Ex Parte Roques et alDownload PDFPatent Trial and Appeal BoardMay 18, 201814182611 (P.T.A.B. May. 18, 2018) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE FIRST NAMED INVENTOR 14/182,611 02/18/2014 Bernard Roques 22428 7590 05/22/2018 Foley & Lardner LLP 3000 K STREET N.W. SUITE 600 WASHINGTON, DC 20007-5109 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. 065691-0603 1631 EXAMINER BASQUILL, SEAN M ART UNIT PAPER NUMBER 1613 NOTIFICATION DATE DELIVERY MODE 05/22/2018 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): ipdocketing@foley.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte BERNARD ROQUES, HERVE PORAS, and MARIE-CLAUDE FOURNIE-ZALUSKI 1 Appeal 2016-005500 Application 14/182,611 2 Technology Center 1600 Before RICHARD M. LEBOVITZ, RYAN H. FLAX, and DAVID COTTA, Administrative Patent Judges. LEBOVITZ, Administrative Patent Judge. DECISION ON APPEAL This appeal involves claims directed to compounds of the general formula (I) and their use to treat pain. The Examiner rejected the claims as obvious under 35 U.S.C. § 103 and on the ground of non-statutory double- patenting. Appellants appeal the rejections pursuant to 35 U.S.C. § 134. We have jurisdiction under 35 U.S.C. § 6(b ). The rejections are affirmed. 1 The Appeal Brief ("Appeal Br.") 2 lists Pharmaleads SA as the real-party- in-interest. 2 The Specification is referred to as "the '611 application." Appeal 2016-005500 Application 14/182, 611 STATEMENT OF THE CASE An oral hearing was held on April 3, 2018. The transcript of the hearing will be entered into the record in due course. The Examiner rejected claims 17, 18, and 20-26 as follows: Claims 17, 18, and 20-36 under 35 U.S.C. § I03(a) as obvious in view ofFoumie-Zaluski et al. (U.S. Pat. No. 6,518,260 Bl, issued Feb. 11, 2003) ("Foumie-Zaluski"), Chen et al., Long Lasting Antinociceptive Properties of Enkephalin Degrading Enzyme (NEP and APN) Inhibitor Prodrugs, 44 J. MED. CHEM. 3523-30 (2001) ("Chen"), and Gallop (U.S. Pat. Appl. Publ. 2006/0111325 Al; May 25, 2006). Ans. 2. Claims 17, 18, and 20-36 on the ground ofnonstatutory double patenting over claims 1-8 of U.S. Patent No. 8,703,747. Ans. 8. We summarily affirm this rejection because no response was made to it in the Appeal Brief. A Reply Brief was filed on May 9, 2016. Any argmnent raised in the reply brief which was not raised in the appeal brief, or is not responsive to an argument raised in the examiner's answer, including any designated new ground of rejection, will not be considered by the Board for purposes of the present appeal, unless good cause is shown. 37 C.F.R. § 4I.4l(b)(2). The Reply Brief contains new arguments on pages 3-5. Although Appellants state that these arguments are responsive to a misinterpretation by the Examiner of the Gallop publication (Reply Br. 2), Appellants did not establish that the Examiner's statements in the Answer were substantially different from those made in the Final Action, so as to warrant new evidence and arguments. The new argument is alleged to rebut the Examiner's alleged statement that "Gallop' s results would apply to all active compounds 2 Appeal 2016-005500 Application 14/182, 611 containing an amine." Reply Br. 2. However, the Examiner's basis for the rejection in the Final Action was that it would have been obvious to have used Gallop's moiety on the compounds disclosed in Foumie-Zaluski. Final Act. 7, 11. Appellants did not explain how this reasoning changed in the Answer. The rule, supra, is clear about when new arguments are permitted and Appellants did not establish that such circumstances were met. Consequently, the new arguments raised in the Reply Brief will not be considered. A declaration by Barnard Roques, Ph.D., was provided under 3 7 C.F.R. 1.132.3 ("Roques Deel.") Dr. Roques is a co-inventor of the application at issue in this appeal, a co-inventor of Foumie-Zaluski, and co- author of Chen. CLAIM 17. Claim 1 7 is directed to a compound having the general formula (I) as follows: R1-NH-CH(R2)-P(=O)(OR3)-CH2-C(Ri)(Rs)-CONH-CH(R6)-COOR7 The Claim Appendix to the Appeal Brief further specifies requirements for substituents R1-R7. OBVIOUSNESS REJECTION Claim 1 7 is directed a genus of compounds of the general formula I. All the compounds have a phosphonic acid (P=O(O-)) moiety. The 3 The Figures in the Roques declaration were illegible in parts. Appellants provided a copy of the figures at the request of the panel in the oral hearing. The Figures are attached to this Decision. 