Ex Parte Kangawa et alDownload PDFPatent Trial and Appeal BoardMar 24, 201610554875 (P.T.A.B. Mar. 24, 2016) 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. 10/554,875 09/19/2006 Kenji Kangawa 69740.000004 9887 21967 7590 03/24/2016 HUNTON & WILLIAMS LLP INTELLECTUAL PROPERTY DEPARTMENT 2200 Pennsylvania Avenue, N.W. WASHINGTON, DC 20037 EXAMINER HEARD, THOMAS SWEENEY ART UNIT PAPER NUMBER 1675 MAIL DATE DELIVERY MODE 03/24/2016 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 KENJI KANGAWA and HIROSHI HOSODA1 ____________ Appeal 2013-006829 Application 10/554,875 Technology Center 1600 ____________ Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and JOHN G. NEW, Administrative Patent Judges. JENKS, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134(a) involving claims directed to a method of treating hepatopathy comprising the administration of a ghrelin polypeptide derivative. The Examiner rejects the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 According to Appellants, the Real Party in Interest is Kenji Kangawa. (App. Br. 3.) Appeal 2013-006829 Application 10/554,875 2 STATEMENT OF THE CASE The Specification discloses that “ghrelin is a peptide consisting of 28 amino acids residues which were found in the stomach, and the serine residue at position 3 is modified with an octanoyl group . . . . It is shown that ghrelin acts on Growth Hormone Secretagogue-Receptor (GHS-R) . . . , and is an endogenous brain-gut hormone which stimulates GH secretion from pituitary gland. (Spec. 3: 16–20.) “[A] polypeptide derivative having an activity of binding to GHS-R . . . have an activity of promoting hepatocyte proliferation.” (Spec. 5: 11–15.) Claims 20, 27–30, 32 and 48–53 are on appeal,2 and can be found in the Claims Appendix of the Appeal Brief. Claim 20 is representative of the claims on appeal, and reads as follows: 20. A method for treating hepatopathy comprising administering to a mammal a polypeptide derivative consisting of an amino acid sequence selected from the amino acid sequences of SEQ ID NOS: 1 to 16, 19 to 22, or combinations thereof, wherein the second or third amino acid residue from the amino-terminus of said amino acid sequence comprises a serine or a group represented by the formula (2): wherein R3 represents -T2-P2-Q2 or P2-Q2, wherein T2 represents methylene; P2 represents -CO-O-; and Q2 represents an optionally substituted C1-20 alkyl group, 2 Appellants acknowledge that claims 26 and 31 are pending but presently withdrawn from consideration. (App. Br. 3.) Appeal 2013-006829 Application 10/554,875 3 and wherein said polypeptide derivative has growth hormone secretagogue receptor binding and elevating intracellular calcium ion concentration activities, or a pharmacologically acceptable salt thereof, and further wherein said polypeptide promotes hepatic regeneration and/or recovery of hepatic function. (App. Br. Claims Appendix.) Appellants request review of the Examiner’s rejection of claims 20, 27–30, 32, and 48–53 under 35 U.S.C. § 103(a) over Bednarek3 and/or Kangawa4 in view of Matsumoto5, Tacke-I,6 Skakkebræk 7,8and Wonke.9 As Appellants do not argue the claims separately, we focus our analysis on claim 20, and claims 27–30, 32 and 48–53 stand or fall with that claim. 37 C.F.R. § 41.37 (c)(1)(iv). The Examiner takes the position that ghrelin “is known in the art to induce GH [growth hormone], and GH is known to increase IGF-1 [(insulin- like growth factor-1)], which is beneficial to those in need of treatment for 3 Bednarek, WO 01/92292 A2, published Dec. 6, 2001. 4 Kangawa et al., US 7,385,026 B1, issued June 10, 2008. 5 Matsumoto et al., Structure-Activity Relationship of Ghrelin: Pharmacological Study of Ghrelin Peptides, 287 Biochem. and Biophys. Res. Comm. 142–146 (2001). 6 Tacke et al, Ghrelin is a parameter of catabolism in patients with chronic liver disease, Hepatology 530A (October 2002)(hereinafter “Tacke-I”). 7 Skakkebræk et al., US 5,492,891, issued Feb. 20, 1996. 8 We note that the prosecution history refers to the Skakkebræk patent as “Anderson.” (See App. Br. 6 and Ans. 4.) We will refer to the reference as “Skakkebræk.” 