Ex Parte McCray et alDownload PDFPatent Trial and Appeal BoardJan 18, 201712433659 (P.T.A.B. Jan. 18, 2017) Copy Citation 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. 12/433,659 04/30/2009 Paul B. McCray 17023.089US1 9544 53137 7590 01/20/2017 VIKSNINS HARRIS & PADYS PLLP 7851 Metro Parkway Suite 325 Bloomington, MN 55425 EXAMINER BURKHART, MICHAEL D ART UNIT PAPER NUMBER 1633 NOTIFICATION DATE DELIVERY MODE 01/20/2017 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): docketing @ vhpglobalip .com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte PAUL B. McCRAY and PATRICK L. SINN Appeal 2014-001108 Application 12/433,659 Technology Center 1600 Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and JOHN G. NEW, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1 under 35U.S.C. § 134 involving claims to administering a lentiviral vector encoding a therapeutic protein in at least two consecutive dosages. The Examiner rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. Statement of the Case Background “Mucosal innate and adaptive immune responses against the vector or vector-encoded proteins represent a significant impediment to clinical 1 Appellants identify the Real Party in Interest as University of Iowa Research Foundation (see App. Br. 2). Appeal 2014-001108 Application 12/433,659 applications and are well documented for viral vectors such as adenovirus” (Spec. 1:17—19). “Thus, a major limitation for gene transfer is the inability to re-administer vectors, e.g., as transgene expression wanes, and methods for such administration are needed” (Spec. 1:28—30). The Claims Claims 1—4 and 6—22 are on appeal. Independent claim 1 is representative and reads as follows: 1. A method for treating a patient, comprising administering a lentiviral vector that comprises a nucleotide sequence encoding a therapeutic protein to a tissue of the respiratory system of the patient, wherein the administration comprises administering the lentiviral vector in at least two consecutive dosages, wherein two consecutive dosages of the administration are separated by an interval of more than one day. The Issue The Examiner rejected claims 1—4 and 6—22 under 35 U.S.C. § 103(a) as obvious over Sinn,2 Wang,3 and Hyde4 (Ans. 2—5). The Examiner finds that “though Sinn et al suggest the treatment of cystic fibrosis, a disease of the airway epithelia, by gene therapy using AcGP64-pseudotyped SIV lentiviral vectors, there is no actual disclosure of 2 Sinn et al., Persistent Gene Expression in Mouse Nasal Epithelia following Feline Immunodeficiency Virus-Based Vector Gene Transfer, 79 J. Virology 12818-27 (2005) (“Sinn”). 3 Wang et al., Feline immunodeficiency virus vectors persistently transduce nondividing airway epithelia and correct the cystic fibrosis defect, 104 J. Clinical Investigation R55—R62 (1999) (“Wang”). 4 Hyde et al., Repeat administration of DNA/liposomes to the nasal epithelium ofpatients with cystic fibrosis, 7 Gene Therapy 1156—65 (2000) (“Hyde”). 2 Appeal 2014-001108 Application 12/433,659 targeting airway epithelial cells, or of using the CF transmembrane regulator (CFTR) gene” (Ans. 3). The Examiner finds Wang teaches “an FIV lentiviral vector encoding the CFTR gene” (Ans. 3). The Examiner finds that Hyde teaches “repeat administration of CFTR DNA constructs to the nasal epithelium of patients with cystic fibrosis, further suggesting that repeated administration of the gene transfer vector is required for long-term gene expression” (Ans. 4). The Examiner finds it obvious to “introduce a variety of repeated dose administration or escalation procedures. One would have been motivated to do so because repeated administration of the gene transfer vector is often required for long-term gene expression” (Ans. 5). The issue with respect to these rejections is: Does the evidence of record support the Examiner’s conclusion that Sinn, Wang, and Hyde render the claims obvious? Findings of Fact 1. Sinn teaches “[o]ne aim of gene transfer vector development is to create vehicles to efficiently, safely, and persistently express therapeutic genes in the appropriate cell types. For cystic fibrosis gene therapy, the goal is to deliver the cystic fibrosis transmembrane conductance regulator (CFTR) to surface epithelial cells of the conducting airways” (Sinn 12818, col. 1, citations omitted). 2. Sinn teaches “an FIV pseudotype using GP64 from Autagrapha californica multicapsid nucleopolyhedrovirus (AcMNPV) transduces primary cultures of human airway epithelia from the apical surface and 3 Appeal 2014-001108 Application 12/433,659 mediates persistent gene transfer to the respiratory epithelia of mice” (Sinn 12819, col. 1). 3. Sinn teaches “1.25 x 107 transducing units (TU) of FIV vector in a 50-pl volume were delivered to the nasal epithelia in anesthetized mice via direct instillation.. . . Mice received either a single dose or seven doses over seven consecutive days” (Sinn 12820, col. 1). 4. Sinn teaches “[g]ene transfer efficacy was further evaluated 3, 9, 19, 25, 35, and 50 weeks following vector delivery. Luciferase expression from AcGP64-Luc (with or without MC) remained constant over the tested time period. Conversely, Ad-Luc expression dropped sharply between the 3-week and 9-week time points” (Sinn 12822, col. 1—2). 