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 .
Response to Amendment
The amendment filed 23 June 2026 is acknowledged. Claims 1-3, 5, 9, 16, and 24-34 are amended.
Claim Status
Claims 1-3, 5, 9, 16, and 24-34 are pending and under examination in the instant office action.
Withdrawal of Rejections
The rejection of claims 1-3, 5, 9, 16, and 24-34 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of the amendments to the claims.
The rejection of claims 5, 28, and 33 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of the amendments to the claims.
The rejection of claims 1-3, 5, 9, 16, and 24-34 for scope of enablement is withdrawn in view of the amendments to the claims and Applicant’s arguments in regard to “antibody fragments” (Remarks 6/23/2026 p. 10-11).
The rejection of Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over US 20070231333 A1 to Boghaert et. al. published 4 October 2007 (Of record, PTO-892 dated 5/19/2025) as applied to claim 1 above, and further in view of WO 2019027973 to Sandesh et. al. (Of record, PTO-892 dated 5/19/2025); and US 20170210803 to Willingham et. al. (Of record, PTO-892 dated 5/19/2025) is withdrawn in view of the amendments to the claims.
The provisional rejection of claims 1-3, 5, 9, 16, and 24-29 on the ground of nonstatutory double patenting as being unpatentable over claim 2-5, 7, 9, 20, 21, 23, and 32 of copending Application No. 17725544 (reference application) is withdrawn in view of the approved terminal disclaimer filed 6/23/2026.
The provisional rejection of claims 30-44 on the ground of nonstatutory double patenting as being unpatentable over claim 2-5, 7, 9, 20, 21, 23, and 32 of copending Application No. 17725544 (reference application) as applied to claim 9 above and further in view of Mishra, Rosalin, et al. "HER3 signaling and targeted therapy in cancer." Oncology reviews 12.1 (2018): 355 published May 16 2018 is withdrawn in view of the approved terminal disclaimer filed 6/23/2026.
The provisional rejection of claims 9 and 24-34 on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 17/532919 (reference application) is withdrawn in view of the approved terminal disclaimer filed 6/23/2026.
The provisional rejection of claims 1-3, 5, and 16 on the ground of nonstatutory double patenting as being unpatentable over claims 1-73 of copending Application No. 18/025849 (reference application) in view of US 20070231333 A1 to Boghaert et. al. published 4 October 2007 is withdrawn in view of the approved terminal disclaimer filed 6/23/2026.
The provisional rejection of claims 9 and 24-34 on the ground of nonstatutory double patenting as being unpatentable over claims 1-41 of copending Application No. 18/696453 (reference application) in view of Mishra, Rosalin, et al. "HER3 signaling and targeted therapy in cancer." Oncology reviews 12.1 (2018): 355 published May 16 2018 is withdrawn in view of the approved terminal disclaimer filed 6/23/2026.
Specification- Maintained
The use of the terms Taxotere, Abraxane, Sutent, and Nexavar ([202], [204]) which are trade names or a marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Response to arguments
Although Applicant has amended to include the proper trade mark symbols at [0225], [0226], and [0228] of the specification, the specification still contains improperly identified instances at [202] line 3 and line 6-7 and [204] lines 3 and 6. The Applicant argues that paragraphs [202] and [204] do not recite the trade names or trade marks (Remarks 6/23/2026 p. 8). For clarity, the trade marks are found in the below-marked paragraphs [202] and [204] of the Specification filed 3/23/2022 pages 52-53 in the screen captures below:
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Claim Rejections - 35 USC § 103- Maintained
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 1-3 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over US 20070231333 A1 to Boghaert et. al. published 4 October 2007 (Of record, PTO-892 dated 5/19/2025).
Regarding claim 1, Boghaert et. al. discloses a therapeutic composition and method for the treatment of a cancer comprising administering an anti-human 5T4 antibody or antibody-drug conjugate [0002], [210] in combination with a second therapeutic agent [0024]; wherein the anti-5T4 antibody of the invention may comprise a high energy radioisotope that is conjugated to the anti-5T4 antibody and that the anti-5T4 radioisotopes may be suitable for radiotherapy [121-122] and wherein the anti-5T4/drug conjugates may be administered with additional therapeutic agents [0211] such as at least one radiotherapeutic agent and a CD47 blockade via anti-CD47 antibodies [0215]. The anti-5T4 antibody of the radioimmunoconjugate is a monoclonal antibody [0011].
Regarding claims 2-3 and 19-22, Boghaert et. al. discloses that the conjugated radioisotope may be an alpha emitter or a beta emitter [0215].
Regarding claim 7, the monoclonal antibody is an anti-5T4 antibody [0002, 0011, 121-122] and are “agents having anti-cancer activity in 5T4-expressing cells such as cancer cells from squamous/adenomatous lung carcinoma (non-small-cell lung carcinoma), invasive breast carcinoma, colorectal carcinoma, gastric carcinoma, squamous cervical carcinoma, invasive endometrial adenocarcinoma, invasive pancreas carcinoma, ovarian carcinoma, squamous vesical carcinoma, and choriocarcinoma” [0116].
Regarding claims 16, the anti-CD47 antibody is an additional therapeutic agent [0211, 0215] (reads on discrete molecule).
Boghaert does not explicitly teach the method of treating cancer comprising a radiolabeled anti-5T4 antibody in combination therapy, wherein the additional therapeutic agent is the anti-CD47 antibody, and anti-SIRPɑ antibody, or a SIRPɑ Fc fusion protein.
It would have been prima facie obvious for a person of ordinary skill in the art, before the effective filing date, to treat a mammalian subject having cancer with a combination of an anti-5T4 monoclonal antibody conjugated to a high energy radioisotope for the treatment of cancer as taught by Boghaert et. al. in combination with an additional therapeutic agent as taught by Boghaert et. al., wherein the additional therapeutic agent is an anti-CD47 antibody as taught by Boghaert et. al. to benefit from the combination anti-cancer therapy as taught by Boghaert. This would have a reasonable expectation of success because Boghaert teaches the anti-cancer therapy benefits of radionuclide-conjugated 5T4 monoclonal antibodies and anti-CD47 antibodies, and an artisan would expect suitable anti-cancer benefits from using them in combination.
