Ex Parte Koeffler et alDownload PDFPatent Trial and Appeal BoardJan 17, 201813419610 (P.T.A.B. Jan. 17, 2018) 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. 13/419,610 03/14/2012 H. Phillip Koeffler GUR-0005-US 5636 35938 7590 Acuity Law Group, P.C. 12707 High Bluff Drive Suite 200 San Diego, CA 92130-2037 01/19/2018 EXAMINER AULT, ADDISON D ART UNIT PAPER NUMBER 1636 NOTIFICATION DATE DELIVERY MODE 01/19/2018 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): docketing @ acuitylg.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte H. PHILLIP KOEFFLER, IDO WOLF, TAMAR RUBINEK, BELLA KAUFMAN, AND LILACH ABRAMOVITCH Appeal 2016-004476 Application 13/419,6101 Technology Center 1600 Before RICHARD J. SMITH, TAWEN CHANG, and DEVON ZASTROW NEWMAN, Administrative Patent Judges. NEWMAN, Administrative Patent Judge. DECISION ON APPEAL This appeal under 35 U.S.C. § 134 involves claims to methods for treating cancer using a soluble polypeptide. The Examiner entered final rejections that the claims lacked written description and are obvious. We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. 1 Appellants identify the Real Party in Interest as Tel Hashomer Medical Research Infrastructure and Services Ltd. and Cedars-Sinai Medical Center. App. Br. 4. Appeal 2016-004476 Application 13/419,610 STATEMENT OF THE CASE Background The Specification discloses “the use of the klotho protein for the treatment and diagnosis of cancer, such as breast cancer and pancreatic cancer as well as other IGF-1 dependent cancers.” Spec. 1:16—18.2 The Claims Claims 1—4, 9, 16, 17, and 29-31 are pending. Claim 4 is withdrawn from consideration. Claims 1—3, 9, 16, 17, and 29-31 are rejected. Sole independent claim 1 is illustrative and reads as follows: 1. A method comprising: administering to a subject with cancer a pharmaceutically effective amount of a composition comprising: (a) a soluble polypeptide consisting of an extracellular domain of a klotho protein, wherein the klotho protein is encoded by one of SEQ ID NOS: 1, 2, 3, 4, 5, 11, 12, 13, 14 or 15; or (b) a soluble polypeptide consisting of an amino acid sequence selected from the group consisting of residues 31 to 982 of SEQ ID NO: 1, residues 34 to 1012 of SEQ ID NO: 1, residues 34 to 549 of SEQ ID NO: 2, residues 31 to 982 of SEQ ID NO: 3, and residues 36 to 1014 of SEQ ID NO: 3; or (c) a soluble polypeptide consisting of an amino acid sequence having at least 80% homology to a polypeptide defined in (a) or (b); and a pharmaceutically-acceptable carrier. App. Br. 17 (Claims Appendix). 2 We note the Specification pages are not numbered. We refer to the Specification herein as if the pages were numbered sequentially beginning with the title page. 2 Appeal 2016-004476 Application 13/419,610 The Issues The following rejections are before us to review: I. Claims 1, 2, 3, 9, 16, 17, and 29—31 are rejected under 35 U.S.C. § 112(a) or 35 U.S.C. § 112 (pre-AIA), first paragraph, as lacking written description. II. Claims 1,9, 16, 17, and 29 are rejected under pre-AIA 35 U.S.C. § 103(a) as obvious over Hanai,3 Nemoto,4 and Kurosu.5 III. Claims 2 and 3 are rejected under 35 U.S.C. § 103(a) as obvious over Hanai, Nemoto, Kurosu, and Monosov.6 IV. Claims 30-31 are rejected under pre-AIA 35 U.S.C. § 103(a) as obvious over Hanai, Nemoto, Kurosu, Iversen,7 and An.8 I - WRITTEN DESCRIPTION The Examiner finds the rejected claims are “drawn to a method of administering a set of polypeptides comprising ‘an extracellular domain of a klotho protein. [’] The rejected claims thus comprise a set of polypeptides that encompass polypeptides from two to nearly 1000 amino acids [and are] administered in ‘a pharmaceutically effective amount.’” Ans. 5. The 3 WO/27885, published May 18, 2000 (“Hanai”). As did the Examiner, we rely on the machine translation from JP99/06152. 4 US 2005/0208015 Al, published Sep. 22, 2005 (“Nemoto”). 5 Hiroshi Kurosu et al., Suppression of Aging in Mice by the Hormone Klotho, 309(16): Science, 1829-1833 (2005) (“Kurosu”). 6 US RE39,337 E, issued Oct. 10, 2006 (“Monosov”). 7 US 2003/0087861 Al, issued May 8, 2003 (“Iversen”). 8 Anetal.,US 2003/0211077A1, published Nov. 13,2003 (“An”). 3 Appeal 2016-004476 Application 13/419,610 Examiner finds “[n]o description is provided of specific structure/function relationships between the tumor shrinking activity observed by Applicants and the polypeptide sequences claimed by applicant.” Id. at 6. The Examiner finds the Specification does not describe “activities of polypeptides having 80%, 90% or 99% sequence homology compared to the recited polypeptides, or how the observed tumor shrinking activity relates to the art-recognized klotho activities of regulating appetite and longevity.” Id. The Examiner further relies on a “guidance document distributed to examiners on 12/29/2005” as the basis for finding that “based on the Office’s guidance, Claim 1 (c) is interpreted to be open to short sequences containing only a fraction of the recited sequence.” Id. at 6—7. Based on this interpretation, the Examiner finds that the examples provided in the Specification “are only