5. Wang teaches “[g]ene therapy is the most direct means to correct the Cl" transport defect responsible for cystic fibrosis (CF) lung disease” (Wang R55, col. 1). 6. Wang teaches “[sjeveral problems limit the application of gene transfer to correct the cystic fibrosis (CF) CF transport defect in airway epithelia. These include . . . failure of transgene expression to persist, and immune responses to vectors or vector-encoded proteins. To address these issues, we used a feline immunodeficiency virus-based (FIV-based) vector” (Wang R55, abstract). 7. Wang teaches: A further encouraging result of this work was the normal morphology of the airway tissues after gene transfer. There was no evidence of cellular infiltration with immune effector cells when the rabbit airways were examined at the level of light microscopy. Although this does not eliminate the possibility of any immune response, it contrasts with the 4 Appeal 2014-001108 Application 12/433,659 cellular responses noted with adenoviral vectors. Studies with HIV-based lentiviral vectors to date show no evidence of cellular immune responses at the sites of administration in vivo. Furthermore, HIV-based vectors and MuLV vectors can be administered a second time in vivo, suggesting that humoral immune responses may not prevent repeated dosing. (Wang R60, col. 2; citations omitted; emphasis added). 8. Wang teaches that in “cells transduced with adenovirus, AIsc(iBMx/Forsk) gradually declined over time. In contrast, the net AIsc(iBMx/Forsk) in FIV transduced cells remained stable” (Wang R58, col. 2 to 3). 9. Hyde teaches “[g]ene transfer to the airways, to correct the underlying genetic defect, is a potential treatment for CF . . . gene delivery systems investigated to date include recombinant adenovirus, recombinant adeno-associated virus (AAV), and cationic liposomes. All have resulted in relatively low levels of gene expression in the airways” (Hyde 1156, col. 1— 2). 10. Hyde teaches “[tjwelve CF patients were enrolled in the study: 10 received DNA/liposomes and two received a placebo (Table 1). Each subject attended the clinic as an outpatient on 24 occasions receiving three doses of DNA/liposomes or placebo, administered 4 weeks apart” (Hyde 1157, col. 1). 11. Hyde teaches “adenoviral gene expression is transient, necessitating repeat administration; clinical studies have shown that adenoviral gene transfer results in loss of efficacy upon repeat administration, due to the production of neutralising antibodies. AAV may 5 Appeal 2014-001108 Application 12/433,659 prove useful for CFTR airway gene transfer in the future” (Hyde 1156, col. 2; citation omitted). Principles of Law “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Inti Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). “If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” Mat417. Analysis We adopt the Examiner’s findings regarding the scope and content of the prior art (Ans. 2—5; FF 1—11). Sinn, whose aim is to treat cystic fibrosis by delivery of the CFTR gene (FF 1), administers a lentiviral vector that expresses a marker gene to nasal epithelia (FF 2, 4) where the lentiviral vector was administered in seven consecutive dosages separated by an interval of one day (FF 3). Wang also aims to treat cystic fibrosis by delivery of CFTR (FF 5) and teaches that issues with prior vectors include immune responses (FF 6) but that lentiviral vectors “show no evidence of cellular immune responses at the sites of administration in vivo” “suggesting that humoral immune responses may not prevent repeated dosing” (FF 7). Hyde also aims to treat cystic fibrosis by delivery of CFTR (FF 9) and teaches administering a liposomal vector in three dosages “administered 4 weeks apart” (FF 10). We agree with the Examiner that the claimed method would have been obvious over the teachings of Sinn, Wang, and Hyde because “repeated 6 Appeal 2014-001108 Application 12/433,659 administration of the gene transfer vector is often required for long-term gene expression” (Ans. 5; cf. FF 7). We address Appellants’ arguments below. Claim 1 Appellants contend, based on upon the Specification, that “local and systemic immune responses to adenoviral and AAV vectors effectively prevent their repeated pulmonary administration” (App. Br. 10) and that therefore “one of skill in the art would expect that administration of viral vectors may provide for transgene expression in vivo for a period of time but that repeated administrations would be progressively less effective due to a patient’s adaptive immunity” (id.). We find this argument unpersuasive because none of the cited references rely upon adenoviral or AAV vectors, but Sinn and Wang rather suggest the use of lentiviral vectors (FF 2, 6). Indeed, Sinn, Wang, and Hyde each recognize problems with adenovirus and AAV systems including low maintenance of gene transfer (FF 4), decline of correction of the CFTR Cl transport (FF 8) and low levels of gene expression (FF 9). While the artisan might expect adenovirus and AAV systems to become less effective due to adaptive immunity, the artisan would reasonably expect lentiviral vectors to overcome these problems because Wang specifically teaches that the lentiviral system was selected to address these issues (FF 6) and particularly teaches that lentiviral vectors are