Claim Rejections - 35 USC § 103- Modified, necessitated by amendment
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over US 20070231333 A1 to Boghaert et. al. published 4 October 2007 (Of record, PTO-892 dated 5/19/2025) as applied to claim 1 above, and further in view of Song, Hong, et al. "Radioimmunotherapy of breast cancer metastases with α-particle emitter 225Ac: comparing efficacy with 213Bi and 90Y." Cancer research 69.23 (2009): 8941-8948 (Of record, PTO-892 dated 1/23/2026); WO 2019027973 to Sandesh et. al. (Of record, PTO-892 dated 5/19/2025); and US 20170210803 to Willingham et. al. (Of record, PTO-892 dated 5/19/2025).
The teachings of Boghaert et. al. in regards to claim 1 are in the 103 rejection above.
Boghaert discloses that radioisotopes that may be conjugated to the anti-5T4 antibody include 225-Actinium [0122]. Boghaert et. al. also teaches that “an effective dose will be in the range from about 0.01 mg/m2 to about 50 mg/m2, such as from about 0.1 mg/m2 to about 20 mg/m2, or about 15 mg/m2, which dose is calculated based on the amount of anti-5T4 antibody. For a radiolabeled anti-5T4 antibody, an effective dose is typically in the range from about 1 mCi to about 300 mCi, normally about 5 mCi to 100 mCi, depending on the radioisotope and the binding affinity of the antibody” [0207]. Boghaert does not explicitly disclose an antibody composition 225Ac-labeled 5T4-binding monoclonal antibody or 5T4-binding monoclonal antibody fragment wherein the composition comprises a radiation dose of 0.1-2.0 µCi/kg body weight of the subject and a non-radiolabeled 5T4-binding monoclonal antibody or non-radiolabeled 5T4 monoclonal antibody fragment and a protein dose of 0.1-5.0mg/kg body weight of the subject and wherein the CD47 blockade is administered at a total dose of 0.05-5.0 mg/kg body weight of the subject.
This deficiency is partially resolved by Song et. al. and WO2019027973 to Sandesh et. al.
Song et. al. teaches that radioimmunotherapy of metastatic cancer using alpha-particle emitters is promising because they can delivery highly focus energy are a short path (Introduction ¶1). Song et. al. teach that previous preclinical studies found that 213Bi is therapeutically more effective than the β-emitter, 90Y in metastatic colon cancer model. Song et. al. teaches that in a rat lung metastasis model, HER-2/neu antibody conjugated 225Ac was the most effective (p. , Fig. 2). Song et. al. concludes “The higher potency and longer half-life of 225Ac overcame the ∼35% lower immunoreactivity of 225Ac-7.16.4 compared with 213Bi-7.16.4” and “In conclusion, we have shown that α-particle emitter 225Ac-labeled mAb is very effective, better than the α-emitter, 213Bi, and the β-emitter, 90Y, in prolonging the survival of neu-N transgenic mice bearing lung metastases” ().
Sandesh et. al. teaches a 225Ac anti-CD38 radionuclide labelled monoclonal antibody and teaches an effective amount of the labeled antibody comprises a radiation dose of 0.1 to 10 0.1-2.0 µCi/kg body weight of the subject [0130] and at dose ranges selected from a group including 1ug/kg to 1mg/kg [129],[0134].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, particular choose 225Ac out of the radionuclide labels taught by Boghaert in order to benefit from the effectiveness against metastasis in solid tumors and the higher potency and longer half-life of 225Ac labeled monoclonal antibody as taught by song. This would have a reasonable expectation of success because both Boghaert and Song et. al. teach radioimmunoconjugates for the treatment of cancer and Boghaert et. al. teaches that a person of ordinary skill in the art can select the particular radionuclide and dose for the application. Further, a person of ordinary skill in the art would understand that other anti-tumor target antibodies such as that of Boghaert could be conjugated to the 225Ac and achieve the benefits as taught by Song et. al. because the 225Ac would be expected to still have the same potency and half-life properties. It further would have been obvious, at the time of filing, for a person of ordinary skill in the art to optimize the dose of the radioimmunotherapy in part based on the radionuclide as taught by Boghaert using the 225Ac radioimmunotherapy (µCi and total protein) doses as taught by Sandesh, resulting in a composition comprising both labeled and unlabeled anti-5T4 antibody in order to get the optimal antibody and radiotherapy doses in the same composition. This would have a reasonable expectation of success because a person of ordinary skill in the art would use known ranges of similar radioimmunoconjugates in order to optimize the dose for the particular antibody affinity, subject, and radionuclide as taught by Boghaert and Sandesh.
Boghaert et. al. in view of Sandesh et. al. does not teach that the CD47 blockade is administered at a total dose of 0.05-5.0 mg/kg body weight of the subject.
This is resolved by Willingham et. al. Willingham et. al. teaches combination treatments of CD47 blockade in combination with an immunomodulatory anti-cancer therapy (Abstract, [0115]), wherein the therapeutic dosage may be about 0.01 to about 5mg/kg of the host body weight [120]. Example dosages can be 1 mg/kg body weight or 10 mg/kg body weight with the range of 1-10 mg/kg [120].
It would have been prima facie obvious for a person of ordinary skill in the art, before the effective filing date, to optimize the anti-CD47 blockade dose within the disclosed preferred range of about 0.1 to about 5mg/kg or 1-10mg/kg body weight in a combination therapy with a second monoclonal antibody in order to determine the effective dose in combination with a second antibody at less than 1mg/kg body weight to predictable effect because both Boghaert and Willingham teach combination antibody therapies comprising anti-CD47 antibodies. See MPEP §2144.05.
Claim Rejections - 35 USC § 103- Maintained
Claims 9, 24-27, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over WO2019028555 to Maruthachalam et. al. published 14 February 2019 (Of record, PTO-892 dated 1/23/2026) in view of U.S. 20180251558 to Maute et. al. published 8 September 2018 (Of record, PTO-892 dated 5/19/2025) as evidenced by Cruz-Nova, Pedro, et al. "Radiobiological effect of alpha particles. The scientific basis of targeted alpha-particle therapy." Nuclear Medicine and Biology 146 (2025): 109044 (Of record, PTO-892 dated 1/23/2026) and Behr, Thomas M., et al. "High-linear energy transfer (LET) α versus low-LET β emitters in radioimmunotherapy of solid tumors: therapeutic efficacy and dose-limiting toxicity of 213Bi-versus 90Y-labeled CO17-1A Fab′ fragments in a human colonic cancer model." Cancer research 59.11 (1999): 2635-2643 (Of record, PTO-892 dated 1/23/2026).
