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Claims 20, 28, 30, 36, and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, and there being no allowable generic or linking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 traversed the election of Group I and the species set forth on Page 4 in the reply filed on 12/12/2025. However, the requirement was still deemed proper and therefore made FINAL in the OA of 1/30/2026.
Status of Claims
Cancelled: 1-30, 33, 35
New: 38-45
Withdrawn: 36, 37
Examined Herein: 31, 32, 34, 38-45
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.
Withdrawn Rejections
All rejections of claims 18, 19, 21-27, 29, 33, and 35 are hereby withdrawn; their cancellation moots the rejections.
The rejection of claims 31, 32, and 34 under 35 U.S.C. 103 over Blackwell and Bianchi is hereby withdrawn in view of Applicant’s amendments to claim 31, which now recites new limitations, and Applicant’s persuasive arguments that Blackwell and Bianchi do not teach the claim limitations as amended. [Remarks - 4/29/2026, Page 10, Paragraph 2]
The rejection of claims 32 and 34 under 35 U.S.C. 103 over Blackwell, Bianchi, and Kokov is hereby withdrawn in view of Applicant’s amendments to claim 32, which now recites new limitations, and Applicant’s persuasive arguments that Blackwell, Bianchi, and Kokov do not teach the claim limitations as amended. [Remarks - 4/29/2026, Page 13, Paragraph 1]
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 31, 38, 40, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Larsen (US 2019/0194087 A1, Published 6/27/2019), in view of Metz (US 2018/0155402 A1, Published 6/7/2018).
With respect to claim 31, Larsen discloses a conjugate comprising:
(i) a protein
(ii) a chelator, TCMC,
(iii) a radionuclide, Pb-212,
wherein said protein has binding specificity for HER2,
wherein said chelator is covalently connected to said protein, and
wherein said radionuclide is bound to said chelator. [Larsen, 0028-0029, 0034, 0075, 0077, 0080, 0084]
Larsen further discloses the protein may be a monoclonal antibody, a polyclonal antibody, antibody fragment, a synthetic protein, and a peptide. [Larsen, 0028-0029, 0034]
In a specific embodiment, Larsen discloses a conjugate comprising;
(i) a protein/monoclonal antibody, trastuzumab,
(ii) a chelator, TCMC,
(iii) a radionuclide, Pb-212,
wherein said protein has binding specificity for HER2,
wherein said chelator is covalently connected to said protein, and
wherein said radionuclide is bound to said chelator. [Larsen, 0119]
With respect to claim 40, Larsen discloses the radionuclide is Pb-212. [Larsen, 0034, 0077, 0119]
With respect to claim 44, Larsen discloses a pharmaceutical composition comprising the conjugate and a pharmaceutically acceptable carrier or excipient. [Larsen, 0048-0050]
Larsen does not disclose the protein is an ankyrin repeat protein that comprises an amino acid sequence that is at least 85% identical to any one of SEQ ID NOs: 15 to 18 and has binding specificity for DLL3 and for human serum albumin.
