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
Claims 20, 28, 30, 36, and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, and there being no allowable generic or linking claim.
Applicant's election with traverse of Group I and the species set forth on Page 4 in the reply filed on 12/12/2025 is acknowledged.
The traversal is on the ground(s) that: “The Requirement merely asserts without evidentiary support that examining all groups would require a "serious search and/or examination burden" if restriction were not required. Requirement at p. 3. Such conclusory statements do not satisfy the Office's obligation to demonstrate why examination of these claims together would be unduly burdensome.” [Reply 12/12/2025, Page 2-Page 3 (Paragraph 1) and Page 4 -Page 5 (Paragraph 1)]
This is not found persuasive because the Examiner is not aware of any requirement in the MPEP that states the Office must demonstrate why examination of distinct claims together would be unduly burdensome by providing “evidentiary support.” Rather, MPEP 808.02 states in order to establish reasons for insisting upon restriction the Examiner must explain why there would be a serious search and/or examination burden on the examiner if restriction is not required by showing that the inventions are likely to raise serious examination issues. The Examiner satisfied this burden in the OA of 10/15/2025 by stating “There is a serious search and/or examination burden for the patentably distinct species as set forth above because… the species/groupings of the patentably indistinct species require a different field of search (e.g., searching different classes/subclasses or employing different search strategies or search queries).” Thus, the Office has satisfied the obligation set forth in the MPEP by demonstrating why examination of these claims together would be unduly burdensome.
The traversal is on the ground(s) that: “Applicant respectfully submits that the search and examination of all pending claims can be conducted without undue burden because the prior art search for these groups would be largely coextensive.” [Reply 12/12/2025, Page 3, Paragraph 2]
The Examiner disagrees with this assertion for the reasons set forth in the OA of 10/152025.
The traversal is on the ground(s) that: “Further, the method claims of Groups II and III are not independent inventions since they depend from and incorporate all of the limitations of the conjugate of claim 18 in Group I.” [Reply 12/12/2025, Page 3, Paragraph 3]
The Examiner disagrees with this assertion for the reasons set forth in the OA of 10/15/2025. Whether or not an invention depends from and incorporates all of the limitations of another invention is not the criterion used to determine whether inventions are independent. Please see MPEP 806 for the appropriate criterion applied by the Office.
The traversal is on the ground(s) that: “The alleged species (i.e., different SEQ ID NOs, chelators, and isotopes) fall within the same technical field and would be captured by the same prior art searches.” [Reply 12/12/2025, Page 5, Paragraph 2]
The Examiner disagrees with this assertion for the reasons set forth in the OA of 10/15/2025. Moreover, the species election requirement is directed to a single conjugate, rather than to individual components thereof (i.e. the different SEQ ID NOs, chelators, and isotopes), as they are considered only as part of the conjugate. The Office does not treat these components as isolated species. Furthermore, whether or not the pending claims fall within the same technical field or are captured by the same prior art searches is not the criterion for determining whether species are independent or distinct. Please see MPEP 806 for the appropriate criterion applied by the Office.
The traversal is on the ground(s) that: “Moreover, radionuclides Pb-212 and Pb-203 are not patentably distinct species.” [Reply 12/12/2025, Page 5, Paragraph 3]
The Office acknowledges the Applicant’s statement that radionuclides Pb-212 and Pb-203 are not patentably distinct species. Accordingly, the Office will treat Pb-212 and Pb-203 as a single radionuclide component of the conjugate. (As explained above, the species election requirement is directed to a single conjugate, rather than to individual components thereof. The Office does not treat these components as isolated species). However, this statement by the Applicant does not render the overall election of species requirement improper, nor does it warrant withdrawal thereof.
The requirement is still deemed proper and is therefore made FINAL.
Status of Claims
Withdrawn: 20, 28, 30, 36, 37
Examined Herein: 18, 19, 21-27, 29, 31-35
Priority
Acknowledgment is made of applicant's claim for priority under based upon an application filed in PRO 63/627,705 on 1/31/2024, PRO 63/550,951 on 2/7/2024, EP24305751 on 5/14/2024, EP24306567 on 9/25/2024, and EP24306765 on 10/21/2024.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Drawings
The drawings received on 1/30/2025 are 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.