9 Wonke et al, New Approaches to the Management of Hepatitis and Endocrine Disorders in Cooley's Anemia, 850 Annals New York Academy of Sciences 232–241 (1998). Appeal 2013-006829 Application 10/554,875 4 liver diseases (hepatopathy).” (Ans. 21.) The Examiner finds that Bednarek and Kangawa each teach the claimed ghrelin analogs (see Ans. 7). Kangawa “teach the Ghrelin peptides instantly claimed as a potent ligand for the growth hormone (GH) secretagogue receptor in vitro and in vivo, Kangawa . . . does not teach the use of Ghrelin for the treatment of hepatopathy.” (Ans. 7.) The Examiner relies on the other references to establish a nexus between Ghrelin and IGF-1 [levels], and this was demonstrated in both mouse and, more importantly, [in] humans suffering from hepatitis (a form of hepatopathy). . . . There is more than a reasonable expectation of success and ample motivation to administer Ghrelin to increase GH, which in turn, increases IGF-1 which is beneficial to those patients with liver diseases (hepatopathy). (Ans. 21.) Appellants contend that the Examiner has not established a prima facie case (see App. Br. 6–10), that there would be no reasonable expectation of success (see App. Br. 10–12), that Tacke-II10 teaches away from the use of ghrelin in treating hepatopathy (see App. Br. 12), and that the Examiner did not consider the Hayashi’s Declaration (see App. Br. 12). The issue is: Does the preponderance of evidence of record support the Examiner’s conclusion that the combination of references renders the claimed treatment method obvious? Findings of Fact We adopt the Examiner’s findings and analysis concerning the scope and content of the prior art. The following facts are repeated for reference convenience. 10 Frank Tacke et al., Ghrelin in chronic liver disease, 38 J. Hepatology 447–454 (2003). Appeal 2013-006829 Application 10/554,875 5 FF1. Bednarek teaches “truncated ghrelin analogs active at the GHS receptor. Ghrelin is a naturally occurring modified peptide. The analogs can bind to the GHS [(growth hormone secretagogue)] receptor and, preferably, bring about signal transduction.” (Bednarek3: 6–8.) The structure of human ghrelin is as follows: (Id. at 3.) FF2. Bednarek teaches “[g]hrelin analogs can be administered to a subject” including humans. (Bednarek 5: 23.) Bednarek teaches administering an effective amount of the ghrelin analog to subjects for “achieving a beneficial effect.” (Id. at 28: 6–8 (claim 15).) In addition, Bednarek teaches “[a] method for stimulating growth hormone secretion comprising the step of administering to a subject an effective amount of” ghrelin analog. (Id. at 29: 1–3 (claim 17).) FF3. Kangawa teaches a “peptide-type compound which induces secretion of growth hormone provides a peptide-type compound which induces secretion of growth hormone and which has the activity of increasing the intracellular calcium ion concentration.” (Kangawa, Abstract.) Kangawa teaches SEQ ID NO: 3 which is identified as an “[a]mino acid sequence for human endogenous peptides of growth hormone secretagogue.” (Id. at col. 93.) FF4. Matsumoto teaches the minimal structural requirements that maintains ghrelin activity (see Matsumoto Table 1) and also teaches the production of ghrelin analogs. “To compare the effect of bonding Appeal 2013-006829 Application 10/554,875 6 structures on ghrelin activity, we altered the ester bond between octanoic acid and the Ser3 side chain to a more chemically stable thioether and ether.” (Id. at 144, see also Table 2.) FF5. Matsumoto teaches the administration of the ghrelin and ghrelin analogs to subjects, in this case rat, and monitors the secretion of growth hormone. “The level or GH in plasma, stimulated by the intravenous injection of compound 23 (5 µg/head, iv), is equivalent to that produced by treatment with native rat ghrelin (5 µg/head, iv)” (Matsumoto 144, see also Fig. 1.) FF6. Tacke-I teaches that [g]hrelin was significantly elevated and IGF-1 reduced in CLD [chronic liver disease] patients compared with healthy controls. IGF-1 levels inversely correlate with Child's classification. . . . [However,] ghrelin levels did not correlate with liver function. . . . Our results suggest a central role of ghrelin in the pathophysiology of metabolic disturbances in patients with end- stage cirrhosis. Further studies should evaluate ghrelin as a prognostic parameter and as a potential treatment option. (Tacke-I.) FF7. Skakkebræk teaches the administration of human growth hormone to patients with chronic liver disease. (Skakkebræk, Abstract.) [I]n patients with liver cirrhosis the concentration of IGF-1 in the blood is very low, while GH, which stimulates the synthesis and release of IGF-1 from the liver, is present in a very high concentration. Therefore it seems that GH is present in relative excess, however an excess that cannot be used and which consequently is excreted in the urine. . . . it is possible by administration of GH to the already existing surplus to increase the also above mentioned very low IGF-1 concentration considerably. (Id. at 2: 29–44; see also 3: 4–25.) Appeal 2013-006829 Application 10/554,875 7 FF8. Wonke discloses the administration of “rhGH (0.1 unit/kg body weight/day s.c for four days) followed by measurements of IGF1, and insulin-like growth factor and their binding protein (IGFBP3) levels in the serum.” (Wonke 237.) Principle of Law “Obviousness does not require absolute predictability of success . . . all that is required is a reasonable expectation of success.”’ In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009) (citing In re O’Farrell, 853 F.2d 894, 903- 904 (Fed. Cir. 1988)). Analysis The Examiner finds, and Appellants do not contest, that Bednarek and/or Kangawa teach the claimed ghrelin analogs. (See App. Br. 7; Ans. 7; see FF1 and FF2.) Appellants, however, contend that the secondary references “do not remedy the deficiencies of either Bednarek and/or Kangawa because none of these secondary references specifically teaches or suggests administering ghrelin for the purposes of a treating hepatopathy, much less provide a reasonable expectation of success that such administration would be successful even if one of ordinary skill in the art had effected the proposed combination.” (App. Br. 7.) After considering the evidence and the arguments, we conclude the evidence favors the Examiner’s conclusion of obviousness. Accordingly, we adopt the Examiner’s reasoning (see Grounds of Rejection, Ans. 5–10), and agree that the Examiner properly found Appellants’ arguments unpersuasive (see Response to Argument, Ans. 10–22). We address Appellants’ arguments below. Appeal 2013-006829 Application 10/554,875 8 We are not persuaded by Appellants’ contention that the Examiner has not presented a prima facie case of obviousness based on the combination of the disclosed references (see App. Br. 6–10). Bednarek and Kangawa each teach the claimed ghrelin analogs (FF1 and FF2). In addition, Bednarek teaches that these analogs are administered to subjects for the purpose of achieving a beneficial effect (FF2). In other words, Bednarek instructs the administration of ghrelin analogs. Although, Bednarek does not disclose what condition or patient population should be treated with the ghrelin analogs, the reference does disclose that these analogs will stimulate growth hormone secretion (FF2). Matsumoto teaches the administration of ghrelin peptides to rats and observes the increase of plasma growth hormone levels (FF4 and FF5; see also Ans. 7–8). Skakkebræk teaches the administration of growth hormone to patients with chronic liver disease in order to increase the low IGF-1 levels in this patient population (FF7). Wonke teaches the administration of growth hormone and tracking IGF-1 levels in patients (FF8; see Ans. 9 (“the administrating of GH correlates to serum IGF-I levels are a measure of the level of resistance upon administration of GH as a treatment, demonstrating a connection between GH and IGF-1”)). Tacke-I teaches that although ghrelin levels do not correlate with liver function, the reference never the less suggests that further studies should be conducted to evaluate the use of ghrelin in treatment options (FF6). The claims are directed to treating hepatopathy, i.e., any disease of the liver, by administering of ghrelin analogs having the recited structure as disclosed in claim 20. There appears to be no dispute that the structures taught in Bednarek and Kangawa each meet the limitations the claimed Appeal 2013-006829 Application 10/554,875 9 ghrelin analogs (FF1 and FF3). Additionally, Bednarek also teaches administration of these ghrelin analogs to patients in order to stimulate a beneficial effect or to stimulate growth hormone secretion (FF2). The art suggests administering growth hormone to a patient population that has chronic liver disease, for the purpose of increasing the IGF-1 levels produced by the liver (see FF7 and FF8). Skakkebræk teaches that it would be beneficial to increase GH in patients with chronic liver disease, even though that patient population already has high GH levels in the blood (FF7). Skakkebræk explains that the administration of GH increases the available GH in the patient and allows for an increase the production of IGF-1 from the liver (FF7). Thus, the art suggests that in patients with chronic liver disease it would be beneficial to increase the levels of GH even further in order to increase IGF-1 production from the liver. The art teaches that increasing GH levels in the plasma can