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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/18/2025 has been entered.
Claims Status
Claims 1-3, 11, 17, 20, 22-23, 25, 27, and 34 are pending.
Claims 1 and 23 are amended.
Claims 4-10, 12-16, 18-19, 21, 24, 26, 28-33, and 35-37 are canceled.
Claims 1-3, 11, 17, 20, 22-23, 25, 27, and 34 are under examination.
Withdrawn
The rejection of claims 23 and 31 under 35 U.S.C. 112(b) are withdrawn. Applicant has amended claim 23 and canceled claim 31 to overcome the rejections.
The 112(a) enablement rejection as applied to claim 25 is withdrawn. Applicant presents a persuasive argument on page 7 of the remarks that claim 25 is to a pharmaceutical composition and does not depend from claim 1.
Maintained Rejections
Claim Rejections - 35 USC § 112(a)
Enablement
This rejection has been modified solely to address the amendment to claim 1 requiring that the anti-CD20 antibody is administered concomitantly with, or up to 24 hours before, said 4-1BB agonist. The Examiner has set forth a rejection under 35 U.S.C. 103 addressing the embodiment of instant claim 1 of the rituximab being administered 24 hours prior (i.e. encompassed in “up to 24 hours”) to the 4-1BB agonist. This 112(a) rejection addresses the other embodiments of the rituximab being administered concomitantly with the 4-1BB agonist, the rituximab being administered less than 24 hours prior to the 4-1BB agonist, and the Obinutuzumab being administered up to 24 hours prior to the 4-1BB agonist.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 11, 17, 20, 22-23, 27, and 34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for synergy when administering rituximab 24 hours prior to the 4-1BB agonist and for co-administering Obinutuzumab and the 4-1BB agonist, does not reasonably provide enablement for any other timing regimen (i.e. rituximab administered concomitantly with the 4-1BB agonist, rituximab administered less than 24 hours prior to the 4-1BB agonist, and Obinutuzumab administered up to 24 hours prior to the 4-1BB agonist). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 1 is drawn to a method for treating or delaying progression of a B-cell lymphoma or leukemia, comprising administering a therapeutically effective amount of a 4-1BB agonist and an anti-CD20 antibody to an individual in need thereof, wherein administration of said 4-1BB agonist and an anti-CD20 antibody treat the B-cell lymphoma or leukemia synergistically as compared to administration of said 4-1BB agonist or said anti-CD20 antibody alone; wherein said anti-CD20 antibody is rituximab or Obinutuzumab; and wherein said anti-CD20 antibody is administered concomitantly with, or up to 24 hours before, said 4-1BB agonist; and wherein the 4-1BB agonist is an antigen binding molecule comprises the sequences selected from the groups of a) – f). Claim 2 adds the limitation of wherein the 4-1BB agonist and the anti-CD20 antibody are administered concomitantly, and claim 3 adds the limitation of wherein the 4-1BB agonist and the anti-CD20 antibody are administered together in a single composition.
Factors to be considered in determining whether undue experimentation is required, are set forth in In re Wands 8 USPQ2d 1400. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art and (8) the breadth of the claims.
(4) The nature of the invention and (8) The breadth of the claims:
Regarding claims 1-3, the nature of the invention is a method for treating or delaying progression of a B-cell lymphoma or leukemia, comprising administering a therapeutically effective amount of a 4-1BB agonist and an anti-CD20 antibody to an individual in need thereof, wherein administration of said 4-1BB agonist and an anti-CD20 antibody treat the B-cell lymphoma or leukemia synergistically as compared to administration of said 4-1BB agonist or said anti-CD20 antibody alone; wherein said anti-CD20 antibody is rituximab or Obinutuzumab; and wherein said anti-CD20 antibody is administered concomitantly with, or up to 24 hours before, said 4-1BB agonist; and wherein the 4-1BB agonist is an antigen binding molecule comprises the sequences selected from the groups of a) – f), and wherein said 4-1BB agonist and anti-CD20 antibody are administered concomitantly or together in a single composition. Therefore, the nature of the invention is a chemical case, where there is natural unpredictability in performance of certain species or sub-combinations other than those specifically enumerated; see MPEP 2163. Accordingly, it is the Office’s position that undue experimentation would be required to use the claimed product, with a reasonable expectation of success, because it would not be predictable from the disclosure of any one timing regimen what other timing regimens may or may not be synergistic; see MPEP 2164.03.
