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 .
Claims Status
Claims 1-16,20,21 and 67-69 are pending in the application. Claims 20 and 21 are withdrawn from further consideration.
Any objections and/or rejections from previous office actions that have not been reiterated in this office action are obviated.
Declaration/Affidavit
The declaration under 37 CFR 1.132 filed 9/2/25 is insufficient to overcome the rejection of claims 1-16 and 67-69 based upon 35 U.S.C. 103 as set forth in the last Office action because:
The declaration states that Dex500 clearing agents had been diafiltered with cutoff at either 30 or 100 kDa wherein the diafiltration with a 100 kDa cutoff to remove low-MW compounds significantly decreased tumor penetration of DOTAM-bound dextran fragments.
Therefore, the present application provides robust evidence that the claimed clearing agent provides a good clearance from the body together with an improved, i.e. lower, clearing agent penetration into tumors compared to a clearing agent which does not satisfy the molecular weight requirements recited in the present claim 1. The inventors discovered that good clearance from the blood can be achieved together with low clearing agent penetration into tumors when using DOTAM + dextran-based clearing agent.
The statements of “significantly decreased tumor penetration” and “good clearance from the
blood together with an improved, i.e. lower, clearing agent penetration into tumors” are subjective
statements that do not provide quantitative data and do not provide evidence of superior results.
The reference of Davis teaches of a radionuclide delivery agent comprising DOTA or a DOTA variant.
The DOTA or DOTA variants comprise
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wherein X comprises -C(=O)NHRd is stated in a finite list of X moieties.
The DOTA or DOTA variants may be further conjugated to a carbohydrate, such as dextran (p10, [0104-0105), therefore yielding dextran-DOTA (variant) (i.e. DOTAM + dextran-based clearing agent).
The dextran-based blocking/clearing agents of Davis are used in a 3-step PRIT application wherein the dextran-based blocking/clearing agent clears very rapidly from the blood and provides the advantage of essentially complete blocking/clearance of unbound/residual bsAb in the blood.
The bsAb of Davis specifically bind to the DOTA and DOTA variants and therefore, it would have been obvious to one of ordinary skill in the art that both the DOTA and/or DOTA variants, such as DOTAM will bind the targeted bsAb and unbound/residual bsAb of the PRIT application. The dextran-based blocking/clearing agent provides an 84-fold higher tumor uptake of the bsAb relative to that observed when 177Lu-DOTA is used alone.
Therefore, the dextran-based blocking/clearing agent is not taken up in the tumor tissue, is very rapidly cleared from the blood and binds to unbound/residual bsAb that results in enhanced binding of target bsAb with 177Lu-DOTA to yield excellent tumor:blood ratios.
The declaration further states that Dex70 showed extensive uptake of the clearing agent into the tumor while Dex500 showed little tumor penetration due to the wide MW range of molecules that are present in any batch of clearing agent, regardless of specified size. Because of this, the greater the specified clearing agent size, the lower risk of introducing low-MW fragments that can penetrate tumors.
The reference of Davis discloses that the dextran-based blocking agents comprising 500 kDa aminodextran which has a greater specified MW and therefore, predictably provides a lower risk of introducing low-MW fragments that can penetrate tumors.
The reference of Pu et al. teaches that dextran with extremely narrow molecular weight
distribution is demanded for clinical use wherein the dextran is purified by fractional ultrafiltration.
The ultrafiltration of Pu et al. encompasses the ultrafiltration of the disclosure.
Also, dextran 500 is known in the art to comprise a MW 440,000-560,000, as evidenced by MCE
MedChemExpress Dextran T500 (2025).
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) 1-16 and 67-69 is/are rejected under 35 U.S.C. 103 as being unpatentable over Davis et al. (US 2010/0254987A1) in view of Pu et al. (Carbohydr. Polym. 87 (2012) 1257-1260), as evidenced by MCE MedChemExpress Dextran T500 (2025) and in further view of Davis Orcutt et al. (Nucl. Med. Biol. 2011, 38, 223-233).
