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 merit.
Claims 150-161 are new.
Objections and Rejections Withdrawn
The claim rejections of claims 3 and 79 are moot in view of claim cancelation.
The objection to the Drawings and Specification are withdrawn in view of the amended specification that identifies the SEQ ID NO: in Fig 7.
The previous rejection of claims 4, 8, 80, and 84 under 35 U.S.C. 112(a) is withdrawn in view of claim amendment.
The previous rejection of claim 76 and 133 under 35 U.S.C. 102(a)(1) is withdrawn in view of claim amendment.
The previous rejection of claims 1-2, 4-14, 16, 32-35, 57, 60, 73-78, 80-90, 92-100, 102-112, 128, 131-134, 137 under 35 U.S.C. 103 is withdrawn in view of claim amendment.
The previous rejection of claims 1-2, 4-14, 16, 32-35, 57, 60, 73-78, 80-90, 92-100, 102-112, 128, 131-134, 137 under nonstatutory double patenting of 17/154,144 is withdrawn in view of copending application abandonment.
The previous rejection of claim 76 under nonstatutory double patenting of 18/516,304 is withdrawn in view of claim amendment.
The previous rejection of claim 76 under nonstatutory double patenting of 18/707,865 is withdrawn in view of claim amendment.
Claim Interpretation
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 Rejections Necessitated by Amendment
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 (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 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
– 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; 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 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 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
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
The Office admits that McDevitt 2018's disclosed dose of 0.3 μCi falls short of the
claimed targeted radioactivity from about 50 μCi to about 350 μCi. (Action at p. 17). The Office alleges that Kratochwil describes a higher dose of radioactivity (6.4 MBq), and that one of skill in the art would have increased the dose disclosed in McDevitt 2018 to the dose of Kratochwil to arrive at the claimed targeted radioactivity. The only rationale provided by the Office for such a modification is that McDevitt 2018's "0.3 μCi was not curative to subjects with prostate cancer so a higher dose would be needed." (Id at p. 19, first full paragraph). This, however, contradicts McDevitt 2018' s finding that a single dose of its radioimmunoconjugate eradicated disease and prolonged survival in animal models.
Specifically, McDevitt 2018 describes that a single administration of actinium-225
labeled hullB6 antibody ([225 Ac ]hu 11B6) eradicates disease and significantly prolongs survival in animal models of prostate cancer. (McDevitt 2018, Abstract).
The Office mistakenly alleges that Fig. I and the corresponding legend provide support for the conclusion that a dose of 0.3 μCi was not curative. In Fig. 1, McDevitt 2018 describes the use of the [225 Ac ]hu l 1B6 radioimmunoconjugate in the rodent models of prostate cancer at a single dose of 300 nCi/mouse (McDevitt 2018, Figure IC). McDevitt 2018 concludes that this dose is therapeutically effective as it "significantly enhanced the animals' survival:"
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In other words, McDevitt 2018 demonstrates a therapeutically effective treatment that eliminated tumors in half of the treated animals. McDevitt 2018 explains that a single dose of its radioimmunoconjugate eradicates disease and significantly prolongs survival in animal models because the DNA damage induced by the radioimmunoconjugate upregulates KLK2, which in tum increases prostate cancer targeting by the radiolabeled antibody [225 Ac ]hu l 1B6, 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). 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.
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 22 5 Ac- PSMA-617 was not "curative" and that three, or four, cycles, each delivering 6.4 MBq or 9-10 MBq radioactivity, 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 to be three times or four times that of the dose in Kratochwil to be "curative." This modification would not have let 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 prima facie 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.
In response, Applicant's arguments filed 10/23/2025 have been fully considered but they are not persuasive. The obvious rational is above.