The claims broadly encompass administration with rituximab or Obinutuzumab at any time up to 24 hours before the specific 4-1BB agonist, or administration with rituximab or Obinutuzumab and the specific 4-1BB agonist concomitantly, yet the administration must still result in treating the B-cell lymphoma or leukemia synergistically. Thus, there would be undue experimentation because there is no reason that one of ordinary skill in the art would expect the administration of the combination of rituximab or Obinutuzumab and the 4-1BB agonist at a regimen other than administering rituximab 24 hours prior to the 4-1BB agonist and administering Obinutuzumab and the 4-1BB agonist concomitantly to be synergistic.
(2) The state of the prior art and (4) The predictability or unpredictability of
the art:
The state of the art regarding a specific combination of rituximab and a 41BB agonist is discussed in Kohrt et al., 2010 (05/22/2024 PTO-892). Kohrt teaches that anti-CD137 mAb significantly enhances anti-tumor activity of rituximab leading to complete tumor resolution and provided superior reduction in tumor burden, but that sequential administration of anti-CD20 mAb rituximab followed by the anti-CD137 mAb is required for the synergistic effect [page 2, see Results section]. Further, Kohrt et al., 2011 (05/22/2024 PTO-892) teaches synergistic reduction in tumor size when administering rituximab on day 3 and an anti-CD137 antibody on day 4, but there was not a synergistic reduction in tumor size when rituximab and the anti-CD137 antibody were administered on the same day [page 2427, Figure 4A].
Thus, the cited references demonstrate that rituximab and a 41BB agonist are only synergistic when the rituximab is administered before the 41BB agonist (anti-CD137 mAb) with a one day gap (i.e. 24 hours), whereas the combination is not synergistic when administered on the same day (i.e. concomitantly, the limitation of claim 2, or together in a single composition, the limitation of claim 3).
(6) The amount of direction or guidance provided by the inventor; (7) The
existence of working examples:
The specification teaches administering rituximab and the 41BB agonist with a gap of 24 hours to achieve synergistic reduction of tumor volume [see Example 4 of the instant specification]. Further, the specification teaches administering Obinutuzumab (GAZYVA) and the 41BB agonist concomitantly to achieve synergistic reduction of tumor volume [see Example 5 of the instant specification].
However, while the specification provides these two examples of rituximab and Obinutuzumab administered with the 41BB agonist at specific timing regimens, Applicant has not provided any guidance as to what other specific timing regimens would result in synergistically treating the B-cell lymphoma or leukemia (i.e. rituximab administered concomitantly with the 4-1BB agonist, rituximab administered less than 24 hours prior to the 4-1BB agonist, and Obinutuzumab administered up to 24 hours prior to). Thus, support is not provided for the breadth of the claims.
In conclusion, the claimed invention does not provide enablement for treating or delaying progression of a B-cell lymphoma or leukemia, comprising administering a therapeutically effective amount of a 4-1BB agonist and an anti-CD20 antibody to an individual in need thereof, wherein administration of said 4-1BB agonist and an anti-CD20 antibody treat the B-cell lymphoma or leukemia synergistically as compared to administration of said 4-1BB agonist or said anti-CD20 antibody alone; wherein said anti-CD20 antibody is rituximab or Obinutuzumab; wherein said anti-CD20 antibody is administered concomitantly with, or up to 24 hours before, said 4-1BB agonist, and wherein the 4-1BB agonist is an antigen binding molecule comprises the sequences selected from the groups of a) – f), as encompassed by the instant claims.
