RESPONSE TO APPLICANT’S AMENDMENT
1. Applicant's amendment, filed 09/04/2026, is acknowledged.
2. Claims 1-2, 4-6, 8-14, and 51-52 are pending.
3. Claim 5 stands withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
4. Claims 1-2, 4, 6, 8-14 and 51-52 are under examination as they read on a method of treating multiple myeloma, lymphoma, acute myeloid leukemia (AML), prostate cancer or mRCC with an anti-CD46 antibody conjugated to a cytotoxic effector and an agent that is IMid and optionally in combination with SEGRAM and the species YS5 comprising the VH CDR1-3 of SEQ ID NOs: 80, 81, 82 and VL CDR1-3 of SEQ ID NOs: 83, 84, 85 and a chemotherapeutic agent as the cytotoxic effector with IMid treatment, wherein the IMid is pomalidamide.
5. Applicant’s IDS, filed 09/04/2026, is acknowledged.
6. The following new grounds of rejection are necessitated by the amendment submitted 09/04/2026.
7. 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.
8. Claims 1-2, 4, 6, 8-14 and 51-52 stand rejected under 35 U.S.C. 103 as being unpatentable over WO2016040683 (IDS) or Sherbenou et al (J Clin Invest. 2016;126(12):4640–4653, IDS) each in view of Holstein et al (Drugs. 2017 Apr;77(5):505–520) for the same reasons set forth in the previous Office Action mailed 05/04/2026.
9. Claims 1-,2, 4, 6, 8-14 and 51-52 stand rejected under 35 U.S.C. 103 as being unpatentable over US 11434301 (IDS), in view of Holstein et al (Drugs. 2017 Apr;77(5):505–520) for the same reasons set forth in the previous Office Action mailed 05/04/2026.
Applicant’s arguments, filed 09/04/2026, have been fully considered, but have not been found convincing.
Applicant points to an unexpected and more than additive effect is achieved by the claimed invention. In particular, Applicant points to paragraph [0058] of the application as filed, the inventors hypothesized that IMiDs induce expression of CD46 in cancer cells thereby allowing for improved efficacy of anti-CD46 antibodies, which can be linked to effector molecules such as a cytotoxins. Building on this hypothesis, the inventors have surprisingly discovered that the initial administration of an IMiD agent alone followed by the administration of an anti-CD46 antibody linked to an effector molecule as claimed can result in significant unexpected improvement of the efficacy of the anti- CD46 antibody drug conjugate (ADC).
Applicant points to the Examples of the present application demonstrate the effect of combining an anti-CD46 ADC with an IMiD agent as a second compound for use in the treatment of cancer. Notably, the improved anti-tumor effects shown in the Examples arise from a functional interaction between the combination of the presently claimed features, namely, the use of an agent that increases CD46 expression in cancer cells which can then be targeted by an ADC which specifically binds to CD46. The data generated by the present inventors demonstrate that this functional interaction gives rise to an anti-tumor efficacy which is more than merely additive.
For instance, Example 1 and FIGS. 1 and 2 show that CD46 expression is upregulated in a multiple myeloma cell line (RPMI8226) following pre-treatment with the IMiDs pomalidomide or lenalidomide, and that higher levels of CD46 expression persist following initial exposure to the two IMiDs. In addition, Example 4 and FIG. 6 further show that CD46 expression is upregulated in multiple myeloma cells following pre-treatment with pomalidomide, and CD46 expression was enhanced following treatment with pomalidomide in combination with dexamethasone.
The unexpected effect achieved by the combination of the antibody that specifically binds to CD46 and an agent that increases CD46 expression in cancer cells as claimed is further exemplified by Example 2 and FIG. 3 of the application as filed. Specifically, RPMI8226 cells seeded at 5,000 per well were exposed to 3.3 pM, 5 pM, and 10 pM pomalidomide for 7 days. The cells were then washed and treated with a CD46 ADC. Cell viability was measured 96 hours post CD46 ADC treatment. Notably, a 100-fold change in the EC65 (i.e., 35 % viability) was observed with CD46 ADC treatment following pre-treatment with pomalidomide as compared to the treatment with the CD46 ADC alone. This unexpected result was also observed in analogous experiments using lenalidomide (see, FIG. 4 of the application as filed). In particular, a ~ 100-fold change in the EC65 (i.e., 35 % viability) was also observed with CD46 ADC treatment following pre- treatment with lenalidomide as compared to the treatment with the CD46 ADC alone.
