Ex Parte Sharp et al

Patent Trials and Appeals BoardJun 26, 2019

13128800 - (D) (P.T.A.B. Jun. 26, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 13/128,800 11/18/2011 32425 7590 06/28/2019 NORTON ROSE FULBRIGHT US LLP 98 SAN JACINTO BOULEVARD SUITE 1100 AUSTIN, TX 78701-4255 FIRST NAMED INVENTOR Zelton Dave Sharp 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. UTSK.P0408US/l 000086950 3489 EXAMINER SIMMONS, CHRIS E ART UNIT PAPER NUMBER 1629 NOTIFICATION DATE DELIVERY MODE 06/28/2019 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): aoipdocket@nortonrosefulbright.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte ZEL TON DA VE SHARP, JOHN R. STRONG, VERONICA GALVAN, SALVA TORE ODDO, and HERBERT G. WHEELER1 Appeal 2018-008436 Application 13/128,800 Technology Center 1600 Before DONALD E. ADAMS, ERIC B. GRIMES, and RYAN H. FLAX, Administrative Patent Judges. GRIMES, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. Â§ 134(a) involving claims to a method of extending the lifespan of a mammal, which have been rejected as indefinite and obvious. We have jurisdiction under 35 U.S.C. Â§ 6(b ). We affirm. 1 Appellants identify the Real Parties in Interest as The Board of Regents of The University of Texas System and Southwest Research Institute. Br. 1. Appeal2018-008436 Application 13/128,800 STATEMENT OF THE CASE "[T]he invention relates to microcapsules that include an inhibitor of the mammalian target of rapamycin (mTOR), and methods of treating or preventing age-related diseases, disorders, and conditions in a subject using [the] microcapsules." Spec. 1. "The inhibitor of mTOR may be rapamycin." Id. at 4. The Specification states that "[ m ]icroencapsulation improves therapeutic efficacy compared to formulations that are not encapsulated." Id. at 2-3. The microcapsules can include a core that is encased in a coating. Id. at 3. In some embodiments, "the coating provides for delayed release of the inhibitor of mTOR and/or preferential release of the therapeutic agent in the intestinal tract of a subject (i.e., an enteric coating)," such as "Eudragit S 100, cellulose acetate phthalate (CAP), a methyl acrylate-methacrylic acid copolymer," etc. Id. The Specification states that, "[ f]or example, ... microencapsulated rapamycin fed late in life extends lifespan in genetically heterogenous [sic] mice." Id. at 2. "Prolongation of lifespan ... refers to a greater lifespan of the subject than the subject would otherwise live in the absence of the microcapsules." Id. at 7. "An estimate of the lifespan the subject would have otherwise lived in the absence of the microcapsules can be obtained, for example, from demographic studies, Social Security Administration Life Tables, and scientific literature concerning lifespan." Id. Claims 57, 62, 67----69, 73-79, 81, and 86-88 are on appeal. Claim 86 is representative and reads as follows: 86. A method for extending lifespan in a mammalian subject comprising administering to the subject an effective amount of a pharmaceutical or nutraceutical composition comprising 2 Appeal2018-008436 Application 13/128,800 microencapsulated rapamycin, wherein the rapamycin is encased in a coating that includes a water insoluble polymer, wherein the water insoluble polymer is a methyl methacrylate- methacrylic acid copolymer, and wherein the lifespan is extended to greater than the life expectancy of the mammalian subject. The claims stand rejected as follows: Claims 57, 62, 67----69, 73-79, 81, and 86-88 under 35 U.S.C. Â§ 112, second paragraph, as indefinite (Ans. 3) and Claims 57, 62, 67----69, 73-79, 81, and 86-88 under 35 U.S.C. Â§ I03(a) as obvious based on Sehgal, 2 Bedrosian, 3 Penhasi, 4 and Blagosklonny5 (Ans. 4). I The Examiner has rejected all of the claims on appeal on the basis that "the limitation, 'wherein the lifespan is extended to greater than the life expectancy of the mammalian subject' ... renders the claims indefinite because it is not controlled via a positive, pro-active step other than administering the claimed composition and, therefore, is indefinite for not being further limiting." Ans. 3. The Examiner also reasons that one cannot reasonably know the life expectancy of any given person with any true accuracy given that several methods may be chosen. There are various approaches to determining an individual's likely longevity with varying results .... Moreover, physicians do poorly at predicting life expectancy and tend to 2 Sehgal et al., US 5,066,493, iss. Nov. 19, 1991. 