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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 42-43 and 53-67 in the reply filed on 08/24/2026 is acknowledged.
Claims 44-50 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group 2 (claims 44-50), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/24/2026.
Election of Species
Applicant’s election of species in the reply filed on 08/24/2026 is acknowledged. The specific species for claims are shown below.
As to claim 54, applicant’s election of y is 0 in the reply filed on 08/24/2026 is acknowledged.
As to claim 55, applicant’s election of the radioisotope is 18F in the reply filed on 08/24/2026 is acknowledged.
As to claim 61, applicant’s election of the radioisotope is 68Ga in the reply filed on 08/24/2026 is acknowledged.
As to claims 56 and 57, applicant’s election of the prosthetic group is
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in the reply filed on 08/24/2026 is acknowledged.
As to claims 58 and 59, applicant’s election of the chelator
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in the reply filed on 08/24/2026 is acknowledged.
As to claim 62, applicant’s election of La is -(CR6H)q-(CH2)q-C(=O)-NR-(CH2)q-O-, wherein first and second q are 0 and third q is 3; Lb is absent; Lc1 is
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, wherein V is -C(O)-, t2, p2, p3, and m1 are 0, and Tz is absent; Lc2 is
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, wherein t2 is 2, p1, p2, p3, and m1 are 0 and Tz is absent in the reply filed on 08/24/2026 is acknowledged.
As to claim 64, applicant’s election of La is
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; Lb is absent; Lc1 is
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;
Lc2 is
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, wherein u is 1 in the reply filed on 08/24/2026 is acknowledged.
As to claims 65, applicant’s election of
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in the reply filed on 08/24/2026 is acknowledged.
As to claim 67, applicant’s election of
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in the reply filed on 08/24/2026 is not allowed. The elected species is not in the list of compounds to be selected.
Status of Application
Applicant’s addition of new claim(s) 92-95 in the reply filed on 08/24/2026 is acknowledged.
Applicant’s amendments of claim(s) 44, 54, 62, and 64 in the reply filed on 08/24/2026 is acknowledged.
Applicant’s withdrawal of claim(s) 63 in the reply filed on 08/24/2026 is acknowledged.
Claim 67 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as not belonging to the elected species within Group 1 (claims 42-43 and 53-67) in the reply filed on 08/24/2026.
Claims 42-50, 53-67, and 92-95 are under examination.
Drawings
The drawings are objected to because of the following informalities.
Figures 1-3, 9A-9B, 15, 16, and 20 contain structures that are blurry and difficult to read.
Figures 5-6 peak numbers are blurry and difficult to read.
Figure 7 images and font are blurry and difficult to read.
Figures 10A, 10B, 11C, 11D, 12D are not clear which bar corresponds to which legend.
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
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it is not on a separate piece of paper. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claim 62 is objected to because of the following informalities: there is a typographical error for linker (b) in that it does not show the squiggle line to the left of the t2 group, indicating the point of attachment. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 53-54 and 62 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential structural cooperative relationships of elements, such omission amounting to a gap between the necessary structural connections. See MPEP § 2172.01. The omitted structural cooperative relationships are as follows:
As to claim 53, La and Lb are capable of forming a chemical bond with each other and A, B, C1 and C2. It is unclear whether a linker can connect to all four simultaneously under normal conditions (e.g. hydrogen bonding), or whether the linker can be made capable through derivatization to form a covalent bond with all four, or whether the linkers are connected to each other so that A, B, C1, and C2 are linked to each other through the linkers.
As to claim 53, it is unclear whether “bi-functionalized linker” means there are only two attachments in a linker or whether there are two functional groups functionalizing the linker.
As to claim 53, the phrase “capable of forming bonds with each other” renders the structure of formula (III) unclear as to whether there is a central carbon or not at the middle of the structure of formula (III).
As to claim 54, when y = 0 or 1, it is unclear whether the valency of the five-membered ring is fulfilled by a lone pair or by a hydrogen.
As to claim 62, the structure for the group option (b) (pg 13, line 11) does not indicate the second point of attachment. Therefore, it is unclear whether the group has a second point of attachement or where the second point of attachment is located.
Claim Interpretation
Claim 53 recites “prosthetic group” (pg 4, line 1). The examiner notes that the specification does not define prosthetic group. However, the examiner notes that the use of “prosthetic group” in the specification (pg 24, lines 6-9; pg 40; line 6; pg 41, line 8-9) is consistent with meaning a group that can have a radioisotope. Furthermore, the use of prosthetic group in pg 24, lines 6-9, is a radiolabeled prosthetic group. Therefore, the examiner interprets “prosthetic group” as a prosthetic group which may be radiolabeled but is not necessarily radiolabeled. Therefore, for the purposes of examination, the examiner interprets any prior art containing a substituent group which can be labeled with a radioisotope, regardless as to whether it is radiolabeled, as reading on prosthetic group.
Claim 53 recites “bi-functionalized linker”. The examiner notes that the specification does not define “bi-functionalized linker”. It is unclear whether the bi-functionalized means there are two functional groups present on the linker or if the linker can connect to functional groups. However, the examiner notes the specification uses this language to describe a connection through a bond (pg 52, lines 6-11, fourth compound of the list contains no chemical group linker between the chelator and the central carbon) or through a chemical moiety (pg 52, lines 6-11, the fourth compound of the list contains a chemical group between the targeting moiety and the central carbon) to connect the different groups of formula (III). Therefore, for the purposes of examination, the examiner interprets any prior art containing a bond or chemical group linking portions of formula (III) as reading on “bi-functionalized linker”.
