Kowa Company, Ltd.Download PDFPatent Trials and Appeals BoardMay 15, 20202019001405 (P.T.A.B. May. 15, 2020) 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. 14/162,181 01/23/2014 Haruki Shibata P23320US01 4155 38834 7590 05/15/2020 WESTERMAN, HATTORI, DANIELS & ADRIAN, LLP 8500 LEESBURG PIKE SUITE 7500 TYSONS, VA 22182 EXAMINER STRONG, TORI ART UNIT PAPER NUMBER 1629 NOTIFICATION DATE DELIVERY MODE 05/15/2020 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): patentmail@whda.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte HARUKI SHIBATA, YASUNOBU YOSHINAKA, and KIMIYUKI SHIBUYA __________ Appeal 2019-001405 Application1 14/162,181 Technology Center 1600 __________ Before DONALD E. ADAMS, ERIC B. GRIMES, and RACHEL H. TOWNSEND, Administrative Patent Judges. TOWNSEND, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to a method of treating non-alcoholic steatohepatitis, which have been rejected as obvious and for obviousness-type double patenting. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. STATEMENT OF THE CASE Appellant’s Specification explains that non-alcoholic fatty liver disease (“NAFLD”) is a fatty hepatic disorder. (Spec. ¶ 3.) NAFLD is 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the real party in interest as KOWA COMPANY, LTD. (Appeal Br. 2.) Appeal 2019-001405 Application 14/162,181 2 classified into steatosis and nonalcoholic steatohepatitis (NASH). (Id.) “The therapy of NASH is, in principle, an improvement in lifestyle based on the diet and exercise therapy for lifestyle-related diseases such as obesity, diabetes, dyslipidemia, and hypertension.” (Id. ¶ 5.) Because it is “difficult to improve the lifestyle,” drug therapy is provided that targets, among other things, “lipid metabolism abnormality.” (Id.) “[T]he number of the patients with NASH is expected to increase, and it is desired to establish a method of treating NASH.” (Id.) Appellant’s invention is directed at such a method. Claims 1 and 2 are on appeal.2 Claim 1 is representative and reads as follows: 1. A method of treating non-alcoholic steatohepatitis comprising: administering a drug comprising an effective amount of 2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4- bis(methylthio)-6-methyl-3-pyridyl]acetamide, an acid-addition salt thereof, or a solvate of the same to a patient in need thereof. (Appeal Br. 17.) The prior art relied upon by the Examiner is: Name Reference Date Shibuya US 6,969,711 B2 Nov. 29, 2005 K. Tolman and A. Dalpiaz, Treatment of non-alcoholic fatty liver disease, 3(6) Therapeutics and Clinical Risk Management 1153–63 (2007) R. Vuppalanchi and N. Chalasani, Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: Selected practical issues in their evaluation and management, 49(1) Hepatology 306–17 (2009) 2 Claims 3–14 remain pending but are withdrawn from consideration on appeal. Appeal 2019-001405 Application 14/162,181 3 The following grounds of rejection by the Examiner are before us on review: Claims 1 and 2 under 35 U.S.C. § 103(a) as unpatentable over Shibuya, Vuppalanchi, and Tolman. Claims 1 and 2 on the ground of non-statutory obviousness-type double patenting as being unpatentable over claims 1–7 of Shibuya and Vuppalanchi. DISCUSSION The Examiner finds that the claims as “broadly and reasonably interpreted” include any treatment of the claimed disease, which includes “co-morbidities that are part of the pathogenesis of the disease.” (Final Action 5.) Shibuya teaches the claimed compound, and that it is in a class of compounds that are “inhibitors of acyl coenzyme A cholesterol acyltransferase (ACAT).” (Final Action 6.) The Examiner further notes that Shibuya teaches that ACAT inhibitors cause the following cascade of events: inhibiting cholesterol ester production in the liver and suppressing secretion of VLDL (very low density lipoprotein) from the liver. (Id.at 6–7; Ans. 7.) The Examiner explains that this suppression “implicitly teaches a reduction in fats that [are] secreted from the liver.” (Final Action 8.) The Examiner further explains that the inhibition aspect “leads to free cholesterol readily being taken up by high-density lipoprotein (HDL) and metabolized in the liver (col. 2, l. 45–49).” (Id.) In sum, the Examiner finds that Shibuya teaches the claimed compound results in “cholesterol reduction in the blood and VLDL suppression from the liver.” (Id.; see also Ans. 12 (Shibuya Appeal 2019-001405 Application 14/162,181 4 teaches