Ex Parte Witney et alDownload PDFPatent Trial and Appeal BoardMay 14, 201814956431 (P.T.A.B. May. 14, 2018) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 14/956,431 12/02/2015 24504 7590 05/16/2018 THOMAS I HORSTEMEYER, LLP 3200 WINDY HILL ROAD, SE SUITE 1600E ATLANTA, GA 30339 FIRST NAMED INVENTOR Timothy Witney 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. 221907-1115 4621 EXAMINER DONOHUE, SEAN R ART UNIT PAPER NUMBER 1618 NOTIFICATION DATE DELIVERY MODE 05/16/2018 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): uspatents@tkhr.com ozzie. liggins@tkhr.com docketing@thomashorstemeyer.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte TIMOTHY WITNEY, MICHELLE L. JAMES, and SANJIV S. GAMBHIR Appeal2017-004794 1 Application 14/956,431 Technology Center 1600 Before FRANCISCO C. PRATS, RYAN H. FLAX, and TIMOTHY G. MAJORS, Administrative Patent Judges. PRATS, Administrative Patent Judge. DECISION ON APPEAL This appeal under 35 U.S.C. § 134(a) involves claims directed to compounds that act as pyruvate kinase M2 activators, claims directed to chemical precursors to the activator compounds, and claims directed to methods of using the activators to detect cells expressing pyruvate kinase M2. The Examiner rejected the claims for obviousness. We have jurisdiction under 35 U.S.C. § 6(b)(l). We reverse. 1 Appellants state that the "real party in interest of the instant application is The Board of Trustees of the Leland Stanford Junior University." Appeal Br. 2. Appeal2017-004794 Application 14/956,431 STATEMENT OF THE CASE The Specification discloses that the enzyme pyruvate kinase (PK) "consists of four isoforms, of which the spliced variant, PKM2, is preferentially expressed in all cancers studied to-date, regardless of their tissue of origin." Spec. 12 (citation omitted); see also id. at 13 ("PKM2 is overexpressed in tumors."). Appellants' invention is directed to the synthesis of radionuclide-labeled PKM2 activators that bind to the enzyme, thereby allowing the use of positron emission tomography (PET) to detect tumors that express the enzyme. Id. at 14. Claims 1, 3, and 7 illustrate the subject matter on appeal, and read as follows: 1. A pyruvate kinase M2 activator precursor wherein said precursor is 4-(( 4-((2,6-difluorophenyl)sulfonyl)piperazin-1- yl)sulfonyl)phenol (I) having the formula: F i ;\ i S-N N-S OH 11 \_/ II 0 0 F I 2 Appeal2017-004794 Application 14/956,431 3. A pharmaceutically acceptable probe composition comprising a Positron Emission Tomography (PET)-detectable radiolabelled probe, wherein said probe has the formula: F ~ ;\ i S-N N-S II \__/ II 0 0 F wherein R1 is selected from the group consisting of: 11C-methoxy, 18F-fluoromethoxy-, 18F-fluoroethoxy-, and 18F-fluoropropoxy-. 7. A method of detecting a cell or a population of cells expressing pyruvate kinase M2, said method comprising: (i) contacting a cell or population of cells with a pharmaceutically acceptable PET-detectable radiolabelled probe composition comprising at least one probe having a radionuclide and having the formula: F ~ ;\ i S-N N-· S II \__/ II 0 0 F wherein R1 is selected from the group consisting of: 11C-methoxy, 18F-fluoromethoxy-, 18F-fluoroethoxy-, and 18F-fluoropropoxy-; and (ii) detecting pyruvate kinase M2-specific binding of the radionuclide-containing probe within the cell or population of cells by detecting the presence of the radionuclide in the cell or population of cells. Appeal Br. 17-19. 3 Appeal2017-004794 Application 14/956,431 The following rejections are before us for review: (1) Claims 1---6, under 35 U.S.C. § I03(a) as being unpatentable over Boxer,2 Lim, 3 Halldin, 4 Zhang, 5 and Gao6 (Ans. 3-7); and (2) Claims 7-14, under 35 U.S.C. § I03(a) as being unpatentable over Boxer, Becker,7 Ametamey, 8 Halldin, Zhang, and Wong9 (id. at 7-9). OBVIOUSNESS-CLAIMS 1---6 The Examiner's Prima Facie Case In rejecting claims 1---6 over Boxer, Lim, Halldin, Zhang, and Gao, the Examiner cited Boxer as disclosing the preparation of PKM2 activators similar to the compounds recited in claims 1-6. Ans. 3--4. The Examiner noted, in particular, Boxer's compound 23 as being similar in structure to the claimed compounds. Id. 2 Matthew B. Boxer et al., Evaluation of Substituted N,N'- Diarylsulfonamides as Activators of the Tumor Cell Specific M2 Isoform of Pyruvate Kinase, 53 J. MED. CHEM. 1048-55 (2010). 3 US 2008/0294289 Al (published Nov. 27, 2008). 4 Christer Halldin et al., PET Studies with Carbon-I I Radioligands in Neuropsychopharmacological Drug Development, 7 CURRENT PHARM. DES. 1907-29 (2001 ). 