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 .
Status of the Claims
Claims 1-10, 12-14, 25-26, 28, 42, 44-49 are pending.
Claim 1-9, 13, 28, 42, 44-46, and 47-48 are newly amended.
Claims 10, 13-14, 25-26, 28, 42, 44-49 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/11/2025.
Claims 1-9 and 12 have been examined on their merits.
Specification
The disclosure is objected to because of the following informalities: the specification as amended (paragraphs [0059] and [0241]) as newly amended recite references to “crossed hatching” and “solid fill” in regards to Fig. 7. However, it is unclear in Fig. 7 (specifically, Fig. 7B) what “crossed hatching” and “solid fill”, since multiple objects appear to be cross-hatched, while no object appears to have a solid fill.
Appropriate correction is required.
Drawings
The drawings are objected to because: Figs. 4B and 5A-5D are illegible and fail to describe structural details described in the specification.
In regards to Fig. 4B, the figure describes the priority of genes (grouped 1-4) based on the number of screens they were significant in (see paragraph [0055]). However, the dots/points (which appear to have been originally rendered in color) cannot be effectively interpreted when rendered in black and white (thus, it is unclear what these dots refer to).
Similarly, Figs. 5A-5D refer to dots/points showing flow cytometry validation of screen hits following RNP knockout (see paragraph [0057]). According to the specification, “ Points are colored based on two independent guide RNAs. Points show the median of 3 biological donors and error bars show the range.” However, when rendered into black and white these points are not distinguishable.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The rejection of claims 1 and 12 under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US20190106710A1) in view of Heikkinen et al. (Human Mutation, 2017) is withdrawn in order to address the claims as necessitated by amendment and in order to incorporate Zhang et al (Leukemia Research, 2013, hereafter “Zhang YC”).
The rejection of claims 2-3 and 6-9 under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US20190106710A1) in view of Heikkinen et al. (Human Mutation, 2017) as evidenced by Arce et al. (Nature, 2025) ) is withdrawn in order to address the claims as necessitated by amendment and in order to incorporate Zhang et al (Leukemia Research, 2013, hereafter “Zhang YC”).
The rejection of claim 5 under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US20190106710A1) in view of Heikkinen et al. (Human Mutation, 2017), as applied to claim 1 above, and further in view of Yonekura et al. (BMC Research Notes, 2018) ) is withdrawn in order to address the claims as necessitated by amendment and in order to incorporate Zhang et al (Leukemia Research, 2013, hereafter “Zhang YC”).
Claim Interpretation
In regards to the term “genetic modification”, the specification does not explicitly define this term. While, the term could broadly be defined to refer to any change in the genome of a T cell, including natural mutations, in the art, the term appears to have the specific meaning of using bioengineering techniques in order to introduce changes to a cell’s genome (as in “genetically modified”).
Indeed, as specifically defined by Merriam-Webster (retrieved from internet 09/24/2025, previously cited), the term “genetic modification” means “the modification of an organism's genetic material that involves using applied techniques of genetics and biotechnology to alter or delete a DNA segment or to insert a new DNA segment from a different species in order to express or suppress a targeted trait or traits.”
Furthermore, while the instant specification does not explicitly define “genetic modification”, in regards to the term “modifying’, the specification states, “the phrase ‘modifying’ refers to inducing a structural change in the sequence of the genome at a target genomic region in a T cell” (paragraph [0077]; emphasis added), which implies that modification requires biotechnological manipulation.
Therefore, the term “genetic modification”, has been interpreted as defined by Merriam-Webster, and has been interpreted as requiring a biotechnological step, and is synonymous with “genetically modified”, and has not been interpreted as referring to phenomena such as natural mutations.
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 4 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.
Scope of the Claim
Claim 4 depends from claim 1. Claim 1 requires a CD4-CD8+ or CD4+CD8- T cell with at least a genetic modification or heterologous polynucleotide that inhibits MED12 or a heterologous polynucleotide that encodes MED12.
Claim 4 encompasses the composition of claim 1 wherein the T cell comprises (a) a further genetic modification or heterologous polynucleotide that inhibits or (b) a further heterologous polynucleotide that encodes the genes as in claim 4 (including ETS1, etc.).
As a result, expression of FOXP3 is increased relative to a T cell that does not comprising a gene as in (a) or (b).
In regards to option claim 4 option (a), the genes may be ETS1, MYBL2, MYB, TP53, FLI1, SATB1, MBD2, ZBTB7A, DNMT1, TFDP1, SMARCB1 or MAF.
