Ex Parte Yla-HerttualaDownload PDFPatent Trials and Appeals BoardJun 11, 201914787887 - (D) (P.T.A.B. Jun. 11, 2019) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 14/787,887 10/29/2015 22925 7590 06/13/2019 Pharmaceutical Patent Attorneys, LLC 801 Brickell Avenue 9th Floor #9101 Miami, FL 33131-4924 FIRST NAMED INVENTOR Seppo Yla-Herttuala 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. US61/820869 1065 EXAMINER ARON, KIMBERLY A ART UNIT PAPER NUMBER 1633 NOTIFICATION DATE DELIVERY MODE 06/13/2019 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): mark. pohl@ licensinglaw. net docket@LicensingLaw.net administration@LicensingLaw.net PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Exparte SEPPO YLA-HERTTUALA Appeal2019-000643 Application 14/787,887 Technology Center 1600 Before DEBORAH KATZ, ULRIKE W. JENKS, and JOHN G. NEW, Administrative Patent Judges. KATZ, Administrative Patent Judge. DECISION ON APPEAL Appeal2019-000643 Application 14/787,887 Introduction Appellant1 seeks our review, under 35 U.S.C. § 134(a), of the Examiner's decision to reject claims 1-15, 17-21, and 41. 2 (Appeal Brief filed May 6, 2018 ("App. Br.") 8-13.) We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. Appellant's Specification provides a method for treating glioblastoma by locally intraoperatively administering adenovirus-mediated Herpes- Simplex virus thymidine kinase ("AdvHSV-tk") gene therapy in conjunction with ganciclovir. (Specification ("Spec.") 2:14--22.) The Specification explains that transduced cells produce thymidine kinase, which phosphorylates ganciclovir into cytotoxic ganciclovir triphosphate, a nucleotide analogue that selectively kills dividing cells by being incorporated into DNA. (Spec. 3:1-5.) The Specification further discloses that temozolomide was added to AdvHSV-tk/ganciclovir therapy. (See Spec. 5: 1-19.) The Specification states that "[a]ccounting for actual temozolamide [sic] use in a statistical analysis which included temozolamide [sic] as a time dependent covariate, [Appellant] demonstrated a significant benefit for the primary endpoint ... which even became more apparent in the subgroup with MGMT non-methylated status." (Id.) Appellant's claim 1 recites3: A method of treating glioblastoma in a human comprising: 1 Appellant reports that the real party in interest is Gliotherapy Limited. (App. Br. 3.) 2 Claims 16 and 22--40 are cancelled. 3 Appellant's claim 11 provides a step "a." (App. Br. 15.) The Examiner entered separate rejections of claims 1 and 11, as discussed in the analysis section. 2 Appeal2019-000643 Application 14/787,887 b. surgically resecting at least part of said glioblastoma, and then administering locally about the surgical resection site after surgical resection, about Ix 1012 particles of replication-deficient adenovirus serotype 5 with E 1 and partial E3 deletions, and containing the cDNA for HSV-tk which is able to phosphorylate ganciclovir, then c. administering gancyclovir 5mg / kg i.v., twice daily, and administering temozolomide, the ganciclovir and temozolomide administered in an amount effective to treat glioblastoma. (App. Br. 15.) The Examiner rejected the claims under 35 U.S.C. § 103 as follows (Final Office Action mailed November 2, 2017 ("Final Act.")): Claims References Final Office Action Citation 1-10, 13-15, and Immonen, 4 Langford, 5 5-9 17-20 and Rainov6 11 and 12 Immonen, Langford, 9-10 Rainov, and Cankovic 7 21 Immonen, Langford, 13-15 and Chang8 4 Immonen et al., "AdvHSV-tk Gene Therapy with Intravenous Ganciclovir Improves Survival in Human Malignant Glioma: A Randomised, Controlled Study," 10 MOLECULAR THERAPY 967-72 (2004). 5 Langford et al., "A preclinical assessment of the safety and biodistribution of an adenoviral vector containing the herpes simplex virus thymidine kinase gene (Cerepro®) after intracerebral administration," 11 J. GENE MED. 468- 76 (2009). 6 Rainov et al., "Temozolomide enhances herpes simplex virus thymidine kinase/ganciclovir therapy of malignant glioma," 8 CANCER GENE THERAPY 662---68 (2001 ). 7 Cankovic et al., "A simplified laboratory validated assay for MGMT promoter hypermethylation analysis of glioma specimens from formalin- fixed paraffin-embedded tissue," 87 LAB. INVESTIGATION 392-97 (2007). 8 Chang et al., US 2014/0120157 Al, published May 1, 2014. 3 Appeal2019-000643 Application 14/787,887 41 Immonen, Langford, 15-16 Chang, and Cankovic Findings of Fact 1. The Specification states "[c]linical experience with [AdvHSV- Tk] has shown very promising efficacy in three phase I/II studies . . . . In the first two phase I studies optimal dose (1x1012 vp) and transduction efficiency were determined." (Spec. 3:9-11, citing Sandmair9 and Puumalainen. 