Ex Parte Talalay et al

Patent Trial and Appeal BoardNov 26, 2018

14358712 (P.T.A.B. Nov. 26, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 14/358,712 05/15/2014 128643 7590 11/26/2018 Cermak Nakajima & McGowan LLP 127 S. Peyton Street, Suite 210 Alexandria, VA 22314 FIRST NAMED INVENTOR Paul Talalay 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. 134-010 4579 EXAMINER THOMAS, TIMOTHY P ART UNIT PAPER NUMBER 1611 MAIL DATE DELIVERY MODE 11/26/2018 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 Exparte PAUL TALALAYand YUSUKE USHIDA Appeal 2017-011419 1 Application 14/358,712 Technology Center 1600 Before RICHARD M. LEBOVITZ, ULRIKE W. JENKS, and RACHEL H. TOWNSEND, Administrative Patent Judges. LEBOVITZ, Administrative Patent Judge. DECISION ON APPEAL This appeal involves claims directed to methods of enhancing the enzymatic activity of acetaldehyde dehydrogenase. The Examiner rejected the claims under 35 U.S.C. Â§ 103 as obvious and under 35 U.S.C. Â§ 112 as indefinite. Appellants appeal the Examiner's determination that the claims are unpatentable. We have jurisdiction under 35 U.S.C. Â§ 6(b). We affirm. 1 The Appeal Brief (entered Mar. 13, 2017, "Appeal Br.") lists The Johns Hopkins as the real party in interest. The Appeal Brief states that the application is exclusively licensed to Brassica Protection Products LLC. Appeal 2017-011419 Application 14/358,712 STATEMENT OF THE CASE Claims 6, 8, 12, 19-22, and 29 stand rejected by the Examiner as follows: Claims 6, 8, 12, 19-22, and 29 under pre-AIA 35 U.S.C. Â§ 112, second paragraph or 35 U.S.C. Â§ 112(b) as indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention. Non-Final Office Action (Oct. 12, 2016, "Non-Final Act.") 4. Claims 6, 8, 12, 19-22, and 29 under pre-AIA 35 U.S.C. Â§ 102(b) as anticipated by or, in the alternative, under pre-AIA 35 U.S.C. Â§ 103(a) as obvious in view Monika Okulicz et al., In Vivo Metabolic and Antioxidative Effects of Sulphoraphane Derived From Broccoli in Water- and Ethanol- Drinking Rats, 60(3) POL. J. FOOD NUTR. SCI. 289-94 (2010) ("Okulicz") as evidenced by EVAN'S AWESOMEA/B TOOLS, Two-SAMPLE T-TEST, http://www.evanmiller.org/ab-testing/t-test.html (last visited Oct. 11, 2016). Non-Final Act. 7. Claim 21, the only independent claim on appeal, reads as follows (indentations added for clarity): 21. A method comprising administering to a subject a composition comprising a compound selected from the group consisting of an isothiocyanate (ITC), a glucosinolate, sulforaphane, erucin, iberin, benzyl-ITC, phenethyl-ITC, propyl-ITC, hexyl-ITC, 4RB-ITC (4-rhamno benzyl-ITC), withaferin A, TP-225, celastrol, tricyclic (cyano enones)[,] TBE-31, bis(benzylidenes), HBB-2, HBB-4, a flavonoid, BNP (Beta naptho flavonoid,) 2 Appeal 2017-011419 Application 14/358,712 pinostrobin, tectochrisin, kaempferide, a stilbenoid, resveratrol, a sesquiterpene, and zerumbone in an amount sufficient to enhance the enzymatic activity of one or more acetaldehyde dehydrogenase in the subject and thereby inhibit the increase in blood acetaldehyde levels associated with consumption of alcohol, and wherein the composition is administered to the subject prior to consumption of alcohol. The Examiner requested that Appellants elect a compound species for examination purposes. Appellants' elected sulforaphane, which is the only compound under review in this Decision. Non-Final Act. 2. REJECTION UNDERÂ§ 112 The Examiner rejected the claims as indefinite in the recitation of "in an amount sufficient to enhance the enzymatic activity of one or more acetaldehyde dehydrogenase in the subject and thereby inhibit the increase in blood acetaldehyde levels associated with the consumption of alcohol." The Examiner stated it is not clear "what amounts achieve the function recited." Non-Final Act. 4. Under 35 U.S.C. Â§ 112, second paragraph, or 35 U.S.C. Â§ 112(b) a patent must "conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention." Â§ 112(b) requires the claims "to be cast in clear-as opposed to ambiguous, vague, indefinite-terms." In re Packard, 751 F.3d 1307, 1313 (Fed. Cir. 2014). The rationale for requiring such "reasonable precision" in claim language is because "[i]t is the claims that notify the public of what is within the protections of the patent, and what is not." Id. 3 Appeal 2017-011419 Application 14/358,712 In this case, we agree with Appellants that one of ordinary skill in the art would understand that any amount of compound which achieved the claimed response would fall within the scope of the claim. Similar language has been found to be definite underÂ§ 112, second paragraph, where it was concluded that a person of ordinary skill in the art could determine the