This is not found persuasive for the following reasons:
The experiments reported in the instant specification cannot be clearly equated with the claimed invention. The showing of surprising results is not commensurate in scope with the invention as claimed. The results reported in the specification fail to establish that the results achieved occurred exclusively in an embodiment of the invention as recited in claim 1 (e.g., in vivo treatment, multiple myeloma, lymphoma, acute myeloid leukemia(AML), prostate cancer and metastatic renal cell carcinoma (mRCC) in a human, genus of anti-CD46 antibody linked to a genus of cytotoxic effector, a genus of IMiD, and a genus of a glucocorticoid receptor agonists or modulators) renders the observations not commensurate in scope to claim 1, indeed, not drawn to the invention as claimed at all. The results are, therefore, of limited value in overcoming the Examiner’s strong prima facie case. The claims are directed to a genus of CD46 antibodies (internalizing and nonintegrating antibodies and binding differ CD46 regions), a genus of linkers, a genus of cytotoxic effector a different type of cancer treatments, a genus of IMiD a genus of glucocorticoid receptor agonists or modulators, while the showings of unexpected results is limited to a particular multiple myeloma cell line (in vitro) , RPMI8226, a unknown anti-CD46 antibody and unknow ADC, and specific glucocorticoid receptor agonist or modulator, dexamethasone. MPEP §716.02(d). Not all the combinations would result in the surprising effect of enhancing the anti-tumor activity of anti-CD46 antibody ADC, IMID and optional with a glucocorticoid receptor agonist or modulator. There is no showing that other embodiments falling within the claim will behave in a similar manner.
The in vitro showings are limited to pre-treatment with Pomalidomide significantly enhances the efficacy of the Anti-CD46 ADC. It eliminates the survival plateau seen in the control (35% viability), driving maximum cell death down toward 5% to 15% viability at higher doses (Fig. 3). Similar results obtained for Lenalidomide. It is not clear what is meant by EC65 (Fig. 4). Example 4 shows that Pomalidomide lead-in plus pom/dexamethasone (dex)/CD46 ADC combination further enhances CD46 expression (FIG. 6) and anti-tumor potency (FIG. 7).
The present invention is not obvious in view of the cited references
Applicant submits that there is no teaching or suggestion in either primary reference to combine the anti-CD46 ADC described therein with an IMiD agent. Even assuming arguendo that such a teaching or suggestion existed in the primary references (not admitted), one of ordinary skill in the art would have had myriad anti-cancer therapies that they could consider combining with the anti-CD46 ADC described therein. Each of these additional cancer therapies would have different mechanisms of action and would not necessarily induce increased expression of CD46 on cancer cells. To assert that one of ordinary skill in the art would have in fact found themselves specifically directed to combinations of an anti-CD46 ADC with an IMiD agent starting from either primary reference requires the impermissible use of hindsight based on knowledge of the present invention. Moreover, there is no hint in either primary reference that this combination would result in an unexpectedly effective cancer treatment. Nor would it have been obvious to one of ordinary skill in the art that combining an IMiD agent specifically with an anti-CD46 ADC would lead to a more than additive improvement in anti-cancer efficacy. Therefore, it would not have been obvious to one of ordinary skill in the art to arrive at the present invention in view of the teachings of the primary references.
This is not found persuasive because given that IMiDs have contributed to the marked improvement in outcomes for patients with multiple myeloma and that pomalidomide has been used in combination with the other typical classes of myeloma drugs, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combined the IMids drugs taught by Holstein et al in the multiple myeloma treatment taught by `301 patent. It is prima facie obvious to combine two compositions each of which is taught by prior art to be useful for same purpose in order to form third composition that is to be used for very same purpose; idea of combining them flows logically from their having been individually taught in prior art. In re Kerkhoven, 205 USPQ 1069, CCPA 1980. See MPEP 2144.06. Further, “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc. 550 U.S. 398, 416 (2007).
Applicant submits that Holstein et al. does not remedy the deficiencies of the teachings of the primary references. Notably, Holstein et al. does not teach or suggest that treatment with IMiDs lead to the overexpression of CD46 in cancer cells. Indeed, there is no mention at all in any of the cited references that treatment with IMiD agents would lead to an upregulation of CD46 expression. Thus, one of ordinary skill in the art would not have been motivated to combine the anti-CD46 ADC of either primary reference with the IMiDs described in Holstein et al. As such, they would not have arrived at a combination of an anti-CD46 ADC and an IMiD agent that increases CD46 expression for treating multiple myeloma, lymphoma, acute myeloid leukemia (AML), prostate cancer or metastatic renal cell carcinoma (mRCC) as claimed without exercising inventive skill. To assert otherwise requires the impermissible use of hindsight.
This is not found persuasive because obviousness can be established for achieving the claimed method for different reasons and the prior art/examiner does not need to know all of the properties of the claimed invention In re Dillon, 16 USPQ2d 1897 (Fed. Cir. 1990); however there must be some suggestion or motivation. Therefore, the reason or motivation to combine may often suggest doing what the inventor has done, but for a different purpose or to solve a different problem than that asserted by the inventor. See MPEP 2144.
