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 .
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 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.
DETAILED ACTION
The amendments filed on 9/11/2025 which claims 34-35 were amended and claims 36-38 were newly added is acknowledged. Claim 28 was canceled.
Claims 2-7, 9-10, 21-22, 24, and 29-38 are pending in the instant application.
Priority
This application is a 371 of PCT/US2019/027815 filed on 4/17/2019 which claims priority to the provisional application 62/658792 filed on 4/17/2018.
Election/Restriction
Applicant’s election without traverse of Group III, claims 21-27, drawn to a product: isolated CD4+ Th9 cells expressing Traf6 and Eomes and/or Ki67, in the reply filed on 8/9/2023 remains in effect. Within the elected group, claims 21-22 were amended and claims 23 and 25-27 were canceled. Claims 31-35 were newly added.
Claims 2-7, 9-10, and 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim.
claims 21-22, 24,29-35, 37-38
Claims 21-22, 24, 29-35, and 37-38 are examined herein.
Withdrawn Rejections
The rejection of claim 34 under § 112(b) is withdrawn in light of the amendments; the claim no longer recites “such as.”
The rejection of claim 35 under § 112(b) is withdrawn in light of the amendments; the claim now refers to the scFv binding CD19.
The rejection of claim 28 under § 112(d) is withdrawn in light of the amendments; the claim was canceled.
Objections to the Claims
Claim 34 contains an embedded list that is not properly separated, please replace “mutated antigens derived from protein products of mutated oncogenes KRAS, NRAS, and HRAS” with “protein products of mutated KRAS, protein products of mutated NRAS, protein products of mutated HRAS”
Claim Rejections – 35 USC § 112(b)
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 34 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 34
Claim 34 is rendered indefinite because it (i) contains two conjunctions and (ii) is drawn to a list of cancer antigens to be selected from, wherein some of the list items are not cancer antigens or unclear. Regarding (i) the presence of multiple conjunctions in a list that does not show distinctive sub-lists, creates confusion as to whether the list of a, b, c, and d, and e is to be interpreted as selecting from (a, b, c, and d) or (e); or if the list is to be interpreted as a, b, c, d, or e; thus rendering this claim structure indefinite. Regarding (ii) it is unclear what the entry “surviving” in line 15 means. The entry “ETV6/AML” refers to a gene mutation in acute myeloid leukemia and not a cancer antigen. The entry “NPM/ALK” is presumed to refer to “NPM-ALK” (ALK anaplastic lymphoma kinase) however it is unclear if this is the correct interpretation. It is unclear what the entry “mutated antigens derived from protein products of mutated oncogenes KRAS, NRAS, and HRAS” means. In one interpretation this refers to (a) a protein product created from mutated KRAS, NRAS, or HRAS; or (b) a protein product created from KRAS/NRAS/HRAS that undergoes a second mutation process, post-translationally. The presence of these list items as exemplary cancer antigens renders the claim indefinite, as one of skill in the art would not know the structure of the antigen given these multiple interpretations.
Claim Rejections – 35 USC § 112(a)
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.
Claim 34 is 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.
Claim 34
Claim 34 refers to “mutated antigens derived from protein products of mutated oncogenes KRAS, NRAS, and HRAS,” wherein one of skill in the art would not know which of these protein products were (i) satisfy the limitation of being mutated (as addressed in the 112(b) rejection above); (ii) which protein products of thee above would be effective cancer antigens; and (iii) what antibodies or fragments thereof are capable of binding this variety of protein products. Applicant can meet the written description requirement by supplying a representative number of species or by describing the core structure necessary for preserving the function. Applicant has not provided an example of “mutated antigens derived from protein products of mutated oncogenes KRAS, NRAS, and HRAS” in order to address (i). Applicant has not described the core structure these protein products must possess to address (ii). Applicant has not described the core structure or any representative antibodies/fragments that have are able to bind these products to address (iii). As a result, applicant has failed to meet the written description requirement.
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.
