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 and species A is claim 7, L is claim 9, B is a chelating agent and compound XY-FAP-02 in the reply filed on 8/12/25 is acknowledged.
Claims 6,8,10-12,15-18 and 23-27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected groups and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/12/25.
Drawings
The petition to accept colored drawings was accepted on 8/10/21.
Claim Rejections - 35 USC § 112
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 1-5,7,9,13,14,21 and 22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph.
Claims 1-5,7,9,13,14,21 and 22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claimed Markush structures contain a combination of numerous possible variations of substituents, numerous substituted 5 to 10-membered heterocyclic ring structures, numerous linkers and numerous reporter moiety chelating agents that the scope of the claim cannot be determined. While breadth alone is not indefinite, the instant claims have an almost unlimited number of possible combinations of chemical moieties that it is not possible to determine the metes and bounds of the claims.
Claims 1-5,7,9,13,14,21 and 22 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
A Markush claim contains an “improper Markush grouping” if: (1) the species of the Markush group do not share a single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a "single structural similarity” when they belong to the same recognized physical or chemical class or to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the specification or known in the art to be functionally equivalent (see Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, p. 7166, left and middle columns, bridging paragraph).
The claims are directed to compounds used for imaging and/or radiotherapy of cells highly expressing FAP that comprise a combination of numerous possible alternative variations of substituents, numerous substituted 5 to 10-membered heterocyclic ring structures, numerous linkers and numerous reporter moiety chelating agents.
Applicant attention is directed to the third paragraph of MPEP 803.02 which discloses: “Since
the decisions in In re Weber, 580 F.2d 455, 198 USPQ 328 (CCPA 1978) and In re Haas, 580 F.2d 461, 198 USPQ 334 (CCPA 1978), it is improper for the Office to refuse to examine that which Applicants regard as their invention, unless the subject matter in a claim lacks unity of invention. In re Harnisch, 631 F.2d 716, 206 USPQ 300 (CCPA 1980); and Ex parte Hozumi, 3 USPQ2d 1059 (Bd. Pat. App. & Int. 1984). Broadly, unity of invention exists where compounds included within a Markush group (1) share a common utility, and (2) share a substantial structural feature essential to that utility.”
In the instant case, if it is asserted that the claims share a common utility, it is noted the only shared structure of the proline ring, but they may be substituted with a plethora of different and distinct chemical moiety combinations. In addition, the wide variety of rings optionally containing one or more heteroatoms does not allow the genus to have an art recognized classification. Hence, the Markush grouping is improper.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1) (emphasis provided).
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.
Claim(s) 1-5,7,9,13,14,21 and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zimmerman et al. (US2010/0098633A1) in view of Jansen et al. (US2014/0357650A1) and Jansen et al. (ACS Med. Chem. Lett. 2013, 14, 491-496).
Zimmerman et al. (US2010/0098633A1) discloses radiopharmaceuticals comprising a proline moiety and a chelated-radionuclide adapted for radioimaging and radiotherapy of diseases
PNG
media_image1.png
90
282
media_image1.png
Greyscale
,
PNG
media_image2.png
78
320
media_image2.png
Greyscale
wherein U is -B(OH)2, -CN, etc.; G is H, alkyl, etc.; V is a bond, (CH2-CH2-X)n, etc.; W is H, NHR’; X is O,S, CH2, etc.; the metal is a metallic moiety include a radionuclide for PET, SPECT; chelate is a chelating moiety that coordinates with the radionuclide (p1-2, [0008-0021],[0029]; p3, [0048-0049]; p6, [0087-0099]; p8, [0108-0110]; p9, [0111-0117]).
The
PNG
media_image3.png
82
150
media_image3.png
Greyscale
encompasses the
PNG
media_image4.png
94
134
media_image4.png
Greyscale
of the instant claims.
The chelating moieties include DOTA, DTPA, etc. (p7, [0100]; p43, compounds 22,23) that
encompasses the chelating agent of the instant claims.
The linker
PNG
media_image5.png
40
60
media_image5.png
Greyscale
encompasses the linkers of the instant claims.
The compounds comprise a functionalized proline moiety capable of selectively inhibiting seprase (FAP-α) (p1, [0007]; p2, [0029]).
The compounds may be combined with a pharmaceutically acceptable carrier (p2, [0031]; p16, [0137]) that encompasses the pharmaceutically acceptable carrier of the instant claims.
Zimmerman et al. does not disclose the 5- or 6-membered N-containing aromatic or non-
aromatic mono- or bicyclic heterocycle
PNG
media_image6.png
42
78
media_image6.png
Greyscale
moiety.
