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 .
Acknowledgement of Receipt
Applicant’s Response, filed 10/24/2025, in reply to the Office Action mailed 5/19/2025, is acknowledged and has been entered. Claims 21, 22 and 24 have been amended. Claims 25-41 are newly added. Claims 21, 22 and 24-41 are pending and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. New grounds for rejection are set forth herein, necessitated by claim amendment. The Examiner’s response to Applicant’s arguments is incorporated below.
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.
Claim(s) 21, 22, 24-29 and 33-41 are rejected under 35 U.S.C. 103 as being unpatentable over Rosch et al. (US 2017/0327520) in view of Pandya et al. (Chem. Sci., 2017, 8, p. 2309-2314), in further view of Bordoloi et al. (Dalton Trans., 2015, 44, p. 4963-4975).
Rosch teaches the object of providing a pharmaceutical with an accumulation at bones, in particular at bone tumors, that is increased in comparison to the prior art. A better accumulation ratio for bone-to-blood and bone-to-soft tissue, a greater binding yield to bone tumors, and an efficient renal excretion of unbound pharmaceutical should hereby be achieved. Depending on the selection of the radionuclide, the bisphosphonate derivatives according to the invention should be usable for molecular imaging, in particular as a PET diagnostic agent, and as an endoradiotherapeutic agent.
This object is achieved via a compound V comprising a chelator X and one or more targeting vectors (TV) conjugated with the chelator X, said targeting vectors having the structure -L1-R1-L2-R2-L3-R3 (paragraph 0019-20+).
The chelator X is selected from the group comprising EDTA (ethylenediamine-tetraacetate), EDTMP (diethylenetriamine penta(methylene phosphonic acid)), DTPA (diethylenetriamine pentaacetic acid) and its derivatives, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), etc. (paragraph 009).
The compound V comprises a chelator X and one or more targeting vectors conjugated with the chelator X, said targeting vectors having the structure -L1-R1-L2-R2-L3-R3. The compound V especially has the one of the following structures
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, etc. paragraph 0054+.
An exemplary compound is of Formula III (paragraph 0072):
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The present invention also relates to the use of a compound V according to the invention as a labelling precursor for the production of a medicine or pharmaceutical. The invention also relates to the use of a pharmaceutical of such a pharmaceutical in an imaging process by means of positron emission tomography or single photon emission computer tomography. The pharmaceutical according to the invention is suitable for use in a treatment or therapy process. It is especially suitable for use in a method for treatment of bone diseases and bone tumors. Such a method for the treatment of bone diseases and bone tumors is therefore according to the invention. Such methods in particular include methods for use of the pharmaceutical in the treatment of diseases of non-manifested bone metastases. These methods preferably include the accumulation in the tumor cells in order to inhibit farnesyl pyrophosphate synthesis (FPPS). Other medical methods and uses of the pharmaceutical according to the invention include the imaging of pharmacokinetic processes (such as heart diseases) by means of positron emission tomography or single photon emission computer tomography. The pharmaceutical may also be used in vivo or ex vivo as an additive in artificial bone substance, in bone cement, or in bone implants.
The invention further relates to the use of a compound V according to the invention in conjunction with a metallic isotope M (such as gadolinium) to produce a pharmaceutical, wherein the metallic isotope M is preferably selected from among the isotopes 44Sc, 47Sc, 55Co, 62Cu, 64Cu, 67Cu, 66Ga, 67Ga, 68Ga, 89Zr, 86Y, 90Y, 90Nb, 99mTc, 111In, 135Sm, 159Gd, 149Tb, 160Tb, 161Tb, 165Er, 166Dy, 166Ho, 175Yb, 177Lu, 186Re, 188Re, 213Bi and 225Ac. (paragraph 0082-3).
Rosch does not specifically recite wherein 89Zr is in the 4+ oxidation state, and
does not specifically recite imaging and therapy of vascular calcification/atherosclerosis.
Pandya teaches that zirconium-89 (89Zr: (t1/2 = 78.4 h, β+: 22.8%, Eβ+max = 901 keV; EC: 77%, Eγ = 909 keV)) is a positron-emitting radionuclide currently being tested in over 30 clinical trials involving monoclonal antibodies (mAbs); its radioactive half-life complements the biological half-life of a circulating antibody in vivo. Standard practice within the radiopharmaceutical industry requires 89Zr to be attached to an antibody through desferrioxamine (DFO) or its analogs, which are derivatives of the iron chelator desferral, a growth-promoting agent secreted by Streptomyces pilosus. Despite the widespread use of DFO in 89Zr-immuno-PET applications, the unsaturated coordination sphere of 89Zr–DFO is believed to be responsible for its observed instability in preclinical animal models, and significant effort has been expended to develop improved 89Zr(iv)-chelators.