3 Bedrosian, US 2007/0185150 Al, pub. Aug. 9, 2007. 4 Penhasi, US 2006/0251720 Al, pub. Nov. 9, 2006. 5 Blagosklonny, WO 2008/022256 A2, pub. Feb. 21, 2008. 3 Appeal2018-008436 Application 13/128,800 underestimate how long patients have left to live .... Clearly, one of ordinary skill in the art is not apprised of the metes and bounds of the claimed invention. Id. The Examiner cites Shavelle6 and Leung7 in support of this position. Id. We agree with the Examiner that the claims are indefinite because it is unclear what is encompassed by "life expectancy." The Specification states that "[a]n estimate of the lifespan the subject would have otherwise lived in the absence of the microcapsules can be obtained, for example, from demographic studies, Social Security Administration Life Tables, and scientific literature concerning lifespan." Spec. 7. That statement, however, refers to the "lifespan" of a subject, not "life expectancy," and the terms apparently are not synonymous, since the claims state that "the lifespan is extended to greater than the life expectancy of the mammalian subject." Claim 86 ( emphasis added). Clearly, lifespan cannot be greater than life expectancy if the two terms mean the same thing. The Specification does not define the term "life expectancy." Appellants argue that the "wherein" clause of the claims "is supported throughout the specification," and cite pages 33-34 and Figure 1 as showing "an extension of lifespan of. . rapamycin-treated mice past the life expectancy of the mice." Br. 4. Appellants also argue that [ w ]hile there may be other methods to determining an individual's life expectancy, the current claims particularly point 6 Shavelle et al., Rating the Raters: Evaluating the Predictions from a Life Expectancy Rating Service, 41 J. INSUR. MED. 178-90 (2009). 7 Leung et al., Challenging the 10-year rule: The accuracy of patient life expectancy predictions by physicians in relation to prostrate cancer management, 6 CAN. UROL. Assoc. J. 367-73 (2012). 4 Appeal2018-008436 Application 13/128,800 out and distinctly claim "life expectancy of the mammalian subject". Accordingly, a general definition of "life expectancy", such as that defined by the Organization for Economic Co- operation and Development (OECD), suffices to define the metes and bounds of the currently claimed subject matter. Id. at 5. 8 These arguments, however, are inconsistent. The Specification, at pages 33-34, 9 discusses the "median and maximum life-span" of mice that were fed encapsulated rapamycin, compared to control mice. Spec. 33. The Specification states that, "mice fed rapamycin were longer lived than controls (P<0.0001) in both males and females .... Expressed as life expectancy at 600 days (the age of first exposure to rapamycin), the effect sizes were 28% for males and 38% for females." Id. The Specification's use of "life expectancy," therefore, refers to rapamycin-treated subjects compared to otherwise identical subjects that were not treated with rapamycin. The OECD definition that Appellants point to, on the other hand, refers to "life expectancy" in a much broader context. It states: "Life expectancy at birth and ages 40, 60, 65 and 80 is the average number of years that a person can be expected to live, assuming that age-specific mortality levels remain constant." Br., Exhibit A. The OECD definition thus does not refer to a certain cohort of subjects who are exposed to certain conditions, as compared to an otherwise identical cohort of subjects exposed to different conditions. Thus, the term "life expectancy" is apparently used 8 In their arguments regarding the Â§ 103 rejection, Appellants point to an OECD "glossary of statistical terms" that was submitted during prosecution. Br. 5---6. 9 The results shown graphically in Figure 1 are the same as those discussed at page 33 of the Specification. 5 Appeal2018-008436 Application 13/128,800 to mean two different things in the two sources of support cited by Appellants. In addition, even assuming the OECD definition is applicable, it is unclear how it would be applied to the claimed method, because it states that people have life expectancies at birth and at ages 40, 60, 65, and 80, which implies that people have different life expectancies at different ages. With respect to the claimed method, it is unclear whether the subject's "life expectancy" refers to their life expectancy at the time they were born, or their life expectancy based on their age when they were first administered rapamycin, or their life expectancy based on