Specifically as it relates to the combination of rituximab and the 4-1BB agonist, the claimed invention does not provide enablement for treating the B-cell lymphoma or leukemia synergistically when the rituximab and 4-1BB agonist are administered concomitantly or wherein the 4-1BB agonist is administered less than 24 hours prior to the 4-1BB agonist, as encompassed by instant claims 1 and 2, or together in a single composition, as encompassed by instant claim 3. The lack of enablement for these limitations is further evidenced by the cited art (i.e. see Kohrt references above). Additionally, the claimed invention does not provide enablement for treating the B-cell lymphoma or leukemia synergistically when the Obinutuzumab is administered up to 24 hours prior to the 4-1BB agonist.
Thus for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the teachings in the art, and the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Claims 2-3, 11, 17, 20, 22-23, 27, and 34, which depend from claim 1, are therefore rejected for the same reasons set forth above.
Claim Rejections - 35 USC § 103
This rejection has been modified solely to address the amendment to claim 1 requiring that the said anti-CD20 antibody is administered concomitantly with, or up to 24 hours before, said 4-1BB agonist. The Examiner is interpreting “up to 24 hours before” as encompassing 24 hours.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1, 11, 17, 22, 25, 27, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Amann (WO 2016075278; 09/19/2023 PTO-892) in view of Mohrbacher, 2005 (09/19/2023 PTO-892), and Kohrt et al., 2011 (05/22/2024 PTO-892)
Regarding claims 1, 17, and 27, Amann teaches a TNF family ligand trimer-containing antigen binding molecule (4-1BB agonist) where the target cell antigen is CD19 [page 8, lines 8-18] and that the trimer contains ectodomains (three ectodomains) [page 4, lines 5-9 and claim 1]. Amann further teaches that the TNF family ligand trimer-containing antigen binding molecule comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO:313, a second heavy chain comprising the amino acid sequence of SEQ ID NO:314, and two light chains comprising the amino acid sequence of SEQ ID NO:279 [page 81, lines 23-25]. Amann also teaches that the TNF family ligand trimer-containing antigen binding molecule is 4-1BBL [page 5, line 21]. Amann further teaches that the biological activity of the TNF family ligand trimer-containing antigen binding molecules is agonistic [page 97, lines 18-19]. Amann also teaches that the TNF family ligand trimer-containing antigen binding molecules of the invention can be formulated, dosed, and administered [page 101, lines 5-10] and is used for the treatment of cancer by administering to an individual a therapeutically effective amount of the TNF family ligand trimer-containing antigen binding molecule [page 101, 20-25]. Amann further teaches that the cancer to be treated can be B-cell lymphoma, B-cell leukemia, non-Hodgkin lymphoma and acute lymphoblastic leukemia [page 101, lines 30-31].
SEQ ID NO: 313 has 100% sequence identity to SEQ ID NO: 51 of the instant application, SEQ ID NO: 314 has 100% sequence identity to SEQ ID NO: 52 of the instant application, and SEQ ID NO: 279 has 100% sequence identity to SEQ ID NO: 48 of the instant application. Therefore, this meets the limitations of option f) of the claim.
However, Amann does not teach administering a therapeutically effective amount of an anti-CD20 antibody with the 4-1BB agonist, wherein said anti-CD20 antibody is rituximab or Obinutuzumab, wherein the administration of said 4-1BB agonist and anti-CD20 antibody treat the B-cell lymphoma or leukemia synergistically as compared to administration of said 4-1BB agonist or said anti-CD20 antibody alone, or wherein said anti-CD20 antibody is administered concomitantly with, or up to 24 hours before, said 4-1BB agonist.
