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 .
Summary
Claims 27-46 are pending in this office action. Claims 1-26 are cancelled. All pending claims are under examination in this application.
Priority
The current application filed on February 08, 2024 is a 371 of PCT/EP2022/072494 filed August 10, 2022. The current application claims foreign priority to GB2111553.0 filed on August 11, 2021.
Information Disclosure Statement
Receipt of the Information Disclosure Statements filed on February 8, 2024 and July 23, 2025 are acknowledged. A signed copy of both documents are attached to this office action.
Claim Objections
Claims 27-46 are objected to because of the following informalities:
Claim 27: Please ensure the body of the claim contains a space between C1-C4 and alkyl group instead of C1-C4alkyl group. This error is repeated multiple times, for example, C5-C12aryl, C1-C4alkoxy, etc. Also, please begin the numbering with Formula I instead of Formula II. Adjust the Formula numbers accordingly throughout the claims.
Dependent claims 28-30, 32-34, and 36-46 are included here because they fail to cure the defects of claim 27.
Claim 28, 31, 32, 37, 39, 40, and 42: In a similar manner to claim 27 [spacing], these claims also feature multiple errors.
Dependent claims 29, 33, 35 are included here because the fail to cure the defects of their corresponding independent claim.
Claim 42: Please be more specific when the Applicant claims, “a buffering agent, a reducing agent, an intermediate co-ligand, and a conjugated diphosphine precursor compound…” There is a full array of reagents that could meet this limitation and some are suitable while others are not.
Claims 43 and 44: From a practicality point of view, how was the Applicant going to control the half-life if a radioelement is placed in a kit? It will immediately start to decay. This will cause problems for the consumer. Also, dependent claims 43 and 44 are included here because they fail to cure the defect of claim 42.
Appropriate correction is required.
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.
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 non-obviousness.
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.
Claims 27-46 are rejected under 35 U.S.C. 103 as being unpatentable over Hungnes et al. (EP Workshop on Phosphorus Chemistry, 2019) in view of Maina et al. (US2007/0041903A1), Lewis et al. (J. Chem. Soc., Dalton Trans., 1997), and Doorn et al. (J. Chem. Soc., Perkin Trans. 2, 1990).
[The Examiner is going to introduce each reference and then combine them in the rejection of the instant claims.]
1. Hungnes et al.
Hungnes et al. is the closest prior art to the present invention as it teaches a new biocompatible diphosphine-peptide chelator: attaching peptides to 99mTc(V) for targeted SPECT imaging of disease (see title). Also, Hungnes et al. disclose over 30 million routine nuclear imaging procedures are carried out annually using the gamma-emitting radionuclide technetium-99m (99mTc, T1/2 = 6 hours), yet few 99mTc-labelled peptide based molecular imaging agents have reached clinical trials, mainly due to complicated radiolabelling procedures. We report a novel diphosphine-based bioconjugate that can be labelled efficiently with 99mTc in a single step using simple kit-based methods suitable for clinical translation.
Reaction of 2,3-bis(diphenylphosphino)maleic anhydride (BMA) with the primary amine of a cyclic "RGD" peptide, which targets avb3 integrin receptors, provided a ring-opened diphosphine chelator-peptide, DPP-RGD. A single-step kit-based process was developed to radiolabel DPP-RGD with generator-produced, aqueous [99mTcVIIO4]- in thirty minutes to give two isomers of [99mTcVO2(DPP-RGD)2]+ in radiochemical yields >95%.
Non-radioactive rhenium (Re) complexes serve as excellent models for their radioactive 99mTc analogues mainly due to the lanthanide contraction. The Re homologues of the new 99mTc bioconjugates were prepared. Detailed NMR studies and mass spectrometry revealed that the isomeric complexes are cis- and trans-[ReVO2(DPP-RGD)2]+. The 99mTc and Re complexes exhibit near-identical chromatographic behaviour, as determined by HPLC with radioactivity and UV detection, suggesting that the 99mTc and Re complexes are isostructural.
The combination of 99mTc and two RGD peptides in [99mTcVO2(DPP-RGD)2]+ enables whole body detection of avb3 integrin-expressing tumours, tumour vasculature and inflamed tissue. The targeting abilities of [99mTcVO-2(DPP-RGD)2]+ has been demonstrated in vitro and in vivo. Non-invasive SPECT imaging of mice with rheumatoid arthritis showed that [99mTcVO-2(DPP-RGD)2]+ clears rapidly from the bloodstream, accumulates in inflamed joints and is predominantly excreted renally.
