DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s reply filed on 6/25/2026 is acknowledged. Claims 1, 3, 5, 7, 15-17, 19, 21-24 and 26-32 are pending. Claims 2, 4, 6, 8-14, 18, 20 and 25 are canceled. Claims 1, 15-16, 22-24 and 29 have been amended.
3. Claims 1, 3, 5, 7, 15-17,19, 21-24 and 26-32 are under examination.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on 6/25/2026 has been considered by the examiner.
Rejections Withdrawn
5. The rejection of claims 1, 3, 5, 7, 15-17, 19, 21-24 and 26-32 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in view of applicant’s amendments.
6. The rejection of claims 1, 3-5, 7, 15-19 and 21-32 under 35 U.S.C. 103 as being unpatentable over Grigg et al (Haematologica 2017, 102(4):765-772, PTO-892 dated 4/14/2025), in view of Fujimura et al (HemaSphere, June 2020, 4(1): 622, abstract no. EP1329, IDS filed on 6/7/2022) is withdrawn in view of applicant’s submission of an English translation of the certified copy of the foreign priority application.
7. The rejection of claims 1, 5, 15-16, 19, 22-24, 26 and 29-32 under 35 U.S.C. 103 as being unpatentable over Khurana et al. (SAGE Open Med Case Rep., Jan 2019, 7: 1-3, IDS filed on 11/20/2023) and Dumontet e al. (US 2009/0246197A1, pub date: 10/1/2009, IDS filed on 6/7/2022) is withdrawn in view of applicant’s persuasive arguments.
Rejections Maintained
Claim Rejections - 35 USC § 102
8. 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.
9. Claims 1, 3, 5, 15-17, 19, 22-24, 26-27 and 29 remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Clinical Trial NCT03269669 (version 109, posted on 9/25/2018).
Regarding claims 1, 3, 5, 16-17, 19 and 23-24, 26-27, NCT03269669 (v.109) discloses a method of treating patients with relapsed or refractory follicular lymphoma, comprising administering to the patients therapeutically amounts of obinutuzumab and chemotherapy comprising doxorubicin, vincristine sulfate and prednisone (see Study Description and Arm III), wherein the patients with relapsed or refractory follicular lymphoma included the patients who have failed to treatment comprising bendamustine obinutuzumab x 3 cycles (under Eligibility). Follicular lymphoma is a non-Hodgkin’s lymphoma, and is a B cell lymphoma characterized by CD20 positivity. Obinutuzumab and chemotherapy comprising doxorubicin, vincristine sulfate and prednisone would inherently enhance cell cycle arrest or cell death as recited in claim 23, and enhance cell cycle arrest in G0/G1 phase as recited in claim 26.
Regarding claims 15, 22 and 29, NCT03269669 (v.109) discloses that obinutuzumab is administered by IV, which meets the limitation that obinutuzumab is administered in a pharmaceutical composition.
Applicant’s Arguments
The response states that Applicant respectfully disagrees with the Office's characterization of the Inclusion Criteria section of CT669. In particular, Applicant notes that the Inclusion Criteria section of CT669 instead states "[p]atients must have either failed to achieve a complete remission, or must have relapsed within 2 years after completing first line bendamustine-containing chemotherapy ... examples of eligible 1st line treatment regiments [include] [b]endamustine obinutuzumab x 3 cycles" (emphasis added). See CT669, page 15.
Therefore, contrary to the Office's allegation, CT669 is entirely silent with respect to treating any patient having an obinutuzumab-tolerant cancer. Instead, the patients either (i) did not achieve a complete remission, which does not indicate that the patient failed to respond to obinutuzumab treatment (e.g., the patient may have achieved a partial remission or otherwise exhibited a clinical response, such as stabilization of disease) or (ii) achieved remission (complete or partial) but relapsed thereafter.