Mohrbacher teaches that rituximab is an anti-CD20 antibody used for treatment for non-Hodgkin’s lymphoma (NHL) [page S19, left column, second paragraph]. Mohrbacher also teaches administering 375 mg/m2 to patients [page S19, left column, fourth paragraph] and that rituximab exhibited very strong and consistent efficacy to treat B cell lymphomas (NHL) [page S19, right column, second paragraph].
Kohrt teaches that an anti-CD137 (4-1BB) agonistic mAb enhances the antilymphoma activity of rituximab (anti-CD20) by enhancing antibody-dependent cell-mediated cytotoxicity (ADCC) [see Abstract]. Kohrt further teaches that although anti-CD20 and anti-CD137 mAbs both had antitumor activity when used as single agents, their combination significantly enhanced tumor regression and survival [page 2427, left column, second paragraph] and that synergistic antitumor activity in lymphoma cells lines was observed when anti-CD20 mAb was administered on day 3 before the anti-CD137 mAb on day 4 (i.e. 24 hours before) [page 2427, right column, second paragraph]. Kohrt also teaches that the combination of anti-CD137 agonistic mAb with rituximab significantly improved the rate of tumor regression and survival over rituximab alone in a human lymphoma xenotransplant model [page 2428, right column, first paragraph].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered the 4-1BB agonist, as taught by Amann, in combination with the anti-CD20 antibody rituximab, as taught by Mohrbacher. One would have been motivated to administer the 4-1BB agonist and the rituximab together because both are known to treat non-Hodgkin’s lymphoma. MPEP 2144.06 states “it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Therefore, it would have been obvious to combine the separate, known compositions for the same purpose of treating non-Hodgkin’s lymphoma. Further, it would have been obvious to one of ordinary skill in the art to have administered the rituximab 24 hours prior to the 4-1BB agonist. One would have been motivated to follow this administration regimen because Kohrt teaches that there was synergistic antitumor activity in lymphoma cells lines when rituximab was administered on day 3 before the anti-CD137 mAb on day 4 (i.e. 24 hours before). Further, the claim 1 limitation of “wherein administration of said 4-1BB agonist and an anti-CD20 antibody treat the B-cell lymphoma or leukemia synergistically as compared to administration of said 4-1BB agonist or said anti-CD20 antibody alone” is a result effective variable. Since Kohrt teaches administering both a 4-1BB agonist and an anti-CD20 antibody to the same subject, any result thereof, including synergistic results, would therefore be inherent. Moreover, this is the expected result because Kohrt teaches that the administration of the 4-1BB agonist and the anti-CD20 antibody resulted in synergistic outcomes when the rituximab is administered 24 hours prior to the 4-1BB agonist and that although anti-CD20 and anti-CD137 mAbs both had antitumor activity when used as single agents, their combination significantly enhanced tumor regression and survival.
Claim 11 is included in this rejection because Amann teaches the TNF family ligand trimer-containing antigen binding molecule comprising (a) at least one moiety capable of specific binding to a target cell antigen and (b) a first and a second polypeptide that are linked to each other by a disulfide bond, wherein the antigen binding molecule is characterized in that the first polypeptide comprises two ectodomains of a TNF ligand family member or two fragments thereof that are connected to each other by a peptide linker and in that the second polypeptide comprises only one ectodomain of said TNF ligand family member or a fragment thereof [page 4, lines 2-9]. Amann also teaches that the TNF family ligand trimer-containing antigen binding molecule is 4-1BBL [page 5, line 21] and that the target antigen can be CD19 [page 8, lines 14-17].
Claim 22 is included in this rejection because Amann teaches administering the TNF family ligand trimer-containing antigen binding molecule intermittently such as every week or every three weeks (intervals from about one week to three weeks) [page 104, lines 10-11] and Mohrbacher teaches administering rituximab 375 mg/m2 weekly (intervals from about one week) for 4 weeks [page 1, right column, fourth paragraph].
Claim 25 is included in this rejection because Amann teaches a pharmaceutical composition comprising the TNF family ligand trimer-containing antigen binding molecule of the invention and at least one pharmaceutically acceptable excipient [page 17, lines 21-23].