Regarding claims 9 and 25, Maruthachalam et. al. teaches a therapeutic composition and a method of treatment of HER3-expressing cancer comprising administering an effective amount of an immunoconjugate to a subject in need thereof, wherein the HER3 expressing cancer is breast cancer, gastric cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, or colon cancer (Abstract, [0031], [00167]). In one embodiment, the animal is a mammal or a human [00169]. The immunoconjugate comprises an anti-HER3 monoclonal antibody or antigen-binding fragment thereof ([0006],[0098]). One embodiment of the immunoconjugate is the anti-HER3 antibody conjugated to a cytotoxic radionuclide [00121].
Regarding claim 26, Maruthachalam et. al. teaches the radionuclides may be selected from a group including 212Bi [00121], which is an alpha-particle emitting radionuclide (as evidenced by Cruz-Nova, Pedro, et al. see p. 2 left column ¶3). Regarding claim 27, teaches the radionuclides may be selected from a group including 90Y [00121], which is a beta-particle emitting radionuclide (as evidenced by Behr, Thomas M., et al., Abstract).
Maruthachalam et. al. does not teach a method of treating one of the recited cancer subtypes comprising administering to a mammal an anti-HER3 monoclonal antibody conjugated to a cytotoxic radionuclide, comprising administering to the mammalian subject an effective amount of one or more CD47 blockades, wherein the one or more CD47 blockades comprises one or more of an anti-CD47 antibody, an anti-SIRPɑ antibody, or a SIRPɑ Fc fusion protein.
This deficiency is resolved by Maute et. al.
Maute et. al. teaches a method of inducing phagocytosis of a target cell and treating an individual having cancer comprising administering an anti-CD47/SIRPɑ agent in combination with an agent that potentiates activity or otherwise increases therapeutic effect by co-administration of an anti-class I/LILRB1 agent, an agent the opsonizes a target cell, and an anti-CD47/SIRPɑ agent [160]. The agent that opsonizes a target cell is any agent that can bind to a target cell (e.g. a cancer cell) and opsonize a target cell. Example agents are monoclonal antibodies for the treatment of solid tumors, for example Cetuximab (anti-EGFR) and Trastuzumab (anti-HER2) [0163]. In exemplary embodiments, the anti- CD47/SIRPɑ agent is the anti-CD47 antibody Hu5F9-G4 ([0015], [0104], [0112]). Maute et. al. teaches that the combinations with the highest phagocytosis against breast cancer cell lines are combinations including traditional anti-cancer monoclonal antibodies (cetuximab, trastuzumab, and panitumumab) and the anti-CD47 5F9-G4 compared to the traditional monoclonals alone (Fig. 17).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the anti-HER3 radionuclide immunoconjugate of Maruthachalam et. al. as an additional therapeutic in combination with the anti-CD47 antibody combination therapy of Maute et. al. in order to benefit from the additional anti-cancer phagocytosis benefits as taught by Maute et. al and to increase the breadth of cancer antigens targeted as suggested by Maute et. al. This would have a reasonable expectation of success because Maute et. al. suggest that any antibody that targets and opsonizes the cancer cell such as a monoclonal antibody targeting cancer antigens EGFR and HER is suitable in combination to induce phagocytosis, and therefore an artisan would understand that other cytotoxic anti-cancer agents such as the anti-HER3 radionuclide immunoconjugate of Maruthachalam et. al. would be similarly suitable opsonization agents.
Regarding claims 24 and 29, the modified method of Maute and Maruthachalam et. al. as described above teaches that the anti-CD47 antibody and the anti-HER3 antibody are discrete antibodies.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over WO2019028555 to Maruthachalam et. al. published 14 February 2019 (Of record, PTO-892 dated 1/23/2026) in view of U.S. 20180251558 to Maute et. al. published 8 September 2018 (Of record, PTO-892 dated 5/19/2025) as applied to claims 9 and 25 above, and further in view of Song, Hong, et al. "Radioimmunotherapy of breast cancer metastases with α-particle emitter 225Ac: comparing efficacy with 213Bi and 90Y." Cancer research 69.23 (2009): 8941-8948 (Of record, PTO-892 dated 1/23/2026); WO 2019027973 to Sandesh et. al. (Of record, PTO-892 dated 5/19/2025); and US 20170210803 to Willingham et. al. (Of record, PTO-892 dated 5/19/2025).
The teachings of Maruthachalam et. al. and Maute et. al. in regards to claims 9 and 25 are in the 103 rejection above.
Maruthachalam et. al. and Maute et. al. do not teach the method wherein the method comprises administering a composition 225Ac tagged monoclonal antibody and a radiation dose of 0.1-2.0 µCi/kg body weight of the subject and a protein dose of 0.1-5.0mg/kg body weight of the subject and wherein the CD47 blockade is administered at a total dose of 0.05-5.0 mg/kg body weight of the subject.
This deficiency is partially resolved by Song et. al.
Song et. al. teaches that a 225-Ac conjugated anti-HER2 antibody more significantly prolonged lifespan in mouse models of NT2.5 cancer mouse models in vivo compared to Bi-213 and Y-90 (Fig. 2) on both early-treated and late stage metastases of the model (See Fig. 2C and Fig. 3). Song et. al. teaches “The improved efficacy of α-emitter 225Ac over 213Bi and 90Y can partially be attributed to the higher radiation doses that micrometastases receive from 225Ac. 225Ac emits four α-particles along its decay chain and deposits a total energy of 4.50 × 10−12 J/Bq s, 3.2 and 30.0 times higher than that by 213Bi and 90Y. Furthermore, the majority of α-radiation will be absorbed locally, whereas most of the β-particle energy from 90Y will be deposited outside of micrometastases”.
