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 of Group I , with traverse, in the reply filed on 12/17/2025 is acknowledged. It is noted that Applicant amended Group II , claims 10 to be dependnet from Group I; elected claim 1) , and cancelled Group II: claims 7-9. Applicant asserts that the Requirement for separate election of Group I and Group II should now be deemed moot. Applicant argues that the Examiner's stance [that Groups I-II lack unity because the technical features linking Group I and Group II (a solid support to which a chemical entity is attached, characterized in that the chemical entity possesses inverse electron demand Diels-Alder cycloaddition reactivity) are not novel over the prior art document (US Patent Publication No. 20080131353) which teaches a Diels-alder reactive solid support column in paragraphs [0006]- [0007] is now considered moot by pending claims 1-6 and 10-14, as now amended. Applicant’s arguments have been considered but the Examiner asserts that the restriction between Groups I and II is still applicable because the amendment to the product claims (10-14), such that a clearing trap is for carrying out the method of claim 1, amounts to an intended-use of the product itself and does not distinguish over the structural features of the product. Accordingly, groups lack a special technical feature and the restriction is considered to be proper. Claims 1-6 and 10-14 are pending, of which claims 10-14 are withdrawn from consideration as being directed to a non-elected invention. Claims 1-6 are examined herein on the merits for patentability. The election of the first diene shown in claim 4 as first chemical entity species, and the first dienophile shown in claim 4 as second chemical entity species are acknowledged. Claim Objections Claim 6 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple depen dent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, the claim has not been further treated on the merits. 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 appl icant regards as his invention. Claims 1-6 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 recites “part of such agent” in line 2, the phrase renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claim 1 further recites “the first chemical entity” in line 3. There is insufficient antecedent basis for this limitation in the claim. Claim 1 further recites “the patient” in line 6. There is insufficient antecedent basis for this limitation in the claim. It is noted that “a subject” is recited in lines 5 and 10, it is unclear if the patient and the subject are intended to be the same individual. Claim 3 recites “selected from the group comprising” in line 20, see MPEP § 2173.05(h), which states “[ i ]f a Markush grouping requires a material selected from an open list of alternatives (e.g., selected from the group ‘comprising’ or ‘consisting essentially of’ the recited alternatives), the claim should generally be rejected under 35 U.S.C. 112(b) as indefinite because it is unclear what other alternatives are intended to be encompassed by the claim.” Claim 4 recites “selected from the group comprising” in lines 2 and 7, see MPEP § 2173.05(h), which states “[ i ]f a Markush grouping requires a material selected from an open list of alternatives (e.g., selected from the group ‘comprising’ or ‘consisting essentially of’ the recited alternatives), the claim should generally be rejected under 35 U.S.C. 112(b) as indefinite because it is unclear what other alternatives are intended to be encompassed by the claim.” Claim 5 recites the phrase “such as” in lines 2 and 6-8, the phrase renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). 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. Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, 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. The claim recites the following limitation: However, claim 3, from which claim 4 depends, does not feature a corresponding structure according the first structure shown above, Applicant’s elected species with regard to dienophile. For example, claim 4 recites , etc. with regard to limitation W, the variables do not correspond to the first structure of claim 3, as they all feature at least an extra atom (O, NH, etc.). Clarification is requested. 