Ex Parte Shin et alDownload PDFPatent Trial and Appeal BoardJul 21, 201612665007 (P.T.A.B. Jul. 21, 2016) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 12/665,007 08/30/2010 4743 7590 07/25/2016 MARSHALL, GERSTEIN & BORUN LLP 233 SOUTH WACKER DRIVE 6300 WILLIS TOWER CHICAGO, IL 60606-6357 FIRST NAMED INVENTOR Seung-Uon Shin 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. 32286/50556 7463 EXAMINER AEDER, SEAN E ART UNIT PAPER NUMBER 1642 NOTIFICATION DATE DELIVERY MODE 07/25/2016 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): mgbdocket@marshallip.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte SEUNG-UON SHIN, JOSEPH DAVID ROSENBLATT, and SHERIE L. MORRISON Appeal2014-004500 Application 12/665,007 1 Technology Center 1600 Before FRANCISCO C. PRATS, JOHN G. NEW, and RYAN H. FLAX, Administrative Patent Judges. FLAX, Administrative Patent Judge. DECISION ON APPEAL This is a decision on appeal under 35 U.S.C. § 134(a) involving claims directed to an isolated chimeric fusion protein with an anti-tumor antigen binding domain from an anti-HER2 or anti-EGFR antibody and a human endostatin protein (or fragment) with a proline to alanine amino acid substitution at pos. 125 (and pharmaceuticals/kits therewith). Claims 20-23, 25-35, 45--47, 49-55, 57, 58, and 65 are on appeal as rejected under 35 U.S.C. § 103(a). We have jurisdiction under 35 U.S.C. § 6(b). We affirm. 1 The Real Party in Interest is University of Miami. App. Br. 3. Appeal2014-004500 Application 12/665,007 STATEMENT OF THE CASE The Specification describes that the invention is generally directed to compositions and methods of targeting and modulating, e.g., treating, tumor cells, i.e., cancer. Spec. i-f 1. The focus of the Specification is a chimeric fusion of two molecules, one of which being a tumor antigen targeting domain (binding domain), e.g., anti-HER2/neu, and the other being an anti- tumor effector function domain, e.g., endostatin. Spec. i-fi-1 1, 10-92. Fig. IA illustrates such a chimeric molecule and is reproduced below: «HER 2-hUEndo aH ER 2 .. m£ndo..f' 125A !'IG. l.I\ Endostatin-- Endostatin ___ · {P125A} Specification Figure IA shows "a schematic diagram showing anti-HER2 IgG 3-human endostatin fusion proteins [where t ]he endostatin domains [] are indicated by an arrow" and position 125 on a mutated P125A-endostatin is shown by a darker line, indicated as "P125A." Spec. i-f 95. The Specification explains, "[i]ntroduction of a point mutation into human endostatin at position 125 (proline to alanine; huEndo-P125A) enhances endothelial cell binding, anti-angiogenic activity, and anti-tumor activity as compared to the wild type endostatin molecule." Spec. i-f 126. 2 Appeal2014-004500 Application 12/665,007 The appealed claims can be found in the Claims Appendix of the Appeal Brief. Claims 20, 45, and 65 are independent claims. Claim 45 is representative and reads as follows: 45. An isolated chimeric fusion protein comprising an anti- tumor antigen binding domain from an anti-HER2 or anti-EGFR antibody and at least one human endostatin protein or fragment thereof, wherein the at least one human endostatin protein or fragment thereof comprises a proline to alanine amino acid substitution at position 125 of human endostatin. App. Br. 19 (Claims App'x). The following rejection is on appeal: Claims 20-23, 25-35, 45--47, 49-55, 57, 58, and 65 rejected under 35 U.S.C. § 103(a) over Shin, 2 Yokoyama-1, 3 and Yokoyama-2. 4 DISCUSSION We adopt the Examiner's findings of fact, reasoning on scope and content of the prior art, and conclusions set out in the Final Action and Answer. We identify the following only to highlight certain facts: 2 U.S. Patent Application Pub. No. US 2005/0008649 Al (published Jan. 13, 2005) (hereinafter "Shin"). 3 Y. Yokoyama & S. Ramakrishnan, Improved Biological Activity of a Mutant Endostatin Containing a Single Amino-Acid Substitution, 90 BRITISH J. CANCER 1627-35 (2004) (hereinafter "Yokoyama-I"). 