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 1-12 are pending in this office action. All pending claims are under examination in this application.
Priority
The current application was filed on March 6, 2024 is a 371 of PCT/JP2022/010452 filed on March 10, 2022. The current application claims foreign priority to JP2021-096432 and JP2021-039885 filed on June 9, 2021 and March 12, 2021, respectively.
Information Disclosure Statement
Receipt of the Information Disclosure Statements filed on September 11, 2023 and October 11, 2023 are acknowledged. A signed copy of both documents are attached to this office action.
Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because Figures 3 and 7 are blurry and the text is not readable. Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Claim Objections
Claims 1-12 are objected to because of the following informalities:
Claim 1: Please delete “[Formula 1].”
Dependent claims 2-6 are included in this objection because they do not cure the defect of claim 1.
Claims 3, 5, 7, and 11-12: In a similar manner, please delete “[Formula X],” where X varies based on the claim.
Claims 5 and 11: Please delete the text “a group.” There is no group, only one compound.
Claim 8: Please include L5-L10 together and delete, “and L7 is an alkylene group, provided that one or more -CH2- of the alkylene group may optionally be substituted with -O-, -S-, -NH-, or -CO-.” This phrase is repetitive of the previous limitation originally not inclusive of L7.
Claims 7-12: Please identify the acronym PET once in full. Thereafter, the acronym can be used within the claims.
Claim 7: Please use the Roman numeral for four (IV) instead of six (VI) to match dependent claims 8-12.
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 1-12 are rejected under 35 U.S.C. 103 as being unpatentable over Nakamura (JP2019038778A) over Nakamura (WO2017026276A1), Dumelin et al. (Angewandte Chemie International Edition, 2008), Tsukada et al. (JP2019001761A), Wang et al. (Chemical Communications, 2018), and Kettenbach et al. (Pharmaceuticals, 2018).
[The Examiner is going to introduce each reference and then combine them where appropriate to reject the instant claims.]
1. Nakamura
Nakamura is the closest prior art to the present invention as it teaches boron-containing folic acid derivative (see title). Additionally, Nakamura discloses a new boron agent that allows a boron neutron capture therapy even for a BPA insusceptible cancer patient. The present invention provides a boron-containing amino acid derivative represented by the following general formula (I) [R does not exist or denotes an amino acid residue, L denotes a linker, X denotes a group induced from a water-soluble boron cluster containing B], or a boron-containing amino acid derivative represented by the following general formula (II) [Ra denotes an amino acid residue, L does not exist or denotes a linker, X denotes a group induced from a water-soluble boron cluster containing B]. There is also provided a composition for boron neutron capture therapy containing the derivative (see abstract).
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2. Nakamura ‘276
Nakamura ‘276 teaches pharmaceutical composition containing conjugate of boron-containing compound and protein (see title). In addition, Nakamura discloses that in order to establish a means for selectively delivering a large amount of boron to a tumor tissue, provided is a pharmaceutical composition containing a conjugate of a compound represented by formula (I): X-L-Y (in the formula, X represents a group including 10B, L represents a linker, and Y represents a group bound to a lysine residue), and a tumor-accumulative protein having a lysine residue, wherein the molar ratio (mol number of the compound/mol number of the protein) of the compound and protein contained in the composition exceeds 10 (see abstract).
3. Dumelin et al.
Dumelin et al. teach a portable albumin binder from a DNA-encoded chemical library (see title). Furthermore, Dumelin et al. disclose albumin represents the most abundant protein in human plasma, at a concentration of 45 mg mL-1. To keep physiological production rates to a minimum, albumin displays a long circulatory half-life in mammals thanks to its size above the renal filtration threshold and its unique ability to interact with the neonatal FcRn receptor. Fusions of biopharmaceuticals to albumin or to albumin-binding peptides have been devised to expose the body to adequate concentrations of the therapeutic agent for a sufficiently long period of time, thus improving efficacy and reducing the number of injections (see first paragraph).
