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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06 November 2025 has been entered.
Status of the Claims
Applicant’s submission filed 06 November 2025 has been entered. Claims 1-4, 6-8, 10-12, 15-16, 18-19, 21, 23, and 26-27 are pending. Claim 10 has been amended. Therefore, prosecution on the merits continues for claims 1-4, 6-8, and 10-12 as being drawn to the elected invention, with claims 15-16, 18-19, 21, 23, and 26-27 withdrawn for reading on the non-elected invention(s). All arguments have been fully considered with the status of each prior ground of rejection set forth below.
Status of Prior Rejections/Response to Arguments
RE: Objection to claim 10
Applicant’s amendments correcting the grammar of instant claim 10 obviates the objection of record.
Therefore, the objection is withdrawn.
RE: Rejection of claims 1-4, 7-8, and 10-12 under 35 USC 103 over Paulos et al in view of Hidalgo et al
Applicant’s arguments presented in the Remarks filed 06 November 2025 have been fully considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. More specifically, the Examiner notes that Applicant’s traversal of the rejection concerned the use of Hidalgo et al as a secondary reference, as Hidalgo et al do not disclose a single CD4+ CTL population expressing the recited markers. The Examiner has considered Applicant’s arguments with regard to Hidalgo et al and the pending claims, and agrees. As such, the rejection is withdrawn. The Examiner further notes Applicant did not specifically traverse any teaching or matter regarding Paulos et al.
Therefore, the rejection is withdrawn in light of a new rejection utilizing Patil et al.
New Grounds of Rejection
Claim Interpretation
Instant claim 1 is directed to an ex vivo population of cytotoxic CD4+ T cells expressing GZMB, GZMH, GNLY, NKG7, PRF1, and KLRG1; wherein the cytotoxic CD4+ T cells have been selectively expanded and activated ex vivo through antigen stimulation, cytokine conditioning, and cell sorting to have enhanced cytolytic capabilities compared to non-antigen-stimulated and non-cytokine- conditioned CD4+ T cells. This is a product-by-process limitation. Product-by-process claims are considered only in so far as the method of production affects the structure of the final product. In the instant case, there is no evidence that the antigen stimulation, cytokine conditioning, and cell sorting imparts any particular structure or significance to the ex vivo population of cytotoxic CD4+ T cells expressing GZMB, GZMH, GNLY, NKG7, PRF1, and KLRG1. Thus, the claim will be interpreted as if cytotoxic CD4+ T cells expressing GZMB, GZMH, GNLY, NKG7, PRF1, and KLRG1 derived from any source or production method fulfills the recited claim limitation. See MPEP § 2113.
Furthermore, each of claims 7-8 are also determined to be product-by-process limitations, as they only define the source of the CD4+ T cells to be used. The limitations of the process of production are considered only in so far as the process of production imparts distinct structural or chemical characteristics or properties to the claimed product. See MPEP § 2113. In the case of defining the source of cells, the source of the cells is only considered in so far as the source defines the cell as having distinct biochemical or morphological characteristics. In the instant case, the source of the CD4+ T cells does not impart a distinction to the cells, but rather their physical and structural characteristics dictates their classification as a particular cell type.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-4, 6-8, and 10-12 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a nature-based product without significantly more.
Claim 1 is directed to an ex vivo population of cytotoxic CD4+ T cells expressing GZMB, GZMH, GNLY, NKG7, PRF1, and KLRG1; wherein the cytotoxic CD4+ T cells have been selectively expanded and activated ex vivo through antigen stimulation, cytokine conditioning, and cell sorting to have enhanced cytolytic capabilities compared to non-antigen-stimulated and non-cytokine- conditioned CD4+ T cells. Instant claim 1 comprises a product-by-process limitation, as can be observed in the Claim Interpretation section above and is incorporated in its entirety herein.
It is of note that the TCR sequences recited in instant claim 6 are from naturally-occurring cytotoxic CD4+ T cells that have not been externally manipulated. See Paragraph [0071] and [00160]-[00163] of instant Specification filed 15 October 2020. Therefore, instant claim 6 is included in this rejection.
Claim 12 is directed to a pharmaceutical composition for adoptive cell therapy, wherein the composition comprises the ex vivo enriched population of cytotoxic CD4+ T cells according to claim 1 and a pharmaceutically acceptable excipient.
The Examiner would also like to put Applicant on notice that, although this rejection was previously considered and withdrawn in prior Office actions (04 March 2024 and 19 November 2024), it is being reinstated in light of reconsideration of the claims and the new reference of Patil et al.
