Ex Parte Guilford et alDownload PDFBoard of Patent Appeals and InterferencesJul 9, 201211163979 (B.P.A.I. Jul. 9, 2012) Copy Citation MOD PTOL-90A (Rev.06/08) APPLICATION NO./ CONTROL NO. FILING DATE FIRST NAMED INVENTOR / PATENT IN REEXAMINATION ATTORNEY DOCKET NO. 11/163,979 11/06/2005 Guilford, F. Timothy EXAMINER Daneker, McIntire, Schumm, Prince, Manning & Widmann, P.C. One N. Charles Street Suite 2450 Baltimore, MD 21201 Kishore, Gollamudi ART UNIT PAPER NUMBER 1612 MAIL DATE DELIVERY MODE 07/10/2012 PAPER 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. UNITED STATES DEPARTMENT OF COMMERCE U.S. Patent and Trademark Office Address : COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov UNITED STATES PATENT AND TRADEMARK OFFICE _____________________________________________________________________________________ UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES __________ Ex parte F. TIMOTHY GUILFORD and BRIAN CHARLES __________ Appeal 2012-001137 Application 11/163,979 Technology Center 1600 __________ Before ERIC GRIMES, FRANCISCO C. PRATS, and ULRIKE W. JENKS, Administrative Patent Judges. JENKS, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims directed to liposomal formulations containing glutathione. The Examiner has rejected all pending claims. We have jurisdiction under 35 U.S.C. § 6(b). We reverse. Appeal 2012-001137 Application 11/163,979 2 STATEMENT OF THE CASE Claims 1-2, 5-6, 9-10, 13-14, 17-18, 29-31, 39, 41, and 48 are on appeal, and can be found in the Appendix of the Appeal Brief (App. Br. 21- 24). The invention is directed at liposomal formulations containing glutathione for oral administration. Claim 1 is representative of the claims on appeal, and reads as follows: 1. A pharmaceutical composition enabling delivery after oral administration of a therapeutically effective amount of glutathione (reduced) comprising: a therapeutic dose of a reduced glutathione stabilized in a liposomal pharmaceutical carrier capable of being ingested orally, and capable of delivering glutathione (reduced) in a physiologically active state to improve symptoms in disease states by transfer of the glutathione into animal cells, where the concentration of reduced glutathione in the entrapped aqueous space of the liposomes is at least about 123 mM. The following grounds of rejection are before us for review: I. The Examiner has rejected claims 1-2, 5-6, 9-10, 13-14, 17-18, 29-31, 39, 41 and 48 under 35 U.S.C. § 112 second paragraph. II. The Examiner has rejected claims 1, 9, 13 and 17 under 35 U.S.C. § 103(a) as unpatentable over Wendel 1 or Junghans. 2 1 Wendel et al., Drug-Induced Lipid Peroxidation in Mice-III – Glutathione Content of Liver, Kidney and Spleen After Intravenous Administration of Free and Liposomally Entrapped Glutathione, 31 Biochemical Pharmacology 3607-3611 (1981). 2 Junghans et al., Carotenoid-Containing Unilamellar Liposomes Loaded with Glutathione: a Model to Study Hydrophobic-Hydrophilic Antioxidant Interaction, 33 Free Rad. Res 801-808 (2000). Appeal 2012-001137 Application 11/163,979 3 III. The Examiner has rejected claims 1-2, 5-6, 9-10, 13-14, 17-18, 30, 31, 39, 41 and 48 under 35 U.S.C. § 103(a) as unpatentable over Smith. 3 IV. The Examiner has rejected claims 2, 5-6, 10, 14, 18 and 30 under 35 U.S.C. § 103(a) as unpatentable over Wendel or Junghans in view of Smith and/or Barenholz. 4 V. The Examiner has rejected claims 1, 9, 13, 17, 29, 31, 39 and 48 under 35 U.S.C. § 103(a) as unpatentable over Bharath 5 and/or Sechi 6 in combination with Jellinger 7 and Micklus. 8 VI. The Examiner has rejected claims 2, 5-6, 10, 14, 18, 30 and 41 under 35 U.S.C. § 103(a) as unpatentable over Bharat and/or Sechi in combination with Jellinger and Micklus, further in view of Abeliovich 9 and or Barenholz. 3 Smith, US 6,764,693 B1, issued Jul. 20, 2004. 4 Barenholz et al., US 2003/0059462 A1, published Mar. 27, 2003. 5 Bharath et al., Glutathione, iron and Parkinson’s disease, 64 Biochemical Pharmacology 1037-1048 (2002). 6 Sechi et al., Reduced Intravenous Glutathione in the Treatment of Early Parkinson’s Disease, 20 Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1159-1170 (1996). 7 Jellinger, Kurt A., The Role of Iron in Neurodegeneration – Prospects for Pharmacotherapy of Parkinson’s Disease, 14 Drugs & Aging 115-140 (1999). 8 Micklus et al., US 2002/0025313 A1, published Feb. 28, 2002. 