Claims 18, 19, 21-27, 29, and 35 rejected under 35 U.S.C. 112(a), because the specification, while being enabling for SEQ ID NO: 1-4 and 11-18, does not reasonably provide enablement for more including every other ankyrin repeat domain with binding specificity for DLL3.
Furthermore, claims 31-34 rejected under 35 U.S.C. 112(a), because the specification, while being enabling for SEQ ID NO: 1-4 and 11-18, does not reasonably provide enablement for more including every other ankyrin repeat domain that is 80% identical to SEQ ID NO: 15-18 with binding specificity for DLL3 and human serum albumin.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to how to make and how to use the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." The factors most relevant to the instant rejection are:
(A) The breadth of the claims;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims – MPEP 2164.08
With respect to the breadth of a claim, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate with the scope of protection sought by the claims. The propriety of a rejection based upon the scope of a claim relative to the scope of the enablement concerns (1) how broad the claim is with respect to the disclosure and (2) whether one skilled in the art could make and use the entire scope of the claimed invention without undue experimentation.
The scope of claim 1 includes every ankyrin repeat domain with binding specificity to DLL3. The scope of claim 31-34 includes every ankyrin repeat domain that is 80% identical to SEQ ID NO: 15-18 with binding specificity to DLL3 and human serum albumin.
One skilled in the art could not make and use the entire scope of the claimed invention without undue experimentation because the specification has not provided sufficient biochemical information that distinctly identifies an ankyrin repeat domain (ARD) (other than SEQ ID NO: 1-4 and 11-18) that binds DLL3 or DLL3 and human serum albumin. The specification fails to provide sufficient guidance and direction as to how the skilled artisan can make such binding domains commensurate in scope with the claimed invention. The specification fails to provide any guidance on how to make the ankyrin repeat domain readable upon the scope.
The Level of Predictability in the Art – MPEP 2164.03
The "predictability or lack thereof" in the art refers to the ability of one skilled in the art to extrapolate the disclosed or known results to the claimed invention. If one skilled in the art can readily anticipate the effect of a change within the subject matter to which the claimed invention pertains, then there is predictability in the art. On the other hand, if one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art.
Ngo teaches that the amino acid positions within the polypeptide/protein that can tolerate change such as conservative substitution or no substitution, addition or deletion which are critical to maintain the protein's structure will require guidance (see Ngo et al., 1994, The Protein Folding Problem and Tertiary Structure Prediction, pp. 492-495 in particular). Minor structural differences among structurally related compounds or compositions can result in substantially different or deleterious biological activities.
In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. This is because in art areas having a high degree of uncertainty (i.e. the unpredictable arts) it is not reasonably predictable from the disclosure of one species, what other species will work. Thus, although the specification discloses SEQ ID NO: 1-4 and 11-18, it is not reasonably predictable from the disclosure what other ankyrin repeat domain will bind with specificity to DLL3 or what other ankyrin repeat domains that are 80% identical to SEQ ID NO: 15-18 will bind with specificity to DLL3 and human serum albumin.
The amount of direction provided by the inventor/The existence of working examples
The specification provides specific ankyrin repeat domains (SEQ ID NO: 1-4 and 11-18) with binding specificity to DLL3 and/or DLL3 and human serum albumin. However, the specification fails to provide which segments in the ankyrin repeat domain(s) contribute to its ability to bind with specificity to DLL3 and/or DLL3 and human serum albumin.
As is evidenced in the instant application, various additions, substitutions or deletions and the like provide a range of activities, not all which are necessarily predictive of ankyrin repeat domains. (see Specification – Example 1-3) Since the amino acid sequence of a polypeptide determines its structural property, predictability of which amino acid fragment can retain the functional capabilities of the ankyrin repeat domains comprising polypeptide requires knowledge of, and guidance with regard to, which segments in the polypeptide's sequence contribute to its function.
