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 .
Status of Application
Applicant’s cancellation of claim(s) 20-27 in the reply filed on 6/19/2024 is acknowledged.
Applicant’s amendments of claim(s) 3-9, 11, 13-16, and 18-19 in the reply filed on 6/19/2024 is acknowledged.
Claims 1-19 are under examination.
Drawings
The drawings are objected to because of the following reasons:
Figures 1, 4B, 5, 6, and 13 are blurry and difficult to read.
Fig 2D is unclear as to which bar corresponds to untreated and Mn-EOB-PC2A due to grayscale.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 2, 7, and 16 are objected to because of the following informalities:
Claim 2 says “chelating” and it should read “chelating agent” of similar.
Claim 7 says “includes small” but it should read “includes a small” or similar.
Claim 16 says “chelating” but it should read “chelating agent” or similar.
Appropriate correction is required.
Claim 4 and 5 are objected to because of the following informalities:
Claim 4, line 4 recites “X1” while the formula of line 3 recites “X1”
Claim 5, line 9 recites “-L-T or -T” instead of “-L1-T1 or -T1”.
Appropriate correction is required.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-5, 7, and 15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kálmán, F. K.; et al. Mn(II)-Based MRI Contrast Agent Candidate for Vascular Imaging, J. Med. Chem. 2020, 63, 6057-6065.
Kálmán, F. K.; et al. (hereafter referred to as Kálmán) is drawn to manganese-based MRI contrast agents with targeting capabilities (title; abstract). Kálmán teaches MRI contrast agents are excellent for imaging soft tissue (pg 6057, col 1, para 1, lines 1-3), and manganese contrast agents is a reasonable alternative to gadolinium contrast agents (pg 6057, col 1, para 2, lines 1-3). Kálmán teaches that pyclen chelators serve as a good platform for manganese (II) complexation due to efficient relaxation enhancement and kinetic inertness improved conditional stability when compared to more common DOTA chelators. (pg 3058, col 1, para 1, lines 1-9). Kálmán also found that due to the improved kinetic inertness of the complex, an acetate arm normally used for binding the metal, can be switched with a biphenyl group (pg 6058, col 1, para 1, lines 9-17) to obtain a hydrophobic portion and targeting capabilities while maintaining a strong and inert metal coordination (pg 6058, col 1, para 1, lines 17-21). Particularly interesting is that Kálmán teaches that the biphenyl substituent has a similar effect on Pyclen as it does on other chelators like EDTA and DTPA and that the authors claim to have an expectation to this positive consequence due to the sterics and lipophilic/lipophobic adjustments of biphenyl and other benzyl-containing substituents (pg 6058, col 1, para 2, lines 1-12). Furthermore, Kálmán teaches a method of making the contrast agent (pg 6058, Scheme 1) and a composition of the complex (pg 6060, col 2, para 4, lines 1-5) and i.v. administration (pg 6061, Figure 3, caption) and results of imaging after the administration (pg 6061, Figure 3, caption).
As to claim 1, Kálmán teaches a tissue-specific manganese based magnetic resonance imaging agent comprising the formula T-L-C wherein T is the cell specific or tissue specific targeting moiety, C is at least one pyclen based chelating agent complexed with a Mn ion, and L is an optional linker covalently linking T and C (abstract figure).
As to claim 2, Kálmán teaches a pyclen triacetate (pg 6058, Chart 1, structure PCTA), pyclen diacetate (pg 6058, Chart 1, structures PC2A, PC2A-EA, PC2A:PB) and a derivative thereof (pg 6058, Chart 1, structures PC2A, PC2A-EA, PC2A:PB).
As to claim 3, Kálmán teaches pyclen-3,9-diacetate (pg 6058, Chart 1, structure PC2A) or pyclen-3,6,9-triacetate (pg 6058, Chart 1, structure PCTA).
As to claim 4, Kálmán teaches an agent of formula where Y1, Y2, and Y3 are H; where X1, X2, X3, X4, X5, and X6 are H; where Z1, Z2, and Z3 are each independently H, -CH2-C(O)O- or -T1; where T1 is cell specific or tissue specific targeting moiety; and where Z2 is -T1 (pg 6058, Chart 1, structure PC2A:BP).
