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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/7/2025 has been entered.
Claims 1-3, 8, 9, 11, 13, 15, 18, 21, 23, 25, 28, 29, 31, 36-39, 41, 45-47, 50, 53, 55, 59, 60, 65-67, 83-95, 97-99, 102-105 and 107 are pending. Claims 1-3, 8, 9, 11, 13, 15, 18, 21, 23, 25, 28, 29, 31, 45-47, 50, 53, 55, 59, 60, 65-67, 83-85, 89-95, 103-105 are withdrawn. Claims 36-39, 41, 86-88, 97-99, 102 and 107 are currently under examination.
Claim Rejections - 35 USC § 112
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 36-39, 41, 86-88, 97-99, 102 and 107 are rejected 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The written description requirement is set forth by 35 U.S.C. 112, first paragraph which states that the: “specification shall contain a written description of the invention. . .[emphasis added].” The written description requirement has been well established and characterized in the case law. A specification must convey to one of skill in the art that “as of the filing date sought, [the inventor] was in possession of the invention.” See Vas Cath v. Mahurkar 935 F.2d 1555, 1560 19 USPQ2d 1111, 1117 (Fed. Cir. 1991). Applicant may show that he is in “possession” of the invention claimed by describing the invention with all of its claimed limitations “by such descriptive means as words, structures, figures, diagrams, formulas, etc., that fully set forth the claimed invention.” See Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997).
In analyzing whether the written description requirement is met, it is first determined whether a representative number of species have been described by their complete structure. Next, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics.
The claimed composition of claim 36 comprises a population of activated T cells and a detectable amount of a pICF, wherein this population of activated T cells is purified and having an Effective E:T ratio of 1:10 or higher, wherein E:T is between the number of T cells after exposure to the pICF, and number of target cancer cells killed by said T cells. The claimed genus of T cell population encompasses a wide range of different types of T cells, activated by a wide range of different type of bispecific or multi-specific antibody, under different condition, including both in vitro or in vivo, at various length of exposure time, at various concentration, wherein the target cancer cell also encompasses a wide range of different types of cancer cells. In example 2, the specification describes activating T cells with CD3CD19 BsMAb with 8 concentrations, and following 144 hour of incubation with malignant B cells, the effective ration of E:T is 1:5.7 (page 94, 2nd paragraph). In Example 3, the specification describes activating T cells with CD123CD3 bispecific BsMAb, and following 120 hours incubation with carious concentrations of BsMAb, the Effective E:T ratio various with sample, one being 1:0.8, another being 1:7.1 (page 95, 2nd paragraph and Figure 8). Example 6 demonstrates the killing capacity of sorted CD8+CD25+ T cells following CD123CD3 treatment, reaching maximum of 1:1 (Figure 12, and page 99, 3rd paragraph). Example 13 describes activating T cells by using CD123CD3 with bone marrow from adult AML using normal media or autologous plasma, only when T cells are incubated with autologous plasma achieves Effective E:T of 1:21, but not normal media (page 109, Table 2). Example 15 describes treating T cells with CD123CD3 with one patient sample of AML for different concentration for 144 hours achieves effective E:T ratio 1:100 (page 111, 2nd paragraph). In example 17, the specification describes paired sample from bone marrow and peripheral blood from 5 AML patients were incubated with eight different concentration of CD3xCD123 for 72 hours, and determined for E:T ratio. The specification teaches E:T ratios are higher in bone marrow than that from peripheral, but only one sample (1) from bone marrow showed effective E:T being 1: 24.46. Besides the three instances, there is no other description of a composition that comprises T cells having E:T ratio 1:10 or higher and a detectable amount of bispecific or multi-specific antibody. In view of the large genus of the activated T cells as claimed, the specification fails to describe a representative number of species by their complete structure, or other identifying characteristics to establish a structural functional relationship between T cells activated by bispecific or multi-specific antibody, and having Effective E: T ratio being 1:10 or higher.
