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 .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 3/4/2026 is acknowledged. The election of SEQ ID 10 (177Lu-PP-F11N) as species is also acknowledged. Claims 22-42 are pending, of which claims 36-42 are withdrawn as being directed to a non-elected invention. Claims 22-35 encompass the elected invention and species and are examined herein on the merits for patentability.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 22-35 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The terms "rapalogs" and "gastrin analogues" render the claims unclear, since it is not known to the skilled reader which structures are intended to be encompassed by these terms. The terms referring to "analogues" include an unlimited number of compounds obtainable from another compound by some undetermined chemical modification, including compounds which are structurally remote from the starting material, as well as functional derivatives sharing only a similar pharmacological or biological activity. There is, however, no clear definition to which extent rapamycin and gastrin peptides may be modified, and in what way, while still being regarded as "analogues". This has the effect that the person skilled in the art cannot decide clearly which compounds are to be covered by the claims and which are not, and the claims are not particularly pointed out. As such, the metes and bounds of the claims are not clearly set forth and the scope of the invention cannot be distinctly ascertained.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 22, 31, 32 and 34 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dumont et al. (J. Nucl. Med., 2013, 54(5), 762-769).
Dumont discloses that the gastrin-releasing peptide receptor (GRPr) is overexpressed in prostate cancer and is an attractive target for radionuclide therapy. In addition, inhibition of the protein kinase mammalian target of rapamycin (mTOR) has been shown to sensitize various cancer cells to the effects of radiotherapy. Methods: To determine the effect of treatment with rapamycin and radio therapy with a novel 177Lu-labeled GRPr antagonist (177Lu-RM2, BAY 1017858) alone and in combination, in vitro and in vivo studies were performed using the human PC-3 prostate cancer cell line. PC-3 cell proliferation and 177Lu-RM2 uptake after treatment with rapamycin were assessed in vitro. To determine the influence of rapamycin on 177Lu-RM2 tumor uptake, in vivo small-animal PET studies with 68Ga-RM2 were performed after treatment with rapamycin. To study the efficacy of 177Lu-RM2 in vivo, mice with subcutaneous PC-3 tumors were treated with 177Lu-RM2 alone or after pretreatment with rapamycin. Radiotherapy using a 177Lu-labeled GRPr antagonist alone or in combination with rapamycin was efficacious in inhibiting in vivo tumor growth and may be a promising strategy for treatment of prostate cancer (page 762).
It was hypothesized that RM2 labeled with the b-emitter 177Lu may be an effective tool for therapy of prostate cancer. Agents that sensitize malignant cells to radiation would amplify tumor response while minimizing toxicity to sur rounding organs by lowering effective therapeutic doses, a strategy that has been successfully used in other malig nant diseases to improve local control and survival out comes (28–30). In this study, we investigated the novel GRPr antagonist 177Lu-RM2 (BAY 1017858) alone and in combination with the mTOR inhibitor rapamycin using in vitro and in vivo models of PC-3, an androgen-independent human prostate cancer cell line with known upregulation of the PI3K/Akt/mTOR pathway, with the rationale of sensitizing prostate cancer cells to the effects of radiation by mTOR kinase inhibition (page 763).
The effect of combination therapy on tumor growth was eval uated in vivo using female athymic nude mice with subcutaneous PC-3 xenografts treated with 37 MBq (300 pmol) of 177Lu-RM2 alone or rapamycin daily (4 mg/kg) for 72 h, followed by 37 MBq of 177Lu-RM2. Control groups consisted of animals receiving PBS (untreated) or rapamycin (4 mg/kg) daily for 72 h (page 764).
Rapamycin at 10 nM had the greatest cytostatic effect in PC-3 cells without causing impairment of 177Lu-RM2 up take (Supplemental Fig. 2); thus, this dose was chosen for in vitro therapy studies. Combination treatment was more effective than either agent alone (page 765).
mTOR inhibitors are routinely used in the clinic to pre vent transplant rejection, and several agents are currently approved for the treatment of various malignancies. Everolimus was approved by the Food and Drug Administration in 2009 for treatment of refractory renal cell carcinoma and received approval earlier this year for use in patients with progressive pancreatic tumors of neuroendocrine origin. Generally, these medications are considered safe, with side effects that are limited and clinically manageable. There is a strong rationale for mTOR inhibition in advanced prostate cancer given the high prevalence of activation of the PI3K/ AKT pathway due largely to the loss of expression function of the tumor suppressor phosphatase and tensin ho molog and the association of this pathway with adverse pathologic features, recurrence after radical prostatectomy, and systemic treatment resistance (page 767).