Therefore, there is insufficient direction (with the exception of SEQ ID NO: 1-4 and 11-18) as to how to make and how to use different ankyrin repeat domains that have binding specificity to DLL3 and/or DLL3 and human serum albumin, including domains that are 80% identical to SEQ ID NO: 15-18, as encompassed by the claims.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure - MPEP 2164.06
In the chemical arts, the guidance and ease in carrying out an assay to achieve the claimed objectives may be an issue to be considered in determining the quantity of experimentation needed.
The fact that minor structural differences among structurally related compounds or compositions can result in substantially different or deleterious biological activities and the lack of knowledge of, and guidance with regard to, which segments in the polypeptide's sequence contribute to its ability to bind with specificity to DLL3 and/or DLL3 and human serum albumin, it would take undue trials and errors to practice the claimed invention.
Therefore, in view of the foregoing factors, the instant disclosure does not contain sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Claim Rejections - 35 USC § 102
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)(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.
Claims 18, 19, 21, 22, 24, and 35 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Blackwell (WO2024/107762 A2, Filed 11/14/2023).
With respect to claim 18 and 35, Blackwell discloses a conjugate comprising:
a miniprotein, including a designed ankyrin repeat domain (DARPin), with binding specificity for a target protein in Table 10 including DLL3,
a chelator, DOTA, and
a radionuclide, Pb-212,
wherein said chelator is covalently connected to said ankyrin repeat domain with binding specificity for DLL3,
wherein said radionuclide is bound to said chelator, and
wherein said radionuclide is Pb-212. [Blackwell, 00128, 00468 and Table 10; See also 0109, 00115, 00145]
Blackwell does not expressly spell out that the conjugate comprises an ankyrin repeat domain with binding specificity for DLL3. However, an ankyrin repeat domain is one of the specified miniproteins and DLL3 is one of the specified target proteins in Table 10. Thus, a person of skill in the art, reading Blackwell, would ‘at once envisage’ the claimed conjugate arrangement comprising an ankyrin repeat domain with binding specificity for DLL3. MPEP 2131.02(III) Therefore, the limitations of claim 18 and 35 have been met.
With respect to claim 19, Blackwell discloses the ankyrin repeat domain with binding specificity for DLL3 binds DLL3 with a KD value of 10 nM or below, thus meeting the limitations of claim 19. Specifically, Blackwell discloses the ankyrin repeat domain binds specifically with DLL3. [Blackwell, 00468] Blackwell defines specific binding as about 10-7 to 10-9M, which equates to 100 nM to 1 nM. [Blackwell, 00145] Thus, Blackwell discloses the ankyrin repeat domain with binding specificity for DLL3 binds DLL3 with a KD value of 100 nM to 1 nM, including 10 nM or below.
With respect to claim 21, Blackwell discloses the chelator is DOTA, thus meeting the limitations of claim 21. [Blackwell, 00468]
With respect to claim 22, Blackwell discloses the chelator has a structure of Formula (I), wherein R1, R2, and R3 are independently OH, and wherein the dotted line represents the covalent connection to said ankyrin repeat domain with binding specificity for DLL3, thus meeting the limitations of claim 22. [Blackwell, 00198, 00468]
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[Illustration drawn by the Examiner based on the description of the conjugate provided by Blackwell in paragraph 00468]
With respect to claim 24, Blackwell discloses the conjugate further comprises a connector, PEG,
wherein said connector is covalently connected to said ankyrin repeat domain with binding specificity for DLL3 and to said chelator, and wherein said conjugate has the formula: D-Co-Ch-R, wherein D is said ankyrin repeat domain with binding specificity for DLL3, Co is said connector, Ch is said chelator, and R is said radionuclide, thus meeting the limitations of claim 24. [Blackwell, 00128, 0468 and Table 10]
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.
Claims 18, 19, 21-26, 29, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Blackwell, as applied to claim 18, 19, 21, 22, 24, and 35 above.
With respect to claim 18 and 24, Blackwell discloses the teachings above.