As to claim 5, Kálmán teaches the agent comprising the formula where Z1 and Z3 are CH2-C(O)O- and Z2 is -T1 or H or -CH2-C(O)O- (pg 6058, Chart 1, structures PCTA, PC2A, PC2A:BP); where T1 is cell specific or tissue specific targeting moiety; and where at Z2 is -T1 (pg 6058, Chart 1, structure PC2A:BP).
As to claim 7, Kálmán teaches the at least one targeting moiety includes a small molecule (abstract; pg 6058, Chart 1, structure PC2A:BP).
As to claim 15, Kálmán teaches the targeting moiety is directly linked to the chelating agent (abstract; pg 6058, Chart 1, structure PC2A:BP).
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 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) 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kálmán, F. K.; et al. Mn(II)-Based MRI Contrast Agent Candidate for Vascular Imaging, J. Med. Chem. 2020, 63, 6057-6065 and Le Fur, M.; et al. (US 10,711,001 B2).
Kálmán, F. K.; et al. (hereafter referred to as Kálmán) is drawn to manganese-based MRI contrast agents with targeting capabilities (title; abstract). Kálmán teaches MRI contrast agents are excellent for imaging soft tissue (pg 6057, col 1, para 1, lines 1-3), and manganese contrast agents is a reasonable alternative to gadolinium contrast agents (pg 6057, col 1, para 2, lines 1-3). Kálmán teaches that pyclen chelators serve as a good platform for manganese (II) complexation due to efficient relaxation enhancement and kinetic inertness improved conditional stability when compared to more common DOTA chelators. (pg 3058, col 1, para 1, lines 1-9). Kálmán also found that due to the improved kinetic inertness of the complex, an acetate arm normally used for binding the metal, can be switched with a biphenyl group (pg 6058, col 1, para 1, lines 9-17) to obtain a hydrophobic portion and targeting capabilities while maintaining a strong and inert metal coordination (pg 6058, col 1, para 1, lines 17-21). Particularly interesting is that Kálmán teaches that the biphenyl substituent has a similar effect on Pyclen as it does on other chelators like EDTA and DTPA and that the authors claim to have an expectation to this positive consequence due to the sterics and lipophilic/lipophobic adjustments of biphenyl and other benzyl-containing substituents (pg 6058, col 1, para 2, lines 1-12). Furthermore, Kálmán teaches a method of making the contrast agent (pg 6058, Scheme 1) a composition of the complex (pg 6060, col 2, para 4, lines 1-5) and i.v. administration (pg 6061, Figure 3, caption) and results of imaging after the administration (pg 6061, Figure 3, caption).
As to claim 6, Kálmán teaches a pyclen chelator with two acetates bound to a manganese and T1 is a cell specific or tissue specific targeting moiety (abstract; pg 6058, Chart 1, structure PC2A:BP).
Kálmán does not teach the pyclen-3,6-diacetate derivative with the non-acetate substituent on position 9.
Le Fur, M.; et al. (US 10,711,001 B2, hereafter referred to as Le Fur) is drawn to macrocyclic ligands with picolinate ligands useful for medical imaging, targeting, and treatment of cancers, and methods of making the same (title; abstract). Le Fur teaches methods of preparing targeted and personalized treatments in oncology for detection and treatment (col 1, lines 21-24) where the imaging can be done by fluoroscopy, echography, or MRI (col 1, lines 39-40) and where the ligands must create stable complexes with the metal ions and be able to ideally target to avoid unnecessary diffusion to unwanted tissues (col 1, lines 49-52). Le Fur teaches Pyclen-based macrocyles (col 2, Formula I) which can contain a variety of substituents. However, Le Fur especially teaches acetate/acetic acid or picolinate N-substituents (col 2, lines 41-54, Formula II; col 3, lines 63-67) and that these structures have good thermodynamic stability and good kinetic inertia (col 4, lines 12-14) and can be made in a composition for targeting (col 4, lines 14-23). Le Fur teaches a variety of metal ions can be used cancer treatment (col 4, lines 57-63), and teaches the same chelator system can be used for imaging when an imaging suitable metal is chosen such as Gd for MRI (col 5, lines 57-52). With respect to the structures, Le Fur teaches pyclen compounds with 0-3 acetates with a corresponding 3-0 picolinate N-substituents (col 10, lines 50-65, structure Pc-2a1pa sym; col 11, structures Pc-2a1pa asym, Pc-1a2pa sym, Pc-1a2pa asym, and Pc3pa) and pharmaceutical compositions of these compounds (col 14, lines 1-12) and methods of making the compound (col 23-24, Synthetic scheme of example 1; col 49 lines 46-67; col 50, lines 1-15).