3 Appeal 2016-005500 Application 14/182, 611 compounds comprise an N-protecting group of formula R1 genus. R1 is reproduced below: -C( =O )-0-C(R 8)(R9)-0C( =O )-R 10 As noted above, the Claim Appendix to the Appeal Brief further specifies requirements for R1. Claim 23, which depends from claim 1, recites a list of 14 species of the genus of compounds encompassed by claim 17. The Examiner found that Foumie-Zaluski describes a chemical compound having a part of the structure of the first and second species listed in claim 23, but which lack the claimed N-protecting group of R1. Final Act. 4--5. These species correspond to the compounds of Example 3 (Spec. 38) ("compound 3 ") and Example 4 (Spec. 41) ( compound 4 ), respectively: 2-(2-biphenyl-4-ylmethyl-3-{hydroxyl-[ 1-(1-isobutyryloxy- ethoxycarbonylamino )-ethyl ]-phosphinoyl }-propionylamino )- prop ionic acid benzyl ester ( compound 3) 2-(2-biphenyl-4-ylmethyl-3-{hydroxyl-[ 1-(1-isobutyryloxy- ethoxycarbonylamino )-ethyl]-phosphinoyl }-propionylamino )- propionic acid ( compound 4) The Examiner found that the compounds in Foumie-Zaluski contain a phosphonic acid moiety ("phosphinoyl" moiety in compounds 3 and 4 above) as do the claimed compounds. Final Act. 5. The Examiner found that the Chen publication (listing Foumie- Zaluski as co-author) discloses that the same compounds of Foumie-Zaluski, and ones structurally related to them, have poor bioavailability and central nervous system availability. Id. The Examiner found that Chen addressed this problem by modifying the phosphonic acid moiety present in the compounds. Id. This modification to the phosphonic acid moiety is not the same modification which is claimed. 4 Appeal 2016-005500 Application 14/182, 611 The Examiner found that Gallop describes an alternative way of improving bioavailability of drug compounds having a phosphonic acid moiety by modifying the free N-group with an acyloxyalkyl, the same type of group as the R1 moiety of recited in claims 17 and 23. Final Act. 6-7. The Examiner found, however, that compounds of Gallop are not the same as those which are disclosed in Foumie-Zaluski and Chen. Id. The Examiner stated that Gallop teaches that "the body will metabolize the prodrug compound to the parent active agent gradually, sustaining bioavailability by the cleavage of the bonds." Id. at 7. The Examiner concluded that it would have been obvious to one of ordinary skill the in art to have modified a compound of Foumie-Zaluski with Gallop's N-protecting group to improve the compound's bioavailability. Id. at 8. Is there a reason to modify Fournie-Zaluski compounds? Appellants contend that one of ordinary skill in the art would not have had reason to modify the Foumie-Zaluski compounds with Gallop's N- protecting group ( corresponding to the R1 group of the claim 17 genus of compounds and the R1 group of compounds Examples 3 and 4 of claim 23) because The N-protecting groups improve oral bioavailability of compounds already exhibiting an activity via oral route, such as baclofen or aminophosphinic compounds for instance, by facilitating the crossing of the intestinal barrier. Gallop fails to disclose protecting groups improving the effective duration of the drugs. Instead, Gallop discloses how to improve their uptake in the intestine and/or colon, as needed to be suitable for their use in sustained release formulations. Appeal Br. 10. 5 Appeal 2016-005500 Application 14/182, 611 Appellants further argue: The Office erred in asserting that Gallop suggests that the protective group can be used to improve bioavailability and therefore makes it possible to administer by oral route a compound which is not water soluble. To the contrary, all the compounds quoted in Gallop already have good oral bioavailability. Appeal Br. 13. Appellants' arguments do not establish that the Examiner erred in finding it obvious to have combined Foumie-Zaluski, Chen, and Gallop. Gallop teaches that certain drugs, such as baclofen, "lack the requisite physicochemical characteristics for effective passive permeability across cellular membranes," and instead require active transport to pass from the GI tract into the systemic circulation. Gallop ,r 56. Gallop also teaches that such drugs are rapidly cleared from the