On the basis of evidence suggesting mTOR inhibition sensitizes cells to ionizing radiation, we chose to pursue a pretreat ment strategy with rapamycin because we felt that this was the most straightforward method to evaluate whether rapamycin before 177Lu-RM2 treatment would have an additive effect. However, alternative methods such as concurrent mTOR inhibitor or radiopeptide therapy or mTOR inhibitor treatment with fractionated radiopeptide dosing should be evaluated (page 768).
It is noted that the instant composition may be formulated in separate dosage forms, as in dependent claim 31, and the kit of claim 32 does not require any additional components other than the rapamycin and gastrin analog components.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 22-35 are rejected under 35 U.S.C. 103 as being unpatentable over Dumont et al. (J. Nucl. Med., 2013, 54(5), 762-769) in view of Behe et al. (US 2016/0256580).
Dumont teaches that the gastrin-releasing peptide receptor (GRPr) is overexpressed in prostate cancer and is an attractive target for radionuclide therapy. In addition, inhibition of the protein kinase mammalian target of rapamycin (mTOR) has been shown to sensitize various cancer cells to the effects of radiotherapy. Methods: To determine the effect of treatment with rapamycin and radio therapy with a novel 177Lu-labeled GRPr antagonist (177Lu-RM2, BAY 1017858) alone and in combination, in vitro and in vivo studies were performed using the human PC-3 prostate cancer cell line. PC-3 cell proliferation and 177Lu-RM2 uptake after treatment with rapamycin were assessed in vitro. To determine the influence of rapamycin on 177Lu-RM2 tumor uptake, in vivo small-animal PET studies with 68Ga-RM2 were performed after treatment with rapamycin. To study the efficacy of 177Lu-RM2 in vivo, mice with subcutaneous PC-3 tumors were treated with 177Lu-RM2 alone or after pretreatment with rapamycin. Radiotherapy using a 177Lu-labeled GRPr antagonist alone or in combination with rapamycin was efficacious in inhibiting in vivo tumor growth and may be a promising strategy for treatment of prostate cancer (page 762).
It was hypothesized that RM2 labeled with the b-emitter 177Lu may be an effective tool for therapy of prostate cancer. Agents that sensitize malignant cells to radiation would amplify tumor response while minimizing toxicity to sur rounding organs by lowering effective therapeutic doses, a strategy that has been successfully used in other malig nant diseases to improve local control and survival out comes (28–30). In this study, we investigated the novel GRPr antagonist 177Lu-RM2 (BAY 1017858) alone and in combination with the mTOR inhibitor rapamycin using in vitro and in vivo models of PC-3, an androgen-independent human prostate cancer cell line with known upregulation of the PI3K/Akt/mTOR pathway, with the rationale of sensitizing prostate cancer cells to the effects of radiation by mTOR kinase inhibition (page 763).
The effect of combination therapy on tumor growth was eval uated in vivo using female athymic nude mice with subcutaneous PC-3 xenografts treated with 37 MBq (300 pmol) of 177Lu-RM2 alone or rapamycin daily (4 mg/kg) for 72 h, followed by 37 MBq of 177Lu-RM2. Control groups consisted of animals receiving PBS (untreated) or rapamycin (4 mg/kg) daily for 72 h (page 764).
Rapamycin at 10 nM had the greatest cytostatic effect in PC-3 cells without causing impairment of 177Lu-RM2 up take (Supplemental Fig. 2); thus, this dose was chosen for in vitro therapy studies. Combination treatment was more effective than either agent alone (page 765).
mTOR inhibitors are routinely used in the clinic to pre vent transplant rejection, and several agents are currently approved for the treatment of various malignancies. Everolimus was approved by the Food and Drug Administration in 2009 for treatment of refractory renal cell carcinoma and received approval earlier this year for use in patients with progressive pancreatic tumors of neuroendocrine origin. Generally, these medications are considered safe, with side effects that are limited and clinically manageable. There is a strong rationale for mTOR inhibition in advanced prostate cancer given the high prevalence of activation of the PI3K/ AKT pathway due largely to the loss of expression function of the tumor suppressor phosphatase and tensin ho molog and the association of this pathway with adverse pathologic features, recurrence after radical prostatectomy, and systemic treatment resistance (page 767).
