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 .
Election/Restrictions
Applicant’s election without traverse of DOTAGA-DBCO,
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, as the ligand and acetic acid as the water soluble organic compound in the reply filed on November 17, 2025 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
DOTA-DBCO (2,2′,2′′,2′′′-(1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid-dibenzocyclooctyne) and DOTAGA-DBCO (1,4,7,10-Tetrakis(1,1-dimethylethyl) (|A1S)-|A10-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate-dibenzocyclooctyne) were found to be obvious variants upon search and examination of the claims.
Claim Rejections - 35 USC § 112 – Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3 and 4 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Line 2 of each claim recites the limitation "the water-soluble organic compound". There is insufficient antecedent basis for this limitation in the claim as claim 1 recites “a water-soluble organic compound having one or two sulfo groups” and “a water-soluble compound organic compound having one or two carboxy groups” but not the broader genus of “water-soluble organic compound” as used in the dependent claims.
Please clarify.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1 – 5 are rejected under 35 U.S.C. 103 as being unpatentable over Dudkin et al. (WO 2019/125982; cited on IDS filed July 13, 2023) in view of Lewis et al. (Bioconjugate Chem, 1994).
Dudkin et al. discloses methods of radiolabeling polypeptides, in particular using click chemistry to label a polypeptide with a radiometal ion (p 1, ln 15 – 17). When labeling a polypeptide with a radiometal ion, method of making steps disclosed include providing a radiocomplex comprising the radiometal associated with a chelating moiety comprising a chelant covalently linked to a second click reaction partner, the first click reaction partner being covalently linker to the polypeptide to be labeled (e.g., p 5, ln 4 – 10). The radiometal can be 89Zr associated with a chelating moiety linked to a second click chemistry reaction partner like DOTA-DBCO (p 9, ln 11 – 16). Chelation of the metal is at low or high pH and/or high temperature conditions for maximum efficiency, without risk of inactivating the alkyne reaction partner (p 9, ln 20 – 23). In a preferred embodiment, the chelating moiety is of formula (II) on p 18, which is DOTAGA. Embodiment 17 is a method of labeling a polypeptide with 225Ac, 111In or 89Zr as the radiometal with the chelating moiety comprising DOTAGA-DBCO (p 32, ln 25 – p 33, ln 2). Example 5 (p 45, ln 24 – p 46, ln 16) dissolves the radio metal source (225Ac or 111In) in HCl that was then mixed with a solution of tetramethylammonium acetate with a final solution pH of around 6.5 and about 5.5, respectively for the two different metals, DOTA-GA-DBCO and NaOH. The pKa of acetate/acetic acid is 4.76 (p 6 of acetic acid Safety Data Sheet from Jubilant Ingrevia that accompanies this action), so acetic acid will be present particular at a pH around 5.5. The vial was placed on a shaker block at 80°C or 60°C respectively at 290 rpm for 30 minutes and then the vial was allowed to cool to room temperature. With a total reaction volume of 75 µL and 7.5 µmol of the acetate containing buffer, the final concentration was approximately 0.4 M (mol/L) in each of the aforementioned reactions. 89Zr-DOTA-GA-DBCO was synthesized in an analogous manner (p 47, ln 1 - 19) using although HEPES buffer at pH 7.5 was used with incubation at 90°C for 60 minutes. With a total reaction volume of 210 µL and 150 µmol of HEPES buffer, the final buffer concentration was approximately 0.7 M. The presence of organic solvents in the reaction mixture is not disclosed so the reaction solution contains no organic solvents.
Labeling with 89Zr to DOTAGA at an acidic pH is not explicitly disclosed.
Lewis et al. studied the attachment of DOTA to proteins after activation of a single carboxyl group and the radiolabeling of the protein conjugated with 111In(III) or 90Y(III) was carried out (abstract). Conditions utilizing elevated temperatures, optimized pH and appropriate buffers were explored in order to achieve rapid and efficient radiolabeling (p 566, col 1, ¶ 3). High specific activity was achieved in acetate and TRIS buffers but the presence of citrate inhibited the labeling reaction and increasing the temperature from 25°C to 43°C greatly increased the efficiency of radiometal incorporation and the kinetic stability of the radioconjugate (abstract).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to optimize the pH, buffer and temperature of 89Zr complex formation with DOTAGA-DOBC. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Dudkin et al. discloses low or high pH and/or high temperature conditions can be used for the complexation reactions and Lewis et al. discloses that these factors and the buffer used can affect the rate and efficiency of radiolabeling. Different buffers are required depending on the desired pH and Lewis et al. discloses that different buffers can also alter the extent of radiolabeling. Therefore the pH, buffer and temperature used when preparing complexes of radiometals such as 89Zr with a chelator such as DOTA or DOTAGA are clearly result effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal pH, buffer and temperature for complex formation in order to best achieve the desired results. There is no evidence of record as to the criticality of claimed parameters such as pH and the sulfo or carboxyl containing water soluble organic compound.