Regarding the pyclen-3,6-diacetate derivative with the non-acetate substituent on position 9, Le Fur teaches a pyclen-3,6-diacetate derivative with the non-acetate substituent on position 9 (claim 4, lines 50-67, structure Pc-2a1pa asym).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the symmetric structure of PC2A:BP with acetates on positions 3 and 9 of Kálmán to include and asymmetric structure where the acetates are on positions 3 and 6 as taught by Le Fur because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of PC2A:BP with acetates on positions 3 and 9 to acetates on positions 3 and 6.
A person of ordinary skill in the art would have had a reasonable expectation of success in placing the non-acetate substituent at position 3 or 9 because the prior art of Kálmán teaches the non-acetate substituent works on a variety of chelators and more particularly, the prior art of Le Fur teaches the substituent can be on any non-aromatic N-substituent of the Pyclen. Additionally, the prior art of Le Fur disclosed that placing the non-acetate substituent on position 3 or 9 (Pc1a2pa asym) is more stable in terms of inertia than placing the non-acetate N-substituent on position 6 (col 56, lines 21-25; col 56, lines 35-50). The prior art shows the structural similarity of an aromatic ring of Le Fur is structurally similar to the structural features of Kálmán where the biphenyl ring is separated from the pyclen by a methylene unit. The skilled artisan would have been motivated to modify the position of substitution on the pyclen to position 3 or 9 because Le Fur discloses that N-substituents at that location can improve inertial stability while maintaining good MRI properties.
Claim(s) 8-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kálmán and Le Fur as applied to claim 6 above, and further in view of Islam, M. K.; et al. Synthesis and Evaluation of Manganese(II)-Based Ethylenediaminetetraacetic Acid-Ethoxybenzyl Conjugate as a Highly Stable Hepatobiliary Magnetic Resonance Imaging Contrast Agent. 2018, 29, 3614-3625. The teachings of Kálmán and LeFur as applied in the previous rejection are incorporated in this rejection.
As to claim 8, Kálmán teaches the agent of claim 1 with a targeting moiety that binds to the tissue of a subject (pg 6061, col 2, para 2, lines 1-8; pg 6061, Figure 3).
Kálmán does not teach the targeting moiety binds to hepatocytes and/or liver tissue of a subject.
Islam, M. K.; et al. (hereafter referred to as Islam) is drawn to synthesis and evaluation of manganese-based chelators as stable liver-targeting MRI contrast agents (title; abstract). Islam teaches a variety of chelators (EDTA, DPDP, DTPA, BOPTA) with phosphate, BTA, acetate, benzyl, and ethoxybenzyl substituents (pg 3615, Chart 1). Islam teaches that compared to the other liver-targeting substituents, ethoxybenzyl (EOB) has high kinetic stability reducing side effect risks of toxicity of metal release though the chelator still needs improvement (pg 3615, Table 1; pg 3615, col 1, para 1, lines 1-10). They show that EOB works on different chelators (pg 3616, Table 1, compound Mn-EDTA-EOB and Gd-DTPA-EOB; pg 3616, col 2, para 2, lines 2-5). Islam teaches the EOB substituent improves relaxivity by as much as 20% on EDTA (pg 3616, col 2, para 2, lines 5-8) and improved transmetalation stability (pg 3617, col 1, para 2, lines 16-20; pg 3617, col 2, Figure 2). Islam suggests the possible reason for the improved stability is that the EOB substituent increases the rigidity of the chelator complex (pg 3617, col 2, para 1, lines 1-2). Islam also teaches the synthesis (pg 3615, Scheme 1) and the liver tissue and hepatic uptake biodistribution (pg 3618, Figure 3) and MRI images (pg 3618, Figure 4).