representative of a small subset of potential peptides comprising an extracellular domain of klotho [and] not necessarily predictive of efficacy of those peptides.” Id. at 7. The Examiner concludes: Given the very large genus of klotho encompassed by the rejected claims, and given the limited description provided by the prior art and specification with regard to short polypeptides with pharmaceutical efficacy, the skilled artisan would not have been able to envision a sufficient number of specific embodiments that meet the functional limitations of the claims to describe the broadly claimed genus of klotho peptides. Id. at 7—8. The issue with respect to this rejection is whether a preponderance of the evidence supports the Examiner’s conclusion that the Specification fails to adequately describe the claimed method. 4 Appeal 2016-004476 Application 13/419,610 Appellants contend that the Examiner’s interpretation of the claims is not consistent with that of the ordinarily skilled artisan, who, because “the term ‘extracellular domain’ has a specific meaning within the art in the context of type-I transmembrane proteins . . . would not interpret [extracellular domain] to ‘encompass polypeptides from two to nearly 1000 amino acids’ as stated in the rejection.” App. Br. 6—7. Appellants argue “there is no evidence that something as short as two amino acids would be considered by one of skill in the art to be a Klotho extracellular domain” and that the Examiner’s interpretation is not confined to the scope of the claims Id. at 7. The Examiner responds that claim 1 (c), which recites “a soluble polypeptide consisting of an amino acid sequence having at least 80% homology to a polypeptide defined in (a) or (b)” recites no length and no function and “lacks any indication that the soluble polypeptide is klotho.” Ans. 17. Appellants reply that “a sequence which is only a dipeptide would not have at least 80% homology to any polypeptide defined in (a) or (b)” and note that because element (c) recites “a soluble peptide consisting of’ that the “entire sequence of the soluble peptide of part (c) must exhibit 80% homology to a much longer sequence.” Reply Br. 4. Accordingly, Appellants argue, the skilled artisan “would not interpret this to ‘encompass polypeptides from two to nearly 1000 amino acids.’” Id. We agree with Appellants that the Examiner has not shown that the Specification fails to adequately describe the claimed method. A description adequate to satisfy 35 U.S.C. § 112, first paragraph, 5 Appeal 2016-004476 Application 13/419,610 must “clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.” In other words, the test for sufficiency is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date. AriadPharms., Inc. v. EliLilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (citation omitted, alteration in original). Here, the relevant claim term is “a soluble polypeptide consisting of an amino acid sequence having at least 80% homology to a polypeptide defined in (a) or (b).” The Specification discloses all of the sequences stated in (a) and (b), and the skilled artisan would have been able to assess whether a peptide was at least 80% homologous to any of these peptides using sequence alignment technologies available in the art, such as those used by Examiners to identify prior art sequences (e.g., “BLAST”). Moreover, we agree with Appellants that the skilled artisan would have understood the claim language “consisting of’ to require 80% homology to the entire sequence, and because the sequences are each nearly 1000 base pairs in length, such homology would not be possible with the small dimer peptides the Examiner finds fall within the claim scope. See SEQ ID NOS: 1, 2, 3, 4, 5, 11, 12, 13, 14, and 15, and the claim language 1(b), requiring homology to “an amino acid sequence selected from the group consisting of residues 31 to 982 of SEQ ID NO: 1, residues 34 to 1012 of SEQ ID NO: 1, residues 34 to 549 of SEQ ID NO: 2, residues 31 to 982 of SEQ ID NO: 3, and residues 36 to 1014 of SEQ ID NO: 3,” each of which measures nearly 1000 base pairs. 6 Appeal 2016-004476 Application 13/419,610 In this regard, we are also unpersuaded by the Examiner’s argument that the Specification lacks “specific structure/fimction relationships between the tumor shrinking activity observed by Applicants and the polypeptide sequences claimed by applicant.” Ans. 6. The Specification contains examples disclosing use of the polypeptides to create an expression vector that encodes the klotho polypeptide, along with methods to express and subsequently isolate the soluble klotho protein. See, e.g., pages 23—26 of Specification. Methods of using the proteins to perform the claimed method of treatment are disclosed in subsequent examples on pages 26—33 of the Specification. Given the required homology of over 80% to the claimed (disclosed) sequences, we find that the detailed information in the Specification would have reasonably conveyed to the skilled artisan that the inventor possessed the claimed subject matter as of the filing date. Ariad, 598 F.3d 1336. We therefore reverse