expected avoid adaptive immunity and allow repeated dosing (FF 7). Appellants contend that Sinn and Hyde “do not teach or suggest administering two consecutive dosages of the lentiviral vector, where the 7 Appeal 2014-001108 Application 12/433,659 dosages are separated by an interval of more than one day” (App. Br. 11) and that “it was surprisingly established, in view of what was known about other viral vector systems, that gene expression could increase additively following repeated retroviral dosages at one-week or two week intervals, without the development of systemic or local neutralizing antibodies” (id.). We do not find this argument persuasive because Sinn exemplifies administering seven doses of lentiviral vectors over seven consecutive days (FF 3) and Wang teaches that the absence of immune response allows lentiviral vectors to be administered “a second time in vivo” (FF 7). To the extent that “more than one day,” a period of 24 hours and one minute, differs from the period of one day, or 24 hours, “a prima facie case of obviousness exists when the claimed range and the prior art range do not overlap but are close enough such that one skilled in the art would have expected them to have the same properties.” In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). Here, Appellants provide no reason to believe that delay of a single minute on the administration of Sinn’s lentiviral vectors would result in any different result. Indeed, Appellants provide no persuasive evidence of an unexpected result for any delivery time frame. We recognize the teaching in the Specification that “[sjurprisingly, reporter gene expression also increased additively following each of 7 doses of FIV delivered over consecutive weeks (1 dose/week), without the development of systemic or local neutralizing antibodies” (Spec. 22:27—30), but agree with the Examiner that Hyde “suggests a variety of dose administration or escalation procedures in order to achieve long-term gene expression” (Ans. 7). That is, we agree 8 Appeal 2014-001108 Application 12/433,659 with the Examiner that the expected result of administering additional doses would be to increase gene expression as a larger number of cells became productively infected with the lentiviral vector. Appellants do not explain why an additive result from adding more vector would be unexpected. Moreover, Appellants have not provided evidence comparing this result to the closest prior art of Sinn, showing that administration of seven doses of lentiviral vector over seven days would not obtain the same additive effect as that obtained over consecutive weeks. 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.”). Appellants contend Hyde et al. teach the use of a completely different gene transfer system than the present invention in an attempt to overcome the problems of adaptive immunity, Hyde et al. acknowledged the problem that researchers had discovered with gene transfer as a possible treatment for cystic fibrosis, namely that repeated administration of gene vector will likely be required for long-term gene expression (App. Br. 11). We find this argument unpersuasive because Hyde’s concerns with adaptive immunity are solely addressed to adenovirus vectors (FF 11), and Wang evidences that this concern regarding immunity is not relevant to lentiviral vectors such as those of Sinn and Wang which “show no evidence of cellular immune responses at the sites of administration in vivo” (FF 6—7). The Examiner solely relies upon Hyde to demonstrate that repeated administrations of a CFTR containing vector may be performed over 9 Appeal 2014-001108 Application 12/433,659 timeframes other than Sinn’s daily administration for seven days, including administrations 4 weeks apart (FF 3, 10). Appellants contend that in “order to circumvent these limitations of viral-based gene transfer systems, Hyde et al. proposed that liposomes be used an alternative system. Thus, Hyde et al. teaches away from the present invention, namely, the use of a viral-vector administration system” (App. Br. 12). We find the teaching away arguments unpersuasive. A teaching away requires a reference to actually criticize, discredit, or otherwise discourage the claimed solution. See In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004) (“The prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed”). Appellants do not identify, and we do not find any teaching in Hyde that criticizes, discredits, or discourages the use of lentiviral vectors such as those suggested by Sinn and Wang (FF 2,6). Indeed, Hyde specifically recognizes that AAV vectors may be useful (FF 11), suggesting that it is only adenovirus vectors that result in neutralizing antibodies that prevent gene transfer and never teaching away from lentiviral vectors. We recognize, but find unpersuasive, Appellants’ contention that the “fact that the inventors proceeded contrary to the accepted wisdom at the time the application was filed is evidence of nonobviousness” (App. Br. 12). Neither Appellants argument nor the Specification provide any evidence that there was “accepted wisdom” that lentiviral vectors could not be re administered. Indeed, the evidence suggests the opposite as Sinn and Wang 10 Appeal 2014-001108 Application 12/433,659 specifically evidence that