BMA can be coupled to a range of biomolecules through a primary amine to form bis(DPP-peptide) bioconjugates that are easily radioiabelled with 99mTc. This makes BMA and bis(diphosphine)-based chelators excellent candidates for the development of clinicaily translatable, easily radiolabelled, target-specific 99mTc radiotracers (see abstract).
2. Mania et al.
Mania et al. teach modified minigastrin analogs for oncology applications (see title). Additionally, Mania et al. disclose that the invention is directed to modified minigastrin analogs. It further relates to labeling such modified minigastrin analogs
with metallic radionuclides. The invention further relates to methods for making such novel modified minigastrin analogs, their labeling with metallic radionuclides and their use in oncology applications as in the targeted diagnostic imaging and staging of CCK-2/gastrin-R-positive neoplasms in man with SPECT (technetium-99m), or PET (technetium-94m), or eventually in targeted radionuclide therapy (rhenium-
188) (see abstract).
3. Lewis et al.
Lewis et al. teach diphosphine bifunctional chelators for low-valent metal ions. Crystal structures of the copper(I) complexes [CuCIL12 and [CuL12 [PF6]
[L1 = 2,3-bis(diphenylphosphino)maleic anhydride]. Furthermore, Lewis et al. disclose the chelating diphosphine 2,3-bis(diphenylphosphino)maleic anhydride (L1) reacted with CuCI to give [CuCIL12] 1a in which the copper is bound to three phosphorus atoms and one chlorine in a pseudo-tetrahedral structure, as demonstrated by X-ray crystallography. Compound L1 reacted with [Cu(MeCN)4][PF6] to give the red salt [CuL1
2][PF6] 1b in which the copper is bound by four phosphorus atoms of two chelating bidentate ligands, as demonstrated by X-ray crystallography. Addition of chloride ions to 1b quantitatively affords 1a. Complex 1a can be converted quantitatively into [CuL12[NO3] 1c by treatment with AgNO3. These complexes reacted quantitatively with water, benzylamine and methanol to give the corresponding [CuL22]+ 2 [CuL32]+ 3 and
[CuL42]+ 4 where L2 = 2,3-bis(diphenylphosphino)maleic acid and L3 and L4 are the monobenzylamide and monomethyl ester derivatives, respectively, of L2. Uncomplexed L1 can also be hydrolysed to L2 or derivatised with benzylamine or methanol to give L3 and L4 respectively. Compounds L2, L3, and L4 and reacted with copper-(I) or -(II)
salts to yield salts of 2, 3 and 4. This chemistry provides versatile routes to the synthesis of stable bioconjugates containing copper or radiocopper and of derivatised solids containing pendant diphosphine ligands (see abstract).
4. Doorn et al.
Doorn et al. teach formation and reactions of bis(phosphino)succinic anhydrides (see title). In addition, Doorn et al. disclose a route to 2,3-bis(phosphino)succinic anhydrides and related compounds is described. The compounds are formed by reaction of a secondary phosphine with maleic anhydrides which bear a leaving group at the alkenic carbon atom. The reaction of bromomaleic anhydride with
diphenylphosphine proceeds via diphenylphosphinomaieic anhydride. An acid -catalysed Michael addition leads to cis-2,3-bis(diphenylphosphino)succinic anhydride, which in turn rearranges to the trans isomer by an acid-catalysed process. The trans isomer was isolated as a hydrobromide. The formation of diphosphines from the corresponding maleic acids and esters has also been observed. A primary phosphine does not lead to a phosphinosuccinic anhydride.
Addition of a base to the bis(phosphino)succinic anhydride generally leads to the elimination of the phosphine moiety. However, the anhydride ring can be opened with sodium methoxide and a diphosphine, with both a carboxylic acid and a carboxylate ester moiety, is formed in moderate yield. Two conformers or isomers of this compound are obtained, both of which decarboxylate readily to give methyl 2,3-bis(diphenyiphosphino)propanoate.
Co-ordination of the diphosphine system to Pt11 prevents both the elimination of secondary phosphine and the decarboxylation of carboxylic groups (see abstract).