Blackwell does not explicitly disclose the conjugate further comprises a tag, wherein said tag comprises a cysteine (claim 23), or the connector comprises a maleimide or a derivative thereof (claim 25) or the conjugate further comprises a half-life extending moiety (claim 26).
However, with respect to claim 23, Blackwell discloses the DARPin may comprise a cysteine tag (or multiple cysteine residues that crosslink to maintain a very stable, folded state for a peptide of its length). [Blackwell, 00161]
With respect to claim 25, Blackwell discloses the linker/connector may be a PEG linker or a maleimide linker. [Blackwell, 0069]
With respect to claim 26, Blackwell discloses the conjugate (specifically the miniprotein) may further comprise a half-life extending moiety, an albumin binding domain. [Blackwell, 00288]
Modifying the conjugate disclosed by Blackwell by adding a cysteine tag results in the conjugate of claim 23.
Modifying the conjugate disclosed by Blackwell by replacing the PEG linker/connector with a maleimide linker results in the conjugate of claim 25.
Modifying the conjugate disclosed by Blackwell by adding a half-life extending moiety (an albumin binding domain) to the DARPin results in the conjugate of claim 26.
Modifying the conjugate disclosed by Blackwell by adding a cysteine tag and a half-life extending moiety (an albumin binding domain) to the DARPin results in the conjugate of claim 29.
It would be obvious to one of ordinary skill in the art to modify the conjugate disclosed by Blackwell by adding a cysteine tag and have a reasonable expectation of success. Blackwell discloses a conjugate comprising a DARPin. Blackwell discloses the DARPin may comprise a cysteine tag (which Blackwell describes as cysteine residues that crosslink to maintain a very stable, folded state for a peptide of its length). In view of this express teaching by Blackwell, it is reasonable to expect the conjugate may be modified by adding a cysteine tag. One would have been motivated to do so because it is prima face obvious to modify a reference when the rationale for doing is expressly contained in the prior art. MPEP 2144(I) In the instant case, Blackwell discloses adding a cysteine tag to the DARPin enables the DARPin to maintain a very stable, folded state for a peptide of its length. [Blackwell, 00161] Therefore, one would have been motivated to modify the conjugate disclosed by Blackwell by adding a cysteine tag because Blackwell explains that doing so enables the DARPin to maintain a very stable, folded state for a peptide of its length.
It would be obvious to one of ordinary skill in the art to modify the conjugate disclosed by Blackwell by replacing the PEG linker/connector with a maleimide linker and have a reasonable expectation of success. Blackwell discloses a conjugate comprising a DARPin conjugated to a chelator via a PEG linker/connector. However, Blackwell discloses the linker/connector may be a PEG linker or a maleimide linker. In view of this express teaching by Blackwell, it is reasonable to expect the conjugate may be modified by replacing the PEG linker/connector with a maleimide linker. One would have been motivated to do so because the selection of a known material based on its suitability for its intended use is prima facie obvious. MPEP 2144.07 In the instant case, Blackwell discloses maleimide is a suitable linker, or moiety that is used to conjugate a miniprotein to a chelator. [Blackwell, 0069, 00127] Therefore, the selection of a maleimide linker based on its suitability as a moiety that is used to conjugate a DARPin to a chelator is prima facie obvious.
It would be obvious to one of ordinary skill in the art to modify the conjugate disclosed by Blackwell by adding a half-life extending moiety (an albumin binding domain) to the DARPin and have a reasonable expectation of success. Blackwell discloses a conjugate comprising a DARPin. Blackwell discloses the conjugate (specifically the DARPin) may further comprise a half-life extending moiety, an albumin binding domain. In view of this express teaching by Blackwell, it is reasonable to expect the conjugate may be modified by adding a half-life extending moiety (an albumin binding domain) to the DARPin. One would have been motivated to do so because it is prima face obvious to modify a reference when the rationale for doing is expressly contained in the prior art. MPEP 2144(I) In the instant case, Blackwell discloses adding a half-life extending moiety to the DARPin can extend the circulating half- life of the amino acid sequence. [Blackwell, 00288] Therefore, one would have been motivated to modify the conjugate disclosed by Blackwell by adding a half-life extending moiety to the DARPin because Blackwell explains that doing so can extend the circulating half- life of the amino acid sequence.