circulation, requiring frequent dosage. Id. at ,r 57. Gallop teaches that sustained release formulations are generally used to address rapid clearance problems, but such formulations don't work effectively with compounds such as baclofen because, as the drug passes through the GI (gastro-intestinal tract), the drug moves into regions of the GI which lack the active transporter and therefore do not have an effective level of absorption. Id. For this reason, Gallop sought to develop compounds "which are well absorbed in the large intestine and/ or colon and hence suitable for oral sustained release formulations" of GABA8 receptor antagonists and specifically, drugs which comprises a phosphonic acid moiety. Id. at ,r 58. Gallop accomplished this purpose by making acyloxyalkyl carbamate prodrugs, drugs which comprise the same N- protecting group as claimed. Id. at ,r 59. 6 Appeal 2016-005500 Application 14/182, 611 Appellants' assertion about Gallop' s drug already being orally bioavailable is not pertinent because Gallop explained that, although the drugs are absorbed in certain parts of the intestine (and orally bioavailable because of this), their inability to be absorbed from other parts of the GI tract and to cross the blood-brain barrier hampered achieving effective systemic levels without frequent dosing. Gallop ,r 56. In other words, Gallop's N- protecting group was used as a solution to solve a problem with drugs whose oral bioavailability was hindered by ineffective absorption in the GI tract because they "lack the requisite physicochemical characteristics for effective passive permeability across cellular membranes." Id. Thus, while Gallop was addressing bioavailability based on oral administration, the underling mechanism was absorption across cell membranes. The pertinent issue is whether one of ordinary in the art would have sought to modify the Foumie-Zaluski compounds with Gallop's N- protecting group. Appellants did not dispute that Gallop's N-protecting group is the same group present in compounds 3 and 4 of claim 23. As found by the Examiner, Chen explicitly teaches that compounds with a phosphonic acid moiety have a bioavailability problem. Final Act. 6. Chen explained that compounds with the phosphonic acid group, present in both the claimed and Foumie-Zaluski compounds, required high intravenous dosages to obtain an analgesic effect in mice, which was interpreted to indicate a reduced passage into the brain of these compounds due to the presence of three highly polar functions. To increase their brain penetration, polar functions could be transiently protected by lipophilic groups, able to be cleaved in vivo by biologically dependent processes. 7 Appeal 2016-005500 Application 14/182, 611 Chen 3524. In other words, Chen's compounds were poorly absorbed through tissue just as were the compounds Gallop sought to improve. Chen addresses this problem by introducing "protecting groups ... on the phosphinic function." Id. at 3527. Hecker,4 cited by Appellants, also teaches that the phosphonic acid is a cause of the poor bioavailability. Hecker teaches: Phosphonic acids are rarely found in drug candidate molecules, despite the potential of this functional group to provide unique binding interactions with a target enzyme or receptor. ... Much of the reluctance to use these groups stems from their high charge and consequently the inability of these molecules to achieve high concentrations at the target site due to poor oral bioavailability and/or cell penetration. Hecker 2328. Thus, although Chen does not teach that its compounds with a phosphonic acid have poor oral bioavailability, this was because the delivery route utilized by Chen was intravenous administration, which doesn't involve an oral route. However, the disclosed compounds had reduced passage into the brain (Chen 3524). Chen's teaching about decreased brain passage of the drugs is consistent with this characteristic being due to the same cell penetration mechanism described in Hecker (see above quoted passage) and Gallop, namely, because of the presence of the phosphonic acid in the drug compound. Chen teaches the acyloxyalkyl modification to protect the phosphonic acid and improve the drug's bioavailability ("to improve the poor central bioavailability of their precursors"). Chen Abstract. Hecker teaches that the acyloxyalkyl group is "[ o ]ne of the most commonly used" modifications in prodrugs to address the problem with the 4 Hecker et al., 51 J. Med. Chem. 2328-2345 (2008). 