the claimed compounds provides “overall reduction of cholesterol in the blood through prevention of esterification and promoting metabolism.”).) Thus, the Examiner concludes that “Shibuya provides guidance to the compounds having an effect outside of the liver ultimately having an antihyperlipemic effect, which appears to be ACAT-1 activity.” (Id.) The Examiner recognizes that Shibuya does not teach treating NASH with the claimed compound. (Final Action 7.) However, the Examiner concludes that Vuppalanchi and Tolman provide motivation for treating NASH with the claimed compound with a reasonable expectation of success. (Id. at 8.) In particular, the Examiner finds that both references “teach weight loss has improved the progression of the disease.” (Final Action 6.) In particular, explains the Examiner, Vuppalanchi teaches that NAFLD is associated with obesity and hyperlipidemia and that treatment involves reducing fat or reducing risk factors, such as weight loss for obese patients. (Final Action 7.) The Examiner explains that NAFLD “is the disease that encompasses and leads to NASH; where it can be simple steatosis (NAFLD) or steatohepatitis (NASH).” (Ans. 10.) The Examiner finds that Tolman teaches treatment of NAFLD and explicitly teaches that “obesity promotes progression of the disease (p. 1154, col. 1, para. 6)” and that “the only categories of therapeutic intervention include[] targeting steatosis, fat in the liver, or the pathogenesis of progression (p. 1156, col. 1 para. 4).” (Final Action 7; see also Ans. 11 (Tolman “teaches that dyslipidemia is in the pathogenesis of the disease.”).) The Examiner concludes that Tolman establishes “that treating obesity and dyslipidemia is a standard method for treating NAFLD.” (Final Action 7.) Appeal 2019-001405 Application 14/162,181 5 In light of the foregoing, the Examiner concludes that one of ordinary skill in the art would have had a reasonable expectation of success in treating NASH with the claimed compound disclosed in Shibuya; stating: Vuppalanchi and Tolman provide a rationale for targeting hyperlipemia for treating NAFLD which leads to NASH and further an example of treating NASH. The prior art provides a rationale for administering antihyperlipemic agent to an overall patient population with hyperlipemia, as well as the subgenus patient population of NASH. (Ans. 11; see also Ans. 14 (“The conclusions drawn are based on the nexus that Shibuya teaches the claimed compound to have antihyperlipemic activity and Vuppalanchi and Tolman teaching the pathogenic association hyperlipidemia with NASH and exemplifying treatment of NASH with an antihyperlipemic agent.”).) We agree with the Examiner’s findings regarding Shibuya teaching antihyperlipemic effects of the claimed compound in the blood and conclusion of obviousness. Appellant asserts that NASH involves the abnormal retention of lipids in the liver and the inventors unexpectedly found that the claimed compound “reduces the levels of cholesterol and triglyceride in the liver while significantly inhibiting TNF-α expression and reduces the level of macrophages in the liver i.e., treats NASH” and that Shibuya’s teaching of “a suppression of secretion in VLDL from the liver to the blood should not be interpreted as a reduction of fat in the liver.” (Reply Br. 2; Appeal Br. 6– 7 (“since cholesterol in the blood decreases due to suppression of VLDL secretion from the liver, increase of liver fat may be expected but decrease thereof should generally never be readable from Shibuya.”).) Appellant’s arguments that the Examiner’s rejection is in error stem in large Appeal 2019-001405 Application 14/162,181 6 part from a difference in interpretation of the claimed method. Appellant argues that “[t]he Examiner is narrowly construing the present invention as reducing cholesterol, or that a reduction of cholesterol is a treatment of NASH” but NASH “is broader than cholesterol.” (Reply Br. 2.) We agree with the Examiner’s claim construction, and do not find it to be a narrow construction. Rather, the Examiner’s construction is properly a broad construction consistent with Appellant’s Specification. In re Hyatt, 211 F.3d 1367, 1372 (Fed. Cir. 2000) (“[D]uring examination proceedings, claims are given their broadest reasonable interpretation consistent with the specification.”) Appellant’s Specification states: The therapy of NASH is, in principle, an improvement in lifestyle based on the diet and exercise