The test for 101 eligibility of judicial exceptions can be found at MPEP § 2106:
“First, the claimed invention must be to one of the four statutory categories. 35 U.S.C. 101 defines the four categories of invention that Congress deemed to be the appropriate subject matter of a patent: processes, machines, manufactures and compositions of matter.”
“Second, the claimed invention also must qualify as patent-eligible subject matter, i.e., the claim must not be directed to a judicial exception unless the claim as a whole includes additional limitations amounting to significantly more than the exception. The judicial exceptions (also called "judicially recognized exceptions" or simply "exceptions") are subject matter that the courts have found to be outside of, or exceptions to, the four statutory categories of invention, and are limited to abstract ideas, laws of nature and natural phenomena (including products of nature). Alice Corp. Pty. Ltd. v. CLS Bank Int'l, 573 U.S. 208, 216, 110 USPQ2d 1976, 1980 (2014) (citing Ass'n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 589, 106 USPQ2d 1972, 1979 (2013).”
“The Supreme Court in Mayo laid out a framework for determining whether an applicant is seeking to patent a judicial exception itself, or a patent-eligible application of the judicial exception. See Alice Corp., 573 U.S. at 217-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. 66, 101 USPQ2d 1961). This framework, which is referred to as the Mayo test or the Alice/Mayo test, is discussed in further detail in subsection III, below. The first part of the Mayo test is to determine whether the claims are directed to an abstract idea, a law of nature or a natural phenomenon (i.e., a judicial exception). Id. If the claims are directed to a judicial exception, the second part of the Mayo test is to determine whether the claim recites additional elements that amount to significantly more than the judicial exception. Id. citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966). The Supreme Court has described the second part of the test as the "search for an 'inventive concept'". Alice Corp., 573 U.S. at 217-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966).”
Examiners should determine whether a claim satisfies the criteria for subject matter eligibility by evaluating the following steps outlined in a flow chart at MPEP 2106(III) and 2106.04(II)(A):
Step 1: is the Claim to a process, machine, manufacture or composition of matter? If Yes, proceed to Step 2A;
Step 2A, prong one: Is the Claim directed to a law of nature, a natural phenomenon (product of nature), or an abstract idea? If Yes, proceed to Step 2A, prong two;
Step 2A, prong two: Does the claim recite additional elements that integrate the judicial exception into a practical application? If No, proceed to Step 2B;
Step 2B: Does the claim recite additional elements that amount to significantly more (an inventive concept) than the judicial exception? If No, the claim is not eligible subject matter under 35 USC 101.
With regard to Step 1: YES, the claims are each directed to a composition of matter, or product.
With regard to Step 2A, prong one: YES, the instant claim 1 is directed to an ex vivo population of cytotoxic CD4+ T cells, which are nature-based products. More specifically, since the instantly claimed cytotoxic CD4+ T cells comprise a product-by-process limitation – see Claim Interpretation section above – the claimed cytotoxic CD4+ T cells are compared to the closest naturally occurring counterpart, which are cytotoxic CD4+ T cells, per se. Thus, there is no marked different between the claim and product of nature. See, for example, the description of cluster 2 in Pages 5-6; Figures S4A, S4C, and S5A; and Table S5 in Patil et al (Sci Immunol, 2018), wherein the naturally-occurring CD4+ CTLs express each of GZMA, GZMB, GZMH, GNLY, NKG7, PRF1, and KLRG1 and have a higher cytotoxic potential compared to the other clusters of CD4+ cells.
The same is true for the pharmaceutical composition comprising the CD4+ CTLs of claim 1.
With regard to Step 2A, prong two: No, the claims do not include any additional elements that integrate the judicial exceptions into a practical application. Integration into a practical application requires additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that the claim is more than a drafting effort designed to monopolize the exception.
The claims do not modify or transform the naturally occurring CD4+ CTLs, nor apply the CD4+ CTLs for a particular treatment or medical condition, nor imposes a meaningful limit on the CD4+ CTLs recited therein.
Furthermore, in regards to the pharmaceutical composition, stating that the cytotoxic CD4+ T cell composition is suitable for adoptive immunotherapy does not add a meaningful limitation, and is nothing more than an attempt to generally link the product of nature to a particular technological environment.
With regard to Step 2B: No, the claim does not provide any additional elements that amount to significantly more (an inventive concept) than the judicial exception.
Taken together, the claims encompass natural products. The judicial exceptions are not integrated into practical applications as iterated above. The claim does not include additional elements
that are sufficient to amount to significantly more than the judicial exception as iterated above.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 7-8, and 10-11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Patil et al (Sci Immunol, 2018). Patil et al has a publication date of 19 January 2018.
