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 .
Claim Objections
Claims 1, 21, 22 are objected to because of the following informalities: claims 1, 21, 22 recite HBED, acronyms should be spelled out on firs occurrence. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-7, 10, 12-16, 21-25 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.
Claims 1, 21, 22 recite a free chelating ligand selected from desferrioxamine, a desferrioxamine analogue and HBED, or a combination thereof, it is unclear if the limitations of desferrioxamine analogue and HBED are required to be in combination, or may be used independently.
Claims 5 and 13 recite the limitation of wherein the desferrioxamine chelating ligand is selected from DFO, DFO*, DFOSq, DFONCS, DFO*Sq and DFO*NCS, it is unclear if these terms are sufficiently defined in the specification, or well known in the art.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liu (CN 11141625A).
With respect to claim 17, Liu teaches labeling of radioactive metal ions to drug molecules is generally achieved by using bifunctional chelating agents, DFO is a metal ion chelator, and under extreme pH conditions, some biological molecules such as antibodies will precipitate or aggregate and lose their biological activity (Background), using iron treated deferoxiamine (DFO) reacted with drug molecules such as tumor-targeting antibodies, polypeptides, under mild, near physiological pH conditions to label conjugates for use as imaging agents (technical field a process of preparing a conjugate of a desferrioxamine chelating ligand linked with a protein, the process comprising combining at substantially neutral pH), in example 1, and antibody composition (a second composition comprising a protein) is combined with compound I-a in DMSO (p. 5, a composition comprising an iron chelated desferrioxamine chelating ligand and a polar organic solvent), with respect to the limitation of to thereby form an iron complexed conjugate of the desferrioxamine chelating ligand complexed to iron linked with the protein, examiner notes "Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed. A “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003); MPEP §2111.04). Where a reference discloses the terms of the recited method steps, and such steps necessarily result in the desired and recited effect, the fact that the reference does not describe the recited effect in haec verba is of no significance because the reference meets the claim under the doctrine of inherency."
.
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) 1-3, 5-7, 10, 12, 16, 21-25 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Liu (CN 11141625A).
With respect to claims 1 and 22, Liu teaches labeling of radioactive metal ions to drug molecules is generally achieved by using bifunctional chelating agents, DFO is a metal ion chelator, and under extreme pH conditions, some biological molecules such as antibodies will precipitate or aggregate and lose their biological activity (Background), using iron treated deferoxiamine (DFO) reacted with drug molecules such as tumor-targeting antibodies, polypeptides, under mild, near physiological pH conditions to label conjugates for use as imaging agents (technical field, process for preparing a conjugate of a desferrioxamine chelating ligand linked with a protein, the process comprising exposing an iron complexed conjugate, an iron complexed conjugate comprising the desferrioxamine chelating ligand complexed to iron linked with the protein), with steps including a ferrichlor succinimide activated ester that undergoes a condensation reaction with a drug molecule and then it competes with the metal chelating agent to remove Fe3+; (p. 2-3, to thereby remove iron from the desferrioxamine chelating ligand of the iron chelated conjugate and provide the conjugate of the desferrioxamine chelating ligand linked with the protein that is substantially free of chelated iron), ), with respect to the limitation of to thereby form an iron complexed conjugate of the desferrioxamine chelating ligand complexed to iron linked with the protein, examiner notes "Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed. A “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003); MPEP §2111.04). Where a reference discloses the terms of the recited method steps, and such steps necessarily result in the desired and recited effect, the fact that the reference does not describe the recited effect in haec verba is of no significance because the reference meets the claim under the doctrine of inherency."
Liu teaches the ferrichlor succinimide activated ester undergoes a condensation reaction with a drug molecule, and then it competes with the metal chelating agent to remove Fe3+ (p. 3), compound I-a (the DFO/Fe=) in DMSO solution, providing DFO chelating agent; in the examples addition of EDTA or NTA (chelating agents) and removal of iron with a metal chelating agent, using aminotriacetic acid (NTA), hydroxyethylidene diphosphonic acid (HEDP), diethylenetriaminepentaacetic acid (DTPA), preferably EDTA, at physiologic pH, and also teaches DFO is a metal ion chelator, such that if Liu’s DFO in DMSO is not considered to provide free DFO, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add DFO as a chelating agent, as Liu teaches DFO is a chelating agent.