Tetraazamacrocycles such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) remain a largely unexplored class of ligands due to a perceived inability to form stable 89Zr-complexes. Although only anecdotal evidence has appeared in the literature, instability is believed to arise from chelation by the four macrocycle nitrogen atoms and four oxygen atoms of the pendant arms rather than eight oxygen donors, which are believed to be preferred by the oxophilic 89Zr4+ ion. As a result, little is known regarding their Zr coordination chemistry or use in 89Zr-radiopharmaceutical development. Despite well-reasoned arguments to the contrary, it seemed reasonable to posit that tetraazamacrocycles would be useful in 89Zr-radiopharmaceutical applications, since several Zr–cyclam complexes have been described previously. Additionally, we reasoned that their use would be advantageous since (1) they demonstrate enhanced stability over acyclic ligands due to the macrocyclic effect; (2) various functional groups can be introduced into the macrocycle's backbone or pendant arms to modulate the ligand's stereo- and coordination chemistry; (3) bifunctional chelators derived from these ligands allow them to be conjugated to various peptides, proteins, and antibodies; and (4) they have been used successfully in a number of radiopharmaceutical applications and clinical trials (page 2309).
Here we document our initial investigations into the use of tetraazamacrocycles as 89Zr-chelators. We describe the synthesis and complete characterization of Zr–DOTA, Zr–DOTAM, and Zr–DOTP (Fig. 1), and describe the first crystal structure of Zr–DOTA, which reveals a saturated coordination sphere around the Zr4+ ion. Finally, we evaluate the radioactive analogs in vitro and in vivo, and show that 89Zr–DOTA demonstrates behaviour that is superior to 89Zr–DFO. To the best of our knowledge, this is the first report to evaluate tetraazamacrocycles as 89Zr-chelators and to provide a rationale for their exceptional and unpredicted in vivo behaviour.
Fig. 3 shows PET maximum-intensity projection images comparing 89Zr–DOTA and 89Zr–DFO.
The synthetic methodologies we describe here can facilitate systematic study of 89Zr coordination chemistry using inorganic chemistry, radiochemistry and molecular imaging techniques to elucidate how to create 89Zr-radiopharmaceuticals with excellent stability in vivo.
This report is the first to describe the structural characterization of Zr–DOTA using single-crystal X-ray diffraction and the use of tetraazamacrocycles as 89Zr-chelators. In all studies, 89Zr–DOTA demonstrated superior in vivo behaviour compared to 89Zr–DFO, which is considered the “gold standard” in clinical 89Zr-radiopharmaceutical development. These results refute current thinking regarding the use of tetraazamacrocycles as 89Zr-chelators, and may provide a way to enhance development of radiolabeled agents for precision medicine applications (page 2312).
It would have been obvious to one of ordinary skill in the art at the time of the invention that to select 89Zr as a suitable radionuclide for preparation of chelator bisphosphonate conjugates for use as radiopharmaceuticals in diagnostic imaging as taught by Rosch. One would have been motivated to do so, with a reasonable expectation of success because Rosch teaches 89Zr to be one of a few suitable radionuclides to be used in such methods. It would have been further obvious that 89Zr is in the 4+ oxidation state because Pandya teaches that 89Zr 4+ forms complexes with DOTA derivatives with excellent stability in vivo. Regarding claim 17 Rosch further teaches DTPA to be suitable for conjugation to bisphosphonates.
Bordoloi teaches that techetium-99m (99mTc) complexes of MDP (methylene diphosphonate, 1, Fig. 1) and related 1,1-bisphosphonates such as HDP (hydroxymethylene diphosphonate) have been used successfully for decades in the clinic for acquiring planar and SPECT images of osteoblastic processes associated with bone tumours and metastases. Another 1,1-bisphosphonate analogue, HEDP (2) has found use in palliative treatment of bone metastases with the beta-emitting rhenium isotopes rhenium-186 (186Re) and rhenium-188 (188Re).
In addition to the need for improved in vivo stability and therapeutic efficacy of bone-targeting rhenium complexes, new applications are emerging for imaging calcification (or decalcification) processes that place more stringent demands on imaging agents than conventional imaging of osteoblastic bone metastases. For example, imaging osteolytic lesions characteristic of multiple myeloma has very poor sensitivity with conventional 99mTc-bisphosphonate complexes, and imaging soft tissue calcification associated with cardiovascular diseases such as atherosclerosis and arterial calcification may require complexes with improved imaging characteristics because the lesions are small and mineral content and mineralization/demineralization rates may be low (page 4963).