Claims 31, 32, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Blackwell, in view of Bianchi (WO2022/190016 A1, Published 9/15/2022).
With respect to claim 31, Blackwell discloses a conjugate comprising:
a miniprotein, including a designed ankyrin repeat domain (DARPin),
a chelator, DOTA, and
a radionuclide, Pb-212,
wherein said DARPin has binding specificity for a target protein in Table 10 including DLL3,
wherein said chelator is covalently connected to said DARPin,
wherein said radionuclide is bound to said chelator, and
wherein said radionuclide is 212Pb. [Blackwell, 00128, 00468 and Table 10; See also 0109, 00115, 00145]
Blackwell further discloses the conjugate (specifically the DARPin) may further comprise a half-life extending moiety, an albumin binding domain, that has binding specificity for albumin. [Blackwell, 00288]
With respect to claim 32, Blackwell discloses a conjugate, wherein said conjugate has a structure of Formula (VI):
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[Illustration drawn by the Examiner based on the description of the conjugate provided by Blackwell in paragraph 00468]
wherein R1, R2, and R3 are independently OH,
wherein A is CaHbNcOd, wherein a, b, c, and d, are integers;
wherein R4 is an DARPin that has binding specificity for a target protein in Table 10 including DLL3, and
wherein R5 is a chelated radionuclide, wherein said radionuclide is Pb-212. [Blackwell, 00128, 00468 and Table 10; See also 0109, 00115, 00145]
With respect to claim 34, Blackwell discloses A in Formula (VI) is -CH2-CH2-.
Blackwell discloses the chelator is linked to the DARPin via a PEG linker. [Blackwell, 00468] However, Blackwell discloses the linker may be a PEG linker or a maleimide linker. [Blackwell, 0069] Blackwell also discloses the conjugate may further comprise a half-life extending moiety, an albumin binding domain, that has binding specificity for albumin. [Blackwell, 00288] Blackwell discloses the DARPin may comprise a cysteine tag (or multiple cysteine residues that crosslink to maintain a very stable, folded state for a peptide of its length). [Blackwell, 00161]
Blackwell does not disclose the ankyrin repeat protein comprises an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 15 to 18. (claim 31)
However, with respect to claim 31, Bianchi discloses an ankyrin repeat protein, DARPin Protein #16 (SEQ ID NO: 39), comprising an amino acid sequence that is 86% identical to SEQ ID NO: 15, and wherein said ankyrin repeat protein has binding specificity for human serum albumin and CD3. [Bianchi, Page 175, Sequence Table, SEQ ID NO: 39]
Modifying the conjugate disclosed by Blackwell by adding the albumin binding domain of DARPin Protein #16 results in the conjugate of claim 31, wherein the ankyrin repeat protein has binding specificity for DLL3 and HSA.
Modifying the conjugate disclosed by Blackwell by adding the albumin binding domain of DARPin Protein #16, adding a cysteine tag to the DARPin, and replacing the PEG linker with maleimide, results in the conjugate of claim 32, wherein said conjugate has a structure of Formula (VI):
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[Illustration drawn by the Examiner based on the description of the conjugate provided by Blackwell in paragraph 00468, in view of the aforementioned modifications described in paragraph 00161 and 0069]
wherein the ankyrin repeat protein has binding specificity for DLL3 and HSA.