In regards to claim 4 option (b), the genes may be TAF5L, FOXP3, GATA3, STAT5B, FOXP1, STAT5A, PTEN or FOXO1.
Under the written description guidelines (see MPEP 2163) the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002)
Accordingly, to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.
Actual Reduction to Practice
In regards to claim 4, while the specification that knockout ETS1, MYBL2, MYB, TP53, FLI1, SATB1, MBD2, ZBTB7A, DNMT1, TFDP1, SMARCB1 or MAF, results in increased expression of FOXP3 in cells (paragraph [0241]; Fig. 7F), the specification explicitly states that knockout of TAF5L, FOXP3, GATA3, STAT5B, FOXP1, STAT5A, PTEN or FOXO1 decreases expression of FOXP3 (paragraph [0241]).
In regards to what is meant by “a heterologous polynucldeotide that encodes a TAF5L, etc.” as in option (b), the specification indicates that these genes may be knocked out with at CRISPR constructs to establish heterologous polynucleotides (paragraphs [0008, 0028]). Thus, a heterologous polynucleotide that encodes TAF5L, etc. can explicitly reduce expression of any of the named genes in option (b). Taken together, it would suggest that heterologous polynucleotides encoding TAF5L, FOXP3, GATA3, STAT5B, FOXP1, STAT5A, PTEN or FOXO1 would be expected to decrease, not increase, expression of FOXP3.
Furthermore, in regards to option (a), while as above, the specification demonstrates that a genetic modification or heterologous polypeptide that inhibits ETS1, MYBL2, MYB, TP53, FLI1, SATB1, MBD2, ZBTB7A, DNMT1, TFDP1, SMARCB1 or MAF can increase expression of FOXP3, the specification does not provide embodiments wherein a T cell comprising both a modified or heterologous MED12 and also a modified or heterologous ETS1, MYBL2, MYB, TP53, FLI1, SATB1, MBD2, ZBTB7A, DNMT1, TFDP1, SMARCB1 or MAF, results in an increase in relative expression of FOXP3.
State of the Art and Quantity of Experimentation
Turning to the art, as evidenced by Yonekura et al. (BMC Research Notes, 2018), heterologous polynucleotides such as siRNAs directed to FOXP3 (a claimed embodiment) results in knockdown of FOXP3 in T cells (Title, Abstract, p1; Methods, p1).
Thus, directing a heterologous polynucleotide that knocks out FOXP3 would in fact be expected to result in decreased (not increased) relative expression of that gene.
In regards to the effects of knock-out of MED12, while post-filing, as evidenced by Arce et al. (Nature, 2025), knockout of MED12, leads a negative fold-change in gene expression of FOXP3 for resting Treg and stimulated T effector cells and does not indicate that it leads to a positive fold-change in FOXP3 for any cell type (Fig. 4c, p935).
The art is completely silent on whether a genetic modification of heterologous polypeptide directed towards MED12 and a subsequent genetic modification of heterologous polypeptide directed towards any of the genes as in claim 4 results in increased expression of FOXP3.
As a result, the state of the art indicates that making the claimed T cell with the claimed property is not well-established, would require undue experimentation, and a person of ordinary skill in the art would neither expect nor predict the claimed increase in FOXP3 in a T cell comprising a modified or heterologous MED12 gene and a further modified or heterologous gene from options (a) or (b) in claim 4.
Conclusion
Therefore, the Examiner concludes that there is insufficient written description of the instantly claimed T cell that comprises a modified or heterologous MED12 gene and a further modified or heterologous gene from options (a) or (b) in claim 4. Specifically, there is limited description of the structure-function relationship between the claimed cell and its property of decreasing relative expression of FOXP3, and the Examiner further concludes a skilled artisan would find the specification inadequately describes the claimed T cell.
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, 6-9, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US20190106710A1, previously cited) in view of Heikkinen et al. (Human Mutation, 2017, previously cited) and Zhang et al. (Leukemia Research, hereafter “Zhang YC”) as evidenced by Arce et al. (Nature, 2025, previously cited).
In regards to claim 1, Zhang teaches genetically modified cells (claim 12) that can be derived from T-cell lymphoma (and thus T cells) (paragraph [0048]). Zhang teaches that the MED12 (which is a nuclear factor) gene can be specifically targeted for modification (paragraphs [0501, 0509]). Zhang teaches that these cells may be engineered with multiple regulatory elements (claim 1), and therefore, can comprise at least one factor.