Combination of Hungnes et al., Mania et al., Lewis et al., and Doorn et al.
Regarding instant claim 27, Hungnes et al., Mania et al., Lewis et al., and Doorn et al. teach a conjugated diphosphine precursor compound according to Formula (II) that is suitable for preparing a conjugated radiolabelled agent. The necessary citations within Hungnes et al., Mania et al., Lewis et al., and Doorn et al. that correspond to instant claim 27 are compiled within Table I.
Table I
Instant Claim 27
Hungnes et al., Mania et al., Lewis et al., and Doorn et al. Citations
A conjugated diphosphine precursor compound according to Formula (II) that is suitable for preparing a conjugated radiolabelled agent:
Hungnes et al. disclose the preparation of the radiocomplex [99mTcVO2(DPP-RGD)2]+ for use in medical SPECT imaging from the diphosphine chelator-peptide DPP-RGD which in turn is obtained in a ring-opening reaction of 2,3-bis(diphenylphosphino)maleic anhydride with the primary amine of a cyclic RGD peptide. Hungnes et al.Hungnes also describes corresponding non-radioactive rhenium complexes.
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Doorn et al. disclose diphosphines of general formula:
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(see page 480, right column within Doorn et al.) Furthermore, Doorn et al. disclose the following thirteen R groups:
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(see page 481, Table 1 within Doorn et al.) The Doorn et al. disclosure allows for other substituted aryl derivatives as shown in entries 9-12.
Lewis et al. disclose copper complexes of the following cyclic anhydride which can be subsequently opened with an amine of choice:
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(see page 856 within Lewis et al.). The metal complexes disclosed by Lewis et al. lay the groundwork for a skilled artisan (POSITA; person of ordinary skill in the art) to install a radioelement such as 99mTc [disclosed by Hungnes et al. above].
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Finally, Mania et al. disclose ligands comprising modified minigastrin (peptide) analogues (see title, abstract, and claims within Mania et al.). The amine portion of the modified minigastrin analogue [targeting the cholecystokinin-2 receptor] could open the anhydride disclosed by Lewis et al. to afford the LIG group. The Mania et al. disclosure allows the use of the modified minigastrin analogues (LIGAND) instead of the RGD cyclic peptide(LIGAND) disclosed by Hungnes et al.
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Hungnes et al. with the teachings of both Doorn et al. and Lewis et al. to afford the diphosphines of choice, and Mania et al. to install the minigastrin ligand instead of the RGD peptide ligand. The motivation for doing so would have been to develop a diphosphine chelator that targets the cholecystokinin-2 receptor.
Therefore, instant claim 27 is taught in full by the disclosures of Hungnes et al., Mania et al., Lewis et al., and Doorn et al. for the remainder of the dependent claims.
Regarding instant claim 28, Hungnes et al., Mania et al., Lewis et al., and Doorn et al. teach a conjugated diphosphine precursor compound according to Formula (IIa) that is suitable for preparing a conjugated radiolabelled agent.
Please see the discussion and citations within instant claim 27 (Table I). Additionally, both the RGDfK pentapeptide and the PSMAt dipeptide (Lys((PEG)4)-uredo-Glu are commercial and could be purchased through the vendor Peptide Synthetics (Hampshire, UK). Therefore, along with the minigastrin peptide analogue discussed within instant claim 27, both the RGD and PSMAt peptides could be used as LIGAND groups [through the opening of the cyclic anhydride with an amine moiety] targeting additional biological receptors.
Regarding instant claims 29-35, Hungnes et al., Mania et al., Lewis et al., and Doorn et al. teach a conjugated diphosphine precursor compound according to the instant claim Formula that is suitable for preparing a conjugated radiolabelled agent.
Please see the discussion and citations within instant claim 27 (Table I) and instant claim 28.
Regarding instant claims 36-40, Hungnes et al., Mania et al., Lewis et al., and Doorn et al. teach a radiolabelled diphosphine complex comprising at least two compounds ordinated with one or more radionuclides from the selected group.
Please see the discussion and citations within instant claim 27 (Table I) and instant claim 28. In addition, Mania et al. disclose the use of both 99mTc and 188Re (see abstract within Mania et al.). The ratio of cis- and trans- isomers would be controlled by both thermodynamic and kinetic properties.
