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 .
DETAILED ACTION
Claims 1-2, 4-16, 32-35, 57, 60, 73-78, 80-100, 102-112, 128, 131-134, 137, and 150-161 are pending in the instant application and being examined on the merits.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/7/2026 has been entered.
Objections and Rejections Withdrawn
The previous rejection of claims 1-2, 4-16, 32-35, 57, 60, 73-78, 80-100, 102-112, 128, 131-134, 137, and 150-161 under 35 U.S.C. 103 is withdrawn to clarify reasons for increasing the dosage of a radioconjugate in humans from a xenograft mouse subject with prostate cancer.
The previous rejection under nonstatutory double patenting of 18/516,304 is withdrawn in view of copending application abandonment.
Claim Interpretation
Regarding instant claims 1 and 133, a “patient” is interpreted as a human patient as defined in the specification filed 10/23/2025 on page 10 lines 18-19, wherein the specification defines the term “patient” as used herein refers to a human.
Claim Objections
Claims 1-2, 4-16, 32-35, 57, 60, 73-78, 80-100, 102-112, 128, 131-134, 137, and 150-161 are objected to because of the following informalities: the abbreviation hK2 is not defined as human kallikrein 2 in the claim prior to introduction. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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 1-2, 4-16, 32-35, 57, 73-75, 133-134, and 150-156 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-2, 4-16, 32-35, 57, 73-75, 133-134, and 150-156 claim a method of treating cancer with a radioconjugate with binding specificity for hK2, but the cancer is not required to express the radioconjugate target hK2 or be prostate cancer. The specification does not teach an effective method of treatment of cancers are not prostate cancer or do not express hK2 and only prostate cancer is known to express hK2.
Scope of the claimed genus
A method of treating cancer in a patient is claims 1-2, 4-16, 32-35, 57, 73-75, 133-134, and 150-156 comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a radioconjugate and one or more pharmaceutically acceptable excipients, but the cancer is not required to express hK2.
Summary of Species disclosed in the original specification
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The instant specification taught 23 patients with metastatic castration-resistant prostate cancer (mCRPC) were dosed 225 Ac-DOTA-hl 1B6 across 4 radioactivity dose levels of 50, 100, 150 and 200 μCi in the 69086420PCR1001 study, the median number of doses received was 2 doses (range: 1 to 6), and the median treatment duration was 1.87 months (range: 1 to 10.8) (page 112, Interim Clinical Results). No dose-limiting toxicities (DLT) were reported at any of the 4 radioactivity dose levels. Signals of efficacy in these participants include, for example, PSA decreases of
50% or more from baseline in patients at radioactive doses greater than or equal to 100 µCi (page 112, Interim Clinical Results). Inclusion criteria for the patients included:
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(page 107). Expression of hK2 was not determined in the metastatic prostate cancer patients, but histological confirmation of mCRC was required. No non-prostate cancer patients were tested.
State of the Relevant Art
The prior art has taught that human kallikrein peptidase 2 (hK2) is a prostate specific enzyme whose expression is governed by the androgen receptor (AR) (McDevitt MR et al. (Nature Communications 2018 9 1629 1-11, reference of record) (“McDevitt 2018”), abstract). McDevitt 2018 taught the binding and internalization of the hK2 antibody hu11B6 has been engineered to perform several important tasks: 1) targeting and binding hK2, an epitope expressed exclusively on prostate tissue and cancer in vivo; 2) internalizing and transporting radionuclide cargo inside the cell to optimize the geometry of parent and progeny alpha decay (page 7, right column, last paragraph). McDevitt 2018 taught a method of effectively treating a subject with prostate cancer with a therapeutically effective amount of a pharmaceutical composition 225Ac-DOTA-hu11B6 was administered intravenously to the subject (Fig 1 and Fig 1 legend; and Fig. 3).
The Human Protein Atlas taught prostate cancers displayed moderate to strong cytoplasmic positivity of hK2, while all other cancer tissues were negative
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(The Human Protein Atlas, KLK2 2019 (https://web.archive.org/web/20190609141437/http://www.proteinatlas.org/ENSG00000167751-KLK2/pathology) page 2).
Thus, the prior art taught only prostate cancer expresses hK2 and hK2 is required for radioconjugate targeting.
Claims 1-2, 4-16, 32-35, 57, 73-75, 133-134, and 150-156 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for: 1) treating prostate cancer; does not reasonably provide enablement for: 1) treating non-prostate cancers. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
Claims 1-2, 4-16, 32-35, 57, 73-75, 133-134, and 150-156 claim a method of treating cancer with a radioconjugate with binding specificity for hK2, but the cancer is not required to express the radioconjugate target hK2 or be prostate cancer. The specification does not teach an effective method of treatment of cancers are not prostate cancer or do not express hK2 and only prostate cancer is known to express hK2. Only prostate cancer is known to express hK2.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These
factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(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.
Scope of the claimed genus and nature of the invention.
Methods of treating cancer in a patient are present in claims 1-2, 4-16, 32-35, 57, 73-75, 133-134, and 150-156 comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a radioconjugate and one or more pharmaceutically acceptable excipients, but the cancer is not required to express hK2 or be prostate cancer. Only prostate cancer is known to express hK2.
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure.
The instant specification taught 23 patients with metastatic castration-resistant prostate cancer (mCRPC) were dosed 225 Ac-DOTA-hl 1B6 across 4 radioactivity dose levels of 50, 100, 150 and 200 μCi in the 69086420PCR1001 study, the median number of doses received was 2 doses (range: 1 to 6), and the median treatment duration was 1.87 months (range: 1 to 10.8) (page 112, Interim Clinical Results). No dose-limiting toxicities (DLT) were reported at any of the 4 radioactivity dose levels. Signals of efficacy in these participants include, for example, PSA decreases of
50% or more from baseline in patients at radioactive doses greater than or equal to 100 µCi (page 112, Interim Clinical Results). Inclusion criteria for the patients included:
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(page 107). Expression of hK2 was not determined in the metastatic prostate cancer patients, but histological confirmation of mCRC was required. No non-prostate cancer patients were tested.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art.
The prior art has taught that human kallikrein peptidase 2 (hK2) is a prostate specific enzyme whose expression is governed by the androgen receptor (AR) (McDevitt MR et al. (Nature Communications 2018 9 1629 1-11, reference of record) (“McDevitt 2018”), abstract). McDevitt 2018 taught the binding and internalization of the hK2 antibody hu11B6 has been engineered to perform several important tasks: 1) targeting and binding hK2, an epitope expressed exclusively on prostate tissue and cancer in vivo; 2) internalizing and transporting radionuclide cargo inside the cell to optimize the geometry of parent and progeny alpha decay (page 7, right column, last paragraph). McDevitt 2018 taught a method of effectively treating a subject with prostate cancer with a therapeutically effective amount of a pharmaceutical composition 225Ac-DOTA-hu11B6 was administered intravenously to the subject (Fig 1 and Fig 1 legend; and Fig. 3).
The Human Protein Atlas taught prostate cancers displayed moderate to strong cytoplasmic positivity of hK2, while all other cancer tissues were negative
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(The Human Protein Atlas, KLK2 2019 (https://web.archive.org/web/20190609141437/http://www.proteinatlas.org/ENSG00000167751-KLK2/pathology) page 2).
Thus, the prior art taught only prostate cancer expresses hK2 and hK2 is required for radioconjugate targeting.
Claim Rejections – 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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 1-2, 4-14, 16, 32, 57, 60, 73, 76-78, 80-90, 92, 103-107, 109, 112, 133-134, 137, and 150-161 are rejected under 35 U.S.C. 103 as being unpatentable over McDevitt MR et al. (Nature Communications 2018 9 1629 1-11, reference of record) (“McDevitt 2018”) and Kratochwil C et al. (Journal of Nuclear Medicine December 2016, 57 (12) 1941-1944, reference of record) and evidenced by US 20190169312 (Timmermand POV et al. reference of record).
Regarding instant claims 1-2, 4-14, 60, 73, 76, 76-78, 80-90, 109, 133, 137, and 150-161, McDevitt 2018 taught a pharmaceutical composition of the radioimmunoconjugate 225Ac-hu11B6, wherein DOTA-chelated 225Ac is conjugated to the hK2 antibody hu11B6 (page 6, right column, last paragraph). Timmermand evidenced the humanized 11B6 antibody comprised a heavy chain of SEQ ID NO:12 and a light chain of SEQ ID NO:13 (page 20, paragraph 428) and binds to hK2 (page 3, paragraph 46). Regarding instant claims 1-2, 4-14, 60, 73, 76, 78, 80-90, 109, 133, 137, and 150-161, McDevitt 2018 taught a method of effectively treating a subject with prostate cancer with a therapeutically effective amount of a pharmaceutical composition 225Ac-DOTA-hu11B6 was administered intravenously to the subject at a dose of 0.3 µCi, but was not curative to all xenograft mouse subjects as indicated by the 50% survival rate (Fig 1 and Fig 1 legend; and Fig. 3). Regarding instant claim 16, McDevitt 2018 taught a single 11.1 kBq dose of [225Ac]hu11B6 is 300 nCi on 5 μg antibody (page 9, left column, Pharmacokinetic tissue distribution). McDevitt 2018 taught the purified radioimmunoconstruct was formulated in a solution of 1% human serum albumin and 0.9% sodium chloride (Normal Saline Solution) for intravenous injection (pages 9-10, bridging paragraph). McDevitt 2018 taught the untoward off-target salivary and kidney uptake of [225Ac]PSMA-617 may well limit the utility of this small molecule in treating prostate cancer as these healthy tissues also express PSMA (page 6, right column, Discussion, paragraph 1).