On the basis of evidence suggesting mTOR inhibition sensitizes cells to ionizing radiation, we chose to pursue a pretreat ment strategy with rapamycin because we felt that this was the most straightforward method to evaluate whether rapamycin before 177Lu-RM2 treatment would have an additive effect. However, alternative methods such as concurrent mTOR inhibitor or radiopeptide therapy or mTOR inhibitor treatment with fractionated radiopeptide dosing should be evaluated (page 768).
It is noted that the instant composition may be formulated in separate dosage forms, as in dependent claim 31, and the kit of claim 32 does not require any additional components other than the rapamycin and gastrin analog components.
Dumont does not specifically teach wherein the gastrin analogue is 177Lu-DOTA-DGlu-DGlu-DGlu-DGlu-DGlu-DGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2.
Behe teaches a gastrin analogue that shows high uptake in CCK-2 receptor positive tumors and simultaneously a very low accumulation in the kidneys. This is achieved by a mini-gastrin analogue PP-F11 having the formula: PP-F11-X-DGlu-DGlu-DGlu-DGlu-DGlu-DGlu-Ala-Tyr-Gly-Trp-Y-Asp-Phe-NH.sub.2, wherein Y is an amino acid replacing methionine and X is a chemical group attached to the peptide for diagnostic and/or therapeutic intervention at CCK-2 receptor relevant diseases. Very suitable compounds with respect to a high tumor to kidney ratio are mini-gastrin analogues with six D-glutamic acids or six glutamines. These compounds still possess a methionine which can be oxidized easily which is a disadvantage for clinical application under GMP due to the forms which may occur. The elimination of the methionine leads to a lower affinity to oxidation which in general favors the tumor-kidney-ratio. Ideally, the methionine is replaced by norleucine. This PP-F11N mini gastrin exhibits currently the best tumor-kidney-ratio and is the most promising candidate.
FIG. 1 illustrates the mini-gastrin analogue PP-F11 that has been derived from the COST initiative mentioned above. The modified mini-gastrin analogue PP-F11N has been achieved by the exchange of the oxidizable amino acid methionine with norleucin. DOTA stands for 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. The molecule consists of a central 12-membered tetraaza ring. DOTA is used as a complexing agent, especially for lanthanide ions. Its complexes have medical applications as contrast agents and cancer treatments (paragraph 0017).
Labelling of the peptide PPF11N with Lu-177 is taught in paragraph 0040.
177Lu-PP-F11 (the linear mini-gastrin analogue with six D-Glu residues, hereinafter called PP-F11) exhibited best properties for future radio nuclide therapy due to its high favorable accumulation in the tumor accompanied by a low accumulation in the kidneys (paragraph 0006).
It would have been obvious to one of ordinary skill in the art at the time of the invention substitute 177Lu-PP-F11 as a functionally equivalent radiolabeled gastrin analog to 177Lu-labeled GRPr antagonist, 177Lu-RM2, used in combination therapy with rapamycin taught by Dumont when the teaching of Dumont is taken in view of Behe. The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. ___, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. One such rationale includes the simple substitution of one known element for another to obtain predictable results. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. See MPEP 2143.
In the instant case, the substituted components and their functions were known in the art at the time of the instant invention. One of ordinary skill in the art could have substituted one known radiolabeled gastrin analogue for another, and the results of the substitution would have been predictable, that is provision of combination therapy rapamycin and a radiolabeled gastrin analog. Further, one would have been motivated to provide 177Lu-PP-F11 as the radiolabeled gastrin analogue because Behe teaches that it exhibited best properties for future radio nuclide therapy due to its high favorable accumulation in the tumor accompanied by a low accumulation in the kidneys (paragraph 0006). Regarding claims 23, 30 and 33, Everolimus is further taught to be a suitable mTOR inhibitor used in clinical practice and would have been an obvious functional equivalent to rapamycin.
Conclusion
No claims are allowed at this time.
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/LHS/
/Michael G. Hartley/ Supervisory Patent Examiner, Art Unit 1618