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 .
Claims 1-15, 17, and 26 have been cancelled.
Applicant's arguments filed 7/2/2026 have been fully considered but they are not persuasive.
The rejection of claims 16, 18-19, 23, 25, and 27 under 35 U.S.C. 102(a)(1) as being anticipated by Bender et al. (WO 2018/142322, of record) is withdrawn in view of applicant’s arguments..
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 28 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 28 is confusing in reciting “wherein the hyperproliferative hematological disorder is refractory to and/or has relapsed after treatment with a chemotherapeutic agent other than a BTK inhibitor…” as claim 16 requires that the subject has become refractory to and/or has relapsed after treatment with a BTK inhibitor. If the claim intended that the subject has become refractory to and/or has relapsed after other treatments in addition to BTK inhibitors, the claim language of claim 28 as it depends upon claims 16 and 27 does not make this clear. See by comparison claim 29.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 16, 18-25, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Bender et al. (WO 2018/142322, of record) in view of Woyach et al. (2017) and Back et al. (WO 2017/025569, of record).
Bender et al. discloses administering an anti-CCR7 antibody to a subject to treat hyperproliferative hematological disorders such as chronic lymphocytic leukemia (CLL), non-Hodgkin’s lymphoma, and Burkitt’s lymphoma. The antibody can be chimeric, humanized or human. The cancer can be a resistant or relapsed cancer, including a cancer resistant to tyrosine kinase inhibitors. See at least paragraph [0284-0290]. The inhibitor ibrutinib is disclosed. See at least paragraphs [0297-0298]. It would have been known as a Bruton tyrosine kinase (BTK). The antibody can be administered with other drugs including a Bcl-2 inhibitor such as venetoclax or navitoclax. The anti-CCR7 antibody can also be administered with chemotherapeutic agents such as fludarabine and cyclophosphamide. Administering idelalisib is disclosed. Co-administration can be concurrent or sequential. See at least abstract, paragraphs [0012-0014, 0025, 0030, 0056, 0292-0298, 0306-0307, 0309]. Bender et al. fairly includes the treatment of treatment naïve patients for an anti-CCR7 antibody or Bcl-2 inhibitor as no requirement for any pre-treatment is disclosed. (See instant claim 27.) The anti-CCR7 antibodies can be administered with Bcl-2 inhibitors such as venetoclax. The anti-CCR7 antibody can be conjugated to the Bcl-2 inhibitor. See paragraphs [0307 and 0309 ] and claim 22. See also claims 29-30 and 39-40.
With respect to claim 16, the disclosure of sequential administration in paragraphs [0292-0298] fairly includes treating with the BTK inhibitor first and followed later by treating with the anti-CCR7 antibody and Bcl-2 inhibitor such as venetoclax or navitoclax. Bender et al. fairly discloses administering an anti-CCR7 antibody and a Bcl-2 inhibitor after the cancer (such as CLL) has become resistant (i.e. refractory) to treatment with tyrosine kinase inhibitors.
Bender et al. does not disclose the CCR7 antibody limitations of claims 20-24 or specifically disclose treating a subject that is refractory to and/or has relapsed after treatment with a Bruton tyrosine kinase (BTK) inhibitor. However, treating a subject that is refractory to and/or has relapsed after treatment with a tyrosine kinase inhibitor generally is disclosed and inhibitors such as ibrutinib are disclosed. Ibrutinib would have been a known BTK inhibitor at the time of the effective filing date as evidenced by Woyach et al.
Woyach et al. discloses treating ibrutinib-refractory chronic lymphocytic leukemia (CLL) with other therapeutics, including Bcl-2 inhibitors such as venetoclax. Ibrutinib is a BTK inhibitor. See at least abstract, Table 1, and pages 1272-73 starting at section on clinical data for treatment of patients after ibrutinib relapse.