the rejection under 35 U.S.C. § 112, first paragraph, for lack of adequate written description. II-OBVIOUSNESS Issue The Examiner has rejected all of the claims as obvious based on Hanai, Nemoto, and Kurosu, by themselves, or combined with Monosov or with Iversen and An. Ans. 8—16. The same issue is dispositive for all of the rejections. The Examiner finds that Hanai teaches “administration to a subject with cancer a pharmaceutically-acceptable carrier with klotho protein ... as a treatment for cancer-associated cachexia.” Ans. 10. The Examiner finds Hanai teaches “administering a polypeptide 752 amino acids in length, 7 Appeal 2016-004476 Application 13/419,610 wherein the polypeptide comprises a region encompassing an extracellular domain of klotho that has over 80% homology with residues 29-568 of Seq ID No. 1 and a second domain, an IgGl domain ... as a therapeutic.” Id. at 11. The Examiner finds that “Hanai, in teaching treatment of cancer- associated cachexia, would suggest to one of ordinary skill treatment of a subject undergoing treatment for cancer with klotho in conjunction with other therapeutics.” Id. The Examiner finds that Hanai does not “explicitly teach administration of a combination therapy comprising klotho extracellular domain and other agents,” but finds Nemoto teaches “administering klotho . . . solubilized by glycerol-derived compounds.” Id. at 11—12. The Examiner finds Kurosu teaches “administration of a peptide ‘consisting of the 952-amino acid extracellular domain of klotho extracellular peptide to mice” and “demonstrates that one of ordinary skill at the time of invention could formulate active klotho ‘consisting of an extracellular domain of klotho for delivery of active klotho to a subject.” Id. at 12. The Examiner concludes that the ordinarily skilled artisan would have found it obvious “to modify the formulation of klotho protein and administration to subjects with cancer of Hanai with the formulation of klotho protein and administration of klotho to subjects in need thereof of Nemoto and Kurosu.” Id. In particular, the Examiner finds the artisan “would have been motivated to combine the inventions in order to formulate active klotho for administration to human subjects in need thereof’ using the “formulation of native klotho peptide(s) of Nemoto and Kurosu” because 8 Appeal 2016-004476 Application 13/419,610 “Hanai teaches that active klotho domains can be used to treat subjects with cancer in order to decrease wasting associated with cancer.” Id. at 13. The issue with respect to this rejection is whether a preponderance of the evidence supports the Examiner’s conclusion that Hanai, Nemoto, and Kurosu disclose the claimed subject matter. Appellants argue that the rejection should be reversed because the skilled artisan would not have found it obvious to modify Hanai by using a klotho extracellular domain instead of a Klotho-Fc dimer. App. Br. 9. Appellants argue that Hanai “teaches administration of ‘chimeric polypeptides’ which comprise an immunoglobulin Fc region fused to two Klotho polypeptides ... in a mouse model of cancer cachexia.” Id. Appellants argue that the art establishes that “cachexia is notoriously hard to treat; in fact, few if any current therapeutic approaches are successful.” Id. Appellants cite Beck and Reichert9 as teaching that Fc fusions such as those of Hanai are known to alter the serum half-life of proteins due to pH-dependent binding to the neonatal Fc receptor (FcRn), which salvages the protein from being degraded in endosomes; and to provide effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) or phagocytosis. ... Far from being a simple “carrier,” Fc fusions alter the biological and pharmacological characteristics of a protein, relative to those of the protein itself. Id. at 9-10. Appellants argue that in light of “unpredictability, one of skill in the art would not assume that removing the Fc portion of the Hanai Klotho- 9 Alain Beck and Janice Reichert, Therapeutic Fc-fusion proteins and peptides as successful alternatives to antibodies, 3(5): mAabs. 415-416 (2011). 9 Appeal 2016-004476 Application 13/419,610 Fc dimer, which would presumably result in a monomeric Klotho protein which is cleared more quickly and has different pharmacologic properties that the fusion of Hanai, would provide any therapeutic benefit.” Id. at 10. Appellants argue that the skilled artisan would believe that “removing the Fc portion of the Hanai Klotho-Fc dimer would, inter alia, be thought by the skilled artisan to impair ‘bioavailability or biological half-life’” and thus not “[motivate the skilled artisan] to arrive at the present invention by modifying the cited art.” Id. Appellants argue that a similar Fc dimer, etanercept, is “an Fc dimer of a portion of the TNF- a receptor [that exists] as single pass type-I transmembrane proteins in nature.” Id. at 11. Appellants note that “the Fc- dimeric structure of etanercept ‘makes it a 50- to 100-fold more potent binder of TNF-a than the unconjugated soluble TNF-a receptor” [meaning] that “without its dimeric structure, [the] soluble TNF-a receptor lacks a