Davis et al. (US 2010/0254987A1) discloses dextran-based blocking agents comprising 500 kDa aminodextran conjugated to a DOTA wherein the resulting compound can include 100-150 (e.g. about 130) DOTA molecules per aminodextran (p3, [0020]).
The aminodextran encompasses the aminodextran of the instant claims.
The 500 kDa molecular weight of the aminodextran encompasses the average molecular weight of dextran is 200-800 kDa, optionally about 500 kDa of the instant claims 1,7 and 10.
The 500 kDa aminodextran has [Symbol font/0x7E]136 amino groups per dextran molecule (p19, [0179]).
The 100-150 (e.g. about 130) DOTA molecules per aminodextran encompasses the x ≥ 1 of the instant claim 2, and wherein x is 20 or more, 25 or more, 30 or more, 35 or more, 40 or more or 50 or more of the instant claim 3.
The number of DOTA comprising 150 molecules per aminodextran ([Symbol font/0x7E]136 amino groups
per aminodextran molecule) encompasses the at least 1% of the number of DOTAM groups as a
percentage of the number of glucose units of aminodextran of the instant claim 6.
The DOTA chelates to a variety of metals, such as Bi, Pb, etc. (p10, [0104]) which encompasses the metal ion and essentially stable metal ion, such as Bi, Pb, etc. of the instant claims 11,12,14 and 15.
The aminodextran-based blocking agent is used for the diagnosis and/or treatment of cancer and/or infectious disease via a pretargeted radioimmunotherapy (PRIT) application (abstract; p4, [0036]).
The diagnostic or treatment methods (PRIT) include a step of administering an engineered protein, such as a bispecific antibody (bsAb), administering an aminodextran- DOTA blocking agent and subsequently administering a radiolabeled-DOTA (variant) (p3, [0020]; p7, [0064]; p20, [0185]).
The bsAb specifically binds a metal-chelate comprising DOTA or an active variant (p7, [0064]).
Davis et al. does not explicitly disclose that the dextran-based blocking agents comprises DOTAM.
Davis et al. discloses DOTA (variant) include
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wherein X comprises -C(=O)NHRd; Rd comprises H, C1-6alkyl or C1-6haloalkyl; L1 comprises C1-6alkylene and L2 comprises C2-4 straight chain alkylene; and also provided that the valency of each atom in the optionally substituted moieties is not exceeded (p9-10, [0085-0102]).
The X comprising -C(=O)NHRd DOTA (variant) encompasses the DOTAM of the instant claims.
The Rd comprising H, C1-6alkyl or C1-6haloalkyl encompasses the RN is H C1-6alkyl or C1-6haloalkyl of the instant claims 1 and 67.
The L1 comprising C1-6alkylene encompasses the L1 is C1-4alkylene of the instant claims 1 and 67.
The L2 comprising C2 alkylene encompasses the L2 is C2 alkylene of the instant claims 1 and 67.
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 DOTA chelating moiety of the blocking agent for the DOTAM variant as Davis et al. teaches of DOTA variants, such as
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wherein X comprises -C(=O)NHRd that may further be conjugated to dextran (p10, [0104]) yielding dextran-DOTA (variant) (i.e. DOTAM + dextran-based clearing agent).
The bsAb specifically binds a metal-DOTA complex or a DOTA variant and therefore, it would
have been predictable to substitute the known DOTA chelator for the known DOTAM chelator (DOTA
variant) to analogously and specifically bind unbound/residual bsAb, respectively, to provide the advantage of essentially complete blocking/clearance of unbound/residual bsAb in the blood.
Also, it would have been predictable to one of ordinary skill in the art to utilize the same chelator structure for both the chelator of the radionuclide delivery agent used for binding the targeted bsAb and for the dextran-chelator blocking agent to bind unbound/residual bsAb, for example Davis teaches of DOTA chelator for both the radionuclide delivery agent 177Lu-DOTA and aminodextran-DOTA clearing/blocking agent of the PRIT method.
Davis et al. does not explicitly disclose forming a
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.