The knowledge from prior art does not remedy the deficiency because prior art does not measure Effective E:T ratio. The affidavit filed on 4/25/2024 indicates that activated T cells does not necessarily kill cancer cells, and the cell-killing activity of activated T cell must be decided on a case-by case basis (see Table 1, and paragraph 7). As such, whether the broadly claimed genus of activated T cells, activated by a wide range of pICF, under wide range of condition, having Effective E:T ratio to a wide range of target cancer cell would have E:T ratio being 1:10 and higher is unpredictable. The specification thus fails to describe the claimed genus of composition in such a way to convey a skilled artisan had possession of the invention at the time the application was filed. Dependent claims 37-39, 41, 86-88, 97-99, 102 and 107 are rejected for same reason because they depend on claim 36.
Response to Arguments
In response to this rejection, Applicant submitted a second declaration under 37 CFR 1.132 to provide calculated effective E:T ratios for the experiments of Example 10 of the instant application. Applicant asserts that sixteen samples of T cells analyzed from Example 10, nine samples have Effective E:T ratios of 1 activated T cell to 10 or more target cancer cells, which is in addition to three examples from Examples 13, 15 and 25. Applicant concludes that with the evidence provided in the second declaration, a representative number of species of the claimed effective E:T ratios higher than 1:10 are provided.
The declaration under 37 CFR 1.132 filed 8/7/2025 is insufficient to overcome the rejection of claims 36-39, 41, 86-88, 97-99, 102 and 107 based upon 112a as set forth in the last Office action because for following reasons.
The declaration provide an assessment of Effective E:T ratio of activated T cells of Example 10 of the specification, using data of sixteen samples of T cells shown in Figure 16, at three different time points (72, 96 and 120 h). The Effective E:T ratio was calculated. Applicant asserts that among 16 samples of T cells analyzed, nine samples have Effective E:T ratios of 1 activated T cell to 10 or more target cancer cells.
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Applicant asserts the above table showed 9 more example of activated T cells that have effective ratio higher than 1:10.
The 2nd declaration has been fully considered. From the teaching of the specification (Example 10 and Figure 16), there are 17 BM samples from AML patients being analyzed. Bone marrow samples were collected and contacted with CD123/CD3 BsMAb, control antibodies or neither, and samples were incubated for 72, 96 or 120 hours, followed by addition of antibodies and AML blast population. The specification teaches there is a very high level of interpatient variability in both the kinetics and efficiency of the blast depletion and the proliferation of the CLT population. The specification teaches further work needs to be done to see if there is a correlation between these results and the clinical response of the patients (page 105-106). Based on the teaching from these teaching, it is unclear, whether the above calculated E:T ratio in supplemental table 1 are from 9 different patient samples, or same sample measured at different time points. It is apparent that at 72 h, there are 5/17 samples demonstrated E:T ratio higher than 1:10, at 96 h, only 3/17 samples have E:T ratio higher than 1:10, and at 120 h, there is only 1/17 sample has E:T ratio higher than 1:10, and all of which are BM sample contacted with CD123CD3 bispecific antibody and AML. As discussed in the previous office action, the claimed genus of T cell population encompasses a wide range of different types of T cells, activated by a wide range of different type of bispecific or multi-specific antibody, under different condition such as in vitro or in vivo, various length of exposure time, various concentration of the bispecific or multi-specific antibody, wherein the target cancer cell also encompasses a wide range of different type of cancer cells. The additional information (at most 9 sample) from same antibody CD123/CD3 and same type of cancer does not sufficiently represent such a large genus of activated T cell as claimed. The teaching from the specification indicates there is high degree of interpatient variability, and variability for the length of exposure (see table above) and the type of media being used during the exposure (page 109, lines 3-4, and Table 2). Such teaching is also supported by Applicant’s own admission in the 1st declaration that “the cell killing activity of activated T cells must be decided on a case-by case basis.” (paragraph 7). As such, whether the broadly claimed genus of activated T cells, activated by a wide range of pICF of bispecific or multi-specific antibodies, under wide range of condition would have effective E:T ratio to a wide range of target cancer cell higher than 1:10 is unpredictable. The addition of at most 9 samples from same bispecific antibody and same target cancer cells does not provide sufficient representation to the broad genus as claimed in claim 36. Therefore, this rejection is still considered proper and thus maintained.