Patil et al disclose ex vivo clusters of CD4+ cytotoxic T lymphocytes (CTL), wherein the CD4+ CTLs in cluster 2 express each of GZMA, GZMB, GZMH, GNLY, NKG7, PRF1, and KLRG1 and have a higher cytotoxic potential compared to the other clusters of CD4+ cells (Pages 5-6; Figure S4A,S4C, S5A; Table S5).
Accordingly, Patel et al anticipate the claims as follows:
Regarding claims 1 and 10: Instant claim 1 comprises product-by-process language. The effect of the product-by-process language is discussed above – see Claim Interpretation – and is incorporated herein in its entirety.
Accordingly, Patil et al disclose an ex vivo cluster – or population – of CD4+ CTLs that express each of GZMA (claim 10), GZMB, GZMH, GNLY, NKG7, PRF1, and KLRG1 that have a higher cytotoxic potential compared to the other clusters of CD4+ cells. This therefore reads on the ex vivo population of cytotoxic CD4+ T cells of instant claim 1.
Regarding claims 7-8: The instant claims include additional product-by-process language. The effect of the product-by-process language is discussed above – see Claim Interpretation – and included herein. As such, the source of the CD4+ CTLs does not impact the CD4+ CTLs, per se, and thereby draws to the ex vivo population detailed in instant claims 7-8.
It is also of note, however, that Patil et al further disclose that the CD4+ cells are obtained from a biological sample comprising peripheral blood (Page 9).
Regarding claim 11: As aforementioned in the discussion of claim 1, Patil et al disclose an ex vivo population of CD4+ CTLs that express each of GZMB, GZMH, GNLY, NKG7, PRF1, and KLRG1 that have a higher cytotoxic potential compared to the other clusters of CD4+ cells. As these CD4+ CTLs are substantially identical to the ex vivo population of cytotoxic CD4+ T cells of the instant disclosure, they will inherently be capable of killing autologous cancer cell. See MPEP § 2112.01. This therefore reads on the ex vivo population of cytotoxic CD4+ T cells of the instant claim.
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, 7-8, and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Paulos et al (WO 2017/189526 A1, of record) in view of Patil et al (Sci Immunol, 2018).
Paulos et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2). Patil et al is considered prior art under 35 USC 102(a)(1). Patil et al anticipate instant claims 1, 7-8, and 10-11 based on the Claim Interpretation section above. However, the following rejection relies on an alternative interpretation wherein the production method does impose significant structural or functional characteristics to the ex vivo population of cytotoxic CD4+ T cells.
Regarding claims 1 and 10: Paulos et al disclose an ex vivo population of selectively expanded and activated CD26high CD4+ T cells that express GZMK, KLRB1, GZMA, CCL4, CCL5, CXCR6, PRF1, KLRG1, and LAG3, wherein the expansion and activation steps involve sorting the CD4+ T cells based on CD26 expression, stimulating the CD26high CD4+ T cells with irradiated HLA-A2+ allogeneic lymphocytes, and conditioning and expanding the CD26high CD4+ T cells in the presence of IL-2 (Paragraph [0028], [0038], [0049], [0090], [0093]-[0095], [0097], [00189]-[00191], [00222]; Figures 6B, 14F, 16).
Paulos et al further disclose that an enriched population of CD4+ T cells comprising at least 80% of the activated CD26high CD4+ T cells have an enhanced cytolytic ability compared to other CD4+ T cell subsets (Paragraphs [0016]-[0019], [00167], [00171], [00186], [00189]; Figures 8G, 16A).
Paulos et al do not disclose that cytotoxic CD26high CD4+ T cells express Granzyme B (GZMB), Granzyme H (GZMH), granulysin (GNLY), or NKG7, as required by instant claim 1.
Patil et al, however, disclose clusters of CD4+ cytotoxic T lymphocytes (CTL), wherein the CD4+ CTLs in cluster 2 express each of GZMA, GZMB, GZMH, GNLY, NKG7, PRF1, and KLRG1, and have a higher cytotoxic potential compared to the other clusters of CD4+ cells (Pages 5-6; Figure S4A,S4C, S5A; Table S5).