However, with respect to claim 31 and 38, Metz discloses the following ankyrin repeat proteins, which comprise an amino acid sequence that is at least 85% identical to SEQ ID NOs: 15 to 18 and have binding specificity for HER2:
Protein #21 (SEQ ID NO: 21) comprises an amino acid sequence that is 88.9% identical to SEQ ID NO: 15, 88.0% identical to SEQ ID NO: 16, 87.8% identical to SEQ ID NO: 17 and 89.0% identical to SEQ ID NO: 18;
Protein #23 (SEQ ID NO: 23) comprises an amino acid sequence that is 88.4% identical to SEQ ID NO: 15, 87.4% identical to SEQ ID NO: 16, 87.5% identical to SEQ ID NO: 17 and 88.0% identical to SEQ ID NO: 18;
Protein #24 (SEQ ID NO: 24) comprises an amino acid sequence that is 89.7% identical to SEQ ID NO: 15, 88.8% identical to SEQ ID NO: 16, 87.9% identical to SEQ ID NO: 17 and 87.9% identical to SEQ ID NO: 18;
Protein #25 (SEQ ID NO: 25) comprises an amino acid sequence that is 89.7% identical to SEQ ID NO: 15, 88.8% identical to SEQ ID NO: 16, 87.9% identical to SEQ ID NO: 17 and 89.4% identical to SEQ ID NO: 18; [Metz, Figure 4B, 0006, 0014, 0021, 0121, 0123, 0124, 0125, 0147, 0148, 0153, 0159]
Metz further discloses that Protein #21 unites the functionality of trastuzumab and pertuzumab in one molecule and induces apoptosis in HER2 expressing cells. [Metz, 0045] Moreover, Metz demonstrates that Protein #21 is more efficacious than trastuzumab. For example, Metz discloses that Protein #21 is more efficacious in inhibiting tumor growth in GXA3039 (gastric cancer) and BT474 (breast cancer) tumor xenograft mouse models than Trastuzumab. [Metz, Figure 4C & 4D, 0014, 0147]; See also 0149, 0168]
Modifying the [212Pb]-TCMC-trastuzumab conjugate disclosed by Larsen by replacing the protein/monoclonal antibody with Protein #21, results in the conjugate of claim 31; wherein, the ankyrin repeat protein comprises an amino acid sequence that is 89% identical to SEQ ID NO: 15, 88% identical to SEQ ID NO: 16, 88% identical to SEQ ID NO: 17 and 89% identical to SEQ ID NO: 18.
Modifying the [212Pb]-TCMC-synthetic protein conjugate disclosed by Larsen by replacing the protein with Protein #21 or #23, results in the conjugate of claim 31;
wherein, the ankyrin repeat protein (Protein #21) comprises an amino acid sequence that is 89% identical to SEQ ID NO: 15, 88% identical to SEQ ID NO: 16, 88% identical to SEQ ID NO: 17 and 89% identical to SEQ ID NO: 18; or
wherein, the ankyrin repeat protein (Protein #23) comprises an amino acid sequence that is 88% identical to SEQ ID NO: 15, 87% identical to SEQ ID NO: 16, 88% identical to SEQ ID NO: 17 and 88% identical to SEQ ID NO: 18.
With respect to claim 38, a prima facie case of obviousness exists where the claimed ranges do not overlap with the prior art but are merely close. MPEP 2144.05(I). In the present case, Protein #21 is 89% identical to SEQ ID NO: 18. Thus, the difference between an ankyrin repeat protein that is 89.0% and 90% identical to SEQ ID NO: 18 is 1.0%. These values are so mathematically close that the differences between them are virtually negligible absent any showing of unexpected results or criticality. Accordingly, one of skilled in the art would expect Protein #21 to exhibit substantially similar properties to an ankyrin repeat protein that is 90% identical to SEQ ID NO: 18.
Modifying the [212Pb]-TCMC-synthetic protein conjugate disclosed by Larsen by replacing the protein with Protein #24 or #25, results in the conjugate of claim 31 and 38;
wherein, the ankyrin repeat protein (Protein #24) comprises an amino acid sequence that is 90% identical to SEQ ID NO: 15, 89% identical to SEQ ID NO: 16, 88% identical to SEQ ID NO: 17 and 88% identical to SEQ ID NO: 18; or
wherein, the ankyrin repeat protein (Protein #25) comprises an amino acid sequence that is 90% identical to SEQ ID NO: 15, 89% identical to SEQ ID NO: 16, 88% identical to SEQ ID NO: 17 and 89% identical to SEQ ID NO: 18;
In each instance, the ankyrin repeat proteins (Protein #21, #23, #24, #25) comprise an amino acid sequence that is at least 85% identical to any one of SEQ ID NOs: 15 to 18, and thus necessarily has binding specificity for DLL3 and for human serum albumin. MPEP 2112.01(II).
