FORMULATIONS AND KITS FOR RADIOTHERAPY AND DIAGNOSTIC IMAGING

§103 §112 §DOUBLEPATENT

DETAILED ACTION Notice of Pre-AIA or AIA Status The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Claims Status Claims 1-14 are pending in the application. Claim Rejections - 35 USC § 112 The following is a quotation of 35 U.S.C. 112(d): (d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph: Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. Claim 11 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The structure of the compound of formula (II) of the instant claims 11 comprises PNG media_image1.png 98 360 media_image1.png Greyscale and does not include a linker group corresponding to the R2 linker group located between the MeCOSar chelator and the NH moiety of the PNG media_image2.png 66 96 media_image2.png Greyscale linker group of the compound PNG media_image3.png 116 314 media_image3.png Greyscale . There is a bond between the MeCOSar chelator and the NH moiety of the PNG media_image4.png 50 82 media_image4.png Greyscale . Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. Claim Rejections - 35 USC § 103 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. Claim(s) 1-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zeglis et al. (US 2016/0331852A1) in view of Donnelly et al. (US 9,701,694B2) and Paterson et al. (Dalton Trans. 2014, 43, 1386-1396) and in further view of Chen et al. (US2007/0269375A1). Zeglis et al. (US 2016/0331852A1) discloses a kit comprising 64Cu-sarcophagine-based tetrazine radioligand PNG media_image5.png 224 394 media_image5.png Greyscale (64Cu-Tz-SarAr) (FIGs. 3C, 5 and 7; p5, [0042]) that encompasses the 64Cu-chelated compound of Formula (II) PNG media_image6.png 102 450 media_image6.png Greyscale of the instant claims 1 and 10 wherein R1 is NH2 of the instant claim 4, R2 comprises an aminobenzyl group of the instant claim 6, R3 is a propylene group of the instant claim 7 and R4 is a phenylene group of the instant claim 9 The kit comprises a plurality of containers, wherein each container has a type selected from an ampule, vial, reservoir, etc. (p5, [0042]) that encompasses the kit comprising multiple containers of the instant claims. One container comprises 64CuCl2 solution (FIG. 7; p10, [0114]; p19, [0153]) that encompasses the container comprising a solution of Cu ions of the instant claims. The 64Cu encompasses the copper radioisotope, such as 64Cu of the instant claims 12 and 13. One container comprises Tz-SarAr (FIG. 7; p5, [0042]; p10, [0114]; p19, [0153]) that encompasses the container comprising the compound of formula II of the instant claims. The kit further includes a second container comprising a targeting moiety-transcyclooctene (TCO), such as huA33-TCO conjugate (p5, [0042]; (p7, [0081]; p19-20, [0155]) that is used in a pretargeted in vivo click chemistry method with 64Cu-Tz-SarAr to provide site specific imaging and therapy of cancer (title; p2, [0015-0017]; p8, [0104-0105],[0107]) that encompasses the compound that can bind to a tumor or cancer site and comprise a functional group that reacts with a tetrazine moiety of the compound of Formula (II) of the instant claim 14. Zeglis et al. does not disclose a.) lyophilized compound, b.) a container comprising sodium chloride and ethanol; or c.) instructions. Donnelly et al. (US 9,701,694B2) discloses nitrogen-containing macrocyclic conjugates as radiopharmaceuticals for use in radiotherapy and diagnostic imaging (title; abstract). The nitrogen-containing macrocyclic conjugates comprise Formula I PNG media_image7.png 92 180 media_image7.png Greyscale wherein L is a nitrogen-containing macrocyclic; X is a linking moiety and Y is a group consisting of N(R2)2, molecular recognition moiety, etc. (column 4, lines 18+; column 6, lines 38+). The nitrogen-containing macrocyclic metal chelators include PNG media_image8.png 110 363 media_image8.png Greyscale (columns 19,20) wherein the carboxy terminus is reacted with a the nitrogen of a reactive element on the molecular recognition unit (column 19, lines 60+; schemes 1,2; column 33, lines 8-17). The nitrogen-containing macrocyclic ligand chelates a metal ion, such as 64Cu, 67Cu, etc. (HCl) (column 11, lines 45+; column 64, lines 25+; claim 14). The nitrogen-containing macrocyclic conjugates may be formulated into a pharmaceutical composition. The pharmaceutical composition is provided in a kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical composition. The kit comprises sterile vials to admix the components prior to use and written materials, such as instructions for use (column 29, lines 52+). Various containers of the kit comprises sterile non-aqueous solutions, adjuvants, etc. The non- aqueous solutions comprise ethanol, etc. (column 30, lines 21-27) and the adjuvants comprise sodium chloride (column 30, lines 35-41). The conjugate is provided in the kit as sterile powders for reconstitution (column 30, lines 21-33). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the ethanol solution to advantageously reconstitute the powder conjugate (i.e. lyophilized) within a container prior to mixing with the radionuclide with a reasonable expectation of success. Also, it would have been predictable to combine the ethanol with sodium chloride in a container to provide isotonicity to the resulting 64Cu-Tz-SarAr formulation. Furthermore, it is obvious to vary and/or optimize the amount of ethanol and sodium chloride provided in the composition, according to the guidance provided by Donnelly et al., to provide a composition having the desired properties such as reconstitution and isotonicity. It is noted that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Zeglis et al. does not disclose the compound of Formula (II) wherein R2 comprises a benzyl group or the compound of the instant claim 11 PNG media_image9.png 108 382 media_image9.png Greyscale . Donnelly et al. further discloses that the nitrogen-containing macrocyclic conjugates comprise Formula I PNG media_image7.png 92 180 media_image7.png Greyscale wherein the X linking moiety comprises C1-C12 alkyl, C6-C18 aryl, etc. (column 5, lines 12-35). The nitrogen-containing macrocycle comprises PNG media_image8.png 110 363 media_image8.png Greyscale wherein the carboxy terminus (or an activated form thereof) can be reacted with a the nitrogen of a reactive element on the molecular recognition unit as stated above. Paterson et al. (Dalton Trans. 2014, 43, 1386-1396) discloses the compounds PNG media_image10.png 396 153 media_image10.png Greyscale wherein R is = NH2 (or CH3 (MeCOSar) (Fig. 1) (Scheme 1). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the SarAr metal chelator of the 64Cu-Tz-SarAr of Zeglis et al. with the Sar derivative chelator comprising a benzylene group linker X of Donnelly et al. to examine the pharmacokinetic properties for use in the pretargeting method of Zeglis et al. The reference of Paterson et al. teaches of a SarAr or MeCOSar metal chelator, with the analogous linker PNG media_image11.png 82 250 media_image11.png Greyscale to the SarAr or MeCOSar derivatives of Donnelly et al. used for pretargeted in vivo click chemistry and therefore, it would have been predictable to one of ordinary skill in the art to substitute the MeCOSar derivatives of Donnelly et al. for the SarAr derivative of Zeglis et al. to provide different compounds comprising a tetrazine moiety able to undergo a click reaction with a TCO conjugate in the pretargeting method for the advantage of therapy and imaging of cancer. Zeglis et al. does not disclose the percentage of ethanol, about 0.5 % (v/v) to about 0.7% (w/v) gentisic acid or methionine stabilizers. Chen et al. (US2007/0269375A1) discloses stabilized radiopharmaceutical formulations, for imaging and radiotherapy, using stabilizers that improve the radiostability of radiotherapeutic and radiodiagnostic compounds (abstract; p11, [0137]; p12, [0143]). Radioisotopes, such as 64Cu, 67Cu, etc. cause radiolytic damage to radiolabeled compound and can cause serious problems during preparation because of the destructive properties of the emissions (p1, [0015-0016]; p4, [0048]; p6-7, [0058]). Inhibitors of radiolysis, such as gentisic acid, methionine, benzyl alcohol, etc. can be used to prevent radiolytic decomposition, etc. (p2, [0019],[0026]; p3, [0026],[0035]; p13-14, [0166-0168]; p23, [0267]; p24, [0283]). A radiolysis stabilizing solution containing a mixture of gentisic acid (sodium gentisate), ascorbic acid (sodium ascorbate), etc. in a physiologically acceptable salt solution (e.g. sodium chloride, etc.) and one or more amino acids, such as methionine are added to the radiolabeled compound immediately following the radiolabeling reaction (p2-3, [0026-0027]; p13, [0164-0165]; p14, [0167]; p18, [0184]; claim 162). A alternative and highly preferably method is to add different potential stabilizers directly to the reaction mixture during chelation (p19, [0209]). The preparation of a radioconjugate involves initially dissolving the conjugate in an alcohol, such as 10% ethanol (p10, [0134]; p22, [0257]). The preparations may be prepared as a single-vial kit or a multi-vial kit where the components can be in different vials and where the constituents can be present in lyophilized form (p13, [0160-0161]; p17, [0178]; p24, [0284]). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize an ethanol radiolysis stabilizing solution comprising combinations the of gentisic acid and/or methionine, etc. stabilizers for 64Cu-Tz-SarAr/derivative compositions of the combined references for the advantage of reducing any potential radiolysis that may occur due to the destructive properties of the emissions from the 64Cu, as taught by Chen et al. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the gentisic acid (sodium gentisate) and sodium chloride in 10% ethanol within separate containers and then provide methionine in a separate container as Chen et al. teaches of adding a potential stabilizer solution directly to the reaction mixture during chelation and then subsequently adding the methionine separately after the radiolabeling reaction which would require different containers. Furthermore, it is obvious to vary and/or optimize the amount of gentisic acid, sodium chloride, and/or methionine provided in the composition, according to the guidance provided by Chen et al., to provide a composition having the desired properties such as reduce radiolysis and provide stabilization of the radiopharmaceutical conjugate against radiolysis. It is noted that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Double Patenting The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying- online/eterminal-disclaimer. Claims 1-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,738,100B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the aqueous formulation of U.S. Patent No. 11,738,100B2 comprising PNG media_image12.png 198 256 media_image12.png Greyscale , about 0.6 to about 1.2 % (w/v) sodium chloride, about 0.06 (w/v) sodium gentisate, about 1 mg/mL to about 4 mg/mL L-methionine and about 4% (v/v) to about 10% (v/v) ethanol prepared via the process for preparing an aqueous formulation encompasses the kit comprising a container of the compounds of formula (II), a container comprising a solution of Cu ions, a container comprising about 4% (v/v) to about 10% (v/v) ethanol and about 0.5% (v/v) to about 0.7% (w/v) sodium gentisate, a container comprising about 4% (v/v) to about 10% (v/v) ethanol and about 0.6 % to about 1.2% (w/v) sodium chloride of the instant claims. The kit comprising a lyophilized compound of formula (II) of the instant claims can be used in the process for preparing an aqueous formulation of U.S. Patent No. 11,738,100B2 via dissolving the compound of Formula (I). The coper radioisotopes, such as 60Cu, 61Cu, 64Cu and 67Cu of U.S. Patent No. 11,738,100B2 encompass the coper radioisotopes, such as 60Cu, 61Cu, 64Cu and 67Cu of the instant claims. The compound of Formula (II) PNG media_image13.png 92 258 media_image13.png Greyscale comprising R1 is alkyl or amino, R2,R3 and R4 are linker groups, not excluding benzylene or aminobenzylene and R5 is H, alkyl or heteroaryl of U.S. Patent No. 11,738,100B2 and the kit comprising a container comprising a solution of Cu ions, a container comprising 4% (v/v) to 10% (v/v) ethanol and about 0.6% (w/v) sodium gentisate, a container comprising 4% (v/v) to 10% (v/v) ethanol and about 0.6 % to about 1.2% (w/v) sodium chloride and instructions encompasses PNG media_image14.png 114 310 media_image14.png Greyscale wherein R1 is alkyl or amino, R2,R3 and R4 are linker groups and R5 is H, alkyl or heteroaryl and the kit of the instant claims stated above. Conclusion No claims are allowed at this time. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MELISSA JEAN PERREIRA whose telephone number is (571)272-1354. The examiner can normally be reached M9-3, T9-3, W9-3, Th9-2, F9-2. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Hartley can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /MELISSA J PERREIRA/Examiner, Art Unit 1618