also be achieved by administering ghrelin and ghrelin analogs (FF5, see also FF2). We agree with the Examiner’s conclusion that it would have been obvious to administer ghrelin or ghrelin analogs to patient with chronic liver disease in order to increase the GH level in the plasma and thereby increase IGF-1 production from the liver (Ans. 9–10) as suggested by the teachings of Skakkebræk and Matsumoto. The limitation that the “polypeptide promotes hepatic regeneration and/or recovery of hepatic function” is a property that is associated with the structure of the ghrelin analog compound. “Newly discovered results of known processes directed to the same purpose are not patentable because such results are inherent.” Bristol-Myers Squibb Co. v. Ben Venue Labs., Appeal 2013-006829 Application 10/554,875 10 Inc., 246 F.3d 1368, 1376 (Fed. Cir. 2001). The combination of Bednarek and Matsumoto suggests that administration of ghrelin analogs to patients necessarily results in increasing growth hormone levels in plasma (see FF1, FF2, FF4, and FF5). Here, the art suggests that increasing in GH levels would also inherently increase IGF-1 levels (see FF2, FF3, FF5, and FF7). Appellants contend that there is no reasonable expectation of success in combining the teachings of the references. Specifically, Appellants contend that the teachings of Tacke-I and Tacke-II “demonstrating a lack of reasonable expectation of success.” (App. Br. 11.) We are not persuaded by Appellants’ contention that there is no expectation of success that increasing growth hormone levels using ghrelin in a subject would not also result an increase in IGF-1 production. Tacke-II teaches that “[g]hrelin showed significant but relatively weak correlation with various parameters in patients with CLD [chronic liver disease].” (Tacke-II, 450; see also FF6.) Tacke-II discloses that Child C. cirrhosis shows increased serum ghrelin concentrations. (Tacke-II, 450.) As recognized by the Examiner “[i]n both Tacke I and Tacke II, a lack of correlation between liver function and GH levels are admitted, but benefits are still envisioned and stated despite an unproven assumption (hypothesis) that GH would not increase IGF-1.” (Ans. 12.) Furthermore, Tacke-II suggests that “ghrelin could potentially counteract these challenges in Child C, cirrhosis by its various metabolic function besides GH release, like induction of hyperglycemia, modulation of energy balance, stimulation of appetite and food intake . . . . Given the wide-spread presence of GH secretagogue binding sites in numerous human tissues . . . , probably not all of the peripheral ghrelin effects have been discovered yet.” (Tacke-II, 450.) Appeal 2013-006829 Application 10/554,875 11 In other words, Tacke-II says that even if we do not know the actual mechanism of action for ghrelin in a patient with liver disease it would still be beneficial to administer ghrelin because there are numerous ghrelin binding sites throughout the body. Appellants contend that Tacke-II teaches away from the use of ghrelin in treating hepatopathy (see App. Br. 12). Specifically, Appellants contend that “one of ordinary skill in the art, reading Tacke[-]I and [Tacke-]II in their entireties, would conclude that these references direct the skilled person to consider targeting ghrelin for treatment-not to use ghrelin as a therapeutic agent.” (Reply Br. 4.) We are not persuaded by Appellants’ contention that the references would suggest targeting ghrelin as the therapeutic rather than using ghrelin as a therapeutic agent. Even though both Tacke-I and Tacke-II state the ghrelin levels are not correlated with liver function, both articles still suggest ghrelin as a potential therapeutic. (See Ans. 13.) Tacke-II discloses that “[s]erum ghrelin levels were significantly elevated in Child C liver cirrhosis compared with CLD patients. . . . In contrast, IGF-1 levels significantly decreased with every stage of cirrhosis according to Child’s criteria.” (Tacke-II, 448–449.) Just because ghrelin levels are high does not mean that the ordinary artisan would not be motivated in increase the levels ghrelin even further in order to direct a downstream effect. Here, the teachings of Skakkebræk are informative because they suggest that it would still be beneficial to increase GH in patients with chronic liver disease, a population that already has high GH in the blood, in order to make sufficient GH available to the liver in order to increase the production of IGF-1 from the liver (FF7). We are not persuaded by Appellants’ contention that