4 Yumi Yokoyama & S. Ramakrishnan, Addition of Integrin Sequence to a Mutant Human Endostatin Improves Inhibition of Tumor Growth, 111 INT. J. CANCER 839--48 (2004) (hereinafter "Yokoyama-2"). 3 Appeal2014-004500 Application 12/665,007 FINDINGS OF FACT FF 1. Shin disclosed "[ c ]himeric molecules comprising endostatin and all or a portion of an lg (lg) molecule are used to treat tumors. A chimeric molecule, including endostatin fused to an lg domain of an anti- HER2/neu antibody exhibited longer serum half-life and stability than native endostatin[,] ... preferentially localized to CT26-HER2 tumors[, and exhibited c]learance ... 6 fold faster than ... anti-HER2/neu IgG3 .... Anti-HER2/neu IgG3-endostatin inhibited tumor growth more effectively than endostatin alone, anti-HER2/neu IgG3 antibody, or the combination of antibody and endostatin." Shin Abstract; see also Final Action 3, 7-8, 11 and Ans. 2-3, 7, 11-13 (discussing Shin). FF2. Shin disclosed "[i]n another embodiment of the invention, the chimeric polypeptide of the invention, e.g., a endostatin construct, is a fusion constn.1ct of a modified or an unmodified endostatin with a modified or an unmodified modulatory or cytotoxic molecule." Shin i-f 136; see also Final Act. 3 (discussing Shin); cf Reply Br. 11 (contending Shin neither provides motivation to alter its constructs to result in claimed invention nor teaches to apply its fusion proteins to endostatin P125A). FF3. Shin disclosed that it was within the ordinary skill in the art to produce and characterize a chimeric anti-HER2/neu IgG3-endostatin fusion molecule. Shin i-fi-1275-276 (Example 5); see also Final Action 2 (discussing Shin). FF 4. Y okoyama-1 disclosed: Human endostatin has an internal Asn-Gly-Arg (NGR) motif at position 126-128 following a proline at position 125. Asn-Gly- 4 Appeal2014-004500 Application 12/665,007 Arg contammg peptides have been shown to target tumour vasculature and inhibit aminopeptidase N activity. We previously compared the in vitro and in vivo biological activities of native endostatin and endostatin with a proline to alanine mutation (P125A-endostatin). P125A-endostatin exhibited greater inhibition of both endothelial cell proliferation and human ovarian cancer growth compared to native endostatin. . .. P125A-endostatin bound to endothelial cells more efficiently than native endostatin and exhibited greater inhibition of not only proliferation but also migration of endothelial cells. P125A- endostatin also localised into tumour tissue to a higher degree than the native protein, and displayed greater inhibition of growth of colon cancer in athymic mice. Both proteins inhibited tumour cell-induced angiogenesis effectively. Real-time PCR analysis showed that both native and P125A-endostatin decreased expression of key proangiogenic growth factors. Vascular endothelial growth factor and angiopoietin I were downregulated more by the mutant. These studies suggest that the region around P 125 can be modified to improve the biological activity of endostatin. Yokoyama-I 1627 (Abstract); see also Final Action 3-5, 7-13 and Ans. 4-- 11 (discussing Yokoyama). FF5. Y okoyama-1 disclosed: In order to determine whether the mutant protein was folded properly, gross secondary structural analysis of the P125A mutant was compared to the native protein made in the same expression system. The CD spectra of native and P125A human endostatin showed identical profiles, indicating that the two proteins have similar gross secondary structures (Figure IB). Yokoyama-I 1629 (right col.), 1630 (Figure IB); see also Final Action 3--4, 8 and Ans. 4, 7-8 (discussing the structural similarities between native human endostatin and P125A human endostatin). 