McDevitt 2018 did not teach: 1) treating a human patient; 2) dosing of a radiometal providing a targeted radioactivity of 50-350 µCi per dose; 3) wherein the dose is between 2-10 mg of antibody; 4) wherein the composition contains a pharmaceutically acceptable excipient of a radioprotectant, but this is obvious in view of Kratochwil.
Regarding instant claims 1, 10-14, 32, 57, 60, 73, 77, 86-90, 109, 134, 137, and 150-161, Kratochwil taught an effective method of treating human prostate cancer in humans wherein the pharmaceutical composition of 225Ac-PSMA-617 and the pharmaceutically acceptable excipient ascorbic acid was administered to human patients with prostate cancer, wherein 9-10 MBq was administered bimonthly to patient A (page 1942, right column, Clinical Course of Patient A, paragraph 1 and Fig. 1) and 6.4 MBq was administered bimonthly to patient B (pages 1942-1943, bridging paragraph and Fig. 3), wherein the treatment was effective at decreasing tumor growth. Regarding instant claims 150-152, Kratochwil taught the bimonthly administration was every 8 weeks in patient A (Fig. 2B) and patient B (Fig 4B), wherein administration of 3 doses was effective. Kratochwil taught both patients experienced a prostate specific antigen decline to below the measurable level and showed a complete response on imaging and no relevant hematologic toxicity was observed (abstract). Regarding instant claims 32 and 77, Kratochwil taught the pharmaceutically acceptable excipient ascorbic acid was added to a pharmaceutical composition of 225Ac-PSMA-617 to minimize radiolytic degradation of 225Ac-PSMA-617 (page 1942, right column, second column), wherein 225Ac is a radiometal bound to a DOTA chelator conjugated to a PSMA targeting molecule (page 1941, left column last paragraph; and page 1941, right column, second to last column).
Regarding instant claims 1-2, 4-14, 16, 32, 57, 60, 73, 76-78, 80-90, 92, 103-107, 109, 112, 133-134, 137, and 150-161, it would have been obvious for a person having ordinary skill in the art to take the method of McDevitt 2018 of:
effectively treating a subject with prostate cancer with a therapeutically effective amount of a pharmaceutical composition 225Ac-DOTA-hu11B6 in saline by administered intravenously to the subject at a dose of 0.3 µCi, wherein the treatment was not curative to all xenograft animals
– and using the teachings of Kratochwil to include in the method:
treating a human patient; 2) a bimonthly dosing of a radiometal providing a targeted radioactivity of 50-350 µCi per dose every 8 weeks for 3 doses for a human effective dose; 3) a dose between 2-10 mg of antibody; and 4) a pharmaceutically acceptable excipient of the radioprotectant ascorbic acid.
This is obvious because 0.3 µCi was not curative to all xenograft mouse subjects with prostate cancer so a higher dose would be expected to be required for a human effective dose and: 1)-2) Kratochwil taught an effective method of treating human prostate cancer in human patients wherein a pharmaceutical composition of 225Ac-DOTA-PSMA-617 and the pharmaceutically acceptable excipient ascorbic acid was administered to human patients with prostate cancer, wherein 9-10 MBq was administered bimonthly to patient A and 6.4 MBq was administered bimonthly to patient B, wherein treatment every 8 weeks for 3 doses was effective at decreasing prostate tumors. Thus, 6.4 to 10 MBq is an effective dose of a prostate cancer targeting agent conjugated to 225AC-DOTA. 3) McDevitt taught a single 11.1 kBq dose of [225Ac]hu11B6 is 300 nCi on 5 μg antibody. Thus, a 10 MBq dose would equate to about 270 µCi (10 MBq/11.1 kBq * 300 nCi) on about 5 mg of antibody (10 MBq/11.1 kBq * 5 µg antibody); and 4) Kratochwil taught the pharmaceutically acceptable excipient and radioprotectant ascorbic acid was added to a pharmaceutical composition of 225Ac-PSMA-617 to minimize radiolytic degradation of 225Ac-PSMA-617.
There is a reasonable expectation of success because: 1-2) humans administered 3 doses of 6.4 to 10 MBq bimonthly, every 8 weeks for 3 doses, of a prostate cancer targeting agent conjugated to 225AC-DOTA were effectively treated and decreased prostate tumors; 2-3) the effective dose of 10 MBq dose of 225Ac is about 270 µCi and would equate to about 5 mg of antibody; and 4) Kratochwil taught the pharmaceutically acceptable excipient and radioprotectant ascorbic acid was added to a pharmaceutical composition of 225Ac-PSMA-617 to minimize radiolytic degradation of 225Ac-PSMA-617. Further, McDevitt 2018 taught the untoward off-target salivary and kidney uptake of [225Ac]PSMA-617 may well limit the utility of the PSMA targeting small molecule in treating prostate cancer as these healthy tissues also express PSMA, so an hK2 targeting antibody would be preferred.
This would produce a method of effectively treating a human patient with prostate cancer (instant claim 60 and 137) by intravenously administering a single dose (instant claim 73) bimonthly of every 8 weeks (instant claim 150) three times for a total of 3 doses (instant claim 151), which is between once every 4-12 weeks (instant claim 57 and 134), with a therapeutically effective amount of a pharmaceutical composition formulated for intravenous administration (instant claim 109) comprising the radiometal conjugate 225Ac-DOTA-hu11B6, wherein 225Ac is a radiometal (instant claims 10-11 and 86-87), wherein 225Ac-DOTA is a radiometal chelator complex (instant claim 12-14, and 88-90), wherein the humanized 11B6 antibody specifically binds hK2 (instant claims 2 and 78) and is comprised of a heavy chain of SEQ ID NO:12 and a light chain of SEQ ID NO:13, which is identical to the claimed heavy chain of SEQ ID NO:12 and light chain of SEQ ID NO:13 (instant claims 4-5, 8-9, 80-81, 84-85, 154, 156, 158, and 160) and includes the heavy and light chain constant regions of instant SEQ ID NO:10 and 11, respectively (instant claims 6-7, 82-83, 153, 155, 157, and 159), and the pharmaceutically acceptable excipient radioprotectant of ascorbic acid (instant claims 32 and 77) in saline to the subject at a dose of about 270 µCi on about 5 mg of antibody (instant claims 16, 112, and 152), wherein the formulation comprising saline and ascorbic acid does not contain a preservative (instant claim 103); sucrose (instant claim 104); or monosaccharides, disaccharides, oligosaccharides or polysaccharides (instant claim 105-107) (instant claims 1, 76, 133, and 161).
Response to Arguments
Applicant does not agree with these rejections at least because the combination of the cited references does not teach or suggest each and every element of the claims and would not have led those of skill in the art to the methods and pharmaceutical compositions as claimed
The Office maintains that while "McDevitt 2018 did not teach: 1) treating a human
patient; 2) dosing of a radiometal providing a targeted radioactivity of 50-350 µCi per dose; 3) wherein the dose is between 2-10 mg of antibody; 4) wherein the composition contains a pharmaceutically acceptable excipient of a radioprotectant," these features are allegedly obvious in view of Kratochwil. (Action at p. 6). Allegedly, it would have been obvious for a person of ordinary skill in the art (POSITA) to modify McDevitt 2018's method by including in the method these missing features from Kratochwil. The Office again alleges that the motivation for this modification stems from the alleged lack of "curative" treatment in McDevitt 2018. (Action at p. 7).
Applicant argues claims 1-14, 16, 32, 57, 60, 73, 76-90, 92, 103-107, 109, 112, 133, 134, and 137 are not obvious over McDevitt 2018, Kratochwil, and Timmermand at least because there would have been no reason to modify McDevitt 2018 in view of Kratochwil
Applicant disagrees for at least the following reasons.
One of ordinary skill in the art would not have modified McDevitt 2018 to
arrive at the claimed targeted radioactivity
McDevitt's method is therapeutically effective with only a single
administration that delivers lower ionizing radiation than Kratochwill
According to the Office, the claimed method"[] is obvious because 0.3 μCi [of McDevitt 2018] was not curative to subjects with prostate cancer so a higher dose would be needed and: 1 )-2) Kratochwil taught an effective method of treating human prostate cancer patients wherein a pharmaceutical composition of 225Ac-DOTA-PSMA-617 ... was administered to human patients with prostate cancer, wherein 9-10 MBq was administered bimonthly to patient A and 6.4 MBq was administered bimonthly to patient B, wherein treatment every 8 weeks for 3 doses was effective at decreasing prostate tumors." (Action at p. 7). However, the Office provides no reasoning or evidence in support of its conclusion that a POSITA would consider McDevitt 2018's method to be "not curative." Indeed, as explained more fully below, McDevitt 2018 achieves the same therapeutic result as Kratochwil but with considerably less ionizing radiation.
Kratochwil discloses in the clinical course of patient A that PSMA-positive lesions in this patient visually disappeared after three cycles of bi-monthly treatments, each with an irradiating dose 1000x higher1 than what was used by McDevitt 2018:
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(Kratochwil at p. 1942, right column, under title "Clinical Course of Patient A").
Kratochwil also discloses in the clinical course of patient B that complete remission was achieved after three cycles of bi-monthly treatments:
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McDevitt 2018, discloses similar results with a single and considerably lower irradiating dose of 300 nCi:
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(McDevitt 2018 at p. 5, right column, first full paragraph, emphasis added).