It would be obvious to one of ordinary skill in the art to modify the [212Pb]-TCMC-trastuzumab conjugate disclosed by Larsen by replacing the protein, trastuzumab, with Protein #21 and have a reasonable expectation of success. Larsen discloses a conjugate comprising [212Pb]-TCMC and a protein, having binding specificity for HER2. In a specific embodiment, Larsen discloses the protein is a monoclonal antibody, trastuzumab. However, Larsen additionally discloses the protein may be a polyclonal antibody, antibody fragment, a synthetic protein, or a peptide. Metz discloses an ankyrin repeat protein, Protein #21, that has binding specificity for HER2. Metz further discloses Protein #21 unites the functionality of trastuzumab and pertuzumab in one in one molecule. Thus, Larsen establishes that the protein component of the disclosed [212Pb]-TCMC conjugate may include a monoclonal antibody or synthetic protein that exhibits binding specificity for HER2 and Metz establishes that Protein #21 is a synthetic protein that exhibits biding specificity for HER2 and encompasses the functionality of trastuzumab. Accordingly, the combined teachings of Larsen and Metz suggest that Protein #21 may function as the synthetic protein component of the 212Pb-TCMC conjugate disclosed by Larsen, as it exhibits the binding specificity for HER2 contemplated by Larsen. Therefore, it is reasonable to expect the conjugate disclosed by Larsen may be modified by replacing trastuzumab with Protein #21. 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 present case, Metz demonstrates that Protein #21 is more efficacious than trastuzumab. For example, Metz discloses that Protein #21 is more efficacious in inhibiting tumor growth in GXA3039 (gastric cancer) and BT474 (breast cancer) tumor xenograft mouse models than Trastuzumab. [Metz, Figure 4C & 4D, 0014, 0147]; See also 0149, 0168] Therefore, one would have been motivated by the expectation that replacing trastuzumab with Protein #21 would render the conjugate disclosed by Larsen more efficacious in inhibiting tumor growth.
It would be obvious to one of ordinary skill in the art to modify the [212Pb]-TCMC-protein conjugate disclosed by Larsen so that the protein is Protein #21, #23, #24, or #25 and have a reasonable expectation of success. Larsen discloses a conjugate comprising [212Pb]-TCMC and a protein having biding specificity for HER2. Larsen discloses the protein is a monoclonal antibody, a polyclonal antibody, antibody fragment, a synthetic protein, or a peptide. Metz discloses several synthetic ankyrin repeat proteins, including Protein #21, #23, #24, and #25, that have biding specificity for HER2. Thus, Larsen establishes that the protein component of the disclosed [212Pb]-TCMC conjugate may include a synthetic protein that exhibits binding specificity for HER2 and Metz establishes that Protein #21, #23, #24, and #25 are synthetic proteins that exhibit biding specificity for HER2. Accordingly, the combined teachings of Larsen and Metz suggest that Protein #21, #23, #24, or #25 may function as the synthetic protein component of the [212Pb]-TCMC conjugate disclosed by Larsen, as they each independently exhibit the binding specificity for HER2 contemplated by Larsen. Therefore, it is reasonable to expect the conjugate disclosed by Larsen may be modified so that the protein is Protein #21, #23, #24, or #25. One would have been motivated to do so because the selection of a known component based on its suitability for its intended use is prima facie obvious. MPEP 2144.07. In the present case, Metz discloses that Protein #21, #23, #24, and #25 are synthetic proteins that exhibit biding specificity for HER2. [Metz, Figure 4B, 0006, 0014, 0021, 0121, 0123, 0124, 01250147, 0148, 0153, 0159] Therefore, the selection of Protein #21, #23, #24, or #25 based on its suitability as a synthetic protein that has binding specificity for HER2 is prima facie obvious.
Claims 31, 32, 34, 38, 40, 41, 43, 44, and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Schultz (US 2025/0186630 A1, Filed 12/12/2023), in view of Rigamonti (US 2021/0395318 A1, Published 12/23/2021).
With respect to claim 31, Schultz discloses a conjugate comprising:
(i) a protein
(ii) a chelator, TCMC,
(iii) a radionuclide, Pb-212 or PB-203,
wherein said protein has binding specificity for FAP and HSA,
wherein said chelator is covalently connected to said protein, and
wherein said radionuclide is bound to said chelator.
[See Embodiment of Formula I when:
Y is DOTAM (TCMC);
L is -CH2-CH2- (an aliphatic linker of 2 carbons);
C is
PNG
media_image1.png
211
206
media_image1.png
Greyscale
] [Schultz, 0069-0087, 0091, 0098, 0102, 0117-0120, 0144]
With respect to claim 32, Schultz disclose a conjugate of Formula (VI):
PNG
media_image2.png
424
708
media_image2.png
Greyscale
[Structure drawn by Examiner used CAS Draw based on the embodiment of Formula I disclosed by Schultz. The structure is for illustration purposes only.]