Regarding:
The only rationale provided by the Office for such a modification is that McDevitt 2018's "0.3 μCi was not curative to subjects with prostate cancer so a higher dose would be needed." (Id at p. 19, first full paragraph)
This is incorrect. As indicated above and in the previous Office Action dated 4/23/2025:
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
– 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; 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 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 and the pharmaceutically acceptable excipient ascorbic acid was administered to human patients with prostate cancer, wherein 9-10 MBq was administered bimonthly, every 8 weeks for 3 doses, to patient A and 6.4 MBq was administered bimonthly to patient B, wherein the treatment 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 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
Regarding, the Office mistakenly alleges that Fig. 1 and the corresponding legend provide support for the conclusion that a dose of 0.3 μCi was not curative:
McDevitt Fig. 1C shows that in an animal subjects that 50% of the animal subjects died
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. Thus, all animals were not cured. McDevitt 2018 did teach 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 (Fig 1 and Fig 1 legend; and Fig. 3) as described above.
Regarding:
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
As described above, the obvious rational includes Kratochwil. Kratochwil taught an effective method of treating human prostate cancer 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 the 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. Thus, McDevitt 2018 and Kratochwil teach the claimed treatment dose in humans as obvious with a reasonable expectation of success in the obvious rational above.
Regarding:
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
and
Per the Office's own rationale, those of ordinary skill in the art would have needed to modify McDevitt 2018's single dose to be three times or four times that of the dose in Kratochwil to be "curative.":
the combined method of McDevitt 2018 and Kratochwil was not described by the Examiner as a curative dose for all human patients. As stated above, “This would produce a method of effectively treating a human patient with prostate cancer…”. 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 which was administered intravenously to the subject at a dose of 0.3 µCi, but was not curative. The dose of 0.3 µCi in animal subjects would thus be obvious to increase to a higher dose taught by Kratochwil used in humans. Regarding the increased dose, Kratochwil taught multiple cycles for treatment in Kratochwil Fig. 1 - Fig. 4. Thus, increase of Kratochwil's dose three or four times is not required for a human effective dose.
One of ordinary skill would have been motivated to modify the dose of
McDevitt 2018 as described above. Further, the teachings of Kratochwil that humans administered 6.4 to 10 MBq bimonthly of a prostate cancer targeting agent conjugated to 225AC-DOTA were effectively treated and decreased prostate tumors provide a reasonable motivation for exchanging the dose of an animal study of McDevitt 2018.
Applicant argues
The radioconjugates of McDevitt 2018 and Kratochwil are not
interchangeable
Applicant argues 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 225Ac- 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. 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 (DL T) or on-treatment deaths were reported at any of the doses tested and no dose reductions were necessary. Additionally, decreases of 50% or more from baseline of prostate specific antigen (PSA) were also observed. 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. Accordingly, those of ordinary skill in the art would not have arrived at the claimed methods and compositions from McDevitt 2018, Kratochwil, and Timmermand. Also, modifying the method of McDevitt 2018 in view of Kratochwil and Timmermand would not have led those of ordinary skill in the art to the methods of claims 1-14, 16, 32, 57, 60, and 73 and the compositions of claims 76-90, 92, 103-107, 109, and 112 as claimed. For at least these reasons, claims 1, 2, 4-14, 16, 32, 57, 60, 73, 76-78, 80-90, 92, 103-107, 109, 112, 133, 134, and 137 are not obvious over McDevitt 2018, Kratochwil, and Timmermand.
In response, Applicant's arguments filed 10/23/2025 have been fully considered but they are not persuasive. Regarding Kratochwil, Kratochwil taught a method of an effective treatment of prostate cancer in human patients by administering a prostate cancer targeted radioconjugate, 225Ac- PSMA-617, which targets prostate-specific membrane antigen (PSMA) on prostate cancer cells (citation above). McDevitt 2018 taught a method of an effective treatment of prostate cancer in animal subjects by administering a prostate cancer targeted radioconjugate, 225Ac-DOTA-hu11B6, which targets prostate-specific membrane antigen (PSMA) on prostate cancer cells (citation above). Thus, the methods and pharmaceutical compositions of Kratochwil and McDevitt 2018 are not starkly different as both teach a method of an effective treatment of prostate cancer in subjects with prostate cancer by administering a prostate cancer targeted radioconjugate comprising 225Ac, which targets prostate-specific antigens on prostate cancer cells. The dose of 225Ac used in an effective human radioconjugate would be obvious with a reasonable expectation of success to include in the radioconjugate of McDevitt 2018.