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) 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Theodor et al. ( EP 1346730 ) in view of Steen et al. (Biomaterials, 2018, 179, 209-245). Theodor teaches methods, compounds, compositions and kits useful for delivering to a target site a targeting moiety that is conjugated to one member of a ligand/anti-ligand pair. After localization and clearance of the targeting moiety conjugate, direct or indirect binding of a diagnostic or therapeutic agent conjugate at the target site occurs (paragraph 0001). P retargeting involves target site localization of a targeting moiety that is conjugated with one member of a ligand/anti-ligand pair; after a time period sufficient for optimal target-to-non-target accumulation of this targeting moiety conjugate, active agent conjugated to the opposite member of the ligand/anti-ligand pair is administered and is bound (directly or indirectly) to the targeting moiety conjugate at the target site (two-step pretargeting ) (paragraph 0022). In Example IX, a two step pre-targeting method is taught. A NR-LU-13-avidin conjugate is prepared . A 99m Tc-chelate-biotin conjugate is also prepared. The NR-LU-13-avidin conjugate is administered to a recipient and allowed to clear from the circulation. One of ordinary skill in the art of radioimmunoscintigraphy is readily able to determine the optimal time for NR-LU-13-avidin conjugate tumor localization and clearance from the circulation. At such time, the 99m Tc-chelate-biotin conjugate is administered to the recipient. Because the 99m Tc-chelate-biotin conjugate has a molecular weight of ≈ 1,000, crosslinking of NR-LU-13-avidin molecules on the surface of the tumor cells is dramatically reduced or eliminated. As a result, the 99m Tc diagnostic agent is retained at the tumor cell surface for an extended period of time. Accordingly, detection of the diagnostic agent by imaging techniques is optimized; further, a lower dose of radioisotope provides an image comparable to that resulting from the typical three-step pretargeting protocol. Optionally, clearance of NR-LU-13-avidin from the circulation may be accelerated by plasmapheresis in combination with a biotin affinity column . Through use of such column, circulating NR-LU-13-avidin will be retained extracorporeally, and the recipient's immune system exposure to a large, proteinaceous immunogen (i.e., avidin) is minimized. Exemplary methodology for plasmapheresis/column purification useful in the practice of the present invention is discussed in the context of reducing radiolabeled antibody titer in imaging and in treating tumor target site. Briefly, for the purposes of the present invention, an example of an extracorporeal clearance methodology may include the following steps: administering a ligand- or anti-ligand-targeting moiety conjugate to a recipient; after a time sufficient for localization of the administered conjugate to the target site, withdrawing blood from the recipient by, for example, plasmapheresis; separating cellular element from said blood to produce a serum fraction and returning the cellular elements to the recipient; and reducing the titer of the administered conjugate in the serum fraction to produce purified serum; infusing the purified serum back into the recipient. Clearance of NR-LU-13-avidin is also facilitated by administration of a particulate-type clearing agent (e.g., a polymeric particle having a plurality of biotin molecules bound thereto). Such a particulate clearing agent preferably constitutes a biodegradable polymeric carrier having a plurality of biotin molecules bound thereto. Particulate clearing agents of the present invention exhibit the capability of binding to circulating administered conjugate and removing that conjugate from the recipient. Particulate clearing agents of this aspect of the present invention may be of any configuration suitable for this purpose (paragraph 039 6 -0400). Theodor uses biotin/avidin as a molecular recognition element ligand pair rather than TCO / tetrazine click chemistry for administration of a targeting vector conjugate to a subject, passing blood through a solid support bound to a complementary molecular recognition element, and to returning blood to a subject as a means of extracorporeal clearance methodology . Steen teaches that p retargeted nuclear imaging and radiotherapy have recently attracted increasing attention for diagnosis and treatment of cancer with nanomedicines. This is because it conceptually offers better imaging contrast and therapeutic efficiency while reducing the dose to radiosensitive tissues compared to con ventional strategies. In conventional imaging and radiotherapy, a directly radiolabeled nano-sized vector is administered and allowed to accumulate in the tumor, typically on a timescale of several days. In contrast, pretargeting is based on a two-step approach. First, a tumor-accumulating vector carrying a tag is administered followed by injection of a fast clearing radiolabeled agent that rapidly recognizes the tag of the tumor-bound vector in vivo. Therefore, pretargeting circumvents the use of long-lived radionu clides that is a necessity for sufficient tumor accumulation and target-to-background ratios using conventional approaches (abstract). In general, there are two types of pretargeting systems: (I) non covalent high-affinity interactions and (II) covalent bond formations via bioorthogonal chemistry. The first pretargeting strategies developed fall within the