Ex Parte Pitner et alDownload PDFPatent Trial and Appeal BoardMay 31, 201612681438 (P.T.A.B. May. 31, 2016) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE FIRST NAMED INVENTOR 12/681,438 04/02/2010 William-Robert Pitner 23599 7590 06/03/2016 MILLEN, WHITE, ZELANO & BRANIGAN, P.C. 2200 CLARENDON BL VD. SUITE 1400 ARLINGTON, VA 22201 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. MERCK-3700 4324 EXAMINER KOSACK, JOSEPH R ART UNIT PAPER NUMBER 1626 NOTIFICATION DATE DELIVERY MODE 06/03/2016 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@mwzb.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte WILLIAM-ROBERT PITNER, JENS EICHHORN, JOERG VON HAGEN, PETER A. LELAND, and GRAHAM B.I. SCOTT Appeal2014-003342 Application 12/681,438 1 Technology Center 1600 Before DEMETRA J. MILLS, ULRIKE W. JENKS, and JOHN G. NEW, Administrative Patent Judges. NEW, Administrative Patent Judge. DECISION ON APPEAL 1 Appellants state the real party-in-interest is Merck Patent GmbH. App. Br. 1. Appeal2014-003342 Application 12/681,438 SUMMARY Appellants file this appeal under 35 U.S.C. § 134(a) from the Examiner's Final Rejection of claims 1, 4--6, 8, and 9 as unpatentable under 35 U.S.C. §103(a) as being obvious over the combination of Christian Lange et al., Ionic Liquids as Refolding Additives: N'-alkyl and N'-(w- hydroxyalkyl) N-methylimidazolium chlorides, 14 PROTEIN SCIENCE 2693- 701 (2005) ("Lange") and Earle et al. (WO 2006/072775 A2, July 13, 2006) ("Earle"). 2,3 We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. NATURE OF THE CLAIMED INVENTION Appellants' invention is directed to the use of ionic liquids comprising a cation with at least one electron donor region and one positively charged electrostatic region, which are spatially distinct from each other, for protein refolding. Appellants also claim a method for refolding proteins using ionic liquids. Abstract. REPRESENTATIVE CLAIM Appellants argue the claims together. App. Br. 3. Claim 1 is representative and recites: 2 Claims 2, 3, 7, 10, and 11 are canceled. See Claims, submitted March 14, 2014. Claims 12-15 are withdrawn. App. Br. 3. 3 The Examiner also rejected claim 4 as unpatentable under 35 U.S.C. § 112, second paragraph, for failing to particularly point out and distinctly claim the subject matter of the invention. Final Act. 2. This rejection has been withdrawn by the Examiner. Ans. 5. 2 Appeal2014-003342 Application 12/681,438 1. A method for the refolding, the increase of the thermal stability and/or the decrease of the aggregation of proteins, wherein the proteins to be treated are contacted with a liquid medium comprising at least one ionic liquid which comprises a cation with at least one electron donor region and at least one positively charged electrostatic region which are spatially distinct from each other, of the formula with R1' to R4 ' each, independently of one another, denot[ing] -H, -CN, -OR', -NR'2, -P(O)R'2, -P(O)(OR')2, -P(O)(NR'2)2, -C(O)R', -C(O)OR', -C(O)NR'2-, -S02NR' 2, -N02, straight-chain or branched alkyl having 1-20 C atoms, straight-chain or branched alkenyl having 2-20 C atoms and one or more double bonds, straight-chain or branched alkinyl having 2-20 C atoms and one or more triple bonds, saturated, partially or fully unsaturated cycloalkyl having 3-7 C atoms, which may be substituted by alkyl groups having 1---6 C atoms, saturated, partially or fully unsaturated heteroaryl, heteroaryl---C1---C6-alkyl or aryl-C1-C6-alkyl, 3 Appeal2014-003342 Application 12/681,438 App. Br. 7. where the substituents R 1', R2 ', R3, and/or R4 , together may also form a ring system, where one or more substituents R1' to R4 ' may be partially or fully substituted by halogens, in particular -F and/or -Cl, or -OH, -OR', -CN, -C(O)OH, -C(O)NR' 2, S02NR2, -C(O)X, -S020H, -S02X or -N02, but where R1' and R4 ' cannot simultaneously be fully substituted by halogens, and where one or two non- adjacent carbon atoms of the substituents R1, to R4 , which are not bonded to the heteroatom may be replaced by atoms and/or atom groups -0-, -S-, -S(O)-, -S02-, -S020-, -C(O)-, -C(O)O-, -N+R' 2-, -P(O)R'O-, -C(O)NR' -, -S02NR' -, -OP(O)R'O-, -P(O)(NR' 2)NR' -, -PR' 2=N- or -P(O)R' -, R' = H, non-, partially or perfluorinated C1- to C6-alkyl, C3- to C7 cycloalkyl, or unsubstituted or substituted phenyl, and X = halogen, with the proviso that the pyridinium cation has at least one substituent R1' to R4 ' per molecule which is -CN, -OR', -NR' 2, -P(O)R' 2, -P(O)(OR')2, -P(O)(NR' 2)2, -C(O)R', -C(O)OR', -C(O)NR'2, -S02NR'2 or -N02 and/or at least one substituent R 1' to R 4 ' per molecule which is substituted with-OR', -CN, -C(O)OH, -C(O)NR'2, -S02NR'2, -C(O)X, -S020H, -S02X or -N02 or in which one or two non-adjacent carbon atoms which are not bonded to the heteroatom are replaced by atoms and/or atom groups selected from -0-, -S-, -S(O)-, -S02, -S020-, -C(O)-, -C(O)O-, -N+R' 2-, -P(O)R'O-, -C(O)NR' -, -S02NR' -, - OP(O)R'O-, -P(O)(NR' 2)NR' -, -PR' 2=N- and -P(O)R' - . ISSUES AND ANALYSES We agree with, and adopt, the Examiner's findings and conclusion that the appealed claims are prima facie obvious over the cited prior art references. We address the arguments raised by Appellants on appeal below. 