a Appeal 2013-006829 Application 10/554,875 12 disclosure of high ghrelin level in patients with liver disease would teach away from using ghrelin as a therapeutic agent, especially since Tacke-I and more importantly Tacke-II teaches that not all “peripheral ghrelin effects have been discovered yet.” (Tacke-II, 451.) We agree with the Examiner conclusion that the references do not teach away from the combination (see Ans. 10–15.) Appellants contend that the Examiner did not consider the Hayashi's Declaration (see App. Br. 12.) “The treatment of hepatopathy operates through a GH-independent pathway” (Reply Br. 6, citing Hayashi Declaration; see also App. Br. 13–14.) We are not persuaded by Appellants contention that the Examiner did not consider the Hayashi Declaration. The Hayashi Declaration attempts to establish that ghrelin acts by a pathway that is independent of growth hormone. (Hayashi Declaration 10 (“effects of ghrelin on DMN-induced hepatopathy model are exerted by GH-independent actions of ghrelin”).) As explained by the Examiner that “[d]espite the apparent finding in the Declaration in dwarf mice, a finding that GH is not involved in the pathway for Dwarf mice, cannot negate what is found in humans. The finding that it can work in a genetically odd mouse line, does not render the findings of Ghrelin in humans, and [furthermore,] contradicts what Appellants have already asserted in the patents.” (Ans. 19–20 (emphasis omitted).) We agree with the Examiner’s position that teaching the mechanism of action of ghrelin is not persuasive to overcome the obviousness rejection that is based on the combination of references. To confirm something that was already suggested in the art – in this case that not all peripheral effects of ghrelin have been discovered yet (Tacke-II, 451) – is not inventive. “Scientific Appeal 2013-006829 Application 10/554,875 13 confirmation of what was already believed to be true may be a valuable contribution, but it does not give rise to a patentable invention.” Pharma Stem Therpeutic, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (2007) While Appellants do present arguments directed to evidence that the administration of ghrelin “cannot sustain levels of GH secretion necessary to elicit IGF-1 production” (Reply Br. 7, citing Exhibits A–E), we note that absent a showing of good cause, the Board is not required to address arguments in the Reply Brief that could have been presented in the principal Brief and lack opportunity for an informative response by the Examiner. See Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (“informative”). (“Properly interpreted, the Rules do not require the Board to take up a belated argument that has not been addressed by the Examiner, absent a showing of good cause.”). Additionally, we note that Appellants contend that Office Action of Dec. 16, 2001 contains a new rejection and, therefore, the Final Rejection was made prematurely (App. Br. 14). We direct the Appellants’ attention to MPEP § 1201, which states: The line of demarcation between appealable matters for the Board and petitionable matters for the Director of the U.S. Patent and Trademark Office (Director) should be carefully observed. The Board will not ordinarily hear a question that should be decided by the Director on petition, and the Director will not ordinarily entertain a petition where the question presented is a matter appealable to the Board. (MPEP § 1201, 9th ed.) In the present case, Appellants have not filed a petition to resolve the Examiner’s premature holding of finality. Any question as to prematurity of a Final Rejection should be raised, if at all, while the application is still Appeal 2013-006829 Application 10/554,875 14 pending before the primary Examiner. It is reviewable by petition under 37 C.F.R. § 1.181 and thus not within the jurisdiction of the Board. We conclude that the evidence cited by the Examiner supports a prima facie case of obviousness with respect to claim 20, and Appellants have not provided sufficient rebuttal evidence or secondary considerations that outweighs the evidence supporting the prima facie case. As Appellants do not argue the claims separately, claims 27–30, 32, and 48–53 fall with claim 20. 37 C.F.R. § 41.37 (c)(1)(iv). SUMMARY We affirm the rejection of claim 20 under 35 U.S.C. § 103(a) over Bednarek and/or Kangawa in view of Matsumoto, Tacke, Skakkebræk, and Wonke. Claims 27–30, 32 and 48–53 fall with claim 20. 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 Copy with citationCopy as parenthetical citation