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 .
Acknowledgement of Receipt
Applicant’s Response, filed 6/17/2026, in reply to the Office Action mailed 12/18/2025, is acknowledged and has been entered. Claims 1-9, 17-19, 24-26, 28 and 30 are pending and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments and the Declaration of Inventor Orchard have been fully considered. The response to Applicant’s arguments and the Declaration are 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/Ila(early phase) Study of Targeted Radiotherapy alone for Stem Cell Transplant Conditioning in Systemic AL Amyloidosis", https://ictrptest.azurewebsites.net/Trial2.aspx?TrialD=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, for reasons set forth in the previous Office Action.
Response to arguments
Applicant argues that WHO fails to disclose or suggest administering a dose of between about 30 and 60 MBq/kg lbw. Applicant asserts that WHO is a clinical trial protocol submitted for WHO clinical-trial registration entry which discloses the intention to conduct a study but provides no experimental results, no dose-response data, and no indication that any particular dose within the claimed range would be effective as monotherapy. The Declaration of Inventor Orchard notes that "Concentration number: 2-5" entry in the WHO clinical trial register does not refer to MBq/kg dosage and that this entry refers to antibody concentration and not to a dosage of the administered activity. Applicant asserts that a skilled person reading the WHO entry would not understand "Concentration number: 2-5" to be a therapeutic administered activity for bone marrow conditioning. WHO, pg. 1. Applicant notes that ti the prior Phase I/Benes dose-escalation data, 5 MBq/kg delivered a mean absorbed marrow dose of only about 4.12 Gy (citing Benes, Table 2), which is far below the absorbed marrow-dose levels used by Schulz for myeloablation/conditioning (16-20 Gy in the non-malignant group and 30-40 Gy in malignant patients), citing Schulz, pg. 4643. Accordingly, 2-5 MBq/kg would not be understood as the disclosed therapeutic conditioning dose for the claimed monotherapy. Applicant further argues that WHO does not teach BW250/183 or an isothiocyanate linker on the CD66-binding component-NH-CS-NH-Bn-CHX-A"-DTPA.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is acknowledged that WHO does not teach wherein a therapeutic RIC is administered at a dose of between about 30 and 60 MBq/kg lean body weight. However, see MPEP 2145. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. Where an applicant’s reply establishes that each of the applied references fails to teach a limitation and addresses the combined teachings and/or suggestions of the applied prior art, the reply as a whole does not attack the references individually as the phrase is used in Keller and reliance on Keller would not be appropriate. This is because “[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA].” In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012). In the instant case, the rejection is based upon the combined teachings of WHO, Benes and Schultz, both of which teach radiolabeled BW250/183 for targeted irradiation of bone marrow, including Benes teaching a dose of 35 MBq/kg as preferable dose, and Schultz teaching a targeted irradiation of bone marrow via delivery of BW250/183 labeled with 111In or 90Y complexed with 2-(p-SCN-Bz-)-6-DTPA 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. As such it is considered that the claimed dosage of the anti-CD66 antibody would have been an amount known to one of skill in the art for targeted bone marrow irradiation.
Applicant further argues that Ozaki, Benes, and Schulz fail to cure the deficiencies of WHO. Applicant asserts that Ozaki does not disclose any anti-CD66 RIC, antibody, or dosage. Ozaki is directed to the treatment of multiple myeloma (MM) via "ASCT [autologous stem cell transplantation] with intermediate-dose melphalan", NOT AL-amyloidosis. Applicant argues that Benes fails to disclose BW 250/183 linked via CHX-A"-DTPA. Moreover, Benes discloses doses up to 37.5 MBq/kg but exclusively in combination with high-dose melphalan or reduced-intensity conditioning regimens, e.g., 90Y-labelled anti-CD66 was used in addition to the scheduled transplant conditioning." Citing Benes, paragraph 0058, and that Benes does not disclose monotherapy.
