to the surviving bystander cells.” (Redondo 394, left col.) Redondo reports that “the up-regulation of this gene is closely associated with the different steps of tumor progression from normal tissue to premalignant and malignant breast lesions.” (Id. at 398, left col.) Redondo concludes that “the detection of clusterin in breast carcinoma suggests that this protein may have a role in breast tumorigenesis and progression although it has not been shown to possess clinical utility as a survival prognostic factor.” (Id. at 398, right col.) We agree with the Examiner that the method of claim 25 would have been obvious to a skilled artisan based on the above teachings. Specifically, Milella teaches that combining trastuzumab with an antisense oligonucleotide directed at Bcl-2/Bcl-XL “resulted in a significantly stronger induction of apoptosis” and “proapoptotic synergism.” (Milella 7747, abstract; 7752, right col.) Similarly, Biroccio teaches that antisense oligonucleotides directed at clusterin “synergistically enhance the effect of cytotoxic chemotherapy.” (Biroccio 6582, right col.) Gleave ’591 confirms Biroccio’s disclosure with its teaching that a specific antisense oligonucleotide directed at clusterin (ISIS 112989) “resulted in reduced tumor volume” when combined with taxol or mitoxanthrone. (Gleave ’591132) Gleave ’591 also suggests that ISIS 112989 is “likely to show synergistic activity” when combined with a variety of other chemotherapeutic agents. (Id.) Redondo teaches that up- 6 Appeal 2015-007240 Application 12/886,027 regulation of clusterin is associated with tumor progression. (Redondo 398, left col.) Thus, a person of ordinary skill in the art would have reasonably expected that combining ISIS 112989 with trastuzumab would result in a stronger induction of apoptosis because both bcl-2/bcl-XL and clusterin are active in the apoptotic pathway. In addition, given clusterin’s demonstrated or suggested synergism with a variety of anticancer agents, a skilled artisan would have reasonably expected that the combination of trastuzumab and clusterin would provide greater-than-additive anticancer activity. A skilled artisan therefore would have had a reason to combine the elements of claim 25 in the manner claimed, and would have had a reasonable expectation of success in doing so. Appellants argue that the evidence does not support replacing Milella’s antisense targeting bcl-2/bcl-XL with Biroccio’s antisense targeting clusterin because these antisense-targeted compounds are not equivalents. (Appeal Br. 3.) Appellants argue that “while both targets may be involved in apoptosis, this is a complex process with many points for regulation and there is no evidence that clusterin acts in a manner similar to Bcl-2 and/or Bc1-Xl in regulating apoptosis.” (Id. at 4.) This argument is not persuasive. It is true that clusterin has a different biological activity than bcl-2 and bcl-XL, so they are not “equivalent” in the sense of carrying out the same function. The relevant portion of Biroccio’s Figure 1, as reproduced in the Appeal Brief, is shown below: 7 Appeal 2015-007240 Application 12/886,027 DRUGS #11 «#«# IP / & $ £fc X X, / „ 5 . -\ '*/* /\, \ f Cyt s / ' : Xx ! . /X. V ’^Sv * Sfi J'C:SS{X§ -;r\ i ■ / 'x Casjs-S ■;--1 XX VXJ tfs APOPTOSIS .vV.X-x.X'-' 4 -T■x' * .v**' <■ This portion of Biroccio’s Figure 1 shows the proteins involved in the pathway leading to apoptosis. Clusterin is shown in the middle of the right side; bcl-2 and bcl-XL are shown at the right hand side of a mitochondrion. Importantly, the activities of each of clusterin, bcl-2, and bcl-XL are all shown as blocking the pathway leading to apoptosis. Specifically, clusterin is shown to block the activity of APAFl/Casp-9, which would inhibit the apoptotic pathway at that point. Bcl-2 is shown to block Cyt c, which is the previous step in the same pathway. Bcl-XL is shown to block Smac, which itself has the activity of blocking clusterin; by blocking clusterin, Smac prevents clusterin from inhibiting apoptosis (by blocking 8 Appeal 2015-007240 Application 12/886,027 APAFl/Casp-9), so by blocking Smac, bcl-XL allows clusterin to carry out its inhibition of APAFl/Casp-9 and thereby inhibit apoptosis. Thus, clusterin, bcl-2, and bcl-XL were known to have the same effect of inhibiting the pathway leading to apoptosis, albeit at different points in that pathway. For this reason, a skilled worker would have considered it obvious to use an antisense oligonucleotide directed at clusterin in place of Milella’s antisense oligonucleotide directed at bcl-2/bcl-XL with a reasonable expectation of obtaining a similar result. Appellants also argue that they have shown synergism between trastuzumab and an antisense oligonucleotide targeting clusterin. (Appeal Br. 6). Appellants point to the data shown in the Specification’s Examples 2-4 and Figures 2 and 4. (Id. at 6—7.) We agree that the evidence shows a synergistic result for the combination of trastuzumab and an antisense oligonucleotide directed at clusterin. The dispositive question, then, is whether that synergism was unexpected. See In re Kollman, 595 F.2d 48, 55 n.6 (CCPA 1979) (“Synergism, in and of itself, is not conclusive of unobviousness in that synergism might be expected.”); In re Huellmantel, 324 F.2d 998, 1003 (CCPA 1963) (“[W]e attribute no