Further, McDevitt 2018's treatment significantly increased the lifespan of tumor-bearing mice:
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While the Office points to McDevitt 2018's Fig. le with an observation that "50% of the animal subjects died. Thus, animals were not cured" (Action, at p. 15), McDevitt 2018 specifically states that half of the animals treated with [225 Ac]hu11B6 were alive and tumor-free at the end of the study, demonstrating a curative treatment with half of the treated animals. Moreover, the treated group showed a median survival over five times longer than that of the control group. It would be clear to POSITA that the two treatments with the two different therapeutic agents, at two different doses and frequencies, were about equal in efficacy, as they both achieved complete tumor regression and increase in life span. McDevitt 2018 achieved this effective treatment with a single irradiating dose that was about 1 000x lower than that used by Kratochwil. There simply would have been no reason for those of ordinary skill in the art to reach for the significantly higher radiation doses of Kratochwil to achieve the same result achieved by McDevitt 2018. In the absence of Applicant's disclosure, there would have been no reason for those of ordinary skill in the art to modify McDevitt 2018 as proposed by the Office to arrive at the claimed targeted radioactivity.
For at least these reasons, POSITA would have not modified the method of McDevitt 2018 in view of Kratochwil, and in the absence of Applicant's disclosure, would have not arrived at the methods as claimed.
McDevitt 2018, being aware of Kratochwil's disclosed treatment, chose a significantly lower dose to achieve similar therapeutic outcomes
Kratochwil's disclosure was fully available to McDevitt 2018, because Kratochwil was
published two years before McDevitt 2018. However, McDevitt 2018 does not utilize
Kratochwil' s dosing or administration frequency. Moreover, McDevitt 2018, citing Kratochwil as citation 15, specifically characterizes Kratochwil's method as "delivering extremely large doses of ionizing radiation over microscopic dimensions," and concludes that agents like 225 AcPSMA-617 used by Kratochwil at high doses may have off-target salivary and kidney uptake, which "may well limit the utility of this small molecule in treating prostate cancer as these healthy tissues also express PSMA." (McDevitt 2018, at p. 6, right column, under title "Discussion").
For this additional reason, McDevitt 2018 and Kratochwil would have provided no
reason for POSITA to have modified the method of McDevitt 2018 in view of Kratochwil, as proposed by the Office.
McDevitt 2018 provides an equally therapeutically effective method like that of Kratochwil with a significantly lower dose administered once by utilizing a therapy with a feed-forward mechanism
McDevitt 2018 demonstrates a therapeutically effective treatment that eliminates tumors
with a single dose of its radioimmunoconjugate - the radiolabeled antibody [225 Ac]hu11B6. The immunoconjugate eradicates disease and significantly prolongs survival in animal models because the DNA damage induced by the radioimmunoconjugate upregulates KLK2, which in turn increases prostate cancer targeting by the radiolabeled antibody [225 Ac ]hu11B6, thereby creating a unique feed-forward mechanism that increases the specific binding of the antibody of the radioimmunoconjugate to KLK2. (McDevitt 2018, Abstract and Figure 7). Even as tumors shrink, the immunoconjugate continues to accumulate at the site of the shrinking tumor:
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From this disclosure, POSITA would consider attempting a dose that is lower, not higher, than that disclosed by McDevitt 2018, given that the feed-forward mechanism concentrates and amplifies the ionizing radiation at the target site. For this additional reason, those of ordinary skill in the art would not have looked to Kratochwil for disclosure of a therapeutically effective dose.
Also, those of ordinary skill in the art would not consider these results "therapeutically effective ... but[] not curative," as alleged by the Office, because McDevitt 2018's radioimmunoconjugate eliminated tumors and prolongs survival of the treated animals only after a single administration with the feed-forward mechanism of its radioimmunoconjugate.
Further, McDevitt 2018 includes exclusively animal model data, which - regardless of any demonstrated efficacy - would not allow one of skill in the art to arrive at the claimed treatment dose in humans.
Moreover, even if one of ordinary skill in the art were to tum to Kratochwil for a curative dose, he or she would be required to increase Kratochwil's dose three or four times to achieve a curative effect with a single administration. This is because Kratochwil discloses that its dose of 6.4 MBq (about 173 μCi) or 9-10 MBq (about 243-270 μCi) of 225 Ac- PSMA-617 was not "curative" with a single administration and that three, or four, cycles, each delivering 6.4 MBq or 9-10 MBq radioactivity bimonthly, were needed to achieve a decrease in prostate tumors and remission. (Kratochwil, page 1942, right column, first paragraph under "Results," and page 1943, left column, first paragraph).
Per the Office's own rationale, those of ordinary skill in the art would have needed to modify McDevitt 2018's single dose of 0.3 μCi thousand fold and administer it three times or four times to be "curative." This modification would not have led those of ordinary skill in the art to the claimed methods and pharmaceutical compositions that recite "a targeted radioactivity from about 50 μCi to about 350 μCi per dose of the pharmaceutical composition at the time of dosing."
Thus, one of ordinary skill would not have been motivated to modify the dose of
McDevitt 2018 to arrive at the claimed targeted radioactivity. For this reason, Examiner has failed to establish a primafacie case of obviousness. It is well settled that the mere fact that the prior art could be modified as proposed by the Examiner is not sufficient to establish a prima facie case of obviousness. See In re Fritch, 972 F.2d 1260, 1266 (Fed. Cir. 1992) (There must be an explanation of why the prior art would have suggested to one of ordinary skill in the art the desirability of the modification). In the absence of Applicant's disclosure, there would have been no reason for those of ordinary skill in the art to modify McDevitt 2018 to arrive at the claimed
targeted radioactivity.
There would have been no reasonable expectation of success in modifying the dosage of McDevitt 2018 in view of Kratochwil
Even if POSITA looked to McDevitt 2018 and Kratochwil, there is nothing in the two references that would have pointed him or her toward the particular range of doses now claimed with any reasonable expectation of successfully treating a cancer in a patient with the immunoconjugate as claimed. There is no evidence of record indicating that he or she would have had a reasonable expectation of success in identifying a therapeutically effective dose for the immunoconjugate as claimed.
The in vivo efficacy testing in McDevitt 2018 clearly demonstrates that doses as low as 0.3 μCi are particularly effective because of the feed-forward mechanism of the
radioimmunotherapy associated with [225 Ac]hu11B6. This would not have suggested to those of ordinary skill in the art to increase McDevitt 2018's therapeutically effective dose 1000-fold and still retain an expectation that the subject would be treated without off-target side effects and toxicities, when McDevitt 2018 demonstrates that the [225 Ac]hul 1B6 can accumulate in spleen, liver, and saliva even at such low dose. (McDevitt 2018 at Figure 5). These results reveal what one of skill in the art would appreciate about radioimmunoconjugate dosing; namely, that selection of a therapeutically effective dose is uncertain and cannot be predicted a priori.
B. The radioconjugates of McDevitt 2018 and Kratochwil are not interchangeable
The Office considered Applicant's reply, but maintained that "McDevitt 2018 taught the untoward off-target salivary and kidney uptake of [225 Ac]PSMA-617 may well limit the utility of this small molecule in treating prostate cancer as these healthy tissues also express PSMA" and that "[t]hus, exchange of one the PSMA targeting moiety which is known to have off-target effects for another known effective targeting moiety of hu11B6 would be obvious with a reasonable expectation of success for a person having ordinary skill in the art." (Action at p. 20).
The Office's reasoning directly contradicts the Office's proposed modification of
McDevitt 2018 in view of Kratochwil. A POSITA would not have selected Kratochwil's high dose for "curing" prostate cancer because he or she would have viewed the high dose as contributing to the off-target salivary and kidney uptake of the immunoconjugate. McDevitt 2018's Figure 5 demonstrates off-target accumulation of the PET reporter for its immunoconjugate, reporting accumulation in salivary glands and liver, even when administered at McDevitt 2018's low dose. Given this accumulation in healthy tissues, and the feed-forward mechanism of radiation at the target site, POSITA would have been discouraged from increasing the dose used by McDevitt 2018.
For this additional reason, those of ordinary skill in the art would not have looked at
Kratochwil to modify the method of McDevitt 2018.
The radioconjugate of Kratochwil is substantially different from an
immunoconjugate
Even if one of ordinary skill in the art had been motivated to increase the claimed dose of McDevitt 2018, which Applicant denies, they would not have looked to Kratochwil to supply this missing feature.
Kratochwil was cited for its purported disclosure of 225 Ac- PSMA-617 a small molecule radioconjugate that targets prostate-specific membrane antigen (PSMA). Kratochwil does not disclose immunoconjugates, or radioimmunoconjugates, of any kind. Nor does Kratochwil disclose any conjugate that targets hK2. There is no evidence of record that one of ordinary skill in the art would consider the small molecule anti-PSMA radioconjugate of Kratochwil to be interchangeable with the anti-hK2 radioimmunoconjugate of McDevitt 2018. Certainly, there is no evidence that one of skill in the art would have applied the dose of Kratochwil to McDevitt 2018 with any reasonable expectation of success.
Moreover, because the McDevitt 2018 and Kratochwil references involve starkly
different compounds (i.e., an immunoconjugate versus a small molecule radioconjugate), one of skill in the art would not have considered combining the teachings of the two references, let alone selecting a dose from Kratochwil and applied to the compound of McDevitt 2018. It is only with the aid of Applicant's disclosure that the benefits of the claimed methods and compositions becomes apparent. As the Federal Circuit has stated, "[t]o draw on hindsight knowledge of the patented invention, when the prior art does not contain or suggest that knowledge, is to use the invention as a template for its own reconstruction-an illogical and inappropriate process by which to determine patentability." Sensonics, Inc. v. Aerosonic Corp., 81 F.3d 1566, 1570 (Fed. Cir. 1996). Here, the Office has cherry-picked two references to arrive at the claimed methods and compositions in the absence of a relevant teaching or suggestion in the cited references. This is improper hindsight.
