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 .
Acknowledgement of Receipt
Applicant’s Response, filed 2/20/2026, in reply to the Office Action mailed 10/20/2025 is acknowledged and has been entered. Claims 1, 4-6, 10, 12-14, 16 and 17 have been amended. Claims 18 and 19 are newly added. Claims 1-6 and 8-19 are pending, of which claims 12-17 are withdrawn from consideration at this time as being drawn to a non-elected invention. Claims 1-6, 8-11, 18 and 19 encompass the elected invention and are examined herein on the merits for patentability.
Response to Arguments
Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. New grounds for rejection are set forth herein, necessitated by claim amendment. The terminal disclaimer over Application Serial No. 18/280,881 has been accepted.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 19 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The claim is directed the H-tetrazine compound according to claim 1, wherein said one or more group(s) providing a lipophilicity of c logD7.4 <-3 to the compound of Formula I is N substituted with CH2N(CH₂COOH)₂. However, the specification as filed does not provide support for a compound having a group providing a lipophilicity which is N substituted with CH2N(CH₂COOH)₂. The specification refers to various compounds of the invention set forth in published paragraphs 0023-27+), such as a wherein a group providing a lipophilicity may be PG1:
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, the specification does not provide a compound having N substituted with CH2N(CH₂COOH)₂. This is a new matter rejection.
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 1-6, 8-11, 18 and 19 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. Claim 1 is directed to a H-tetrazine compound, having the following formula I: wherein R1-R5 are independently selected from: a radionuclide selected from 18F, 123I, 124I, 131I or 211At; one or more group(s) providing a lipophilicity of c log D7.4<−3 to the compound of Formula I independently selected from the group consisting of a hydroxy group, a sulfonamide, a sulfonyl group, amine, etc. in lines 1-5+ of the claim. However, the last phrase of the claim as amended recites “wherein one of R1-R₅ is a radionuclide and at least one or more of the remaining R1-R5 is a/are group(s) providing a lipophilicity of c logD₇ 4 < - 3 is N substituted with two carboxyl-containing substituents, and any R1-R5 remaining thereafter is/are H.
Accordingly, as defined by the last phrase of the claim the only available substituents for the claimed compound are a radionuclide selected from 18F, 123I, 124I, 131I or 211At, at least one N substituted with two carboxyl-containing substituents, and the remaining variables R1-5 are H. Therefore, the various other substituents such as hydroxy, sulfonamide, sulfonyl, amine, etc. set forth in lines 5+ on pages 1-2 of the claim set are extraneous and cannot be one of variables R1-5 according to the last phrase of the claim. As such, the metes and bounds of the claims are not clearly set forth and the scope of the invention cannot be distinctly ascertained. For the purpose of performing prior art search, the claims are interpreted such that the recitation “wherein one of R1-R₅ is a radionuclide and at least one or more of the remaining R1-R5 is a/are group(s) providing a lipophilicity of c logD₇ 4 < - 3 is N substituted with two carboxyl-containing substituents, and any R1-R5 remaining thereafter is/are H” is a required component of the claims. Clarification is requested.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2-6 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragrph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 2-3 recite “wherein one or more group(s) providing a lipophilicity of c log D7.4<−3 to the compound of Formula I is selected from: —OH, NR7R8, CH2N(CH2COOH)2, CH2NHCH2COOH, CH2NRCH2COOH, etc. However, claim 1 requires that one of R1-R₅ is a radionuclide and at least one or more of the remaining R1-R5 is a/are group(s) providing a lipophilicity of c logD₇ 4 < - 3 is N substituted with two carboxyl-containing substituents, and any R1-R5 remaining thereafter is/are H.
Claim 4 recites “wherein one or more of the remaining R1-R5 groups is selected from the polar groups PG1-PG5”.
Claim 5 recites a compound selected from formula Ia and Ib. However, claim 1 requires that one of R1-R₅ is a radionuclide and at least one or more of the remaining R1-R5 is a/are group(s) providing a lipophilicity of c logD₇ 4 < - 3 is N substituted with two carboxyl-containing substituents, and any R1-R5 remaining thereafter is/are H.
Claim 6 recites a compound of formula Ic. Claim 1 requires at least one of R1-R5 is a/are group(s) is N substituted with two carboxyl-containing substituents. As such, the structure shown includes an additional CH2 and is outside the scope of claim 1.
As such each of the cited dependent claims include variables that are outside the scope of the independent claim, which requires that one of R1-R₅ is a radionuclide, at least one or more of the remaining R1-R5 is N substituted with two carboxyl-containing substituents, and any R1-R5 remaining thereafter is/are H.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
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.
Claim(s) 1-6, 8-11 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Hildebrand et al. (WO 14/065860).
Hildebrand teaches compounds of Formula I-III (pages 4,5 and 13+), including Formula 1, as shown:
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,
including wherein A may be phenyl; R1 may be hydrogen (page 14).