5 Appeal2014-004500 Application I2/665,007 FF6. Yokoyama- I disclosed "In spite of the nonconservative substitution of a proline to alanine, the mutant protein was expressed in soluble form and was biologically active. The CD spectrum showed that PI25A-mutation did not cause major structural change." Yokoyama-I I633 (right col.); see also Final Action 3--4, 8, and Ans. 4, 7-8 (discussing the structural similarities between native human endostatin and PI25A human endostatin). FF7. Yokoyama-I disclosed PI25A-endostatin was more effective at binding endothelial cells (HUVEC) (7I %) than native endostatin (38.5%). Yokoyama-I I629 (right col.), I630 (Figure IC); see also Final Action, e.g., 4 and Ans., e.g., 3, 7 (discussing Yokoyama-I). FF8. Yokoyama-I disclosed, "PI25A-endostatin inhibited endothelial cell proliferation more efficiently than native endostatin." Yokoyama-I I629 (right col.); see also Final Act., e.g., I I (discussing Yokoyama-I). FF9. Yokoyama- I disclosed "[ t ]umour localisation is improved by PI25A-mutation [of endostatin]." Yokoyama-I I630 (both col. and Figure IE); see also Final Action, e.g., 4 (discussing improved localization with mutation). FFIO. Yokoyama-I disclosed "neither the native nor the PI25A mutant showed any inhibition of aminopeptidase N activity even at 5 µM concentration." Yokoyama-I I 63 I (right col.); see also Reply Br. 4--8 (contending Yokoyama- I did not show improved antitumor effect of mutant endostatin). 6 Appeal2014-004500 Application I2/665,007 FFI 1. Yokoyama-I disclosed "both endostatin and PI25A-endostatin treatment significantly inhibited angiogenesis in vivo (Figure 3H, I and Figure 4)." Yokoyama-I I63I (right col.); see also Reply Br. 4--8 (contending Yokoyama-I did not show improved antitumor effect of mutant endostatin). FF I 2. Yokoyama- I disclosed: mRNA levels of major proangiogenic growth factors (tumour cell derived) and receptors expressed on host endothelial cells were downregulated by endostatin or PI25A-endostatin treatment. Moreover, VEGF and AngI expression were significantly decreased by PI25A-endostatin when compared to native endostatin. Angiopoietin 2 transcript was not detected in any of the samples analysed. Basic FGF-related transcript levels were equally decreased by both the native and mutant endostatin. Yokoyama-I I 632 (left col.); see also Reply Br. 6 (contending inconsistent effects of mutant endostatin reported by Yokoyama- I). FF13. Yokoyama-I disclosed "alginate beads of Pl25A-endostatin was more effective in inhibiting MAI48 ovarian cancer growth when compared to the native protein given under similar condition (Calvo et al, 2002). These results were confirmed in a human colon cancer model system (Figure 6)." Yokoyama-I I632 (right col.) (75% vs 30%. tumor growth inhibition, respectively); see also Reply Br. 4 (contending no data on improvement using mutant endostatin in bolus form). FF I 4. Yokoyama- I disclosed: cell attachment assays showed that PI25A-endostatin bound more avidly than native endostatin. Enhanced binding to endothelial cells led to improved biological activity, indicated by the results of endothelial cell proliferation and migration assays. In both the assays, the PI25A-mutation increased bioactivity of 7 Appeal2014-004500 Application I2/665,007 endostatin. Enhanced binding to endothelial cells also led to improved tumour localisation of endostatin. The homing specificity of endostatin to tumours compared to lung or liver tissue was also improved by PI25A-mutation. Yokoyama-I I 634 (paragraph spanning left and right cols.); cf Reply Br. 7 (contending cited references teaching of PI25A endostatin tumor inhibition based solely on impermissible hindsight). FF I 5. Yokoyama- I disclosed: In summary, these studies show that human endostatin can be genetically modified to improve its ability to bind and inhibit endothelial cells. Higher binding also coincided with changes in potency in inhibiting cell proliferation and migration, and in homing to tumours. Such differences in tumour-homing properties can contribute to improved antitumour activity of mutant endostatin. Yokoyama-I I 634 (right col.); cf Reply Br. 7 (contending cited references teaching of PI25A endostatin tumor inhibition based solely on impermissible hindsight). FF I 6. Y okoyama-2 disclosed "the PI 25A mutation did not affect the biologic activity of endostatin but in fact had better antiangiogenic activity when compared to the native molecule. Further modification of PI25A- endostatin with the RGD motif showed specific and increased binding to endothelial cells, and the increased binding coincided with improved antiangiogenic properties." Yokoyama-2 839 (Abstract); cf Reply Br. 7 (contending cited references teaching of PI 25A endostatin tumor inhibition based solely on impermissible hindsight). 