9 Abeliovich et al., US 2006/0171935 A1, published Aug. 3, 2006. Appeal 2012-001137 Application 11/163,979 4 ISSUES Did the Examiner err in concluding that the claims are indefinite under 35 U.S.C. §112, second paragraph? Does the evidence of record support the Examiner’s conclusion that the claims are obvious under 35 U.S.C. §103 (a) in light of the cited references? FINDINGS OF FACT FF1. The Examiner acknowledges that different size liposomes “might contain the same molar concentrations of the active agents” (Ans. 10). FF2. Wendel disclosed liposomes containing glutathione (GSH) at a concentration of 25 mg/ml (Wendel 3608). FF3. Junghans disclosed liposomes containing GSH at 100 mM (Junghans 802). This is equivalent to a concentration of 30.7 mg/ml (Ans. 6). FF4. Smith disclosed liposomal formulations containing GSH and selenium (Smith col. 25, l. 60 to col. 26, l. 53). Smith disclosed GSH treatment protocols with a daily dosing of GSH of 0.5 g/Kg (intravenous) or 1 Kg/M 2 (topical) (Smith, col. 25, ll. 45-60, esp. ll. 56-57). Smith discloses treatment with a dosage of GSH from 0.001-2.0 g/kg. (Smith claim 1.) FF5. Smith disclosed oral administration of liposomes even though that route of administration may be controversial (Smith col. 13, ll. 44-51). FF6. Barenholz provided generic pharmaceutical compositions comprising liposomes formulated for oral administration. (Barenholz claims 11, 12, and Appeal 2012-001137 Application 11/163,979 5 15.) Liposomes included antioxidants such as selenium and GSH. (Id. 3, ¶ 0039.) PRINCIPLES OF LAW “The test for definiteness is whether one skilled in the art would understand the bounds of the claim when read in light of the specification.” Miles Laboratories Inc. v. Shandon Inc., 997 F.2d 870, 875 (Fed. Cir. 1993). A rejection for obviousness must include “articulated reasoning with some rational underpinning to support the legal conclusion.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), quoting In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). ANALYSIS I. The Examiner has rejected all claims on appeal under 35 U.S.C.§ 112, second paragraph, on the basis that reciting 123 millimolar (mM) amounts of the active ingredient without reciting the sizes of the liposomes is not meaningful (Ans. 5). The Examiner takes the position [s]ince 1 molar concentration is a molecular weight of a compound in 1000 ml of an aqueous medium (1 mole in 1000 ml), 1 ml of this solution is still one molar, but the amount of the active agent is 0.001 moles. Therefore, both 1 micrometer size liposomes and 10 nm size liposomes might contain the same molar concentrations of the active agents, but the mole or weight amounts of the active agent in 1 nm size liposome will be 1000 times less than that in 1 micrometer liposome. (Ans. 10-11.) Appeal 2012-001137 Application 11/163,979 6 Appellants argue that the limitation regarding internal GSH concentration of the liposomes at 123 mM is precise, clear, correct, and unambiguous (App. Br. 12). Measurements of the concentration of a compound in solution, such as molarity or percentage solution notation (e.g., w/w and w/v), are easily obtainable, convertible and comparable (App. Br. 13). We agree with Appellants that the Examiner has not adequately shown the claims are indefinite. “The test for definiteness is whether one skilled in the art would understand the bounds of the claim when read in light of the specification.” Miles Laboratories Inc. v. Shandon Inc., 997 F.2d 870, 875 (Fed. Cir. 1993). The claims are directed at the concentration of the glutathione that is entrapped in the aqueous space of the liposomes. The liposomes are made using a film of lipids that is then sonicated with an aqueous solution containing the reduced glutathione (Spec. 17-18, Example 1a; 19, Example 2). In the Specification’s examples, the concentration of the glutathione in the aqueous phase is at least 123 mM (Keller Dec. 3-4 10 ), and presumably the aqueous phase that is entrapped in the liposomes will have that same concentration. The Examiner admits that regardless of size, the liposomes “might contain the same molar concentrations of the active agents” (FF1). The Examiner asserts that depending on the size of the liposome the mole or weight amounts will change (Ans. 10). However, the claims are directed to a composition comprising liposomes with a 123 mM concentration of GSH, not an amount specified by weight or number of 10 Declaration of Brian Keller under 37 C.F.R. § 1.132, executed on April 13, 2010. Appeal 2012-001137 Application 11/163,979 7 moles, in the entrapped aqueous phase. The molar concentration of GSH inside the liposomes is the same as the starting aqueous solution during the liposome production. Reading the claims in light of the specification we do not find the claims indefinite. Thus, we reverse the Examiner’s rejection of the claims on the grounds of lack of clarity. II. The Examiner has rejected claims 1, 9, 13, and 17 under 35 U.S.C. § 103(a) as unpatentable over Wendel or Junghans. In making an obviousness rejection the Examiner must first identify the scope and content of the prior art. Graham v John Deere Co., 383 U.S. 1, 17 (1966). Thus we first turn to the prior art. Wendel disclosed the production of liposomes for intravenous administration of encapsulated GSH. The liposomal GSH concentration is 25 mg/ml (FF2). 