specific amounts without undue experimentation. Geneva Pharms. v. GlaxoSmithKline PLC, 349 F.3d 1373, 1383-84 (Fed. Cir. 2003) ("'effective amount' is a common and generally acceptable term for pharmaceutical claims and is not ambiguous or indefinite, provided that a person of ordinary skill in the art could determine the specific amounts without undue experimentation."). Thus, as long as the amounts can be determined without undue experimentation, the claim is not indefinite. Example 14 of the Specification (Spec. ,r,r 201-203) provides an experimental protocol in which the inventors determined a specific dosage of compound that in mice inhibited the increase in blood acetaldehyde levels associated with the consumption of alcohol as required by claim 21. This example provides explicit guidance on how to determine values that fall within the scope of the claim. For the foregoing reason, we reverse the rejection of claims 6, 8, 12, 19-22, and 29 under pre-AIA 35 U.S.C. Â§ 112, second paragraph or 35 U.S.C. Â§ 112(b). REJECTION BASED ON OKULICZ Claim 21 is directed to a method of administering a compound to a subject, where the compound is selected from a list of compounds which includes the elected sulforaphane ("SF"). The compound is administered in 4 Appeal 2017-011419 Application 14/358,712 an amount which is "sufficient to enhance the enzymatic activity of one or more acetaldehyde dehydrogenase in the subject" and "thereby inhibit the increase in blood acetaldehyde levels associated with consumption of alcohol." Thus, administration of the compound in the claimed sufficient amounts necessarily results ("thereby") in inhibiting the increase in blood acetaldehyde levels. As explained in the Specification, ethanol is metabolized to acetaldehyde "which is mutagenic and carcinogenic, and is responsible for the unpleasant symptoms of heavy alcohol consumption and health damage." Spec. ,r 4. The Specification teaches that acetaldehyde is metabolized to non-toxic acetate by acetaldehyde dehydrogenases ("Aldh"). Id. However, the Specification teaches that, in certain populations of humans, acetaldehyde dehydrogenases are polymorphic and mutated which can lead to less or no activity, making "such persons ... highly sensitive to the consumption of alcohol" and its subsequent damage. Id. To address this problem, the Specification discloses a list of compounds which increase the activity of acetaldehyde dehydrogenases. Id. ,r 26 (The Specification identifies the compounds as "phase 2 inducers," but does not explain the meaning of the term. Id. ,r,r 11, 18). Although the Specification describes using the compounds to address alcohol toxicity in humans, the claims are not so limited, but rather comprise administering the listed compounds to any "subject," including humans and experimental animals. The Examiner rejected the claims as anticipated by Okulicz. Okulicz describes administering sulforaphane (SF) derived from broccoli to ethanol- drinking rats. Okulicz 289 (Abstract). The Examiner found that male Wistar rats, who were provided a 10% ethanol solution (an "alcohol") as the 5 Appeal 2017-011419 Application 14/358,712 sole drinking fluid, were administered a dosage of 1.2 mg of SF ( calculated by the Examiner) for two weeks while drinking the ethanol solution. Non- Final Act. 8. The Examiner further found that the examples in the Specification administered 0.89 mg (5 Âµmol) and 3.5 mg (20 Âµmol) of SF to mice (mg calculations also made by the Examiner). Id. The Examiner found that the lower dosage of 0.89 mg (5 Âµmol) up-regulated Aldh2 (a specific species of the Aldh enzyme) in the liver, which was statistically different from the control with no SF. Id. at 9--10. The Examiner found that since Aldh2 activity is enhanced by the dosage of0.89 mg of SF, the claimed mechanism through which SF and other "phase 2" inducers exert their action ("sufficient to enhance the enzymatic activity of one or more acetaldehyde dehydrogenase in the subject"), one of ordinary skill in the art would have reasonably expected that such dosage would also "thereby inhibit the increase in blood acetaldehyde levels associated with consumption of alcohol" as recited in the claim. Id. at 11. The Examiner also found that since the rats were drinking ad libitum an ethanol solution as the sole fluid, the rats would have consumed the SF "'prior to consumption of alcohol"' as required by the claim, i.e., they would drink the ethanol solution after being administered SF since the solution was the only fluid available to them. Id. Because Okulicz' s administered dosage of 1.2 mg of SF is higher than the Specification dosage of 0.89 mg which elevated Aldh2 levels in mice, the Examiner found that