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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 6/10/2026 has been entered.
Claims 2-7, 9-10 were canceled. Claims 39-56 were newly added.
Claims 21-22, 24, 29-35, 37-56 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, claim 22 is amended and claims 23 and 25-27 were canceled. Claims 39-56 were newly added.
Note: claims 45-49 and 54-56 are reiterations of previously withdrawn claims 2, 4-7, 3, and 9-10, respectively. These claims were reiterated to correct the claim dependency order, which originally placed claims 2, 4-7, 3, and 9-10 as dependent on claim 21. These claims are thus still withdrawn according to the restriction requirement because they represent a patentably distinct invention from Group III, because they are drawn to a method that incorporates administering a vaccine in addition to the CD4+ Th9 cells or describe a method that further requires administering another T cell (effector or memory). The vaccine as claimed can comprise any structure and target any pathogen/protein/cell/disease known in the prior art.
Newly submitted claims 50-53 are also directed to a method that comprises administering a vaccine, so these are also withdrawn from consideration.
Since applicant has received an action on the merits for the originally presented invention drawn to the composition and not to the method claims, the composition claims have been constructively elected by original presentation for prosecution on the merits. Accordingly, claims withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claims 45-56 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.
21-22, 24, 29-35, 37-44
Claims 21-22, 24, 29-35, and 37-44 are examined herein.
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 37-44 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). As a secondary evidentiary reference, Lu (doi: 10.1016/j.ccell.2024.06.008) teaches that 50% of Th9 cells express Ki67 when they enter a proliferative state (Fig 5; pg 1053, col 2, para 1). Lu teaches over 80% of wild-type Th9 cells express Ki67, when they enter a hyperproliferative state in response to tumors (pg 1053, col 2, para 1). Lu states that Th9 cells are unique in this ability to enter a “hyperproliferative state” in response to stimulation when compared to Th1 and Th17 cells (Fig 5C and 5D; pg 1053, col 2, para 1-2). Taken together, these evidentiary references establish that these Ki67 expression percentages are inherent properties of Th9 cells which occur in the absence of any modification made by the practitioner. Furthermore, Yu teaches that wild-type Th9 cells exhibit anti-tumor activity via upregulating the expression of Eomes and Traf6 (abstract). This further corroborates the teachings of Baumjohann which establish that Eomes and Traf6 are native to Th9 and are activated in the absence of any bioengineering on behalf of a practitioner. In essence, the following limitations of instant claim 21 are drawn solely to inherent properties of Th9 cells and are independent of any bioengineering efforts on behalf of the practitioner:
“a nucleotide sequence that encodes Traf6 and Eomes whereby the nucleotide sequence is expressed to produce the Traf6 protein and Eomes protein in the cell… wherein each of the CD4 + Th9 cells has the phenotype of a mature effector T cell and wherein at least 50% of the cells in the plurality are Ki67+ cells.”
The remaining limitations are drawn to a generic chimeric antigen receptor.
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). Sadelain teaches the T cells of the invention are optionally CD4+ T helper cells, such as Th9 cells (pg 54, para 00193).
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, 37-39
Regarding claims 34-35 and 37-39, 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.
*Claim 40-43
Regarding claims 40-43, Sadelain teaches the mesothelin (MSLN) as a suitable cancer antigen that can be targeted using a CAR (pg 91, para 00270). Sadelain teaches mesothelin is associated with mesothelioma, ovarian cancer, and lung cancer (pg 88, para 00269).
*Claim 44
Regarding claim 44, Sadelain teaches melanoma-associated antigen 1 (melanoma antigen
family A1, MAGE-A1) as being a suitable cancer antigen (pg 92, para 00270).
Relevant Prior Art
Sommermeyer (doi: 10.1038/leu.2015.247) teaches a method of treating cancer using CAR-T modified CD4+ T cells, wherein the CAR targets CD19 (abstract). Sommermeyer compares TN, TCM, and TEM cells using FACS, noting that CD4+ TN cells exhibited the greatest efficacy in treating tumors in mice (Fig 3e).
Allowable Subject Matter
Applicant has provided evidence of unexpected results, showing that the combination of isolated Th9 cells expressing a CD19-targeting CAR are surprisingly more effective in treating cancer than the Th1 cells expressing the same CAR (Fig 18, reproduced below).