Claim 34 is included in this rejection because Kohrt further teaches that although anti-CD20 (rituximab) and anti-CD137 mAbs both had antitumor activity when used as single agents, their combination significantly enhanced tumor regression and survival [page 2427, left column, second paragraph]. The examiner is interpreting this to be that the cancer was poorly responsible to the rituximab alone compared to the combination of rituximab and anti-CD137.
Claims 20 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Amann (WO 2016075278; 09/19/2023 PTO-892) in view of Mohrbacher, 2005 (09/19/2023 PTO-892), and Kohrt et al., 2011 (05/22/2024 PTO-892), as applied to claims 1, 11, 17, 22, 25, 27, and 34 above, and further in view of Gabellier et al., 2016 (09/19/2023 PTO-892), Walter et al., 2016 (09/19/2023 PTO-892), and Gazyva, 2017 (09/19/2023 PTO-892).
The teachings of Amann, Mohrbacher, and Kohrt are above.
However, Amann, Mohrbacher, and Kohrt do not teach that that the anti-CD20 antibody is Obinutuzumab, or that a pretreatment with Obinutuzumab is performed prior to the treatment with the 4-1BB agonist and the anti-CD20 antibody, wherein the period of time between the pretreatment and said administering of a therapeutically effective amount of 4-1BB agonist and Obinutuzumab to said individual is sufficient for the reduction of B-cells in the individual in response to the Obinutuzumab.
Regarding claim 20, Gabellier teaches that Obinutuzumab, a type II glycoengineered anti-CD20 antibody [see Abstract], was used to treat patients with non-Hodgkin’s lymphoma (NHL) [page 89, left column, second-third paragraphs and page 89, right column, first-second paragraphs]. Gabellier also teaches that Obinutuzumab, when compared with rituximab, had improved antibody-dependent cell cytotoxicity (ADCC) and direct cell death [page 91, left column, second paragraph].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the anti-CD20 antibody, as taught by Mohrbacher and Kohrt, to be Obinutuzumab, as taught by Gabellier. One would have been motivated to make this modification because Gabellier teaches that Obinutuzumab treats NHL and that is has improved ADCC and direct cell death over rituximab.
Claim 23 is included in this rejection because since it would have been obvious to use Obinutuzumab in the combination therapy, it also would have been obvious to administer a pretreatment of Obinutuzumab prior to the combination treatment because Gazyva teaches the benefits of a loading dose of Obinutuzumab of increasing the amount of this antibody in a first cycle before continuing on with additional cycles at the same dose. While Gazyva includes chemotherapies in all cycles, it would have been obvious that the 4-1BB agonist was not necessary for the loading dose because Gazyva does not teach any benefit to a loading dose for the second chemotherapy so, a person of ordinary skill in the art would have been motivated to include the 4-1BB agonist in a second and subsequent cycle once the target dose of Obinutuzumab had been reached. Additionally, Gazyva teaches administering the loading doses at days 1, 2, 8, and 15 of a 28 day cycle in cycle 1, and then only administering on day 1 of each subsequent 28 day cycle. Absent evidence to the contrary, these intervals would be sufficient to reduce B-cell in the individual in response to the Obinutuzumab. Further, the treatment being sufficient for the reduction of B-cells in the individual in response to the Obinutuzumab is a property of the Obinutuzumab itself. Applicant is reminded that chemical compounds and their properties are inseparable (In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA1963)), as are their processes and yields (In re Von Schickh, 362 F.2d 821, 150 USPQ 300 (CCPA 1966)). A person of ordinary skill in the art would recognize that the reduction of B-cell is a property of the Obinutuzumab.