Claim 53 recites “capable of forming a chemical bond with each other and A, B, C1, and C2”. The examiner notes that it is unclear how the linkers form bonds with each other and A, B, C1 and C2, whether the linker itself is directly bound to each group and directly bound to the other linker or whether the linker is connected through chemical bonds indirectly to the other groups and linker. The examiner notes that in some embodiments of formula (III), there is only one linker group from which the prosthetic group, chelator, and targeting moiety are bound (pg 52, lines 6-7, compound 1) and where the prosthetic group and targeting moiety are each bound to a central carbon to which the chelator is also bound (pg 52, line 5-7, fourth compound). Therefore, for the purposes of examination, the examiner interprets the phrase to mean any linker which is connected through other groups or directly to A, B, C1 and C2 and the other linker. Therefore, any prior art reading on linkers in the molecule connecting moieties to each other, reads on this claim limitation.
Claim 54 recites “y is independently an integer selected from the group consisting of 0, 1, and 2”. The examiner notes that when “y” is “0” nothing is bound to the positions. The examiner notes that for the purposes of examination, when y is “0” or “1”, the other moiety attached to that position to fulfill valency is interpreted as hydrogen. Therefore, any prior art containing R1x, R2x, and R3x’ or hydrogen atoms reads on this claim limitation.
Claim 62 recites
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(pg 13, line 11). The examiner notes that the squiggle line to the left of the t2 group is missing. For the purposes of examination, the examiner interprets the second point of attachment of this bi-functionalized linker as being to the left of the t2 group.
Claim 66 recites “C2 is covalently bound to the chelating group C1”. The examiner notes that the specification does not define this phrase. Therefore, in view of the election of species and for the purposes of examination, the examiner interprets this phrase to mean that the prosthetic group is covalently connected directly or indirectly and does not have to be directly bound to the chelator and any prior art containing a prosthetic group and a chelator that are in any way connected through covalent bonds as reading on this limitation.
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) 53 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Liu, Z.; et al., US 2024/0042066 A1.
Liu, Z.; et al. (hereafter referred to as Liu) is drawn to compounds with a chelator, albumin binding unit, and fibroblast activation protein inhibitor unit for diagnosis and treatment of diseases (title; abstract). Liu teaches that quinoline-based small molecule radiopharmaceuticals targeting FAP were shown to be useful for rapidly binding to human and mouse FAP (pg 1, para [0006], lines 1-7) and the inhibitor does not cross-react with DPP family member DPP4 enabling more development (pg 1, para [0006], lines 8-10) and that connecting a FAP inhibitor to a DOTA chelator with a radioactive nuclide enables good pharmacokinetic properties and that it has high contrast and high sensitivity (pg 1, para [0006], lines 15-18). Liu teaches a trifunctional compound of formula C-AB-FAPI, where C is a chelator, AB is an albumin binding unit, and FAPI is a fibroblast activation protein inhibitor unit (pg 1, para [0007], lines 1-6; pg 12, para [0077]). Liu teaches a variety of chelators can be substituted for each other (pg 2, para [0008]; pg 7, para [0067], lines 1-8) and a variety of FAPI unites can be substituted for each other with different linkers (pg 2, para [0009]) and the albumin binding group is the 4-iodo-phenyl group (pg 2, para [0010], lines 1-4). Liu teaches a variety of radionuclides can be used such as 18F and 68Ga (pg 4, para [0014], line 1-2; pg 4, para [0015], lines 1-2). Liu teaches synthesis of the compounds (pg 22, para [0124]).
As to claim 53, Liu teaches a compound of formula (III) where A is a targeting moiety for fibroblast activation protein alpha (FAP-α), B is absent, C1 is a chelating moiety, C2 is a prosthetic group (pg 3, para [0011], lines 1-3, labeled in structure reproduced below) and La is a bi-functionalized linker forming a chemical bond with A and the central carbon (pg 3, para [0011], lines 1-3), Lb is absent; and Lc1 is a bi-functionalized linker forming bonds between the chelator and the central carbon, Lc2 is a bi-functionalized linker forming bonds between the prosthetic group and the central carbon (pg 3, para [0011, lines 1-3).
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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) 42-43 and 53-60 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu, Z.; et al., US 2024/0042066 A1 and Yang, X.; et al., US 2020/0330624 A1 (as cited in the IDS filed on 10/04/2024).
Liu, Z.; et al. (hereafter referred to as Liu) is drawn to compounds with a chelator, albumin binding unit, and fibroblast activation protein inhibitor unit for diagnosis and treatment of diseases (title; abstract). Liu teaches that quinoline-based small molecule radiopharmaceuticals targeting FAP were shown to be useful for rapidly binding to human and mouse FAP (pg 1, para [0006], lines 1-7) and the inhibitor does not cross-react with DPP family member DPP4 enabling more development (pg 1, para [0006], lines 8-10) and that connecting a FAP inhibitor to a DOTA chelator with a radioactive nuclide enables good pharmacokinetic properties and that it has high contrast and high sensitivity (pg 1, para [0006], lines 15-18). Liu teaches a trifunctional compound of formula C-AB-FAPI, where C is a chelator, AB is an albumin binding unit, and FAPI is a fibroblast activation protein inhibitor unit (pg 1, para [0007], lines 1-6; pg 12, para [0077]). Liu teaches a variety of chelators can be substituted for each other (pg 2, para [0008]; pg 7, para [0067], lines 1-8) and a variety of FAPI unites can be substituted for each other with different linkers (pg 2, para [0009]) and the albumin binding group is the 4-iodo-phenyl group (pg 2, para [0010], lines 1-4). Liu teaches a variety of radionuclides can be used such as 18F and 68Ga (pg 4, para [0014], line 1-2; pg 4, para [0015], lines 1-2). Liu teaches synthesis of the compounds (pg 22, para [0124]).
As to claim 53, Liu teaches a compound of formula (III) where A is a targeting moiety for fibroblast activation protein alpha (FAP-α), B is absent, C1 is a chelating moiety, C2 is a prosthetic group (pg 3, para [0011], lines 1-3, labeled in structure reproduced below) and La is a bi-functionalized linker forming a chemical bond with A and the central carbon (pg 3, para [0011], lines 1-3), Lb is absent; and Lc1 is a bi-functionalized linker forming bonds between the chelator and the central carbon, Lc2 is a bi-functionalized linker forming bonds between the prosthetic group and the central carbon (pg 3, para [0011, lines 1-3).