their age each time they are administered rapamycin, or something else. In short, the claim language does not make clear what effect is required in order for a method of administering rapamycin to fall within the scope of claim 86. Claims 57 and 67, the other independent claims, also include the language discussed above. Thus, all of the claims on appeal are indefinite for the reasons discussed above. We affirm the rejection of claims 57, 62, 67----69, 73-79, 81, and 86-88 under 35 U.S.C. Â§ 112, second paragraph. II The Examiner has rejected all of the claims on appeal as obvious based on Sehgal, Bedrosian, Penhasi, and Blagosklonny. The Examiner finds that "Sehgal teaches methods of using rapamycin ... to reduce the tumor size and prolong the survival time of mammal[s]." Ans. 5. "Sehgal specifically demonstrated that rapamycin inhibits growth of colon tumor and extended the lifespan of mice with colon tumors." Id. 6 Appeal2018-008436 Application 13/128,800 The Examiner finds that "Sehgal does not expressly teach microencapsulated rapamycin encased in methyl methacrylate-methacrylic acid copolymer," but "Bedrosian is directed to methods for treating cancer in a patient with rapamycin analogs," including rapamycin itself, and "[ o ]ral administration of the drug is of particular interest." Id. at 6. "Solid dosage forms are often preferred for oral administration and include ... tablet[s]." Id. "The tablet may further comprise a film-coat such as an enteric layer." Id. "The enteric layer comprises a methacrylic acid methyl methacrylate copolymer." Id. at 7. The Examiner also cites Penhasi as disclosing a methacrylic acid methyl methacrylate copolymer as an enteric coating. Id. The Examiner concludes that it would have been obvious to "treat[] colon cancer and prolong extend [sic] the life expectancy of a mammal with the cancer by administering rapamycin as disclosed by Sehgal by encapsulated nanoparticles of the rapamycin in an enteric coating to control the release of the rapamycin as suggested by Bedrosian." Id. The Examiner reasons that "[t]he 'extending lifespan' limitation is considered a function or property of the drug because when the drug is administered to a subject, the function of prolongation of the lifespan of the subject cannot be separated from the drug." Id. The Examiner also notes that "Blagosklonny states the following: ' ... rapamycin can be used in the methods of the invention to delay, prevent, or treat age-related diseases and prolong human life span by inhibiting aging."' Id. at 7-8. Finally, the Examiner finds that "Sehgal demonstrated that administration of rapamycin increased the lifespan of mice afflicted with several different cancer types, including colon cancer" and concludes that "it is clear that rapamycin was known for increasing the lifespan." Id. at 8. 7 Appeal2018-008436 Application 13/128,800 We agree with the Examiner that the claimed method would have been obvious to a person of ordinary skill in the art based on the cited references. Sehgal discloses that "rapamycin reduces tumor size in and prolongs the survival time of tumor bearing mammals." Sehgal 1 :43--45. Sehgal discloses that rapamycin can be administered in capsules or tablets. Id. at 1 :56-59. Sehgal determines survival time in reference to control (untreated) animals. 10 Bedrosian discloses "administration of an mTOR inhibitor to a patient in need thereof, especially to a cancer patient." Bedrosian ,r 1. Bedrosian states that "mTOR inhibitors include, among others, sirolimus (rapamycin)." Id. ,r 2. "Oral administration of the drug, e.g., in tablet or capsule form, is of particular interest." Id. ,r 12. "The tablet may further comprise a film-coat to control the release of the rapamycin analog." Id. ,r 38. "The film coating may also be an enteric layer comprising an enteric polymer, for delayed release of the rapamycin analog .... Suitable enteric polymers are well known to those of skill in the art (WO O 1/051031) and include, without limitation, methyl metacrylate [sic] polymers, methacrylic acid co-polymers," etc. Id. ,r 39. Enteric coatings include those made from "poly(methacrylic acid, methyl methacrylate) 1: 1." Penhasi ,r 62. Blagosklonny discloses "methods for treating or preventing an age- related disease, condition, or disorder comprising administering a therapeutically effective amount of an inhibitor of TOR to a patient in need thereof." Blagosklonny 5 :21-23. "In one embodiment of the invention, the 1Â° For example, Sehgal states that "T/C % = Median Survival Time (MST) in days of treated animals (T)/control animals (C) x 100." Sehgal 3:22-24. 