re-administration of lentiviral vectors was not only possible, but performed by Sinn (FF 3) and suggested by Wang (FF 7). “[Attorney argument [is] not the kind of factual evidence that is required to rebut a prima facie case of obviousness.” In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997). Appellants contend “the Examiner is using impermissible hindsight gleaned from the Applicant’s specification in stating that one of ordinary skill in the art at the time the application was filed would have found it obvious to re-administer the retroviral vector using the claimed invention” (App. Br. 12-13). We are not persuaded. While we are fully 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. In the instant case, Sinn specifically teaches re-administration of a lentiviral vector by administering seven doses over seven days (FF 3) and Wang specifically teaches lentiviral vectors “can be administered a second time in vivo” (FF 7). Thus, rather than hindsight, the prior art predictably suggests to re-administer lentiviral vectors (FF 3, 7). Appellants contend “the examiner must provide evidence as to why someone of skill in the art would have expected a lentiviral system to be different from other known viral vector-based systems, and why the skilled 11 Appeal 2014-001108 Application 12/433,659 person would expect a lentiviral vector to be more similar to a liposome system than to another viral vector system” (Reply Br. 10). We do not find this argument persuasive because the Examiner has provided evidence that other viral vector systems are flawed and lentiviral systems superior in causing a reduced immune response. As already noted, Hyde teaches that adenovirus and AAV result in low levels of gene expression (FF 9) and Wang teaches problems with “immune responses to vectors or vector-encoded proteins” (FF 6) that are overcome by use of lentiviral vectors (FF 7). The Examiner substantively relies upon Hyde simply to evidence that gene transfer vectors may be administered over periods including four weeks (FF 10), and Hyde expressly teaches that liposomes are a known equivalent method of viral delivery (FF 9). Appellants provide no evidence rebutting this equivalence demonstrated by Hyde. Claim 15 Appellants contend “Sinn et al., Hyde el al., and Wang el al. either singly or in combination, do not teach all of the elements of the claim 15, in particular, repeated administration of a viral vector to respiratory tissue with an interval of about one week between at least two of the doses” (App. Br. 13). We are not persuaded. Both Sinn and Wang teach re-administration of lentiviral vectors, including over intervals of one day (FF 3, 7). Hyde teaches that re-administration of gene transfer agents may be performed four weeks apart (FF 10). Thus, the prior art suggests varying time periods for administration of gene transfer vectors, rendering the interval between 12 Appeal 2014-001108 Application 12/433,659 administration being a routinely optimizable variable. We therefore agree with the Examiner that “it is not inventive to discover the optimum or workable ranges by routine experimentation” (Ans. 7). See In re Aller, 220 F.2d 454, 456 (CCPA 1955). Appellants provide insufficient evidence of unexpected results based on a comparison of any specific administration interval with the closest prior art of Sinn. Claim 16 We recognize, but find unpersuasive, Appellants’ contention that “Sinn et al., Hyde el al., and Wang el al. either singly or in combination, do not teach all of the elements of the claim 16, in particular, repeated administration of a viral vector to respiratory tissue with an interval of about one month between at least two of the doses” (App. Br. 16). As discussed above, the interval of administration is a routinely optimizable variable and Hyde specifically teaches administration four weeks apart (FF 10). Thus, we agree with the Examiner that “Sinn and Hyde et al clearly teach[] and suggest[] a variety of dose administration or escalation procedures in order to achieve long-term gene expression, which has been routine in the art at time the instant invention was filed” (Ans. 7). Claim 20 We recognize, but find unpersuasive, Appellants’ contention that “Sinn et al., Hyde et al., and Wang et al. either singly or in combination, do not teach all of the elements of the claim 20, in particular, administration of at least 10 doses of viral vector to respiratory tissue with an interval of about one week between at least the doses” (App. Br. 18). As with the specific intervals of administration, the number of doses reasonably represents an 13 Appeal 2014-001108 Application 12/433,659 optimizable variable, with Sinn teaching administration of either 1 or 7 doses (FF 3), Wang teaching single or multiple administration (FF 7), and Hyde teaching administering 3 doses (FF 10). Appellants provide no evidence of any unexpected result rebutting the prima facie case of obviousness. Conclusion of Law The evidence of record supports the Examiner’s conclusion that Sinn, Wang, and Hyde render the claims obvious. SUMMARY In summary, we affirm the rejection of claims 1—4 and 6—22 under 35 U.S.C. § 103(a) as obvious over Sinn, Wang, and Hyde. 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 14 Copy with citationCopy as parenthetical citation