With respect to claim 2, the process of claim 1 is taught above. Liu teaches targeting antibodies (p. 3, wherein the protein is a protein targeting agent).
With respect to claim 3, the process of claim 1, is taught above. Liu teaches antibodies (p. 3).
With respect to claim 5, the process of claim 1, is taught above. Liu teaches DFO as discussed above the desferrioxamine chelating ligand is selected from DFO, DFO*, DFOSq, DFONCS, DFO*Sq and DFO*NCS.
With respect to claim 6, the process of claim 1, is taught above. Liu teaches coupling with succinimide ester (p. 2, the peptide or protein is linked to the desferrioxamine chelating ligand through a covalent linker selected from a covalent bond and succinyl).
With respect to claim 7, the process of claim 1, is taught above. Liu teaches the antibody mixed with compound I-a at room temperature for 2 hours and then EDTA is added and reacted at 35 C for 30 minutes, as noted above Liu’s compound I-s comprises DFO, the step of exposing the iron complexed conjugate with the free chelating agent is conducted at a temperature of about 20C to about 25C (p. 5).
With respect to claim 10, the process of claim 1, is taught above. Liu teaches condensation reaction with a drug molecule at preferably a pH of 7-7.8 (p. 3), the pH is from about 7 to about 8.
With respect to claim 12, the process of claim 1, is taught above. Liu teaches the antibody diluted with HEPES buffer solution with compound I-a added, and addition of EDTA, (examples 1, 4), HEPES is an aqueous buffer, the conjugate is exposed to the free chelating ligand in a solvent comprising water.
With respect to claim 16, the process of claim 1, is taught above. Liu teaches prior to the exposing step, conjugating an iron chelated desferrioxamine chelating ligand with a protein to provide a conjugate of the protein linked with the desferrioxamine chelating ligand complexed to iron (p. 3, steps (1), (2), p. 5).
With respect to claim 21, the process of claim 17, is taught above. Liu teaches the ferrichlor succinimide activated ester undergoes a condensation reaction with a drug molecule, and then it competes with the metal chelating agent to remove Fe3+ (p. 3), compound I-a (the DFO/Fe compound) in DMSO solution, providing DFO chelating agent; in the examples addition of EDTA or NTA (chelating agents) and removal of iron with a metal chelating agent, using aminotriacetic acid (NTA), hydroxyethylidene diphosphonic acid (HEDP), diethylenetriaminepentaacetic acid (DTPA), preferably EDTA, at physiologic pH, and also teaches DFO is a metal ion chelator, such that if Liu’s DFO in DMSO is not considered to provide free DFO, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add DFO as a chelating agent, as Liu teaches DFO is a chelating agent.
With respect to claims 23-25, process of claims 1, 17, and 22 is taught above. Examiner notes that “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior art product was made by a different process”, In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). Further, “although produced by a different process, the burden shifts to applicant to come forward with evidence establishing an unobvious difference between the claimed product and the prior art product”, In re Marosi, 710 F.2d 798, 802, 218 USPQ 289, 292 (Fed. Cir. 1983). See MPEP 2113. Liu teaches an antibody conjugate.
Claim(s) 4 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Liu (CN 11141625A), in view of Codd (US PG Pub 2025/0025582).
With respect to claim 4, the process of claim 1, is taught above. Liu teaches monoclonal antibodies, but does not teach the protein is girentuximab. However, the use of girentuimab for use in imaging agents is known in the art as shown by Codd, Codd teaches
Codd teaches pharmaceutical agents and compositions comprising chelating ligands and radionuclide complexes conjugated to an antibody (0001-0034), conjugated with a chelating ligand (0243-0249), chelating ligands include DFOB (0022-0022, 0145-0217), typically the antibodies or fragments are monoclonal antibodies directed against a desired antigen or hapten, antibodies include girentuximab (0247, 0357, 0371, 439-0440). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use girentuximab, as girentuximab is known in the art as shown by Codd, and depending on the desired specificity (0249).