Response to Arguments
The rejections of claims 1-3, 11, 17, 20, 22-23, 27, and 34 under 35 U.S.C. 112(a) enablement are maintained. On pages 6-7 of the remarks, Applicant argues that claim 1 has been amended to recite “said anti-CD20 antibody is administered concomitantly with, or up to 24 hours before, said 4-1BB agonist” which captures what the Office Action states is enabled. This is not found persuasive because the claim, as amended, still encompasses rituximab administered concomitantly with the 4-1BB agonist, rituximab administered at less than 24 hours prior to the 4-1BB agonist, and Obinutuzumab administered 24 hours hour prior to the 4-1BB agonist, which are embodiments that are not enabled as stated in the previous and current rejections. See above. Applicant further argues that the citation of Kohrt (2011) never compares the combination of rituximab plus 4-1BB agonist to rituximab alone or 4-1BB agonist alone; thus, Fig. 4A of Kohrt cannot demonstrate or disprove the existence of synergy between the two. This is not found persuasive because while Kohrt may not have specifically disclosed the data, Kohrt did compare the rituximab alone on day 3, the anti-CD137 mAb (4-1BB agonist) alone on day 4, and both the rituximab on day 3 and anti-CD137 mAb on day 4 [see page 2425, left column, fourth paragraph], determined that the addition of anti-CD137 mAb significantly increased rituximab-induced ADCC compared to rituximab alone, and then concluded that there was a synergistic reduction in tumor size when administering rituximab on day 3 and an anti-CD137 antibody on day 4, but that there was not a synergistic reduction in tumor size when rituximab and the anti-CD137 antibody were administered on the same day [page 2427 and Figure 4A]. Applicant additionally argues that even if the teachings of Kohrt were characterizable as synergy, Kohrt uses a 4-1BB monoclonal antibody, not a 4-1BBL construct as specified in the present claims. This is not found persuasive because the instant claims are drawn to a 4-1BB agonist and not to a 4-1BBL construct as Applicant is arguing. Applicant further argues that a person of skill in the art would reasonably expect that where rituximab and a 4-1BBL construct work synergistically where the rituximab is administered 24 hours prior to the 4-1BBL construct, would work synergistically as well where another CD20 antibody, Obinutuzumab, is administered 24 hours prior to the 4-1BBL construct, and the Office provides no evidence to the contrary. This is not found persuasive because again, the claims are to a 4-1BB agonist and not to a 4-1BBL construct. To the extent this argument applies to the instantly claimed 4-1BB agonist, this is still not found persuasive because Applicant has not demonstrated why it would reasonably be expected that treatment with Obinutuzumab 24 hours prior to the 4-1BB agonist would be synergistic. Synergy in its nature is unpredictable and a substitution of rituximab for Obinutuzumab with the expectation that synergy would be maintained is not routine. Therefore, undue experimentation would be necessary to determine if the Obinutuzumab administered 24 hours prior to the 4-1BB agonist would synergistically treat B-cell lymphoma or leukemia. The burden is on Applicant to establish results are unexpected and significant. See MPEP 716.02(b).