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 21-22, 24, 29-35, and 37-38 are rejected under 35 U.S.C. 103 as being unpatentable over Baumjohann et al. (Nat Rev Immunol. 2013 Sep;13(9):666-78) in view of Sadelain et al. (WO2017180989). This rejection has been modified to solely address the amendments.
claim 21
Regarding claims 21, Baumjohann teaches CD4+ T helper (Th) cells can differentiate into several subsets of effector T helper cells, such as Th9 cells (pg 666, col 1, para 1). Thus meeting the limitation of “mature effector T cell”. Baumjohann teaches microRNAs (miRNAs) are small, endogenously expressed nucleotides that regulate gene expression, determine cell identity and function (pg 666, col 2, para 1). Baumjohann teaches the miRNA called miR-146a targets the gene Traf6, which inhibits T cell activation and population expansion (Figure 1 caption). Baumjohann teaches the protein EOMES is also involved in the signaling cascade for differentiating T cells (Figure 2 caption). Baumjohann teaches that these CD4+ T cells are native to mice and humans (pg 667, col 2, para 1). Taken together Baumjohann teaches Th9 cells are naturally occurring in humans and other species, as are the genes and corresponding proteins of Traf6 and Eomes. Since the Th9 cell of Baumjohann is the same as the Th9 cell instantly claimed, the property of “expressing Ki67” is an inherent property. See MPEP § 2112(I) and 2112(II). As an evidentiary reference, DiRosa et al. (Front Immunol. 2021 Sep 28;12:756641) teaches that T cells when they enter a proliferative state, they express Ki67, thus this protein is commonly used as a marker of cells preparing for or in the process of dividing. DiRosa teaches that Ki-67 supports chromosome architecture organization and nucleolar assembly upon mitosis, helps remove cytoplasm from the reassembling nucleus during mitotic exit, and regulates heterochromatin compaction and gene expression in proliferating cells (pg 1, para 1-pg 2 para 1). Thus Ki67 is a native protein that wild type T cells normally express under normal conditions during their lifetime.
Baumjohann does not teach the Th9 cells comprising a chimeric antigen receptor that targets cancer cells.
Sadelain teaches T cells comprising a transgene that encodes a CAR (pg 13, para 0044). Sadelain teaches the T cell expresses a CAR which can comprise a CD28, CD27, and/or 4-1BB co-stimulatory domain(pg 19, para 0068). Sadelain teaches the CAR can also comprise a CD3 zeta domain (pg 35, para 00139). Sadelain teaches the CAR binds to a cancer antigen (pg 35, para 00141). Sadelain teaches the car comprises an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the extracellular domain is an scFv that binds to a cancer antigen (pg 85, para 00261). Sadelain teaches Sadelain teaches the T cell is CD4+ subtype of T cell, such as a Th9 cell (pg 35, para 00142; claim 19). Sadelain teaches the CAR can target suitable cancer antigens such as CD19 (pg 91-92, para 00270).
It would have been obvious to combine the teachings of Baumjohann and Sadelain because both references utilize CD4+ Th9 cells to treat cancer. Baumjohann teaches that Th9 cells naturally comprise the gene Traf6 and express the proteins Eomes, CD4, and Ki67. Sadelain also teaches that CD4+ Th9 cells can be engineered to express a CAR comprising a CD19 extracellular domain as part of a method of treating cancer. One of skill in the art would have had a reasonable expectation of success because Sadelain teaches that CARs that target CD19, are capable of target cancer cells, and can be successfully incorporated into a population of Th9 cells.
claim 22
Regarding claim 22, Sadelain teaches stimulating T cells using CD19+ antigen-presenting cells (APCs) (pg 171, para 00722; pg 166, para 00711). Sadelain teaches using the APCs to stimulate expansion of the T cells (pg 58, para 00199). Thus meeting the limitation of the T cells being “primed” with cancer-antigen-loaded APCs, as CD19 is a cancer antigen.