Further, 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). Thus, 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.
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 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 1-14, 16, 32, 57, 60, 73, 76-90, 92, 97, 102-107, 109, 112, 128, 133, 134, and 137 are not obvious over McDevitt 2018, Kratochwil, and Timmermand.
In response, Applicant's arguments filed 10/23/2025 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 1-14, 16, 32-35, 57, 60, 73, 76-90, 92-94, 103-107, 109, 112, 133, 134, and 137 are not obvious over McDevitt 2018, Kratochwil, and Liu.
In response, Applicant's arguments filed 10/23/2025 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 1-14, 16, 32, 57, 60, 73-90, 92, 103-107, 109, 112, 133, 134, and 137 are not obvious over McDevitt 2018, Kratochwil, and DeNardo.
In response, Applicant's arguments filed 10/23/2025 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 1-14, 16, 32, 57, 60, 73, 76-90, 92, 97, 102-107, 109, 111, 112, 128, 131, 134, and 137 are not obvious over McDevitt 2018, Kratochwil, Timmermand, Thiele, McDevitt 2002, and Vivier..
In response, Applicant's arguments filed 10/23/2025 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 1-14, 16, 32, 57, 60, 73, 76-90, 92, 95-100, 102-112, 128, 131-134, and 137 are not obvious over McDevitt 2018, Kratochwil, Timmermand, Thiele, McDevitt 2002, McDevitt 1999, Liu, Warne, and Kang..
In response, Applicant's arguments filed 10/23/2025 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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 4-11,15-16, 32, 57, 60, 73, 76-78, 80-87, 91, 103-107, 109, 112, 133-134, 137, and 150-160 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-9, 11-22, 25-29, 40, 44, and 48-51 of copending Application No. 18/516,304 in view of 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).
‘304 claim 29 taught a radioimmunoconjugate with the structure:
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227
172
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, wherein M+ is 225Ac, and wherein the h11B6 antibody is mAb. 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).
‘304 taught a compound of formula (I):
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212
243
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in copending claims 1-5, 7-9, 11-12, wherein the formula is conjugated to an antibody in copending claims 19-21, wherein the antibody is h11B6 in copending claim 22, wherein a pharmaceutical composition comprising an immunoconjugate and a pharmaceutically acceptable carrier is claimed in copending claim 40,
‘304 taught a radiometal complex of formula (I-M+):
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183
251
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, (II-M+)
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201
227
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, or (III-M+)
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202
248
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in copending claims 13-15, wherein the metal is actinium-225 (225Ac) in copending claims 16-18, wherein the formula is conjugated to an antibody in copending claim 25, wherein the antibody is h11B6 in copending claim 27, wherein a pharmaceutical composition comprising an immunoconjugate and a pharmaceutically acceptable carrier is claimed in copending claim 44.
The claims of ‘304 did not teach: 1) dosing of a radiometal providing a targeted radioactivity of 50-350 µCi per dose; 2) wherein the dose is between 2-10 mg of antibody; 3) wherein the composition contains a pharmaceutically acceptable excipient of a radioprotectant; 4) intravenous dosing; and 5) administering the pharmaceutical composition to a human cancer patient for the treatment of cancer, but this is obvious in view of McDevitt 2018 and Kratochwil.
Regarding instant claims 1-2, 4-11,15-16, 32, 57, 60, 73, 76-78, 80-87, 91, 103-107, 109, 112, 133-134, 137, and 150-160, 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, 4-11,15-16, 32, 57, 60, 73, 76-78, 80-87, 91, 103-107, 109, 112, 133-134, 137, and 150-160 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 (Fig 1 and Fig 1 legend; and Fig. 3). Regarding instant claim 76, 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).
