Ichiro Hisatome et al.

Patent Trials and Appeals Board

Sep 6, 2019

13439936 - (D) (P.T.A.B. Sep. 6, 2019)

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. 13/439,936 04/05/2012 Ichiro HISATOME HISA3001D/TL 8981 23364 7590 09/06/2019 BACON & THOMAS, PLLC 625 SLATERS LANE FOURTH FLOOR ALEXANDRIA, VA 22314-1176 EXAMINER MAIER, LEIGH C ART UNIT PAPER NUMBER 1623 NOTIFICATION DATE DELIVERY MODE 09/06/2019 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): MAIL@BACONTHOMAS.COM PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte ICHIRO HISATOME, YASUAKI SHIRAYOSHI, HIROYUKI TAKEYA, RYOTA TESHIMA, and YASUNARI MIKI ____________ Appeal 2018-004733 Application 13/439,936 Technology Center 1600 ____________ Before JEFFREY N. FREDMAN, JOHN G. NEW, and JAMIE WISZ, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1,2 under 35 U.S.C. § 134(a) involving claims to a method for treating acidic urine, and for identifying effects of the treatment. The Examiner rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. 1 Appellants identify the Real Parties in Interest as Tottori University and Marine Products Kimuraya Co., Ltd. (see App. Br. 2). 2 We have considered and herein refer to the Specification of Apr. 5, 2012 (“Spec.”); Final Office Action of July 3, 2017 (“Final Act.”); Appeal Brief of Nov. 29, 2017 (“App. Br.”); Examiner’s Answer of Feb. 7, 2018 (“Ans.”); and Reply Brief of Apr. 4, 2018 (“Reply Br.”). Appeal 2018-004733 Application 13/439,936 2 Statement of the Case Background Acidic urine is associated with patients having metabolic syndromes including hypertension, hyperlithuria, hyperlipemia, disorders of glucose metabolism, obesity as well as kidney function disorders including urinary caleulus and proteinuria (see Spec. 2:10-15). Prior art treatments of acidic urine include “alkalinizing agent such as a sodium/potassium citrate preparation, and sodium bicarbonate” (Spec. 2:16-18). The Specification teaches “a food/drink for improving an acidic urine, comprising fucoidan or a fucoidan-containing material as an active ingredient, characterized in that a urinal pH is persistently increased” (Spec. 3:20-23). The Claims Claims 1, 3, 5, 13, and 15-19 are on appeal. Independent claim 1 is representative and reads as follows: 1. A method for treating acidic urine, and for identifying effects of the treatment, comprising: (a) administering to a patient in need thereof an effective amount of fucoidan or a fucoidan-containing material, (b) determining the pH increase by comparing the pH of the patient’s urine before breakfast on the day before initiation of treatment with the pH of the patient’s urine before breakfast 7 days from initiation of treatment; (c) identifying: (i) whether the treatment results in an increase in the pH before breakfast of the patient’s urine of 0.2 or more, and (ii) whether the treatment results in a patient’s urine pH of 6.0 or higher but not exceeding 6.6; and (d) identifying that the treatment is effective when: (i) the treatment results in an increase in the pH before breakfast of the patient’s urine of 0.2 or more, and Appeal 2018-004733 Application 13/439,936 3 (ii) the treatment results in a patient’s urine pH of 6.0 or higher but not exceeding 6.6, wherein prior to treatment said patient has an acidic urine; wherein the fucoidan or fucoidan-containing material is orally administered; wherein the amount of fucoidan administered is 600 mg or more per day; wherein the fucoidan-containing material is a seaweed or an extract thereof; wherein the seaweed is a brown algae; wherein the brown algae is mozuku or wakame; and wherein prior to treatment the pH of the patient’s urine is lower than 6.0. The Rejection3 The Examiner has rejected claims 1, 3, 5, 13, and 15-19 under 35 U.S.C. § 103(a) as obvious over Veena,4 Khan,5 Coe,6 and Ogawa7 (Final Act. 3-6). The Examiner finds Veena teaches “chemical alterations of urine in experimental hyperoxaluria and a biochemical approach to its treatment using fucoidan” (Final Act. 4). The Examiner finds Veena studied four groups of rats and teaches “control rats . . . had a urinary pH of 7.53” while 3 The Examiner withdrew the rejection under 35 U.S.C. § 112, first paragraph (see Ans. 3). 4 Veena et al., Physico-chemical alterations of urine in experimental hyperoxaluria: a biochemical approach with fucoidan, 59 J. PHARMACY AND PHARMACOLOGY 419-427 (2007). 5 Khan, Animal models of kidney stone formation: an analysis, 15 WORLD J. UROL. 236-43 (1997). 6 Coe et al., Kidney stone disease, 115, J. CLIN. INVESTIGATION 2598-608 (2005). 