Jansen et al. (US2014/0357650A1) discloses the FAP inhibitors
PNG
media_image7.png
114
262
media_image7.png
Greyscale
for treatment and/or prevention of FAP-related disorders (abstract; p3, [0024]; p10, [0113]; p19, [0239]), such as
PNG
media_image8.png
103
296
media_image8.png
Greyscale
PNG
media_image9.png
129
307
media_image9.png
Greyscale
PNG
media_image10.png
122
296
media_image10.png
Greyscale
PNG
media_image11.png
122
299
media_image11.png
Greyscale
wherein R1 and R2 are H, -OH, halogen, etc. (p3, [0025];
p5, [0070-0071]; p9, [0114]).
The R3 is H, -CN, -B(OH)2, etc. (p4, [0026]; p5, [0072]; p9, [0115]).
The R4 is H (p4, [0027]; p6, [0073]; p9, [0116]).
The
PNG
media_image6.png
42
78
media_image6.png
Greyscale
moiety comprises
PNG
media_image12.png
200
290
media_image12.png
Greyscale
PNG
media_image13.png
198
282
media_image13.png
Greyscale
(p6, [0088]; p12, [0173]; p15, [0212]) that encompasses the corresponding
PNG
media_image14.png
43
87
media_image14.png
Greyscale
5 to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle of the instant claims.
The R5-R7 are H, -OH, oxo, -halo, C1-6alkyl, -O-C1-6alkyl optionally substituted with 1-3 substituents (p4, [0028]; p4-6, [0050-0089]; p10, [0117],[0122]; p13-16, [0176-0215])
The inhibitors may comprise stereoisomers, tautomers, racemates, salts, hydrates or solvates thereof (p3, [0024]; p10, [0113]) which encompasses the stereoisomers, tautomers, racemates, salts, hydrates or solvates thereof of the instant claims.
Jansen et al. (ACS Med. Chem. Lett. 2013, 14, 491-496) discloses FAP inhibitor (serine protease)
scaffolds having the structure
PNG
media_image15.png
145
209
media_image15.png
Greyscale
and substituting the quinoline ring at varying positions (abstract; Table 3).
The N-acyl-glycyl-(2-cyanoprolidine) scaffold has significant potential to deliver FAP inhibitors with good selectivity toward PREP and the dipeptidyl peptidases and previously the most potent compound identified is (N-(1-naphthoyl)-Gly-(2-cyanopyrrolidine) (p492, left column, second paragraph).
The quinoline containing compounds have 60 times more FAP-affinity than the initial N-(1-naphthoyl) based FAP inhibitors
PNG
media_image16.png
148
188
media_image16.png
Greyscale
(p492, right column, second full paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of
the claimed invention to substitute the FAP inhibitors of Zimmerman et al. with a
PNG
media_image6.png
42
78
media_image6.png
Greyscale
moiety comprising
PNG
media_image12.png
200
290
media_image12.png
Greyscale
PNG
media_image13.png
198
282
media_image13.png
Greyscale
to attach the metal chelating agent for the advantage of site selective targeting of the inhibitors to seprase (FAP-α) for diagnostic imaging and/or therapeutic treatment of FAP-related diseases/disorders wherein the quinoline containing FAP inhibitors have 60 times more FAP-affinity than the previously known potent N-(1-naphthoyl) FAP inhibitors.
Therefore, it would have been predictable to one of ordinary skill in the art to attach the metal chelate of the FAP inhibitors of Zimmerman et al. via a quinoline moiety as the improvement to the FAP inhibitors advantageously provide substantially more potent and selective inhibitors.
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 1-5,7,9,13,14,19,21 and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 42-46,53,54,58-60 and 64 of copending Application
No. 18/553,092 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the compounds of Formula (III) of copending Application No. 18/553,092 encompass the compounds of Formula (I) B-L-A of the instant claims. The targeting moiety structure for FAP-α, A, of copending Application No. 18/553,092 is analogous to the targeting moiety for FAP-α, A, of the instant claims.
The linker, L, of copending Application No. 18/553,092 having bi-functionalization that encompasses the linker, L, having bi-functionalization of the instant claims.
The chelating agent of copending Application No. 18/553,092 is analogous to the chelating agent, B, of the instant claims.