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Liu does not teach radiolabeled prosthetic groups.
Yang, X.; et al. (hereafter referred to as Yang) is drawn to imaging and radiotherapeutic agents targeting fibroblast-activation protein-alpha and their use in imaging and treating FAP-alpha related diseases and disorders (title; abstract). Yang teaches fibroblast-activation protein-alpha expression has been detected on the surface of fibroblasts in the stroma surround >90% of the epithelial cancers examined (pg 1, para [0003], lines 1-4) and it is a characteristic marker for carcinoma-associated-fibroblast which is critical in promoting angiogenesis, proliferation, invasion, and inhibition of tumor cell death (pg 1, para [0003], lines 6-19) and because it is expressed in tumor stroma, anti-FAP antibodies are useful for radioimmunotargeting of malignancies (pg 1, para [0004], lines 1-4). Yang teaches compounds of a general structure B-L-A (pg 1, para [0005], col 1, lines 1-3), where A is a targeting moiety for FAP-alpha, B is an optical or radiolabeled functional group, and L is a linker having bi-functionalization (pg 1, para [0005], col 2, lines 1-5). Yang teaches a number of radionuclides for imaging (pg 4, Table 1) and a number of FAP-alpha targeting moieties (pg 7, para [0063]-[0065]), and a generic linker to connect A and B (pg 8, para [0066]) and a variety of radiolabeled prosthetic groups (pg 10, para [0080]) and a variety of chelating groups (pg 10, para [0081]). Yang teaches the FAP-α targeting moiety (pg 16, para [0084]). Yang teaches a method for imaging a disease or disorder associated with FAP-alpha by administering a compound comprising an optical or radiolabeled functional group suitable for optical imaging, PET imaging, or SPECT imaging (pg 2, para [0011], lines 1-8). Yang teaches pharmaceutical compositions and administration of the compounds (pg 17, para [0087], lines 1-7) and synthesis of the FAP targeting group (pg 27, para [0214]) and chelator to the FAP targeting group (pg 29, para [0216]).
Regarding radiolabeled prosthetic groups, Yang teaches radiolabeled prosthetic groups, reproduced below, where X can be 18F or 124I and n can be 3 (pg 9, para [0079], lines 1-13; pg 10, para [0079], lines 1-3).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the prosthetic group of Liu to include a radioisotope as taught by Yang 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 radiolabeled albumin-binding prosthetic group.
A person of ordinary skill in the art would have had a reasonable expectation of success in radiolabeling the prosthetic group of the trifunctional compound because the prior art of Liu disclosed trifunctional compounds known to have prosthetic groups of 4-iodo-phenyl groups. Additional prior art of Yang suggested radiolabeled prosthetic groups to have similar behavior because of the potential 4-[124I]iodo-phenyl between them involves known chemistry.
The skilled artisan would have been motivated to radiolabel the prosthetic group because radiolabeling helps in detection and diagnosis of diseases and radiolabeling with 124I or 18F has the potential for PET imaging which could be used in concert with the chelator metal for dual imaging. Therefore, it would have been prima facie obvious to combine the teachings of Liu with Yang.
Alternatively to the above, Yang teaches formula (III) where B and Lb are absent and C1 and Lc1 are absent, where A is a targeting moiety for FAP-α (pg 4, par a[0033], line 4-5; claim 1) and C2 is a prosthetic group (claim 9), and La is a bi-functionalized linker capable of forming a bond to C2 (pg 4, para [0033], lines 9-10, claim 1; pg 8, para [0068], lines 1-3; pg 8, para [0070]) and Lc2 is a bi-functionalized linker capable of forming a bond to A (pg 4, para [0033], lines 9-10, claim 1; pg 8, para [0068], lines 1-3; pg 8, para [0070]).
Yang does not expressly teach a single embodiment comprising all the features of the claimed product. However, it would be prima facie obvious prior to the effective filing date of the claimed invention to combine the embodiments of A, La, C2, and Lc2 taught by Yang as a skilled artisan recognizes that these claim elements are known in the art and that a person of ordinary skill in the art could have combined the claim elements as claimed by known methods, and that in combination, each element merely performs the same function as it does separately. Therefore, a person of ordinary skill in the art would have recognized that the results of the combination were predictable.
As to claim 54, Yang teaches the compound wherein A is a FAP-α targeting moiety, reproduced below (pg 16, para [0084], line 1-4), where the point of attachment of the FAP- α binding ligand to the linker La or Lb is on carbon atom 6 of the quinolinyl ring, each y is 0 (pg 16, para [0084], line 1-4).
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As to claim 55, Yang teaches a prosthetic group with 18F, reproduced below (pg 9, para [0079], lines 1-3; pg 10, para [0080], line 4).
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As to claim 56, Yang teaches the prosthetic group is selected as the compound reproduced below wherein X is -C(=O)-, and a radioisotope is 18F, and n is 0 (pg 10, para [0080], line 4).
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As to claim 57, Yang teaches the prosthetic group is a compound from the list, reproduced below (pg 10, para [0080], line 4).
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As to claim 58, Liu teaches a compound wherein C1 is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) (pg 3, para [0011], line 3).
As to claim 59, Liu teaches C1 is a chelating agent reproduced below, chelator is an excerpt from a structure in Liu (pg 3, para [0011], line 3).
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As to claim 60, Liu teaches the radiometal (pg 14, para [0085], lines 1-3; pg 14, para [0086], lines 1-2).
As to claim 61, Liu teaches the radiometal is 67Ga (pg 14, para [0085], lines 1-3; pg 14, para [0086], lines 1-2).
As to claim 42, Liu teaches a pharmaceutical composition (pg 4, para [0016], lines 1-2).