Still, Blackwell and Bianchi do not explicitly disclose that the ankyrin repeat protein comprises an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 15 to 18. However, to retain the binding capabilities of the ankyrin repeat protein disclosed by Blackwell and of SEQ ID NOs: 15 to 18 to DLL3, the internal repeat modules for each DARPin must be substantially similar. Additionally, the internal repeat modules responsible for the binding capabilities of the ankyrin repeat protein disclosed by Blackwell and of SEQ ID NOs: 15 to 18 to HSA, are substantially similar. Moreover, Bianchi establishes that a DARPin with binding specificity for albumin and an additional target protein can have a sequence that is at least 80% identical to SEQ ID NOs: 15 to 18. Accordingly, adding the albumin binding domain disclosed by Bianchi to the internal repeat modules responsible for binding DLL3 disclosed by Blackwell, would reasonably result in a DARPin with binding specificity for albumin and an additional target protein, DLL3. In view of the teachings of Bianchi, it is reasonable to expect that this modified DARPin could achieve at least 80% identity to SEQ ID NOs: 15 to 18.
It would be obvious to one of ordinary skill in the art to modify the conjugate disclosed by Blackwell by adding the albumin binding domain of DARPin Protein #16 and have a reasonable expectation of success. Blackwell discloses a conjugate comprising a DARPin that binds with specificity to a target protein, DLL3. Blackwell further discloses the conjugate may comprise a half-life extending moiety, an albumin binding domain. Bianchi discloses a DARPin, DARPin Protein #16, comprising an albumin binding domain that binds to human serum albumin and an additional target protein. Thus, the combined teachings of Blackwell and Bianchi suggest the DARPin that binds to human serum albumin disclosed by Bianchi may function as the albumin binding domain in the conjugate disclosed by Blackwell. Therefore, it is reasonable to expect the conjugate disclosed by Blackwell may be modified by adding the albumin binding domain of DARPin Protein #16. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II) In the instant case, Blackwell discloses adding a half-life extending moiety to the DARPin can extend the circulating half- life of the amino acid sequence. [Blackwell, 00288] Therefore, one would have been motivated by the expectation that the addition of the albumin binding domain of DARPin Protein #16 to the DARPin disclosed by Blackwell would extend the circulating half- life of the amino acid sequence.
It would be obvious to one of ordinary skill in the art to modify the conjugate disclosed by Blackwell by adding a cysteine tag and have a reasonable expectation of success. Blackwell discloses a conjugate comprising a DARPin. Blackwell discloses the DARPin may comprise a cysteine tag (which Blackwell describes as cysteine residues that crosslink to maintain a very stable, folded state for a peptide of its length). In view of this express teaching by Blackwell, it is reasonable to expect the conjugate may be modified by adding a cysteine tag. One would have been motivated to do so because it is prima face obvious to modify a reference when the rationale for doing is expressly contained in the prior art. MPEP 2144(I) In the instant case, Blackwell discloses adding a cysteine tag to the DARPin enables the DARPin to maintain a very stable, folded state for a peptide of its length. [Blackwell, 00161] Therefore, one would have been motivated to modify the conjugate disclosed by Blackwell by adding a cysteine tag because Blackwell explains that doing so enables the DARPin to maintain a very stable, folded state for a peptide of its length.
It would be obvious to one of ordinary skill in the art to modify the conjugate disclosed by Blackwell by replacing the PEG linker/connector with a maleimide linker and have a reasonable expectation of success. Blackwell discloses a conjugate comprising a DARPin conjugated to a chelator via a PEG linker/connector. However, Blackwell discloses the linker/connector may be a PEG linker or a maleimide linker. In view of this express teaching by Blackwell, it is reasonable to expect the conjugate may be modified by replacing the PEG linker/connector with a maleimide linker. One would have been motivated to do so because the selection of a known material based on its suitability for its intended use is prima facie obvious. MPEP 2144.07 In the instant case, Blackwell discloses maleimide is a suitable linker, or moiety that is used to conjugate a miniprotein to a chelator. [Blackwell, 0069, 00127] Therefore, the selection of a maleimide linker based on its suitability as a moiety that is used to conjugate a DARPin to a chelator is prima facie obvious.
Claims 32-34 are rejected under 35 U.S.C. 103 as being unpatentable over Blackwell and Bianchi, as applied to claim 32 and 34 above, and further in view of Kokov (Review 212Pb: Production Approaches and Targeted Therapy Applications, 1/13/2022, Phamaceutics, 14, 189).