While Zhang teaches T cells and MED12 as options for types of cancers or sequences that can be targeted for modification, respective, such “picking and choosing” within several variables does not necessarily give rise to anticipation. Corning Glass Works v. Sumitomo Elec., 868 F.2d 1251, 1262 (Fed. Circ. 1989).
In the instant case, since Zhang does not provide any specific teaching to select this specific combination of variables, anticipation cannot be found.
However, according to KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)), “[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious” and continuing, “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious”, the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” Furthermore, addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.” Id.
Therefore, consistent with the reasoning, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have selected different types of cancer cells or sequences that can targeted for modification, from within the disclosure of to arrive at methods and compositions “yielding no more than one would expect from such an arrangement.”
Additionally, a person of ordinary skill in the art would have been motivated to target MED12 for genetic modification in T cells because Heikkinen teaches that mutations in MED12 are associated with T-cell acute lymphoblastic leukemia (T-ALL, a neoplastic disease) (Abstract; right column, p269).
Furthermore, because Zhang teaches that an object the invention is to provide compositions related to generating models to study proliferative disorders and can be used to study hematopoietic tumors of lymphoid lineage (of which T-ALL is a type) (paragraph [0049]), and teaches that MED12 is essential for cancer cell survival (paragraph [00208]), it could have been done with predictable results and a reasonable expectation of success.
In regards to the phenotype of the T cell being CD4-CD8+ specifically, a person of ordinary skill in the art would have been motivated to choose this phenotype because as taught by Zhang YC, CD4-CD8+ T cells (referred to as “CD8+ CD4-“) are a leukemic T-ALL cell subpopulation with distinct properties compared to other phenotypes (specifically, CD8+CD4+ cell) (Title, Abstract, p1592). More specifically, a person of ordinary skill in the art would have been motivated to use CD4-CD8+ T cells because Zhang YC teaches that CD4-CD8+ T cells are less susceptible to rapamycin (Title, Abstract, p1592), and therefore, would want to test knock out/down of a gene essential in a leukemic cell subpopulation with drug resistance.
Furthermore, because as above, Zhang teaches that an object the invention is to provide compositions related to generating models to study proliferative disorders and can be used to study hematopoietic tumors of lymphoid lineage (of which T-ALL is a type and of which of CD8+CD4- are a known subpopulation of), it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 2, as above, Zhang teaches that MYB can also be an inhibition target for neoplastic diseases (claim 1; paragraph [0044]; paragraphs [0504, 507]) (of which T-ALL is a known type).
A person of ordinary skill in the art would have been motivated to further target MYB in order to study interactions the context of this disease state. Furthermore, since Zhang teaches MYB can be a target for inhibition for neoplastic diseases, it could have been done with predictable results and a reasonable expectation of success.
In regards to whether expression of CTLA4 (claim 2) is increased in the T cell relative the expression of CTLA4 in a T cell not comprising the genetic modification or heterologous nucleotide as in claim 2, as above, Applicant should note that this is a natural property of functioning of the cell.
According to MPEP 2112, “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that “just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel.” Id.
Moreover, there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).
In the instant case, the claims suggest that genetic modification of T cell in regards to MED12 and MYB is sufficient to cause subsequent increases in CTLA4 (different genes). Thus, since the T cell as taught above, comprises that genetic modification of T cell in regards to MED12 and MYB it would be expected to naturally possess the property of exhibiting increased CTLA4 or IL2RA expression.
Furthermore, as evidenced by Arce et al. (Nature, 2025), perturbance (knockout) of MED12 results in both increases and decreased in CTLA4 and IL2RA over time (Extended Data Fig. 2g; Fig. 2b, p932).
Thus, inhibition of MED12 in T cells itself is sufficient to cause increased expression of CTLA4 in T cells.
In regards to claims 3 and 6-9, Zhang teaches that PTEN can also be an inhibition target for neoplastic diseases (claim 1; paragraph [0044]; paragraph [0445], Table A, p48, table C, p52; paragraph [0450]) (of which T-ALL is a known type). A person of ordinary skill in the art would have been motivated to further target PTEN in order to study interactions the context of this disease state. Furthermore, since Zhang teaches PTEN can be a target for inhibition for neoplastic diseases, it could have been done with predictable results and a reasonable expectation of success.
In regards to claims 7 and 8 specifically, Zhang teaches that genes may be targeted by CRISPR-induced modification of target sequences within a genome (claim 1; paragraph [0476]). As this engineered gene is synthetic, it is not found in nature, and is therefore, a heterologous polynucleotide.