As would be evident to one of ordinary skill in the art, dosing amounts and regimens are specific to individual therapeutic agents and cannot be blindly swapped, especially in the highly uncertain field of prostate cancer therapeutics. This is especially true for targeted therapeutic agents for which the optimal dose may vary based on the identity of the target and the targeting mechanism and composition of the therapeutic agent. Given that McDevitt 2018 and Kratochwil describe starkly different compounds, with substantially different mechanisms of action, POSITA would not have expected that the dose of Kratochwil would be in any way applicable to the treatment method of McDevitt 2018 or to the radioimmunoconjugate as claimed.
Applicant's method provides a safe and effective targeted treatment with radioactivity
The disclosures of McDevitt 2018 and Kratochwil are in stark contrast with Applicant's own disclosure of a safe and effective targeted radioactivity. Specifically, Example 6 of the application as filed contains interim clinical trial results in cancer patients: no dose-limiting toxicities (DLT) or on-treatment deaths were reported at any of the doses tested and no dose reductions were necessary. In addition, when 23 participants with metastatic castration-resistant prostate cancer (mCRPC) were treated with 225 Ac-DOTA-hl 1B6 at a dose of greater than or equal to 100 μCi, the levels of the prostate specific antigen (PSA) decreased by 50% or more from baseline. This improvement was an important indicator of anti-tumor activity of the tested radioconjugate. Table 3 of the application describes that the PSA response is an important endpoint for measuring anti tumor activity of the radioconjugate therapy (see Applicant, pages 106 and 107, and page 112, lines 17-19). Therefore, the PSA levels in the participants who received the radioconjugate improved, and the radioconjugate demonstrated an antitumor activity. Accordingly, the application demonstrates that methods and radioconjugates falling
within the scope of the claims provide important anti tumor activity.
Timmermand was cited for its purported disclosure of "the humanized l 1B6 antibody comprised a heavy chain of SEQ ID NO: 12 and a light chain of SEQ ID NO: 13 (page 20, paragraph 428) and binds to hK2 (page 3, paragraph 46)." (Action, at paragraph bridging pages 16 and 17). Timmermand does not cure the deficiencies of McDevitt 2018 and Kratochwil with respect to the methods and compositions as claimed. Therefore, there would have been no reason to modify McDevitt 2018 in view of Kratochwil and Timmermand specifically in a direction to arrive at the claimed methods and compositions.
In response, Applicant's arguments filed 7/7/2026 have been fully considered but they are not persuasive. As indicated in the obvious rational above, it would have been obvious for a person having ordinary skill in the art to take the method of McDevitt 2018 of: effectively treating a subject with prostate cancer with a therapeutically effective amount of a pharmaceutical composition 225Ac-DOTA-hu11B6 in saline by administered intravenously to the subject at a dose of 0.3 µCi, wherein the treatment was not curative to all xenograft animals
– and using the teachings of Kratochwil to include in the method:
treating a human patient; 2) a bimonthly dosing of a radiometal providing a targeted radioactivity of 50-350 µCi per dose every 8 weeks for 3 doses for a human effective dose; 3) a dose between 2-10 mg of antibody; and 4) a pharmaceutically acceptable excipient of the radioprotectant ascorbic acid.
This is obvious because 0.3 µCi was not curative to all xenograft mouse subjects with prostate cancer so a higher dose would be expected to be required for a human effective dose and: 1)-2) Kratochwil taught an effective method of treating human prostate cancer in human patients wherein a pharmaceutical composition of 225Ac-DOTA-PSMA-617 and the pharmaceutically acceptable excipient ascorbic acid was administered to human patients with prostate cancer, wherein 9-10 MBq was administered bimonthly to patient A and 6.4 MBq was administered bimonthly to patient B, wherein treatment every 8 weeks for 3 doses was effective at decreasing prostate tumors. Thus, 6.4 to 10 MBq is an effective dose of a prostate cancer targeting agent conjugated to 225AC-DOTA. 3) McDevitt taught a single 11.1 kBq dose of [225Ac]hu11B6 is 300 nCi on 5 μg antibody. Thus, a 10 MBq dose would equate to about 270 µCi (10 MBq/11.1 kBq * 300 nCi) on about 5 mg of antibody (10 MBq/11.1 kBq * 5 µg antibody); and 4) Kratochwil taught the pharmaceutically acceptable excipient and radioprotectant ascorbic acid was added to a pharmaceutical composition of 225Ac-PSMA-617 to minimize radiolytic degradation of 225Ac-PSMA-617.
Thus, the obvious rational indicates that 0.3 µCi was not curative to all xenograft animal subjects with prostate cancer, and Kratochwil taught 6.4 to 10 MBq is an effective dose of a prostate cancer targeting agent conjugated to 225AC-DOTA in humans. Using a radioactivity dose known to be effective in humans for the radioconjugate 225Ac-DOTA-hu11B6 which has been shown to effectively target hK2 expressing cancer cells is obvious with a reasonable expectation of success.
Regarding the Office provides no reasoning or evidence in support of its conclusion that a POSITA would consider McDevitt 2018's method to be "not curative”: As described above, McDevitt 2018 taught a method of effectively treating a subject with prostate cancer with a therapeutically effective amount of a pharmaceutical composition 225Ac-DOTA-hu11B6 was administered intravenously to the subject at a dose of 0.3 µCi, but was not curative to all xenograft mouse subjects as indicated by the 50% survival rate (Fig 1 and Fig 1 legend; and Fig. 3). McDevitt Fig. 1C shows that in animal subjects that 50% of the animal subjects died
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. Thus, not all animals were cured and identifying a human effective dose would be required. While McDevitt shows promising results with the radioconjugate, a person having ordinary skill in the art would look for a human effective dose for treating human. Thus, using radioactive doses of a radioconjugate in humans with known human effective doses is obvious with a reasonable expectation of success.
Regarding: i) McDevitt 2018 achieves the same therapeutic result as Kratochwil but with considerably less ionizing radiation; ii) McDevitt 2018 specifically states that half of the animals treated with [225 Ac]hu11B6 were alive and tumor-free at the end of the study with a median survival about 5 times longer; iii) It would be clear to POSITA that the two treatments with the two different therapeutic agents, at two different doses and frequencies, were about equal in efficacy, as they both achieved complete tumor regression and increase in life span; iv) McDevitt 2018 achieved this effective treatment with a single irradiating dose that was about 1000x lower than that used by Kratochwil:
McDevitt administers the radioconjugate to mice, while Kratochwil teaches administering a radioconjugate to humans. A person having ordinary skill in the art would obviously use a dose of a radioconjugate at doses that were known to be effective in humans. While McDevitt 2018 taught that the [225 Ac]hu11B6 effectively targeted cancer cells in human cancer xenografts in mice, exchange of the dose to a dose known to be effective in humans is obvious with a reasonable expectation of success. Thus, there is a valid reason for those of ordinary skill in the art to reach for the known human effective radiation doses of Kratochwil.
Regarding McDevitt 2018, citing Kratochwil as citation 15, specifically characterizes Kratochwil's method as "delivering extremely large doses of ionizing radiation over microscopic dimensions,":
Kratochwil states:
“Alpha particle drugs are now recognized as mainstream pharmacologic agents, delivering extremely large doses of ionizing radiation over microscopic dimensions corresponding to only a few cell diameters. FDA approval of XofigoTM ([223Ra]RaCl2), safe and effective pre- and clinical application of [213Bi]Lintuzumab and [225Ac]Lintuzumab, and compassionate use of [225Ac]PSMA-617 have all demonstrated potent bioactivity with an ability to provide tumor control in man. When an alpha particle emitting radionuclide accumulates at the sites of malignancy, they locally deposit a high absorbed dose to the tumor target cells; normal healthy tissue is largely spared unless the delivery vehicle accumulates there in addition to tumor.” (Kratochwil, page 6, right column, second paragraph)
Thus, the “extremely large doses of ionizing radiation” referenced by the Applicant is a mainstream pharmacologic agent that is beneficial as FDA approval of XofigoTM ([223Ra]RaCl2), safe and effective pre- and clinical application of [213Bi]Lintuzumab and [225Ac]Lintuzumab, and compassionate use of [225Ac]PSMA-617 have all demonstrated potent bioactivity with an ability to provide tumor control in man. Knowledge of the study of Kratochwil would not cause McDevitt to choose a human dose of [225Ac].
Regarding 225AcPSMA-617 used by Kratochwil at high doses may have off-target salivary and kidney uptake, which "may well limit the utility of this small molecule in treating prostate cancer as these healthy tissues also express PSMA." (McDevitt 2018, at p. 6, right column, under title "Discussion"), the obvious rational indicates that the radioconjugate 225Ac-DOTA-hu11B6 uses a hK2 antibody, not a PSMA antibody. Thus, the healthy tissues that express PSMA would not be anticipated to be affected by the radioconjugate.
Regarding the feedforward mechanism and amplification at the ionizing radiation at the target site, this feedforward mechanism would increase delivery of the radioconjugate to the tumor in comparison to healthy tissues over time and would provide a better therapeutic index, not worse, for higher doses of the 225Ac. As above, Kratochwil states,
“Alpha particle drugs are now recognized as mainstream pharmacologic agents, delivering extremely large doses of ionizing radiation over microscopic dimensions corresponding to only a few cell diameters. FDA approval of XofigoTM ([223Ra]RaCl2), safe and effective pre- and clinical application of [213Bi]Lintuzumab and [225Ac]Lintuzumab, and compassionate use of [225Ac]PSMA-617 have all demonstrated potent bioactivity with an ability to provide tumor control in man. When an alpha particle emitting radionuclide accumulates at the sites of malignancy, they locally deposit a high absorbed dose to the tumor target cells; normal healthy tissue is largely spared unless the delivery vehicle accumulates there in addition to tumor.” (Kratochwil, page 6, right column, second paragraph)
Thus, a person having ordinary skill in the art would consider a higher dose beneficial and multiple administrations would further promote tumor uptake.