11 Junghans disclosed liposomes containing 100 mM or 30.7 mg/ml GSH (FF3). The next step is to identify the difference between the prior art and the claimed invention. Graham, 383 U.S. at 17. Neither Wendel nor Junghans disclose liposomes containing 123 mM glutathione. Once the differences between the prior art and the claimed invention have been identified, the next step is to identify motivation or a reason why persons of ordinary skill in the art would have been prompted to combine the prior art to have made the claimed invention. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007). Here the Examiner asserts “it would have been obvious to one of ordinary skill in the art . . . to increase the amounts of 11 Since 30.7 mg/ml GSH is equivalent to 100 mM (FF3), 25 mg/ml GSH is equivalent to 81.4 mM. Appeal 2012-001137 Application 11/163,979 8 GSH in the liposomes” (Ans. 6). Appellants contend that the present application contains liposome having an entrapped GSH concentration of 123 mM (or 37.8 mg/ml) and neither reference teaches or suggests increasing the internal GSH concentration of the liposomes (App. Br. 16-17). We agree with the Appellants that the Examiner has not articulated a reason for combining the references to arrive at an entrapped aqueous concentration of 123 mM GSH. A rejection for obviousness must include “articulated reasoning with some rational underpinning to support the legal conclusion.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), quoting In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). While the Examiner urges that no criticality has been asserted for the claimed concentration (Ans. 6), Appellants explained that the 123 mM GSH concentration was experimentally determined because they needed to balance taste while providing the highest dose possible in order to increase patient compliance (Keller Dec. 4). The Examiner even acknowledges that the Keller Declaration provides the description of the encapsulation of GSH in 123 mM amounts and the product made by 'Your Energy Systems, LLC' markets a liposomal product for oral delivery under the trademark 'READYSORB' and that the product has been and continues to be a commercially successful product. (Ans. 14.) The Examiner has not addressed the reason why the ordinary artisan based on the prior art would arrive at liposomes with an entrapped reduced GSH concentration of 123 mM. The Examiner asserts “it would have been Appeal 2012-001137 Application 11/163,979 9 obvious to one of ordinary skill in the art to encapsulate glutathione at a desired concentration including the claimed amount in Smith” (Ans. 6). Smith, however, is silent with regard to the actual liposomal concentrations of GSH, and the Examiner has provided no evidence or sound technical reasoning (e.g., because of Smith’s dosages and the solubility of GSH) to support a conclusion that the claimed concentration would have been inherent in Smith. Thus, the Examiner has not shown that Smith would direct the ordinary artisan to increase the liposomal concentration of GSH in the liposomes of Wendel or Junghans. As noted above, Appellants explained that the 123 mM GSH concentration was experimentally determined while balancing factors such as treatment dose and taste with patient compliance (Keller Dec. 4). Because the Examiner has not articulated a reason for the ordinary artisan to arrive at a concentration of at least 123 mM GSH, we reverse the rejection of claims 1, 9, 13 and 17 under 35 U.S.C. § 103(a). III. The Examiner has rejected claims 1-2, 5-6, 9-10, 13-14, 17-18, 30, 31, 39, 41, and 48 under 35 U.S.C. § 103(a) as being obvious over Smith. Smith disclosed liposomes containing GSH and selenium (FF3). Smith is silent with regard to the amount of GSH encapsulated within the liposomes (Ans. 6-7). The Examiner takes the position that the ordinary artisan would be motivated to manipulate the amounts and sizes of the liposomes since they depend on the