one of ordinary skill in the art would have had reason to believe that the higher dosage of Okulicz would also elevate Aldh2 levels in the animals, and "thereby inhibit the increase in blood acetaldehyde 6 Appeal 2017-011419 Application 14/358,712 levels associated with consumption of alcohol," the necessary result of SF administration. Id. at 11. Appellants contend that at "no point" in the Specification do "the inventors suggest that administration of the low dose of sulforaphane," which they do not dispute is 0.89 mg, "inhibits the increase in blood acetaldehyde levels associated with alcohol consumption, as required by the present claims." Appeal Br. 8. Appellants argue that the only dosage shown to be sufficient to meet the limitations of the claims is the 20 Âµmol dosage, which they do not dispute is equivalent to a dosage of 3 .5 mg as calculated by the Examiner. Id. at 7. Appellants admit no other dosage other than 3.5 mg of SF was shown in the Specification to "inhibit the increase in blood acetaldehyde levels associated with consumption of alcohol" as required by claim 21. Id. Appellants state that it is "possible" that lower dosages would be effective, "but that is not the standard for inherency." Id. at 8. Rather, Appellants state that "the fact that a certain result may occur or be present in the prior art is not sufficient to establish the inherency of that result or characteristic. See, e.g., In re Rijckaert, 9 F.3d 1531, 1534 ... (Fed. Cir. 1993)." Id. Appellants also argue that increase in Aldh2 referenced by the Examiner was for the enzyme in the liver and that the "amount of enzyme sufficient to decrease blood acetaldehyde levels in response to alcohol consumption is based on the enzyme produced throughout the body of the animal, not merely in liver." Appeal Br. 9. For this reason, Appellants state "it is not safe to conclude that Aldh2 levels in liver are an adequate proxy for the measurement of blood acetaldehyde levels reported by the present inventors, and required by the claims." Id. 7 Appeal 2017-011419 Application 14/358,712 Appellants' arguments do not persuade us that the Examiner erred. It is well-established that merely recognizing something that was not known before is insufficient to render an old process again patentable. In re Cruciferous Sprout Litig., 301 F.3d 1343, 1351 (Fed. Cir. 2002); see also In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990); Perricone v. Medicis Pharm. Corp., 432 F.3d 1368, 1378-79 (Fed. Cir. 2005); In re Omeprazole Patent Litig., 483 F.3d 1364, 1373 (Fed. Cir. 2007). [A] prior art reference may anticipate when the claim limitation or limitations not expressly found in that reference are nonetheless inherent in it. . . . Inherency is not necessarily coterminous with the knowledge of those of ordinary skill in the art. Artisans of ordinary skill may not recognize the inherent characteristics or functioning of the prior art. MEHL/Biophile Int'! Corp. v. Milgraum, 192 F.3d 1362, 1365 (Fed. Cir. 1999). Thus, simply because Okulicz did not recognize that administering SF inhibited blood acetaldehyde level in the rats is insufficient to patentably distinguish it from the claimed subject matter. Appellants argue that because it is only "possible" that doses lower than 3.5 mg (20 Âµmol) would be effective, that the Examiner has not sufficiently established inherent anticipation. Appeal Br. 8. According to Appellants this is so because case law holds that the fact "that a certain result may occur or be present in the prior art is not sufficient to establish the inherency of that result or characteristic." Id. While it is true that inherency is not established by probabilities, "if the prior art necessarily functions in accordance with ... the claimed limitations, it anticipates." In re Cruciferous Sprout, 301 F .3d at 1349 ( quoting MEHL/Biophile Int 'l Corp. v. 8 Appeal 2017-011419 Application 14/358,712 Milgraum, 192 F.3d 1362, 1365 (Fed. Cir.I 999)). That is, an "invention is inherent and in the public domain if it is the 'natural result flowing from' the explicit disclosure of the prior art." Schering Corp. v. Geneva Pharms., Inc., 339 F.3d 1373, 1379 (Fed. Cir. 2003); see also In re Oelrich, 666 F.2d 578, 581 (CCPA 1981): If. .. the disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function, it seems to be well settled that the disclosure should be regarded as sufficient [to be inherent anticipation]. (quoting Hansgirg v. Kemmer, 102 F.2d 212,214 (1939)). We conclude here, that the Examiner had a "sound basis" for believing that the process carried out in the prior art necessarily produces the same result as claimed. In re Spada, 911 F.2d 705, 708 (Fed. Cir. 1990)). Thus, the