5 Ming-Rong Zhang and Kazutoshi Suzuki, {1 8F]Fluoroalkyl Agents: Synthesis, Reactivity and Application for Development of PET Ligands in Molecular Imaging, 7 CURRENT TOPICS MED. CHEM. 1817-28 (2007). 6 Mingzhang Gao et al., Simple synthesis of carbon-I I-labeled chromen-4- one derivatives as new potential PET agents for imaging of DNA-dependent protein kinase (DNA-PK) in cancer, 70 APPLIED RADIATION AND ISOTOPES 1558---63 (2012). 7 US 2012/0108631 Al (published May 3, 2012). 8 US 2010/0056533 Al (published Mar. 4, 2010). 9 Nicholas Wong et al., PKM2, a Central Point of Regulation in Cancer Metabolism, 2013 INT. J. CELL BIOL. 1-11 (2013). 4 Appeal2017-004794 Application 14/956,431 The Examiner conceded, however, that Boxer did not disclose a compound of formula I, as recited in claims 1, 2, and 6. Id. at 4. The Examiner also conceded that Boxer did not disclose any of the 11C-methoxy-, 18F-fluoromethoxy-, 18F-fluoroethoxy-, or 18F-fluoropropoxy-, compounds recited in claims 3---6, or methods of their synthesis. Id. To address those deficiencies, the Examiner cited Zhang as teaching that it was known in the art to use 11C and 18F to label organic compounds for use in in vivo PET imaging-based biochemical studies, and that one method of accomplishing that labeling was the 11C-methylation of a hydroxyl group of a compound of interest in a manner similar to that recited in Scheme B of Appellants' claim 6. Id. at 5---6. The Examiner cited Halldin as disclosing 11C-methylation of the hydroxyl group target molecules as a widely used approach for labeling molecules of interest, and noted Halldin's disclosure that substituting 11C for naturally occurring carbon did not change the biochemistry of the molecule. Id. at 6. The Examiner cited Lim as disclosing that 18F-fluoroalkylation of the hydroxyl group of target molecules, in a manner similar to that recited in Scheme C Appellants' claim 6, was a known method of isotopically labeling molecules of interest. Id. at 6-7. The Examiner similarly cited Gao as disclosing 11C-methylation of the hydroxyl group of a molecule of interest, producing "carbon-I I-labeled chromen-4-one derivatives as new potential PET agents for imaging of DNA-dependent protein kinase (DNA-PK) in cancer." Id. at 7. Based on the references' combined teachings, the Examiner reasoned: 5 Appeal2017-004794 Application 14/956,431 Id. It would have been obvious to a person of ordinary skill in the art at the time of invention to modify the composition and methods of Boxer et al. (i.e., N,N'-diarylsulfonamide, 23, and method of synthesis) by simply preparing an 0-desmethyl-precursor as taught by Zhang et al., Halldin et al., Lim et al., and Gao et al. because it would advantageously enable rapid labeling with positron emitting radioisotopes carbon- I I and fluorine-18 and subsequent PET imaging of PKM2 in tumor cells. Analysis As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992): [T]he examiner bears the initial burden . . . of presenting a prim a facie case of unpatentability .... After evidence or argument is submitted by the applicant in response, patentability is determined on the totality of the record, by a preponderance of evidence with due consideration to persuasiveness of argument. InKSR Int'! Co. v. Teleflex Inc., 550 U.S. 398 (2007), although the Supreme Court emphasized "an expansive and flexible approach" to the obviousness question, id. at 415, the Court also reaffirmed the importance of determining "whether there was an apparent reason to combine the known elements in the fashion claimed by the patent at issue." Id. at 418 ( emphasis added). Thus, the "mere fact that the prior art may be modified in the manner suggested by the Examiner does not make the modification obvious unless the prior art suggested the desirability of the modification." In re Fritch, 972 F.2d 1260, 1266 (Fed. Cir. 1992). Moreover, "[i]t is impermissible to use the claimed invention as an instruction manual or 'template' to piece 6 Appeal2017-004794 Application 14/956,431 together the teachings of the prior art so that the claimed invention is rendered obvious." Id. Ultimately, therefore, "[i]n determining whether obviousness is established by combining the teachings of the prior art, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re GPAC Inc., 57 F.3d 1573, 1581 (Fed. Cir. 199 5) (internal quotations omitted). In the present case, having carefully considered the arguments and evidence advanced by Appellants and the Examiner, Appellants persuade us