therapy for lifestyle- related diseases such as obesity, diabetes, dyslipidemia, and hypertension. However, it is actually difficult to improve the lifestyle and thus drug therapy targeting insulin resistance, oxidative stress, lipid metabolism abnormality, or hypertension which is considered to be an important factor for the progression of NASH is provided. (Spec. ¶ 5.) In other words, Appellant’s Specification teaches broadly that treatment of NASH includes drug therapy that targets lipid metabolism abnormality. As the Examiner noted, Appellant’s claim “does not require that treatment be focused on reducing fat in the liver only.” (Final Action 5.) Thus, we conclude that Appellant’s claimed method of treatment includes administering an effective amount of the claimed compound that targets abnormal lipid metabolism of a patient, and is not limited to achieving a reduction of fat in the liver. And for this reason, we disagree with Appellant’s argument that a method for treating NASH by targeting a comorbidity (which the Examiner indicates to be treating hyperlipemia, (see, e.g., Ans. 9–10)) “is not an actual treatment option for NASH” (Appeal Br. Appeal 2019-001405 Application 14/162,181 7 8). Additionally, for this reason, we do not find Appellant’s arguments that Shibuya does not describe or suggest a change in the accumulated cholesterol in the hepatocytes due to inhibition of ACAT activity (Appeal Br. 11) or the reduction of cholesterol and triglyceride in the liver (Reply Br. 2–3) to be persuasive of non-obviousness. That Shibuya does not teach these results in the liver does not negate the teaching of antihyperlipemic effects that Shibuya does teach, which will be discussed below. Tolman teaches that NAFLD “refers to a broad spectrum of liver disease which varies from bland steatosis (NAFLD) to steatohepatitis (NASH) to progressive fibrosis and, ultimately, cirrhosis with portal hypertension.” (Tolman 1153; see also Vuppalanchi 3 (“The NAFLD can be categorized into simple steatosis and steatohepatitis (NASH).”).) We agree with the Examiner (1) that Vuppalanchi “explicit[ly] teach[es] that hyperlipidemia is associated with NAFLD” (Ans. 10–11 (citing Vuppalanchi 2)); and (2) that Tolman indicates that dyslipidemia is one of the most common causes of NAFLD (Ans. 11 (citing Tolman 1154)). Furthermore, Tolman teaches that “[t]he presence of insulin resistance and/or obesity permits/promotes disease progression” (Tolman 1154) and that “[t]reatment falls into two categories: targeting either the steatosis or the pathogenesis of progression” (id. at 1156). Tolman further states that “[i]n general, factors that decrease steatosis consist of weight loss or pharmacologic therapy directed at insulin resistance or dyslipidemia.” (Id. (emphasis added); see also id. at 1160 (“Patients with insulin resistance can be treated with thiazolidinediones while patients with dyslipidemia can be treated with lipid lowering agents.”).) Vuppalanchi is consistent with Tolman’s teaching that treatment includes targeting comorbidity. Vuppalanchi states: Appeal 2019-001405 Application 14/162,181 8 [i]t is generally recommended that overweight and obese patients with NAFLD lose 7-10% of their body weight by dietary modification and exercise over the course of 6-12 months. This is based on short-term studies showing that gradual weight loss of this magnitude improves insulin resistance and hepatic histology. Vuppalanchi 5. Appellant does not dispute that “obesity and dyslipidemia is characterized by cholesterol and fats in the blood, not just focused in the liver.” (Final Action 5.) Furthermore, Appellant does not dispute that Shibuya teaches or suggests the claimed compound suppresses VLDL secretion from the liver to blood which results in a decrease in cholesterol in the blood (Appeal Br. 7) or that inhibition of production of cholesterol ester by the ACAT inhibitor leads to free cholesterol readily being taken up by high-density lipoprotein and being metabolized in the liver (Final Action 8, Ans.8). Instead, Appellant argues just that Shibuya does not teach a reduction of fat in the liver. (Appeal Br. 6; Reply Br. 3 (“Column 2, lines 45 to 49 of Shibuya . . . is referring only to the suppression of cholesterol accumulation at the focus site of atherosclerosis.”); id. at 4 (“The Examiner argues the effect of ACAT inhibitors on reducing fat in the liver is recognized in the ‘state of the art’ but has provided no