8 Appeal2018-008436 Application 13/128,800 aging process is inhibited or retarded by administering a therapeutically effective amount of an inhibitor of the TOR pathway (a TOR inhibitor) to a patient. In this manner, cell aging, organism aging, or age-related diseases are treated or prevented." Id. at 12:27-30. "Direct inhibitors of TOR include rapamycin." Id. at 12:34. "Thus, rapamycin can be used in the methods of the invention to delay, prevent, or treat age-related diseases and prolong human life span by inhibit aging." Id. at 7:31-33. Based on these teachings, it would have been obvious to administer rapamycin to a mammalian subject such as a mouse (Sehgal) or a human patient (Bedrosian, Blagosklonny) in order to prolong the survival of a subject with cancer (as taught by Sehgal) or to inhibit the aging process, prevent organism aging, and prolong human life span (as taught by Blagosklonny). In addition, it would have been obvious to administer the rapamycin in a dosage form (e.g., a tablet 11) coated with a methyl methacrylate-methacrylic acid copolymer, because that copolymer is a known enteric polymer (Bedrosian, Penhasi) and Bedrosian expressly suggests using an enteric coating to allow "delayed release of the rapamycin analog." Bedrosian ,r 39. The cited references thus would have made obvious the method of claim 86. 11 Although claim 86 recites "microencapsulated" rapamycin, the Specification states that "microcapsules may be of any size .... For example, the maximum diameter of the microcapsule may be about ... 1. 0 cm or greater." Spec. 4. The Specification also states that, in some embodiments, "the microcapsule includes a single core that is encased in a coating." Id. at 3. The broadest reasonable interpretation of "microencapsulated" rapamycin therefore includes a standard-sized tablet. 9 Appeal2018-008436 Application 13/128,800 Appellants argue that "[ n Jone of Sehgal, Blagosklonny, or Bedrosian teach or exemplify an extension of lifespan past life expectancy." Br. 6. Specifically, "[a]ccording to the OECD ... , the definition of life expectancy is the average number of years that a person can be expected to live .... The life expectancy is a statistical measure of the average time an organism is expected to live, based on their current age and other demographic factors." Id. at 5---6. Appellants argue that "none of the cited art teaches an extension of lifespan beyond life expectancy, as exemplified by the current application." Id. at 6. As discussed above with respect to the indefiniteness rejection, the evidence that Appellants point to in the Specification is not consistent with the proffered OECD definition of "life expectancy." Regardless of which definition is applied, however, the cited prior art suggests that administering rapamycin will achieve it: Sehgal states that rapamycin prolongs the survival time of tumor-bearing mice compared to untreated control mice, and Blagosklonny states that a therapeutically effective amount of rapamycin will inhibit the aging process, prevent organism aging, and prolong human life span. Thus, the cited references suggest, even if they don't exemplify, extending the life span of a mammalian subject to greater than its life expectancy by administering rapamycin. Appellants also argue that, "[a]s shown in the evidence presented in the declaration of record (Declaration of Dr. Sharp dated Sept. 17, 2015) and reproduced below, eRapa (the currently claimed composition) shows unexpected properties compared to that what [sic] is seen in the prior art 10 Appeal2018-008436 Application 13/128,800 (compare with RADOOl data from Fujishita et al.; cited in an IDS on 9/17 /2015)." Br. 6-7. 12 This argument is unpersuasive, for several reasons. First, the declaration states that the graph that is reproduced in the Appeal Brief shows the survival of F AP mice ( mice modeling the disease of familial adenomatous polyposis ) .... This chart shows data of microencapsulated rapamycin ( eRapa) from our lab that was published and presented as Exhibit D in the declaration filed February 18, 2015. Also included in this chart is data from Fujishita ... , which shows the survival of PAP mice treated with unencapsulated everolimus. Sharp Deel. ,r 3. The graph in the Appeal Brief thus does not represent a side-by-side comparison of mice treated with two different compositions, but a comparison of results from an experiment using eRapa under