4. Tuskada et al.
Tuskada et al. teach tumor imaging agent, and oncotherapeutic agent for boron-neutron capture therapy (see title). Also, Tuskada et al. disclose a tumor imaging agent exhibiting a sufficiently high accumulation ratio between tumor cells and normal cells. The tumor imaging agent comprises a radioactive labeling compound represented by general formula (1) or a salt thereof. In the general formula (1), R represents -F, -CH, -CFH, or -CFF (see abstract).
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5. Wang et al.
Wang et al. teach the efficiency of 18F labelling of a prostate specific membrane antigen ligand via strain-promoted azide-alkyne reaction: reaction speed versus hydrophilicity (see title). Furthermore, Wang et al. disclose the 18F labeling of a prostate specific membrane antigen (PSMA) ligand via a strain promoted oxa-dibenzo-cyclooctyne (ODIBO)- or bicyclo[6.1.0]nonyne (BCN)-azide reaction. Although
ODIBO reacts with azide 20 fold faster than BCN, in vivo PET imaging suggests that 18F-BCN-azide-PSMA demonstrated much higher tumor uptake and a much higher tumor to background contrast. (see abstract).
6. Kettenbach et al.
Kettenbach et al. teach comparison study of two differently clicked
18F-folates—lipophilicity plays a key role (see title). Additionally, Kettenbach et al. disclose that within the last decade, several folate-based radiopharmaceuticals for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been evaluated; however, there is still a lack of suitable 18F-folates for clinical PET imaging. Herein, we report the synthesis and evaluation of two novel 18F-folates employing strain-promoted and copper-catalyzed click chemistry. Furthermore, the influence of both click-methods on lipophilicity and pharmacokinetics of the 18F-folates was investigated. 18F-Ala-folate and 18F-DBCO-folate were both stable in human serum albumin. In vitro studies proved their high affinity to the folate receptor (FR). The lipophilic character of the strain-promoted clicked 18F-DBCO-folate (logD = 0.6) contributed to a higher non-specific binding in cell internalization studies. In the following in vivo PET imaging studies, FR-positive tumors could not be visualized in a maximum intensity projection images. Compared with 18F-DBCO-folate, 18F-Ala-folate (logD = -1.4), synthesized by the copper-catalyzed click reaction, exhibited reduced lipophilicity, and as a result an improved in vivo performance and a clear-cut visualization of FR-positive tumors. In view of high radiochemical yield, radiochemical purity and favorable pharmacokinetics, 18F-Ala-folate is expected to be a promising candidate for FR-PET imaging (see abstract).
Combination of Nakamura, Nakamura ‘276, and Dumelin et al.
Regarding instant claim 1, Nakamura, Nakamura ‘276, and Dumelin et al. teach a boron agent for boron neutron capture therapy (BNCT). The necessary citations within Nakamura, Nakamura ‘276, and Dumelin et al. that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Nakamura, Nakamura ‘276, and Dumelin et al. Citations
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Nakamura discloses a boron-containing folic acid derivative characterized by being represented by general formula (I) (see the claims, paragraph [0008], example 3, and figure 4 all within Nakamura; also see Figure I below), wherein X in general formula (I) is a group derived from a water-soluble boron cluster containing 10B and indicates that said compound is a boron medical agent for boron neutron capture therapy (BNCT), effective also for BPA-insensitive cancer patients, and that when the boron-containing folic acid derivative (PBC 1 and 3) was administered to a cancer-grafted mice, uptake of the boron-containing folic acid derivative to a tumor was observed (see the Examples within Nakamura).
Figure I
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Nakamura does not indicate that the boron medical agent contains a group binding to albumin. However, Nakamura ’276 indicates that serum albumin was introduced into a boron medical agent (MID) used for BNCT, and high accumulation of the boron medical agent and the anti-tumor effects thereof in tumor-grafted mice were confirmed (the claims and the Examples within Nakamura ‘276).
Dumelin et al. disclose the potent albumin-binding derivative within Figure II:
Figure II
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(see page 3200-3201, In summary paragraph within Dumelin et al.).