The compound of Formula (I) of copending Application No. 18/553,092 and the compound of Formula (I) of the instant claims, have the same properties and are capable of the same functions, such as being used for the method of imaging a disease or disorder associated with fibroblast-activation protein-α, a method of inhibiting fibroblast-activation protein-α and the method for treating a fibroblast-activation protein-α disease or disorder.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-5,7,9,13,14,19,21 and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 28-32,39 and 40 of copending Application No. 19/172,114 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the low molecular weight compounds of Formula (I) B-L-A of copending Application No. 19/172,114 encompass the compounds of Formula (I) B-L-A of the instant claims. The targeting moiety structure for FAP-α, A, of copending Application No. 19/172,114 is analogous to the targeting moiety for FAP-α, A, of the instant claims.
The
PNG
media_image17.png
46
74
media_image17.png
Greyscale
of copending Application No. 19/172,114 represents a quinolinyl ring having a point of attachment to the remainder of the FAP binding moiety at the 4-position of the quinolinyl ring that encompasses the quinolinyl moiety of the instant claims.
The linker, L, having bi-functionalization of copending Application No. 19/172,114 encompasses the linker, L, having bi-functionalization of the instant claims.
The chelating group of copending Application No. 19/172,114 is analogous to the chelating agent, B, of the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-5,7,9,13,14,19,21 and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 71,72,80,83 and 84 of copending Application No. 18/990,863 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the compounds of Formula (I) B-L-A of copending Application No. 18/990,863 encompass the compounds of Formula (I) B-L-A of the instant claims. The targeting moiety structure for FAP-α, A, of copending Application No. 18/990,863 is analogous to the targeting moiety for FAP-α, A, of the instant claims.
The
PNG
media_image17.png
46
74
media_image17.png
Greyscale
of copending Application No. 18/990,863 comprises a quinolinyl ring having a point of attachment to the remainder of the FAP-α targeting moiety at the 4-position of the quinolinyl ring that encompasses the quinolinyl moiety of the instant claims.
The linker, L, of copending Application No. 18/990,863 having bi-functionalization encompasses the linker, L, having bi-functionalization of the instant claims.
The radiolabeled functional group, B, suitable for PET, SPECT of copending Application No. 18/990,863 is analogous to the chelating agent of the instant claims.
The compound of Formula (I) of copending Application No. 18/990,863 and the compound of Formula (I) of the instant claims, have the same properties and are capable of the same functions, such as being used for the method of imaging a disease or disorder associated with fibroblast-activation protein-α, a method of inhibiting fibroblast-activation protein-α and the method for treating a fibroblast-activation protein-α disease or disorder.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-5,7,9,13,14,19,21 and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,938,201. Although the claims at issue are not identical, they are not patentably distinct from each other because the low molecular weight compounds of Formula (I) B-L-A of U.S. Patent No. 11,938,201B2 encompass the compounds of Formula (I) B-L-A of the instant claims. The targeting moiety structure for FAP-α, A, of U.S. Patent No. 11,938,201B2 is analogous to the targeting moiety for FAP-α, A, of the instant claims.
The
PNG
media_image17.png
46
74
media_image17.png
Greyscale
U.S. Patent No. 11,938,201B2 represents a 5 to 10-membered N-containing
aromatic encompasses the quinolinyl moiety of the instant claims.
The linker, L, of U.S. Patent No. 11,938,201B2 having bi-functionalization encompasses the linker, L, having bi-functionalization of the instant claims.
The radiolabeled functional group suitable for PET, SPECT of U.S. Patent No. 11,938,201B2 encompasses the chelating agent, B, of the instant claims.
Claims 1-5,7,9,13,14,19,21 and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 12,115,233. Although the claims at issue are not identical, they are not patentably distinct from each other because the low molecular weight compounds of Formula (I) B-L-A of U.S. Patent No. 12,115,233B2 encompass the compounds of Formula (I) B-L-A of the instant claims. The targeting moiety structure for FAP-α, A, of U.S. Patent No. 12,115,233B2 is analogous to the targeting moiety for FAP-α, A, of the instant claims.
The
PNG
media_image17.png
46
74
media_image17.png
Greyscale
of U.S. Patent No. 12,115,233B2 represents a quinolinyl ring having a point of attachment to the remainder of the FAP binding moiety at the 4-position of the quinolinyl ring that encompasses the quinolinyl moiety the instant claims.
The linker, L, of U.S. Patent No. 12,115,233B2 having bi-functionalization encompasses the linker, L, having bi-functionalization of the instant claims.
The chelating group, of U.S. Patent No. 12,115,233B2 is analogous to the chelating agent, B, of the instant claims.
Conclusion
Claim 20 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MELISSA JEAN PERREIRA whose telephone number is (571)272-1354. The examiner can normally be reached M9-3, T9-3, W9-3, Th9-2, F9-2.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use
the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Hartley can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MELISSA J PERREIRA/Examiner, Art Unit 1618