8 Appeal 2016-005500 Application 14/182, 611 phosphonic acid moiety and improve bioavailability. Hecker 2328. Gallop' s drugs also have a phosphonic acid and Gallop is simply making use of this same phosphonic modification. Gallop ,r 59. Appellants did not persuasively dispute this. Hecker also teaches: Application to Phosphonates. The first report of the use of an acyloxyalkyl prodrug on a phosphonic acid was its application to the antibiotic fosfomycin in 1969. Since then, it has seen continued use, typically being the first prodrug type tried when a prodrug of a phosphonic acid is desired. Hecker 2329. Hecker provides evidence that the type of modification utilized in Gallop to protect phosphonic moieties - the same chemical moiety present in Foumie-Zaluski's compounds - is typically the first modification tried to improve a drug's bioavailability. Hecker establishes that this was well-known at the time of the invention. (Hecker is a "perspective" article on, or review of, the existing literature.) Thus, the Examiner had strong evidence to conclude that Gallop' s modification was not restricted to the specific drugs described in Gallop' s published patent application, but was generally applicable to compounds with a phosphonic acid moiety- the same chemical group present in the claimed compounds and those ofFoumie-Zaluski, Chen, and Gallop. In sum, the preponderance of the evidence establishes that there was a well-established reason to have utilized the N-protecting group described in Gallop (the R1 group of rejected claims 17 and 23) to improve by the bioavailability of Foumie-Zaluski's compounds. The phosphonic moiety in Foumie-Zaluski's compounds had a well-known problem in hampering a drug's bioavailability because of reduced cell penetration (see Chen, Hecker, 9 Appeal 2016-005500 Application 14/182, 611 and Gallop) and the modification in Gallop was a well-known solution to it, as established by Reeker's review. Was there a reasonable expectation of success? Appellants contend that one of ordinary skill in the art would not have had an expectation of success of arriving at the claimed compounds because difficulties had been encountered in the prior art in designing drugs with protective moieties (Appeal Br. 9) and one could not have predicted how Gallop's protecting group would affect the compounds of Foumie-Zaluski (id. at 10). In addition to this, Appellants argue the compounds described in Foumie-Zaluski have central activity, as those do in Gallop (id. at 10, 12). In contrast, Appellants contend that their compounds have peripheral activity: A skilled artisan reading Gallop would not have expected to obtain a purely peripheral activity by simply introducing a specific N-protecting group ( see Figures of present specification). Indeed, the compounds of the present invention are completely inactive on the central nervous system when administered via oral route, as demonstrated by the hot-plate test. Appeal Br 13. Appellants provided evidence that the compounds of Examples 3, 4, and 8 described in the '611 application have only peripheral activity in contrast to those in Gallop which also have central activity. Spec. 84. The compounds of Examples 3 and 4, are recited in the Markush group of claim 23, but compound 8 does not appear to be in the group. Appellants have not indicated whether they consider compound 8 to fall within the scope of claim 17. 10 Appeal 2016-005500 Application 14/182, 611 The inventors treated mice with formalin to induce pain ("formalin test") and showed that the analgesic effects produced by compounds 3, 4, and 8 were blocked by an antagonist that was unable to cross the blood brain barrier, indicating that the compounds' activities were peripheral, not central. Spec. 84. Compound 4 was further tested in a neuropathic pain model (PSNL) and it was demonstrated that its analgesic activity was also blocked by an antagonist unable to cross the blood brain barrier, providing evidence that the compound's activity was peripheral and not central. Roques Deel. (Fig. 2C). Compound 9 was shown in the Roques Declaration to have an analgesic effect in the formalin test. Roques Deel. (Fig. 3). However, it was not determined by Dr. Roques whether compound 9's activity was abolished by