10) 2. Immonen teaches that gene therapy with AdvHSV-tk and ganciclovir "may be an effective adjuvant treatment for patients with operable primary or recurrent high-grade glioma." (Immonen 971.) 3. Immonen teaches a method of treating glioblastoma by resecting as much of the identified tumor tissue as possible, administering 10 ml of 3xl010 plaque-forming units ("pfu") AdvHSK-tk directly into the healthy tissue of the wound bed after tumor resection, and intravenously administering ganciclovir at a dose of 5 mg/kg administered twice daily. (Id.) 4. Langford teaches administering intracerebral and intravenous doses of AdvHSK-tk in combination with ganciclovir to rats for a preclinical assessment of safety and biodistribution. (Langford 468.) 9 Sandmair et al., "Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses," 11 HUMAN GENE THERAPY 2197-205 (2000). 10 Puumalainen et al., "Beta-galactosidase gene transfer to human malignant glioma in vivo using replication-deficient retroviruses and adenoviruses," 9 HUMAN GENE THERAPY 1769-74 (1998). 4 Appeal2019-000643 Application 14/787,887 5. Langford teaches intracerebrally administering AdvHSK-tk as a low dose of2xl09 virus particles ("vp") and a high dose of lxl010 vp. (Id. at 469, Table 1.) 6. Langford teaches "the levels of [AdvHSK-tk] that were detected were related to the dose," as administering the high dose of AdvHSK-tk increased the copies/µg DNA of AdvHSK-tk in the brain compared to the low dose. (See id. at 475, Table 3.) 7. Langford teaches that "single-dose administration of [AdvHSK- tk] to the rat via the i.v. route (2.0x 1010 vp/ml or 2.0x 1011 vp/ml) or the i.e. route (2.0x 109 vp/ml or 1x1010 vp/ml) was well tolerated." From a toxicological perspective, changes observed in the brain after i.e. injection were mild and similar to control, and "systemic toxicological findings were minimal and probably reflected an inflammatory response to the vector, which was transient in nature." (Id. at 476.) 8. Rainov teaches temozolomide has been used in clinical trials for high-grade glioma and glioblastoma, and the standard dose in patients previously untreated by chemotherapy is 200 mg/m2. (Rainov 662---663, 666.) 9. Rainov teaches that "HSV-tk/[ganciclovir] gene therapy and [temozolomide] chemotherapy can be combined for enhanced cytotoxicity of malignant glioma." (Id. at 664.) 10. Rainov teaches "[r]igorous examination ... of data from cell culture allowed us to clearly identify a synergy between the two drugs at all effect levels. This was additionally proven in an animal study utilizing exactly the same cell clones and drugs." (Id. at 666.) 5 Appeal2019-000643 Application 14/787,887 11. Rainov teaches "[b ]esides the synergistic cytotoxic effect, another advantage of combining HSV-tk/[ganciclovir] gene therapy with [temozolomide] would be the fact that this combination of drugs may reduce toxicity toward the host ... and may decrease the impact of possible acquired drug resistance of the tumor cells." (Id. at 667.) 12. Chang teaches "[t]he current standard of therapy for glioblastoma multiforme (GBM) is surgical resection, followed by radiotherapy and chemotherapy with Temozolomide (TMZ)." (Chang ,r 5.) Analysis Rejection over Immonen, Langford, and Rainov The Examiner determines that it would have been obvious for one of ordinary skill in the art to combine Immonen's surgical resection and AdvHSV-tk/ganciclovir therapy with administration of temozolomide because the combined prior art teaches both treatments were known for treating glioblastoma. (See Final Act. 8; FFs 2, 3, 8.) The Examiner finds Rainov provides the rationale to combine the therapies by teaching that treatment with ganciclovir and temozolomide results in a synergistic effect. (Id.) The Examiner acknowledges that Immonen does not disclose administering about 1012 virus particles into the brain. (Final Act. 6; FF 3.) However, the Examiner finds Langford "establishes that the number of viral particles administered intracerebrally is a result-effective variable because she demonstrates that viral-particle dosage achieves a recognized result: increased HSV-tk DNA delivered to the brain." (Final Act. 7; FFs 5, 6.) We agree. Because the number of viral particles is a result effective variable, the 6 Appeal2019-000643 Application 14/787,887 Examiner determines that identifying the optimum or workable ranges of viral-particle dosage would have required only routine experimentation for the skilled artisan in order to optimize the dose. (See id.) Appellant argues that "[t]he artisan would not have found it obvious to increase Langford's dose by two orders of magnitude because Langford's data imply that such an increased dose would provoke inflammation so severe as to exceed Langford's measurement scale." (Reply Brief filed November 1, 2018 ("Reply Br.") 3.) In particular, Appellant cites Langford's Table 2 for showing "that viral vector induces brain inflammation in a dose-dependent manner." (Id. at 2, citing Langford 474.) A portion of Table 2 of Langford is reproduced below: bt•.::.