As to claim 43, Liu teaches a composition comprising one or more pharmaceutically acceptable excipients (pg 4, para [0016], lines 2-4).
Claim(s) 62, 64-66, and 92-95 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu and Yang as applied to claims 42-43 and 53-62 above, and further in view of Banerjee, S. R.; et al., Sequential SPECT and Optical Imaing of Experimental Models of Prostate Cancer with a Dual Modality Inhibitor of the Prostate-Specific Membrane Antigen, Angew. Chem. Int. Ed., 2011, 50, 9167-9170 (as cited in the IDS filed on 10/04/2024). The teachings of Liu and Yang as applied in the previous rejection are incorporated in this rejection.
As to claim 62, Liu teaches the compound where A, La, C1, Lc1, C2, and Lc2 are present (pg 3, para [0011], line 3).
Liu does not teach a linker La is –(CR6H)q-CH2)q-C(=O)-NR-(CH2)q-O-, wherein the first and second q are 0 and the third q is 3.
Liu does not teach a linker Lc1 is
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, where V is -C(O)-, t2, p2, p3, and m1 are 0, and Tz is absent.
Liu does not teach a linker Lc2 is
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, where t2 is 2 and p1, p2, p3, and m1 are 0 and Tz is absent.
Regarding a linker La, Yang teaches a La linker is –(CR6H)q-CH2)q-C(=O)-NR-(CH2)q-O-, wherein the first and second q are 0 and the third q is 3, reproduced below (claim 19). Lb is absent.
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the linker La of Liu with the Linker as taught by Yang because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of the linker of Yang in the trifunctional compound of Liu.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the linker of Yang in place of the linker of Liu because the prior art of Liu disclosed trifunctional compounds for FAP-α targeting and PET imaging known to work successfully with a variety of linkers including a portion of the linker containing a propyl group with a nitrogen and oxygen on either end (pg 8, para [0071]). Additional prior art of Yang suggested compounds with the smaller linker connecting FAP-α targeting and PET imaging capabilities to have similar imaging and binding properties.
The skilled artisan would have been motivated to substitute the linkers because adjusting the linker length between the targeting moiety and the imaging moieties can affect the clearance, FAP binding and ease of synthesis. Therefore, it would have been prima facie obvious to combine the teachings of Liu with Yang.
Regarding Lc1, Yang teaches Lc1 is as reproduced below where t2, p2, p3, and m1 are each 0 and V is -C(O)-, and Tz is absent (pg 8, para [0067], lines 1-33; pg 8, para [0069], lines 1-2).
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Regarding Lc2, Yang teaches Lc2 is as reproduced below where t2 is 2 and p1, p2, p3, and m1 are each 0 and Tz is absent (pg 8, para [0067], lines 1-33; pg 8, para [0068]; pg 8, para [0069], lines 1-2). This is equivalent to a linking group consisting of two methylene units.
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Regarding Lc1, Yang teaches Lc1 is as reproduced below where p2, p3, and m1 are each 0 and V is -C(O)-, and Tz is absent (pg 8, para [0067], lines 1-33; pg 8, para [0069], lines 1-2).
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Yang does not teach where t is 0.
Banerjee, S. R.; et al. (hereafter referred to as Banerjee) is drawn to dual-modality imaging agents for sequential SPECT and optical imaging of animal models (title). Banerjee teaches two major issues that contribute to mortality among prostate cancer patients is inability to predict aggressive diseases and difficulty in assuring a clear surgical margin during prostatectomy (pg 9167, col 1, para 1, lines 1-6) and standard imaging agents do not enable good imaging (pg 9167, col 1, para 1, lines 10-18). Banerjee teaches dual-modality imaging agents combine the sensitivity of radionuclide imaging with the high sensitivity and resolution of near-infrared fluorescence imaging (pg 9167, col 1, para 2, lines 1-6) and that PSMA-targeted radiopharmaceutical imaging in experimental models with radionuclides and chelators and organic fluorescent molecules is possible (pg 9167, col 2, para 2, lines 1-16). Banerjee teaches a dual modality SPECT/NIRF imaging agent that has high and specific uptake in xenografts and pharmacokinetics suitable for targeting PSMA in vivo (pg 9167, col 2, para 3, lines 1-4) and the compound with dual modality is reproduced and annotated below (pg 9168, Scheme 1, final structure of the synthesis). Banerjee teaches the radiolabeling moiety as DOTA, the targeting moiety for PSMA, and the optical moiety as attaching to an IR dye, such as IRDye800CW (pg 9167, col 2, para 3, lines 7-20; pg 9168, Scheme 1, compound 1). Banerjee teaches synthesis (pg 9168, Scheme 1) and the in vivo testing in mouse models (pg 9169, Figure 1).
Regarding t is 0, Banerjee teaches a trifunctional compound with a linker between the chelator and the central carbon (equivalent to Lc1) where t is 0, reproduced below where Lc1 is in the annotated box (pg 9168, Scheme 1).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the linker of Liu and Yang to include t is 0 in the linker Lc1 as taught by Banerjee 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 an amide linker between the chelator and the central carbon.
A person of ordinary skill in the art would have had a reasonable expectation of success in continuing to modify the linker between the chelator and the central carbon because the prior art of Yang disclosed that the alkyl portion, “t” could range from 1-8 (Yang, pg 8, para [0067], lines 2-3) known to connect chelators and targeting moieties. Additional prior art of Banerjee suggested “t” is 0 to have similar ability to connect chelators to targeting moieties.
The skilled artisan would have been motivated to modify “t” in the linker to be “0” because the conjugation reaction between the chelator and the central carbon moiety can be simplified since the intermediate step of attaching the alkyl portion is removed. Therefore, it would have been prima facie obvious to combine the teachings of Liu and Yang with Banerjee.