The Examiner acknowledges that the prior art does not expressly teach that the IMid agent increases CD46 expression in cancer cells, but alleges that such feature would naturally and necessarily flow from administration of IMiDs in vivo because the process of the prior art is materially and manipulatively indistinguishable from the claimed method and inherently leads to the claimed outcome, i.e., increasing CD46 expression in cancer cells. Applicant disagrees and submits that the inventors have surprisingly discovered that the initial administration of an IMiD agent alone followed by the administration of an anti-CD46 ADC resulted in significant unexpected improvement of the efficacy of the anti-CD46 ADC. Indeed, the Examples demonstrate the profound cancer cell killing effects (e.g., ~ 100-fold change in the EC65) observed with anti-CD46 ADC treatment following pre-treatment with an IMiD agent as compared to the treatment with the CD46 ADC alone. Importantly, the cited references do not teach or suggest the sequential administration of an IMiD agent and an anti-CD46 ADC as claimed or appreciate the functional interaction between the combination when administered sequentially, namely, that the IMiD agent increases CD46 expression in cancer cells which can then be targeted by an ADC which specifically binds to CD46. Thus, even assuming arguendo that one of ordinary skill in the art would have been motivated to combine the cited references (not admitted), the claimed method is still materially and manipulatively distinguishable from the process arising out of the alleged combined disclosure because the prior art does not teach or suggest the sequential administration of an IMiD agent and an anti-CD46 ADC as claimed or the unexpected effects that result therefrom.
This is not found persuasive because the showing of surprising results in the specification cannot be clearly equated with the claimed invention. The showing of surprising results is not commensurate in scope with the invention as claimed as discussed above.
10. 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.
11. Claims 1-2, 4, 6, 8-14 and 51-52 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-5, 7, 10-13, 24-29 and 45-59 of copending Application No. 18260657 (reference application) in view of US 11434301 (IDS) for the same reasons set forth in the previous Office Action mailed 05/04/2026.
Applicant’s arguments, filed 09/04/2026, have been fully considered, but have not been found convincing.
Applicant requests that the Examiner hold this rejection in abeyance until this application is otherwise in condition for allowance.
The rejection is maintained until Applicant fully addresses the rejection.
12. Claims 1-2, 4, 6, 8-14 and 51-52 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 5-9, 11-16, 18-21, 35, and 65-70 of copending Application No. 18271206 (reference application) in view of WO2016040683 (IDS) and Holstein et al (Drugs. 2017 Apr;77(5):505–520), for the same reasons set forth in the previous Office Action mailed 05/04/2026.
Applicant’s arguments, filed 09/04/2026, have been fully considered, but have not been found convincing.
Applicant points out that independent claims 1 and 21 of the '206 application are directed to the combination of an anti-CD46 antibody linked to a cytotoxic effector and a glucocorticoid receptor agonist or modulator, while independent claims 35 and 70 of the '206 application are directed to the combination of an anti-CD46 antibody linked to a cytotoxic effector and a STAT3 inhibitor. By contrast, amended claim 1 is directed to the combination of an anti- CD46 antibody linked to a cytotoxic effector and an IMiD agent. The secondary references simply fail to teach, suggest, or provide one of ordinary skill in the art with any motivation whatsoever to replace the glucocorticoid receptor agonist or modulator or the STAT3 inhibitor required by the claims of the '206 application with an IMiD agent.
This is not found persuade because the combined reference teachings arrived to the claimed invention. It remains the Examiner’s position that given that the same anti-CD46-ADC target multiple myeloma as taught by WO2016040683 and Holstein et al, those of skilled in the art would have had a reason to use the an anti-CD46-ADC taught in the `206 application in the treatment of multiple myeloma cancer in combination with the IMiDs agent taught by Holstein. It is prima facie obvious to combine two compositions each of which is taught by prior art to be useful for same purpose in order to form third composition that is to be used for very same purpose; idea of combining them flows logically from their having been individually taught in prior art. In re Kerkhoven, 205 USPQ 1069, CCPA 1980. See MPEP 2144.06. Further, “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc. 550 U.S. 398, 416 (2007).
13. No claim are allowed.
14. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Fotiou et al. Pomalidomide- and dexamethasone-based regimens in the treatment of refractory/ relapsed multiple myeloma. Cancers (Basel). 2023 Nov 9;15(22):5335.
Fotiou et al demonstrate the curative potential of CD46–ADC via its ability to abrogate disease engraftment of primary MM cell xenografts. In combination with a recent clinical trial, this study supports the continued study of CD46 as a therapeutic target in MM.
15. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
16. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form.
September 30, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644