claim 24
Regarding claim 24, since the Th9 cell of Baumjohann is the same as the Th9 cell instantly claimed save for the CAR, the property of having “cytolytic activity as strong as a Th1 cell” is an inherent, naturally-occurring property of Th9 cells as described in the previous office action. See MPEP § 2112(I) and 2112(II). The addition of the CAR thus serves to enhance the cytolytic activity of the Th9 cells even further, which would be enhanced relative to Th1 cells that did not express the cancer-targeting CAR. Thus rendering obvious the limitation of having “cytolytic activity as strong as a Th1 cell”.
claim 29-30
Regarding claims 29-30, as discussed previously in the 103 rejection of claim 21, CD4+ Th9 cells comprising DNA that encodes Traf6 and Eomes, wherein Ki67 is expressed, are naturally occurring properties and phenomena of naturally occurring Th9 cells, as previously discussed in the rejection of claim 21. The additional limitation of requiring a non-naturally occurring CAR has also been addressed in the rejection of claim 21. The remaining limitation of requiring the population of cells being reduced to just a single cell, is one that could be easily rendered obvious by one of ordinary skill in the art. “A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR, 550 U.S. at 421, 82 USPQ2d at 1397. “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. at 418, 82 USPQ2d at 1396. In the instant case, one of ordinary skill in the art would be able to envisage any number of Th9 cells comprising a CAR, even a single cell. See MPEP § 2141(II)(C). Thus rendering obvious a population comprising one Th9 cell.
Sadelain teaches T cells comprising a transgene that encodes a CAR (pg 13, para 0044). Sadelain teaches the T cell expresses a CAR which can comprise a CD28, CD27, and/or 4-1BB co-stimulatory domain(pg 19, para 0068). Sadelain teaches the CAR can also comprise a CD3 zeta domain (pg 35, para 00139). Sadelain teaches the CAR binds to a cancer antigen (pg 35, para 00141). Sadelain teaches the car comprises an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the extracellular domain is an scFv that binds to a cancer antigen (pg 85, para 00261). Sadelain teaches Sadelain teaches the T cell is CD4+ subtype of T cell, such as a Th9 cell (pg 35, para 00142; claim 19). Sadelain teaches the CAR can target suitable cancer antigens such as CD19 (pg 91-92, para 00270). Sadelain teaches stimulating T cells using CD19+ antigen-presenting cells (APCs) (pg 171, para 00722; pg 166, para 00711). Thus meeting the limitation of the T cells being “primed” with cancer-antigen-loaded APCs, as CD19 is a cancer antigen.
claim 31-33
Regarding claims 31-33, Sadelain teaches the costimulatory domain of the CAR can comprise CD28 (pg 19, para 0068).
*claims 34-35, 37-38
Regarding claims 34-35 and 37-38, Sadelain teaches the CAR can target suitable cancer antigens such as CD19 (pg 91-92, para 00270). Sadelain teaches the cancer can be a blood cancer, such as a lymphoma (pg 112, para 00320), and that CD19 is a molecule expressed in B cells, thus the CAR of the invention by targeting CD19, targets B cells leading to B-cell death (pg 174, para 00727). Thus satisfying the limitation of treating B cell lymphoma via inducing B-cell death via a CD19-targeting CAR.
Response to Arguments
Applicant’s arguments filed on 9/11/2025 have been fully considered but they are not persuasive.
112(b); pg 7, para 4
Applicant argues that they have addressed all of the sources of indefiniteness in claim 34.
Examiner points out that Applicant applicant’s amendments have generated new issues of indefiniteness, similar to the ones previously addressed.
103; pg 8, para 1-5
Applicant argues that the indicated figures of 1D and 8D have an expressed CAR in light of paragraphs 0008 and 0015, respectively. Applicant argues that Examiner’s argument regarding the silence of these figures on Ki67 expression levels is undermined by Examiner’s assertion that Ki67 is a protein inherent to the cells.