The rejections of claims 1, 11, 17, 20, 22-23, 25, 27, and 34 under 35 U.S.C. 103 are maintained. On page 8 of the remarks, Applicant argues the rationale for combining the cited references, which refers to In re Kerkhoven, is not applicable to the present claims because the technology involved is more complex than the mere mixing of two detergents. This is not found persuasive because Applicant is disparaging Kerkhoven as merely “detergents” and not applicable to biotechnology while overlooking the point of the ruling that individual compositions with a specific activity would be expected to retain that activity when combined with other compositions that have that same activity. Applicant further argues that the non-enablement rejection considered the effect of substitution of anti-CD20 antibodies other than rituximab and Obinutuzumab to be too unpredictable for the claims to be enabling but also states that substitution of the CD137 antibody disclosed in Kohrt for the recited 4-1BB agonist is predictable enough to be obvious and that this inconsistency does not establish a prima facie case of obviousness. This is not found persuasive because the art has demonstrated that rituximab (i.e. an anti-CD20 antibody) combined with a CD137 (i.e. 4-1BB) agonist when administered 24 hours apart is synergistic but fails to be synergistic when administered concomitantly. See response to arguments for the enablement rejection above for further reply. Applicant provides no objective evidence of rituximab and another 4-1BB agonist that when administered 24 hours apart fails to be synergistic. The art (i.e. Kohrt references) establishes that synergy one day apart is not predictive of synergy when given concomitantly. Moreover, Applicant is arguing that synergistic effects are predictive of untested results, and in a similar logic, what the art teaches is rituximab and an anti-CD137 antibody when administered 24 hours apart result in a similar synergistic effect as that disclosed in the instant specification [see Example 4]. CD137 is a synonym for 4-1BB. The instant claims are directed to a 4-1BB agonist and the anti-CD137 antibody of Kohrt is also disclosed as an agonist. Therefore, both are 4-1BB agonists and while each may have different mechanisms of action, each are expected to be similar enough to have synergistic effects and there is no evidence to the contrary. The mechanisms of rituximab and the 4-1BB agonist at a very specific timing regimen (i.e. administered 24 hours apart) are expected to be synergistic in the same way they are expected to not be synergistic at a different timing regimen (i.e. administered concomitantly).
The rejections of claims 20 and 23 under 35 U.S.C. 103 are maintained. It is noted that Applicant continues to address claims 18-19 and 32, however, these claims are canceled. On page 9 of the remarks, Applicant argues that Gabellier, Walter, and Gazyva do not resolve the defects of the combination of Amann, Mohrbacher, and Kohrt. This is not found persuasive because no such deficiency exists. See above.
Applicant further argues claim 23, stating that the Examiner has used hindsight reasoning to establish the obviousness rejection of claim 23 and that only through hindsight could the disclosure of Gazyva be converted into a suggestion to pretreat with Obinutuzumab first, and then administer the combination. This is not found persuasive because in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Applicant does not point to any specific fact of the rejection that is gleaned only from Applicant’s specification, the Examiner did not use knowledge gleaned only from Applicant’s disclosure to make the obviousness rejection, and the Examiner did not argue that because Gazyva does not disclose pretreatment with something other than Obinutuzumab, it must have been obvious to pretreat using Obinutuzumab. Rather, the Examiner clearly articulated that it would have been obvious to administer a pretreatment of Obinutuzumab prior to the combination of Obinutuzumab and the 4-1BB agonist because Gazyva teaches the benefits of a loading dose of Obinutuzumab of increasing the amount of this antibody in a first cycle before continuing on with additional cycles, and while Gazyva includes chemotherapies in all cycles, it would have been obvious that the 4-1BB agonist was not necessary for the loading dose because Gazyva does not teach any benefit to a loading dose for the second therapeutic so, a person of ordinary skill in the art would have been motivated to include the 4-1BB agonist in a second and subsequent cycle once the target dose of Obinutuzumab had been reached. See rejection above. Applicant further argues that the Office Action states that the argument of “because Gazyva does not teach any benefit to a loading dose for the second therapeutic, a person of ordinary skill in the art would have been motivated to include the 4-lBB agonist in a second and subsequent cycle” is different words for the same argument of “because Gazyva does not disclose pretreatment with something other than Obinutuzumab, it must have been obvious to pretreat using Obinutuzumab.” This is a misrepresentation of the Examiner’s obviousness rationale because this section was taken out of context of the entire statement and these are not simply equivalents for the same argument. See above. Applicant reiterates the argument that only through hindsight could the disclosure of Gazyva be converted into a suggestion to pretreat with Obinutuzumab first, and then administer the combination of Obinutuzumab and 4-lBB agonist (not chemotherapy) thereafter. This is not found persuasive for the same reasons as addressed above and the response to the argument is incorporated herein and will not be reiterated. See above.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brittney E Donoghue whose telephone number is (571)272-9883. The examiner can normally be reached Mon - Fri 7:30 - 3:30.
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) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at (571) 272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675