certain conditions, with results from a different experiment using a different active agent, unencapsulated, under other conditions. It is therefore unclear what probative value the submitted data have with respect to nonobviousness. In addition, the reference that is cited in the Sharp Declaration ("Exhibit D in the declaration filed February 18, 2015") 13 describes "enteric- targeted rapamycin ( eRapa)" or "microencapsulated rapamycin" (Exhibit D, pages 2, 4), but does not describe the eRapa composition as rapamycin encapsulated with a methyl methacrylate-methacrylic acid 12 Citing the declaration under 37 C.F.R. Â§ 1.132 of Zelton Dave Sharp ("Sharp Deel."), filed Sept. 17, 2015, and Fujishita et al., Inhibition of the mTORCJ pathway suppresses intestinal polyp formation and reduces mortality in Apcf1716 mice, 105 PNAS 13544--49 (2008). 13 Declaration under 37 C.F.R. Â§ 1.132 ofZelton Dave Sharp, filed Feb. 18, 2015, Exhibit D. 11 Appeal2018-008436 Application 13/128,800 copolymer, as required by the claims on appeal. Thus, it is unclear whether the results shown in the graph represent those of the composition recited in the claims. To the extent that Appellants are relying on the evidence as showing unexpected results, it is deficient for additional reasons. First, Exhibit D shows administration of microencapsulated rapamycin to mice that "exhibit multiple intestinal neoplasia" (Exhibit D, abstract) and so the closest prior art would appear to be Sehgal, which administered unencapsulated rapamycin to tumor-bearing mice, rather than Fujishita, which administered unencapsulated everolimus. "To be particularly probative, evidence of unexpected results must establish that there is a difference between the results obtained and those of the closest prior art, and that the difference would not have been expected by one of ordinary skill in the art at the time of the invention." Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967,977 (Fed. Cir. 2014). Second, the claims encompass treating any mammalian subject, including healthy subjects, and the proffered evidence only shows results for mice that have a mutation in the adenomatous polyposis coli (APC) gene that makes them susceptible to intestinal neoplasia. Id. Appellants have presented no evidence or sound technical reasoning to establish that the results shown are commensurate in scope with the claims. "Evidence of unexpected results must be reasonably commensurate with the scope of the claims." In re Huai-Hung Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011). Appellants also argue that "the use of rapamycin for achieving the effect described in the current claims is not a property of the drug," but of 12 Appeal2018-008436 Application 13/128,800 rapamycin microencapsulated in a methyl methacrylate-methacrylic acid copolymer, as shown by post-filing data with APCMinJ+ mice using a different rapamycin formulation [that] did not achieve the recited effect ( see, Koehl et al., Exhibit B; cited in an IDS on November 18, 2011), shows that only about 30% of the APCMinJ+ -treated mice are alive at 364 days (Koehl et al., FIG. 2). This is in stark contrast to treatment of APCMinJ+ mice with the composition of the current claims, where 100% are alive at 364 days (Hasty et al., FIG. 2A; submitted in an IDS on September 17, 2015). Br. 7-8. This argument also fails, because Appellants have not identified the evidence it is based on. Appellants cite a reference by Koehl et al. as Exhibit B in an Information Disclosure Statement (IDS) filed November 18, 2011, but the official record of the instant application does not include an IDS filed on November 18, 2011. Appellants provide no other identification of the Koehl et al. reference. Thus, even if the graph shown in the Appeal Brief accurately depicts the data shown in the cited Hasty et al. reference, Appellants have not identified the source of the data alleged to be shown in the Koehl et al. reference, and therefore it is unclear what probative value, if any, the cited evidence has with respect to nonobviousness. For the reasons discussed above, we affirm the rejection of claim 86 under 35 U.S.C. Â§ 103(a) based on Sehgal, Bedrosian, Penhasi, and Blagosklonny. Claims 57, 62, 67----69, 73-79, 81, 87, and 88 were not argued separately and therefore fall with claim 86. 37 C.F.R. Â§ 41.37(c)(l)(iv). SUMMARY We affirm both of the rejections on appeal. 13 Appeal2018-008436 Application 13/128,800 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. Â§ 1.136(a). AFFIRMED 14