7 Ogawa et al., Impact of sodium-potassium citrate therapy on the circadian rhythm of urinary uric acid and urate saturation in normal individuals, 39 ACT UROL. JAPAN 883-90 (1993). Appeal 2018-004733 Application 13/439,936 4 “fucoidan treated rats had a urinary pH of 7.71, and rats treated with both EG and fucoidan had a urinary pH of 7.68” (id.). The Examiner finds Veena “notes that low urinary pH is indicative of an environment conducive to stone formation” (id.). The Examiner finds Khan evidences that hyperoxaluria “is also a known model of subsequent kidney stone formation” (id.). The Examiner acknowledges that Veena “does not teach oral administration of 600 mg or more of fucoidan per day or the recited pH- measuring protocol” (Final Act. 4). The Examiner finds Coe teaches “that kidney stones form because urine pH is abnormally low. The reference teaches that the prevention and dissolution of stones depends on the ability to increase urine pH above 6.0” (Final Act. 4). The Examiner finds Coe teaches because “stones are a consequence of low urine pH, this gives the practitioner a specific benchmark for optimizing the benefits of therapeutics in prevention/treatment of stones” (id. at 5). The Examiner also finds that Ogawa teaches the “urinary concentration of uric acid fluctuates during the day with the highest concentration in the early morning” and Ogawa “further discusses the treatment goal of eliminating early morning uric acid saturation peaks” (id.). The Examiner finds it obvious “to administer fucoidan to a subject having low pH urine to treat/prevent the formation of kidney stones” and “to account for the known uric acid concentration fluctuations in order to devise the appropriate timing for dosage and pH measurement through routine experimentation” (Final Act. 5). Appeal 2018-004733 Application 13/439,936 5 The issue with respect to this rejection is: (i) Does a preponderance of the evidence of record support the Examiner’s conclusion that specific treatment protocol of the claims would have been obvious over the cited prior art? (ii) If so, have Appellants presented evidence of secondary considerations, that when weighed with the evidence of obviousness, is sufficient to support a conclusion of non-obviousness? Findings of Fact (“FF”) 1. Khan teaches “[a]nimal models . . . are employed in efforts to understand all aspects of the pathogenesis, including the anatomical and physiological role of kidneys and renal tubules. Rats are the animals most commonly used for the study of nephrolithiasis” (Khan 236, col. 2). 2. Khan teaches “[n]ephrolithiasis is defined as the formation of solid phases in urinary passages” and may be “associated with primary hyperoxaluria” (Khan 237, col 2 to 238, col. 1). 3. Veena teaches “[n]ephrolithiasis is a real problem for public health and its increased prevalence and peak of frequency among men between the third and sixth decade explains its high socio-economic cost” (Veena 419). 4. Veena teaches “this study was initiated to explore the effect of fucoidan on urinary stone-forming constituents/modulators” (Veena 420, col. 1). Appeal 2018-004733 Application 13/439,936 6 5. Table 1 of Veena is reproduced below: “The rats were randomly divided into four groups consisting of six rats each as shown in Table 1. In the ethylene glycol (EG) model of hyperoxaluria induction, different concentrations are established” (Veena 420, col. 1). 6. Table 2 of Veena is reproduced below: “Table 2 delineates the changes in the body weight, kidney weight and urinary pH” (Veena 421, col. 1). 7. Veena teaches “a low urinary pH was observed in this study. The low urinary pH was also indicative of an environment conducive to stone formation” (Veena 423, col. 2). 8. Veena teaches: Our findings imply that by decreasing supersaturation, fucoidan could modulate the urinary crystallization process. Further, fucoidan was able to abort the stone retention. Alteration in ECM, which is also an important determinant favouring stone retention, was normalized with fucoidan administration. These findings highlight the protective role of fucoidan in experimental hyperoxaluria. (Veena 426, col. 2). Appeal 2018-004733 Application 13/439,936 7 9. Coe teaches “[h]igh urine pH as a main risk factor for CaP stones” (Coe 2604, col. 1; emphasis omitted). Coe teaches that “[p]revention and even dissolution of UA stones depends upon the ability to increase urine pH above 6.0” (Coe 2605, col. 1). 10. Coe teaches although “potassium citrate salts are effective, they, along with ESWL, may promote the formation of CaP stones, the prevalence of which continues to rise with time. Possibly this means that the use of citrates requires special attention to avoid increasing CaP SS excessively via high urine pH” (Coe 2606, col. 2). 11. Ogawa teaches the “highest urinary uric acid concentration has been reported to occur between 5:00 and 8:00 am in healthy individuals, while the urinary pH remains low throughout the night and early morning and usually shows twin peaks in the morning and evening” (Ogawa 883, col. 1-2). 