8 Appeal2014-004500 Application 12/665,007 ANALYSIS We agree that the evidence of record supports the Examiner's prima facie case that the claims would have been obvious over the cited prior art combination. The issue presented is whether the Appellants' evidence supporting their contentions of secondary indicia of nonobviousness, i.e., unexpected results, is sufficient to overcome the established prima facie case of obviousness. 5 We find it is not sufficient. We address Appellants' arguments below. "[B]y definition, any superior property must be unexpected to be considered evidence of non-obviousness. Thus, in order to properly evaluate whether a superior property was unexpected, the [fact-finder must] consider[] what properties were expected." Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir. 2007) (emphasis original; internal citations omitted herein unless otherwise indicated). Here, the Appellants present not-insubstantial evidence of significant experimental results relating to the claimed invention (see generally, App. Br. 8-13); however, on the current record, these results were not "unexpected." 5 See Declaration of Dr. Seung-Uon Shin under 37 C.F.R. § 1.132 dated Apr. 15, 2013 (hereinafter the "Shin Deel.") and Declaration of Dr. Louis Weiner under 37 C.F.R. § 1.132 dated Aug. 13, 2013 (hereinafter the "Weiner Deel."); see also Bookman et al., Evaluation of Monoclonal Humanized Anti-HER2 Antibody, Trastuzumab, in Patients With Recurrent or Refractory Ovarian or Primary Peritoneal Carcinoma With Overexpression of HER2: A Phase II Trial of the Gynecologic Oncology Group, 21 J. CLINICAL ONCOLOGY 283-90 (Jan. 15, 2003) (hereinafter "Bookman"). 9 Appeal2014-004500 Application 12/665,007 As determined by the Examiner, Shin showed synergy in combining an anti-HER2/neu IgG3 and a native endostatin into a fused chimeric molecule. 6 FF 1. Moreover, Shin disclosed that its fused chimeric molecule "inhibited tumor growth more effectively" than its components individually or merely combined. Id. As also determined by the Examiner, Yokoyama-I showed P125A human endostatin was structurally similar to, but better at treating cancer than native human endostatin because the former exhibited greater inhibition of endothelial cell proliferation, more efficient binding to endothelia cells, greater inhibition of endothelial cell migration, higher degree of localization in tumor tissue, and better inhibition of colon cancer growth. FF4-FF6, FF15. In substituting a P125A endostatin for the native endostatin of Shin, a skilled artisan would have sought and expected the improvements offered by the P125A endostatin mutant in addition to the anti-tumor synergy of the Shin chimeric fusion. Expected beneficial results are not evidence of nonobviousness, they are evidence of obviousness. See In re Skoner, 517 F.2d 947, 950 (CCPA 1975). The evidence proffered by Appellants consists of two witness' declarations and a publication directed to research on anti-HER2 antibody therapy. See note 5, supra. The Shin Deel., while offering impressive data on the successful treatment of tumors using the invention, as a whole merely indicates that combining anti-HER2/neu and P125A endostatin, as suggested by Shin and Y okoyama-1, was as successful as these references would lead 6 See Shin i-f 14 7, which teaches "[ t ]he constructs of the present invention may comprise domains originating from one species, e.g., from mammals, such as human." See also id. i-f 297 (identifying human endostatin). 