Regarding those of ordinary skill in the art would not consider these results "therapeutically effective ... but[] not curative," and Kratochwil curative dose:
As indicated in the obvious rational above (emphasis added below), it would be obvious using the teachings of Kratochwil to include in the method:
treating a human patient; 2) a bimonthly dosing of a radiometal providing a targeted radioactivity of 50-350 µCi per dose every 8 weeks for 3 doses for a human effective dose; 3) a dose between 2-10 mg of antibody; and 4) a pharmaceutically acceptable excipient of the radioprotectant ascorbic acid.
This is obvious because 0.3 µCi was not curative to all xenograft mouse subjects with prostate cancer so a higher dose would be expected to be required for a human effective dose: 1)-2) Kratochwil taught an effective method of treating human prostate cancer in human patients wherein a pharmaceutical composition of 225Ac-DOTA-PSMA-617 and the pharmaceutically acceptable excipient ascorbic acid was administered to human patients with prostate cancer, wherein 9-10 MBq was administered bimonthly to patient A and 6.4 MBq was administered bimonthly to patient B, wherein treatment every 8 weeks for 3 doses was effective at decreasing prostate tumors. Thus, 6.4 to 10 MBq is an effective dose of a prostate cancer targeting agent conjugated to 225AC-DOTA. 3) McDevitt taught a single 11.1 kBq dose of [225Ac]hu11B6 is 300 nCi on 5 μg antibody. Thus, a 10 MBq dose would equate to about 270 µCi (10 MBq/11.1 kBq * 300 nCi) on about 5 mg of antibody (10 MBq/11.1 kBq * 5 µg antibody); and 4) Kratochwil taught the pharmaceutically acceptable excipient and radioprotectant ascorbic acid was added to a pharmaceutical composition of 225Ac-PSMA-617 to minimize radiolytic degradation of 225Ac-PSMA-617.
Identifying a human effective dose of McDevitt would not require 3-4 times the dose Kratochwil. The dose of Kratochwil was known to be effective and the obvious rational does not suggest a curative dose is required for the method. Because all mice were not cured by the radioconjugate of McDevitt 2018 and the subjects are mice not humans, a person having ordinary skill in the art would look for a human effective dose.
Regarding a reasonable expectation of success of the dose range, the obvious rational above states, There is a reasonable expectation of success because: 1-2) humans administered 3 doses of 6.4 to 10 MBq bimonthly, every 8 weeks for 3 doses, of a prostate cancer targeting agent conjugated to 225AC-DOTA were effectively treated and decreased prostate tumors; 2-3) the effective dose of 10 MBq dose of 225Ac is about 270 µCi and would equate to about 5 mg of antibody; and 4) Kratochwil taught the pharmaceutically acceptable excipient and radioprotectant ascorbic acid was added to a pharmaceutical composition of 225Ac-PSMA-617 to minimize radiolytic degradation of 225Ac-PSMA-617. Further, McDevitt 2018 taught the untoward off-target salivary and kidney uptake of [225Ac]PSMA-617 may well limit the utility of the PSMA targeting small molecule in treating prostate cancer as these healthy tissues also express PSMA, so an hK2 targeting antibody would be preferred.
Further, the feedforward mechanism would provide more target for the radioconjugate in the tumor cells. Thus, the known human effective dose of a 225AC-DOTA radioconjugate has a reasonable expectation of success for 225Ac-DOTA-hu11B6.
Regarding radioconjugates of McDevitt 2018 and Kratochwil are not interchangeable and off-target accumulation, the known human effective dose of a 225AC-DOTA radioconjugate has a reasonable expectation of success for 225Ac-DOTA-hu11B6 in a human. Further, exchange of the PSMA target would change PSMA off-target issues. The feedforward mechanism would further promote tumor targeting.
McDevitt 2018 taught the 225Ac-DOTA-hu11B6 was specific and effectively targeted the tumor tissue in comparison to healthy tissue. McDevitt 2018 taught: i) hu11B6 demonstrates exquisite targeting specificity for KLK2 (abstract); ii) the increased uptake in VCaP tumor permitted greater clearance from blood compared to LNCaP-AR disease (mean 1.7 ± 0.54 %IA/g vs. 12.0 ± 1.2 %IA/g, respectively at 15 days), wherein the distribution of [225Ac]hu11B6 to other organs was minimal (approximately 11 %IA/g or less) and nonspecific as compared to an isotype matched human IgG control (page 3, left column, second paragraph); and iii) the specific localization of [225Ac]hu11B6 to the targeted lobes of prostate with disease ensures that the absorbed dose from the short range alpha particles is deposited locally at sites of carcinoma, and not to healthy surrounding tissue (pages4-5, bridging paragraph). Thus, the dose of Kratochwil would be expected to be effective for the radioconjugate.
Regarding the radioconjugate of Kratochwil is substantially different from an
Immunoconjugate, the known human effective dose of a 225AC-DOTA radioconjugate that targets prostate cancer by Kratochwil would be obvious with a reasonable expectation of success for the radioconjugate 225Ac-DOTA-hu11B6 which targets prostate cancer. The radioconjugates are not starkly different to a level that the human effective dose of one radioconjugate can’t be used for another radioconjugate.
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).
Regarding Applicant's method provides a safe and effective targeted treatment with radioactivity, the obvious rational above indicates the obviousness and reasonable expectation of success of the method of McDevitt 2018 modified by Kratochwil and evidenced by Timmermand for the claims.
Regarding Timmermand, Timmermand was relied upon to evidence the humanized 11B6 antibody comprised a heavy chain of SEQ ID NO:12 and a light chain of SEQ ID NO:13 (page 20, paragraph 428) and binds to hK2 (page 3, paragraph 46).
Claims 1-2, 4-14, 16, 32, 57, 60, 73, 76-78, 80-90, 92, 97, 102-107, 109, 112, 128, 133-134, 137, and 150-161 are rejected under 35 U.S.C. 103 as being unpatentable over McDevitt MR et al. (Nature Communications 2018 9 1629 1-11, reference of record) (“McDevitt 2018”) and Kratochwil C et al. (Journal of Nuclear Medicine December 2016, 57 (12) 1941-1944, reference of record) as applied to claims 1-2, 4-14, 16, 32, 57, 60, 73, 76-78, 80-90, 92, 103-107, 109, 112, 133-134, 137, and 150-161 above, and further in view of US 20190169312 (Timmermand POV et al. reference of record).
McDevitt 2018 and Kratochwil are described above.
McDevitt 2018 is silent to: 1) a pharmaceutical composition comprising a radioconjugate of 0.1 to 1.0 mg/ml, but this is obvious in view of Timmermand.
Regarding instant claim 128, Timmermand taught stocks of h11B6 conjugated to the chelating agent DTPA in 0.2M Na-acetate pH 5.5 with a protein concentration of 0.9 mg/ml (page 15, paragraph 287) and that the samples were stored in this buffer frozen at -20C. Timmermand taught 177-Lu-DTPA-h11B6 was effective at treating subjects with prostate cancer in vivo (Fig 14).
Regarding instant claims 97, 102, and 128, it would have been obvious for a person having ordinary skill in the art to take the method of McDevitt 2018 and Kratochwil above
– and: 1) exchange the saline for 0.2 M Na-acetate pH 5.5; and 2) include the antibody concentration as about 1 mg/ml as taught by Timmermand.
This is obvious because: 1) 0.2 M Na-acetate pH 5.5 was used as a stock buffer for a h11B6 conjugated chelating agent; and 2) about 1 mg/ml was used as a stock buffer concentration for h11B6.
There is a reasonable expectation of success because: 1) and 2) the h11B6 conjugated to a chelating agent was stored in this buffer with this protein concentration and effectively used in cancer treatment.
This would produce a method of effectively treating a human patient with prostate cancer by intravenously administering a single dose bimonthly with a therapeutically effective amount of a pharmaceutical composition formulated for intravenous administration comprising the radiometal conjugate 225Ac-DOTA-hu11B6, wherein the humanized 11B6 antibody specifically binds hK2 and the pharmaceutically acceptable excipient radioprotectant of ascorbic acid in 0.2 M Na-acetate pH 5.5 (instant claims 97 and 102) to the subject at a dose of about 270 µCi on about 5 mg of antibody, wherein the antibody concentration is 1 mg/ml (instant claim 128).
Response to Arguments
Applicant argues the disclosure in Timmermand does not cure the deficiencies of McDevitt 2018, Kratochwil, and Timmermand with respect to the pharmaceutical composition of claim 76, as discussed above. There would have simply been no reason to modify the composition of McDevitt 2018 in view of Kratochwil and Timmermand. For at least this reason, claims 1, 2, 4-14, 16, 32, 57, 60, 73, 76-90, 92, 97, 102-107, 109, 112, 128, 133, 134, 137, and 150-161 are not obvious over McDevitt 2018, Kratochwil, and Timmermand.
In response, Applicant's arguments filed 7/7/2026 have been fully considered but they are not persuasive. The obvious rational is above. The discussion regarding instant claim 76 and the modification of the method and composition of McDevitt 2018 and Kratochwil is above.
Claims 1-2, 4-14, 16, 32-35, 57, 60, 73, 76-78, 80-90, 92-94, 103-107, 109, 112, 133-134, 137, and 150-161 are rejected under 35 U.S.C. 103 as being unpatentable over McDevitt MR et al. (Nature Communications 2018 9 1629 1-11, reference of record)(“McDevitt 2018”) and Kratochwil C et al. (Journal of Nuclear Medicine December 2016, 57 (12) 1941-1944, reference of record) as applied to claims 1-2, 4-14, 16, 32, 57, 60, 73, 76-78, 80-90, 92, 103-107, 109, 112, 133-134, 137, and 150-161 above, and further in view of Liu S et al. (Bioconjugate Chemistry 2001 12(4) 554-558, reference of record).