Neither of these two patient populations would be considered to have an obinutuzumab-tolerant cancer, because each would have responded to obinutuzumab at the time of the first-line treatment, and there is also no indication that they developed tolerance to obinutuzumab thereafter. Rather, Applicant respectfully submits that a skilled artisan would not consider either failing to achieve complete remission or relapsing after an initial treatment as indicating that a patient was tolerant to the first-line treatment. For example, a patient could have responded to a first-line treatment comprising obinutuzumab (e.g., bendamustine and obinutuzumab) and simply relapsed at a later date. Indeed, nothing in CT669 specifically describes treating any patient having an obinutuzumab-tolerant cancer. Further, Applicant respectfully submits that CT669's disclosure of treating patients including those who had received bendamustine and obinutuzumab for three cycles also fails to anticipate the presently claimed invention, because there is no indication in CT669 regarding whether those patients were tolerant of bendamustine treatment, obinutuzumab treatment, or both. As stated in M.P.E.P. § 2112(IV), "'[a] prior art reference that discloses a genus still does not inherently disclose all species within that broad category' but must be examined to see if a disclosure of the claimed species has been made or whether the prior art reference merely invites further experimentation to find the species" and "[i]n relying upon the theory of inherency, the examiner must provide a basis in fact and/or technical reasoning to reasonably support the determination that the allegedly inherent characteristic necessarily flows from the teachings of the applied prior art" (emphasis original). Importantly, as discussed supra, CT669 only requires that the eligible patients be those who failed to achieve complete remission or relapsed after prior treatment comprising any anti- CD20 antibody, including rituximab or obinutuzumab. A skilled artisan simply would not have understood the Inclusion Criteria of CT669 to be directed specifically and necessarily to a patient having an obinutuzumab-tolerant cancer. Nor, likewise, would the patients within the Inclusion Criteria of CT669 necessarily have an obinutuzumab-tolerant cancer.
On this issue, the Office is also directed to the cited Khurana reference, which supports Applicant's position that failing to achieve a complete remission or relapsing after treatment with obinutuzumab is not indicative that a cancer is obinutuzumab-tolerant. In the Abstract, Khurana describes administering "obinutuzumab for the retreatment in a chronic lymphocytic leukemia patient, who had first achieved partial remission with it and eventually relapsed over a course of 2.5 years" (emphasis added). Khurana states that "[a]fter retreatment with single-agent obinutuzumab, the patient achieved a partial remission again within one cycle and continues to maintain the response status" (emphasis added). Accordingly, Khurana evidences the fact that a patient whose cancer responds to single-agent obinutuzumab is not obinutuzumab-tolerant, and more importantly, the fact that a patient did not exhibit a complete remission and/or relapsed after being administered a first-line treatment does not indicate that the cancer is obinutuzumab-tolerant. In particular, Applicant respectfully submits that a skilled artisan would not administer single-agent obinutuzumab to a patient who is obinutuzumab-tolerant. CT669 fails to anticipate the present claims.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive
Clinical Trial NCT03269669 (v.109) discloses a method of treating patients with relapsed or refractory follicular lymphoma, comprising administering to the patients therapeutically amounts of obinutuzumab and a chemotherapy comprising doxorubicin, vincristine sulfate and prednisone (see Study Description and Arm III), wherein the patients include those who have failed to bendamustine obinutuzumab x 3 cycles (under Eligibility, reproduced below, see last line).
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Because the clinical trial teaches treating patients having relapsed or refractory cancer after previous treatment with bendamustine obinutuzumab x 3 cycles, the cancer would be an obinutuzumab tolerant cancer according to the instant specification. The instant specification discloses “CD-20 positive cancer which was previously treated with obinutuzumab is given as an example of an obinutuzumab tolerant CD20-positive cancer” see [0023] of the instant specification, reproduced below. The instant specification further discloses “an obinutuzumab tolerant cancer is a cancer that either completely lacks responsiveness or does not show a significant response, such as a partial response or a complete response, to a treatment using obinutuzumab.” ([0023])
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Patients who have failed to bendamustine obinutuzumab x 3 cycles would necessarily fail to obinutuzumab treatment. Because if patient was sensitive to obinutuzumab, the cancer would not be a relapsed or refractory cancer. For the foregoing reasons, the rejection is deemed proper and is therefore maintained.
10. Claims 1, 5, 15-16, 19, 22-24, 26 and 29-32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Clinical Trial NCT03467373 v. 6 (pub. date: 10/3/2018).