10 Appeal2014-004500 Application 12/665,007 one to believe. "Synergism, in and of itself, is not conclusive of unobviousness in that synergism might be expected." In re Kollman, 595 F.2d 48, 55 n.6 (CCPA 1979). Here, it was expected and its confirmation by the Appellants' experimental data and witness's opinion is not evidence of nonobviousness. The Weiner Deel. is directed to the witness's opinion that, as of the date of invention, a skilled artisan would not be enthusiastic about using or researching the use of endostatin and related molecules for tumor inhibition. Other than personal knowledge, the witness bases this opinion on the lack of any "explicit or implicit suggestion in any of these references to modify any of the references to result in the claimed invention, and [the afore-discussed] unexpected results." Weiner Deel. i-fi-13, 7. As discussed above, the Shin and Yokohama-I references teach both fusing anti-HER2/neu and endostatin and substituting P125A endostatin for the native to gain improved anti- tumor effects. Thus, we are not persuaded by this testimony. Also, Appellants contend the Bookman reference would dissuade the skilled artisan from looking to anti-HER2 antibodies for cancer treatment. App. Br. 8. Even if this were so, Shin is explicit that combining anti- HER2/neu with endostatin offers significant advantages over the antibody alone. FF 1. Therefore, we are not persuaded by this evidence. Appellants also contend the Examiner failed to provide acceptable reasoning why one of ordinary skill in the art would have found it obvious to modify the references as proposed. App. Br. 6. Appellants also contend the claimed chimeric fusion proteins would not have been expected because an expert in the field aware of the cited references would not have been 11 Appeal2014-004500 Application 12/665,007 motivated to develop a chimeric fusion protein including the endostatin P125A mutation and an antibody/fragment against HER2. Id. The reasoning set forth above shows these arguments to be without merit as the references themselves provide ample motivation for their combination. Appellants also contend that it was unexpected that incorporating the mutant endostatin into the claimed fusion would result in a working protein because proper folding and secondary structure of the resultant chimeric fusion would be unexpected. App. Br. 7. As the Examiner determined, Y okoyama-1 is explicit that the mutant endostatin has essentially the same structure/shape as the native endostatin, which combined and functioned in the chimeric fusion disclosed by Shin. FF5, FF6. Therefore, the Appellants' argument is not persuasive. "[W]hen a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result." KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). "The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results." Id. We are confronted with precisely this circumstance here. The chimeric fusion of anti-HER2/neu and endostatin for cancer therapy was known in the art. FF 1. The fact that the P125A mutant endostatin offered the same biologic activity of native endostatin, but with improved anti-tumor benefits was likewise known. FF4, FF16. Merely substituting the mutant for the native endostatin to yield the predictable result of improved anti-tumor properties would have been 12 Appeal2014-004500 Application I2/665,007 obvious and, so, the preponderance of the evidence supports the Examiner's rejection. For the above reasons, we find claims 20-23, 25-35, 45--47, 49-55, 57, 58, and 65 would have been obvious over Shin, Yokoyama-I, and Yokoyama-2, therefore, the respective rejection is affirmed. SUMMARY The rejection of claims 20-23, 25-35, 45--47, 49-55, 57, 58, and 65 under 35 U.S.C. § I03(a) over Shin, Yokoyama-I, and Yokoyama-2 is affirmed. 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. § I. I36(a). AFFIRMED I3 Copy with citationCopy as parenthetical citation