Regarding the targeting moiety binding to hepatocytes and/or liver tissues of a subject, Islam teaches a contrast agent that binds to hepatocytes and/or liver tissues of a subject (abstract; pg 3615, Table 1; pg 3615, col 1, para 1, lines 1-10; pg 3618, Figure 3).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the vascular targeting moiety of Kálmán with the hepatic targeting moiety as taught by Islam because the substituted components and their functions were known in the art and one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution of a liver targeting moiety for a vascular targeting moiety would have been predictable. See MPEP 2143(I)(B).
A person of ordinary skill in the art would have had a reasonable expectation of success in using a liver targeting moiety of EOB in place of a vascular targeting moiety of biphenyl because first, the prior art of Kálmán teaches that biphenyl and other benzyl-containing substituents work well on EDTA, DTPA, and pyclen (pg 6058, col 1, para 2, lines 1-12) and second, the prior art of Islam teaches a liver targeting moiety of EOB is benzyl-containing and is on EDTA or DTPA. The skilled artisan would have been motivated to substitute the tissue targeting moiety because of the ability to target a hepatic disease or cancer with EOB and Islam teaches that EOB improves stability and relaxivity of the chelators when it is used.
As to claim 9, Islam teaches the targeting moiety is an ethoxybenzyl group (pg 3615, Chart 1; pg 3615, Table 1; pg 3615, col 1, para 1, lines 1-10; pg 3616, Table 1, compound Mn-EDTA-EOB and Gd-DTPA-EOB; pg 3616, col 2, para 2, lines 2-5).
As to claim 10, Kálmán teaches a pyclen diacetate (pg 6058, Chart 1, structures PC2A, PC2A-EA, PC2A:PB) and Islam teaches ethoxybenzyl targeting moieties ((pg 3615, Chart 1; pg 3615, Table 1; pg 3615, col 1, para 1, lines 1-10; pg 3616, Table 1, compound Mn-EDTA-EOB and Gd-DTPA-EOB; pg 3616, col 2, para 2, lines 2-5) and teach the pyclen with ethoxybenzyl targeting group as discussed in claims 8 and 9.
The combined teachings of Kálmán and Islam do not teach the ethoxybenzyl targeting moiety on position 3 or 9 of the pyclen.
Le Fur teaches a pyclen-3,6-diacetate derivative with the non-acetate substituent on position 9 (claim 4, lines 50-67, structure Pc-2a1pa asym).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the combined structure of the pyclen of Kálmán and Islam where the Pyclen has a liver-targeting EOB moiety on position 6 to include the N-substituent position as taught by Le Fur where the liver-targeting EOB moiety is on position 3 or 9 because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of the modifying the structure from where the acetates are on positions 3 and 9 to a structure where the acetates are on positions 6 and position 3 or 9.
A person of ordinary skill in the art would have had a reasonable expectation of success in placing the non-acetate N-substituent on position 3 or 9 because the prior art of Kálmán teaches the non-acetate substituent works on a variety of chelators and more particularly, the prior art of Le Fur teaches the substituent can be on any non-aromatic N-substituent of the Pyclen. Additionally, the prior art of Le Fur disclosed that placing the non-acetate substituent on position 3 or 9 (Pc1a2pa asym) is more stable in terms of inertia than placing the non-acetate N-substituent on position 6 (col 56, lines 21-25; col 56, lines 35-50). The prior art shows the structural similarity of an aromatic ring of Le Fur is structurally similar to the structural features where the biphenyl ring of Kálmán or the phenyl ring of Islam is separated from the pyclen by a methylene unit. The skilled artisan would have been motivated to modify the position of substitution on the pyclen to position 3 or 9 because Le Fur discloses that N-substituents at that location can improve inertial stability while maintaining good MRI properties.
Claim(s) 11-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kálmán, Le Fur, and Islam as applied to claims 6 and 8-10 above, and further in view of Hamon, N.; et al. (US 2021/0017180 A1). The teachings of Kálmán, LeFur, and Islam as applied in the previous rejections are incorporated in this rejection.
