DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims and Previous Objections/Rejections Status
Claims 11-14,16-18,31-41 and 44-52 are pending in the application. Claims 12,13 and 44-46 are withdrawn from consideration. Claims 51 and 52 are newly added in the amendment filed 2/4/26.
Any objections and/or rejections from previous office actions that have not been reiterated in this office action are obviated.
Applicant's arguments filed 2/4/26 have been fully considered but they are not persuasive.
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.
Claim(s) 11,14,16-18,31-41 and 47-52 is/are rejected under 35 U.S.C. 103 as being unpatentable
over Larsen (US 2019/0177345A1) in view of Stenberg et al. (Label Compd Radiopharm 2020;63:129-143), Patel et al. (Molecules 2021, 26, 2162; p1-18) and El Fakiri et al. (Cancers (2021) 13, 3967; p1-30) and in further view of Moon et al. (Theranostics 2021, Vol. 11, Issue 2 958-973) as stated in the office action mailed 11/4/25 but modified to include newly added claims 51 and 52.
Applicant asserts that Larsen does not specifically disclose a method wherein the radiopharmaceutical conjugate prevents or reduces the formation of metastatic bone lesion.
The reference of Larsen was not explicitly used to teach of the prevention or reduction of the formation of metastatic bone lesion but was used to teach of the method of treating skeletal metastases to bone in an individual with advanced metastatic prostate cancer (mCRPC) with 212Pb-SCN-Bn-TCMC-PSMA
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wherein bone lesions occur from skeletal metastases.
The 212Pb-SCN-Bn-TCMC-PSMA targets bone and generates the alpha emitter 212Bi and therefore, the beta emitter 212Pb is used as an indirect alpha source for irradiating the target cells.
The 212Pb-SCN-Bn-TCMC-PSMA also has improved properties for the treatment of skeletal metastases since the daughter nuclide is targetable to circulating cancer cells (CTCs) and prevents recurrence from cancer recolonization of the skeleton due to CTCs.
Also, the 212Pb-SCN-Bn-TCMC-PSMA is taught to have similar binding properties to that of a radiolabeled PSMA-617 conjugate.
The reference of Patel et al. was used to teach that when patients with mCRPC received three cycles of 225Ac-PSMA-617 all visible bone metastases had decreased to a size below the limit of detection
of clinical imaging scanners after 8 weeks.
PSMA-617 binds to PSMA with high affinity and was designed to target PSMA-expressing prostate cancer cells as PSMA is known to be highly expressed on prostate cancer cells at the primary tumor and within visceral and bone metastases.
The reference of Stenberg et al. was used to teach that 212Pb-SCN-Bn-TCMC-PSMA has comparable tumor uptake binding and internalization to [212Pb]Pb-PSMA-617.
The reference of El Fakiri et al. was used to teach that [212Pb]Pb-NG001 (corresponds to 212Pb-SCN-Bn-TCMC-PSMA) exhibited a very fast pharmacokinetic profile that also outperformed current state-of-the-art PSMA-617.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the 212Pb-SCN-Bn-TCMC-PSMA of Larsen decreases skeletal metastases and reduces or prevents bone lesions as 212Pb-SCN-Bn-TCMC-PSMA has comparable tumor uptake to [212Pb]Pb-PSMA-617 and outperformed current state-of-the-art PSMA-617 conjugate, such as 225Ac-PSMA-617 that is taught to decrease all visible bone metastases to a size below the limit of detection of clinical imaging scanners after 8 weeks wherein bone metastases cause bone lesions.
Therefore, it would have been predictable to one of ordinary skill in the art that 212Pb-SCN-Bn-TCMC-PSMA alpha-particle therapy reduces or prevents bone lesions by reducing skeletal metastases below the limit of detection, with a reasonable expectation of success, as bone lesions are caused by skeletal metastases and therefore will be reduced or prevented by the lack of skeletal metastases present.
