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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 4/8/2026 has been entered.
Status of Claims
Claims 1, 3-5, 11, 12, 15, 16, 18 and 19 have been amended. Claims 1, 3-5, 8, 9, 11-16, 18 and 19 are pending and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments and the Declaration of Inventor Longcor have been fully considered. Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. The previous rejections have been modified in view of claim amendment. The Examiner’s response to Applicant’s arguments is incorporated below.
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, 3-5, 8, 9, 11-16, 18 and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/044752 (reference application) in view of Clarke (US 2011/0183866), for reason set forth in the previous Office Action. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to arguments
Applicant requests that this rejection be held in abeyance until the present claims are deemed allowable.
Applicant’s arguments have been fully considered. The rejection is maintained as a terminal disclaimer has not been received at this time.
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) 1, 3-5, 8, 9, 11-16, 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Weichert et al. (US 2007/0020178) in view of Cellectar Biosciences (“Three Abstracts on Dosing Regimens of Cellectar’s CLR 131 in a Variety of Tumor Types Published in the 2017 ASCO Annual Meeting Proceedings,”
https://www.cellectar.com/news-media/press-releases/detail/130/three-abstracts-on-dosing-regimens-of-cellectars-clr-131, 2017), in further view of Cellectar Biosciences (II) (“Fractionated Dosing Improves Tolerability and Safety of Cellectar’s CLR 131 in R/R Multiple Myeloma Patients,” https://www.cellectar.com/news-media/press-releases/detail/187/fractionated-dosing-improves-tolerability-and-safety-of, 2018) and Cellectar Biosciences (III) (“Cellectar Reports Positive Phase 2 Interim Data for CLR 131 in Relapsed/Refractory DLBCL Patients,” https://d1io3yog0oux5.cloudfront.net/_7d4c6abbfa81dd2273f17aa7b5bf9839/cellectar/news/2018-07-18_Cellectar_Reports_Positive_Phase_2_Interim_Data_182.pdf, 2018) and Clarke (US 2011/0183866).
Weichert teaches a method for the treatment of recurrence of cancer, radiation and chemo insensitive cancer or metastasis of cancer in a subject. The method comprises administering to the subject an effective amount of a compound comprising a phospholipid ether analog. In a preferred embodiment, the recurrence of cancer, radiation and chemo insensitive cancer or metastasis of cancer occurs in the group selected from Lung cancer, Adrenal cancer, Melanoma, Colon cancer, Colorectal cancer, Ovarian cancer, Prostate cancer, Liver cancer, Subcutaneous cancer, Squamous cell cancer, Intestinal cancer, Hepatocellular carcinoma, Retinoblastoma, Cervical cancer, Glioma, Breast cancer, Pancreatic cancer and Carcinosarcoma. Also preferably, the phospholipid analog is selected from
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where X is selected from the group consisting of radioactive isotopes of halogen; n is an integer between 8 and 30; and Y is selected from the group comprising NH2, NR2, and NR3, wherein R is an alkyl or arylalkyl substituent; in this method, preferably, X is selected from the group of radioactive halogen isotopes consisting of 18F, 36Cl, 76Br, 77Br, 82Br, 122I, 123I, 124I, 125I, 131I, 211At and combinations thereof (paragraph 0027-9).
Most preferably, the effective amount of phospholipid ether analog is a combination of at least two isotopes, 125I and 131I. Also, preferably, the phospholipid ether is 18-(p-Iodophenyl)octadecyl phosphocholine, 1-O-[18-(p-Iodophenyl)octadecyl]-1,3-propanediol-3-phosphocholine, or 1-O-[18-(p-Iodophenyl)octadecyl]-2-O-methyl-rac-glycero-3-phosphocholine, wherein iodine is in the form of a radioactive isotope (paragraph 0030-1).