12. Ogawa teaches “prevention and treatment for uric acid stones should be directed towards elimination of the urinary uric acid saturation peaks with a minimal increase in the sodium urate and ammonium urate levels” (Ogawa 888, col. 1). 13. Ogawa teaches “this study conducted in normal individuals suggests that the early morning is the critical period for uric acid crystallization and should be targeted in any attempt to reduce the urinary uric acid saturation” (Ogawa 888, col. 2). Principles of Law “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious,” the answer depends on “whether the improvement is more than the predictable use of prior art elements according Appeal 2018-004733 Application 13/439,936 8 to their established functions.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007). Analysis We agree with the Examiner that the combination of Veena, Khan, Coe, and Ogawa renders the claims obvious (Final Act. 3-6; FF 1-13) and we adopt the Examiner’s position as our own. We consider Appellants’ arguments below. Prima facie obviousness Claim 1 Appellants contend Veena does not teach step (b) of claim 1 and “fails to specify in which time zone the urine was alkalized, and fails to show the alkalization before breakfast, which is a technical feature of the presently claimed invention” (App. Br. 13). Appellants further contend Ogawa teaching “that the highest concentration of uric acid is in the morning at most suggests to one of ordinary skill in the art that the collection at the end of the 28 days in Veena should be a morning collection” (id.). Appellants contend that Coe “does not teach oral administration of 600 mg or ore of fucoidan per day or the recited pH-measuring protocol. Yet this aspect of the claim invention is said to be obvious from routine experimentation, without reasoned factual support” (id. at 14). Appellants also contend “[m]echanisms of acidification of urine are completely different between Veena’s model and acidic urea in a human being” (App. Br. 15). Appellants contend that “the conclusion in the rejection that it would be within the scope of the artisan to optimize the dosage of the fucoidan to achieve the necessary urinary pH to accomplish the method, is specifically traversed” (id.). Appeal 2018-004733 Application 13/439,936 9 We do not find these arguments persuasive for two reasons. First, Appellants argue against the references individually rather than the combination of the prior art as a whole. “Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references . . . . [The reference] must be read, not in isolation, but for what it fairly teaches in combination with the prior art as a whole.” In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). Second, we agree with the Examiner that the specific dose and times for administration would be obvious to routinely optimize. See, e.g., Ariosa Diagnostics, Inc. v. Sequenom, Inc., 809 F.3d 1282, 1293 (Fed. Cir. 2015) (“[T]he application of the natural law was merely routine optimization of drug dosage to maximize therapeutic effect.”) As discussed by the Examiner, the combination of references renders claim 1 obvious because Khan informs the ordinary artisan that animal models are used for the study of nephrolithiasis or kidney stones (FF 1, 2). Veena recognizes that nephrolithiasis is a human health concern (FF 3) and uses an animal model to study “the effect of fucoidan on urinary stone- forming” (FF 4). Veena used an animal model in which ethylene glycol treatment induces nephrolithiasis (FF 5). Veena teaches that induction of nephrolithiasis with ethylene glycol reduces urine pH to 5.1 (FF 6) and that the “low urinary pH was also indicative of an environment conducive to stone formation” (FF 7). Veena demonstrates that in the same model, treatment with fucoidan increases urinary pH levels to those of control rats that do not have the nephrolithiasis condition (FF 6). Veena concludes that “fucoidan could modulate the urinary crystallization process. Further, fucoidan was able to abort the stone retention” (FF 8). Appeal 2018-004733 Application 13/439,936 10 Coe also teaches that the ordinary artisan would recognize high urinary pH as a risk factor for kidney stones and that “[p]revention and even dissolution of UA stones depends upon the ability to increase urine pH above 6.0” (FF 9). Lastly, Ogawa teaches the circadian rhythm of urine pH levels, and explains that the highest levels occur between 5 and 8 am (FF 11). Ogawa specifically “suggests that the early morning is the critical period for uric acid crystallization and should be targeted in any attempt to reduce the urinary uric acid saturation” (FF 13; emphasis added). Thus, an ordinary artisan interested in treating nephrolithiasis in humans would have reasonably utilized the effective fucoidan treatment of Veena (FF 3-8) to increase the “urine pH above 6.0” (FF 9)8 based on the pH in the early morning before breakfast (FF 13) because Ogawa suggests targeting this time point. We agree with the Examiner that the ordinary artisan would have found it obvious to test the urinary pH to determine if there was a concern of low pH prior to starting treatment (FF 9) and ensure efficacy just as Veena tested the urinary pH after treatment (FF 6). The specific timepoints at which such testing would occur are optimizable variables. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955) As to the specific 600 mg dose recited in claim 1, Veena treated the animals with a fucoidan dose of 5 mg/kg (FF 5), commensurate to a 600 mg 8 While we agree with Appellants that Coe’s pKa value of ~6.7 is not a pH value (see Coe 2604, col. 2, first paragraph; App. Br. 14), Coe also teaches “to avoid increasing CaP [supersaturation] excessively via high urine pH” (FF 10), reasonably suggesting to optimize urine pH to avoid unduly high levels, as well as levels below pH 6.0 (FF 9). Appeal 2018-004733 Application 13/439,936 11 dose in a 120 kg human. In addition, “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272, 276 (CCPA 1980). We agree with the Examiner that dosing amounts are well known to be results effective variables, and “[t]he optimum dose for each patient, as always, must be set by the physician in charge of the case, taking into account the patient’s size, other medications which the patient requires, severity of the disorder and all of the other circumstances of the patient.” Eli Lilly and Co. v. Actavis Elizabeth LLC, 435 Fed. Appx. 917, 922 (Fed. Cir. 2011) (citing U.S. Patent 5,658,590). We are also not persuaded by Appellants’ contention that “the rejection is clearly based on the hindsight reconstruction of Applicants’ invention which is improper even under KSR” (App. Br. 14). While we are aware that hindsight bias may plague determinations of obviousness, Graham v. John Deere Co., 383 U.S. 1, 36 (1966), we are also mindful that the Supreme Court has clearly stated that the “combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR, 550 U.S. at 416. Here, Coe teaches acidic urine is a risk factor for nephrolithiasis (FF 9) and Veena teaches that acidic urine may be treated with fucoidan (FF 4-7) and Ogawa specifically suggests treatment in the early morning (FF 13). Thus, fucoidan was a known compound for improving acidic urine used at known times for the same reason as suggested by Appellants, with no hindsight required for the treatment. Claim 5 Appellants state that they traverse the Examiner’s finding that “the increase in pH range lasting at least 24 hours would appear to be another Appeal 2018-004733 Application 13/439,936 12 advantage which would follow naturally from following the suggestions of the prior art cannot be the basis for patentability when the differences would be otherwise be obvious” (App. Br. 16). We find this argument unpersuasive because Appellants provide no factual evidence of error by the Examiner. Veena teaches repeated daily administration of fucoidan to rats and reports increased pH (FF 6). The Examiner reasonably finds that administration of the effective fucoidan dose inherently results in the 24 hour increase in urinary pH required by claim 5 in the absence of contrary evidence. “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., Inc., 246 F.3d 1368, 1376 (Fed. Cir. 2001). Claim 16 Appellants reiterate the contentions addressed above regarding claim 1 and we find them unpersuasive for the same reasons given above. Secondary considerations Appellants state that: There are five declarations under 37 CFR 1 .132 of record which have not be discussed in the outstanding final rejection but which provide evidence of the level of skill of one of ordinary skill in the art to which the invention pertains and are related to the factual issues on appeal even though the specific reference discussed therein may not be part of the final rejection. There is also evidence of unexpected results therein. (App. Br. 20). We have reviewed each of the five declarations by Dr. Hisatome. The first declaration addresses “the Office Action dated July 24, 2012” Appeal 2018-004733 Application 13/439,936 13 (Hisatome Decl. I9 ¶ 16). However, that office action relied upon a prior art reference not currently relied upon for obviousness and therefore the Declaration is not relevant to the current rejection. The second declaration addresses the definiteness of “before breakfast” and Veena in combination with different prior art for obviousness (see Hisatome Decl. II10 ¶¶ 15-21). To the extent that there is a question of whether it would have been obvious to measure urine pH in the morning, Ogawa directly suggests the early morning is the critical period of concern (FF 13). We therefore find this declaration unpersuasive