As to claim 64, Yang teaches La is
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(pg 29, para [0217], structure YX-FAP-02); and Yang teaches Lc2 is as reproduced below where t2 is 2 and p1, p2, p3, and m1 are each 0 and Tz is absent (pg 8, para [0067], lines 1-33; pg 8, para [0068]; pg 8, para [0069], lines 1-2). This is equivalent to a linking group consisting of two methylene units.
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Yang does not teach Lc1 is an amide.
Regarding Lc1 is an amide, Banerjee teaches a trifunctional compound with a linker between the chelator and the central carbon (equivalent to Lc1) where t is 0, reproduced below where Lc1 is in the annotated box (pg 9168, Scheme 1).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the linker of Liu and Yang to include t is 0 in the linker Lc1 as taught by Banerjee 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 an amide linker between the chelator and the central carbon.
A person of ordinary skill in the art would have had a reasonable expectation of success in continuing to modify the linker between the chelator and the central carbon because the prior art of Yang disclosed that the alkyl portion, “t” could range from 1-8 (Yang, pg 8, para [0067], lines 2-3) known to connect chelators and targeting moieties. Additional prior art of Banerjee suggested “t” is 0 to have similar ability to connect chelators to targeting moieties.
The skilled artisan would have been motivated to modify “t” in the linker to be “0” because the conjugation reaction between the chelator and the central carbon moiety can be simplified since the intermediate step of attaching the alkyl portion is removed. Therefore, it would have been prima facie obvious to combine the teachings of Liu and Yang with Banerjee.
As to claim 65, Liu teaches a trifunctional chelator of formula (III) where the chelator is DOTA, and there is a prosthetic group and there is a FAP-α targeting moiety (pg 3, para [0011], line 3).
Liu does not teach the FAP-α and linker attachment to the central carbon.
Liu does not teach the prosthetic group is 4-[18F]fluoro-phenyl with an ethyl amide linker.
Liu does not teach the DOTA chelator is connected to the central directly by an amide bond.
Regarding the FAP-α and linker attachment to the central carbon, Yang teaches the FAP-α and linker attachment, reproduced below (Yang, pg 16, para [0084]).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the FAP-α targeting moiety and attachment linker of the trifunctional compound of Liu with the FAP-α targeting moiety and attachment linker as taught by Yang because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of substituting the FAP-α targeting moiety and linker of Yang in place of the one in Liu.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the FAP-α targeting moiety of Yang in place of the FAP-α targeting moiety of Liu because the prior art of Liu disclosed trifunctional compounds with a variety of FAP-α targeting moieties and linkers known to connect well to chelators and prosthetic groups (pg 2, para [0009]). Additional prior art of Yang suggested an additional FAP-α targeting moiety and linker system to have similar ability to be able to connect to a wide variety of chelators (pg 10, para [0081]) or prosthetic groups (pg 10, para [0080]).
The skilled artisan would have been motivated to substitute the FAP-α targeting moiety and linker of Yang in place of the one of Liu because varying the linker or the particular form of the FAP targeting moiety can alter the binding and clearance of the trifunctional compound for better uptake by the cancer. Therefore, it would have been prima facie obvious to combine the teachings of Liu with Yang.
Regarding the prosthetic group is 4-[18F]fluoro-phenyl with an ethyl amide linker, Yang teaches the 4-[18F]fluoro-phenyl prosthetic group, reproduced below (pg 10, para [0080], line 4).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the prosthetic group of Liu to include a radioisotope as taught by Yang 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 radiolabeled albumin-binding prosthetic group.
A person of ordinary skill in the art would have had a reasonable expectation of success in using a radiolabeled prosthetic group of the trifunctional compound because the prior art of Liu disclosed trifunctional compounds known to have prosthetic groups containing halogen-substituted aromatic rings. Additional prior art of Yang suggested radiolabeled halogen substituted aromatic rings to have similar ability to connect to chelators and FAP-α targeting moieties due to the overlap of the chemical structures.
The skilled artisan would have been motivated to radiolabel the prosthetic group because radiolabeling helps in detection and diagnosis of diseases and radiolabeling with 18F has the potential for PET imaging which could be used in concert with the chelator metal for dual imaging. Therefore, it would have been prima facie obvious to combine the teachings of Liu with Yang.
Regarding the ethyl linker between the prosthetic group and the central carbon, Yang teaches a linker where t2 is 2 and p1, p2, p3, and m1 are each 0 and Tz is absent (pg 8, para [0067], lines 1-33; pg 8, para [0068]; pg 8, para [0069], lines 1-2). This is equivalent to an ethyl linking group.
Alternatively, Banerjee teaches a butyl linker to an imaging moiety (pg 9168, Scheme 1). The claimed ethyl linker and prior art butyl linker differ by two -CH2- groups. In cases where the difference is by the successive addition of the same chemical group, e.g. by -CH2- groups), these are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. See MPEP 2144.09(II).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the linker of the prosthetic group of Liu with the butyl linker of the prosthetic group as taught by Banerjee because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of a butyl linker between the central carbon and the prosthetic group.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the butyl linker for the prosthetic group of Banerjee in place of the linker of Liu because the prior art of Liu disclosed trifunctional compounds known to have a linker connecting a prosthetic group to a chelator and targeting moiety. Additional prior art of Banerjee suggested an alternative linker to have similar ability to connect the prosthetic group to the chelating moiety and targeting moiety.
The skilled artisan would have been motivated to substitute the butyl linker of Banerjee in place of the linker of Liu because the butyl linker is part of a lysine group which has three functional groups enabling easy connection of the targeting moiety, chelator, and secondary imaging moiety. Therefore, it would have been prima facie obvious to combine the teachings of Liu with Banerjee.