As to claim 11, Hamon teaches a contrast agent that binds to a cancer cell (pg 7, para [0072]; pg 8, para [0073]).
The combined teachings of Kálmán, Le Fur, and Islam do not explicitly state that the agent binds to a cancer cell antigen.
Hamon, N.; et al. (US 2021/0017180 A1, hereafter referred to as Hamon) is drawn to a pyclen-based macrocyclic ligand and chelators and various substituents for targeting (title; abstract). Hamon teaches using the pyclen-based complexes with metals for medical imaging (pg 1, para [0002]) and that there can be substituents of acetates or picolinates (pg 3, para [0020]) and the picolinates can have chromophore substituents (pg 3, para [0022]-[0026]). Hamon teaches that the chromophores are extended resonance structures of phenyl rings and alkynes, enabling fluorescence (pg 4, structures C-1 and C-2; pg 5, structures C-3 and C-4), and where the structures may be chelated to a wide variety of lanthanide metals (pg 5, para [0040]). Furthermore, Hamon teaches that the compound can be made to recognize a biological target through biomolecules, organic compounds, antibodies, peptides, proteins, lipids, and more (pg 7, para [0071]-[0072]) with cancer antigens (pg 7, para [0072]). Hamon teaches synthesis of the compounds (pg 28, Example 1; pg 29, Example 1-1).
Regarding an agent which binds to cancer cell antigens, Hamon teaches a contrast agent with a targeting moiety with targets cancer antigens, CD20 (pg 7, para [0072]).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the targeting agent of the combined teachings of Kálmán, Le Fur, and Islam to include one that binds to cancer cell antigens as taught by Hamon because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a contrast agent which binds to cancer cell antigens.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the contrast agents to bind to cancer cell antigens because the prior art of Kálmán, Le Fur, and Islam disclosed contrast agents with a variety of substituents and it is known that some of them can target cancers. Additionally, the prior art discloses contrast agents with the same structural base of a pyclen with acetate substituents. And the prior art teaches that the pyclens can have a variety of substituents including targeting moieties. The prior art pyclens and the pyclens disclosed by Hamon are expected to have similar properties because of the overlap of the core structures between them involves the known pyclen with acetate N-substituents and a targeting N-substituents. The skilled artisan would have been motivated to modify the cancer targeting with specific antibodies or small molecules or peptides which bind to cancer cell antigens because it is a common strategy used to target and treat cancers.
As to claim 12, Hamon teaches CEA (pg 7, para [0072], second entry).
Claim(s) 13-14 and 16-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kálmán, Le Fur, Islam, and Hamon as applied to claim 6 and 8-12 above, and further in view of Zheng-Rong, L.; et al (US 10,124,073 B2). The teachings of Kálmán, LeFur, Islam, and Hamon as applied in the previous rejections are incorporated in this rejection.
As to claim 13, Hamon teaches a contrast agent with targeting moieties which can have a peptide targeting moiety (pg 7, para [0072]).
The combined teachings of Kálmán, Le Fur, Islam, and Hamon do not teach an amino acid sequence that specifically binds to EDB-FN or EDA-FN.
Zheng-Rong, L.; et al. (hereafter referred to as Zheng-Rong) is drawn to peptides that target EDB-FN or EDA-FN and methods of using them (title; abstract). Zheng-Rong states that cancer detection and treatment are hindered by the inability to differentiate between cancer cells and normal cells and improving the ability to target the tumor cell or microenvironment could have improvements (col 1, lines 20-38). Zheng-Rong teaches molecular probes with a variety of targeting peptides that are good for targeting EDB-FN or EDA-FN (col 1, lines 50-60) upon administration for imaging (col 1, lines 62-65). The molecular probe can be a MRI contrast agent linked to a peptide through a linker (col 2, line 1; col 2, lines 4-6; Figure 7A). Zheng-Rong teaches that these EDA-FN and EDB-FN peptides (col 12, lines 50-57) can be linked to MRI contrast agents with a wide variety of chelators (col 12, lines 5-33) containing a selection of metals depending on the imaging application (col 12, lines 34-44), and the peptides can be linked to the chelator complex through linkers (col 12, lines 45-49). Zheng-Rong teaches the synthesis of the chelator/metal and peptide complex (Figure 7A).