In certain embodiments, the effective amount of phospholipid ether analog is fractionated. In yet other embodiments, the effective amount of phospholipid ether analog is about 0.5 µCi to about 3 Ci treatable in a linear and dose dependent manner. Other embodiments provide that the dosage is adaptable to the cancer-volume. Yet other embodiments provide that the dosage for radiation insensitive tumor is greater than dosage for radiation sensitive tumor and less than 3 Ci and is adaptable to the cancer-volume (paragraph 0032).
Exemplary compounds include:
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FIG. 11. shows A549 Tumor Xenografts (1 x 106 cells, s.c.) in Female SCID Mice Fractionated Dose (3 x 50 mCi), having 2 independent controls for each dosage. A fractionated dosing of NM404 (e.g. 3 x 50 micro-Ci versus a single dose of 150 micro-Ci) produced the same therapy effect. The fractionated dose may be safer since it is eliminated from normal tissues in between fractionated injections (paragraph 0047).
The PLE compounds may be designed to more accurately estimate the specificity and sensitivity of radiolabeled PLE analogs such as NM404 as an imaging agent in prostate cancer and other cancers. Based upon preclinical models, PLE analogs such as NM404 are likely to exhibit high uptake in tumors giving this agent the significant potential for use in staging, following response to therapy, or potentially as a therapeutic agent when coupled with higher doses of 131I, 125I, or 211At an alpha-emitting halogen with therapeutic efficacy (paragraph 0093).
As shown in FIG. 11 in certain embodiments, the effective amount of phospholipid ether analog is fractionated. The advantage of using fractionated dosage is that it allows for the PLE analog to be removed from normal tissues. As an example, fractionated dosing of NM404 (e.g. 3 x 50 micro-Ci versus a single dose of 150 micro-Ci) produced the same therapy effect, while still providing low doses of compounds which is then eliminated from normal tissues in between fractionated injections (paragraph 0104).
The effective amount of phospholipid ether analog is about 0.5 µCi to about 500 mCi (paragraph 0105).
Weichert does not specifically recite wherein a first dose of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine is administered on day 1; a second dose is administered on one of days 13-18; and a third dose is administered on one of days 55-65 and a fourth dose 7-14 days thereafter.
Cellectar Biosciences teaches preclinical data from three abstracts demonstrating the utility of the company’s lead compound, CLR 131, for use in a variety of tumor types in single-dose and multi-dose regimens.
In the first study, 20 mice were injected with glioma (brain) tumor cells (U87-MG). Investigators then injected two doses of CLR 131 (95.7µCi and 109.0 µCi on day 0 and day 7, respectively) or a control group of I-127-CLR 1404 (N=8 per group). The expected 25-fold increase in tumor burden observed in the control arm over the four-week study was reduced by 50 percent in the CLR 131 arm with additional survival benefit. In fact, the two doses of CLR 131 provided a 50 percent increase in survival over a single dose of CLR 131 in the same model.
The second study involved female mice receiving two doses of CLR 131 (approximately 130 µCi and approximately 145 µCi at days 0 and 20, respectively) as well as a control group of I-127-CLR 1404 (N=8 per group), following injection of female mice with a MES SA/Dx5 cell line (human uterine sarcoma). This model was selected because of its high level of expression of resistance mechanisms these tumor cells exhibit, specifically P-gp efflux pumps that eject many chemotherapeutics from the cell. The active treatment group (CLR 131) experienced a 66 percent reduction of the expected 21-fold increase in tumor burden observed in the control group. This resulted in nearly doubling the survival time for the mice receiving two doses of CLR 131.