Applicant further argues that Schulz teaches BW 250/183 with [2-(p-SCN-Bz)-6-methyldiethylenetriaminepentaacetic acid [DTPA]] and 90Y. Applicant asserts that Schulz describes "[t]his pilot study demonstrates that radioimmunotherapy is effective in achieving myeloablation with low additional toxicity when used in combination with standard or reduced intensity conditioning." Schulz, Abstract. Thus, all patients received either myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) in addition to anti-CD66 radioimmunotherapy Schulz does not disclose or suggest the claimed monotherapy. Applicant notes that Schulz does not disclose CHX-A"-DTPA specifically. It is discussed in the Declaration on p. 4643 that Schulz reports doses in Gray (Gy), not MBq/kg and the Gray values do not correspond to MBq/kg dosages in the claimed range, particularly in the context of monotherapy.
Applicant’s arguments have been fully considered but are not found to persuasive. With regard to the Ozaki reference, it is noted that Ozaki is include to show that patients in the WHO study meet the definition of a patient ineligible for treatment with high dose melphalan, as required by claims 1, 2 and their dependent claims, not for administration of an anti-CD66 antibody itself. With regard to the assertion that Benes teaches doses up to 37.5 MBq/kg but exclusively in combination with high-dose melphalan or reduced-intensity conditioning regimens, it is noted that Benes is relied upon for teaching a known dose of anti-CD66 antibody; WHO is relied upon for monotherapy.
Applicant further argues that in further support, Applicant draws attention to the post-filed evidence submitted herewith. Applicant asserts that in Orchard 2024, all patients in the Orchard 2024 study additionally received "standard conditioning regime" of (HD-melphalan or RIC) alongside the anti-CD66 - confirming that at the time of the study, monotherapy was not the standard of care. Id. The unexpected discovery that anti-CD66 alone is sufficient for conditioning is separately confirmed by the TRALA study results (Orchard et al., Blood, 2021, 138:3819) ("Orchard 2021"), which demonstrated successful engraftment and disease response in all patients receiving 90Y-anti-CD66 "as the sole conditioning agent" at doses of 30-45 MBq/kg lbw. Orchard 2021, Abstract. Applicant further recites that the specific CHX-A"-DTPA chelator structure recited in the present claims and demonstrates improved organ dosimetry compared to earlier chelator variants, citing the Winter document.
Applicant’s arguments have been fully considered but are not found to be persuasive. With regard to the allegation of the unexpected discovery that anti-CD66 alone is sufficient for conditioning, see MPEP 2144. Obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g.,In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). In the instant case, it is respectfully submitted that WHO provides at least a reasonable expectation of success in use of targeted radiotherapy alone for stem cell transplant conditioning in systemic AL amyloidosis, as it was at least envisaged/expected to be the goal of the study. With regard to the assertion that CHX-A"-DTPA demonstrates improved organ dosimetry compared to earlier chelator variants, it is noted that WHO already teaches CHX-A"-DTPA as chelator and Schultz teaches isothiocyanate as a linker between the chelator and antibody.
Applicant further argues that the Office has not presented a convincing line of reasoning that a person of ordinary skill in the art would combine the teachings of WHO with Ozaki, Benes, and Schulz to arrive at the claimed subject matter. Applicant asserts that the references address fundamentally different diseases and patient populations, as WHO is directed to AL-amyloidosis in fit, transplant-eligible patients aged >65 who "satisfy all standard transplant inclusion criteria." WHO, pg. 1. WHO specifically excludes patients with "poor performance, advanced organ involvement or significant cardiac involvement. With regard to Ozaki, Applicant assert that a skilled person would not look to MM treatment paradigms (Ozaki) to inform treatment of AL-amyloidosis (WHO) without a clear teaching or suggestion to do so. Applicant asserts that Benes is directed to hematological malignancies (predominantly myeloma) with all patients receiving additional "scheduled transplant conditioning." Benes, 1 [0058]. Applicant contends that a skilled person would recognize that the conditioning requirements for AL-amyloidosis patients (who are often fragile due to cardiac involvement) differ substantially from those for myeloma patients. Schulz is directed to high-risk pediatric patients with "malignant and nonmalignant diseases." Schulz, Title. The patient population in Schulz - children specifically vulnerable to non-relapse mortality - is entirely different from the population of the present claims (adults ineligible for HD-melphalan with AL-amyloidosis).