Back et al. discloses an anti-CCR7 antibody having a VH of SEQ ID NO: 1 and a VL of SEQ ID NO: 2. See instant claim 24. SEQ ID NOS: 1 and 2 of Back et al. correspond to instant SEQ ID NOS: 1 and 2, respectively. Back et al. discloses a particularly preferred humanized anti-CCR7 antibody having a VH of SEQ ID NO: 61 and a VL of SEQ ID NO: 64. SEQ ID NOS: 61 and 64 correspond to instant SEQ ID NOS: 4 and 5, respectively. An antibody having a heavy chain constant domain of SEQ ID NO: 80 is disclosed. SEQ ID NO: 80 corresponds to instant SEQ ID NO: 10. See at least page 29, lines 13-19. Anti-CCR7 antibodies meeting the limitations of instant claims 20 and 22 are disclosed. See at least page 3, lines 8-15, and page 6, lines 7-15. Anti-CCR7 antibodies meeting the limitations of instant claim 21 are disclosed. See at least page 23, lines 22-25. Treatment of hyperproliferative hematological disorders such as chronic lymphocytic leukemia (CLL) and Burkitt’s lymphoma is disclosed. See also at least abstract; claims; and page 4, lines 8-16; page 5, lines 3-7; page 22, lines 8-21; and page 26, lines 1-4.
It is again noted that page 22 of the instant specification discloses that the CAP-100 antibody was known in the prior art. It is the antibody of Back et al. having a VH of SEQ ID NO: 61, a heavy chain constant domain of SEQ ID NO: 80, and a VL of SEQ ID NO: 64 where these sequences correspond to instant SEQ ID NOS: 4, 10, and 5, respectively. US 2018237529 as disclosed in the instant specification corresponds to U.S. Patent Application Publication 2108/0237529. This is the PGPUB for U.S. application 15/751,169 which was the 371 filing of PCT/EP2016/06905. PCT/EP2016/069095 published as WO 2017/025569.
It would have been obvious to use any of the anti-CCR7 antibodies of Back et al. in the methods of Bender et al. in order to treat hyperproliferative hematological disorders such as chronic lymphocytic leukemia (CLL) and Burkitt’s lymphoma after the subject has developed resistance to or relapsed following BTK inhibitor treatment. Back et al. discloses humanized antibodies as recited in instant claim 23. Bender et al. fairly discloses administering an anti-CCR7 antibody and a Bcl-2 inhibitor after the cancer (such as CLL) has become resistant (i.e. refractory) to treatment with tyrosine kinase inhibitors. Resistance to tyrosine kinase inhibitors such as ibrutinib, a BTK inhibitor, would have been known as taught by Woyach. The prior art to Bender et al and Woyach would have clearly suggested treating BTK inhibitor resistant disorders. Administration of Bcl-2 inhibitors such as venetoclax after the cancer (such as CLL) has become resistant (i.e. refractory) to treatment with BTK inhibitors is taught and suggested by Woyach.
Applicant’s arguments are not persuasive as the prior art fairly suggests the specific clinical scenario recited in the claims.
Applicant’s arguments with respect to Patrussi et al. (2015) and De Rooij (2012) are not persuasive. Down-regulation is not elimination or absence of cell surface CCR7. In addition, there would have been an expectation that cell surface CCR7 levels would rise after discontinuing ibrutinib. There would have been an expectation of some biological effect when administering the CCR7 antibodies. Patrussi et al. (2015) are De Rooij et al. (2012) are older reference than Bender et al. (2018), Woyach (2017), and Back et al. (2017). The prior art would have been aware of the teachings of Patrussi et al. and De Rooij et al. yet Bender et al. discloses administering an anti-CCR7 antibody to a subject to treat hyperproliferative hematological disorders that are resistant to any tyrosine kinase inhibitor. BTK inhibitors would have been known tyrosine kinase inhibitors commonly used to treat these disorders with a known possibility of developing resistance. Furthermore, the teachings of Patrussi et al. are limited to ibrutinib and not all BTK inhibitors embraced by the claims. Only instant claim 25 has a limitation with respect to the particular BTK inhibitor. Finally, applicant points to the instant specification statement on page 3 that "Patrussi et al. (Cancer Res. 2015 Oct 1) disclose that ibrutinib treatment of CLL cells resulted in a significant downregulation in surface CCR7, on the basis of which combining an anti-CCR7 antibody with ibrutinib would not be expected to improve its therapeutic efficacy." However, the claimed method is not combining the anti-CCR7 antibody with ibrutinib, it is administering the anti-CCR7 antibody after discontinuing ibrutinib. The claimed method is not directed to improving therapeutic efficacy. There is no statement that there would have been no biological effect expected in this scenario. It is not agreed that Patrussi et al. and De Rooij et al. teach away.