Applicant asserts that Patel et al. teaches that treatment with 225Ac-PSMA-617 reduced the bone metastases in patients with mCRPC that has spread to bone tissue but does not describe preventing or reducing the formation of a metastatic bone lesion. Patel teaches that the treatment with 225Ac-PSMA-617 reduced the bone metastases to a size below the limit of detection. 225Ac-PSMA-617 is completely different from the conjugate of claim 11 of the instant application, has a different half-life, different charges and particle size.
The reference of Patel et al. was not used to teach of the 212Pb-SCN-Bn-TCMC-PSMA of the instant claims or that 212Pb-SCN-Bn-TCMC-PSMA has the same properties as 225Ac-PSMA-617.
The reference of Patel et al. was used to teach that when patients with mCRPC received three cycles of 225Ac-PSMA-617 all visible bone metastases had decreased to a size below the limit of detection
of clinical imaging scanners after 8 weeks as well as that stated above.
The reference of Larsen was used to teach that 212Pb-SCN-Bn-TCMC-PSMA is used for the method of treating skeletal metastases to bone in an individual with advanced mCRPC as well as that stated above.
The reference of Stenberg et al. was used to teach that 212Pb-SCN-Bn-TCMC-PSMA has comparable tumor uptake binding and internalization to [212Pb]Pb-PSMA-617.
The reference of El Fakiri et al. was used to teach that [212Pb]Pb-NG001 (corresponds to 212Pb-SCN-Bn-TCMC-PSMA) exhibited a very fast pharmacokinetic profile that also outperformed current state-of-the-art PSMA-617.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the 212Pb-SCN-Bn-TCMC-PSMA of Larsen decreases skeletal metastases and reduces or prevents bone lesions as 212Pb-SCN-Bn-TCMC-PSMA has comparable tumor uptake to [212Pb]Pb-PSMA-617 and outperformed current state-of-the-art PSMA-617, such as 225Ac-PSMA-617 that is taught to decrease all visible bone metastases to a size below the limit of detection of clinical imaging scanners after 8 weeks wherein bone metastases cause bone lesions.
Therefore, it would have been predictable to one of ordinary skill in the art that 212Pb-SCN-Bn-TCMC-PSMA alpha-particle therapy reduces or prevents bone lesions by reducing skeletal metastases below the limit of detection, with a reasonable expectation of success, as bone lesions are caused by skeletal metastases and therefore will be reduced or prevented by the lack of skeletal metastases present.
Applicant asserts that Stenberg et al. compares in vitro and in vivo measurements between [212Pb]Pb-NG001 (corresponds to 212Pb-SCN-Bn-TCMC-PSMA) and 177Lu-PSMA-617, but does not describe preventing or reducing the formation of a metastatic bone lesion.
The reference of Stenberg et al. was not used to teach of in vitro and in vivo measurements between [212Pb]Pb-NG001 (corresponds to 212Pb-SCN-Bn-TCMC-PSMA) and 177Lu-PSMA-617 but was used to teach that 212Pb-SCN-Bn-TCMC-PSMA has comparable tumor uptake binding and internalization to [212Pb]Pb-PSMA-617 as well as that stated above.
Applicant asserts that El Fakiri et al. is directed to a general overview of development milestones of PSMA-targeted radionuclide therapy, but does not cure the deficiency of the references cited above.
The reference of El Fakiri et al. was used to teach that [212Pb]Pb-NG001 (corresponds to 212Pb-SCN-Bn-TCMC-PSMA) exhibited a very fast pharmacokinetic profile that also outperformed current state-of-the-art PSMA-617 as well as that stated above.
The reference of Larsen is stated above.
Therefore, it would have been predictable to one of ordinary skill in the art that 212Pb-SCN-Bn-TCMC-PSMA decreases bone metastases as it outperformed current state-of-the-art PSMA-617 that is known to decrease all visible bone metastases to a size below the limit of detection of clinical imaging scanners after 8 weeks and bone lesions are caused by skeletal metastases and therefore will be reduced or prevented by the lack of skeletal metastases present.
Applicant asserts that Moon et al. is cited for its disclosure of the use of bioluminescence imaging and does not cure the deficiency of the references cited above.
