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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/20/2025 has been entered.
Status of Claims
Claims 1, 2, 7, 17, 25, 26 and 30 have been amended. Claims 1-9, 17-19, 24-26, 28 and 30 are pending and are examined herein on the merits for patentability.
Response to Arguments
Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. The previous rejection has been modified in view of claim amendment. The Examiner’s response to Applicant’s arguments is incorporated below.
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) 1-9, 17-19, 24-26, 28 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over World Health Organization, "A Phase I/lla(early phase) Study of Targeted Radiotherapy alone for Stem Cell Transplant Conditioning in Systemic AL Amyloidosis", https://ictrptest.azurewebsites.net/Trial2.aspx?TriallD=EUCTR2015-002231-18-GB (2015) in view of Ozaki et al. (BioMed Research International, 2014, Article ID 394792, 7 pages), in further view of Benes et al. (US 2010/0183505) and Schultz et al., Blood, 2011, 117( 17), p. 4642-4650.
World Health Organization (WHO) teaches a Phase I/lla(early phase) Study of Targeted Radiotherapy alone for Stem Cell Transplant Conditioning in Systemic AL Amyloidosis. Trial subjects include 18 patients over age 65 years. Both III-In and 90-Y labelled anti-66 are taught. CHX A’-DTPA-Anti-CD66 is taught. The main objective of the trail is a phase I/IIa study to assess the use of a [90Y]labeled anti-CD66 as the sole conditioning prior to autologous stem cell transplant conditioning in patients with AL-amyloidosis. The main objective will be to determine the safety and toxicity associated with the use of the [90]labelled antl-CD66 as measured by CTCAE version 4.0 criteria and stem cell engraftment and hence establish the maximum tolerated radiation dese (MTD) over three Infused radiation activity levels. Primary end point(s): Primary objective is: Safety and toxicity of using [90Y}-anti-CD66 as the sole conditioning prior to autologous stem cell transplantation for Al-amyloidosis. In addition the study will allow the assessment of clonal response (as measured by serial FLC assay} and by using established, validated methods of FLOW cytometry to measure the change in malignant plasma cell population. Disease response, cardiac recovery, time to progression and overall survival will also be reviewed, whilst determining the engraftment status of patients. Finally the study will allow the assessment of the dosimetry model previously developed in Phase I and II trials in this patient group.
WHO does not specifically recite that patients are ineligible for treatment with high-dose melphalan preceding hematopoietic stem cell transplantation, recite the specific dosage of BW 250/183 as the antibody or the time frame of administration of RIC prior to stem cell transplantation.
Ozaki teaches that high-dose melphalan (200 mg/m2) as conditioning regimen followed by autologous stem cell transplantation (ASCT) rescue has been established as a standard treatment for patients with multiple myeloma (MM) younger than 65 years of age. However, the role of ASCT in elderly patients older than 65 years remains controversial in the era of novel agents such as thalidomide, bortezomib, and lenalidomide. The efficacy and feasibility of ASCT have been shown in elderly patients by reducing the dose of melphalan to 100–140 mg/m2 (abstract).
Accordingly, elderly patients aged 65 years or older are usually considered as ineligible for high-dose melphalan therapy (200 mg/m2) followed by ASCT. Thus, clinical trials of ASCT have been mostly undertaken in patients younger than 65 years of age, and reports of ASCT performed in elderly patients are hardly available (page 2).
As conditioning regimen before ASCT, reduced dose of melphalan to 100–140 mg/m2 has been used in the elderly patients (page 2).
ASCT can be applied to a selected patient of 65 years of age or older when performance status is fit and no comorbidities/complications are present. Recent studies have demonstrated that ASCT with intermediate-dose melphalan (100–140 mg/m2 ) is a safe and effective treatment modality in patients younger than 70 years of age. Although the benefit of reduced-intensity ASCT had not been clearly demonstrated in the past decade, it can be a viable option if incorporated into sequential treatment strategies along with novel agents. Therefore, the indication of ASCT should be seriously considered in each elderly patient based on the performance status and the presence of complications and/or comorbidities but not on chronological age alone. The sequential approach including ASCT can be challenging but would be feasible approach to further improve the outcome of elderly patients with MM (page 5).