Mateu-Albero et al. (2022) is not prior art but is cited to document that ibrutinib treatment only moderately downregulated the very high expression of CCR7 in CLL cells. The BTK inhibitors acalabrutinib and zanabrutinib did not downregulate cell surface CCR7 levels. CCR7 surface levels were similar to those of naïve patients in CLL cells from ibrutinib relapsed/refractory patients who had stopped ibrutinib. See at least abstract and page 631, left column.
Again, the claims do not require any particular anti-CCR7 antibody. The claims do not require any particular therapeutic effects (including improvements) from any of the agents administered. The claims do not require administering any particular amount of any of the agents.
Claims 16, 18-25, and 27-31 are rejected under 35 U.S.C. 103 as being unpatentable over Parikh (October 2018) in view of Bender et al. (WO 2018/142322, of record), Woyach, Back et al. (WO 2017/025569, of record) and Kristiansen (U.S. Patent Application Publication 2017/0304415).
Bender et al. and Woyach are applied as above.
Back et al. is applied as above. It additionally teaches that mouse antibody 729 corresponds to SEQ ID NOS: 1 and 2. A humanized form of antibody 729 is mAb650. CD20-refractory CLL tumor B-cells, from a patient unresponsive to cytostatics and anti-CD-20 monoclonal antibody therapy and considered to be anti-CD20 therapy resistant, are efficiently killed in the complement dependent cytotoxicity (CDC) assay by mAb729-2A. See at least Figures 1 and 4, Tables 5-6, Examples 2.7, 4.1, 4.2, and 4.3; and pages 44, lines 10-12 and 22-24, paragraphs [0177 and 0191]. Alemtuzumab (an anti-CD52 monoclonal antibody) and rituximab (i.e. rituxan) were used in a refractory assay. All four anti-CCR7 antibodies (11-AE, 11-17, 31-17, 31-AE, see section 5.1) mediated ADCC using isolated PBLs on an alemtuzumab-refractory CLL sample. See at least Example 4.2 and 5.2, Figure 5 and page 44 lines 26-31.
Parikh discloses the standard of care in 2018 for treatment of chronic lymphocytic leukemia (CLL). Treatment with oral targeted therapies such as ibrutinib (a BTK inhibitor), idelalisib and venetoclax (a Bcl-2 inhibitor) and treatment with anti-CD20 monoclonal antibodies such as obinutuzumab and rituximab are disclosed. See at least abstract and introduction. The reference discusses relapsed/refractory CLL progressing on ibrutinib. See pages 5-7 and Figures 2-3.
Kristiansen discloses that alemtuzumab (an anti-CD52 antibody) would have been a known anti-cancer drug for treating B-cell chronic lymphocytic leukaemia (B-CLL).
With respect to claims 16, 18-25, and 27-29, Parikh et al discloses treating a subject with relapsed/refractory CLL (i.e. relapsed after treatment with a chemotherapeutic agent other than a BTK inhibitor, a Bcl-2 inhibitor, and an anti-CCR7 antibody, see instant claims 28-29) who is naïve to ibrutinib (see instant claim 27) with the BTK inhibitor ibrutinib and if the subject then becomes refractory/relapsed to ibrutinib to then treat with a Bcl-2 inhibitor such as venetoclax. See at least Figure 3 of Parikh et al. See also Woyach. It would have been obvious to administer the Bcl-2 inhibitor with an anti-CCR7 antibody, including as a conjugate, as suggested by Bender et al. Back et al. suggests suitable anti-CCR7 antibodies that could be used that meet the limitations of claims 20-24 as set forth above. One would have been motivated to do so to provide alternate methods of therapy when other therapies were ineffective.