With respect to claim 32, Blackwell and Bianchi disclose the teachings above.
Blackwell and Bianchi do not disclose the chelator is TCMC (or R1, R2, and R3 in Formula (VI) is NH2).
However, with respect to claim 33, Kokov discloses that the release of 36% daughter 212Bi from the [212Pb]Pb–DOTA chelate causes uncertain behavior of alpha-emitting progeny radionuclides in the living organism and irradiation of non-target tissues. Currently, the problem is being solved by using TCMC for chelation of 212Pb in the radiopharmaceuticals instead of DOTA. Due to boundary hardness and divalent nature of Pb2+ TCMC strongly binds the Pb2+. The development of TCMC as one of the main ligands for the preclinical and clinical evaluation of 212Pb–radiopharmaceuticals, its clearance, and internalization inside the cancer cells can minimize the toxic effect of the release of 212Bi from the 212Pb–chelate. [Kokov, Page 15, Paragraph 5]
Modifying the conjugate disclosed by Blackwell and Bianchi by replacing DOTA with TCMC results in the conjugate of claim 33, wherein R1, R2, and R3 in Formula (VI) is NH2.
It would be obvious to one of ordinary skill in the art to modify the conjugate disclosed by Blackwell and Bianchi by replacing DOTA with TCMC and have a reasonable expectation of success. Blackwell and Bianchi disclose a conjugate comprising a chelated radionuclide 212Pb-DOTA. Kokov discloses that [212Pb]Pb–DOTA chelate causes uncertain behavior of alpha-emitting progeny radionuclides in the living organism and irradiation of non-target tissues. Kokov discloses this problem is being solved by using TCMC for chelation of 212Pb in the radiopharmaceuticals instead of DOTA, as TCMC strongly binds the Pb2+. Thus, Kokov establishes TCMC is a known alternative to DOTA for chelation of 212Pb in radiopharmaceuticals. Thus, the combined teachings of Blackwell/Bianchi and Kokov suggest that TCMC may replace DOTA in the conjugate, as it comprises a chelated radionuclide 212Pb. Therefore, it is reasonable to expect the conjugate disclosed by Blackwell and Bianchi may be modified by replacing DOTA with TCMC. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II) In the instant case, Kokov discloses TCMC can minimize the toxic effect of the release of 212Bi from 212Pb–chelate. [Kokov, Page 15, Paragraph 5] Therefore, one would have been motivated by the expectation that replacing DOTA with TCMC could minimize the toxic effect of the release of 212Bi from 212Pb–chelate.
Claims 18, 23-25, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Bosshart (US 2024/0132546 A1, Filed 7/30/2023), in view of Hudson (US 2016/0032006 A1, Published 2/4/2016).
With respect to claim 18 and 35, Bosshart discloses a conjugate comprising:
(i) an ankyrin repeat domain that binds to HER2,
(ii) a chelator, maleimide-DTPA,
(iii) a radionuclide,
wherein said chelator is covalently connected to said ankyrin repeat domain,
wherein said radionuclide is bound to said chelator, and
wherein said radionuclide is 111In. [Bosshart, 0160, 0671]
With respect to claim 23, Bosshart discloses the conjugate further comprises a C-terminal GSGSC tag, wherein said tag comprises a cysteine. [Bosshart, 0160]
With respect to claim 24, Bosshart discloses the conjugate further comprises a connector, wherein said connector is covalently connected to said ankyrin repeat domain and to said chelator, and wherein said conjugate has the formula: D-Co-Ch-R, wherein D is said ankyrin repeat domain, Co is said connector, Ch is said chelator, and R is said radionuclide. [Bosshart, Fig 3, 0688-0690]
With respect to claim 25, Bosshart discloses said connector comprises a maleimide. [Bosshart, Fig 3, 0688-0690]
With respect to claim 35, Bosshart discloses a pharmaceutical composition comprising the conjugate or pharmaceutically acceptable salt of claim 18, and a pharmaceutically acceptable carrier or excipient. [Bosshart, 0645, 0647]
Bosshart discloses the radionuclide is 111In. However, in one embodiment, Bosshart discloses the radionuclide may be 212Pb. Bosshart discloses the choice of suitable radionuclides depends on the chemical structure and chelating capability of the chelating agent, and the intended application of the resulting drug (e.g. diagnostic vs. therapeutic). [Bosshart, 0204]
Bosshart does not disclose the ankyrin repeat domain has binding specificity for DLL3.