Claim Rejections - 35 USC § 103
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.
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.
Claim(s) 36-39, 41, 86-88, 97, 99, 102 and 107 is/are rejected under 35 U.S.C. 103 as being unpatentable over Krupka et al (cited previously).
Krupka et al. teach testing the cytotoxicity of AMG 330 activated autologous T cells on AML samples, wherein AMG 330 is CD33/CD3-bispecific T cell engaging (BiTE) antibody (abstract, and page 360, 2nd col., 2nd paragraph). Krupka et al. teaches AML patient samples comprises E:T ratios ranging between 1:3.4 and 1:79. Krupka et al. teaches when cultured in the presence of AMG 330, CD33+ cells (tumor cells) are eliminated almost completely within 28-36 days, whereas the starting E:T is 1:11 (Figure 4B and legend, and page 360, 2nd col., 2nd paragraph). Even though Krupka does not calculate an E:T ratio as activated T cells vs. killing of cancer cells, the graph (4B) showed between day 28 to day 36, the number of T cells is fewer than the starting T cell, whereas the number of CD33+ tumor cells are nearly eliminated. It would have been obvious to an ordinary skilled in the art that the ratio of activated T cells vs. cancer cells being killed by said T cells would have been at least 1:11.
The only difference between the claimed invention of claim 36 and the teaching from Krupka is that there is no specific teaching of purifying this activated population of T cells.
It would have been obvious to an ordinary skill to isolate this population of activated T cells which has high E: T ratio base on the teaching from Krupka. The ordinary skilled in the art would be motivated to do so to further study the characteristic and/or function of said activated T cell to better understand the mechanism of action AMG 330. Since the specification does not define “purify,” isolating the T cells from the long term culture would meet this claim limitation. Therefore, the claimed composition of claim 36 would have been prima facie obvious in view of the teaching from Krupka at the time the application was filed.
Regarding claims 37 and 41, the activated T cells would inherently comprise trogocytotic activated T cells at 30% of total cells because they are activated by BiTE, a pICF, and AML cells.
Regarding claim 38, it would have been inherent that the trogocytotic cells would comprise at least 100 copies of a cell surface marker acquired from the cancer cells because trogocytotic T cells are activated by BiTE, a pICF, and AML cells.
Regarding claim 39, Krupka et al. teach the activated T cells comprises both CD4+ and CD8+ T cells (Figure 5C and legend, page 363, 1st col., 1st paragraph, lines 3-6).
Regarding claim 86, Krupka et al. teach the AML patient samples comprises T cell and CD33+ tumor cells, which meets the limitation of the T cell being an autologous T cell (page 360, 2nd col., lines 1-2).
Regarding claim 87, since the claim just further gives a group of checkpoint inhibitor to choose from (among all the agents recited in claim 86), the teaching from Krupka still renders this claim obvious because it chooses from the group of claim 86, an autologous T cell.
Regarding claim 88, since the activated T cells are in culture, the culture medium meets the limitation of a pharmaceutically acceptable carrier.
Regarding claim 97, Krupka et al. teach AMG 330 is a BiTE antibody (abstract).
Regarding claim 99, Krupka et al. teach AMG 330 is added to culture at a concentration of 5ng/mL. Although it does not teach the concentration by % weight as claimed, it would have been obvious to an ordinary skilled in the art to determine optimal percentage of pICF and T cells in the composition based on the teaching from Krupka that can achieve optimal cancer cell killing activity. optimization of ranges and concentration of drug is well known in and established practice. Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See MPEP 2144.05 II. A.