sufficient therapeutic activity.” Id. Appellants argue that, based on this information, the skilled artisan would not have believed that removing the dimeric structure from the Klotho dimer would improve therapeutic activity. Id. Appellants further argue that Nemoto teaches Klotho amongst a long list of biologically active proteins and “teaches that Klotho must be modified, and not provided as the polypeptides recited in the claims.” Id. at 12. Appellants argue “Kurosu’s publication reports that intraperitoneal injection of ‘a soluble form of Klotho protein comprising the 952 amino acid extracellular domain’ (emphasis added) rapidly increased blood glucose levels by increasing insulin resistance.” Id. at 13. Appellants argue that 10 Appeal 2016-004476 Application 13/419,610 “any treatment which would be expected to increase insulin resistance would not be considered an appropriate treatment for cachexia, as insulin resistance is thought in the art to be a mechanism causing cachexia,” meaning the art teaches away from the proposed combination. Id., citing Honors10 for the understanding that insulin resistance is not appropriate to treat cachexia. Finally, Appellants argue that “suppression of tumor growth by the administration of the polypeptides recited in the claims is unexpected, and of obvious practical benefit.” Id. Findings of Fact 1. Honors discloses that Individuals with cancer commonly experience anorexia, weight loss, and wasting of muscle and adipose tissue [1, 2], These symptoms are also accompanied by a number of metabolic abnormalities, including alterations in carbohydrate, protein, and lipid metabolism, and insulin resistance [3,4], This syndrome, known as cachexia, greatly decreases the quality of life among patients, reducing survival time, and psychological and physical health [5]. In addition, cachectic cancer patients often display more negative side effects during chemotherapy [6, 7]. Some estimates suggest that up to 80% of cancer patients exhibit some degree of cachexia [6, 8, 9], making this a clinically relevant syndrome for which the cause is currently unknown. Honors 5. 10 Mary Honors and Kimberly Kinzig, The role of insulin resistance in the development of muscle wasting during cancer cachexia 3: J. Cachexia Sarcopenia Muscle 5-11 (2012). 11 Appeal 2016-004476 Application 13/419,610 2. Honors discloses that insulin resistance is present during cancer cachexia in animal models and that treatment with insulin and insulin sensitizers improves cachexia symptoms. Id. at 6—7. We agree with Appellants that a preponderance of the evidence does not support the Examiner’s findings that the skilled artisan would have been motivated to combine Hanai, Nemoto, and Kurosu to achieve the claimed method. In particular, we are persuaded by Appellants’ argument that Kurosu, which “[discloses] that intraperitoneal injection of ‘a soluble form of Klotho protein comprising the 952 amino acid extracellular domain’ rapidly increased blood glucose levels by increasing insulin resistance” teaches away from replacing Hanai’s Fc Klotho dimer with the soluble form of Klotho protein because “insulin resistance is thought in the art to be a mechanism causing cachexia.” Reply Br. 6—7. The Examiner does not dispute that Kurosu induces a blood glucose increase or that the art supported a belief in the connection between insulin resistance and cachexia. We agree with Appellants that the evidence of record supports that the skilled artisan would have believed that insulin resistance was a mechanism causing cachexia, and thus, the artisan would not have believed that administering a soluble form of klotho protein would promote treatment of cancer. We are unpersuaded by the Examiner’s argument in response that “coadministration of one drug to offset the effects of another is routine in the art of cancer treatments” because this does not explain why the artisan would have been motivated in the first instance to create the combination in light of Kurosu’s disclosure that use of its klotho formulation increased blood glucose levels, which would exacerbate cachexia in a patient. Rather, 12 Appeal 2016-004476 Application 13/419,610 we agree with Appellants that the skilled artisan would be dissuaded from using Kurosu’s formulation. In this regard, we are similarly unpersuaded by the Examiner’s position (Ans. 19) that the “side effects of the fluorouracil taught by Iverson would clearly motivate one of ordinary skill to coadminister an anti-cachexia agent like klotho with drugs like fluorouracil” {id. at 20) because giving a second drug to address increased cachexia once again does not explain why the artisan would initially have been motivated to make the combination in the first place. Accordingly, because all of the rejections are based on the Examiner’s finding that the skilled artisan would have found it obvious to modify Hanai by using a klotho extracellular domain instead of a Klotho-Fc dimer, we reverse all of the rejections under 35U.S.C. § 103. SUMMARY We reverse all of the rejections on appeal. REVERSED 13 Copy with citationCopy as parenthetical citation