such evidence to base said rational upon.”).)3 3 Appellant refers to two declarations by Shibuya, one submitted June 28, 2016 (the First Shibuya Declaration) and the other submitted January 31, 2017 (the Second Shibuya Declaration) that “explained that the Examiner’s interpretation of the Shibuya reference is incorrect.” (Appeal Br. 8.) However, these declarations do not contradict the Examiner’s interpretation. The First Shibuya Declaration states that “Shibuya is silent about ‘reducing fat in the liver.’” (See First Shibuya Declaration ¶ 5.) The Second Shibuya Appeal 2019-001405 Application 14/162,181 9 Appellant’s argument is not persuasive because the Examiner’s rejection does not rest on a conclusion that Shibuya teaches a reduction of fat in the liver. The Examiner explains that Shibuya teaches that the claimed compound results in a decrease in cholesterol in the blood as a result of stopping production of cholesterol ester in the liver due to ACAT inhibition, which in turn suppresses secretion of VLDL from liver into blood. (See, e.g., Ans. 7.) We understand the Examiner’s position to be that Shibuya teaches suppressing secretion of VLDL into the blood, which thus results in a reduction of lipids/cholesterol in the blood. (Ans. 8–10.) The Examiner indicates that Shibuya teaches an additional antihyperlipemic activity of ACAT inhibition “even outside the liver,” namely that the free cholesterol in cells not in the liver, produced by inhibiting esterification there, is removed from the cells by HDL and transmitted to the liver to be metabolized, and thus accumulation of cholesterol “at the focus site is expected.” (Id. at 8.) We agree with the Examiner that the claimed compounds is, thus, an “antihyperlipemic agent” causing an overall reduction of lipids and cholesterol (id. at 5, 9), regardless of the fact that Shibuya does not clearly teach anything about the claimed Declaration is similar in stating that Shibuya does not describe “the change in the accumulated cholesterol in the hepatocytes” or “to the change of in vivo liver cholesterol accumulation.” (Second Shibuya Declaration ¶ 7 (iv).) As discussed, however, that is not what the Examiner contends Shibuya teaches. Rather as even noted in the First Shibuya Declaration, the Examiner states that “Shibuya teaches the suppression of secretion of VLDL, which implicitly teaches a reduction in fats that is secreted from the liver.” (First Shibuya Declaration ¶ 4 (bold emphasis added).) Appeal 2019-001405 Application 14/162,181 10 compound’s effects in hepatocytes or in changing fat accumulation in the liver (Appeal Br. 8–11; Reply Br. 3–5). The Examiner states: The key take away is that Shibuya recognizes the antihyperlipemic activity of the compounds through the known pathways, particularly when Shibuya states (col.5, 1.5-9, emphasis added): "Those compo[u]nds of the present invention are particularly useful as antihyperlipemic agents having excellent cholesterol-lowering action in blood and also preventive and therapeutic agents for arteriosclerosis, and so on having an suppressing action to foaming of macrophage." Shibuya clearly illuminates the general antihyperlipemic activity of the compounds in conjunction with treating arteriosclerosis. (Ans. 9.) In light of the foregoing, we agree with the Examiner that one of ordinary skill in the art would have found it obvious to administer the compound taught by Shibuya in treating NASH with a reasonable expectation of success. Appellant argues that there can be no reasonable expectation of success because Tolman states: “There are no FDA approved pharmacological agents and, in fact, no FDA guidelines for such drugs despite the fact that NAFLD is the most common liver disease in the US. The treatment used to date are outlined in Table 3. Virtually all are compromised by small numbers and lack placebo control” (Emphasis Added). (Appeal Br. 12 (quoting Tolman 1156).) Appellant further points to the fact that Tolman suggests statins are promising agents for treatment but a study published after Tolman “explains that no significant effect in the treatment of NASH by statin monotherapy was demonstrated as a result of the double- Appeal 2019-001405 Application 14/162,181 11 blinded randomized placebo-controlled trial.” (Id. at 12–13.) We do not find this argument persuasive for the reasons stated by the Examiner. (Ans. 12–13.) FDA approval is not necessary to establish a reasonable expectation of