that the Examiner has not shown by a preponderance of the evidence that the cited references would have rendered obvious the subject matter recited in Appellant's independent claims. In particular, we are not persuaded that the Examiner has explained adequately why, absent impermissible hindsight, the cited combination of references would have suggested the compounds recited in claims 1- 6 to an ordinary artisan. The Examiner's rejection is ultimately premised on the proposition that an ordinary artisan would have been motivated to prepare a 11C-methylated or 18F-alkylated version of Boxer's compound 23, as recited in Appellants' claims 3-6, to allow PET-based imaging of PKM2 in tumor cells. Ans. 7. The Examiner explains further: Boxer teaches that compound 23 ... binds to PKM2. Therefore compound 23 of Boxer represents a suitable starting point for the development of radio ligands that bind to PKM2. Since Boxer teaches that all tumor and cancer cell lines studied to date show exclusive expression of the PKM2 isoform, a person of ordinary skill in the art would have been motivated to select a compound of Boxer for the development of a radio ligand in order to advantageously enable visualization of PKM2 expressing cancer cells. 7 Appeal2017-004794 Application 14/956,431 Id. at 11. As to the precursor compound of formula I recited in Appellants' claims 1, 2, and 6, the Examiner reasoned that, because an ordinary artisan would have been motivated to prepare a 11C-methylated or 18F-alkylated version of Boxer's compound 23, the artisan also would have been motivated to prepare the hydroxyl group-containing precursor compound of formula I to enable the 11C-methylation and/or 18F-alkylation. See id. at 7 ( concluding it obvious to "simply prepar[ e] an 0-desmethyl precursor"). We are not persuaded. We acknowledge Boxer's disclosure that "[a]ll tumors and cancer cell lines studied to date show exclusive expression of the PKM2 isoform." Boxer 1048. Rather than using PKM2 as a way of imaging cancer cells, however, Boxer relates to identifying PKM2 activators. Id. at 1049 (noting that prior data "suggest a[n anti-cancer] therapeutic strategy whereby activation of PKM2 may restore normal cellular metabolism to a state characteristic of normal differentiated cells"). Pursuant to that objective, Boxer discloses a "PKM2 assay capable of identifying inhibitors and activators, the quantitative high-throughput screening ( qHTS) of a large chemical library, and the identification and exploration of the structure activity relationships (SAR) of substituted N,N'- diarylsulfonamides as activators of PKM2." Id. Using its techniques, Boxer discloses that "[s]everal agents are found that have good potencies and appropriate solubility for use as chemical probes of PKM2 including [compounds] 55 ... , 56 ... , and 58 .... " Id. at 1048 (abstract). Thus, rather than compound 23, as identified by the Examiner, Boxer expressly identifies compounds 55, 56, and 58 as having properties making 8 Appeal2017-004794 Application 14/956,431 them suitable for use as chemical probes of PKM2. In addition, the Examiner did not identify any specific teachings in Boxer suggesting that compound 23 has properties sufficiently similar to those of compounds 55, 56, and 58, which also would have suggested using compound 23 as a chemical probe of PKM2. Accordingly, given the absence of any teaching in Boxer specifically suggesting the use of its compounds in radionuclide-based PET imaging, and given Boxer's identification of compounds other than compound 23 as useful tools for analyzing PKM2 activity, and further given the absence of any identified teaching in Boxer suggesting that compound 23 would be useful as a PKM2 analytical tool in a fashion similar to compounds 55, 56, and 58, the Examiner does not persuade us that an ordinary artisan would have selected Boxer's compound for further modification to arrive at the 18F and 11C-labeled compounds in Appellants' claims 3---6, or their precursors recited in claims 1, 2, and 6. See Daiichi Sankyo Co. v. Matrix Labs., Ltd., 619 F.3d 1346, 1354 (Fed. Cir. 2010) ("[T]he lead compound analysis ... requires the challenger to demonstrate ... that one of ordinary skill in the art would have had a reason to select a proposed lead compound or compounds over other compounds in the prior art.") (Citation omitted); see also Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1292 (Fed. Cir. 2012) ("Absent a reason or motivation based on such prior art evidence [ of the proposed lead compound's pertinent properties], mere structural similarity between a prior art compound and the claimed compound does not inform the lead compound selection.") (Emphasis added)(citation omitted). 