Cellectar biosciences II teaches fractionated dosing improves tolerability and safety of cellectar’s CLR 131 in R/R multiple myeloma patients, as in cohort 5 of the company’s ongoing Phase 1b clinical trial evaluating CLR 131 for the treatment of relapsed/refractory (R/R) multiple myeloma (MM). Unlike prior cohorts that used single doses of CLR 131, Cohort 5 utilized a fractionated two dose regimen of 15.625 mCi/m2 given approximately one week apart. This dosing schedule provides higher average drug exposure but lower peak serum levels than non-fractionated dosing potentially reducing adverse events and improving efficacy. The independent Data Monitoring Committee (DMC) determined the fractionated dose used in Cohort 5 to be safe and well tolerated and recommended advancement to a higher dose cohort. Results from Cohort 5 indicate enhanced tolerability and safety in comparison to Cohort 4 despite an 18% increase in total average dose from 55.29 mCi to 65.15 mCi of CLR 131. Patients in Cohort 5 required less supportive care such as transfusions of platelets or packed red blood cells than seen in previous cohorts. Based on the results and DMC recommendation, the company plans to initiate a sixth cohort using a fractionated dose regimen of two doses of 18.75 mCi/m2 administered one week apart and to modify the dosing regimen of its ongoing Phase 2 trial of R/R hematologic malignancies to use fractionated dosing. In addition to the improved safety profile demonstrated in Cohort 5, the company also monitored signals of efficacy. Despite Cohort 5 patients averaging 5 lines of prior systemic therapies, all patients experienced clinical benefit with two patients achieving minimal responses and two stable disease. Furthermore, looking at surrogate markers, patients in Cohort 5 monitored by M-protein showed a nearly 50% further reduction in M-protein than seen in Cohort 4.
Cellectar Biosciences III teaches a phase 2 study is being conducted in approximately 10 leading cancer centers in the United States for patients with relapsed or refractory B-cell hematologic cancers. The hematologic cancers being studied in the trial include multiple myeloma (MM), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), lymphoplasmacytic lymphoma (LPL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), and potentially diffuse large B-cell lymphoma (DLBCL).
The study's primary endpoint is clinical benefit response (CBR), with additional endpoints of progression free survival (PFS), median overall survival (OS) and other markers of efficacy following a single 25.0 mCi/m2 dose of CLR 131, with the option for a second 25.0 mCi/m2 dose approximately 75-180 days later. In addition to the CLR 131 infusion(s), MM patients will receive 40 mg oral dexamethasone weekly for up to 12 weeks. Efficacy responses will be determined by the latest International Multiple Myeloma Working Group criteria.
Clarke teaches use of the therapeutic radionuclide iodine-131 antibody conjugates to kill a targeted cancer stem cell in which injections are repeated twice a week for two to three weeks and the effect on tumor growth rate and size is assessed (paragraph 0467).
It would have been obvious to one of ordinary skill in the art at the time of the invention to administer 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof for treatment of a cancer in a subject, wherein the 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof is administered as a fractionated dose, including via at least third and fourth dosage infusions. One would have been motivated to do so because Weichert teaches that providing three fractionated doses allows for the same therapeutic effect as a single dose and may be safer since it is eliminated from normal tissues in between fractionated injections. Further, Cellectar I teaches a 50 percent increase in survival over upon administration of fractionated doses at day 0 and day 7 compared to a single dose of CLR 131 in the same model. Cellectar II provides a two dose regimen of 15.625 mCi/m2 given approximately one week apart, which provides higher average drug exposure but lower peak serum levels than non-fractionated dosing potentially reducing adverse events and improving efficacy in human patients; and Cellectar III administers a 25.0 mCi/m2 dose of CLR 131, with the option for a second 25.0 mCi/m2 dose approximately 75-180 days later. With regard to the limitations wherein a first dose of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine or a salt thereof is administered on day 1; a second dose is administered on one of days 13-18; and a third dose is administered on one of days 55-65, and a fourth dose 7-14 days thereafter, it is noted that one of ordinary skill in the art can readily optimize effective doses and administration regimens in order to determine the most favorable effect, as it is shown from Weichert and Cellectar I-III to modify the dosage and time between administration of fractionated dosages of 131I-labeled 18-(p-iodo-phenyl)octadecylphosphocholine. Clarke further teaches at least two-six individual doses (twice a week for two to three weeks) and the effect on tumor growth rate and size is assessed using 131I conjugated antibody for targeted treatment of stem cells. One would have been motivated to administer third and fourth fractionate doses in order to utilize the best possible administration of repeat dose intravenous injection composition within the workable parameters described by Weichert and Cellectar I-III in order to produce the best possible treatment method for the individual patient by establishing the best individualized therapy option in view of Clarke. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary. For example, one would have been capable of administering multiple doses (i.e. at least four) and assessing tumor growth as taught by Clarke.