McDevitt 2018 and Kratochwil are described above.
McDevitt 2018 is silent to: 1) a pharmaceutical composition comprising a radioconjugate with ascorbic acid and gentisic acid, but this is obvious in view of Liu.
Regarding instant claims 33-35 and 92-94, Liu taught radical scavengers such as human serum albumin, gentisic acid, and ascorbic acid have been used as stabilizers for the radiolabeled antibodies (page 554, left to right column bridging paragraph). Liu taught a composition comprising radiometal labeled DOTA-peptide conjugate RP697 and the radioprotective radical scavengers gentisic acid and ascorbic acid were used in combination to effectively prevent the radiolytic decomposition of RP697(abstract). Liu taught ascorbic acid and gentisic acid were chosen because they have been approved for pharmaceutical or radiopharmaceutical applications previously (page 554, right column, second paragraph). Liu taught the sodium salt of ascorbic acid and gentisic acid were used (pages 554-555, bridging paragraph). Liu taught radiolysis is caused by the formation of free radicals, wherein free radicals are very reactive toward organic molecules such as peptides (page 556, right column, third paragraph). Liu taught to prevent radiolysis and stabilize the radiolabeled biomolecule, a radical scavenger or radiolytic stabilizer is often used either during or after the radiolabeling (page 556, right column, third paragraph).
Regarding instant claims 33-35 and 92-94, it would have been obvious for a person having ordinary skill in the art to take the method of McDevitt 2018 and Kratochwil above – and include in the composition of the method: 1) the sodium salt of ascorbic acid; and 2) gentisic acid as taught by Liu.
This is obvious because: 1) and 2) Liu taught radical scavengers such as gentisic acid and the sodium salt of ascorbic acid have been used as stabilizers for the radiolabeled antibodies and were effective.
There is a reasonable expectation of success because: 1) and 2) ascorbic acid and gentisic acid were chosen because they have been approved for pharmaceutical or radiopharmaceutical applications previously and were effective at preventing radiolytic decomposition. Further, radiolysis caused by the formation of free radicals are very reactive toward organic molecules such as peptides and to prevent radiolysis and stabilize the radiolabeled biomolecule, a radical scavenger or radiolytic stabilizer is often used either during or after the radiolabeling.
This would produce a method of effectively treating a human patient with prostate cancer by intravenously administering a single dose bimonthly with a therapeutically effective amount of a pharmaceutical composition formulated for intravenous administration comprising the radiometal conjugate 225Ac-DOTA-hu11B6, wherein the humanized 11B6 antibody specifically binds hK2 and the pharmaceutically acceptable excipient radioprotectant of the sodium salt of ascorbic acid (instant claims 33-34 and 92-93) and gentisic acid (instant claims 35 and 94) in saline to the subject at a dose of about 270 µCi on about 5 mg of antibody.
Response to Arguments
Applicant argues the disclosure in Liu does not cure the deficiencies of McDevitt 2018 and Kratochwil with respect to pharmaceutical composition of claim 76 discussed above. For at least this reason, claims 1, 2, 4-14, 16, 32-35, 57, 60, 73, 76-90, 92-94, 103-107, 109, 112, 133, 134, 137, and 150-161 are not obvious over McDevitt 2018, Kratochwil, and Liu.
In response, Applicant's arguments filed 7/7/2026 have been fully considered but they are not persuasive. The obvious rational is above. The discussion regarding instant claim 76 and the modification of the method and composition of McDevitt 2018 and Kratochwil is above.
Claims 1-2, 4-14, 16, 32, 57, 60, 73-78, 80-90, 92, 103-107, 109, 112, 133-134, 137, and 150-161 are rejected under 35 U.S.C. 103 as being unpatentable over McDevitt MR et al. (Nature Communications 2018 9 1629 1-11, reference of record)(“McDevitt 2018”) and Kratochwil C et al. (Journal of Nuclear Medicine December 2016, 57 (12) 1941-1944, reference of record) as applied to claims 1-2, 4-14, 16, 32, 57, 60, 73, 76-78, 80-90, 92, 103-107, 109, 112, 133-134, 137, and 150-161 above, and further in view of DeNardo GL et al. (Cancer 2002 94(4 Suppl):1332-48, reference of record).
McDevitt 2018 and Kratochwil are described above.
McDevitt 2018 is silent to: 1) administering two sub-doses, but this is obvious in view of DeNardo.
Regarding instant claims 74-75, DeNardo taught a two sub-dose fractionation of a radiolabeled antibody was more effective than a single dose for: 1) decreasing tumors and death (Fig. 4) and decreasing toxicity (Fig 7). DeNardo taught fractionation is a strategy for overcoming heterogeneity of monoclonal antibody distribution in the tumor and the consequent nonuniformity of tumor radiation doses (abstract). DeNardo taught advantages of fractionated radioimmunotherapy are the ability to 1) provide patient-specific radionuclide and radiation dosing, 2) control toxicity by titration of the individual patient, 3) reduce toxicity, 4) increase the maximum tolerated dose (MTD) for many patients, 5) increase tumor radiation dose and efficacy, and 6) prolong tumor response by permitting treatment over time (abstract).
Regarding instant claims 74-75, it would have been obvious for a person having ordinary skill in the art to take the method of McDevitt 2018 and Kratochwil above
– and: 1) include administering two sub-doses au taught by DeNardo.
This is obvious with a reasonable expectation of success because: 1) DeNardo taught a two sub-dose fractionation of a radiolabeled antibody was more effective than a single dose for: 1) decreasing tumors and death and decreasing toxicity. Further, fractionated radioimmunotherapy 1) provides patient-specific radionuclide and radiation dosing, 2) controls toxicity by titration of the individual patient, 3) reduces toxicity, 4) increases the maximum tolerated dose (MTD) for many patients, 5) increases tumor radiation dose and efficacy, and 6) prolongs tumor response by permitting treatment over time
This would produce a method of effectively treating a human patient with prostate cancer by intravenously administering two sub-doses (instant claims 74-75) bimonthly with a therapeutically effective amount of a pharmaceutical composition formulated for intravenous administration comprising the radiometal conjugate 225Ac-DOTA-hu11B6, wherein the humanized 11B6 antibody specifically binds hK2 and the pharmaceutically acceptable excipient radioprotectant of ascorbic acid in saline to the subject at a dose of about 270 µCi on about 5 mg of antibody.
Response to Arguments
Applicant argues the disclosure in DeNardo does not cure the deficiencies of McDevitt 2018 and Kratochwil with respect to method of claim 1 discussed above. For at least this reason, claims 1-2, 4-14, 16, 32, 57, 60, 73-78, 80-90, 92, 103-107, 109, 112, 133-134, 137, and 150-161 are not obvious over McDevitt 2018, Kratochwil, and DeNardo.
In response, Applicant's arguments filed 7/7/2026 have been fully considered but they are not persuasive. The obvious rational is above. The discussion regarding instant claim 1 and the modification of the method and composition of McDevitt 2018 and Kratochwil is above.
Claims 1-2, 4-14, 16, 32, 57, 60, 73, 76-78, 80-90, 92, 97, 102-107, 109, 111-112, 128, 131-134, 137, and 150-161 are rejected under 35 U.S.C. 103 as being unpatentable over McDevitt MR et al. (Nature Communications 2018 9 1629 1-11, reference of record)(“McDevitt 2018”), Kratochwil C et al. (Journal of Nuclear Medicine December 2016, 57 (12) 1941-1944, reference of record), and US 20190169312 (Timmermand POV et al. reference of record) as applied to claims 1-2, 4-14, 16, 32, 57, 60, 73, 76-78, 80-90, 92, 97, 102-107, 109, 112, 128, 133-134, 137, and 150-161 above, and further in view of Thiele NA et al. (Angew. Chem. Int. Ed. 2017, 56, 14712 –14717 IDS reference), McDevitt ME et al. (Applied Radiation and Isotopes 2002 57(6) 841-847, reference of record) (“McDevitt 2002”), and Vivier D et al. (J Labelled Comp Radiopharm. 2018 July ; 61(9): 672–692, reference of record).
McDevitt 2018, Kratochwil, and Timmermand are described above.
McDevitt 2018 taught the [225Ac]hu11B6 drug is readily synthesized by the attachment of DOTA-chelated 225Ac and purified in a procedure developed to prepare clinical doses of [225Ac]Lintuzumab and referenced McDevitt 2002.
McDevitt 2018 is silent to: 1) the number of chelator molecules conjugated to the antibody; 2) the composition further comprising non-radiolabeled antibody; and 3) the total amount of the conjugated antibody and non-conjugated antibody not exceeding 10 mg, but this is obvious in view of McDevitt 2002, Thiele, and Vivier.
Regarding instant claims 131-132, McDevitt 2002 taught a two-step synthetic process method to prepare [225Ac]–DOTA–IgG constructs, wherein 225Ac is first chelated to DOTA followed by conjugation to an antibody (abstract). McDevitt 2002 taught 5.4 DOTA were chelated per antibody (page 845, right column, last paragraph). McDevitt 2002 taught radiochemical conjugation yields were low and the final drug had about 1 in 775 IgG molecules that were 225Ac radiolabeled (pages 845-846, right column, last paragraph to next page). McDevitt 2002 taught radiochemical yields of about 10% (Table 1). Thus, using the method of McDevitt 2002 to prepare [225Ac]–DOTA conjugated antibodies would include in the composition non-radiolabeled antibodies. McDevitt 2002 taught because of the extraordinary potency of 225Ac, this methodology has been sufficient to yield enough drug for extensive preclinical therapeutic studies in vivo involving dozens of mice per experiment, toxicology studies in 5 kg primates, and potentially for human clinical trials (pages 845-846, right column, last paragraph to next page). McDevitt 2002 taught therefore, other than for economic considerations, increasing yields may not be essential (pages 845-846, right column, last paragraph to next page).