-f3~::~;,::::~f i:-~1~:::~::Cx1 "i:t~. ~~~-f:~f\~~: :.:,:'~\::.•, .. r:pt·;-.,::~ ·~)::~}$ ijr:J3:, n:.-:::~-~~\~::.~·n ~~t::~ ~~r.-=~:1~~ i:1~t:.rnr.:1~t:)~' :~.~:::; ;::---,:::,:j)'.:"~1 ~~;;~i~~ 1 C.-..:":'""l"'.~ {-1 ,,. ~~M~ ] 0 : ... /~'.;' JL:.£- ;~ ~l1'~ j:)S,~ ft~~~-::~~ ;{) ,,, S~:-1~ {,t ..... , &"\~) ~;--~ ,.-.- .:tn ~r~w-::bs..-: ~~,,,Sf} Table 2 lists neuropathological findings in Male (M) and Female (F) Rats Injected intracerebrally with AdvHSV-tk Appellant argues that a low dose provokes Grade 1 inflammation as opposed to a dose one order of magnitude larger that increases the proportion of animals affected and inflammation severity. (Id.) Appellant argues these data imply that a further increase in order of magnitude "would imply -100% of the animals would be affected by inflammation so severe as to exceed Langford's measurement scale." (Id. at 3.) 7 Appeal2019-000643 Application 14/787,887 We are not persuaded by Appellant's argument. Appellant highlights data from only male rats in Table 2 to argue what is implied by the prior art. (See Langford 474, Table 2.) In contrast, Langford describes Table 2 as showing "minimal numbers of inflammatory cells ... were seen around the injection site," "the inflammatory changes ... were not prolonged," and "[g]rading of these inflammatory responses decreased with time." (Langford 473.) The Examiner finds that when Langford is considered in its entirety, it does not state or imply that the inflammation caused by the high dose renders it unsuitable as an effective therapy. (See Examiner's Answer mailed September 4, 2018 ("Ans.") 18.) Rather, as cited by the Examiner, Langford teaches that both low and high doses were well tolerated, that changes to the brain after injection were mild and similar to those obtained in control animals, and that systemic effects due to inflammatory response were minimal. (See Ans. 18; see also FF 7.) Considering the prior art as a whole, we agree with the Examiner that Langford teaches the dose amount of AdvHSV-tk virus particles is a result effective variable that could have been optimized by a person of ordinary skill in the art using routine experimentation. Appellant argues further that Rainov cannot be combined with Immonen and Langford because Rainov indicates the combination would likely fail. (See App. Br. 9.) In particular, Appellant argues that Rainov teaches that temozolomide is not effective in vivo. (App. Br. 10, citing Rainov Figures 2A, 2B.) Appellant argues that given the known side effects of temozolomide, Rainov teaches that temozolomide would be toxic without providing any therapeutic benefit. (See Reply Br. 4.) 8 Appeal2019-000643 Application 14/787,887 We are not persuaded by Appellant's argument. Again, Appellant highlights isolated data without addressing the prior art as a whole. As stated by the Examiner, the actual in vivo data of FIG. 2B of Rainov shows that the combination of temozolomide and ganciclovir was at least as effective as ganciclovir alone in Rainov's hsv-tk model. (See Ans. 15, citing Rainov 665, Figure 2; 666.) Moreover, Rainov refers to the data as demonstrating synergy between HSV-tk/ganciclovir gene therapy and temozolomide chemotherapy, which may reduce toxicity toward the host and decrease the impact of acquired drug resistance. (See FFs 9-11.) Because the expectation of success need only be reasonable, not absolute, we are not persuaded that the Examiner erred in finding claim 1 obvious over the combination of Immonen, Langford, and Rainov. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007). Accordingly, we sustain the Examiner's rejection. Appellant does not separately argue for the patentability of claims 2- 10 and 13-15, and 17-20, which depend on claim 1. Accordingly, these claims fall with claim 1. See 37 C.F.R. § 4I.37(c)(l)(iv). Rejection over Immonen, Langford, Rainov, and Cankovic The Examiner rejects claims 11 and 12 over the combination of Immonen, Langford, Rainov, and Cankovic. (See Final Act. 9-10.) Claim 11 recites: The method of claim 1, further comprising: a. before administering said adenovirus, assaying said human to determine said human's MGMT promoter methylation status. (App. Br. 15.) 