Regarding the DOTA chelator connected directly to the central carbon by an amide bond, Banerjee teaches a trifunctional compound where the chelator is connected directly to the central moiety by an amide bond (pg 9168, Scheme 1, compounds 1 and [M]1).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the DOTA and DOTA linker of Liu with the DOTA and DOTA linker as taught by Banerjee because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of a DOTA linked directly to the central moiety by an amide bond.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting a DOTA directly bound to the central moiety in place of a DOTA bound through a longer linker because the prior art of Liu disclosed DOTA chelators known to link to the central moiety through the R group of a lysine connecting the chelator to the prosthetic group and the targeting moiety. Additional prior art of Banerjee suggested DOTA chelators linked through the backbone amine of the lysine to have similar ability to connect the DOTA to the prosthetic group and the targeting moiety because of the overlap of structure between them involves known chemistry.
The skilled artisan would have been motivated to substitute the DOTA linkage of Banerjee in place of the DOTA linkage of Liu because the sterics around the chelator can affect the binding properties of the chelated metal. Therefore, it would have been prima facie obvious to combine the teachings of Liu with Banerjee.
As to claim 66, Liu teaches the prosthetic group is covalently bound to the chelating group (pg 3, para [0011], line 3).
As to claim 92, Liu teaches a trifunctional chelator of formula (III) where the chelator is DOTA, and there is a prosthetic group and there is a FAP-α targeting moiety (pg 3, para [0011], line 3).
Liu does not teach the FAP-α and linker attachment to the central carbon.
Liu does not teach the prosthetic group is 4-[18F]fluoro-phenyl with an ethyl amide linker.
Liu does not teach the DOTA chelator is connected to the central directly by an amide bond.
Regarding the FAP-α and linker attachment to the central carbon, Yang teaches the FAP-α and linker attachment, reproduced below (Yang, pg 16, para [0084]).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the FAP-α targeting moiety and attachment linker of the trifunctional compound of Liu with the FAP-α targeting moiety and attachment linker as taught by Yang because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of substituting the FAP-α targeting moiety and linker of Yang in place of the one in Liu.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the FAP-α targeting moiety of Yang in place of the FAP-α targeting moiety of Liu because the prior art of Liu disclosed trifunctional compounds with a variety of FAP-α targeting moieties and linkers known to connect well to chelators and prosthetic groups (pg 2, para [0009]). Additional prior art of Yang suggested an additional FAP-α targeting moiety and linker system to have similar ability to be able to connect to a wide variety of chelators (pg 10, para [0081]) or prosthetic groups (pg 10, para [0080]).
The skilled artisan would have been motivated to substitute the FAP-α targeting moiety and linker of Yang in place of the one of Liu because varying the linker or the particular form of the FAP targeting moiety can alter the binding and clearance of the trifunctional compound for better uptake by the cancer. Therefore, it would have been prima facie obvious to combine the teachings of Liu with Yang.
Regarding the prosthetic group is 4-[18F]fluoro-phenyl with an ethyl amide linker, Yang teaches the 4-[18F]fluoro-phenyl prosthetic group, reproduced below (pg 10, para [0080], line 4).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the prosthetic group of Liu to include a radioisotope as taught by Yang 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 radiolabeled albumin-binding prosthetic group.
A person of ordinary skill in the art would have had a reasonable expectation of success in using a radiolabeled prosthetic group of the trifunctional compound because the prior art of Liu disclosed trifunctional compounds known to have prosthetic groups containing halogen-substituted aromatic rings. Additional prior art of Yang suggested radiolabeled halogen substituted aromatic rings to have similar ability to connect to chelators and FAP-α targeting moieties due to the overlap of the chemical structures.
The skilled artisan would have been motivated to radiolabel the prosthetic group because radiolabeling helps in detection and diagnosis of diseases and radiolabeling with 18F has the potential for PET imaging which could be used in concert with the chelator metal for dual imaging. Therefore, it would have been prima facie obvious to combine the teachings of Liu with Yang.
Regarding the ethyl linker between the prosthetic group and the central carbon, Yang teaches a linker where t2 is 2 and p1, p2, p3, and m1 are each 0 and Tz is absent (pg 8, para [0067], lines 1-33; pg 8, para [0068]; pg 8, para [0069], lines 1-2). This is equivalent to an ethyl linking group.
Alternatively, Banerjee teaches a butyl linker to an imaging moiety (pg 9168, Scheme 1). The claimed ethyl linker and prior art butyl linker differ by two -CH2- groups. In cases where the difference is by the successive addition of the same chemical group, e.g. by -CH2- groups), these are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. See MPEP 2144.09(II).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the linker of the prosthetic group of Liu with the butyl linker of the prosthetic group as taught by Banerjee because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of a butyl linker between the central carbon and the prosthetic group.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the butyl linker for the prosthetic group of Banerjee in place of the linker of Liu because the prior art of Liu disclosed trifunctional compounds known to have a linker connecting a prosthetic group to a chelator and targeting moiety. Additional prior art of Banerjee suggested an alternative linker to have similar ability to connect the prosthetic group to the chelating moiety and targeting moiety.
The skilled artisan would have been motivated to substitute the butyl linker of Banerjee in place of the linker of Liu because the butyl linker is part of a lysine group which has three functional groups enabling easy connection of the targeting moiety, chelator, and secondary imaging moiety. Therefore, it would have been prima facie obvious to combine the teachings of Liu with Banerjee.
Regarding the DOTA chelator connected directly to the central carbon by an amide bond, Banerjee teaches a trifunctional compound where the chelator is connected directly to the central moiety by an amide bond (pg 9168, Scheme 1, compounds 1 and [M]1).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the DOTA and DOTA linker of Liu with the DOTA and DOTA linker as taught by Banerjee because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of a DOTA linked directly to the central moiety by an amide bond.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting a DOTA directly bound to the central moiety in place of a DOTA bound through a longer linker because the prior art of Liu disclosed DOTA chelators known to link to the central moiety through the R group of a lysine connecting the chelator to the prosthetic group and the targeting moiety. Additional prior art of Banerjee suggested DOTA chelators linked through the backbone amine of the lysine to have similar ability to connect the DOTA to the prosthetic group and the targeting moiety because of the overlap of structure between them involves known chemistry.