Benes teaches a personalized treatment procedure consisting of a subsequent use of 111In-labelled anti-CD66 MAb for imaging and exact calculation of 90Y dosimetry adjusted to lean body weight followed by 90Y-labelled anti-CD66 MAb for bone marrow conditioning allows an optimized treatment of each individual patient guaranteeing high efficacy at no additional toxicity (paragraph 0114).
Benes teaches a radioimmunoconjugate (RIC) for the manufacture of a medicament for administration in the therapy of a haematological malignant disorder, wherein the RIC comprises a CD66-binding component and a radionuclide. The haematological malignant disorder is selected from multiple myeloma (MM), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic yndrome (MDS), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL) and lymphoma (i.e. marrow-associated diseases) (see claims 1-2). Therapeutically or diagnostically effective radionuclides are taught (90Y or IIIIn), claims 4-7. Determination of dose comprises administration of a RIC comprising an imaging radionuclide. The CD66-binding component of the imaging RIC and the therapeutic RIC is identical. Determination of dose comprises a calculation based on collected patient data. The CD66-binding component is an antibody, including BW 250/183 (claims 8-13). The radionuclide is covalently linked to the CD66-binding component via a chelating agent. The radionuclide is linked to the CD66-binding component via a structure of the formula -[(chelating agent)-(R1)p-(R2-R3)n]m-(CD66-binding component). The chelating agent may be DTPA, DOTA, etc. The preferred therapeutic dose is about 35 MBq/kg, etc. (claims 17-19).
Schulz teaches that targeted irradiation of the bone marrow with radiolabeled monoclonal antibodies (radioimmunotherapy) represents a novel therapeutic approach with both myeloablative and antileukemic potential.
The anti-CD66 antibody (antigranulocyte, anti–nonspecific cross-reacting antigen 95; BW 250/183) is well characterized with respect to biokinetic data and clinical application in bone marrow (BM) scintigraphy.
The anti-CD66 antibody used in this study is (BW250/183). The labeling with 111In or 90Y was conducted in 2 steps. First, the bifunctional chelator [2-(p-SCN-Bz-)-6-methyldiethylenetriaminepentaacetic acid [DTPA]] was attached to the antibody, and second the radioisotope was bound to the chelator. (Supplemental materials).
Patients received a therapeutic dose of 90Y-labeled anti-CD66 antibody as a single dose by slow intravenous push. The therapeutic 90Y activity was calculated on the basis of the serial total-body gamma camera counts32 with the use of adequate phantoms provided by OLINDA/EXM software33 to deliver a dose to the BM of 30-35 Gy in patients in complete remission, 35 to 40 Gy in patients not in complete remission in the malignant group, and 16-20 Gy in the nonmalignant group.
HCT was performed 14 days after infusion of the radiolabeled antibody (step 2) to avoid relevant irradiation of the graft (page 4646).
It would have been obvious to one of ordinary skill in the art at the time of the invention that patients over 65 years old in the study of WHO would not be eligible for treatment with high-dose melphalan preceding hematopoietic stem cell transplantation when the teaching of WHO is taken in view of Ozaki. One would have been motivated to omit melphalan administration, with a reasonable expectation of success, to such patients because WHO teaches radiotherapy alone for stem cell transplant conditioning, and because Ozaki specifically teaches elderly patients aged 65 years or older are usually considered as ineligible for high-dose melphalan therapy (200 mg/m2) followed by ASCT.
With regard to the limitation wherein treating AL-amyloidosis does not involve administering an additional anti-tumor agent or an immunosuppressive agent at least four weeks before and/or after the stem cell transplantation, it is noted that WHO teaches [90Y]labeled anti-CD66 as the sole conditioning prior to autologous stem cell transplant conditioning in patients with AL-amyloidosis, thus it is considered that additional treatments would not be administered.