magic status to synergism per se since it may be expected or unexpected.”). Here, we conclude that a person of ordinary skill in the art would have reasonably expected the combination of trastuzumab and an antisense oligonucleotide directed at clusterin to be synergistic. As discussed immediately above, clusterin acts on the same pathway, and has the same effect on that pathway (inhibition), as bcl-2 and bcl-XL. Thus, a skilled 9 Appeal 2015-007240 Application 12/886,027 artisan would reasonably expect that inhibiting clusterin with an antisense oligonucleotide directed at it would have an effect similar to that of inhibiting bcl-2 and/or bcl-XL with an antisense directed at one or both of them. Milella reports that “trastuzumab significantly potentiates apoptosis induction by agents (either AS or small molecule antagonists) that interfere with Bcl-2 and/or Bcl-XL expression and function, resulting in a proapoptotic synergism that could be exploited for therapeutic purposes.” (Milella 7752, right col., emphasis added.) Based on this result and the known functions of bcl-2, bcl-XL, and clusterin in inhibiting the apoptotic pathway, a skilled worker would have reasonably expected that combining trastuzumab with an antisense oligonucleotide directed at clusterin would also result in synergism. The cited references also provide evidence that clusterin-directed antisense oligonucleotides act synergistically with other anti-cancer agents. Biroccio reports that “clusterin PS ASOs synergistically enhance the effect of cytotoxic chemotherapy.” (Biroccio 6582, right col.) Gleave ’591 states that clusterin (TRPM-2)-directed antisense oligonucleotides are likely to show synergistic activity when combined with a variety of anti-cancer agents, including “cytotoxic agents (e.g. cyclophosphamide, topoisomerase inhibitors), angiogenesis inhibitors, differentiation agents and signal transduction inhibitors.” (Gleave ’591 132.) Thus, the evidence in the prior art shows that clusterin was expected to act synergistically with a wide variety of anti-cancer agents with different mechanisms of action, and that trastuzumab was known to show synergism 10 Appeal 2015-007240 Application 12/886,027 when combined with an antisense oligonucleotide directed at proteins acting on the same pathway as clusterin, and having the same inhibitory effect on that pathway. A preponderance of the evidence therefore supports the conclusion that a skilled artisan would have expected the combination of trastuzumab and an antisense oligonucleotide directed at clusterin to show synergistic activity. For the reasons discussed above, we affirm the rejection of claim 25 under 35 U.S.C. § 103(a) based on Milella, Biroccio, Gleave ’591, and Redondo. Claims 28—33, 35—41, 43, and 44 have not been argued separately and therefore fall with claim 25. 37 C.F.R. § 41.37(c)(l)(iv). II The Examiner has rejected claims 25, 28—33, 35—41, 43, and 44 for obviousness-type double patenting based on the claims of U.S. Patent 7,368,436 B2 in light of Milella, Biroccio, Gleave ’591, and Redondo. The Examiner finds that it would have been obvious to one of ordinary skill in the art to replace the non-clusterin antisense oligonucleotide of the '436 patent claims with trastuzumab for the purpose of breast cancer treatment because both trastuzumab and clusterin-antisense oligonucleotide were each known to be useful for treating breast cancer thus combining two agents known for the same purpose would have been prima facie obvious. (Non-Final Action 9.) Appellants argue that [t]he claims of the present application read on compositions consisting of two components, only one of which can be an antisense oligonucleotide. Thus, there is no overlap between the claims of this application and the claims of the '436 11 Appeal 2015-007240 Application 12/886,027 patent. . . . The right to exclude granted in the '436 patent therefore would not be extended by the grant of a patent on the presently pending claims, because there is no overlap in claim scope. (Appeal Br. 10.) We agree that the claims in this application and those of the ’436 patent do not justify a rejection for obviousness-type double patenting. “The challenge of a double patenting analysis ... is to understand the scope of the compared claims.” Geneva Pharms., Inc. v. GlaxoSmithKline PLC, 349 F.3d 1373, 1385 (Fed. Cir. 2003). “Its purpose is to prevent an unjustified extension of the term of the right to exclude granted by a patent by allowing a second patent claiming an obvious variant of the same invention to issue to the same owner later.” In re Berg, 140 F.3d 1428, 1431-32 (Fed. Cir. 1998). As Appellants point out, the instant claims are limited to a combination consisting of a monoclonal antibody specific for HER-2 and an antisense oligonucleotide (or RNA interference inducing molecule) that targets clusterin. The claims of the ’436 patent, by contrast, require a specific antisense oligonucleotide that targets clusterin, in combination with either an antisense oligonucleotide that targets another anti-apoptotic protein (’436 patent, claim 1) or an antisense oligonucleotide that binds specifically to a sequence other than clusterin mRNA (’436 patent, claim 5). Because all of the ’436 patent’s claims require an antisense oligonucleotide that is excluded from the combination now