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that, as set forth above, Ozaki is merely include to define a patient as ineligible for high dose melphalan. With regard to the assertion that the references address fundamentally different diseases and patient populations, it is noted that claim 1 does not require a condition, and is directed to any bone marrow conditioning procedure. With regard to claims 2 and 30 directed to AL-amyloidosis, and the assertion that a skilled person would recognize that the conditioning requirements for AL-amyloidosis patients (who are often fragile due to cardiac involvement) differ substantially from those for myeloma patients, and that Schulz is directed to high-risk pediatric patients with "malignant and nonmalignant diseases,” it is noted that in Benes the median age at diagnosis is 60-65 years, which is consistent with the patient population in WHO and further that a variety of disorders may be include leukemia, which may be selected from multiple myeloma (MM), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL) and lymphoma. Schultz is included to demonstrate isothiocyanate as a suitable linker between the chelator and anti-CD66 antibody.
Applicant further argue that Benes and Schultz teach away from monotherapy. However, the primary reference readily teaches monotherapy. Benes and Schultz are relied upon to address known dosage of anti-CD66 for bone marrow conditioning and a linker to link a known chelator to the antibody, respectively. Further it is noted that Benes states that radionucleotides suitable for imaging and/or therapeutic irradiation of bone marrow as well as tumor cells. The RIC administration is preferably a conditioning regimen in combination with further therapeutic measures. See MPEP 2123. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).
Applicant further argues that the present claims demonstrate, contrary to the teaching of the prior art, that 90Y-DTPA-besilesomab administered as the SOLE conditioning agent (without additional chemotherapy) prior to autologous HSCT is safe and effective, asserting that this is a surprising and unexpected result, citing post-filed clinical data.
With regard to the allegation of the unexpected discovery that anti-CD66 alone is sufficient for conditioning, see MPEP 2144. Obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g.,In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). In the instant case, it is respectfully submitted that WHO provides at least a reasonable expectation of success in use of targeted radiotherapy alone for stem cell transplant conditioning in systemic AL amyloidosis, as it was at least envisaged/expected to be the goal of the study.
Applicant further argues that it is not routine to optimize dosage. Applicant asserts that the claimed dose range of 30-60 MBq/kg lbw as monotherapy in HD-melphalan-ineligible patients is not routine optimization for the following reasons becasue no prior art reference teaches this dose range as MONO-therapy. Benes discloses doses up to "37.5 MBq/kg" but only in combination with additional conditioning. Benes, IT [0056], [0058], and [0060]. The therapeutic context is entirely different, doses that work in combination with HD-melphalan cannot simply be transposed to monotherapy without any expectation that they would be effective alone.
Appliant’s arguments have been fully considered but are not persuasive. Benes states in paragraph 0027: The administration of the therapeutic RIC for the treatment of human patients is preferably in a dose of about 10 MBq/kg body weight (bw), preferably of about 15 MBq/kg bw, more preferably of .gtoreq.about 20 MBq/kg bw, still more preferably of about 25 MBq/kg bw, still more preferably of about 30 MBq/kg bw and still more preferably of about 35 MBq/kg bw. The RIC may be administered according to known methods, e.g. by infusion., as such Benes teaches variation in dose. One of ordinary skill could have readily optimized the dosage within the range to determine best result. Further, Benes teaches that the RIC of the invention is preferably administered as conditioning regimen in a therapy which comprises additional measures, e.g. administering an antitumor agent, administering an immunosuppressive agent, and/or stem cell transplantation. As such, the secondary measure may be stem cell transplant, and does not necessarily require an additional antitumor agent. See also MPEP 2123. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). Arguments directed to summarizing the points in the Declaration are incorporated individually as above. The arguments and Declaration have been fully considered but the rejection is maintained.
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.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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