Davis et al. further discloses the method of preparing aminodextran-based blocking agents via reacting aminodextran with DOTA-SCN encompasses the method of preparing the clearing agent of the instant claim 13.
The resulting aminodextran-DOTA (variant) comprises a compound which encompasses the
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of the instant claim 2.
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 DOTA-SCN chelating moiety for a DOTAM-SCN chelating moiety as Davis et al. teaches of their analogous use as metal chelators for PRIT methods and the synthesis method utilizes a chelator-SCN starting compound for coupling with the aminodextran and the DOTAM
specifically binds the free bsAb and provides the advantage of essentially complete blocking/clearance
of residual bsAb in the blood.
Davis et al. does not explicitly disclose the linker
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.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the resulting aminodextran-based blocking agents comprises the linker
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as evidenced by the specification which states that the linking moiety may be formed from the conjugation of an amine and an isothiocyanate (spec p41, [0750]) wherein the
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linker of the instant claim 4 is necessarily formed via the conjugation of an amine of the aminodextran to the isothiocyanate of a DOTAM-SCN.
Davis et al. does not disclose the dextran components or clearing agents of less than a molecular weight cut-offs have been removed of the instant claim 8 and wherein the molecular weight cut-offs is in the ranges of the instant claim 9.
Pu et al. (Carbohydr. Polym. 87 (2012) 1257-1260) discloses that clinical dextran if purified by fractional ultrafiltration wherein dextran with extremely narrow molecular weight distribution is demanded for clinical use (abstract; p1258, left column, third paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize dextran-500 having an extremely narrow molecular weight distribution for the aminodextran-based blocking agents as it is demanded for clinical use and can be effectively accomplished via fractional ultrafiltration with a reasonable expectation of success.
Also, dextran 500 is known in the art to comprise a MW 440,000-560,000, as evidenced by MCE
MedChemExpress Dextran T500 (2025).
Regarding the instant claim 5, Davis et al. does not disclose that the aminodextran is substituted with one or more groups selected from an amino acid and a saccharide other than glucose.
Davis Orcutt et al. (Nucl. Med. Biol. 2011, 38, 223-233) discloses pretargeted immunotherapy (PRIT) and the use of a clearing agent to remove any IgG-like bispecific antibodies that remain the blood wherein the clearing agents comprise DOTA conjugated dextran, albumin blocking agent, cold dose of
DOTA chelate, a galactosylated DOTA-dextran or DOTA-albumin clearing agent or combination thereof
(abstract; p231, 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 DOTAM conjugated dextran for a galactosylated DOTMA-dextran clearing agent in the PRIT method of Davis et al. as Davis Orcutt et al. teaches of the analogous use of a variety of clearing agents for PRIT to predictably and advantageously provide for effective clearing of remaining antibodies in the blood.
Response to Arguments
Applicant's arguments filed 9/2/25 have been fully considered but they are not persuasive.
Applicant’s assertions with regards to Invitrogen are moot as the reference is not used in the instant rejection.
Applicant asserts that one of ordinary skill in the art would not conclude from Davis that any fractions containing the dextran are to be disregarded. Instead, they would readily understand that the SEC column is merely used to dispose of unreacted species which do not match the profile of the dextran product. SEC separates molecules gradually and continuously based on size as they pass through a porous resin, which can result in overlapping elution peaks and does not provide an absolute cutoff where molecules below a certain molecular weight are all excluded or retained – small molecules simply elute later and are not completely separated. The separation techniques described in the present application provide a binary pass/fail separation. The filtration techniques include diafiltration, ultrafiltration, tangential flow or crossflow filtration.
The reference of Davis was not used to teach of disregarding fractions containing the dextran.
The declaration states Dex500 showed little tumor penetration due to the wide MW range of molecules that are present in any batch of clearing agent, regardless of specified size. Because of this, the greater the specified clearing agent size, the lower risk of introducing low-MW fragments that can penetrate tumors.
The reference of Davis discloses that the dextran-based blocking agents comprising 500 kDa aminodextran which has a greater specified MW and therefore, predictably provides a lower risk of introducing low-MW fragments that can penetrate tumors.