Examiner properly established that "the disclosure [ of Okulicz] is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function." Oelrich, 666 F.2d at 581 ( quoting Hansgirg, I 02 F .2d at 214). In this case, the question is whether the Examiner's finding that 0.89 mg of SF elevated Aldh2 levels in the liver of mice was sufficient to establish a sound basis for finding that the higher dosage of SF used in Okulicz ( 1.2 mg) would do the same and meet the claim limitation of "an amount sufficient to enhance the enzymatic activity of one or more acetaldehyde dehydrogenase in the subject and thereby inhibit the increase in blood acetaldehyde levels associated with consumption of alcohol. Once a sound factual basis is established, the Examiner can properly shift the 9 Appeal 2017-011419 Application 14/358,712 burden to applicant to prove that the prior art process does not produce the same result as the claimed process. In re Best, 562 F.2d 1252 (CCPA 1977). Based on the reasoning provided by the Examiner, we find that the evidence was sufficient to shift the burden to Appellants to prove that the claim limitation is not met by Okulicz. The claims require "an amount [of the compound] sufficient to enhance the enzymatic activity of one or more acetaldehyde dehydrogenase in the subject" which "thereby inhibit the increase in blood acetaldehyde levels associated with consumption of alcohol." In other words, when the enzymatic activity is enhanced, the inhibition of blood acetaldehyde levels follows as a consequence. The claim does not require a degree of enzyme enhancement nor a degree of acetaldehyde level inhibition. Nor does the claim require reducing alcohol toxicity. The claim does not even require a human to be administered SF. The Specification states that increases in ALDH expression and/or enzymatic activity of ALDHs, "in liver and other organs enhance the metabolism of acetaldehyde and accelerate the elimination of acetaldehyde from the blood, such as after the consumption of ethanol." Spec. ,r 160. The Specification, in Figure 10, demonstrates that administration of 0. 89 mg of SF increase ALDH in liver. Based on the Specification's statement noted above regarding increases in ALDH expression in liver enhancing acetaldehyde metabolism and accelerating the elimination of acetaldedyhe in from the blood, one of ordinary skill in the art would reasonably expect that the increase in ALDH expression in the liver after the administration of 0. 89 10 Appeal 2017-011419 Application 14/358,712 mg of SF would necessarily enhance the metabolism of acetaldehyde and accelerate the elimination of acetaldehyde from the blood. The Specification further shows that the increase in aldehyde dehydrogenase levels induced by SF administration at 20 Âµmol ( or 3 .5 mg of SF) is followed by a reduction in blood acetaldehyde levels. Spec ,r,r 201- 203 (Example 14); Fig. 9. The fact that the Specification demonstrates this result using 20 Âµmol or 3.5 mg of SF (id.), however, does not limit the claims to this specific dosage or to the reduction amount demonstrated. See e.g., Bayer AG v. Biovail Corp., 279 F.3d 1340, 1348 (Fed. Cir. 2002) ("a court may not read into a claim a limitation from a preferred embodiment, if that limitation is not present in the claim itself.") Appellants have not adequately established that the Specification restricts the claims to this value. While Appellants argue that the Specification at "no point" indicates that the lower amount of SF, namely, 5 Âµmol or 0.89 mg, would meet the claim limitation (Appeal Br. 8), the Specification uses broad language throughout that indicates any effective amount that achieves the desired result is encompassed by invention, and does not indicate that the only effective amount is the single amount described in Example 14. Spec. ,r 102. And, as discussed above, the Specification demonstrates that 0.89 mg increases ALDH expression in liver, which the Specification also indicates would "enhance the metabolism of acetaldehyde and accelerate the elimination of acetaldehyde from the blood," Spec. ,r 160. Such an enhancement of metabolism of aldehyde and elimination of aldehyde from the blood would inhibit the increase in blood acetaldehyde levels associated with consumption of alcohol. The amount of SF utilized in Okulicz of 1.2 mg is even higher than 0.89 mg, and thus would be expected to increase 11 Appeal 2017-011419 Application 14/358,712 expression of ALDH in the liver as well, with the necessary result of enhancing the metabolism of acetaldehyde and accelerating the elimination of acetaldehyde from the blood. This a basic principle in pharmacology that as the dosage of a compound is increased it would be expected to