It would have been obvious for a person of ordinary skill in the art to use a cytotoxic radionuclide anti-HER3 immunoconjugate as taught by modified Maruthachalam et. al. and Maute et. al. substituted with the 225Ac radionuclide of Song et. al. in order to benefit from the higher anti-cancer and anti-metastasis cytotoxicity with 225Ac as compared to other radionuclides as taught by Song et. al. This would have a reasonable expectation of success because an Maruthachalam et. al. teaches that many different cytotoxic radionuclides are acceptable and an artisan would expect that the 225Ac would have a similar anti-metastasis effect when conjugated with a HER2 antibody as with a HER3 antibody.
Modified Maruthachalam et. al. and Maute et. al. in view of Song et. al. does not teach the specific radiation and protein doses of the combination therapy are 0.1-2.0µCi/kg body with of the subject 0.1-5.0mg/kg body weight of the subject, respectively, and the CD47 blockade is at a total dose of 0.05-5.0mg/kg body weight of the subject.
This deficiency is partially resolved by WO2019027973 to Sandesh et. al.
Sandesh et. al. teaches a 225-Ac radionuclide labelled monoclonal antibody and teaches an effective amount of the labeled antibody comprises a radiation dose of selected from a group of ranges including 0.1-2.0 µCi/kg body weight of the subject [0130] and at dose ranges selected from a group including 100ug/kg to 1mg/kg [129],[0134].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the dosing schedule of Sandesh et. al. to modify the composition of Maruthachalam et. al. and Maute et. al. in view of Song et. al. for the purpose of developing an effective dose comprising a radiolabeled antibody and a protein concentration specific to the subject. This would have a predictable effect because both Maruthachalam et. al. and Maute et. al. in view of Song et. al. and Sandesh et. al. teach radiolabeled therapeutic monoclonal antibodies and an artisan would expect to be able to optimize the most effect dose of 225-Ac labeled antibody for both radiation and protein dosing.
Modified Maruthachalam et. al. and Maute et. al. in view of Song et. al. in view of Sandesh et. al. does not teach that the CD47 blockade is administered at a total dose of 0.05-5.0 mg/kg body weight of the subject.
This is resolved by Willingham et. al. Willingham et. al. teaches combination treatments of CD47 blockade in combination with an immunomodulatory anti-cancer therapy (Abstract, [0115]), wherein the therapeutic dosage may be about 0.01 to about 5mg/kg of the host body weight [120]. Example dosages can be 1 mg/kg body weight or 10 mg/kg body weight with the range of 1-10 mg/kg [120].
It would have been prima facie obvious for a person of ordinary skill in the art, before the effective filing date, to optimize the anti-CD47 blockade dose within the disclosed preferred range of about 0.01 to about 5mg/kg or 1-10mg/kg body weight in a combination therapy with a second monoclonal antibody in order to determine the effective dose in combination with a second antibody at less than 1mg/kg body weight to predictable effect because both Boghaert and Willingham teach combination antibody therapies comprising anti-CD47 antibodies. See MPEP §2144.05.
Claims 30-32 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over WO2019028555 to Maruthachalam et. al. published 14 February 2019 (Of record, PTO-892 dated 1/23/2026) in view of U.S. 20180251558 to Maute et. al. published 8 September 2018 (Of record, PTO-892 dated 5/19/2025) as applied to claim 9 above, and further in view of Mishra, Rosalin, et al. "HER3 signaling and targeted therapy in cancer." Oncology reviews 12.1 (2018): 355 published May 16 2018 (Of record, PTO-892 dated 1/23/2026) and US 20170210803 to Willingham et. al. (Of record, PTO-892 dated 5/19/2025) as evidenced by Cruz-Nova, Pedro, et al. "Radiobiological effect of alpha particles. The scientific basis of targeted alpha-particle therapy." Nuclear Medicine and Biology 146 (2025): 109044 (Of record, PTO-892 dated 1/23/2026) and Behr, Thomas M., et al. "High-linear energy transfer (LET) α versus low-LET β emitters in radioimmunotherapy of solid tumors: therapeutic efficacy and dose-limiting toxicity of 213Bi-versus 90Y-labeled CO17-1A Fab′ fragments in a human colonic cancer model." Cancer research 59.11 (1999): 2635-2643 (Of record, PTO-892 dated 1/23/2026).
The teachings of Maruthachalam et. al. in view of Maute et. al. are in regards to claim 9 are in the 103 rejection above.
Regarding claim 31, Maruthachalam et. al. teaches the radionuclides may be selected from a group including 212Bi [00121], which is an alpha-particle emitting radionuclide (as evidenced by Cruz-Nova, Pedro, et al. see p. 2 left column ¶3). Regarding claim 32, Maruthachalam et. al. teaches the radionuclides may be selected from a group including 90Y [00121], which is a beta-particle emitting radionuclide (as evidenced by Behr, Thomas M., et al., Abstract).
Regarding claim 34, the modified method of Maute and Maruthachalam et. al. as described above teaches that the anti-CD47 antibody and the anti-HER3 antibody are discrete antibodies.
Modified Maruthachalam et. al. in view of Maute et. al. does not teach the method wherein the cancer is prostate cancer.
This deficiency is resolved by Mishra and Willingham et. al.
Mishra teaches that increased HER3 expression is associated with ovarian, breast, prostate, gastric, bladder, lung, melanoma, colorectal and squamous cell cancers (p. 46, left column). Mishra et. al. teaches that elevated expression of HER3 in castration-resistant prostate cancer leads to activation of PI3K/AKT signaling and androgen receptor stabilization (p. 46, right column). Mishra et. al. teaches that there are anti-HER3 antibodies and anti-HER3 antibody drug conjugates in preclinical development for prostate cancer (Table 1, see p. 49 “MP-RM-1”; “EV20” and Table 2 p. 50 “Anti-HER3 ADCs).