To achieve the required improvements in in vivo stability and affinity for mineral deposits, we adopted the strategy of separating the metal chelating site from the bisphosphonate (bone targeting) site in a bifunctional molecule. This allows separate control/optimization of metal chelation and bone targeting, exemplified by the ligand DPA-Alendronate (3) and its 99mTc12 and 188Re13 complexes (4) using the readily-synthesized tricarbonyl [M(CO)3] + cores. [188Re]-5 showed higher bone uptake and more prolonged bone retention of 188Re in vivo and higher biological stability compared with 188Re-HEDP (188Re-2) over a 24 hour period.13 The results indicate that [188Re]-5 has potential as an improved palliative agent for bone metastases, but remains non-ideal due to modest uptake in non-target organs such as the liver, attributed to the increased lipophilicity of the complex. In this paper we extend the concept of bifunctional ligands for bone targeting, by synthesizing complexes with increased mineral affinity by the inclusion of two pendant bisphosphonate groups in the molecule, and evaluating them in the challenging setting of an animal model of arterial calcification.
Here we have used the ligand DTC-BP (6), previously used to form a copper-64 complex,19 in a kit-based approach to synthesize the novel bis(bisphosphonate) complex 99mTcN(DTC-BP)2 ([99mTc]-7) and its rhenium analogues 8 and [188Re]-8, and compared their biological behaviour with that of the mono(bisphosphonate) derivative [99mTc]-4 and the conventional bone-imaging agent 99mTc-1 (page 4964).
The new technetium and rhenium complexes with two pendant bisphosphonate groups have been synthesized by simple methods amenable to kit-based radiolabelling. The presence of one and two pendant bisphosphonate groups confers advantages over conventional bisphosphonate complexes in which the bisphosphonate group is involved in technetium or rhenium chelation, in terms of in vivo stability and affinity for hydroxyapatite of synthetic and biological origin. These advantages are likely to be significant in therapeutic applications involving the longer half-life isotopes 186Re and 188Re. All three classes of 99mTc complex described here are capable of imaging vascular soft tissue calcification as well as bone disease (page 4974).
It would have been obvious to one of ordinary skill in the art at the time of the invention that to select 89Zr as a suitable radionuclide for preparation of chelator bisphosphonate conjugates for use as radiopharmaceuticals in diagnostic imaging as taught by Rosch. One would have been motivated to do so, with a reasonable expectation of success because Rosch teaches 89Zr to be one of a few suitable radionuclides to be used in such methods. It would have been further obvious that 89Zr is in the 4+ oxidation state because Pandya teaches that 89Zr 4+ forms complexes with DOTA derivatives with excellent stability in vivo.
It would have been further obvious to one of ordinary skill in the art at the time of the invention to provide 89Zr4+ complexes of a chelating ligand conjugated to a bisphosphonate for using in imaging/therapy of vascular calcification/atherosclerosis when the teachings of Rosch and Pandya are taken in view of Bordoloi. While Rosch teaches imaging of bone with the claimed complexes, imaging of vascular calcification is not specifically taught. However, one would have been motivated to further perform imaging of vascular calcification with a reasonable expectation of success because it is known from Bordoloi that radiolabeled complexes bearing structurally similar bisphosphonate targeting groups are capable of imaging vascular soft tissue calcification as well as bone disease. Further Rosch teaches his complexes to be useful as PET diagnostic agents and endoradiotherapeutic agents, including heart disease.
Response to arguments
Applicant argues that a skilled artisan would not have been motivated to combine the teachings of the cited art, and if they had been so motivated, which Applicant does not concede, the skilled artisan would not have had any reasonable expectation of success in detecting a site of vascular calcification or treating atherosclerosis in a subject. Applicant asserts that Rosch is cited for teaching compounds that will "accumulat[e] at bones," and will have "a better accumulation ratio for bone-to-blood and bone-to-soft tissue". Applicant notes that Bordoloi emphasizes the challenges in detecting vascular calcification, where it teaches (at page 4963) that: "imaging soft tissue calcification associated with cardiovascular diseases such as atherosclerosis and arterial calcification may require complexes with improved imaging characteristics because the lesions are small and mineral content and mineralization/demineralization rates may be low." Applicant aruges that given the teachings of Bordoloi that vascular calcification imaging has unique challenges requiring complexes with improved characteristics, Applicant submits that a person having ordinary skill in the art would not look to the bone targeting compounds disclosed in Rosch for vascular calcification imaging. Applicant asserts that there is nothing in Rosch, or any of the other cited art publications, that would motivate a person having ordinary skill in the art to use the bone-targeting compounds or Rosch for vascular calcification imaging… and the skilled artisan would have had no reasonable expectation of success given the challenges articulated in Bordoloi.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that Bordoloi teaches that bisphosphonate complexes are suitable for use in imaging soft tissue calcification associated with cardiovascular disease, in addition to bone. For example, it is taught that “complexes with two pendant bisphosphonate groups have been synthesised by simple methods amenable to kit-based radiolabelling. The presence of one and two pendant bisphosphonate groups confers advantages over conventional bisphosphonate complexes in which the bisphosphonate group is involved in technetium or rhenium chelation, in terms of in vivo stability and affinity for hydroxyapatite of synthetic and biological origin. These advantages are likely to be significant in therapeutic applications involving the longer half-life isotopes 186Re and 188Re. All three classes of 99mTc complex described here are capable of imaging vascular soft tissue calcification as well as bone disease. The tracers and biological models described here prove a means to study the diagnostic meaning and value of imaging of vascular calcification (page 4974).” As such, it is considered that the argument that one would not look to the bone targeting compounds disclosed in Rosch for vascular calcification imaging is not found to be persuasive.