4 Appeal2014-003342 Application 12/681,438 Issue Appellants argue the Examiner erred in finding a person of ordinary skill in the art would be motivated to combine the teachings of the combined cited prior art and allege the Examiner improperly employed hindsight analysis. App. Br. 4. Analysis Appellants argue Lange teaches refolding of proteins using ionic liquids including ethyl methyl imidazole chloride, and other imidazoles, but neither teaches nor suggests pyridinium or morpholinium compounds.4 App. Br. 3. Appellants contend there is therefore no teaching or suggestion in Lange that would cause one of ordinary skill in the art to modify its teachings to include pyridinium or morpholinium compounds, as required by claim 1. Id. Appellants admit the Examiner was correct in finding that most of the cations of the ionic liquids of Lange also have at least one electron donor region and at least one positively charged electrostatic region, however, Appellants argue, this teaching is insufficient to "form a bridge" between the imidazoles taught by Lange and the pyridines or morpholines required by claim 1. Id. (citing Final Act. 4-5). Rather, assert Appellants, this appreciation of the properties of the compounds taught by Lange is visible only as hindsight by the Examiner. Id. 4 Ionic liquids or liquid salts are ionic species which consist of an organic cation and an inorganic or (less frequently) an organic anion. The ionic liquids used according to Appellants' invention are liquid at room temperature, or if they are not liquid at room temperature, they should at least be present in a liquid form and/or be soluble in the liquid medium under the conditions of treatment. Spec. 11. 5 Appeal2014-003342 Application 12/681,438 Furthermore, Appellants argue, despite the Examiner's finding that Lange teaches a pyridinium-based ionic liquid that has been shown to refold proteins, this N-substituted, pyridinium-based cation does not have the required at least one electron donor region, thereby allegedly undercutting the logic of the Examiner's analysis. App. Br. 4. Appellants also admit that Earle teaches a compound corresponding to the requirements of claim 1, namely ethyldimethylaminopyridinium ("EDMAP") bromide. App. Br. 4. However, Appellants argue, Earle teaches an "enormous generic disclosure" with arguably a single pyridinium cation in a single example (Example 3) of 19 examples. Id. Appellants also assert Earle discloses no utility of the compounds in refolding proteins. Id. Appellants therefore contend that Lange's teaching of an imidazolinium-based ionic liquid with an electron donor region and at least one positively charged electrostatic region which are spatially distinct from each other would not motivate a skilled artisan to look for similar ionic liquids, or to choose EDMAP bromide taught by Earle, without benefit of the disclosures of Appellants' Specification. App. Br. 4. Appellants assert that a person of ordinary skill, upon learning from the teachings of Lange that certain imidazolium based ionic liquids with hydrophobic groups and the N-substituted l-butyl-4-methyl-pyridinium tetrafluoroborate are suitable for refolding proteins would, upon learning the teachings of Earle, not be motivated to choose Earle's pyridinium-based ionic liquids, such as EDMAP bromide, in attempting to refold, increase the thermal stability, and/or decrease the aggregation of proteins, as recited in claim 1. Id. The Examiner responds, arguing that Lange explicitly teaches N- substituted pyridinium ionic liquids as a known ionic liquid and that one of 6 Appeal2014-003342 Application 12/681,438 ordinary skill in the art would be aware of the properties of a known ionic liquid. Ans. 5 (citing Lange 2964). The Examiner finds that although Lange focuses on imidazolium ionic liquids, there is no teaching or suggestion in Lange that would dissuade the person of ordinary skill in the art from trying other ionic liquids. Id. The Examiner also finds, contrary to Appellants' assertion, Earle teaches not a large variety of ionic liquids, but rather ionic liquids with 14 different cations which contain ammonium, pyridinium, morpholinium, and imidazolium ionic liquids. Ans. 6. The Examiner finds Earle explicitly teaches EMDAP bromide, which falls within the scope of the claims on appeal and possesses an amino tether. Id. (citing Earle 20, Example 3). The Examiner admits Earle