Therefore, a person skilled in the art could easily conceived of introducing a group binding to albumin (see the Dumelin et al. citation above) in an attempt to achieve a high accumulation of the boron medical agent in a tumor and anti-tumor effects in Nakamura.
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 Nakamura et al. with the teachings of both Nakamura ‘276 and Dumelin et al. to create an albumin binding BNCT agent by simple substitution of the pteroyl portion of folic acid with a 4-iodophenyl butanoic acid derivative. The motivation for doing so would have been to develop a BNCT agent that binds to albumin.
Regarding instant claims 2 and 4, Nakamura, Nakamura ‘276, and Dumelin et al. teach wherein L1, L2, L3, and L4 in formulas (I) and (II) are each an alkylene group, provided that one or more -CH2- of the alkylene group may optionally be substituted with -O-, -S-, -NH-, or -CO-.
Nakamura discloses the following scheme:
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(see page 9, paragraph [0056] within the Japanese Version of Nakamura). The boxed region is indicative of the linker group, L1, between the pteroyl group and the boron cluster.
Regarding instant claim 3, Nakamura, Nakamura ‘276, and Dumelin et al. teach wherein X in formulas (I) and (II) is a group represented by any of the following formulas (A) to (C):
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Dumelin et al. teach the 4-iodophenyl butanoic acid potent albumin binder. Simple substitution of the pteroyl portion of folic acid present within Nakamura with the 4-iodophenyl butanoic acid variant would be carried out by a skilled artisan (POSITA) under routine conditions. The use of an amide group is also standard operating procedure within a medicinal chemistry lab (carboxylic acid and amine coupling).
Regarding instant claims 5 and 6, Nakamura, Nakamura ‘276, and Dumelin et al. teach wherein Z in formula (II) is a group represented by the following formula (D):
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The attachment of the pteroyl group (folate receptor binding agent), the 4-iodophenyl butanoic variant, and a 10B source similar to Formula II of instant claim 1 would be routine to a skilled artisan (POSITA). All the synthetic pieces of the “puzzle” are present within Nakamura, Nakamura ‘276, and Dumelin et al. Furthermore, the only variable in the analogue is the linking groups. A skilled artisan (POSITA) would modify the derivative with standard functional modifications such as commercially available diamines and amino acids. Moreover, a skilled artisan (POSITA) would take advantage of orthogonal protecting groups to attach one derivative while leaving the remaining functional group protected.
A small set of experiments would determine the optimal linker chain. For example, by selecting linker lengths of four, six, and eight atoms followed by in vitro binding analysis, a skilled artisan (POSITA) would quickly arrive through feedback at the optimal or near optimal length. Therefore, a finite reaction set would be defined.
Combination of Nakamura, Nakamura ‘276, Dumelin et al., Tuskada et al., Wang et al., and Kettenbach et al.
Regarding instant claim 7, Nakamura, Nakamura ‘276, Dumelin et al., Tuskada et al., Wang et al., and Kettenbach et al. teach an imaging agent for PET, comprising a compound represented by the following formula (III) or (IV)
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Please see the discussion and citations within instant claims 1-6 for the necessary rejection text.
Once again, all the synthetic pieces of the “puzzle” are present based on the Nakamura, Nakamura ‘276, Dumelin et al., Tuskada et al., Wang et al., and Kettenbach et al. references. In addition, PET imaging has been widely known (see claim 4 and paragraphs [0011] and [0024] within Tuskada et al.). Radiolabeling with 18F is supplied by both Wang et al. (see Scheme 2 within Wang et al.) and Kettenbach et al. (see Scheme 2 within Kettenbach et al.) employing click chemistry.
Regarding instant claim 8, Nakamura, Nakamura ‘276, Dumelin et al., Tuskada et al., Wang et al., and Kettenbach et al. teach wherein L5-L10 in formulas (III) and (IV) are each an alkylene group, provided that one or more -CH2- of the alkylene group may optionally be substituted with -O-, -S-, -NH-, or -CO-, and one -CH2- of the alkylene group may optionally be substituted with a divalent group formed by a click reaction.
Please see the discussion and citations within instant claim 7 for the necessary rejection text.