an antagonist unable to cross the blood brain barrier - as it was shown to be true for compounds 3, 4, and 8. In sum, Appellants provided adequate evidence that compounds 3, 4, and 8, when modified with the specific R1 group described in Gallop show only peripheral activity in the formalin test and the PSNL test. Appellants' did not adequately establish this fact for compound 9. Appellants also persuasively showed that one of ordinary skill in the art would have expected compounds 3, 4, and 8 to have central activity based on the teachings in Gallop and Foumie-Zaluski. Appeal Br. 10, 12-14, 16-17; Reply Br. 6-7. The Examiner did not challenge the adequacy of the evidence, but rather stated that it was a latent advantage "'which would flow naturally from following the suggestion of the prior art."' Ans. 10. 11 Appeal 2016-005500 Application 14/182, 611 We do not agree with the Examiner's analysis. An unexpected result, as here, is the basis for finding claims unobvious, even when the claimed subject matter is suggested by the prior art. The issue is whether the property relied upon for the unexpected result is latent or inherent to the cited prior art. This is best illustrated in In re Baxter Travenol Labs., 952 F.2d 388 (Fed. Cir. 1991), where the applicant had argued that the claimed plasticized blood donor bag comprised of DEHP had unexpected properties in suppressing the hemolysis of red blood cells stored inside it. Baxter, 952 F .2d at 3 89. The court found that such evidence did not rebut prima facie obviousness because the prior art disclosed a DEHP-plasticized donor bag, and therefore, Baxter's blood bag had the same hemolytic-suppressing function as the prior art - albeit unappreciated at the time of the invention. Baxter, at 391. The court concluded that "[ m Jere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention." Baxter, at 392 (citation omitted). In this case, the Examiner did not establish that the N-protecting R 1 group utilized in compounds 3, 4, and 8 had the latent property of conferring peripheral only activity on a compound. To the contrary, as discussed above and in Appellants' Brief (Appeal Br. 13), Gallop shows that the compounds having the same R1 group have central activity. To say that the peripheral only activity "flow[ s] naturally from following the suggestion of the prior art" (Ans. 10) ignores the role of secondary considerations in an obviousness rejection where an otherwise obvious invention arrived at by "following the suggestion of the prior art" is found to be patentable in view of such secondary considerations. As articulated in Baxter, a key checkpoint in such circumstances is whether the 12 Appeal 2016-005500 Application 14/182, 611 property relied upon to establish non-obviousness is "latent" in the prior art, i.e., a property that operated in the prior art, but had not been recognized before. Here, this is not the case. Nonetheless, assuming that unexpected results have been established, the results must be commensurate with scope of the claim. In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005). Claim 17 is directed to a large genus of compounds, including a genus of R1 protecting groups. Gallop is evidence that different compounds, with the same protecting group, have central activity; however, the same protecting group on compounds 3, 4, and 8 results compounds having only peripheral activity. In view of the differences in activity between Gallop' s results and those described for compounds 3, 4, and 8, it would have been unpredictable whether a compound within the scope of claim 17 modified with the N-protecting group of Gallop would possess central or peripheral activity. Appellants have not explained how the results with a limited number of species establish that the full scope of compounds encompassed by claim 17, and the untested species of claim 23, would have been reasonably expected to each possess peripheral only activity. In sum, the results are not commensurate with the full scope of the claim, For the foregoing reasons, the obviousness rejection of claim 17 is affirmed. Claims 18 and 20-36 were not argued separately and fall with claim 17. 37 C.F.R. § 4I.37(c)(l)(iv). 13 Appeal 2016-005500 Application 14/182, 611 TIME PERIOD No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a)(l )(iv). AFFIRMED 14 Copy with citationCopy as parenthetical citation