Regarding instant claim 111, Thiele taught chelation of 225Ac to the current gold standard, DOTA and macropa, wherein the ligands were incubated with 225Ac in an acetate buffer at pH 5.5–6 and macropa complexed all the 225Ac after merely 5 minutes at room temperature, whereas DOTA only complexed 10% under these conditions (page 14713-14714, last paragraph right column to next page, bridging paragraph).
Regarding instant claim 111, Thiele taught conjugation of the HER2 cancer targeting antibody trastuzumab to determine the average number of ligands per antibody, which was about 2 ligands per antibody for macropa and about 4 for DOTA (page 14715, left column, second paragraph).
Regarding instant claims 131-132, Vivier taught preclinical studies have shown that antibodies with moderate binding affinity for the tumor target were able to achieve higher tumor uptake than counterparts with high affinity for the same target (page 4 paragraph 2). Regarding instant claims 131-132, Vivier taught however, since lowering the binding affinity of the antibody can compromise its specificity for binding to the target, it has been proposed that the binding site barrier may also be overcome by increasing the dose of unlabeled antibody (page 4 paragraph 2). Regarding instant claims 131-132, Vivier taught doing so would facilitate the saturation of the target in the perivascular space of the tumor while allowing the radiolabeled antibody to extravasate further and achieve better tumor penetration (page 4 paragraph 2).
Regarding instant claims 111 and 131-132, it would have been obvious for a person having ordinary skill in the art to take the method of McDevitt 2018, Kratochwil, and Timmermand above – and: 1) prepare the 225Ac-DOTA-hu11B6 using the method of McDevitt 2002, which be expected to yield a composition with non-radiolabeled antibody in the human scaled dose of 5 mg total antibody used in the method above; and 2) use a DOTA chelator to antibody ratio of about 4 as described by Thiele.
This is obvious because McDevitt 2018 taught the [225Ac]hu11B6 drug is readily synthesized by the attachment of DOTA-chelated 225Ac and purified in a procedure developed to prepare clinical doses of [225Ac]Lintuzumab and referenced McDevitt 2002 and: 1) preparation of the 225Ac-DOTA-hu11B6 using the method of McDevitt 2002, which be expected to yield a composition with non-radiolabeled antibody in the human scaled dose of 5 mg total antibody used in the method above; and 2) Thiele taught a conjugation of DOTA to antibody ratio of 4. Further, the unlabeled antibody would be beneficial wherein saturation of the target in the perivascular space of the tumor would allow the radiolabeled antibody to extravasate further and achieve better tumor penetration and treatment as taught by Vivier
There is a reasonable expectation of success because: 1) synthesis of 225Ac-DOTA-hu11B6 includes non-radiolabeled hu11B6 antibody in the mixture and was shown to be effective by McDevitt 2018 and the human dose would be about 5 mg; and 2) Thiele taught chelation of 225Ac to the current gold standard, DOTA in an acetate buffer at pH 5.5–6 using a DOTA to antibody ratio of 4 produced the antibody at about 10%, which is similar to McDevitt 2002. Thus the effectiveness of the antibody would be expected to be the same. Further, the unlabeled antibody would be beneficial wherein saturation of the target in the perivascular space of the tumor would allow the radiolabeled antibody to extravasate further and achieve better tumor penetration and treatment as taught by Vivier
This would produce a method of effectively treating a human patient with prostate cancer by intravenously administering a dose bimonthly with a therapeutically effective amount of a pharmaceutical composition formulated for intravenous administration comprising the radiometal conjugate 225Ac-DOTA-hu11B6, wherein the humanized 11B6 antibody specifically binds hK2 and the pharmaceutically acceptable excipient radioprotectant of ascorbic acid in 0.2 M Na-acetate pH 5.5 to the subject at a dose of about 270 µCi on about 5 mg of antibody, wherein the antibody concentration is about 1 mg/ml, wherein the number of chelator molecules conjugated to the antibody is 1 to about 4 (instant claim 111), wherein the composition further comprises non-radiolabeled antibody (instant claim 131 ), and wherein the total amount of the conjugated antibody and non-conjugated antibody does not exceed 10 mg because the non-labeled antibody is within the 5 mg dose (instant claim 132).
Response to Arguments
Applicant argues the disclosures in Thiele, McDevitt 2002, and Vivier do not cure the deficiencies of McDevitt 2018, Kratochwil, and Timmermand with respect to the composition of claim 76 and 77 discussed above. For at least this reason, claims 1-2, 4-14, 16, 32, 57, 60, 73, 76-78, 80-90, 92, 97, 102-107, 109, 111-112, 128, 131-134, 137, and 150-161 are not obvious over McDevitt 2018, Kratochwil, Timmermand, Thiele, McDevitt 2002, and Vivier.
In response, Applicant's arguments filed 7/7/2026 have been fully considered but they are not persuasive. The obvious rational is above. The discussion regarding instant claims 76-77 and the modification of the method and composition of McDevitt 2018 and Kratochwil is above.
Claims 1-2, 4-14, 16, 32, 57, 60, 73, 76-78, 80-90, 92, 95-100, 102-112, 128, 131-134, 137, and 150-161 are rejected under 35 U.S.C. 103 as being unpatentable over McDevitt MR et al. (Nature Communications 2018 9 1629 1-11, reference of record)(“McDevitt 2018”), Kratochwil C et al. (Journal of Nuclear Medicine December 2016, 57 (12) 1941-1944, reference of record), US 20190169312 (Timmermand POV et al. reference of record), Thiele NA et al. (Angew. Chem. Int. Ed. 2017, 56, 14712 –14717, reference of record), McDevitt ME et al. (Applied Radiation and Isotopes 2002 57(6) 841-847, reference of record) (“McDevitt 2002”), and Vivier D et al. (J Labelled Comp Radiopharm. 2018 July ; 61(9): 672–692, reference of record) as applied to claims 1-2, 4-14, 16, 32, 57, 60, 73, 76-78, 80-90, 92, 97, 102-107, 109, 111-112, 128, 131-134, 137, and 150-161 above, and further in view of McDevitt MR et al. (Journal of Nuclear Medicine 40 1999 (10) 1722-1727, reference of record) (“McDevitt 1999”) , Liu S et al. (Bioconjugate Chemistry 2001 12(4) 554-558, reference of record), Warne NW et al. (European Journal of Pharmaceutics and Biopharmaceutics 2011 78(2) 208-212, reference of record), and Kang J et al. (BioProcess International 2016 14(4) 40-45, reference of record).
McDevitt 2018, Kratochwil, Timmermand, McDevitt 2002, and Thiele are described above.
McDevitt 2018 is silent to: 1) a concentration of 0.5% of ascorbic acid; 2) the sodium salt of ascorbic acid being used; 3) polysorbate 20 in the formulation, but this is obvious in view of McDevitt 1999, Liu, Warne, and Kang.
McDevitt 1999 taught the addition of about 5/L ascorbic acid, which is about 0.5% to the reaction mixture prevented significant loss of radiolabeled antibody during the purification (page 1724, right column, last paragraph). McDevitt 1999 taught radioprotection agents such as l-ascorbic acid were found to be essential in the reproducible production and recovery of immunoreactive (213Bi)CHX-A-DTPA-HuM195 (page 1725, right column, last paragraph). McDevitt 1999 taught in the absence of a radioprotecting agent, losses during purification were high and varied widely, presumably due to protein denaturation in the radiation field generated by the high activity levels of 213B (page 1725, right column, last paragraph).
Liu taught radical scavengers such as ascorbic acid have been used as stabilizers for the radiolabeled antibodies (page 554, left to right column bridging paragraph). Liu taught ascorbic acid has been approved for pharmaceutical use previously (page 554, right column, second paragraph). Liu taught using the sodium salt of ascorbic acid for radiolabeled monoclonal antibodies (pages 554-555, bridging paragraph).
Warne taught based on the commercial experience formulation scientists who developed the previous commercial antibodies, the simple recommendation would be to include some level of polysorbate in the formulation at a concentration suitable to that required by the protein concentration (page 209, paragraph right column, second to last paragraph). Warne taught the decision is no longer whether to include a surfactant in the formulation, but rather to ask how much to include based on its intended purpose such as protection from mechanical agitation (page 209, paragraph right column, second to last paragraph). Warne taught a method for identification of the level of polysorbate, wherein a simple titration of polysorbate-20 or polysorbate 80 is used in a range from 0.005% to 0.2% when suitably stressed to provide a rationale for selection of an appropriate concentration (page 210, left column, last two sentences to right column first two sentences).
Kang taught by studying commercial antibody products, they established a rich database for successful antibody formulations (page 40, middle column, second paragraph). Kang taught although every antibody is unique, the molecules are highly similar structurally (page 40, middle column, second paragraph). Kang taught lessons learned from successful examples are invaluable in developing stable and effective formulations for new antibody formulations (page 40, middle column, second paragraph). Kang taught Table 1 lists excipients used in commercial antibody formulations. Kang taught acetate as a commonly used buffer (page 40, middle column, second bullet) and 80% of formulations used one of three surfactants that includes polysorbate 20 (page 40, middle column, third bullet). Kang taught formulation development wherein stage one identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients (page 42, left column last paragraph to right column, third bullet). Kang taught in just a few weeks, researchers can develop a stable formulation for antibody product development (page 45, left column, second paragraph). Kang taught a range of buffer concentrations are tested to develop the formulation wherein 10-50 mM is tested (Figure 5).