Regarding instant claims 1-2, 4-11,15-16, 32, 57, 60, 73, 76-78, 80-87, 91, 103-107, 109, 112, 133-134, 137,and 150-160, Kratochwil taught an effective method of treating human prostate cancer wherein a 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 151-153, 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, 4-11,15-16, 32, 57, 60, 73, 76-78, 80-87, 91, 103-107, 109, 112, 133-134, 137, and 150-160 it would have been obvious for a person having ordinary skill in the art to take: a radioimmunoconjugate with the structure:
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, wherein M+ is 225Ac, and wherein the h11B6 antibody is mAb in copending claim 29 – and use the teachings of McDevitt 2018 and Kratochwil to include:
1) a dose of a radiometal providing a targeted radioactivity of 50-350 µCi per dose in the composition; 2) a dose between 2-10 mg of antibody; and 3) a pharmaceutically acceptable excipient of the radioprotectant ascorbic acid; 4) intravenous dosing; and 5) administering the pharmaceutical composition to a human cancer patient for the treatment of cancer with a bimonthly dosing of every 8 weeks for 3 doses.
This is obvious because: 1-2 and 5) Kratochwil taught an effective method of treating human prostate cancer 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, every 8 weeks for 3 doses, wherein the treatment 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. McDevitt 2018 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); 3) 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; 4) McDevitt 2018 taught intravenous dosing; and 5) Kratochwil taught an effective method of treating human prostate cancer patients wherein a pharmaceutical composition of 225Ac-DOTA-PSMA-617 and 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. Thus, 225Ac radioconjugates were known to be effective for treating prostate cancer and prostate cancer in humans.
There is a reasonable expectation of success because: 1-2 and 5) humans administered a composition of 6.4 to 10 MBq bimonthly of a prostate cancer targeting agent conjugated to 225AC-DOTA were effectively treated and decreased prostate tumors; Thus, the composition with an effective dose of 10 MBq dose of 225Ac is about 270 µCi and would equate to about 5 mg of antibody; 3) 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; 4) intravenous dosing was effective; and 5) Kratochwil taught an effective method of treating human prostate cancer patients wherein a pharmaceutical composition of 225Ac-DOTA-PSMA-617 and 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. Thus, 225Ac radioconjugates were known to be effective for treating cancer and cancer in humans.
This would produce a method for treating a human patient with prostate cancer (instant claim 60 and 137) by intravenously administering a single dose (instant claim 73) bimonthly, every 8 weeks for 3 doses (instant claims 150-151), which is between once every 4-12 weeks (instant claims 57 and 134), with a therapeutically effective amount of a pharmaceutical composition formulated for intravenous administration (instant claim 109) comprising a radioimmunoconjugate with the structure:
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, wherein M+ is 225Ac which is a radiometal (instant claims 10-11 and 86-87 ), wherein 225Ac-chelator complex structure above is a radiometal chelator complex (instant claims 15 and 91), wherein the h11B6 antibody specifically binds hK2 (instant claims 2 and 78) and 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 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, and 133).
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 4-11,15-16, 32, 57, 60, 73, 76-78, 80-87, 91, 97, 102-107, 109, 112, 128, 133-134, 137, and 150-160 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-9, 11-22, 25-29, 40, 44, and 48-51 of copending Application No. 18/516,304 in view of 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).
The claims of the ‘304 in view of McDevitt 2018 and Kratochwil teach the limitations of claims 1-2, 4-11,15-16, 32, 57, 60, 73, 76-78, 80-87, 91, 103-107, 109, 112, 133-134, 137, and 150-160 for the reasons set forth above.
The claims of the ‘304, McDevitt 2018 and Kratochwil are described above.