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 - 5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11, 12 and 16 - 28 of copending Application No. 17/769,657 in view of Dudkin et al. (WO 2019/125982; cited on IDS filed July 13, 2023) in view of Lewis et al. (Bioconjugate Chem, 1994). The claims of US’675 recite radioactive metal-labeled antibodies with a radioactive-metal containing chelate site of formula (A) as in claim 11. DOTAGA-DBCO can be the chelate moiety used in the complex (see claims 18 and 25).
The process of making the metal chelate complex and specific radioactive metals are not claimed.
Dudkin et al. and Lewis et al. are discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the required radioactive metal chelate complex for the claims of US’657 using the methodology of Dudkin et al. and Lewis et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because the chelate complexes must be prepared in some manner and Dudkin et al. discloses low or high pH and/or high temperature conditions can be used for the complexation reactions and Lewis et al. discloses that these factors and the buffer used can affect the rate and efficiency of radiolabeling. Different buffers are required depending on the desired pH and Lewis et al. discloses that different buffers can also alter the extent of radiolabeling. Therefore the pH, buffer and temperature used when preparing complexes of radiometals such as 89Zr with a chelator such as DOTA or DOTAGA are clearly result effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal pH, buffer and temperature for complex formation in order to best achieve the desired results. There is no evidence of record as to the criticality of claimed parameters such as pH and the sulfo or carboxyl containing water soluble organic compound.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 – 5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 15 of copending Application No. 18/249,753 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both applications have claims drawn to methods of preparing a radioactive zirconium complex with a reaction solution that is not required to contain any organic solvents and a ligand and radioactive zirconium are combined (claim 1). The pH can be in an acidic region (claim 2). Water-soluble organic compounds such as acetic acid can also be present in the reaction solution (claims 8 – 10). The reaction solution can be heated to 30°C – 100°C (claim 11). The required additive of formula (1) in claim 1 and as further defined in dependent claims 6, 7 and 12 read on the ligand compound of the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 – 5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 9 of copending Application No. 18/714,548 in view of Dudkin et al. (WO 2019/125982; cited on IDS filed July 13, 2023) in view of Lewis et al. (Bioconjugate Chem, 1994). The claims of US’548 recite a stabilized radiopharmaceutical composition comprising a polypeptide labeled with a radionuclide such as 89Zr (claims 1 and 6). Chelating agent and radionuclide as in claims 8 and 9 can be present in the radiolabeled polypeptide.
The process of making the metal chelate complex and specific radioactive metals are not claimed.
Dudkin et al. and Lewis et al. are discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the required radioactive metal chelate complex for the claims of US’548 using the methodology of Dudkin et al. and Lewis et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because the chelate complexes must be prepared in some manner and Dudkin et al. discloses low or high pH and/or high temperature conditions can be used for the complexation reactions and Lewis et al. discloses that these factors and the buffer used can affect the rate and efficiency of radiolabeling. Different buffers are required depending on the desired pH and Lewis et al. discloses that different buffers can also alter the extent of radiolabeling. Therefore the pH, buffer and temperature used when preparing complexes of radiometals such as 89Zr with a chelator such as DOTA or DOTAGA are clearly result effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal pH, buffer and temperature for complex formation in order to best achieve the desired results. There is no evidence of record as to the criticality of claimed parameters such as pH and the sulfo or carboxyl containing water soluble organic compound.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 – 5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 6, 9 and 12 - 17 of copending Application No. 18/859,659 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of both applications recite methods of producing radioactive metal complexes in solutions that do not require organic solvents to be present (e.g., claim 1) although organic solvents can be present in the solutions of US’659 (claim 10). The solution comprises water, a buffer containing one or more water-soluble organic compounds have a sulfo or carboxy group and a ligand of formula (1) (claim 1). The radioactive metal nuclide can be 89Zr (claims 2 and 3). The pH of the reaction liquid can be in an acidic region (claim 12) with claimed water-soluble organic compounds having a sulfo or carboxy group including acetic acid (claim 12).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Nissa M Westerberg whose telephone number is (571)270-3532. The examiner can normally be reached M - F 8 am - 4 pm.
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618