Further, Rosch even teaches use of the complexes in imaging heart diseases, at paragraph 0082. “Other medical methods and uses of the pharmaceutical according to the invention include the imaging of pharmacokinetic processes (such as heart diseases) by means of positron emission tomography or single photon emission computer tomography.” As such, it is considered that one would have had motivation and reasonable expectation of success in using the complexes for imaging/therapy of heart diseases.
Claim(s) 21, 22, 24-41 are rejected under 35 U.S.C. 103 as being unpatentable over Rosch et al. (US 2017/0327520) in view of Pandya et al. (Chem. Sci., 2017, 8, p. 2309-2314), in further view of Bordoloi et al. (Dalton Trans., 2015, 44, p. 4963-4975) and Cheong (KR 20170037727).
The rejection over Rosch in view of Pandya and Bordoloi is applied as above.
With regard to claims 30-32, -CH2C(O)NH(CH2)3- is not specifically recited as a linker.
Cheong teaches a manufacturing method of ppyeoam diagnostic radiolabeled kit according to the invention comprises a step for preparing a (a) poly-cyclic aza mark phosphonate compound containing composition.
Specifically, the preparation of the composition containing the polyazamacrocyclic phosphonate compound is carried out by using a polyazamacrocyclic phosphonate compound; A buffer solution having a pH ranging from 3 to 5; And an ascorbic acid-containing mixed solution.
The polyazamacrocyclic phosphonate-based compound is a DOTA derivative chelate compound to be described later, and has a stable chelate with Ga-68 as compared with the conventional EDTMP, and thus has a long storage time and excellent chemical stability, as a target compound.
In this specification "DOTA" is 1,4,7,10-tetraaza bicyclo FIG decane-1,4,7,10-tetraacetic acid (1,4,7,10-tetraazacyclododecane-1,4,7,10-Tetraacetic acid) and is a metal-compatible ligand compound. This compound is a metal-compatible ligand compound used in PET imaging, and it is a ligand compound of Cu-64, Cu-67, Ga-68, Zr-89, Y-86, Y-90, Lu-111, and has an advantage of being able to reduce the cytotoxicity caused by the radioactive subst because it acts to remove the radioactive subst from the body.
The polyazamacrocyclic phosphonate-based compound is a DOTA derivative chelate compound, and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid (1,4,7 , 10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-4-amino-1-hydroxybutylidene-1,1-bisphosphonate; DOTA-HBP ) And 4-bisphosphonomethylcarbamoylmethyl-7,10-biscarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl acetic acid acetic acid (4-{ (Phosphono methyl) carbamoyl methyl}-7,10-bis (carboxymethyl)-1,4,7,10-tetraaza cyclododec-1-yl acetic acid, BPAMD).
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DOTA-HBP
It would have been obvious to one of ordinary skill in the art at the time of the invention that to substitute DOTA-HBP, which features a -CH2C(O)NH(CH2)3- linker between DOTA and bisphosphonate, as a functionally equivalent chelator conjugated to bisphosphonate when the teachings of Rosch, Pandya and Bordoloi are taken in view of Cheong. The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. ___, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. One such rationale includes the simple substitution of one known element for another to obtain predictable results. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. See MPEP 2143. In the instant case, the substituted components and their functions were known in the art at the time of the instant invention. One of ordinary skill in the art could have substituted one known bisphosphonate chelate conjugate for another, and the results of the substitution would have been predictable, that is chelation of a metal by the chelate and targeting function by the bisphosphonate.
Conclusion
No claims are allowed at this time.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618