9 Appeal2019-000643 Application 14/787,887 The Examiner acknowledges that neither Immonen, Langford, nor Rainov discloses assaying the methylation status of the MGMT promoter before administering the adenovirus. (See Final Act. 10.) However, the Examiner finds that Cankovic teaches patients with increased methylation of the MGMT gene are more likely to experience response to therapy and prolonged overall and disease-free survival. (Id., citing Cankovic 392.) Accordingly, the Examiner determines that it would have been obvious to modify the method of disclosed by Immonen, Langford, and Rainov with Cankovic's method of determining a patient's MGMT promoter methylation status in order to predict the clinical outcome of the treatment method. (Id.) Appellant repeats the arguments presented with respect to claim 1. (See Reply Br. 6-8.) We, therefore, sustain the rejection for the reasons set forth above. Rejections in Light of Chang The Examiner rejects claim 21 over the combination of Immonen, Langford, and Chang (see Final Act. 13-15) and claim 41 over the combination of Immonen, Langford, Chang, and Cankovic (see id. at 15- 16.) Claim 21 is similar to claim 1 and recites: A method comprising: a. treating glioblastoma in a human by surgical resection, and then c. administering locally about the surgical resection site after surgical resection, about 1 x 1012 particles of replication- deficient adenovirus serotype 5 with E 1 and partial E3 deletions, and containing the cDNA for HSV-tk which is able to phosphorylate ganciclovir, and then 10 Appeal2019-000643 Application 14/787,887 d. administering to said human gancyclovir 5mg / kg i.v., twice daily, and e. administering to said human temozolomide. (App. Br. 16.) Claim 41 adds step "b. before administering said adenovirus, assaying said human to determine said human' s MGMT promoter methylation status." (Id.) The Examiner rejects claim 41 over the combination of Immonen, Langford, Chang, and Cankovic. (See Final Act. 15-16.) The Examiner cites Chang for its teaching that the current standard therapy for glioblastoma is surgical resection followed by chemotherapy with temozolomide. (Final Act. 15; FF 12.) The Examiner determines it would have been obvious to a person of ordinary skill in the art to combine the treatment method of Immonen and Langford with the standard therapy of Chang. (Id.) Appellant argues that the combined prior art does not teach a dose of 1x1012 virus particles. (Reply Br. 8.) Appellant argues further that "Chang cannot properly be combined with Immonen and Langford because temozolomide imposes systemic chemotherapy's adverse side effects yet Rainov says it provides no therapeutic benefit. While the rejection does not mention Rainov, the agency must nonetheless here consider Rainov." (Reply Br. 8-9.) We have addressed the argument with regard to the amount of virus particles above. Furthermore, we have considered Rainov's teachings above, and we agree with the Examiner that Rainov as a whole suggests that temozolomide with AdvHSV-tk/ganciclovir therapy could have been combined with a reasonable expectation of success. Appellant does not 11 Appeal2019-000643 Application 14/787,887 present any different arguments against Chang, arguing that "[t]emozolomide is temozolomide. Rainov and Chang use the same stuff." (Reply Br. 9.) We agree with Appellant that Rainov and Chang both teach administering temozolomide to treat glioblastoma; however, we do not agree that this contradicts the Examiner's obviousness determination. Rather, we agree with the Examiner that "[a] skilled artisan would have had a reasonable expectation of success, as administration of the HSV-tk adenoviral particles to be used in conjunction with standard care was known in the art at the time of the invention." (Final Act. 15, see also BTG Intl. Ltd. v. Amneal Pharm. LLC, 923 F.3d 1063, 1074 (Fed. Cir. 2019) ("the record shows that a PHOSITA would have a reasonable expectation of success in combining abiraterone and prednisone because they were both together and individually considered promising prostate cancer treatments at the time.").) Accordingly, we sustain the Examiner's rejection of claim 21. Appellant does not present different arguments against the rejection of claim 41. For the reasons explained above, we are not persuaded that the Examiner erred in rejecting claim 41. Conclusion Upon consideration of the record and the reasons given, the rejections of claims 1-15, 17-21, and 41 under 35 U.S.C. § 103 are sustained. Therefore, we affirm the decision of the Examiner. No time period for taking any subsequent action in connection with this appeal may be extended under 3 7 C.F .R. § 1.13 6. AFFIRMED 12 Copy with citationCopy as parenthetical citation