condition to be treated and the severity of the disease (Ans. 7). Appeal 2012-001137 Application 11/163,979 10 Appellants argue that Smith does not disclose the internal GSH concentrations of the liposomes. (App. Br. 17). We agree with Appellants that Smith is silent with regard to GSH concentration in the liposomes. Because the Examiner has not provided us with a rationale to support arriving at 123 mM GSH concentration, we cannot sustain this rejection. We reverse the rejection of 1-2, 5-6, 9-10, 13-14, 17-18, 30, 31, 39, 41, and 48 under 35 U.S.C. § 103(a). IV. The Examiner has rejected claims 2, 5-6, 10, 14, 18 and 30 under 35 U.S.C. § 103(a) as being obvious over Wendel or Junghans in view of Smith and/or Barenholz. The disclosures of Wendel, Junghans and Smith have been discussed above. Wendel and Junghans do not disclose the incorporation of selenium in the liposomes (Ans. 7). Barenholz disclosed liposomes that contain selenium and/or glutathione (FF4). The Examiner takes the position that the ordinary artisan would be motivated to include additional anti-oxidants such as selenium with the expectation of obtaining an additive effect (Ans. 7). We find that Wendel and Junghans disclosed GSH containing liposomes at a concentration of 100mM or below (FF1, FF2). Smith and/or Barenholz generically disclosed GSH and selenium containing liposomes. Both are silent with regard to the concentration of the liposome entrapped GSH. Based on the evidence before us we conclude that the Examiner has not established a prima facie case with regards to liposomes having an Appeal 2012-001137 Application 11/163,979 11 entrapped glutathione concentration of 123 mM. We reverse the rejection of 2, 5-6, 10, 14, 18 and 30 under 35 U.S.C. § 103(a). V. The Examiner has rejected claims 1, 9, 13, 17, 29, 31, 39 and 48 under 35 U.S.C. § 103(a) as unpatentable over Bharath and/or Sechi in combination with Jellinger and Micklus. Bharat disclosed oxidative stress in the substantia nigra due to GSH depletion (Ans. 8). Sechi disclosed a deficiency of reduced GSH in the substantia nigra of Parkinson’s patients (Ans. 8). Jellinger disclosed the use of anti-oxidants or free radical scavengers in combination with iron chelators (Ans. 8). Micklus disclosed liposomal encapsulation of neuromodulators and targeting to the blood brain barrier (Ans. 9). What is lacking in Bharath, Sechi or Jellinger is the use of liposomes (Ans. 8). Micklus taught the use of liposomes and directing the liposomes to the blood brain barrier (Ans. 9). The Examiner takes the position that encapsulating GSH in liposomes to treat Parkinson’s disease would be obvious because the references teach the involvement of GSH in the disease process (Ans. 9). Appellants argue that the references may recognize the potential relationship between GSH and Parkinson’s disease, but the references do not disclose or suggest the presently claimed liposomal compositions (App. Br. 18). We agree with Appellants, that recognizing the association of GSH depletion with a disease state would not lead the ordinary artisan to arrive at liposomes containing a concentration of 123 mM GSH. We reverse the rejection of claims 1, 9, 13, 17, 29, 31, 39 and 48 under 35 U.S.C. § 103(a). Appeal 2012-001137 Application 11/163,979 12 VI. The Examiner has rejected claims 2, 5-6, 10, 14, 18, 30 and 41 under 35 U.S.C. § 103(a) as unpatentable over Bharath and/or Sechi in combination with Jellinger and Micklus, further in view of Abeliovich and or Barenholz. The shortcomings of the Bharath, Sechi, Jellinger and Micklus are discussed above; in addition, none of the references disclosed the use of selenium as an antioxidant. Abeliovich disclosed that selenium is commonly used for the treatment of Parkinson’s disease (Ans. 9), but this does not make up for the previously discussed shortcomings of the Bharath, Sechi, Jellinger and Micklus. We reverse the rejection of claims 2, 5-6, 10, 14, 18, 30 and 41 under 35 U.S.C. § 103(a). CONCLUSION OF LAW The Examiner made an error in finding the claims indefinite under 35 U.S.C. §112, second paragraph. The evidence of record does not support the Examiner conclusion that the invention as a whole would have been obvious. SUMMARY We reverse the rejection of claims 1-2, 5-6, 9-10, 13-14, 17-18, 29-31, 39, 41 and 48 under 25 U.S.C. § 112, second paragraph. Appeal 2012-001137 Application 11/163,979 13 We also reverse the rejection of claims 1-2, 5-6, 9-10, 13-14, 17-18, 29-31, 39, 41 and 48 under 35 U.S.C. § 103(a). REVERSED alw Copy with citationCopy as parenthetical citation