The skilled artisan would have been motivated to substitute the DOTA linkage of Banerjee in place of the DOTA linkage of Liu because the sterics around the chelator can affect the binding properties of the chelated metal. Therefore, it would have been prima facie obvious to combine the teachings of Liu with Banerjee.
As to claim 93, Yang teaches the fluorine atom attached to the pyridyl group is 18F (pg 10, para [0080], line 4).
As to claim 94, Liu teaches the DOTA group is chelated to 67Ga (pg 14, para [0085], lines 1-3; pg 14, para [0086], lines 1-2).
As to claim 95, Yang teaches the FAP-α and linker attachment, reproduced below (Yang, pg 16, para [0084]).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the FAP-α targeting moiety and attachment linker of the trifunctional compound of Liu with the FAP-α targeting moiety and attachment linker as taught by Yang because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of substituting the FAP-α targeting moiety and linker of Yang in place of the one in Liu.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the FAP-α targeting moiety of Yang in place of the FAP-α targeting moiety of Liu because the prior art of Liu disclosed trifunctional compounds with a variety of FAP-α targeting moieties and linkers known to connect well to chelators and prosthetic groups (pg 2, para [0009]). Additional prior art of Yang suggested an additional FAP-α targeting moiety and linker system to have similar ability to be able to connect to a wide variety of chelators (pg 10, para [0081]) or prosthetic groups (pg 10, para [0080]).
The skilled artisan would have been motivated to substitute the FAP-α targeting moiety and linker of Yang in place of the one of Liu because varying the linker or the particular form of the FAP targeting moiety can alter the binding and clearance of the trifunctional compound for better uptake by the cancer. Therefore, it would have been prima facie obvious to combine the teachings of Liu with Yang.
Regarding the prosthetic group is 4-[18F]fluoro-phenyl with an ethyl amide linker, Yang teaches the 4-[18F]fluoro-phenyl prosthetic group, reproduced below (pg 10, para [0080], line 4).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the prosthetic group of Liu to include a radioisotope as taught by Yang 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 radiolabeled albumin-binding prosthetic group.
A person of ordinary skill in the art would have had a reasonable expectation of success in using a radiolabeled prosthetic group of the trifunctional compound because the prior art of Liu disclosed trifunctional compounds known to have prosthetic groups containing halogen-substituted aromatic rings. Additional prior art of Yang suggested radiolabeled halogen substituted aromatic rings to have similar ability to connect to chelators and FAP-α targeting moieties due to the overlap of the chemical structures.
The skilled artisan would have been motivated to radiolabel the prosthetic group because radiolabeling helps in detection and diagnosis of diseases and radiolabeling with 18F has the potential for PET imaging which could be used in concert with the chelator metal for dual imaging. Therefore, it would have been prima facie obvious to combine the teachings of Liu with Yang.
Regarding the ethyl linker between the prosthetic group and the central carbon, Yang teaches a linker where t2 is 2 and p1, p2, p3, and m1 are each 0 and Tz is absent (pg 8, para [0067], lines 1-33; pg 8, para [0068]; pg 8, para [0069], lines 1-2). This is equivalent to an ethyl linking group.
Alternatively, Banerjee teaches a butyl linker to an imaging moiety (pg 9168, Scheme 1). The claimed ethyl linker and prior art butyl linker differ by two -CH2- groups. In cases where the difference is by the successive addition of the same chemical group, e.g. by -CH2- groups), these are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. See MPEP 2144.09(II).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the linker of the prosthetic group of Liu with the butyl linker of the prosthetic group as taught by Banerjee because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of a butyl linker between the central carbon and the prosthetic group.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the butyl linker for the prosthetic group of Banerjee in place of the linker of Liu because the prior art of Liu disclosed trifunctional compounds known to have a linker connecting a prosthetic group to a chelator and targeting moiety. Additional prior art of Banerjee suggested an alternative linker to have similar ability to connect the prosthetic group to the chelating moiety and targeting moiety.
The skilled artisan would have been motivated to substitute the butyl linker of Banerjee in place of the linker of Liu because the butyl linker is part of a lysine group which has three functional groups enabling easy connection of the targeting moiety, chelator, and secondary imaging moiety. Therefore, it would have been prima facie obvious to combine the teachings of Liu with Banerjee.
Regarding the DOTA chelator connected directly to the central carbon by an amide bond, Banerjee teaches a trifunctional compound where the chelator is connected directly to the central moiety by an amide bond (pg 9168, Scheme 1, compounds 1 and [M]1).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the DOTA and DOTA linker of Liu with the DOTA and DOTA linker as taught by Banerjee because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of a DOTA linked directly to the central moiety by an amide bond.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting a DOTA directly bound to the central moiety in place of a DOTA bound through a longer linker because the prior art of Liu disclosed DOTA chelators known to link to the central moiety through the R group of a lysine connecting the chelator to the prosthetic group and the targeting moiety. Additional prior art of Banerjee suggested DOTA chelators linked through the backbone amine of the lysine to have similar ability to connect the DOTA to the prosthetic group and the targeting moiety because of the overlap of structure between them involves known chemistry.
The skilled artisan would have been motivated to substitute the DOTA linkage of Banerjee in place of the DOTA linkage of Liu because the sterics around the chelator can affect the binding properties of the chelated metal. Therefore, it would have been prima facie obvious to combine the teachings of Liu with Banerjee.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 42-43, 53-62, 64-66, and 92-95 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19-22 and 28-31 of copending Application No. 16/758,182 in view of Liu, Yang, and Banerjee. The teachings of Liu, Yang, and Banerjee as applied in the previous rejection are incorporated in this rejection.