The claims of the ‘304 are 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 claims 97, 102, and 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 administering the pharmaceutical composition of ‘304, 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 for treating a human patient with prostate cancer by intravenously administering a single dose bimonthly, every 8 weeks for 3 doses, which is between once every 4-12 weeks, with a therapeutically effective amount of a pharmaceutical composition formulated for intravenous administration comprising a radioimmunoconjugate with the structure:
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, wherein M+ is 225Ac, wherein 225Ac-chelator complex structure above is a radiometal chelator complex, wherein the h11B6 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) at a dose of about 270 µCi on about 5 mg of antibody, wherein the antibody concentration is 1 mg/ml (instant claim 128).
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 4-11,15-16, 32-35, 57, 60, 73, 76-78, 80-87, 91-94, 103-107, 109, 112, 133-134, 137, and 150-160 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-9, 11-22, 25-29, 40, 44, and 48-51 of copending Application No. 18/516,304 in view of 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 Liu S et al. (Bioconjugate Chemistry 2001 12(4) 554-558, reference of record).
The claims of the ‘304 in view of McDevitt 2018 and Kratochwil teach the limitations of claims 1-2, 4-11,15-16, 32, 57, 60, 73, 76-78, 80-87, 91, 103-107, 109, 112, 133-134, 137, and 150-160 for the reasons set forth above.
The claims of the ‘304, McDevitt 2018 and Kratochwil are described above.
The claims of the ‘304 are 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 administering the pharmaceutical composition of ‘304, McDevitt 2018 and Kratochwil above – and include in the composition: 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 for treating a human patient with prostate cancer by intravenously administering a single dose bimonthly, every 8 weeks for 3 doses, which is between once every 4-12 weeks, with a therapeutically effective amount of a pharmaceutical composition formulated for intravenous administration comprising a radioimmunoconjugate with the structure:
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, wherein M+ is 225Ac, wherein 225Ac-chelator complex structure above is a radiometal chelator complex, wherein the h11B6 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 at a dose of about 270 µCi on about 5 mg of antibody.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 4-11,15-16, 32, 57, 60, 73-78, 80-87, 91, 103-107, 109, 112, 133-134, 137, and 150-160 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-9, and 11-53 of copending Application No. 17/522,144 in view of 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 DeNardo GL et al. (Cancer 2002 94(4 Suppl):1332-48, reference of record).
The claims of the ‘304 in view of McDevitt 2018 and Kratochwil teach the limitations of claims 1-2, 4-11,15-16, 32, 57, 60, 73, 76-78, 80-87, 91, 103-107, 109, 112, 133-134, 137, and 150-160 for the reasons set forth above.
The claims of ‘304, McDevitt 2018 and Kratochwil are described above.
The claims of the ‘144 are 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 administering the pharmaceutical composition of ‘304, 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 for treating a human patient with prostate cancer by intravenously administering two sub-doses (instant claims 74-75) bimonthly, wherein the two sub-doses are administered every 8 weeks, which is between once every 4-12 weeks, with a therapeutically effective amount of a pharmaceutical composition formulated for intravenous administration comprising a radioimmunoconjugate with the structure:
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, wherein M+ is 225Ac, wherein 225Ac-chelator complex structure above is a radiometal chelator complex, wherein the h11B6 antibody specifically binds hK2, and the pharmaceutically acceptable excipient radioprotectant of the sodium salt of ascorbic acid and gentisic acid in saline at a dose of about 270 µCi on about 5 mg of antibody.
Claims 1-2, 4-11,15-16, 32, 57, 60, 73, 76-78, 80-87, 91, 97, 102-107, 109, 111-112, 128, 131-134, 137, and 150-160 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-9, 11-22, 25-29, 40, 44, and 48-51 of copending Application No. 18/516,304 in view of 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).
The claims of the ‘304 in view of McDevitt 2018, Kratochwil, and Timmermand teach the limitations of claims 1-2, 4-11,15-16, 32, 57, 60, 73, 76-78, 80-87, 91, 97, 102-107, 109, 112, 128, 133-134, 137, and 150-160 for the reasons set forth above.