[Structure based on embodiment of Formula I when:
Y is DOTAM (TCMC);
L is -CH2-CH2- (an aliphatic linker of 2 carbons);
C is
PNG
media_image1.png
211
206
media_image1.png
Greyscale
] [Schultz, 0069-0087, 0091, 0098, 0102, 0117-0120, 0144]
Wherein,
R1, R2, and R3 are NH2
A is CaHbNcOd, wherein a, b, c, and d are integers
R4 is a protein that has binding specificity for FAP and for human serum albumin
Rs is a chelated radionuclide, Pb-212 or Pb-203.
With respect to claim 34, Schultz discloses A in Formula (VI) is -CH2-CH2-. [Schultz, 0102]
With respect to claim 40 and 43, Schultz discloses the radionuclide is Pb-212. [Schultz, 0117, 0118, 0120]
With respect to claim 44 and 45, Schultz discloses a pharmaceutical composition comprising the conjugate and a pharmaceutically acceptable carrier or excipient. [Schultz, 0239]
Schultz does not disclose the protein comprises an amino acid sequence that is at least 85% identical to any one of SEQ ID NOs: 15 to 18 and has binding specificity for DLL3 and for human serum albumin.
However, with respect to claim 31, 32 and 41, Rigamonti discloses the following ankyrin repeat proteins comprising an amino acid sequence that is at least 85% identical to SEQ ID NOs: 15 to 18 and exhibits binding specificity for FAP, HSA, and CD40:
Protein #5 (SEQ ID NO: 5) comprises an amino acid sequence that is 87.5% identical to SEQ ID NO: 15, 86.8% identical to SEQ ID NO: 16, 86.1% identical to SEQ ID NO: 17 and 86.8% identical to SEQ ID NO: 18;
Protein #6 (SEQ ID NO: 6) comprises an amino acid sequence that is 88.4% identical to SEQ ID NO: 15, 87.5% identical to SEQ ID NO: 16, 86.8% identical to SEQ ID NO: 17 and 87.8% identical to SEQ ID NO: 18;
Protein #7 (SEQ ID NO: 7), SMA087 (SEQ ID NO: 60), SMA095 (SEQ ID NO: 61), SMA091 (SEQ ID NO: 63), and SMA099 (SEQ ID NO: 64) comprise an amino acid sequence that is 88.3% identical to SEQ ID NO: 15, 87.4% identical to SEQ ID NO: 16, 87.1% identical to SEQ ID NO: 17 and 89.4% identical to SEQ ID NO: 18;
AS579 (SEQ ID NO: 65) comprises an amino acid sequence that is 89.5% identical to SEQ ID NO: 15, 88.6% identical to SEQ ID NO: 16, 87.7% identical to SEQ ID NO: 17 and 89.4% identical to SEQ ID NO: 18; [Schultz, 0374, 0386]
Modifying the conjugate disclosed by Schultz by replacing the protein with Protein #5, Protein #6, Protein #7, SMA087, SMA095, SMA091, SMA099, or AS579, results in the conjugate of claim 31 and 32;
wherein, the ankyrin repeat protein (Protein #7, SMA087, SMA095, SMA091, SMA099) comprises an amino acid sequence that is 88% identical to SEQ ID NO: 15, 87% identical to SEQ ID NO: 16, 87% identical to SEQ ID NO: 17 and 89% identical to SEQ ID NO: 18; or
wherein, the ankyrin repeat protein (Protein #6) comprises an amino acid sequence that is 88% identical to SEQ ID NO: 15, 88% identical to SEQ ID NO: 16, 87% identical to SEQ ID NO: 17 and 88% identical to SEQ ID NO: 18; or
wherein, the ankyrin repeat protein (Protein #5) comprises an amino acid sequence that is 88% identical to SEQ ID NO: 15, 87% identical to SEQ ID NO: 16, 86% identical to SEQ ID NO: 17 and 87% identical to SEQ ID NO: 18.