Therefore, it would have been prima facie obvious to substitute the GZMB-, PRF1-, and KLRG1-expressing cytotoxic CD26high CD4+ T of Paulos et al for the CD4+ CTLs of Patil et al expressing GZMB, GZMH, GNLY, NKG7, PRF1, and KLRG1, as doing so would be a simple substitution of one cytotoxic CD4+ T cell for another. See MPEP § 2143(I)(B). One of ordinary skill before the effective filing date of the invention would have recognized that the cytotoxic CD4+ T cells are functionally comparable, as both are characterized by having a strong association to the effector memory phenotype (Paulos et al: Paragraph [0011]; Patil et al: Page 9), and would have thereby been able to substitute the cells with predictable results.
Consequently, Paulos et al as modified by Patil et al render obvious a population of selectively expanded and activated cytotoxic CD4+ T cells that express GZMA (claim 10), GZMB, GZMH, GNLY, NKG7, PRF1, and KLRG1, wherein the expansion and activation steps involve stimulating the cytotoxic CD4+ T cells with irradiated antigen-specific HLA-A2+ allogeneic lymphocytes, and conditioning and expanding the cytotoxic CD4+ T cells in the presence of IL-2. As Patil et al further disclose that the cluster – or population – of cytotoxic CD4+ T cells has an enhanced cytolytic ability compared to other CD4+ T cell subsets, this therefore renders obvious the ex vivo population of cytotoxic CD4+ T cells of instant claim 1.
Regarding claims 2-3: As aforementioned in the discussion of claim 1, Paulos et al disclose that the activated CD26high CD4+ T cells express LAG3. Paulos et al further disclose that the population is depleted of cells that express high levels of specific surface markers, including CD25 (Paragraph [0090]). This therefore reads on the ex vivo population of the instant claims, as the depletion of cells expressing CD25 from the population inherently indicates that the remaining activated CD26high CD4+ T cells in the population lack expression of CD25 (claim 3). This therefore reads on the ex vivo population of cytotoxic CD4+ T cells of instant claim 2.
Regarding claim 4: Following the discussion of claim 1, Paulos et al further disclose that the activated CD26high CD4+ T cells express interferon gamma at higher levels compared to conventional CD4+ T cells (Paragraphs [00161], [00166], [00170]; Figures 2, 8). This therefore reads on the ex vivo population of cytotoxic CD4+ T cells of the instant claim.
Regarding claim 7: The instant claim includes product-by-process language. The effect of the
product-by-process language is discussed above – see Claim Interpretation – and included herein. As
such, the retrieval of the CD4+ T cells from a tumor sample in Paulos et al (Paragraphs [0028], [0049], [0090], [0093]-[0095], [0097], [00222]; Figure 16) draws to the ex vivo population detailed in the instant claim.
It is also of note that Paulos et al further disclose that the CD4+ cells are autologous, and are from a subject suffering from bladder cancer (Paragraphs [0018]-[0019]).
Regarding claim 8: The instant claim includes product-by-process language. The effect of the
product-by-process language is discussed above – see Claim Interpretation – and included herein. As
such, the retrieval of the CD4+ T cells from blood in Paulos et al (Paragraphs [0088], [00161]) draws to the ex vivo population detailed in the instant claim.
It is also of note that Paulos et al further disclose that the CD4+ cells are autologous, and are from a subject suffering from bladder cancer (Paragraphs [0018]-[0019]).
Regarding claim 11: Following the discussion of claim 1, Paulos et al disclose the utilization of the activated CD26high CD4+ T cells for autologous adoptive T cell therapy. Paulos et al further disclose that the therapy involves the administration of the autologous activated CD26high CD4+ T cells to a subject suffering from cancer (Abstract; Paragraphs [0016]-[0019], [0071],[0088], [0093], [00134]). This therefore reads on the ex vivo population of the instant claim, as Paulos et al further disclose that the activated CD26high CD4+ T cells are capable of killing autologous cancer cells (Paragraphs [00163], [00167]).
Regarding claim 12: As aforementioned in the discussion of claim 1, Paulos et al as modified by Patil et al render obvious cytolytic activated CD4+ T cells that at least express GZMB, GZMH, GNLY, NKG7, PRF1, and KLRG1.
Paulos et al further disclose the utilization of the activated CD4+ T cells for autologous adoptive T cell therapy, wherein the activated CD4+ T cells that are comprised within a pharmaceutical composition with a pharmaceutically acceptable excipient are administered to a subject in need thereof (Paragraphs [0016]-[0019], [0077]-[0079], [00132]-[00133]).
This therefore reads on the pharmaceutical composition of the instant claim.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA G WESTON whose telephone number is (571)272-0337. The examiner can normally be reached Monday-Thursday 8AM - 4PM (CT); Friday 8AM - 11AM (CT).
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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633