result in an increase in the measured physiological or pharmacological response to the compound, i.e., a dose-response relationship. Thus, even if the 1.2 mg amount of SF used by Okulicz ( which is higher than the lowest amount in the Specification demonstrated to increase Aldh in the liver) does not reduce levels as much the 3.5 mg shown in Example 14, it would meet the claim limitation as long as some inhibition is accomplished. As explained above, the dose-response relationship between SF administration and the enhancement of Aldh activity/inhibition of acetaldehyde levels provides the factual basis for the Examiner finding that the Okulicz' s example in rats meets all the limitations of claim 21. Appellants also argue that the Examiner only pointed to elevation of Aldh2 levels in the liver, and this is not "an adequate proxy for the measurement of blood acetaldehyde levels" as required by the claims. Appeal Br. 9. This argument does not persuade us that the Examiner erred. The Specification and claims teach that SF enhances acetaldehyde dehydrogenase. Appellants have not provided evidence that an increase in liver activity would be insufficient to meet the claim limitations. In fact, original claim 28 only required enhanced expression in the liver. 2 2 "28. The method of any one of Claims 1, 2, 3 or 4, wherein expression of acetaldehyde dehydrogenase increases in the liver, the forestomach, the glandular stomach, the small intestine or a combination thereof." Spec. 58. 12 Appeal 2017-011419 Application 14/358,712 The Examiner performed a statistical analysis of the data in Figure 10 of the Specification to show that the 0.89 mg value is statistically different from the control. Final Act. 9--10. Appellants contend that the Examiner misinterpreted the data and that the values in the figure were normalized, making the t-test utilized by the Examiner unsuitable. Appeal Br. 8-9. This argument does not persuasively demonstrate an error. Appellants did not adequately identify a deficiency in the Examiner's statistical analysis, particularly why normalized values could not be subjected to at- test. Appellants also argue that "the conditions in the Okulicz study are so different from those in the Examples described in the present specification that it is not reasonable to compare them." Id. at 8. This argument is not persuasive. The principle question in this rejection is whether the Examiner had a sound factual basis to find that, when Okulicz administered 1.2 mg of SF to rats, the SF enhanced the activity of an acetaldehyde dehydrogenase and resulted in inhibiting the increase in blood acetaldehyde levels associated with alcohol consumption. This question was answered in the affirmative. While we agree there are differences in the two studies, Okulicz' s examples fall within the scope of claim 21. The rats in Okulicz ingested ethanol throughout the study, before and after SF administration. Okulicz 289, 290 ("Materials and Methods"). However, the claim does not exclude a subject from having consumed alcohol prior to ingesting SF as they did in Okulicz. See Appeal Br. 8. If Appellants are attempting to exclude this condition from the claim because the SF would not work to enhance the enzyme levels and reduce the increase in acetaldehyde levels, then it would appear that the claims are not enabled 13 Appeal 2017-011419 Application 14/358,712 for their full scope as required by 35 U.S.C. Â§ 112. Nevertheless, Appellants have not provided scientific basis to doubt that administering 1.2 mg of SF to ethanol-drinking rats would not would meet all the limitations of claim 21. As explained above, such dosage is above the dosage of O. 89 mg shown in the Specification to increase acetaldehyde dehydrogenase levels in the liver and, thus, would be reasonably expected by one of ordinary skill in the art to have inhibited acetaldehyde levels in the blood, as did the higher dosages described in the Specification. Appellants have not shown nor explained why differences between Okulicz's study and Example 14 in the Specification would lead to a result different result from what is claimed. An argument made by counsel in a brief does not substitute for evidence lacking in the record. Estee Lauder Inc. v. L 'Orea!, S.A., 129 F.3d 588, 595 (Fed. Cir. 1997). For the foregoing reasons, the anticipation rejection of claim 21 is affirmed. Dependent claims 6, 8, 12, 19, 20, 22, and 29 were not argued separately and, therefore, fall with claim 21. See 3 7 C.F .R. Â§ 4I.37(c)(l)(iv). Because the obviousness rejection of the claims is based on the same facts, we affirm it, as well. TIME PERIOD No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. Â§ 1.136(a)(l )(iv). AFFIRMED 14