Regarding claim 102, the activated T cells in culture meets the limitation of ex vivo.
Regarding claim 107, Krupka et al. teach AMG 330, which comprises a first element binds to CD3, and a second element binds to CD33 (abstract).
Response to Arguments
In response to the rejection, Applicant focusses the argument on Figure 4B from Krupka.
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Applicant states that Figure 4B shows that the CD33+ AML blasts are regrowing when compare the two boxes in the muCD29/CD33 flow cytometry plots, and actually suggests that there is a decline of viable CD3+ T cells in Figure 4B. Applicant argues one cannot conclude that T cells on day 36 of Figure 4B are activated T cells, especially knowing that complete elimination was not achieved at day 36. Applicant argues one cannot know how many T cells are activated on day 36 of Figure 4B. Applicant argues that Krupka does not consider purifying the activated T cells of their assay for preparation of a composition, because Krupka’s intent was to validate that CD33 is a suitable target antigen for BiTE therapy in AML and to establish long-term culture system to closely stimulate therapeutic administration cycles. Applicant questions what population of activated T cells are to be isolated because Krupka is silent regarding this? Applicant argues a person of ordinary skilled in the art would never be motivated to select T cells at 36 of Figure 4B of Krupka because actually are very few T Cells and it appears that any that remain may no longer be activated. A person of ordinary skilled in the art knows that T cells exapand until target cells are gone, at which point the T cells become exhausted and commit apoptosis dues to a process named activation induced death. Applicant argues that claim 36 recites contains the limitation of T cells consisting essentailly of purified T cells having an Effective E:T ratio of 1 activated T cell to 10 or more target cancer cells killed, which is not tuaght by Krupka.
The above argument have been fully considered but deemed unpersuasive. Applicant’s statement of there is tumor regrowth is incorrect with regard to Figure 4B because Krupka explicitly states “a close to complete elimination was achieved within 28-36 days.” (page 360, 2nd col., line 11-12). The sample with limited tumor regrowth at day 36 is shown in Figure 4C, not Figure 4B (page 360, 2nd paragraph, last two lines). Applicant is also mistaken that the rejection suggests to purify the remaining T cells on day 36, the rejection is suggesting that based on the information presented in Krupka, at least one patient sample PT8, contacted with AMG 330 can generate activated T cells having E:T ratio at 1:10 and above. An ordinarys skilled in the art would understand at which time point there are sufficent activated T cells in the culture based on the information presented in Figure 4B.
With regard to the argument that claim 36 recites “consists essentially,” Applicant is reminded that the claim is not reciting “a composition comprising essentially of purfied T cells,” but a composition comprising activated T cells, and the “activated T cells” consists essentially of purified T cells having an effective E:T ratio of 1:10. The composition is thus open ended to encompasses a wide variety of components. As stated in the previous rejection, claim 36 does not recite any limitation with regard to how to use the composition, i.e. cell therapy as alleged by Applicant. Nor does claim 36 recites any limitation with regard to the purification process. As such, an ordinary skilled in the art may isolate said T cells from the cytotoxic assay for any purpose, such as discussed in the rejection, for studying the characteristic of said T cells, would have meet the limitation of purifying said T cells.
With regard to the argument that Krupka does not teach purify the activated T cell, Applicant is reminded that KSR forecloses a specific teaching, suggestion and motivation is required to support the finding of obviousness. Since the specification does not define “purify,” (activated T cells having Effective E:T ratio being 1:10 and higher in example 10, 13 and 15 are not purified) isolating the T cells from the long term culture would meet this claim limitation. Therefore, for reasons discussed in previous office action and set forth above, this rejection is still considered proper and thus maintained.
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/CELINE X QIAN/ Primary Examiner, Art Unit 1637