Regarding instant claim 9, Nakamura, Nakamura ‘276, Dumelin et al., Tuskada et al., Wang et al., and Kettenbach et al. teach wherein X in formulas (III) and (IV) is a group represented by any of the following formulas (A) to (C):
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Please see the discussion and citations within instant claims 3, 6, and 7 for the necessary rejection text.
Regarding instant claim 10, Nakamura, Nakamura ‘276, Dumelin et al., Tuskada et al., Wang et al., and Kettenbach et al. teach the imaging agent for PET to instant claim 7, wherein Y in formulas (III) and (IV) is a group derived from a boron cluster.
Please see the discussion and citations within instant claims 2, 4, and 7 for the necessary rejection text.
Regarding instant claim 11, Nakamura, Nakamura ‘276, Dumelin et al., Tuskada et al., Wang et al., and Kettenbach et al. teach wherein Z in formula (IV) is a group represented by the following formula (D):
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Please see the discussion and citations within instant claims 5-7 for the necessary rejection text.
Regarding instant claim 12, Nakamura, Nakamura ‘276, Dumelin et al., Tuskada et al., Wang et al., and Kettenbach et al. teach wherein the compound represented by formula (IV) is a compound represented by the following formula (IVa):
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Nakamura, Nakamura ‘276, Dumelin et al., Tuskada et al., Wang et al., and Kettenbach et al. supply all the synthetic pieces of the “puzzle.” Please see the discussion and citations regarding all elements except the 18F portion. Wang et al. supplies the fluorine labeled variant, shown below within Figure III:
Figure III
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(see Scheme 2 within Wang et al.). Synthetic modification of the azide portion of the click coupling to form the 1,2,3-triazole would yield the desired functional group for attachment to the macromolecule within instant claim 12.
Analogous Art
The Nakamura, Nakamura ‘276, Dumelin et al., Tuskada et al., Wang et al., and Kettenbach et al. references are directed to the same field of endeavor as the instant claims, that is, a boron agent for BNCT, as disclosed within instant claim 1, or an imaging agent for PET, as disclosed within claim 7.
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 BNCT agent disclosed by Nakamura, using the teachings of Nakamura ‘276, Dumelin et al., Tuskada et al., Wang et al., and Kettenbach et al. in order to arrive at the subject matter of the instant claims.
The Nakamura, Nakamura ‘276, Dumelin et al., Tuskada et al., Wang et al., and Kettenbach et al. references all have considerable overlap in the radioisotope arts. In this instance, Nakamura supplies the template for the pteroyl derived targets, Nakamura ‘276 and Dumelin et al. supply the binding to albumin, while Tuskada et al., Wang et al., and Kettenbach et al. supply the support for the PET imaging agents. All references are directed to radioisotopes and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the six references when seeking to develop a BNCT composition or PET imaging agent.
Given these teachings, a POSITA would have been motivated to combine the template for the pteroyl derived targets as disclosed by Nakamura, the required albumin binding supplied by Nakamura ‘276 and Dumelin et al., and the support for the PET imaging agents disclosed by Tuskada et al., Wang et al., and Kettenbach 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 pteroyl derived targets for BNCT taught by Nakamura along with the use of the necessary claim limitations taught by Nakamura ‘276, Dumelin et al., Tuskada et al., Wang et al., and Kettenbach 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 Nakamura ‘276, Dumelin et al., Tuskada et al., Wang et al., and Kettenbach et al. would have been viewed by a POSITA as routine design optimizations or known modifications for BNCT compositions and PET imaging compounds. The motivation for doing so would have been to synthetically assemble a multi-target BNCT compound or PET imaging agent. Implementing these features in Nakamura’s pteroyl derived targets for BNCT compositions would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Nakamura, Nakamura ‘276, Dumelin et al., Tuskada et al., Wang et al., and Kettenbach et al. provides all the elements of the claimed invention. The resulting BNCT compounds and PET imaging agent, 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN W LIPPERT III whose telephone number is (571)270-0862. The examiner can normally be reached Monday - Thursday 9:00 AM - 5:00 PM.
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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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