However, with respect to claim 18 and 35, Hudson discloses a DARPin may be employed to bind DLL3 for the treatment or prophylaxis of cancer, as DARPin’s are substances capable of immunospecific binding to DLL3. [Hudson, 0009, 0014, 0142]
With respect to claim 19, Hudson discloses highly specific, high-affinity DARPins may have affinities to target proteins in the single-digit nanomolar to picomolar range. [0186]
Modifying the conjugate disclosed by Bosshart by replacing the DARPin with a DARPin that binds to DLL3 and replacing the radionuclide with 212Pb results in the conjugate of claim 18 and 35.
Modifying the conjugate disclosed by Bosshart by replacing the DARPin with a highly specific, high-affinity DARPin that binds to DLL3 with affinity in the single-digit nanomolar to picomolar range and by replacing the radionuclide with 212Pb results in the conjugate of claim 18, 19, and 35.
It would be obvious to one of ordinary skill in the art to modify the conjugate disclosed by Bosshart by replacing the DARPin with a highly specific, high-affinity DARPin that binds to DLL3 with affinity in the single-digit nanomolar to picomolar range and have a reasonable expectation of success. Bosshart discloses a conjugate comprising (i) a DARPin that binds to HER2. Hudson discloses that a highly specific, high-affinity DARPin that binds to DLL3 with affinity in the single-digit nanomolar to picomolar range may be produced. The disclosure of Hudson establishes that a DARPin may have affinity for other targets, including DLL3. Thus, the combined teachings of Bosshart and Hudson suggest that a DARPin that has an affinity for DLL3, may be produced for use in the conjugate disclosed by Bosshart. Therefore, it is reasonable to expect the conjugate disclosed by Bosshart may be modified by replacing the DARPin with a highly specific, high-affinity DARPin that binds to DLL3 with affinity in the single-digit nanomolar to picomolar range. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II) In the instant case, Hudson discloses DLL3 is a membrane protein present in extracts of various disease tissues (e.g. lung cancer, pancreatic cancer and skin cancer) and an affinity reagent, a DARPin that binds to DLL3, may be used a medicament for the treatment or prophylaxis of said cancer. [Hudson, 0003, 0009, 0011, 0014] Therefore, one would have been motivated by the expectation that replacing the DARPin with a highly specific, high-affinity DARPin that binds to DLL3 in the conjugate disclosed by Bosshart could enable the conjugate to be used as a medicament for the treatment or prophylaxis of lung cancer, pancreatic cancer and skin cancer.
It would be obvious to one of ordinary skill in the art to modify the conjugate disclosed by Bosshart by replacing the radionuclide 111In with 212Pb and have a reasonable expectation of success. Bosshart discloses a conjugate comprising a radionuclide, 111In. Bosshart further discloses in one embodiment the radionuclide may be 212Pb and the choice of suitable radionuclides depends on the chemical structure and chelating capability of the chelating agent, and the intended application of the resulting drug. Bosshart establishes that the type of radionuclide used in the conjugate may be modified. In view of this express teaching, it is therefore reasonable to expect the conjugate disclosed by Bosshart may be modified by replacing the radionuclide 111In with 212Pb. One would have been motivated to do so because the selection of a known material based on its suitability for its intended use is prima facie obvious. MPEP 2144.07 In the instant case, Bosshart discloses 212Pb is a suitable radionuclide for use in the conjugate. [Bosshart, 0204] Therefore, the selection of 212Pb based on its suitability as a radionuclide suitable for used in the conjugate disclosed by Bosshart is prima facie obvious.
Conclusion
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/K.A.C./Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618