Regarding the limitation wherein the total effective dose is about 100 mCi/m2 and the four doses are equivalent, it is noted that Weichert teaches the dose may be in the range of is about 0.5 µCi to about 500 mCi (paragraph 0105) and teaches equivalent fractions, Fig 11; one of ordinary skill in the art could have readily selected from within the claimed range as a means of determining a therapeutically effective amount of active agent. In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant clams would have been obvious within the meaning of 35 USC 103(a). Furthermore, differences in concentration or temperature will generally not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; or In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). Accordingly, it would have been further obvious to optimize dosage based on weight of individual patient from among the teachings of Weichert, Cellectar I-III and Clarke. Regarding claim 14, Cellectar Biosciences teaches further administration of dexamethasone.
Response to arguments
Applicant directs the Examiner's attention to Dr. Jarrod Longcor's Declaration under 37 C.F.R. § 1.132 and asserts that per the Declaration, "[t]he total delivered dose for the fractionated dosing formulation over the four individual doses was ≥60 mCi per patient and ≤130 mCi per patient." Declaration, 1 8. Further, "[t]he fractionated dosing method total was 1.2-fold to 2.6-fold of the single bolus method. The Declaration states that more unexpected was the overall response rate of the fractionated dosing method, which far exceeded that of the single bolus method, being 5.4-fold greater for multiple myeloma patients that are quad/penta-drug refractory." Declaration, I 9. Applicant argues that in addition to the foregoing, one skilled in the art would expect that a worsened safety profile would result from an increased administered dose. However, safety data in paragraph 10 of the Declaration for "a fractionated dosing method with single fractionated doses of 15 mCi/m² administered at days 1, 15, 57, and 71" shows that, despite the additional 3ʳᵈ and 4th single fractionated doses yielding a total dose of 60 mCi, the average adverse effects were not made worse. Declaration, 1 10. Applicant submits that the Examiner has not provided any rationale for how the claimed dosing regimen of four single fractionated doses, and extended gap between the 2ⁿᵈ and 3rd doses, would predictably yield the above referenced results. Applicant further argues that Clarke does not describe any days-interval timing of doses and one skilled in the art would not be motivated to turn to an antibody-based therapeutic for a phospholipid ether dosing regimen, and would not turn to a prophetic example without results as in Clarke for a clinical therapeutic protocol as presently claimed. Further, "one skilled in the art would find little to no benefit from Clarke in attempting to modify Weichert." Declaration, 1 12.
Applicant’s arguments have been fully considered but are not found to be persuasive. See MPEP 716.02(e) directed to comparison with closest prior art. An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). "A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference." In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential).
In the instant case, it is respectfully submitted that the unexpected results asserted in the Declaration amount to a comparison between a single bolus of 131I-labeled 18-(p-iodo-phenyl)octadecyl phosphocholine to patients compared to a fractionated dosing formulation was a total dose divided into four individual fractionated doses, page 3. However, each of Weichert, Cellectar biosciences 1 and II teach fractionated dosing of CLR 131. For example, Cellectar biosciences II teaches fractionated dosing improves tolerability and safety of Cellectar’s CLR 131 in R/R multiple myeloma patients. Accordingly, it is considered that the Declaration does not compare the claims to the closest prior art. The Clarke reference is relied upon for further administering multiple doses (i.e. at least four) and assessing tumor growth.
Conclusion
No claims are allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEAH H SCHLIENTZ whose telephone number is (571)272-9928. The examiner can normally be reached Monday-Friday, 8:30am - 12:30pm EST.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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