Claim(s) 1, 21, 22 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Liu (CN 11141625A), alternatively, in view of Savastano (Tales of the Unexpected: The Case of Zirconium(IV) Complexes with Desferrioxamine, 2019).
With respect to claims 1, 21, 22, Liu teaches labeling of radioactive metal ions to drug molecules is generally achieved by using bifunctional chelating agents, DFO is a metal ion chelator, and under extreme pH conditions, some biological molecules such as antibodies will precipitate or aggregate and lose their biological activity (Background), using iron treated deferoxiamine (DFO) reacted with drug molecules such as tumor-targeting antibodies, polypeptides, under mild, near physiological pH conditions to label conjugates for use as imaging agents (technical field, process for preparing a conjugate of a desferrioxamine chelating ligand linked with a protein, the process comprising exposing an iron complexed conjugate, an iron complexed conjugate comprising the desferrioxamine chelating ligand complexed to iron linked with the protein), with steps including a ferrichlor succinimide activated ester that undergoes a condensation reaction with a drug molecule and then it competes with the metal chelating agent to remove Fe3+; (p. 2-3, to thereby remove iron from the desferrioxamine chelating ligand of the iron chelated conjugate and provide the conjugate of the desferrioxamine chelating ligand linked with the protein that is substantially free of chelated iron), with respect to the limitation of to thereby form an iron complexed conjugate of the desferrioxamine chelating ligand complexed to iron linked with the protein, examiner notes "Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed. A “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003); MPEP §2111.04). Where a reference discloses the terms of the recited method steps, and such steps necessarily result in the desired and recited effect, the fact that the reference does not describe the recited effect in haec verba is of no significance because the reference meets the claim under the doctrine of inherency."
Liu teaches the ferrichlor succinimide activated ester undergoes a condensation reaction with a drug molecule, and then it competes with the metal chelating agent to remove Fe3+ (p. 3), compound I-a (the DFO/Fe=) in DMSO solution, providing DFO chelating agent; in the examples addition of EDTA or NTA (chelating agents) and removal of iron with a metal chelating agent, using aminotriacetic acid (NTA), hydroxyethylidene diphosphonic acid (HEDP), diethylenetriaminepentaacetic acid (DTPA), preferably EDTA, at physiologic pH, and also teaches DFO is a metal ion chelator, such that if Liu’s DFO in DMSO is not considered to provide free DFO, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add DFO as a chelating agent, as Liu teaches DFO is a chelating agent.
Alternatively, Savastano teaches Zirconium complexes with Desferrioxamine and its derivatives as imaging agents, DFO is a well-known Fe3 chelator, and Zr4+ has a greater charge than Fe3+ generating stronger electrostatic attraction with the charged ligand and may be more stable (abstract, introduction), EDTA forms complicated complexation, and was abandoned in favor of DFO and strongly competitive hydroxo complexes start being formed from pH 6, where ligand excess is raised to 100-fold, 2:3 species becomes largely prevalent (up to 80%) in the 6.5–7.5 pH range (Figure 4b) (results and discussion), the stabilities of these binuclear complexes are so high that they remain the principal species even in very diluted solutions, under pH and reagent concentrations approaching the conditions used for radiolabeling, and desferrioxamine molecules have been functionalized, e.g., when they have been linked to monoclonal antibodies for the preparation of positron 89Zr-based emitters for PET imaging (Conclusion).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Liu’s taught process of synthesizing imaging agents to use DFO to remove iron, as according to Savastano DFO is a well-known Fe3 chelator, and the stabilities of these binuclear complexes are so high that they remain the principal species even in very diluted solutions, under pH and reagent concentrations approaching the conditions used for radiolabeling, and desferrioxamine molecules have been functionalized, e.g., when they have been linked to monoclonal antibodies for the preparation of positron 89Zr-based emitters for PET imaging.