9 Appeal2017-004794 Application 14/956,431 We acknowledge that Boxer's teachings must be viewed alongside those of the other cited references, and not in isolation. See In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). In the present case, however, Lim, Halldin, Zhang, and Gao describe generic techniques by which molecules of interest may be labeled with either 11C and/or 18F, and the Examiner does not identify any specific teaching in any of those references suggesting the particular selection of Boxer's compound 23 for further modification by the radiolabeling techniques described in Lim, Halldin, Zhang, and Gao. In sum, for the reasons discussed, we not persuaded that the Examiner has explained adequately why, absent impermissible hindsight, the combination of Boxer, Lim, Halldin, Zhang, and Gao would have suggested the compounds recited in claims 1-6, or the synthetic methods recited in those claims, to an ordinary artisan. Thus, even if we were to agree with the Examiner that Appellants' evidence regarding resolving a long-felt need lacked significant probative value, given the cited references' failure to suggest the subject matter recited in claims 1---6, we reverse the Examiner's rejection of those claims. OBVIOUSNESS-CLAIMS 7-14 The Examiner's Prima Facie Case In rejecting claims 7-14 over Boxer, Becker, Ametamey, Halldin, Zhang, and Wong, the Examiner relied on Boxer, Halldin, and Zhang for the teachings discussed above. Ans. 8. The Examiner cited Wong as teaching that PKM2 was known to be a central point in cancer metabolism, had been detected in glioma, and also that 18F-labeled fluorodeoxyglucose had been used to detect tumors using PET imaging. Id. 10 Appeal2017-004794 Application 14/956,431 The Examiner cited Becker as describing sulfonamides as modulators of PKM2 useful for treating cancer, and also disclosing that 18F and 11C-labeled versions of it compounds were useful for PET imaging. Id. The Examiner cited Ametamey as disclosing the use of 18F-labeled folates in PET imaging methods that detect folate receptor-expressing cancer cells in vivo. Id. at 9. Based on the references' combined teachings, the Examiner reasoned that it would have been obvious to Id. modify the compound/method of Boxer et al. (i.e., N,N'- diarylsulfonamide, 23, and method of use) by predictably incorporating a [11 C]methyl or [18F]fluoroethyl and administering for use in PET as taught by Zhang et al., Halldin et al., and Wong et al. because it would advantageously enable early stage diagnosis of cancer in human subject with non- invasive positron emission tomography (PET). Analysis We reverse this rejection as well. Appellants' claims 7-14 recite methods of using the 18F and 11C-labeled compounds of claims 3-6, discussed above, to detect the presence of PKM2-expressing cells by PET imaging. See Appeal Br. 19-20. As addressed above, the Examiner's rationale for preparing the 18F and 11C-labeled compounds used in the methods of claims 7-14 again relies on Boxer's compound 23 as the lead compound. It might be true that Wong, Becker, and Ametamey suggest that certain 18F and 11 C-labeled compounds would be useful for PET imaging of cancer cells. For essentially the reasons discussed above as to claims 3---6, however, the Examiner does not persuade us that, absent impermissible 11 Appeal2017-004794 Application 14/956,431 hindsight, Boxer, Halldin, and Zhang would have suggested preparing the compounds recited in method claims 7-14 from Boxer's compound 23, even when the teachings of Boxer, Halldin, and Zhang are viewed alongside the teachings of Wong, Becker, and Ametamey. In sum, for the reasons discussed above, we not persuaded that the Examiner has adequately explained why, absent impermissible hindsight, the combination of Boxer, Becker, Ametamey, Halldin, Zhang, and Wong would have suggested preparing the compounds used in the methods of claims 7-14. Thus, even if we were to agree with the Examiner that Appellants' evidence regarding resolving a long-felt need lacked significant probative value, given the cited references' failure to suggest methods having all of the features recited in claims 7-14, we reverse the Examiner's rejection of those claims. SUMMARY For the reasons discussed, we reverse both of the Examiner's obviousness rejections. REVERSED 12 Copy with citationCopy as parenthetical citation