With respect to claims 30-31, standard chemotherapeutic agents for treating CLL include anti-CD20 antibodies such as obinutuzumab. See at least Figure 2 of Parikh et al. Administration of this antibody as the first-line treatment which is then followed by ibrutinib treatment when the subject becomes refractory/relapsed to this antibody as outlined above would meet the limitations of claims 28-31. One would have been motivated to do so to provide alternate methods of therapy when other therapies were ineffective.
With respect to claim 31, standard chemotherapeutic agents for treating CLL also include anti-CD52 antibodies such as alemtuzumab. See at least Kristiansen and Back et al. Administration of this antibody as the first-line treatment which is then followed by ibrutinib treatment when the subject becomes refractory/relapsed to this antibody as outlined above would meet the limitations of claims 28-31. In particular, Back et al. suggests that an anti-CCR7 antibody would have been expected to be successful in treating CLL tumor patients unresponsive to anti-CD20 monoclonal antibody therapy and alemtuzumab (anti-CD52 antibody) therapy. One would have been motivated to do so to provide alternate methods of therapy when other therapies were ineffective.
Applicant’s arguments are unpersuasive. Bender et al. does not require administration of ibrutinib following resistance/relapse to this drug and the references to Woyach and Parikh disclose strategies of treatment, including administering a Bcl-2 inhibitor such as venetoclax, when ibrutinib resistance/relapse has occurred. Again with respect to claims 28-31, standard chemotherapeutic agents for treating CLL include anti-CD20 antibodies such as obinutuzumab. See at least Figure 2 of Parikh et al. It would have been obvious to administer a CCL-7 antibody and Bcl-2 inhibitor (as suggested by Bender et al.) in a subject following administration of obinutuzumab as the first-line treatment which was then followed by ibrutinib treatment when the subject becomes refractory/relapsed to obinutuzumab (see claims 28-31) as suggested by the combination of the prior art. One would have been motivated to do so to provide alternate methods of therapy when other therapies were ineffective.
It would have been well understood by those of ordinary skill in the art at the time of the effective filing date to change to a different therapeutic intervention if or when a prior therapeutic intervention became ineffective. That is how medicine is practiced.
Applicant’s arguments with respect to Patrussi et al. (2015) and De Rooij (2012) have been addressed above.
Applicant’s arguments regarding unexpected results and a potential declaration under 37 CFR 1.132 are noted. However, no declaration has been submitted and any unexpected results would have to be commensurate in scope to the claims. That is, demonstrating unexpected results for all CCR7 antibodies, all BTK inhibitors, all Bcl-2 inhibitors, and reflecting all of the different embodiments of administration for all hyperproliferative hematological disorders embraced by the claims.
Yang et al. (U.S. Patent Application Publication 20200222393, filed 30 July 2019) is cited to document the variety of Bcl-2 inhibitors that could be administered to a subject with a hematological malignancy such as CLL wherein the subject is refractory or is resistant to any BTK inhibitor. BKT inhibitors such as ibrutinib, acalabrutinib, and zanabrutinib (see instant claim 25) are disclosed. See at least paragraphs [0011, 0062-0063, 0072, and 100] and Table 2 (starting at page 45).
With respect to the obviousness rejections set forth above, the claims are broad and require no particular therapeutic effect (in either type or degree). The prior art suggests administering the recited agents to treat the recited conditions in the subject population with an expectation of obtaining a biological effect meeting the limitation of treatment. Applicant is reminded that the claims encompass achieving a minimal effect.
Conclusion
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 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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/Marianne P Allen/Primary Examiner, Art Unit 1647
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