Particular compounds of Formula Ib include:
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(page 20).
Particular compounds of Formula III may be:
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(page 32).
The compounds described herein are useful as functionalized 1,2,4,5-tetrazine compounds that can be employed for attachment or incorporation into biological molecules, their ligands, or suitable therapeutic or diagnostic molecules. The compounds can be used in bioorthogonal labeling employing inverse-electron-demand Diels Alder reactions of biological molecules, their ligands, and suitable therapeutic or diagnostic molecules with complementary reaction components that incorporate or attach suitable complementary dienophiles, such as trans-cyclooctenes. The compounds are therefore useful in both diagnostic and therapeutic methods (pages 4-5 and 13+).
The compounds described herein may be used in methods for delivering a "payload," such as a therapeutic or detectable agent, to a biological target. These methods include the use of bioorthogonal chemistry to achieve bioconjugation using the inverse electron demand Diels-Alder reaction to deliver a payload, such as a therapeutic or detectable compound, using specific ligands such as antibodies, small molecules and other biomolecules. The specific ligand is attached, optionally through a linker, to one component of the Diels-Alder pair, and the payload is attached, also optionally through a linker, to the other component. For example, if the ligand is attached to a 1,2,4,5- tetrazine diene, then the payload is attached to a dienophile {e.g., trans-cyclooctene); if the ligand is attached to the dienophile, then the payload is attached to the 1, 2,4,5 -tetrazine diene (page 40).
In some embodiments the payload is a therapeutic agent such as a … radioactive ion or other therapeutic agents.
Radioactive ions include, but are not limited to iodine {e.g., iodine 125 or iodine -131) (page 47-48).
Examples of detectable substances include various organic small molecules, inorganic compounds, nanoparticles, enzymes or enzyme substrates, fluorescent materials, luminescent materials, bioluminescent materials, chemiluminescent materials, radioactive materials, and contrast agents.
Examples of suitable radioactive material include 18F, …123I… 1251, etc. either directly or indirectly, or other radioisotope detectable by direct counting of radioemission or by scintillation counting (page 48-49).
Example 7 is directed to 2-Fluoro-4-(l,2,4,5-tetrazin-3-yl)benzoic acid
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(page 58).
Example 16 is directed to 2-Amino-3-(4-(l,2,4,5-tetrazin-3-yl)phenyl)propanoic acid; 4-(l,2,4,5-Tetrazin-3-yl)phenylalanine
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. See also compounds in claim 18 including: and
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, i.e. which includes a nitrogen and two carboxyl containing moieties including carboxylic acid and a carboxyl as part of the FMOC group.
While Hildebrand does not specifically exemplify a compound according to the instant claims, with regard to claim 5, it would have been obvious to one of ordinary skill in the art to provide 18F as a fluorine isotope in 2-Fluoro-4-(l,2,4,5-tetrazin-3-yl)benzoic acid (Example 7). One would have been motivated to do so, with a reasonable expectation of success, because Hildebrand teaches that a payload (detectable label, e.g.18F) may be attached to a 1,2,4,5-tetrazine diene involved in biorthogonal labeling (page 40).
With regard to claims 1-6 and 8-11, it would have been obvious to one of ordinary skill in the art at the time of the invention to provide a fluorine or iodine label on a compound of Formula Ib (e.g. such as on page 20). One would have been motivated to do so, because Hildebrand teaches that a payload (detectable label, therapeutic agent, e.g.18F, 131I) may be attached to a 1,2,4,5-tetrazine diene involved in biorthogonal labeling (page 40). One would have had a reasonable expectation of success in doing so because Hildebrand shows conjugation of a halogen atom to a phenyl ring in Example 7.
With regard to placement of the halogen and carboxyl or substituted amine on the aromatic ring in instant claims 5 and 6, a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (discussed in more detail below) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990).
Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
With regard to the recitation wherein the variable provides a lipophilicity of clogD7.4 < -3 to the compound, it is noted that a compound and it’s properties are inseparable. “Products of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure or composition as that which is claimed, the properties applicant discloses and/or claims are necessarily present. See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The “discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” See Atlas Power Co. v. Ireco Inc., 51 USPQ 2d 1943, 1947 (Fed. Cir. 1999). Therefore, merely claiming a new use, new function, or new property, which is inherently present in the prior art does not make the claim patentable. See In re Best, 195 USPQ 430, 433 (CCPA 1977), and MPEP § 2112.
With regard to the limitations of claims 10 and 11, wherein radionuclide therapy is applied to target vectors which do not internalize or wherein the compound does not penetrate cell membranes, it is noted that a compound and it’s properties are inseparable. See MPEP 2112.01. “Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Conclusion
No claims are allowed at this time.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEAH H SCHLIENTZ whose telephone number is (571)272-9928. The examiner can normally be reached Monday-Friday, 8:30am - 12:30pm EST.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618