The supplied specification does not include paragraph numbers, thus it is presumed the cited paragraphs are referring to the corresponding “Brief Description of the Drawings.” These paragraphs have been reproduced below, none of which refer to the cells comprising a CAR. Hypothetically, if these descriptions did include a CAR, Applicant has not explained why the results in these figures should be considered surprising. In order to arrive at a verdict of surprising results, applicant must first identify a trend, then explain how the instant invention deviates from that trend. Applicant has described neither.
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Regarding the expression of Ki67, because applicant has claimed that at least 50% of the T cells of their invention express Ki67, then this property must also be reflected in the surprising results provided. If the population of T cells shown in the purportedly surprising results does not exhibit the claimed expression levels of Ki67, then it cannot be used in support of a verdict of surprising results, because it represents a separate invention. The inherency argument used by Examiner regarding Ki67 expression cannot be used in support of these figures representing the instantly claimed invention. However this argument is secondary compared to the absence of a chimeric antigen receptor expressed by these cells, mentioned above, and discussed in depth in the Non-Final Rejection mailed on 3/11/2025.
103; pg 8, para 6
Applicant argues figures 5A-5H are directly relevant to the claims. This argument was addressed previous in the Non-Final Rejection mailed on 3/11/2025.
In essence, the cells described by these figures do not contain a CAR, thus cannot read on the instantly claimed invention that features a CAR. Fig 5A-5H merely state that Th1, Th9, and Th17 cells express Ki67 after being subjected to cytokines, OVA-peptide, anti-CD3 antibodies, and/or NFκB inhibitor, QNZ (instant spec pg 44). Again, no mention of any of these cells expressing the cancer-targeting CAR. Fig 5H has been reproduced below.
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103; pg 9, para 2
Applicant refers to their recent publication Xue et al. (doi: 10.1016/j.ccell.2021.09.011) as indicating both the CD19-CAR and the mesothelin-CAR as examples (arguments pg 2, para 2). Applicant argues “Xue demonstrates the "unprecedented" and surprising antitumor capacity of Th9 cells over Th1 or Th17 cells expressing the same CARs.” Applicant also refers to the surprising results in instant Fig 18 that Examiner indicated as containing a surprising result in the Non-Final Rejection mailed on 3/11/2025.
Firstly, Xue was published on 10/21/2021, whereas the instant application has priority to 4/17/2018. The instant application only discloses the combination of a CD19-CAR in a Th9 cell (Fig 18). It does not disclose any results regarding mesothelin-targeting CARs. It is an applicant's obligation to supply an enabling disclosure without reliance on what others may publish after they have filed an application on what is supposed to be a completed invention. See Glass, 492 F.2d at 1232, 181 USPQ at 34. Thus results of the mesothelin-CAR cannot be awarded the same priority date as the CD19-CAR described in Fig 18. It is also noted that mesothelin-targeted CARs aren’t the subject of any of the currently examined claims.
Secondly, Examiner agrees that the publication of Xue does indeed suggest that Th9 cells are superior over Th1 and Th17 cells, in general. However, this undermines the original verdict of surprising results which was based off of the novel combination of a Th9 cell with a CD19 CAR being a surprisingly effective cancer treatment over the other cell types expressing the same CAR.
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If Applicant is contesting this original finding of surprising results, then the instant invention amounts to a discovery of nature (a property inherent to Th9 cells). In which case, the references supplied in the 103 rejection need not disclose this property of Th9 cells being superior to Th1 and Th17 cells. See MPEP § 2112(I), “Something which is old does not become patentable upon the discovery of a new property.” In essence, instead of the publication of Xue providing support for broadening the claims to any CAR in any Th9 cell population, this publication instead provides evidence in favor of invalidating the surprising results found in the instant application by disclosing that the CAR structure has no bearing on the effectiveness of the instantly claimed invention as an anti-cancer therapeutic.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA ANN ESSEX whose telephone number is 571-272-1103. The examiner can normally be reached Mon - Fri 8:30-5:00.
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/L.A.E./
Examiner, Art Unit 1675
/JEFFREY STUCKER/
Supervisory Patent Examiner, Art Unit 1675