Willingham et. al. teaches a combination therapy of anti-CCR2 with CD47 blockade for CCR2 positive cells such as prostate cancer [0071] and teaches methods for depletion of cancer cells using CD47 blockade therapy [0091] wherein the cancers are selected from a large list of types including prostate cancer [0089].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method of treating with a combination of a radionuclide-conjugated anti-HER3 antibody and an anti-CD47 antibody of Maruthachalam et. al. and Maute et. al. as described in the 103 above in a method of treating prostate cancer to benefit from expanding the treatment group to include an additional high-HER3 expressing cancer as taught by Mishra. This would have a reasonable expectation of success because Mishra teaches the preclinical application of anti-HER3 antibodies including ADCs for prostate cancer therapy and Willingham teaches a combination of CD47 blockade and a second therapeutic (anti-CCR2, also expressed on prostate cancer as taught by Willingham et. al.). Therefore, an artisan would reasonably predict that a combination therapy on anti-CD47 expected to work in prostate cancer and an anti-HER3 antibody-radionuclide conjugate expected to target HER3-positive prostate cancer cells would be expected to successfully treat prostate cancer.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over WO2019028555 to Maruthachalam et. al. published 14 February 2019 (Of record, PTO-892 dated 1/23/2026) in view of U.S. 20180251558 to Maute et. al. published 8 September 2018 (Of record, PTO-892 dated 1/23/2026); Mishra, Rosalin, et al. "HER3 signaling and targeted therapy in cancer." Oncology reviews 12.1 (2018): 355 published May 16 2018 (Of record, PTO-892 dated 1/23/2026); and US 20170210803 to Willingham et. al. (Of record, PTO-892 dated 5/19/2025), as applied to claim 30 above, and in further view of Song, Hong, et al. "Radioimmunotherapy of breast cancer metastases with α-particle emitter 225Ac: comparing efficacy with 213Bi and 90Y." Cancer research 69.23 (2009): 8941-8948 (Of record, PTO-892 dated 1/23/2026) and WO 2019027973 to Sandesh et. al. (Of record, PTO-892 dated 5/19/2025).
The teachings of Maruthachalam et. al., Maute et. al., Mishra, and Willingham et. al. as applied to claim 30 are in the 103 rejection above.
Regarding claim 33, Willingham et. al. further teaches combination treatments of CD47 blockade in combination with an immunomodulatory anti-cancer therapy (Abstract, [0115]), wherein the therapeutic dosage may be about 0.01 to about 5mg/kg of the host body weight [120]. Example dosages can be 1 mg/kg body weight or 10 mg/kg body weight with the range of 1-10 mg/kg [120].
It would have been prima facie obvious for a person of ordinary skill in the art, before the effective filing date, to optimize the anti-CD47 blockade dose within the disclosed preferred range of about 0.1 to about 5mg/kg or 1-10mg/kg body weight in a combination therapy with a second monoclonal antibody in order to determine the effective dose in combination with a second antibody at less than 1mg/kg body weight to predictable effect because both Boghaert and Willingham teach combination antibody therapies comprising anti-CD47 antibodies. See MPEP §2144.05.
Maruthachalam et. al., Maute et. al., Mishra, and Willingham et. al. do not teach wherein the composition comprises a 225-Ac labeled antibody or antibody fragment, the composition comprising a radiation dose of 0.1-2.0 µCi/kg body weight of the subject and a protein dose of 0.1-5.0mg/kg body weight of the subject.
This deficiency is resolved by Song et. al. and Sandesh et. al.
Song et. al. teaches that a 225-Ac conjugated anti-HER2 antibody more significantly prolonged lifespan in mouse models of NT2.5 cancer mouse models in vivo compared to Bi-213 and Y-90 (Fig. 2) on both early-treated and late stage metastases of the model (See Fig. 2C and Fig. 3). Song et. al. teaches “The improved efficacy of α-emitter 225Ac over 213Bi and 90Y can partially be attributed to the higher radiation doses that micrometastases receive from 225Ac. 225Ac emits four α-particles along its decay chain and deposits a total energy of 4.50 × 10−12 J/Bq s, 3.2 and 30.0 times higher than that by 213Bi and 90Y. Furthermore, the majority of α-radiation will be absorbed locally, whereas most of the β-particle energy from 90Y will be deposited outside of micrometastases”.
It would have been obvious for a person of ordinary skill in the art to use a cytotoxic radionuclide anti-HER3 immunoconjugate as taught by modified Maruthachalam et. al., Maute et. al., Mishra, and Willingham et. al. substituted with the 225Ac radionuclide of Song et. al. in order to benefit from the higher anti-cancer and anti-metastasis cytotoxicity with 225Ac as compared to other radionuclides as taught by Song et. al. This would have a reasonable expectation of success because an Maruthachalam et. al. teaches that many different cytotoxic radionuclides are acceptable and an artisan would expect that the 225Ac would have a similar anti-metastasis effect when conjugated with a HER2 antibody as with a HER3 antibody.
Sandesh et. al. teaches a 225-Ac radionuclide labelled monoclonal antibody and teaches an effective amount of the labeled antibody comprises a radiation dose of 0.1 to 10 0.1-2.0 µCi/kg body weight of the subject [0130] and at dose ranges selected from a group including 1ug/kg to 1mg/kg [129],[0134].
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the dosing schedule of Sandesh et. al. to modify the composition of Maruthachalam et. al., Maute et. al., Mishra, Willingham et. al., and Song et. al. for the purpose of developing an effective dose comprising a radiolabeled antibody and a protein concentration specific to the subject. This would have a predictable effect because both Boghaert and Sandesh et. al. teach radiolabeled therapeutic monoclonal antibodies.
Response to Arguments
Applicant’s arguments filed 23 June 2025 have been fully considered but are not persuasive.
Applicant argues that although the anti-5T4 antibodies may be conjugated to a high-energy isotope suitable for radiotherapy, Boghaert provides no working examples involving a radiolabeled anti-5T4 antibody as a therapeutic and rather uses calicheamicin as the cytotoxic payload in all of their working examples. Therefore a person of ordinary skill in the art would understand the “actual teaching” to be directed at anti-5T4/calicheamicin antibody-drug conjugates (Remarks p. 12). This is not persuasive. MPEP §2123 states that “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain” and that “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)”. As described in the 103 rejection above, Boghaert teaches anti-5T4 antibodies conjugated to epitopes suitable for radiotherapy, wherein those suitable epitopes are alpha and beta emitters. A person of ordinary skill in the art would, as described above, understand that the disclosure was not limited to the working embodiment of anti-5T4/calicheamicin but to the entire breadth of appropriate cytotoxic payloads expected to work with the anti-5T4 antibody as disclosed by Boghaert.