Regarding an amino acid sequence that specifically binds to EDB-FN or EDA-FN, Zheng-Rong teaches amino acids that specifically bind to EDB-FN or EDA-FN (col 1, lines 42-43; col 1, lines 50-60; col 6, lines 60-67; col 7, lines 1-18).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the targeting peptides of Hamon to include the EDB-FN and EDA-FN as taught by Zheng-Rong because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a pyclen-based macrocycle with a targeting peptide for EDB-FN or EDA-FN.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the peptides to target EDA-FN or EDB-FN because the prior art of Hamon discloses that a wide variety of peptides can be bound to pyclen-based macrocycles to target a variety of biological targets with success (Hamon, pg 7, para [0072]; pg 8, para [0072]). The prior art suggested that pyclen-based macrocycles work well as MRI contrast agents with a variety of N-substituents. And, the prior art contains similar MRI contrast agent properties because of the overlap of structural similarities of pyclen-based macrocycles complexed to a suitable MRI metal ion (such as gadolinium or manganese).
The skilled artisan would have been motivated to modify the peptide substituents to target EDA-FN or EDB-FN because the presence of these in tumor microenvironments is inversely correlated with cancer aggressiveness and patient survival and are useful for detecting, monitoring, and/or imaging cancer cells in tissue of a subject.
As to claim 14, Zheng-Rong teaches TVRTSAD, NWGDRIL, NWGKPIK, SGVKSAF, GVKSYNE, IGKTNTL, IGNSNTL, IGNTIPV, and LYANSPF, WNYPFRL, SNTSYVN, SFSYTSG, WSPAPMS, TREHPAQ, or ARIIDNA (col 6, lines 60-67; col 7, lines 10-13).
As to claim 16, Zheng-Rong teaches the targeting moiety is linked to the chelating agent with a linker (Figure 7A; col 12, lines 45-49).
As to claim 17, Zheng-Rong teaches a linker that is a hetero-bifunctional linker where reactive groups are separated by at least an alkylene with heteroatoms (col 22, lines 60-63; col 26, lines 14-17).
As to claim 18, Zheng-Rong teaches a linker that includes a C3 alkylene linker (Figure 7A).
As to claim 19, Le Fur teaches pharmaceutical compositions (col 14, lines 1-12).
Nonstatutory 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.
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Claims 1-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 15, and 28 of copending Application No. 18/625,695 in view of Kálmán, Le Fur, Islam, Hamon, and Zheng-Rong.
Instant claims are drawn to tissue-specific manganese-based MRI contrast agents composed of pyclen-based macrocycles with two or three acetate N-substituents and a targeting moiety on a third N-substituent that is ethoxybenzyl for hepatic targeting, or is cancer cell antigen targeting, or is a EDA-FN or EDB-FN targeting peptide sequence with an optional linker between the pyclen chelator and the targeting moiety.
The conflicting claims of copending U.S. Application No. 18/625,695 (hereafter referred to as '695) are drawn to a pyclen-based contrast agent which can chelate manganese and can have two or three acetate N-substituents and a targeting peptide that is connected as an N-substituent through a linker. The targeting moiety peptide targets cancer.
The conflicting claims of '695 do not teach hepatic targeting groups.
The conflicting claims of '695 do not teach ethoxybenzyl substituent.
The conflicting claims of '695 do not teach amino acid sequences which bind specifically to EDA-FN or EDB-FN.
However, these features are known in the art. As noted in the current rejections, the combined
teachings of Kálmán, Le Fur, Islam, Hamon, and Zheng-Rong render obvious instant claims 1-19.
Regarding the hepatic targeting groups, Islam teaches a contrast agent that binds to hepatocytes and/or liver tissues of a subject (abstract; pg 3615, Table 1; pg 3615, col 1, para 1, lines 1-10; pg 3618, Figure 3).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the targeting moeities of the conflicting claims of ‘695 with the hepatic targeting moiety as taught by Islam because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of hepatic targeting moieties.