The claims of the ‘304, McDevitt 2018, Kratochwil, and Timmermand are described above.
McDevitt 2018 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) using a DOTA chelator. 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.
The claims of the ‘304 are 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 administering the pharmaceutical composition of ‘304, McDevitt 2018, Kratochwil, and Timmermand above – and:
1) prepare the 225Ac-macropa-hu11B6 using the method of Thiele wherein the macropa chelator to antibody ratio is about 2;
2) include non-radiolabeled antibody in the composition as described by Vivier; and 3) include a total labeled to unlabeled antibody concentration of 5 mg as described by McDevitt 2018, which included a composition with non-radiolabeled antibody in the human scaled dose of 5 mg total antibody as produced in the method of McDevitt 2002.
This is obvious because: 1) Thiele taught a conjugation of a macropa chelator to antibody ratio of about 2; 2) non-labeled antibody is taught by Vivier to 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; and 3) the effective 225Ac-DOTA-hu11B6 of McDevitt 2018 was prepared using the method of McDevitt 2002, which be expected to yield a composition with non-radiolabeled antibody and radiolabeled antibody in the human scaled dose of 5 mg total antibody used in the method above.
There is a reasonable expectation of success because: 1) Thiele taught effective chelation of 225Ac to macropa ligand with an ratio of about 2 macropa ligands to antibody; 2) including unlabeled antibody in the dose of radiolabeled antibody 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 and more effective tumor treatment; 3) 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. Thus, the including non-radiolabeled antibody with radiolabeled antibody of a dose of about 270 µCi conjugated to
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would be expected to be an effective dose.
This would produce a method for treating a human patient with prostate cancer by intravenously administering a single dose bimonthly, every 8 weeks for 3 doses, which is between once every 4-12 weeks, with a therapeutically effective amount of a pharmaceutical composition formulated for intravenous administration comprising a radioimmunoconjugate with the structure:
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, wherein M+ is 225Ac, wherein 225Ac-chelator complex structure above is a radiometal chelator complex, wherein the h11B6 antibody specifically binds hK2, and the pharmaceutically acceptable excipient radioprotectant of ascorbic acid in 0.2 M Na-acetate pH 5.5 at a dose of about 270 µCi on about 5 mg of antibody, wherein the antibody concentration is 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).
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 4-11,15-16, 32, 57, 60, 73, 76-78, 80-87, 91, 95-100, 102-112, 128, 131-134, 137, and 150-160 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-9, 11-22, 25-29, 40, 44, and 48-51 of copending Application No. 18/516,304 in view of 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”), Vivier D et al. (J Labelled Comp Radiopharm. 2018 July ; 61(9): 672–692, reference of record), 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).
The claims of the ‘304 in view of McDevitt 2018, Kratochwil, Timmermand, Thiele, McDevitt 2002, and Vivier teach the limitations of claims 1-2, 4-11,15-16, 32, 57, 60, 73, 76-78, 80-87, 91, 97, 102-107, 109, 111-112, 128, 131-134, 137, and 150-160 for the reasons set forth above.
The claims of the ‘304, McDevitt 2018, Kratochwil, Timmermand, Thiele, McDevitt 2002, and Vivier are described above.
The claims of ‘304 are 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 administering the pharmaceutical composition of ‘304, 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 for treating a human patient with prostate cancer by intravenously administering a single dose bimonthly, every 8 weeks for 3 doses, which is between once every 4-12 weeks, with a therapeutically effective amount of a pharmaceutical composition formulated for intravenous administration comprising a radioimmunoconjugate with the structure:
PNG
media_image3.png
227
172
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Greyscale
, wherein M+ is 225Ac, wherein 225Ac-chelator complex structure above is a radiometal chelator complex, wherein the h11B6 antibody specifically binds hK2, and the 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) 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).
This is a provisional nonstatutory double patenting rejection.
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.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643