Applicant states that Boghaert “does not teach or suggest the specific combination recited in the amended claim” because paragraph [215] does not suggest the combination, but rather “a non-prioritized laundry list of more than thirty (30) candidate therapeutic antibodies that, according to Boghaert, “may be used alone or as an antibody/drug conjugates” in combination with the anti-5T4 antibody/drug conjugates that are the central focus of Boghaert. (Remarks 6/23/2026 p. 12-13). MPEP §2144.08 states that “The patentability of a claim to a specific compound, species, or subgenus embraced by a prior art genus should be analyzed no differently than any other claim for purposes of 35 U.S.C. 103. "The section 103 requirement of unobviousness is no different in chemical cases than with respect to other categories of patentable inventions." This includes a 1) determination of the scope and content of the prior art; 2) ascertain the differences between the closest disclosed prior art species of record and the claimed species; 3) determine the level of skill in the art; 4) determine whether one of ordinary skill in the art would have had a reason to select including a) the size of the genus b) the express teachings; c) the teachings of structural similarity; d) teachings of similar properties or uses; e) the predictability of the technology; and f) any other teaching to support selection of the species or subgenus. As described in the 103 rejection above, Boghaert explicitly discloses a list of anti-cancer therapies that are suitable for use in combination with the anti-5T4 antibody conjugates of the disclosure. The Examiner would like to remind the applicant first that the prior art is presumed to be operable/enabled (See MPEP §2121). In addition, rather than being a random laundry list of targets, Boghaert is explicitly disclosing a list of well-known therapies that are validated to be useful in the treatment of cancer. MPEP §2144.06 states that: “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”. As of the effective filing date, blockade of CD47 was a widely known cancer therapeutic target. For example, Veillette, André, and Jun Chen. "SIRPα–CD47 immune checkpoint blockade in anticancer therapy." Trends in immunology 39.3 (2018): 173-184 teaches that “Studies largely led by the Weissman group provided compelling indication that interference with the SIRPα–CD47 interaction using blocking anti-CD47 antibodies markedly enhanced the ability of macrophages to engulf tumor cells in vitro [12–14]. These antibodies also promoted elimination of human tumor cells transplanted in nonobese diabetic (NOD) mice lacking T cells, B cells, and NK cells (NOD–SCID-common γ chain or NSG mice). These effects were seen with a broad range of tumor cell types, including hematopoietic and nonhematopoietic cells [12–16]. Anti-CD47 antibodies also synergized with rituximab, a therapeutic antibody recognizing CD20 on human B cells, to eliminate human B lymphoma cells in transplanted NSG mice [12]”. Veillette teaches that this preclinical success lead to the development of additional SIRPα-CD47 blocking agents and that several are being testing in clinical trials.
At the time of filing, this expected therapeutic efficacy was further enhanced with clinical data. As reviewed in Takimoto, C. H., et al. ("The Macrophage ‘Do not eat me’ signal, CD47, is a clinically validated cancer immunotherapy target." Annals of Oncology 30.3 (2019): 486-489; hereinafter ‘Takimoto’) two broad classes of CD47 agents “are showing favorable clinical toxicity profiles and promising antitumor activity has been reported in patients with NHL, cutaneous T-cell lymphoma (CTCL), and ovarian cancer”. Takimoto et. al. further states “Clinical validation of this unique mechanism of action is evidenced by the emergence of strong signals of activity in patients with refractory NHL and CTCL[…] Harnessing the power of the innate immune system and first responder cells such as macrophages has the potential to extend the impact of cancer immunotherapies to benefit a broad range of cancer patients.”
Thus, the suggestion of Boghaert to combine the anti-5T4 drug conjugates of the invention is explicitly directed towards other well-validated anti-cancer targets that a person of ordinary skill in the art would have understood and been able to cater to the particular cancer and available treatments for that cancer. Rather than being “without a teaching of efficacy”, a person of ordinary skill in the art would have understood the disclosure of Boghaert to explicitly suggest efficacy of each of the listed therapies, and therefore created a motivation and a reasonable expectation of success in combining the anti-5T4 conjugates as taught by Boghaert.
Applicant states that the inventor would have to make three independent nonobvious choices: “(1) selecting a radiolabeled anti-5T4 antibody (rather than the anti-5T4/calicheamicin conjugate that is the central focus of Boghaert and the only embodiment exemplified in Boghaert's working examples), (2) selecting an α- or β-particle emitting radionuclide as the radiolabel (Boghaert's[0121]-[0122] mention various radioisotope types without preference), and (3) combining the resulting radiolabeled anti-5T4 antibody specifically with a CD47 blockade (rather than any of the many other candidate combination partners listed in [0215]), for the specific purpose of treating a 5T4-expressing cancer” (Remarks p. 13). As stated above, there is no non-obvious choice to be made in the selection of a radiolabeled anti-5T4 antibody; Boghaert explicitly discloses radiolabeled anti-5T4 antibodies as one of the suitable cytotoxic payloads for the antibody-drug conjugates of the invention and implicitly suggests that all of these known cytotoxic payloads that it discussed are equally suitable for its anti-5T4 cancer therapy. Regarding the alpha- or beta- emitting particles, as described in the 103 rejection above, Boghaert et. al. explicitly teaches that radioisotopes suitable for therapy including alpha and beta-emitters [0121] and that positron and gamma emitters are useful for diagnostic applications [0121]. Thus, a person of ordinary skill in the art would understand that when Boghaert refers to a therapeutic application of the antibody-drug conjugate, as is explicitly disclosed in therapeutic combination with anti-CD47 antibodies, it would have been well understood that Boghaert is referring to the therapeutically suitable alpha and beta emitters. Regarding (3), as described above, Boghaert explicitly teaches each of these options as therapeutically suitable, and each was a well-understood in the art and validated anti-cancer therapy, which a person of ordinary skill in the art would have understood while reading the disclosure of Boghaert. As described above, MPEP §2144.06 states that: “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)” and therefore it would have been obvious, and with a reasonable expectation of success as described in the 103 rejection above, to combine one of the anti-5T4 targeted therapy comprising and alpha or beta radionuclide (for therapeutic purposes as taught by Boghaert) with the anti-CD47 antibodies suitable for cancer therapy as taught by Boghaert. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). The instant rejection takes into account only the explicit disclosures of Boghaert, the level of skill in the art, and the explicit suggestion of Boghaert to combine the inventions as described, as well the background in which a person of ordinary skill in the art would have understood the explicit disclosures of Boghaert.