does not explicitly teach ionic liquids can be used for the claimed method of refolding proteins, but finds Earle does teach that ionic liquids are basic and can be used to catalyze basic processes. Id. (citing Earle 3). The Examiner finds Lange teaches both ethylmethylimidazolium chloride and hydroxyethylmethylimidazolium chloride are effective at refolding lysozyme and that a person of ordinary skill in the art would readily recognize the similarity between the refolding ionic liquids of Lange and the basic ionic liquids of Earle. Ans. 6. The Examiner finds such a person of ordinary skill would recognize that both have a basic heterocyclic ring and a tether that may or may not have a basic group. Id. The Examiner finds the explicit teachings of Lange with respect to pyridinium ionic liquids would naturally lead an artisan of ordinary skill to try the pyridinium ionic liquids taught by Earle, which are within the scope of the claims on appeal, to refold proteins. Id. 7 Appeal2014-003342 Application 12/681,438 Finally, the Examiner finds a person of ordinary skill would be motivated to combine the ionic liquids of Earle, including those falling within the scope of the claims, in the process taught by Lange because Lange teaches that other ionic liquids, including N-substituted pyridiniums, have been used to refold the same protein as those taught by Lange using imidazolium compounds. Final Act. 7. The Examiner concludes a person of ordinary skill would find it obvious that the process would be general for an ammonium or nitrogen heterocyclonium ionic liquid to have an effect on refolding proteins. Id. Finally, the Examiner finds that, because two different classes of ionic liquid taught as being tested by Lange, there would be a reasonable expectation of success that a pyridinium-based ionic liquid, such as those taught by Earle, would work to refold proteins, and concludes that the claims are therefore prima facie obvious over the prior art. Id. We are not persuaded by Appellants' arguments. Lange teaches pyridinium-based ionic liquids are well-known in the art: "These salts [i.e., ionic liquids] generally consist of combinations of organic cations, namely derivatives ofN, N'-substituted imidazolium, N-substituted pyridinium, tetraalkylated ammonium, and tetraalkylated phosphonium, and either organic or inorganic anions." Lange 2694. With respect to pyridinium- based ionic liquids, Lange also teaches: "Preliminary experiments in our laboratory, e.g., had shown that recombinant tissue-type plasminogen activator could be refolded with increasing yields in solutions containing up to 94% (w/v) of the ionic liquid 1-butyl-4-methyl-pyridinium tetrafluoroborate." Id. (citation omitted). Although, as Appellants point out, the N-substituted pyridinium thus taught by Lange does not possess the required "at least one electron donor region and at least one positively 8 Appeal2014-003342 Application 12/681,438 charged electrostatic region which are spatially distinct from each other" required by claim 1, Lange nevertheless suggests to a person of ordinary skill that substituted pyridinium-based ionic liquids could be useful in reforming a denatured protein. Furthermore, Earle teaches, as a preferred embodiment in an example, an ionic liquid substituted-pyridinium compound, EMDAP bromide, which, Appellants admit, falls within the scope of that recited in the claimed method. See Earle 20, Example 3. Although Earle does not teach EMDAP bromide is capable of refolding proteins, we agree with the Examiner that a person of ordinary skill would be motivated to combine the teachings of Earle with that of Lange, because Lange's teaching that N-substituted pyridiniums can be used to refold proteins would provide a reasonable expectation of success when using EMDAP bromide in the same or similar manner. Consequently, we conclude that combining the teachings of Lange and Earle would have been obvious to a person of ordinary skill, requiring not innovation, but ordinary skill and common sense. See KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007). We therefore agree with the Examiner that it would be obvious to combine the references to arrive at the same conclusion and we affirm the rejection of claims 1, 4--6, 8 and 9. 9 Appeal2014-003342 Application 12/681,438 CONCLUSION We agree with the Examiner's findings and conclusions establishing a primafacie case of obviousness and we do not find Appellant's arguments to the contrary persuasive. We consequently affirm the Examiner's rejection of the claims. DECISION The Examiner's rejection of claims 1, 4---6, 8 and 9 as unpatentable under 35 U.S.C. § 103(a) is affirmed. 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). See 37 C.F.R. § 1.136(a)(l )(iv). AFFIRMED rvb 10 Copy with citationCopy as parenthetical citation