It would have been further obvious to one of ordinary skill in the art to administer BW 250/183 as the anti-CD66 antibody in the methods of WHO when the teaching of WHO is taken in view of Benes and Shulz. One would have been motivated to do so, with a reasonable expectation of success, because Benes and Shulz show III-In and 90Y labeled BW 250/183 for successful imaging / conditioning prior to stem cell transplant. HCT was performed 14 days after infusion of the radiolabeled antibody to avoid relevant irradiation of the graft (page 4646). With regard to the limitation wherein the therapeutic RIC is administered at a dose of is between 30 and 60 MBq/kg lean body weight (lbw), Benes teaches the preferred therapeutic dose of radiolabeled anti-CD66 monoclonal antibody is about 35 MBq/kg, etc. (see claims 17-19). Schulz teaches 16-40 Gy as a dosage for 90Y-labeled anti-CD66 antibody. It would have been obvious to select from dosage of radiolabeled anti-CD66 antibody known to be suitable for therapeutic use in bone marrow conditioning and to optimize the dosage as a matter of routine experimentation to determine the effective therapeutic amount. For example, Benes teaches dosimetry study, including dosage escalation studies, including determination of toxicity and efficacy, see e.g. paragraphs 0056+., 0090,0097+. 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).
Response to arguments
Applicant argues that amended claims 1-2, and 30 recite, inter alia, a method comprising administering to a patient a radioimmunoconjugate (RIC), wherein a therapeutic RIC is administered at a dose of between about 30 and 60 MBq/kg lean body weight (lbw). Applicant asserts that WHO fails to disclose or suggest administering a dose of between about 30 and 60 MBq/kg lbw. In addition, WHO makes clear that its methods are for use in fit, transplant-eligible patients, i.e., patients “who satisfy all standard transplant inclusion criteria (good organ function, no significant heart involvement, good performance status.” WHO specifically excludes those with “poor performance, advanced organ involvement or significant cardiac involvement.” WHO, 1. Applicant asserts that there is no disclosure or suggestion in WHO that the RIC dosage should be or could be administered to the claimed patient population, which is explicitly excluded. Applicant argues that the Office attempts to rely upon Ozaki “to show that elderly patients aged 65 years or older (i.e., as included in the WHO study) are usually considered as ineligible for high-dose melphalan therapy.” Applicant asserts that just as there is a patient population under 65 which is excluded by WHO, one of ordinary skill would understand age guides eligibility but fitness is determinative. /d. Further, while Ozaki states “elderly patients aged 65 years or older are usually considered ineligible for high-dose melphalan therapy” it continues on to specify that “elderly patients, if in a fit medical condition, have been considered to be eligible” and lists 7 clinical trials in which the elderly age group, e.g., subjects aged ~65- 70, were administered high-dose melphalan, 1.e., “MEL 200.” Ozaki, 2 and Table 2. Applicant contends that the population addressed in the claims, i.e., those ineligible for high-dose melphalan, is not addressed by WHO or Ozaki either alone or in combination.
Applicant’s arguments have been fully considered but are not found to be persuasive. With regard to the assertion that the population addressed in the claims, i.e., those ineligible for high-dose melphalan, is not addressed by WHO or Ozaki either alone or in combination, it is respectfully submitted that the instant Specification does not define the patient population that is “ineligible for high-dose melphalan.” As such, the claims are being given the broadest reasonable interpretation of the claims that is consistent with an interpretation that those skilled in the art would reach, see MPEP 2111. In the instant case, it is considered that one of ordinary skill in the art would have found it obvious for a patient 65 years or older with systemic AL-amyloidosis to be ineligible for high-dose melphalan because Ozaki teaches that elderly patients aged 65 years or older are usually considered as ineligible for high-dose melphalan therapy (200 mg/m2) followed by ASCT. With regard to the passage cited by Applicant in which “elderly patients, if in a fit medical condition, have been considered to be eligible” it is noted that the full passage on page 2 states that:
Thereafter, elderly patients, if in a fit medical condition, have been considered to be eligible for ASCT irrespective of the chronological age in most institutions. Several single institution studies have reported the experience of ASCT in elderly patients as well as in younger patients (Table 2). As conditioning regimen before ASCT, reduced dose of melphalan to 100–140 mg/m2 has been used in the elderly patients.