Applicant further states that the claimed combination represents a deliberate dual-mechanism therapeutic strategy that exploits the synergistic interaction between two mechanistically distinct anti-cancer modalities: immunogenic cell death caused by anti-5T4 radiolabeled antibodies and CD47 blockade on the resulting damaged or dying cells, and that this mechanism is distinct from Boghaert’s anti-5T4/calicheamicin conjugate. This is not persuasive because, as described above, Boghaert is prior art for all that it contains (MPEP §2123). Boghaert itself does not limit combinations to the anti-5T4/calicheamicin conjugate but, as described in the 103 rejection above, suggests combining any of the entire genus of anti-5T4 conjugates disclosed with other well-known to the art anti-cancer therapies for combination treatment of cancer. The Examiner notes that rationale to combine that is different from the Applicant’s is permissible (MPEP §2144.IV) and therefore a person of ordinary skill in the art need to have explicitly contemplated the particular anti-cancer modalities as recited by Applicant.
Regarding the rejection of claim 5 over Boghaert in view of Sandesh and Willingham. Applicant argues that Sandesh and Willingham do not cure the deficiencies of Boghaert (Remarks p. 14). Applicant’s Arguments regarding the alleged deficiencies of Boghaert are addressed above and are not persuasive. The Examiner would like to note that the arguments are partially moot in view of the new rejection of claim 5, necessitated by amendment, over Boghaert in view of Song, Sandesh and Willingham. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant argues “at most, Sandesh teaches dose ranges for a particular 225Ac-labeled monoclonal antibody in a particular hematologic malignancy context” and that “Willingham’s combinations are with mechanistically distinct immune-checkpoint or agonistic immunotherapy agents, not with radioimmunotherapy” (Remarks p. 14). This is not persuasive because as explained in the 103, a person of ordinary skill in the art would use what was known in the literature to dose-find for a new therapeutic antibody. Applicant argues that the recited protein dose is at the lower end of monoclonal antibody dosing and is consistent with the specification’s teaching of RIT and that Sandesh, Willingham, and Boghaert do not address this RIT-specific dose-mechanism relationship. This is not persuasive. As described in the 103 rejection above, Boghaert claims a range of potential fixed doses. Because Boghaert teaches that it depends to the radioisotope and antibody affinity, a person of ordinary skill in the art would look to antibodies that have previously used the chosen radioisotope for clinical benchmarks. Additionally, Boghaert is not merely contemplating “naked-antibody” dosing as suggested by Applicant’s arguments; Boghaert explicitly discloses radiolabeled dosing. As described in the 103 rejection above, a person of ordinary skill in the art would use known targeted radionuclide antibodies as benchmarks to determine the dosing of a new conjugated antibody to optimize within the wider range known in the prior art. Regarding Willingham, a person of ordinary skill in the art would use a known combination therapy as a benchmark the dosing of the anti-CD47 antibody as taught by Boghaert because Boghaert does not teach a particular dose. Each anti-CD47 blockade would likely have a different ideal dose in combination therapy, but a person of ordinary skill in the art would be motivated to try known ranges first with a reasonable expectation of success as described in the 103 rejection above. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). The above rejection only takes into account the teachings of Boghaert and what steps a person of ordinary skill in the art would take in order to achieve a working embodiment of the therapeutic combination as taught by Boghaert: as described in the 103 rejection above, they would optimize with similar antibodies as taught by Song, Sandesh and Willingham, respectively, in order to arrive at a dose combination for the chosen particular embodiment.
Regarding the rejection of claims 9, 24-27, and 29 over Maruthachalam in view of Maute as evidenced by Cruz-Nova and Behr, Applicant argues that Maruthachalam teaches anti-Her3 binding agents and immunoconjugates, Maruthachalam does not teach or suggest the combination with an anti-CD47 blockade, and that the deficiency is not remedied by Maute because Maute does not teach the anti-CD47 blockade in combination with any anti-HER3 antibody. This is not persuasive. Maute teaches anti-CD47 blockade combined with any antibody that opsonizes cancer. The paragraphs applicant points to HER3 as conspicuously absent from are just exemplary embodiments (e.g. “In some cases”). Maute et. al. specifically states that “Monoclonal antibodies useful in the methods of the invention that have been used in solid tumors include, without limitation, edrecolomab and trastuzumab (herceptin)” [0163]. These are clearly non-limiting examples. The Examiner would also like to respectfully remind the applicant that the prior art is presumed to be operable/enabled (See MPEP §2121). The lack of a working example would not be sufficient for a person of ordinary skill in the art to not understand that any tumor opsonizing antibody, as taught by Maute, is encompassed by the disclosure. There is no evidence that this is not supported by the disclosure of Maute; Maute explicitly states that it would be expected to work with any anti-tumor target. Applicant is reminded that arguments presented by applicant cannot take the place of factually supported objective evidence. See, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984) (MPEP §2145).
Applicant further argues that the mechanism of Maute is Fc-dependent and cites [005-006] and [0161] Maude. Applicant states that this is relevant because independent claim 9 recites, in the alternative “a radiolabeled HER3-binding antibody fragment”. This is not persuasive because this limitation is not required by the claim. The anti-HER3 monoclonal antibody may be a full-length monoclonal antibody as per claim 9, and therefore may have an Fc domain that opsonizes the target cell. Additionally, this Fc-dependent mechanism is only exemplary “For example, any antibody that can bind to a target cell (as defined herein), where the antibody has an FC region, is considered to be an agent that opsonizes a target cell” ([0161], emphasis is the Examiner’s). The fact that this is not limited to naked antibodies is clear from other examples disclosed. Maute et. al. teaches in regards to potential anti-CD20 antibodies to combine with the therapy “Two new monoclonal antibodies targeting CD20, tositumomab and ibritumomab, have been submitted to the Food and Drug Administration (FDA). These antibodies are conjugated with radioisotopes” [0162]. Thus, radioisotope-conjugated antibodies are not expected to be insufficient by Maute in the method, and would not be considered ineligible for substitution by a person of ordinary skill in the art. The Examiner also notes that, even if the prior art of Maute et. al. were not operative for using radionuclides "Even if a reference discloses an inoperative device, it is prior art for all that it teaches." Beckman Instruments v. LKB Produkter AB, 892 F.2d 1547, 1551, 13 USPQ2d 1301, 1304 (Fed. Cir. 1989)” (MPEP 2121.01). Therefore, as described in the 103 rejection above, a person of ordinary skill in the art would be both motivated and have a reasonable expectation of success at combining the anti-tumor HER3 antibodies of Maruthachalam with the anti-CD47 blockade combination therapy of Maute.