Regarding instant claim 41, Hungnes et al., Mania et al., Lewis et al., and Doorn et al. teach a pharmaceutical composition comprising a compound or complex of ub—instant claim 27 in combination with a pharmaceutically acceptable carrier.
Mania et al. disclose the in vivo administration of the modified minigastrin analogues into mice by IV formulation (see paragraph [0051] within Mania et al.). Therefore, a pharmaceutically acceptable carrier is chosen to form the IV formulation prior to administration.
Regarding instant claims 42-44, Hungnes et al., Mania et al., Lewis et al., and Doorn et al. teach a kit for preparing a complex according to instant claim 38, Compound (Tc-III-1-RGD), Compound (186Re-III-1-RGD) or Compound (Re-III-1-RGD) comprising a mixture of a reducing agent, a buffering agent, an intermediate co-ligand and a conjugated diphosphine precursor compound or Compound (II-1-RGD) and the selected radionucleotide.
A skilled artisan (POSITA) could construct a kit to maintain the instant claim 42 based on the previous instant claims. The chemistry reagents would be added as necessary to allow for the synthesis of the desired product.
Regarding instant claims 45 and 46, Hungnes et al., Mania et al., Lewis et al., and Doorn et al. teach a method of treating or diagnosing a disease comprising administering a compound or complex of claim 27, Compound (I-1), Compound (II-1-RGD), Compound (Tc-III- 1-RGD), Compound (186Re-III-1-RGD) or Compound (Re-III-1-RGD) to a subject.
Hungnes et al. disclose the whole-body detection (non-therapeutic) of avb3 integrin-expressing tumors, tumor vasculature, and inflamed tissue (see abstract within Hungnes et al.).
Analogous Art
The Hungnes et al., Mania et al., Lewis et al., and Doorn et al. references are directed to the same field of endeavor as the instant claims, that is, a conjugated diphosphine precursor compound according to the proposed Formula that is suitable for preparing a conjugated radiolabelled agent, as disclosed within instant claim 27.
Obviousness Analysis
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the diphosphine metal complex disclosed by Hungnes et al., using the teachings of Mania et al., Lewis et al., and Doorn et al. in order to arrive at the subject matter of the instant claims.
The Hungnes et al., Mania et al., Lewis et al., and Doorn et al. references all have considerable overlap in the radioisotope arts as it relates to diphosphines. In this instance, Hungnes et al. supplies the template for the diphosphine radioactive and non-radioactive metals, Mania et al. supplies the minigastrin peptide analogue to be used as a ligand, while Lewis et al. and Doorn et al. supply the synthetic support for the diphosphines disclosed in general terms by Hungnes et al. All references are directed to diphosphines that can be used with radioisotopes and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the four references when seeking to develop a therapeutic or imaging diphosphine composition.
Given these teachings, a POSITA would have been motivated to combine the template for diphosphine radioactive and non-radioactive metals as disclosed by Hungnes et al., the minigastrin peptide that can be used as a ligand supplied by Mania et al., and the synthetic support for the diphosphines disclosed by Lewis et al. and Doorn et al.
The modification constitutes a simple substitution of one known element for another to obtain a predictable result [MPEP §2143(I)(B)].
The combination represents the use of a known technique to improve a similar composition in the same way [MPEP §2143(I)(C)].
The art provides a finite number of identified, predictable solutions, and the POSITA would have pursued the claimed configuration with a reasonable expectation of success [MPEP §2143(I)(E); KSR].
The combination of the diphosphine metal complex taught by Hungnes et al. along with the use of the necessary claim limitations taught by Mania et al., Lewis et al. and Doorn et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application.
Furthermore, the additional claim limitations taught by Mania et al., Lewis et al., and Doorn et al. would have been viewed by a POSITA as routine design optimizations or known modifications for diphosphine metal complexes. The motivation for doing so would have been to develop a diphosphine chelator that targets a variety of biological targets. Implementing these features in Hungnes et al. diphosphine radioactive and non-radioactive metal compositions would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Hungnes et al., Mania et al., Lewis et al., and Doorn et al. provides all the elements of the claimed invention. The resulting radioactive and non-radioactive diphosphine metal complexes, constitute no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
Conclusion
No claims are allowed.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615 /Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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