Claim(s) 14, 15, 19 is/are rejected under 35 U.S.C. 103 as obvious over Liu (CN 11141625A), in view of Savastano (Tales of the Unexpected: The Case of Zirconium(IV) Complexes with Desferrioxamine, 2019).
With respect to claims 14, 15, 19, the process of claim 1, is taught above. Liu teaches combining 100 µL of antibody with 30 µL compound I-a and 1 mL chelating agent (examples), while Liu does not explicilty teach an excess, Savastona teaches Zirconium complexes with Desferrioxamine and its derivatives as imaging agents, DFO is a well-known Fe3 chelator, and Zr4+ has a greater charge than Fe3+ generating stronger electrostatic attraction with the charged ligand and may be more stable (abstract, introduction), EDTA forms complicated complexation, and was abandoned in favor of DFO and strongly competitive hydroxo complexes start being formed from pH 6, where ligand excess is raised to 100-fold, 2:3 species becomes largely prevalent (up to 80%) in the 6.5–7.5 pH range (Figure 4b) (results and discussion), the stabilities of these binuclear complexes are so high that they remain the principal species even in very diluted solutions, under pH and reagent concentrations approaching the conditions used for radiolabeling, and desferrioxamine molecules have been functionalized, e.g., when they have been linked to monoclonal antibodies for the preparation of positron 89Zr-based emitters for PET imaging (Conclusion), where ligand excess is raised to 100-fold, 2:3 species becomes largely prevalent (up to 80%) in the 6.5–7.5 pH range (results, the iron complexed conjugate is exposed to a molar excess of the free chelating agent, a molar ratio of the iron complexed conjugate to the free chelating agent is from about 1:50 to about 1:5000.
With respect to claims 14, 15, 19, the process of claim 1, is taught above. Liu teaches combining 100 µL of antibody with 30 µL compound I-a and 1 mL chelating agent (examples), Savastona teaches where ligand excess is raised to 100-fold, 2:3 species becomes largely prevalent (up to 80%) in the 6.5–7.5 pH range (results, the iron complexed conjugate is exposed to a molar excess of the free chelating agent, a molar ratio of the iron complexed conjugate to the free chelating agent is from about 1:50 to about 1:5000.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Liu’s taught process of synthesizing imaging agents to use DFO in excess to remove iron, as according to Savastano DFO is a well-known Fe3 chelator, and the stabilities of these binuclear complexes are so high that they remain the principal species even in very diluted solutions, under pH and reagent concentrations approaching the conditions used for radiolabeling, and desferrioxamine molecules have been functionalized, e.g., when they have been linked to monoclonal antibodies for the preparation of positron 89Zr-based emitters for PET imaging.
Claim(s) 13 is/are rejected under 35 U.S.C. 103 as obvious over Liu (CN 11141625A), in view of Savastano (Tales of the Unexpected: The Case of Zirconium (IV) Complexes with Desferrioxamine, 2019), in view of Donnelly (US PG Pub 2017/0326084).
With respect to claim 13, the process of claim 1, is taught above. Liu does not teach analogues of DFO, or the desferrioxamine analogue is selected from DFO*, DFOSq, DFONCS, DFO*Sq and DFO*NCS. However analogues of DFO are known in the art for use in imaging, as shown by Donnelly, Donnelly teaches imaging agents comprising DFO-based chelators where “DFO-squaramide” or “DFOSq”), and its conjugate with a biological molecule (when complexed to a radionuclide such as .sup.89Zr), is an effective PET imaging agent (0001-0010). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Liu’s tuaght process to include a DFO deriviative such as DFOSq as taught by Donnelly as according to Donnelly, the radiolabelled conjugates of the compounds of formula (I) with target molecules exhibit improved tumour targeting and tissue selectivity over a number of the known radionuclide chelators (particularly other DFO-based chelators) that are used as PET imaging agents (0082-0084).
Conclusion
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/JEANNIE MCDERMOTT/Examiner, Art Unit 1776
/BRADLEY R SPIES/ Primary Examiner, Art Unit 1776
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