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Applicant also provided evidence showing that the combination of Th9 cells expressing a mesothelin-targeting CAR exhibiting the same surprising anticancer activity relative to Th1 cells. See Xue et al. (doi: 10.1016/j.ccell.2021.09.011) as shown below (Fig 2F, arrow).
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The evidence supplied above is sufficient to overturn a verdict of obviousness in the context of a method of treating cancer, wherein the Th9 cells express a CAR that targets either CD19 or mesothelin. Applicant did not provide evidence of other CARs that exhibit this activity.
Response to Arguments
Applicant's arguments filed 6/10/2026 have been fully considered but they are not persuasive.
103; pg 11, para 4
Applicant argues the unexpected results (discussed in the Allowable Subject Matter section) are commensurate in scope with the instant claims.
The nature of unexpected results is that they are unexpected, as a result, one cannot assume that any CAR would exhibit superior results when used in combination with Th9 cells in treating cancer. MPEP § 2145 states:
“When considering whether proffered evidence is commensurate in scope with the claimed invention, Office personnel should not require the applicant to show unexpected results over the entire range of properties possessed by a chemical compound or composition.”
Applicant has provided evidence for only two types of CARs: CD19 and mesothelin; this does not adequately represent the range which encompasses any CAR or even the discretely listed CARs in instant claim 34. Secondly, the surprising results are limited to providing support for a patentable method of treating cancer, however claims 21-22, 24, 29-35, and 37-44 are drawn to a composition comprising Th9 cells with any CAR to be used for any purpose. Thus the surprising results provided are unable to rebut the conclusion of obviousness over the references.
103; pg 11, para 5
Applicant argues the combination of Baumjohann and Sadelain fails to teach all the limitations of claims 21 and 29, specifically the requirement that 50% of the cells express Ki67. Applicant argues DiRosa fails to remedy this deficiency because DiRosa simply teaches that cells express Ki67 during their life cycle when in a proliferative state, but Applicant disagrees that the capacity to express this protein is equivocal to its active expression, thus disputes Ki67 expression is an inherent property to Th9 cells.
To further establish that the expression levels claimed are an inherent property of Th9 cells, independent of their expression of a genetically added protein (i.e. a CAR), the reference of Yu has been added to show that Th9 cells are unique in the way that they are able to enter a hyperproliferative state wherein >50% of the cells will express Ki67. Furthermore, Yu corroborates the findings of Baumjohann that both Traf6 and Eomes are native to wild-type Th9 cells, and these proteins are upregulated in the presence of tumor cells. In essence, the following limitations of instant claim 21 are drawn solely to inherent properties of Th9 cells and are independent of any bioengineering efforts on behalf of the practitioner:
“a nucleotide sequence that encodes Traf6 and Eomes whereby the nucleotide sequence is expressed to produce the Traf6 protein and Eomes protein in the cell… wherein each of the CD4+ Th9 cells has the phenotype of a mature effector T cell and wherein at least 50% of the cells in the plurality are Ki67+ cells.”
The property of Th9 cells expressing CD4, is also an inherent property that defines them as Th9 cells. See Golubovskaya (doi: 10.3390/cancers8030036, Fig 2), regarding Th9 cell differentiation and expression. The remaining limitations are drawn to a generic chimeric antigen receptor.
103; pg 12, para 3
Applicant argues that neither Baumjohann or Sadelain provide an example of a Th9 cell bearing a CAR. Applicant argues these two references fail to disclose any data regarding Th9 cells. Applicant reiterates their statement about surprising results.
Unfortunately, there is no requirement that inventors supply such specific data. MPEP § 2121(I) states: “When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable.”
In the instant case, Sadelain’s suggestion of using CD4+ T helper cells, such as Th9 cells (pg 54, para 00193) as the cell type for incorporating the CAR is sufficient, and thus presumed operable.
103; pg 13, para 3
Applicant argues that their two examples (CD19 and mesothelin CARs in Th9 cells) provides a “proof of concept” that is generalizable to any CAR.
This was addressed previously in the argument pg 11, para 4. In essence, applicant has not established a proof of concept that is commensurate in scope with all CARs. Applicant provided no rationale why one of skill in the art would expect any CAR to work to treat any cancer. For example, what rationale would there be for a CAR that targets malaria be useful for treating cancer; or even within treating cancer: why would one expect a CAR that targets Her2 to be effective in treating a Her2-negative melanoma? These are exemplary species that are implied by the instantly written claims. As a result, the invention as claimed is not commensurate in scope with the evidence provided.
Conclusion
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
Prosecution Insights