Regarding claims 1, 5, 16, 19, 24 and 30-32, NCT03467373 v. 6 teaches a method of treating patients having relapsed and refractory (r/r) non-Hodgkin’s lymphoma (NHL), the method comprising administering to the patients obinutuzumab (G), rituximab (R), plus cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), wherein the NHL is histologically confirmed to express CD20 (title) , and has relapsed/progressed following at least one prior treatment regimen containing R or G (under Inclusion Criteria).
Obinutuzumab and chemotherapy comprising doxorubicin, vincristine sulfate and prednisone would inherently enhance cell cycle arrest or cell death as recited in claim 23, and enhance cell cycle arrest in G0/G1 phase as recited in claim 26.
Regarding claims 15, 22 and 29, NCT03467373 v. 6 discloses that obinutuzumab is administered by IV, which meets the limitation that obinutuzumab is administered in a pharmaceutical composition.
Applicant’s Arguments
The response states that similar to CT669 discussed above, CT373 also does not describe the treatment of any patients having an obinutuzumab-tolerant cancer. As with CT669, the Inclusion Criteria of CT373 includes patients who have relapsed and/or progressed following at least one prior line of treatment comprising rituximab or obinutuzumab.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive.
NCT03467373 v. 6 teaches that the NHL is histologically confirmed to express CD20 (title) and has relapsed/progressed following prior treatment regimen containing obinutuzumab (under Inclusion Criteria).
A cancer that is relapsed/progressed after obinutuzumab treatment is an obinutuzumab tolerant cancer according to the instant specification. The instant specification discloses “CD-20 positive cancer which was previously treated with obinutuzumab is given as an example of an obinutuzumab tolerant CD20-positive cancer” see [0023] of the instant specification, reproduced above. The instant specification further discloses “an obinutuzumab tolerant cancer is a cancer that either completely lacks responsiveness or does not show a significant response, such as a partial response or a complete response, to a treatment using obinutuzumab.” ([0023])
For the foregoing reasons, the rejection is deemed proper and is therefore maintained.
Claim Rejections - 35 USC § 103
11. 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.
12. Claims 1, 3, 5, 7, 15-17, 19, 21-24 and 26-32 remain rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial NCT03269669 (version 109, posted on 9/25/2018), in view of Cheson et al. (J Clin Oncol., Aug 2018, 36(22): 2259-2266).
The teachings of NCT03269669 (v.109) have been set forth above as they apply to claims 1, 3, 5, 15-17, 19, 22-24, 26-27 and 29.
Regarding claims 7, 21 and 28, NCT03269669 (v.109) discloses that the patients must have relapsed within 2 years after completing first line bendamustine-containing chemoimmunotherapy (including an anti-CD20 monoclonal antibody), patients who additionally received any maintenance anti-CD-20 antibody based therapy or consolidative radioimmunotherapy within 2 years of the last dose of the bendamustine therapy are eligible, and the patients included those who have failed to bendamustine obinutuzumab x 3 cycles (under Eligibility).
Regarding claims 30-32, the combined reference teaches treating the patients who have failed to a therapy comprising (i) bendamustine obinutuzumab x 3 cycles and (ii) obinutuzumab maintenance therapy. Maintenance therapy is used to preserve the effect of prior treatment and implies an initial therapeutic response to bendamustine obinutuzumab x 3 cycles. Therefore, a cancer relapsed after a therapy comprising (i) bendamustine obinutuzumab x 3 cycles and (ii) obinutuzumab maintenance therapy meets the limitation “the obinutuzumab-tolerance is an acquired tolerance from being administered a prior treatment with obinutuzumab”.
NCT03269669 (v.109) does not specifically disclose that the anti-CD20-antibody in the maintenance therapy is obinutuzumab.
Cheson et al teaches that obinutuzumab was used in the maintenance therapy for patients who had follicular lymphoma and received obinutuzumab plus bendamustine induction (title and Table 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have included in NCT03269669 (v.109) the patients who had received obinutuzumab plus bendamustine induction and obinutuzumab maintenance therapy in view of NCT03269669 (v.109) and Cheson. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because NCT03269669 (v.109) teaches treating patients who had received bendamustine-containing chemoimmunotherapy (including an anti-CD20 monoclonal antibody), such as bendamustine obinutuzumab, and additionally received any maintenance anti-CD-20 antibody based therapy, and Cheson et al teaches that obinutuzumab was used in the maintenance therapy for patients who had follicular lymphoma and received obinutuzumab plus bendamustine induction (title and Table 1).