of unobviousness as applied to the current obviousness rejection that includes Ogawa. The third declaration asserts unexpected results of the 600 mg/day dose of fucoidan relative to 200 mg/day or 400 mg/day dosing, stating “in 200 mg/day group (n=4) and in 400 mg/day group (n=4), any significant increase of urinal pH was not found at all. On the other hand, as shown in working examples and drawings of the present application, a significant increase of urinal pH was found in 600 mg/day group” (Hisatome Decl. III11 ¶ 17). The Specification teaches that mozuku (mozuku about 60 g + sanbaizu (mixture of vinegar, soy sauce and sugar) about 60 g) was eaten (taken once a day). One time mozuku contained about 600 mg of fucoidan in terms of dry weight). . . . As compared with before eating of mozuku, a urinal pH was significantly shifted to alkaline after eating of mozuku, and a shift width was about 0.2 pH or more. (Spec. 16:1-15). 9 Declaration of Dr. Ichiro Hisatome, dated Sept. 14, 2012. 10 Declaration of Dr. Ichiro Hisatome, dated Jan. 13, 2015. 11 Declaration of Dr. Ichiro Hisatome, dated Apr. 23, 2015. Appeal 2018-004733 Application 13/439,936 14 We find this evidence unpersuasive of unexpected results for several reasons. First, without error bars or statistical information, the change in pH shown in figure 2 of the Specification does not appear substantially different than the change shown for the 400 mg/day fucoidan treatment amounts disclosed in the Hisatome Decl. III ¶ 16. Moreover, given the change in pH from 5.10±0.77 to 7.71±0.51 demonstrated by Table 2 of Veena after administration of 5 mg/kg of fucoidan (FF 6), an increase in urinary pH of at least 0.2 pH units is the expected result, not an unexpected result, of fucoidan treatment. See In re Skoner, 517 F.2d 947, 950 (CCPA 1975) (“Expected beneficial results are evidence of obviousness of a claimed invention. Just as unexpected beneficial results are evidence of unobviousness.”) Second, the evidence is not commensurate in scope with the claim, which is not limited to 600 mg of fucoidan, but encompasses any greater amount based on the “600 mg or more per day” language. Third, the evidence was not compared to the closest prior art of Veena. See In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (“[W]hen unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art.”). Veena discloses fucoidan treatment with 5 mg/kg of body weight. The Hisatome Decl. III does not disclose the body weight of the participants, but treatment of any patients weighing 120 kg or greater would, if administered fucoidan at the dose disclosed by Veena, receive the identical dose as claimed. Appellants do not demonstrate any unexpected results relative to patients receiving such a dose. The fourth declaration states the “remarkable effect of the claimed invention to make a patient’s urinal pH to 6.0 or higher is demonstrated in Appeal 2018-004733 Application 13/439,936 15 working examples of the specification of the present application” (Hisatome Decl. IV12 ¶ 20). We find this argument unpersuasive because, as already discussed, Veena demonstrates a significant increase in urinal pH upon administration of fucoidan, rendering this an expected result (FF 6). The fifth declaration states Veena “is ineligible as a reference cited in the non-final Office Action” because “it cannot be concluded that the increase in urinary pH is caused by fucoidan ingestion” (Hisatome Decl. V13 ¶¶ 19-20). We find this argument unpersuasive because Veena’s data shows that rats subjected to ethylene glycol model of hyperoxaluria induction had reduced urinal pH, but that when those same rats were treated with fucoidan, their pH levels rose significantly (FF 6). Because fucoidan was the dependent variable in Veena’s experiment, and Veena demonstrates increase pH upon fucoidan administration, Veena is reasonably understood as showing that fucoidan administration increases urinary pH. See In re Am. Acad. of Science Tech Center, 367 F.3d 1359, 1370 (Fed. Cir. 2004) (“[T]he Board is entitled to give such weight to declarations as it deems appropriate.”) 12 Declaration of Dr. Ichiro Hisatome, dated Aug. 21, 2015. 13 Declaration of Dr. Ichiro Hisatome, dated Mar. 31, 2016. Appeal 2018-004733 Application 13/439,936 16 Conclusion of Law (i) A preponderance of the evidence of record supports the Examiner’s conclusion that specific treatment protocol of the claims would have been obvious over the cited prior art. (ii) Appellants have not presented evidence of secondary considerations, that when weighed with the evidence of obviousness, is sufficient to support a conclusion of non-obviousness. SUMMARY We affirm the rejection of claims 1, 3, 5, 13, and 15-19 under 35 U.S.C. § 103(a) as obvious over Veena, Khan, Coe, and Ogawa. 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