Instant claims are drawn to a trifunctional compound according to formula (III) comprising a FAP-α targeting moiety and a 1-oxy-3-aminopropyl linker to the central moiety, a DOTA chelator with 67Ga and an amide linker to the central moiety, a 4-[18F]fluoro-pyridyl amide prosthetic group with a ethyl linking group to the central moiety, and a pharmaceutical composition with pharmaceutically acceptable excipients.
The conflicting claims of copending U.S. Application No. 16/758,182 (hereafter referred to as '182) are drawn to a FAP-α binding moiety with a 1-oxy-3-aminopropyl linking group to a DOTA chelator with 67Ga with a linker to the FAP-α linker; and pharmaceutical compositions and excipients comprising the compound.
The conflicting claims of '182 do not teach a trifunctional compound.
The conflicting claims of '182 do not teach a trifunctional compound comprising a 4-[18F]fluoro-pyridyl prosthetic group.
The conflicting claims of '182 do not teach a ethyl linking group from the prosthetic group to the central moiety.
The conflicting claims of '182 do not teach an amide linking group to the central moiety.
Regarding the trifunctional compound, Liu teaches a trifunctional compound (pg 3, para [0011], line 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 compound of the conflicting claims of ‘182 to be trifunctional as taught by Liu because there was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to a person of ordinary skill in the art, to modify the reference or to combine reference teachings and the modification would have yielded the predictable outcome of a trifunctional compound.
A person of ordinary skill in the art would have had a reasonable expectation of success in making a trifunctional compound with the FAP-α targeting moiety and DOTA chelating moiety and a prosthetic group because the conflicting claims of ‘182 disclosed a compound with FAP-α targeting moiety and a DOTA chelating. Additional prior art of Liu suggested a compound that added a prosthetic group into the middle making it trifunctional to have similar ability to target FAP and chelate metals with the DOTA chelating moiety.
The skilled artisan would have been motivated to make the compound trifunctional because the additional functionality can enhance binding or add additional imaging techniques. Therefore, it would have been prima facie obvious to combine the teachings of the conflicting claims of ‘182 with Liu.
Regarding the 4-[18F]fluoro-pyridyl prosthetic group, Yang teaches the 4-[18F]fluoro-phenyl prosthetic group, reproduced below (pg 10, para [0080], line 4).
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Greyscale
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the prosthetic group of the conflicting claims of ‘182 and Liu to include a radioisotope as taught by Yang 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 radiolabeled albumin-binding prosthetic group.
A person of ordinary skill in the art would have had a reasonable expectation of success in using a radiolabeled prosthetic group of the trifunctional compound because the prior art of Liu disclosed trifunctional compounds known to have prosthetic groups containing halogen-substituted aromatic rings. Additional prior art of Yang suggested radiolabeled halogen substituted aromatic rings to have similar ability to connect to chelators and FAP-α targeting moieties due to the overlap of the chemical structures.
The skilled artisan would have been motivated to radiolabel the prosthetic group because radiolabeling helps in detection and diagnosis of diseases and radiolabeling with 18F has the potential for PET imaging which could be used in concert with the chelator metal for dual imaging. Therefore, it would have been prima facie obvious to combine the teachings of the conflicting claims of ‘182 and Liu with Yang.
Regarding the ethyl linker between the prosthetic group and the central carbon, Yang teaches a linker where t2 is 2 and p1, p2, p3, and m1 are each 0 and Tz is absent (pg 8, para [0067], lines 1-33; pg 8, para [0068]; pg 8, para [0069], lines 1-2). This is equivalent to an ethyl linking group.
Alternatively, Banerjee teaches a butyl linker to an imaging moiety (pg 9168, Scheme 1). The claimed ethyl linker and prior art butyl linker differ by two -CH2- groups. In cases where the difference is by the successive addition of the same chemical group, e.g. by -CH2- groups), these are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. See MPEP 2144.09(II).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the linker of the prosthetic group of the conflicting claims of ‘182 and Liu with the butyl linker of the prosthetic group as taught by Banerjee because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of a butyl linker between the central carbon and the prosthetic group.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the butyl linker for the prosthetic group of Banerjee in place of the linker of Liu because the prior art of Liu disclosed trifunctional compounds known to have a linker connecting a prosthetic group to a chelator and targeting moiety. Additional prior art of Banerjee suggested an alternative linker to have similar ability to connect the prosthetic group to the chelating moiety and targeting moiety.
The skilled artisan would have been motivated to substitute the butyl linker of Banerjee in place of the linker of Liu because the butyl linker is part of a lysine group which has three functional groups enabling easy connection of the targeting moiety, chelator, and secondary imaging moiety. Therefore, it would have been prima facie obvious to combine the teachings of the conflicting claims of ‘182 and Liu with Banerjee.
Regarding the DOTA chelator connected directly to the central carbon by an amide bond, Banerjee teaches a trifunctional compound where the chelator is connected directly to the central moiety by an amide bond (pg 9168, Scheme 1, compounds 1 and [M]1).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the DOTA and DOTA linker of the conflicting claims of ‘182 and Liu with the DOTA and DOTA linker as taught by Banerjee because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of a DOTA linked directly to the central moiety by an amide bond.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting a DOTA directly bound to the central moiety in place of a DOTA bound through a longer linker because the prior art of Liu disclosed DOTA chelators known to link to the central moiety through the R group of a lysine connecting the chelator to the prosthetic group and the targeting moiety. Additional prior art of Banerjee suggested DOTA chelators linked through the backbone amine of the lysine to have similar ability to connect the DOTA to the prosthetic group and the targeting moiety because of the overlap of structure between them involves known chemistry.
The skilled artisan would have been motivated to substitute the DOTA linkage of Banerjee in place of the DOTA linkage of Liu because the sterics around the chelator can affect the binding properties of the chelated metal. Therefore, it would have been prima facie obvious to combine the teachings of the conflicting claims of ‘182 and Liu with Banerjee.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/EVAN M LEWOCZKO/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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