first category. They rely on high-affinity interactions between biomolecules such as the bispecific antibody ( bAb ) and hapten recognition, the interaction between ( strept )avidin and biotin, and the hybridization of complementary oligonucleotides. Modern pretargeting strategies rely on bioorthogonal chemical reactions between small molecule tags (page 216). The ( strept )avidin-biotin interaction can in principle be applied in two ways for pretargeted imaging. Either the primary targeting agent can be functionalized with ( strept )avidin and biotin being used as the secondary imaging agent or the primary targeting agent can be functionalized with biotin and ( strept )avidin being used as the secondary imaging agent (page 219+). In section 3.3.2 , covalent bond formations via bioorthogonal chemistry is discussed. For a reaction to be classified as bioorthogonal , several requirements have to be fulfilled. First, the participating groups need to be inert towards other biological functionalities such as amino acid residues, nucleic acids, etc. Second, the groups have to be able to react with each other under biocompatible conditions. Finally, the reaction must be fast and specific. A number of bioorthogonal reactions have been described since the introduction of the term … Nowadays, other biorthogonal reactions have been shown to serve as better alternatives for in vivo applications, two of them, the strain-promoted azide -alkyne cycloaddition (SPAAC) and the tetrazine ligation will be discussed in the following sections. Another and even more powerful bioorthogonal reaction is the tetrazine ligation. Compared to the SPAAC, the tetrazine ligation shows superior re action kinetics, where impressive rate constants up to 10 6 - 7 M 1 s 1 have been reported . In addition, the high specificity, the small molecule character and the orthogonality towards biological moieties make this ligation highly interesting for pretargeting approaches in vivo. In contrast to the standard Diels-Alder reaction (DA) reaction, whichis a [4 + 2] cycloaddition between an electron rich diene and an electron poor dienophile [203], the IEDDA has diene/dienophile pairs with opposite electronic character, i.e. an electron poor diene, the Tz , and an electron rich dienophile (page 225-6). Dienophiles such as TCO and tetrazines are shown in Figure 21. With regard to pretargeting strategies, i n theory, either a Tz derivative or a TCO moiety can be used to functionalize the tar geting vector. The most frequently applied method in nuclear im aging is to functionalize the targeting vector with TCO and radiolabel the Tz counterpart (page 228). As an example, i n order to further increase imaging contrast, a clearing agent was applied in the CC49-TCO/[111In]In-DOTA-PEG11-Tz pretargeting strategy. In these experiments, a galactose-albumin construct was functionalized with Tz -derivatives (9e13 Tz -derivatives/albumin galactose) and used to clear free circulating TCO-functionalized mAbs from the blood to the liver. This type of clearing agent has previously shown promise in pretargeting experiments based on the ( strept )avidin-biotin interaction. The clearing agent was administered to mice pretreated with CC49-TCO 30h earlier. After 3h111In-labeled Tz 1 (Table 3) was injected. This set-up resulted in more than a 100-fold higher imaging contrast compared to the results from the original study (page 229). To date, the t etrazine ligation is the most promising biorthogonal reaction in rodents (page 236). It would have been obvious to one of ordinary skill in the art to substitute Diels- Alder cycloaddition reactive molecular recognition elements, such as TCO / tetrazine as functionally equivalent to for avidin / biotin recognition elements, for use in extracorporeal clearance methodology comprising pretargeting in which TCO/tetrazine is conjugated to an antibody or diagnostic agent as a targeting vector , passing blood through a solid support bound complementary molecular recognition element (tetrazine/TCO, respectively) , and to returning blood to a subject when the teaching of Theodor is taken in view of Steen. One would have been motivated to do , with a reasonable expectation of success, because Steen teaches that the tetrazine ligation is taught to serve as a better alternative for in vivo applications for pretargeted imaging in comparison to biotin / ( strept ) avidin, such as showing high imaging contrast, and that t o date, the t etrazine ligation is the most promising biorthogonal reaction in rodents . Conclusion No claims are allowed at this time. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT LEAH H SCHLIENTZ whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-9928 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT Monday-Friday, 8:30am - 12:30pm EST . Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. 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