Applicant’s Arguments
The response states that as discussed supra, CT669 fails to anticipate the presently claimed invention. CT669 also fails to render as obvious Applicant's finding that a combination treatment comprising obinutuzumab together with prednisolone, prednisone, doxorubicin, or vincristine, or salts thereof, was surprisingly effective at treating obinutuzumab-tolerant cancers and killing obinutuzumab-tolerant cancer cells because, as discussed supra, CT669 does not describe administering such treatment to any obinutuzumab-tolerant patients.
Cheson fails to remedy the deficiencies of CT669, because Cheson is directed to rituximab-refractory indolent non-Hodgkin lymphoma (see title of Cheson), and is entirely silent with regard to any method of treating obinutuzumab-tolerant CD20-positive cancers. Hence, the combination of the cited references fails to teach a feature required by the present claims.
Further, as discussed in Applicant's Reply to the previous Office Action filed January 29, 2026 ("the Previous Reply"), Example 1 of the specification as filed compared the efficacy of combination treatments comprising obinutuzumab and different chemotherapeutic agents at targeting obinutuzumab-tolerant CD20- positive cancer cells, and found that although "the combined use of obinutuzumab with 4-hydroperoxycyclophosphamide exhibited approximately additive effects in all of the obinutuzumab-directed cell death-tolerant clones" (emphasis added), "the combined use of obinutuzumab with doxorubicin, prednisolone, or vincristine exhibited supra-additive effects" (emphasis added). See paragraph [0095] of the specification as filed. These supra-additive effects described in Example 1 are indicative of a surprising synergistic effect of the presently claimed combination treatments for treating obinutuzumab-tolerant cancers as compared to a combination treatment comprising obinutuzumab and an alternative chemotherapeutic agent (e.g., 4-hydroperoxycyclophosphamide), highlighting the surprising efficacy of the presently claimed methods for treating obinutuzumab-tolerant cancers. These surprising and synergistic effects of the presently claimed combination treatment are certainly not described or suggested by the combination of CT669 and Cheson.
In response to Applicant's arguments presented in the Previous Reply, the Office alleges that "[a]ny results observed by applicants for claims 1, 3-5, 15-19, and 22-29 are considered inherent property of the method of [CT669]." Office Action, page 10. Applicant respectfully disagrees. The requirements for inherency are discussed supra. In particular, a finding of inherency requires that the results necessarily flow from the teachings of the applied references. For the reasons discussed supra, CT669 simply does not teach the treatment of any patient having an obinutuzumab-tolerant cancer. Therefore, the surprising supra-additive and synergistic effects of the presently claimed combination treatment discussed in the specification as filed cannot be considered an inherent property of CT669.
For at least these reasons, CT669 and Cheson, whether considered alone or in combination, fail to suggest the presently claimed methods and also fail to suggest the surprising supra-additive and synergistic effects of the presently claimed combination treatment. Reconsideration and withdrawal of this rejection is respectfully requested.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive for the reasons discussed in the 102(a)(1) rejection.
Applicant’s arguments of unexpected results (synergistic effects) have been carefully considered but are not persuasive. As discussed above, claims 1, 3, 5, 15-17, 19, 22-24, 26-27 and 29 are rejected under 102(a)(1) as being anticipated by Clinical Trial. Any results observed by applicants for claims 1, 3, 5, 15-17, 19, 22-24, 26-27 and 29 are considered inherent property of the method of Clinical Trial.
Regarding claims 7, 21 and 28 being rejected under 103, applicant has not shown unexpected results specifically relating to claims 7, 21 and 28.
MPEP 716.02(d) states “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”.
For the foregoing reasons, the rejection is maintained.
Conclusion
13. No claims are allowed.
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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/HONG SANG/Primary Examiner, Art Unit 1646
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