Regarding instant claims 95-96, 98-100, 108, and 110, it would have been obvious for a person having ordinary skill in the art to take the method of McDevitt 2018, Kratochwil, Timmermand, Thiele, McDevitt 2002 above – and: 1) use a concentration of 0.5% of ascorbic acid as taught by McDevitt 1999; 2) use the sodium salt of ascorbic acid as taught by Liu; and 3) use polysorbate 20 or polysorbate 80 in the formulation; and 4) titrate the acetate buffer, polysorbate 20, and polysorbate 80 for an appropriate formulation as taught by Kang.
This is obvious because:
1) McDevitt 1999 taught the addition of about 0.5% ascorbic acid prevented significant loss of radiolabeled antibody during the purification and that radioprotection agents such as l-ascorbic acid were found to be essential in the reproducible production and recovery of an immunoreactive radiotherapeutic;
2) Liu taught ascorbic acid has been approved for pharmaceutical use previously and using the sodium salt of ascorbic acid for radiolabeled monoclonal antibodies;
3) Warne taught: i) the decision is no longer whether to include a surfactant in the formulation, but rather to ask how much to include based on its intended purpose such as protection from mechanical agitation; and ii) a method for identification of the level of polysorbate, wherein a simple titration of polysorbate-20 or polysorbate 80 is used in a range from 0.005% to 0.2% when suitably stressed to provide a rationale for selection of an appropriate concentration;
4) Kang taught although every antibody is unique, the molecules are highly similar structurally and lessons learned from successful examples are invaluable in developing stable and effective formulations for new antibody formulations. Kang taught acetate as a commonly used buffer and that 80% of formulations used one of three surfactants that includes polysorbate 20. Kang taught formulation development wherein stage one identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients. Kang taught a range of buffer concentrations are tested to develop the formulation wherein 10-50 mM is tested.
There is a reasonable expectation of success because:
1) the addition of about 0.5% ascorbic acid prevented significant loss of radiolabeled antibody during the purification and that radioprotection agents previous and was found to be essential in the reproducible production and recovery of an immunoreactive radiotherapeutic;
2) Liu taught ascorbic acid has been approved for pharmaceutical use previously and using the sodium salt of ascorbic acid for radiolabeled monoclonal antibodies;
3) Polysorbate 20 and 80 are present in most antibody formulations and the concentration range of 0.005% to 0.2% has been found to be suitable;
4) Kang taught although every antibody is unique, the molecules are highly similar structurally and lessons learned from successful examples are invaluable in developing stable and effective formulations for new antibody formulations. Kang taught acetate as a commonly used buffer and that 80% of formulations used one of three surfactants that includes polysorbate 20. Kang taught formulation development wherein stage one identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients. Kang taught a range of buffer concentrations are tested to develop the formulation wherein 10-50 mM is tested. Kang taught in just a few weeks researchers can develop a stable formulation for antibody product development.
This would produce a method of effectively treating a human patient with prostate cancer by intravenously administering a dose bimonthly with a therapeutically effective amount of a pharmaceutical composition formulated for intravenous administration comprising the radiometal conjugate 225Ac-DOTA-hu11B6, wherein the humanized 11B6 antibody specifically binds hK2 and the in a formulation of a pharmaceutically acceptable excipient radioprotectant of 0.5% sodium ascorbic acid in a range of 10-50 mM Na-acetate pH 5.5 with a range of 0.005% to 0.2% of polysorbate 20 or polysorbate 80 (instant claims 95-96, 98-100, and 108) to the subject at a dose of about 270 µCi on about 5 mg of antibody, wherein the antibody concentration is about 1 mg/ml, wherein the number of chelator molecules conjugated to the antibody is 1 to about 4, wherein the composition further comprises non-radiolabeled antibody, and wherein the total amount of the conjugated antibody and non-conjugated antibody does not exceed 10 mg because the non-labeled antibody is within the 5 mg dose, wherein the pharmaceutical composition used would naturally be stable at a temperature of about 2-8C for at least 72 h (instant claim 110 ).
Response to Arguments
Applicant argues the disclosures in McDevitt 1999, Liu, Warne, and Kang do not cure the deficiencies of McDevitt 2018, Kratochwil, and Timmermand with respect to the composition of claim 76 discussed above. For at least this reason, claims 1-2, 4-14, 16, 32, 57, 60, 73, 76-78, 80-90, 92, 95-100, 102-112, 128, 131-134, 137, and 150-161 are not obvious over McDevitt 2018, Kratochwil, Timmermand, Thiele, McDevitt 2002, McDevitt 1999, Liu, Warne, and Kang.
In response, Applicant's arguments filed 7/7/2026 have been fully considered but they are not persuasive. The obvious rational is above. The discussion regarding instant claims 76 and the modification of the method and composition of McDevitt 2018 and Kratochwil is above.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-2, 4-14, 16, 32, 57, 60, 73, 76-78, 80-90, 95, 102, 111-112, 133-134, 137, and 153-161 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 8, 10, 16, 18, 20, 22-25, 32, 37, 39, 42, 46, 48-49, and 56 of copending Application No. 19/211,544.
‘544 taught methods for treating a prostate cancer patient with radioconjugates in copending claims 1, 3-6, 8, 10, 16, 18, 20, 22-25, 32, 37, 39, 42, 46, 48-49, and 56.
‘544 taught a method of treating a prostate cancer patient comprising administering to the patient a therapeutically effective first dose of a radioconjugate comprising an antibody having binding specificity for hK2 conjugated to a chelator, wherein 225Ac is chelated to the chelator, and further administering 2 or more doses in copending claim 1, wherein the time period between the first and second administration 12 weeks in copending claim 2, wherein the first dose of the radioconjugate is 150 µCi and the second dose of the radioconjugate is 100 µCi in copending claim 18, wherein the first dose of the radioconjugate is 100-400 µCi in copending claim 10, wherein the second dose of the radioconjugate is 100-250 µCi in copending claim 16, wherein the antibody comprises a VH of ’544 SEQ ID NO:7 and a VL of ‘544 SEQ ID NO:8 or ’544 SEQ ID NO:10 and a VL of ‘544 SEQ ID NO:11 and a chelator of DOTA in copending claim 25, wherein the radioconjugate comprises 2-(4- isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA) an antibody comprising a VH comprising SEQ ID NO:7 and a VL comprising SEQ ID NO:8, an average of about 1-4 chelator molecules conjugated to the antibody with about 50-250 µCi per 2-3 mg of total antibody in copending claim 32, wherein the radioconjugate is administered in a pharmaceutical composition comprising the radioconjugate a radioprotectant, a surfactant, and a buffer with a pH of 5-6 in copending claim 37, wherein the prostate cancer is metastatic castration resistant prostate cancer (CRPC) in copending claim 48.
‘544 does not teach a single embodiment of the method of treating cancer in a patient wherein a pharmaceutical composition is administered comprising the radioconjugate comprising a VH comprising SEQ ID NO:1-3 and a VL comprising SEQ ID NO:4-6, and wherein the radiometal provides a targeted radioactivity from about 50-350 µCi, but this is obvious in view of the copending claims.
Regarding instant claims 1-2, 4-14, 16, 32, 57, 60, 73, 76-78, 80-90, 95, 102, 111-112, 133-134, 137, and 153-161, it would have been obvious for a person having ordinary skill in the art to combine copending claims 1, 2, 10, 16, 18, 25, 32, 37, and 48 for a method of treating a metastatic castration resistant prostate cancer (CRPC) prostate cancer patient comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective first dose of a radioconjugate comprising an antibody having binding specificity for hK2 conjugated to a chelator, wherein 225Ac is chelated to the chelator, and further administering 2 or more doses, wherein the time period between the first and second administration 12 weeks, wherein the first dose of the radioconjugate is 150 µCi or 100-400 µCi and the second dose of the radioconjugate is 100 µCi or 100-250 µCi, wherein the antibody comprises a VH of ’544 SEQ ID NO:7 and a VL of ‘544 SEQ ID NO:8, or ’544 SEQ ID NO:10 and a VL of ‘544 SEQ ID NO:11, and a chelator of DOTA, wherein the radioconjugate comprises 2-(4- isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA) and an average of about 1-4 chelator molecules conjugated to the antibody with about 50-250 µCi per 2-3 mg of total antibody, wherein the pharmaceutical composition comprises the radioconjugate a radioprotectant, a surfactant, and a buffer with a pH of 5-6.
This is obvious with a reasonable expectation of success because the copending claims further claim individual species of the cancer, radioconjugate, and composition of the copending independent claim 1 that are taught to be therapeutically effective in a method of treating prostate cancer.
This would produce a method of treating a metastatic castration resistant prostate cancer (CRPC) prostate cancer patient comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective first dose of a radioconjugate comprising an antibody having binding specificity for hK2 conjugated to a chelator, wherein 225Ac is chelated to the chelator, and further administering 2 or more doses, wherein the time period between the first and second administration 12 weeks, wherein the first dose of the radioconjugate is 150 µCi and the second dose of the radioconjugate is 100 µCi, wherein the antibody comprises a VH of ’544 SEQ ID NO:7 and a VL of ‘544 SEQ ID NO:8, or ’544 SEQ ID NO:10 and a VL of ‘544 SEQ ID NO:11, and a chelator of DOTA, wherein the radioconjugate comprises 2-(4- isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA) and an average of about 1-4 chelator molecules conjugated to the antibody with about 50-250 µCi per 2-3 mg of total antibody, wherein the pharmaceutical composition comprises the radioconjugate and excipients that include a radioprotectant, a surfactant, and a buffer with a pH of 5-6. This meets the claim limitations of instant claims 1-2, 4-14, 16, 32, 57, 60, 73, 76-78, 80-90, 95, 102, 111-112, 133-134, 137, and 153-161.
Conclusion
Claims 1-2, 4-16, 32-35, 57, 60, 73-78, 80-100, 102-112, 128, 131-134, 137, and 150-161 are rejected.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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