Applicant argues that “although independent claim 9 does not recite a specific antibody dose range, the specification and dependent claims further illustrate the mechanistic distinction”. This is not persuasive because the dosages are not recited in the rejected claims and therefore these limitations are not recited in the rejected claims of record.
In regard to the rejection of claim 28 over Maruthachalam in view of Maute, Song, Sandesh, and Willingham, this is not persuasive. In regard to the arguments against Maruthachalam in view of Maute, these are not persuasive for the reasons set forth above. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant further states that at the RIT-characteristic low protein doses, Maute’s Fc-mediated opsonization mechanism would not operate effectively. As described above, Maute gives examples of anti-CD20 radionuclide-conjugated antibodies that may be combined. Applicant is reminded that arguments presented by applicant cannot take the place of factually supported objective evidence. See, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984) (MPEP §2145). In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). The instant 103 rejection takes into account only the teachings of Maruthachalam of anti-HER3 antibody-radionuclide conjugates for the treatment of cancer; the teachings of Maute of anti-CD47 in combination with anti-tumor target therapeutic antibodies; and the teachings of Song, Sandesh, and Willingham as preclinical and clinical benchmarks for dose finding of the combinations as described in the 103 rejection above.
In regard to the rejection of claims 30-32 and 34 over Maruthachalam in view of Maute, Mishra, and Willingham, Applicant traverses the rejection because Mishra and Willingham do not do cure the alleged deficiencies of Maruthachalam in view of Maute (Remarks p. 20). This is not persuasive for the reasons described above. Applicant argues that the rationale that an artisan would have substituted the patient population of prior teachings with HER3-expressing prostate cancer relies on impermissible hindsight reconstruction. This is not persuasive. As described in the 103 rejection above, the combination of treating HER3-positive prostate cancer is disclosed by Mishra; although it is disclosed among other cancers, it would have been obvious to use an anti-HER3 radioimmunotherapy as taught by Maruthachalam against HER3 positive cancers as described in the rejection above. Applicant states “Only Applicant’s own disclosure provides the linkage between HER3-directed radioimmunotherapy and CD47 blockade in the specific context of prostate cancer” (Remarks p. 21). This is not the standard by which obviousness is judged. MPEP §2144.06 states that combining equivalents known for the same purpose is prima facie obvious. As stated in the 103 rejection above, Maruthachalam is directed at treating HER3-positive cancers but does not disclose prostate cancer; Maute is directed at a combination treating with anti-CD47 and any anti-tumor targeting antibody; Mishra et. al. teaches that prostate cancer is a HER3-positive cancer; and Willingham teaches anti-CD47 blockade for prostate cancer. This combination would motivate a person of ordinary skill in the art, with a reasonable expectation of success, to apply the anti-HER3-radionuclide/anti-CD47 combination therapy of Maruthachalam in view of Maute to HER3-positive prostate cancer in order to benefit from a HER3 positive cancer treatment as taught by Maruthachalam and Mishra and to benefit from improved anti-cancer therapy with CD47 as taught by Maute and Willingham because a person of ordinary skill in the art would have a reasonable expectation that the two therapies useful for prostate cancer as taught by Mishra and Willingham would also be useful as a combination as in the modified therapy of Maruthachalam in view of Maute.
Applicant argues that Wang et. al. submitted concurrently with the IDS, demonstrates that CD47 is overexpressed in prostate cancer and that blocking CD47 with anti-CD47 promotes macrophage phagocytosis of cancer cells, and that therefore the claims represent a deliberate dual-mechanism therapeutic strategy. This is not persuasive. The Examiner notes that rationale to combine that is different from the Applicant’s is permissible (MPEP §2144.IV) and therefore a person of ordinary skill in the art need to have explicitly contemplated the particular anti-cancer mechanisms as recited by Applicant.
In regard to the rejection of claim 33 over Maruthachalam in view of Maute, Mishra, Willingham, Song, and Sandesh, Applicant argues that the combinations of Maruthachalam in view of Maute, Mishra, Willingham, Song, and Sandesh fail to establish a prima facie case of obviousness for the reasons described above (Remarks p. 21-22). This is not persuasive for the reasons described above.
Applicant argues that the further combination of all of these references in connection with claim 33 fares no better because “each of the references contributes nothing more than what it teaches individually” and none supplies the motivation to combine a 225-Ac labeled anti-HER3 antibody composition with CD47 blockade for the treatment of prostate cancer at RIT-characteristic dose ranges. This is not true as described in the 103 rejection and response to arguments above. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant further argues that Wang et. al. (2023), demonstrates that CD47 is overexpressed in prostate cancer and that blocking CD47 with anti-CD47 promotes macrophage phagocytosis of cancer cells, and that therefore the claims represent a deliberate dual-mechanism therapeutic strategy. This is not persuasive. The Examiner notes that rationale to combine that is different from the Applicant’s is permissible (MPEP §2144.IV) and therefore a person of ordinary skill in the art need to have explicitly contemplated the particular anti-cancer mechanisms as recited by Applicant. In addition, Wang et. al. is not commensurate in scope with the instant invention and is published later than the instant effective filing date; it does not provide any evidence therefore to the instant consideration of patentability.
In regards to the arguments about the non-statutory double patenting rejections, these are moot in view of the filed terminal disclaimers and the withdrawal of the rejections, above.
Conclusion
No claims are allowed.
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.
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/KATHLEEN CUNNINGCHEN/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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