The reference of Moon et al. was used to teach of weekly bioluminescence imaging to monitor tumor metastasis from castration resistant prostate cancer.
Applicant asserts that the cited references fail to teach the element of administering a
radiopharmaceutical conjugate to a human subject in an amount between about 75 MBq per dose to about 300 MBq per dose.
The reference of Larsen teaches that the 212Pb-Bn-TCMC-PSMA is provided as a pharmaceutical composition is administered between 1MBq and 500 MBq, typically 10-100 MBq.
Applicant asserts that Stuparu has shown that 225Ac-PSMA-617 had little to no improvement between treated and untreated mice with regards to preventing or reducing the formation of bone (femur) metastasis. Stuparu describes the effect of 225Ac-PSMA-617 in an in vivo model of disseminated metastatic prostate cancer using C4-2 cells. Figure 2D illustrates that none of the treatment groups (not treated, left bars; late treatment, center bars; early treatment, right bars) were able to prevent the formation of bone metastasis. All three groups had a similar level, indicating a similar level of metastasis in the bone (femur).
The reference of Stuparu was not a cited reference in the rejection.
The Figure 2D of the reference of Stuparu teaches of whole organ radiance measured ex vivo at time of suffice. The C4-2 cells yielded metastases in the liver, lungs, spleen, stomach, bones and brain-achieving a clinically relevant model of widespread metastatic disease.
The 225Ac-PSMA-617 treatment was used to monitor PSMA-targeted RLT at various disease stages wherein Figure 3 teaches that at 7 weeks post-inoculation of C4-2 cell the early treatment cohort (1 week) had no detectable disease, late treatment cohort (3 weeks) and untreated control both had detectable disease.
The data highlight that the treatment time has an impact on therapeutic effectiveness and emphasize effectiveness of PSMA-targeted therapy even against visceral tissue metastasis, which are more difficult to treat.
Therefore, it would have been predictable to one of ordinary skill in the art to administer
the 212Pb-Bn-TCMC-PSMA of Larsen as an early treatment to provide for the most efficacious treatment and provide for no detectable disease.
Applicant asserts that the claimed method provides evidence of unobvious or unexpected
advantageous properties. Throughout the instant application and in Example 13, the claimed conjugate prevents or reduces the formation of metastatic bone lesion. The reference of Hoyvik teaches that the mice treated with 0.5 MBq or 1.0 MBq with 212Pb-AB001 had no detectable bone metastases.
The disclosure of the instant invention states that the “it is expected that treatment with the 212Pb-compound 1 disclosed will prevent or reduce the formation of distant metastases and in particular prevent or reduce bone lesions” (Example 13) and therefore, the result was not unexpected.
The reference of Larsen teaches that the 212Pb-SCN-Bn-TCMC-PSMA targets bone and generates the alpha emitter 212Bi and therefore, the beta emitter 212Pb is used as an indirect alpha source for irradiating the target cells or tissues.
The reference of Hoyvik teaches that “the enhanced efficacy of 212Pb-AB001 (corresponds to 212Pb-SCN-Bn-TCMC-PSMA) is likely to be attributable predominantly to the physical properties of its alpha-emitting daughters rather than differences in ligand properties.”
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the daughter alpha emitter 212Bi of 212Pb-SCN-Bn-TCMC-PSMA of Larsen has the same properties and is capable of the same functions, such as enhanced efficacy and provide for no detectable bone metastases or bone lesions.
The arguments of counsel cannot take the place of evidence in the record. Examples of attorney statements are not evidence and must be supported by an appropriate affidavit or declaration include statements regarding unexpected results. MPEP § 716.01 (c).
Conclusion
No claims are allowed at this time.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MELISSA JEAN PERREIRA whose telephone number is (571)272-1354. The examiner can normally be reached M9-3, T9-3, W9-3, Th9-2, F9-2.
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/MELISSA J PERREIRA/ Examiner, Art Unit 1618
/Michael G. Hartley/ Supervisory Patent Examiner, Art Unit 1618