success. “Only a reasonable expectation of success, not absolute predictability, is necessary for a conclusion of obviousness.” In re Longi, 759 F.2d 887, 897 (Fed. Cir. 1985). And the absence of FDA guidelines does not contravene the fact that Tolman “explicitly teaches that there are treatment[s] used that have demonstrated improvement.” (Ans. 13.) Regarding the reference offered by Appellant regarding statin monotherapy,4 the Examiner noted, and Appellant does not dispute in reply, that the statin in that reference was a different one than the one that Tolman indicates demonstrated improvement in a patient study. (Id.) Consequently, the information relied on by Appellant does not cast doubt on the reasonable expectation of success of the compound taught in Shibuya, a compound that is also not a statin, for use in treating NASH. In light of the foregoing, we affirm the Examiner’s rejection of claim 1 as being obvious over Shibuya, Vuppalanchi, and Tolman. Regarding claim 2, Appellant urges that unexpected results have been shown because Example 1 of the Specification illustrates that the claimed compound “exhibited a significant decrease in TC and TG in the liver (FIG. 2) and significant decreases in inflammatory cytokine TNF-a expression in the liver and macrophage CD11c (FIG. 3).” (Appeal Br. 15.) According to Appellant, “even if the dose of the compound was in a range that did not 4 We note that the reference submitted as Appendix III was not the Nelson reference to which Appellant referred. Appeal 2019-001405 Application 14/162,181 12 affect the plasma lipid, the compound still had a direct effect on the liver and reduced the levels of cholesterol and triglyceride in the liver.” (Id.) We do not find the evidence establishes non-obviousness, because the claim is not limited to a dose that has the exemplified effects. In other words, the evidence is not commensurate in scope with the claims. In re Dill, 604 F.2d 1356, 1361 (CCPA 1979) (“The evidence presented to rebut a prima facie case of obviousness must be commensurate in scope with the claims to which it pertains.”) Consequently, we also affirm the Examiner’s rejection of claim 2 as being obvious over Shibuya, Vuppalanchi, and Tolman. Obviousness-Type Double Patenting The Examiner relying on the same references set forth above finds the claimed invention obvious. In this rejection, however, the Examiner relies only on the claims of Shibuya that teach the claimed compound and claim 7 that recite a method for therapy of hyperlipemia, among other things, where an effective amount is administered as an ACAT inhibitor, an agent for inhibiting the transportation of intracellular cholesterol, an agent for lowering the cholesterol in blood or an agent for suppressing the storage of cholesterol in macrophage as fat droplets. (Final Action 11 (citing claim 7).) Appellant argues the rejection is in error for the same reasons as discussed with respect to the obviousness rejection. (Appeal Br. 15.) We agree with the Examiner’s rejection in light of claim 7 of Shibuya teaching the use of the claimed compound to achieve therapy of hyperlipemia and Vuppalanchi’s teaching pharmacologic therapy directed toward comorbidity such as dyslipidemia in treating NAFLD. (See Appeal 2019-001405 Application 14/162,181 13 Vuppalanchi 5–8 and Table 6.) As discussed above, we conclude that the claim does not require that the compound will have an effect on reducing fat in liver in order to have a reasonable expectation of success in treating NASH. Moreover, one need not know that such an effect would arise to have a reasonable expectation of success in treating NASH. A reasonable expectation of treating NASH arises from the teaching of claim 7 in Shibuya that hyperlipemia can be treated with the claimed compound and Vuppalanchi’s teaching suggesting treating atherosclerosis and dyslipidemia to treat NAFLD. Consequently, we affirm the Examiner’s rejection of claims 1–2 on the ground of non-statutory obviousness-type double patenting as being unpatentable over claims 1–7 of Shibuya and Vuppalanchi. Appeal 2019-001405 Application 14/162,181 14 DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 2 103 Shibuya, Vuppalanchi, Tolman 1, 2 1, 2 Obviousness-type Double Patenting: Shibuya, Vuppalanchi 1, 2 Overall Outcome 1, 2 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). See 37 C.F.R. § 1.136(a)(1)(iv). AFFIRMED Copy with citationCopy as parenthetical citation