With respect to claim 38 and 41, a prima facie case of obviousness exists where the claimed ranges do not overlap with the prior art but are merely close. MPEP 2144.05(I). In the present case, Protein #7, SMA087, SMA095, SMA091, and SMA099 are 89% identical to SEQ ID NO: 18. The difference between an ankyrin repeat protein that is 89.0% and 90% identical to SEQ ID NO: 18 is 1.0%. Thus, these values are so mathematically close that the differences between them are virtually negligible absent any showing of unexpected results or criticality. Accordingly, one of skilled in the art would expect Protein #7, SMA087, SMA095, SMA091, and SMA099 to exhibit substantially similar properties to an ankyrin repeat protein that is 90% identical to SEQ ID NO: 18.
Modifying the conjugate disclosed by Schultz by replacing the protein with AS579 results in the conjugate of claim 31, 32, 38, and 41;
wherein, the ankyrin repeat protein (AS579) comprises an amino acid sequence that is 90% identical to SEQ ID NO: 15, 89% identical to SEQ ID NO: 16, 88% identical to SEQ ID NO: 17 and 89% identical to SEQ ID NO: 18.
In each instance, the ankyrin repeat proteins (Protein #7, #6, #5, SMA087, SMA095, SMA091, SMA099, AS579) comprise an amino acid sequence that is at least 85% identical to any one of SEQ ID NOs: 15 to 18, and thus necessarily has binding specificity for DLL3 and for human serum albumin. MPEP 2112.01(II).
It would be obvious to one of ordinary skill in the art to modify the conjugate disclosed by Schultz by replacing the protein with Protein #5, Protein #6, Protein #7, SMA087, SMA095, SMA091, SMA099, or AS579 and have a reasonable expectation of success. Schultz discloses a FAP-targeted radioconjugate comprising [212Pb or 203Pb]-TCMC and a binding protein that exhibits specificity for FAP and HSA. Rigamonti discloses several ankyrin binding proteins that exhibit specificity for FAP, HSA, and CD40, including Protein #7, Protein #6, Protein #5, SMA087, SMA095, SMA091, SMA099, or AS579. Thus, Schultz establishes that a FAP-targeted radioconjugate may be formed with [212Pb or 203Pb]-TCMC and a binding protein having specificity for FAP and HSA and Rigamonti establishes that Protein #5, Protein #6, Protein #7, SMA087, SMA095, SMA091, SMA099, or AS579 are binding proteins that exhibit specificity for FAP and HSA. Accordingly, the combined teachings of Schultz and Rigamonti suggest that aforementioned proteins may function as the binding protein component of the [212Pb or 203Pb]-TCMC conjugate disclosed by Schultz, as they each independently exhibit the binding specificity for FAP and HSA contemplated by Schultz. Therefore, it is reasonable to expect the conjugate disclosed by Schultz may be modified by replacing the protein with Protein #5, Protein #6, Protein #7, SMA087, SMA095, SMA091, SMA099, or AS579. 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 present case, Rigamonti discloses that Protein #5, Protein #6, Protein #7, SMA087, SMA095, SMA091, SMA099, or AS579 are multi-specific proteins comprising ankyrin repeat domains with binding specificity for CD40, HSA, and FAP. [Rigamonti, 0002, 00374, 0368] Rigamonti further discloses FAP is expressed in tumor-associated stroma and the disclosed multi-specific proteins are able to target and activate the CD40 receptor locally in FAP-positive tumors and cause substantial antitumor activity in the absence of systemic toxicity. [Rigamonti, 0200, 0433] Therefore, one would have been motivated by the expectation that the aforementioned modification would enable the conjugate disclosed by Schultz to exhibit additional binding specificity for CD40, thereby conferring the ability to locally activate the CD40 receptor in FAP-positive tumors.
Allowable Subject Matter
Claim 39 and 42 objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Response to Arguments
Applicant’s arguments with respect to the rejections over Blackwell, Bianchi, and/or Kokov have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
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 KAILA A CRAIG whose telephone number is (703)756-4540. The examiner can normally be reached Monday-Friday 0800-1600.
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/K.A.C./Examiner, Art Unit 1618 /Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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