The reference of Pu et al. was used to teach that dextran with extremely narrow molecular weight distribution is demanded for clinical use wherein the dextran is purified by fractional ultrafiltration.
The ultrafiltration of Pu et al. encompasses the ultrafiltration of the present application.
Also, dextran 500 is known in the art to comprise a MW 440,000-560,000, as evidenced by MCE MedChemExpress Dextran T500 (2025).
Applicant asserts that neither Davis or Davis Orcutt provide motivation for one of skill to select a chelating agent selected from DOTAM and a functional variant of DOTAM. Davis provides that the dextran-based blocking agent “comprise aminodextran conjugated to DOTA. The function of the blocking agent comprising DOTA is very different to the function of a radionuclide delivery agent comprising DOTA. Notably, the blocking agent, must not only be good at staying in a chelated form which binds well to the antibody but must also, in contrast to the radionuclide delivery agent, show a
suitably low amount of tumor penetration.
The reference of Davis teaches that the radionuclide delivery agent comprises DOTA or a DOTA variant.
The DOTA or DOTA variants comprise
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as well as that stated above.
The DOTA or DOTA variants may be further conjugated to a carbohydrate, such as dextran (p10, [0104-0105), therefore yielding dextran-DOTA (variant) (i.e. DOTAM + dextran-based clearing agent).
Davis teaches that bsAb specifically binds a metal-chelate comprising DOTA or DOTA variant (p7, [0064]).
It would have been obvious to one of ordinary skill in the art to substitute the known DOTA chelator of the clearing agent for another known chelator, such as the DOTAM variant as aminodextran-DOTA variant is capable of specifically binding unbound/residual bsAb in a PRIT application to provide the advantage of essentially complete blocking/clearance of unbound/residual bsAb in the blood.
The bsAb of Davis specifically bind to the DOTA and DOTA variants and therefore, it would have been obvious to one of ordinary skill in the art that both the DOTA and/or DOTA variants will bind both the targeted bsAb and unbound/residual bsAb of the PRIT application. Therefore, it would have been predictable to one of ordinary skill in the art to utilize the same chelator structure for both the chelator of the radionuclide delivery agent used for binding the targeted bsAb and for the dextran-chelator blocking agent to bind unbound/residual bsAb, for example Davis teaches of DOTA for both 177Lu-DOTA and aminodextran-DOTA clearing/blocking agent.
The dextran-based blocking/clearing agent of Davis clears very rapidly from the blood and provides the advantage of essentially complete blocking/clearance of residual bsAb in the blood. The dextran-based blocking/clearing agent provides an 84-fold higher tumor uptake of the bsAb relative to that observed when 177Lu-DOTA is used alone for the PRIT application.
Therefore, the dextran-based blocking/clearing agent is not taken up in the tumor tissue, is very rapidly cleared from the blood and binds to unbound/residual bsAb that results in enhanced binding of target bsAb with 177Lu-DOTA to yield excellent tumor:blood ratios.
Applicant asserts that Davis provides no guidance toward selecting DOTA variant that shows a suitably low amount of tumor penetration. One of ordinary skill would not consider that the variation made to the DOTA in a radionuclide delivery agent are necessarily suitable for use as the blocking agent, and that Davis does not provide guidance regarding whether and what flexibility might be possible for DOTA in the blocking agent, not how changes would affect tumor penetration behavior.
The reference of Davis teaches that the DOTA or active variants comprise
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wherein X comprises -C(=O)NHRd is stated in a finite list of X moieties as well as that stated above.
The reference of Davis teaches that DOTA metal chelates exhibit rapid blood clearance (p20, [0187]) and teaches of the use of DOTA variants including DOTAM. The DOTA and DOTAM have
analogous core structures and therefore, Davis envisioned using DOTA and/or DOTA variants (i.e. DOTAM) analogously for rapid blood clearance.
Conclusion
No claims are allowed at this time.
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/MELISSA J PERREIRA/Examiner, Art Unit 1618