A person of ordinary skill in the art would have had a reasonable expectation of success in using a liver targeting moiety of EOB in place of general cancer targeting moiety because the prior art Islam teaches a liver targeting moiety of EOB is benzyl-containing and works on a variety of chelators. The skilled artisan would have been motivated to substitute the cancer targeting moiety because of the ability to target a hepatic disease or cancer with EOB and Islam teaches that EOB improves stability and relaxivity of the chelators when it is used.
Regarding the ethoxybenzyl substituent on position 3 or 9, Kálmán teaches a pyclen diacetate (pg 6058, Chart 1, structures PC2A, PC2A-EA, PC2A:PB) and Islam teaches ethoxybenzyl targeting moieties ((pg 3615, Chart 1; pg 3615, Table 1; pg 3615, col 1, para 1, lines 1-10; pg 3616, Table 1, compound Mn-EDTA-EOB and Gd-DTPA-EOB; pg 3616, col 2, para 2, lines 2-5) and teach the pyclen with ethoxybenzyl targeting group as discussed in claims 8 and 9.
The combined teachings of Kálmán and Islam do not teach the ethoxybenzyl targeting moiety on position 3 or 9 of the pyclen.
Le Fur teaches a pyclen-3,6-diacetate derivative with the non-acetate substituent on position 9 (claim 4, lines 50-67, structure Pc-2a1pa asym).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the combined structure of the pyclen of the conflicting claims of ‘695 and Kálmán and Islam where the Pyclen has a liver-targeting EOB moiety on position 6 to include the N-substituent position as taught by Le Fur where the liver-targeting EOB moiety is on position 3 or 9 because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of the modifying the structure from where the acetates are on positions 3 and 9 to a structure where the acetates are on positions 6 and position 3 or 9.
A person of ordinary skill in the art would have had a reasonable expectation of success in placing the non-acetate N-substituent on position 3 or 9 because the prior art of Kálmán teaches the non-acetate substituent works on a variety of chelators and more particularly, the prior art of Le Fur teaches the substituent can be on any non-aromatic N-substituent of the Pyclen. Additionally, the prior art of Le Fur disclosed that placing the non-acetate substituent on position 3 or 9 (Pc1a2pa asym) is more stable in terms of inertia than placing the non-acetate N-substituent on position 6 (col 56, lines 21-25; col 56, lines 35-50). The prior art shows the structural similarity of an aromatic ring of Le Fur is structurally similar to the structural features where the biphenyl ring of Kálmán or the phenyl ring of Islam is separated from the pyclen by a methylene unit. The skilled artisan would have been motivated to modify the position of substitution on the pyclen to position 3 or 9 because Le Fur discloses that N-substituents at that location can improve inertial stability while maintaining good MRI properties.
Regarding amino acid sequences which bind specifically to EDA-FN or EDB-FN, Zheng-Rong teaches amino acids that specifically bind to EDB-FN or EDA-FN (col 1, lines 42-43; col 1, lines 50-60; col 6, lines 60-67; col 7, lines 1-18).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the targeting peptides of the conflicting claims of ‘695 and Hamon to include the EDB-FN and EDA-FN as taught by Zheng-Rong because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a pyclen-based macrocycle with a targeting peptide for EDB-FN or EDA-FN.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the peptides to target EDA-FN or EDB-FN because the conflicting claims of ‘695 and the prior art of Hamon discloses that a wide variety of peptides can be bound to pyclen-based macrocycles to target a variety of biological targets with success (Hamon, pg 7, para [0072]; pg 8, para [0072]). The prior art suggested that pyclen-based macrocycles work well as MRI contrast agents with a variety of N-substituents. And, the prior art contains similar MRI contrast agent properties because of the overlap of structural similarities of pyclen-based macrocycles complexed to a suitable MRI metal ion (such as gadolinium or manganese).
The skilled artisan would have been motivated to modify the peptide substituents to target EDA-FN or EDB-FN because the presence of these in tumor microenvironments is inversely correlated with cancer aggressiveness and patient survival and are useful for detecting, monitoring, and/or imaging cancer cells in tissue of a subject.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims allowed.
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/EVAN M LEWOCZKO/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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