It is further noted that WHO does not does not use the terms “fit” to describe the AL-amyloidosis patients. Accordingly, it is considered that given the broadest reasonable interpretation of the claims in view of the state of the prior art, one of ordinary skill in the art would have found it obvious that elderly AL-amyloidosis patients in WHO would be interpreted as ineligible for high dose melphalan, as elderly patients are stated to be usually considered ineligible for high-dose melphalan therapy by Ozaki, which further considers lower doses of melphalan in elderly patients. It is further noted that WHO does not administer melphalan to the patients, and teaches 90Y]labeled anti-CD66 as the sole conditioning agent prior to autologous stem cell transplant conditioning.
Applicant further argues that WHO fails to disclose or suggest the use of the anti-CD66 antibody BW 250/183 and that Benes and Schulz either alone or in combination fail to render obvious the claimed therapeutic RIC range, and therefore fail to cure this deficiency in WHO. Applicant asserts that WHO expressly excludes high-risk transplant ineligible patients covered by the present claims, Benes is specifically directed to standard, transplant-eligible patients who are able to tolerate high-dose melphalan, the opposite of the claimed population. The clinical studies disclosed by Benes focus on adults who meet the conventional criteria for stem cell transplantation, evidenced by the fact that “the majority of patients (10 of 12) were receiving high dose melphalan,” citing paragraph 0058. Applicant argues that Benes fails to disclose or discuss the use of Y-90-labeled anti-CD66 antibodies in patients who are medically ineligible for high-dose melphalan due to comorbidities, advanced age, or organ dysfunction. Applicant contends that the Benes patient population is distinctly different from the patient population recited in the present claims, and that there is no suggestion or discussion which would lead a person of ordinary skill in the art to apply the Benes disclosure to the patient population recited in the present claims. Similarly, Schulz addresses a population of nonmalignant or high-risk pediatric patients, i.e., children specifically vulnerable to “nonrelapse mortality” due to toxicity. Schulz, 4642. For these patients, Schulz deliberately limits the “target dose to the marrow of 16-20 Gray” and further reduces the dose to avoid exceeding organ toxicity thresholds. Applicant asserts that the presently claimed dose range, 1.e., 30 to 60 MBq/kg would correspond to marrow doses far exceeding those Schulz administered to an at-risk population, underscoring that Schulz discloses dose limitation, not escalation for high-risk groups. Therefore, WHO, Ozaki, Benes, and Schulz either alone or in combination fail to provide any disclosure, suggestion, or reasonable expectation of success for administering 30 to 60 MBq/kg RIC dose to patients that are ineligible for high-dose melphalan.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is noted that the instant claims do not recite transpant-ineligble patients, rather high-dose melphalan ineligible patients. It is further noted that WHO does not expressly excludes high-risk transplant ineligible patients, as the intent of WHO is to provide [90Y]-labelled anti-CD66 as the sole conditioning prior to autologous stem cell transplant conditioning in patients with AL-amyloidosis. With regard to the assertion the patient population is distinctly different in Benes and Schultz than the population of the instant claims, it is respectfully submitted that while Benes and Schultz teach another patient populations than that in WHO, each of WHO, Benes and Schultz are directed to bone marrow conditioning upon administration of radiolabeled anti-CD66 immunoconjugates. It would have been obvious to one of ordinary skill in the art to select from known dosages of radiolabeled anti-CD66 antibody known to be suitable for therapeutic use in bone marrow conditioning and to optimize the dosage as a matter of routine experimentation to determine the effective therapeutic amount for a desired patient population. For example, Benes teaches dosimetry study, including dosage escalation studies, including determination of toxicity and efficacy, see e.g. paragraphs 0056+., 0090,0097+. Further Benes states that first results indicate the expected highly efficacious treatment of RIC with respect to progression free survival and overall survival. Results suggest that radiation doses higher than 25 MBq/kg bodyweight may induce a high rate of complete remissions in multiple myeloma patients (paragraph 0097) and about 35 MBq/kg for administration in the therapy of a haematological malignant disorder is preferred (claim 19). Further, each of the dosages set forth in Schultz are within the scope of “about” 30 MBq/kg. Applicant’s arguments have been fully considered but the rejection is maintained.
Conclusion
No claims are allowed at this time.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618