claimed, we agree with Appellants that the claims now on appeal do not represent an obvious variant, and do not provide for an unjustified timewise extension, of 12 Appeal 2015-007240 Application 12/886,027 the claims of the ’436 patent. The rejection for obviousness-type double patenting based on the ’436 patent is reversed. Ill The Examiner has rejected claims 25, 28—33, 35—41, 43, and 44 for obviousness-type double patenting based on the claims of U.S. Patent 7,732,422 B2 in light of Milella, Biroccio, Gleave ’591, and Redondo. The Examiner finds that the ’422 patent’s claims are not patentably distinct from the claims now on appeal because “it would have been obvious to further include trastuzumab . . . because both trastuzumab and clusterin-antisense oligonucleotide were each known to be useful for treating breast cancer.” (Non-Final Action 10.) We agree with the Examiner that the claims on appeal are an obvious variant of the ’422 patent’s claims and therefore are properly rejected for obviousness-type double patenting. Claim 1 of the ’422 patent reads as follows: 1. A pharmaceutical composition, comprising an antisense oligonucleotide which inhibits expression of TRPM-2 by tumor cells, and a pharmaceutically acceptable carrier suitable for human administration for providing the oligonucleotide to a mammalian subject to reduce expression of TRPM-2 wherein the antisense oligonucleotide comprises the sequence given by SEQ ID No. 4. (’422 patent, col. 13,11. 45—51.) SEQ ID No. 4 of the ’422 patent is identical to SEQ ID NO: 4 of the instant application. (See Computer-readable Form (CRF) entered Jan. 6, 2011.) Claim 35 on appeal limits the antisense oligonucleotide recited in claim 25 to the one shown in SEQ ID NO: 4. (Appeal Br. 14.) Thus, at least 13 Appeal 2015-007240 Application 12/886,027 claim 35 on appeal is a species of the generic composition defined by claim 1 of the ’422 patent; specifically, a species that includes both the antisense oligonucleotide of SEQ ID NO: 4 and trastuzumab. Trastuzumab is a well-known anticancer agent for treating breast cancer. (Milella 7747, right col. (“Trastuzumab . . . has consistently shown clinical activity in advanced breast cancer.”).) Trastuzumab has been shown to be synergistic when combined with an antisense oligonucleotide directed at the anti-apoptotic bcl-2 and bcl-XL proteins. (Id. at 7752, right col.) And anti-clusterin antisense oligonucleotides were known to enhance chemo therapy-induced apoptosis. (Biroccio 6582, right col.) Thus, we agree with the Examiner that the species of the ’422 patent’s claim 1 that also contains trastuzumab (i.e., claim 35 on appeal) was an obvious species within the genus defined by claim 1 of the ’422 patent. Appellants argue that “a requirement for a terminal disclaimer in this case would unfairly deny Applicants the full term to which they are entitled, and to which a third party having filed the present application would be entitled.” (Appeal Br. 11.) Appellants argue that There is no logical or rational basis for considering a grant of the patent in this case without a terminal disclaimer to be an improper timewise extension. If the invention is patentable to a third party because it is distinct and unobvious over the cited patent, then it is equally distinct and unobvious to someone who improves on this own prior invention. (Id.) This argument is unpersuasive. For the reasons discussed above, it is doubtful that the claims on appeal would be patentable to anyone. But in any event, 14 Appeal 2015-007240 Application 12/886,027 [tjhere are two justifications for obviousness-type double patenting. The first is “to prevent unjustified timewise extension of the right to exclude granted by a patent no matter how the extension is brought about.” The second rationale is to prevent multiple infringement suits by different assignees asserting essentially the same patented invention. In re Hubbell, 709 F.3d 1140, 1145 (Fed. Cir. 2013) (citation omitted). Thus, requiring a terminal disclaimer here is justified to ensure that the ’422 patent and any patent that might issue based on the instant application remain commonly assigned, to prevent multiple infringement suits based on essentially the same invention (e.g., based on the combination of trastuzumab and the clusterin-directed antisense oligonucleotide of SEQ ID NO: 4). We therefore affirm the rejection of claim 35 for obviousness-type double patenting based on claims 1—5 of the ’422 patent in light of Milella, Biroccio, Gleave ’591, and Redondo. Claims 25, 28—33, 36-41, 43, and 44 have not been argued separately and therefore fall with claim 35. 37 C.F.R. § 41.37(c)(l)(iv). SUMMARY We affirm the rejection of claims 25, 28—33, 35—41, 43, and 44 under 35 U.S.C. § 103(a) based on Milella, Biroccio, Gleave ’591, and Redondo. We reverse the rejection of claims 25, 28—33, 35—41, 43, and 44 for obviousness-type double patenting based on the claims of U.S. Patent 7,368,436 B2 in light of Milella, Biroccio, Gleave ’591, and Redondo. We affirm the rejection of claims 25, 28—33, 35—41, 43, and 44 for obviousness-type double patenting based on the claims of U.S. Patent 7,732,422 B2 in light of Milella, Biroccio, Gleave ’591, and Redondo. 15 Appeal 2015-007240 Application 12/886,027 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 16