In regards to whether expression of CTLA4 (claim 3) is decreased, IL2 (claim 6) is increased, IL2 (claim 7) is decreased, expression of IL2RA is increase (claim 8), or if expression of IL2RA is decreased (claim 9) in the T cell relative the expression of CTLA4/IL2/IL2RA in a T cell not comprising the genetic modification or heterologous nucleotide as in claims 3 and 6-9, Applicant should note that these are natural properties of the cells themselves (see MPEP 2112).
In the instant case, the claims suggest that genetic modification of T cell in regards to MED12 and PTEN is sufficient to cause both subsequent decreases or increases in CTLA1, IL2, or IL2RA (different genes from PTEN). Thus, since the T cell as taught above, comprises that genetic modification of T cell in regards to MED12 and PTEN it would be expected to naturally possess the property of exhibiting respective decreased/increased CTLA4, IL2, or IL2RA expression.
Furthermore, as evidenced by Arce et al. (Nature, 2025), perturbance (knockout) of MED12 results in both increases and decreases in CTLA4, IL2, and IL2RA over time (Extended Data Fig. 2g; Extended Data Figs. 4c and 4d; Fig. 2b, p932).
Thus, inhibition of MED12 in T cells itself is sufficient to cause subsequent respective decreases or increases in CTLA4 or IL2 in T cells.
In regards to claim 12, Zhang teaches that the genetically modified cells may be a population of cells (paragraph [0047]).
Therefore, the combined teachings of Zhang, Zhang YC, and Heikkinen render obvious the invention as claimed.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US20190106710A1, previously cited) in view of Heikkinen et al. (Human Mutation, 2017, previously cited), and Zhang et al. (Leukemia Research, hereafter “Zhang YC”) as evidenced by Arce et al. (Nature, 2025), as applied to claim 1 above, and further in view of Yonekura et al. (BMC Research Notes, 2018, previously cited).
In regards to claim 5, Zhang FOXP3 can also be a target (paragraphs [0443-0445]; Table 2, p49).
A person of ordinary skill in the art would have been motivated to also target FOXP3 because Yonekura teaches that FOXP3 genetic knock-down of FOXP3 (which would be a decreased relative expression of FOXP3) results in growth suppression of T-ALL cells and may be a potential therapeutic target in T-ALL (Abstract, p1).
Furthermore, because Yonekura teaches that FOXP3 can be knocked-down with siRNAs (which are a type of heterologous polynucleotide, see instant specification paragraph [0028]), because MED12 and FOXP3 are both associated with T-ALL, because Zhang teaches that multiple genes can be targeted (claim 2), and because Zhang and Yonekura are both in the same technical field of inducing mutations in T cells in order to study T cell cancers, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Zhang, Heikkinen, Zhang YC, and Yonekura render obvious the invention as claimed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-9 and 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 42-56 and 61 of copending Application No. 18/251696 in view of over Zhang et al. (US20190106710A1, previously cited) and Zhang et al. (Leukemia Research, hereafter “Zhang YC”).
Although the conflicting claims of copending Application No. 18/251696 are not identical to the currently prosecuted claims 1-9 and 12, they are not patentably distinct from each other because the claims of both inventions are drawn to a modified (engineered) T cell (that can be at least CD4+ or CD8+) comprising a heterologous polynucleotide that that inhibits MED12 (claims 42, 44, 46-48, 51-56).
In regards to a T cell with a specific CD4-CD8+ or CD4+CD8- phenotype, a person of ordinary skill in the art would have been motivated to choose this phenotype because as taught by Zhang YC, CD4-CD8+ T cells (referred to as “CD8+ CD4-“) are a leukemic T-ALL cell subpopulation with distinct properties compared to other phenotypes (specifically, CD8+CD4+ cell) (Title, Abstract, p1592). More specifically, a person of ordinary skill in the art would have been motivated to use CD4-CD8+ T cells because Zhang YC teaches that CD4-CD8+ T cells are less susceptible to rapamycin (Title, Abstract, p1592), and therefore, would want to test knock out/down of a gene essential in a leukemic cell subpopulation with drug resistance.
Furthermore, because copending Application No. 18/251696 is drawn to multiple combinations of types of CD4+ or CD8+ T cells (claim 48), it could have been done with predictable results and a reasonable expectation of success.
In regards to the embodiments as in claims 2-9 and 12, genetic modifications directed towards these genes were known in the art before the effective filing date.
As discussed above, Zhang teaches genetically modified cells (claim 12) that can be derived from T-cell lymphoma (and thus T cells) (paragraph [0048]). Zhang teaches that the MED12 (which is a nuclear factor) gene can be specifically targeted for modification (paragraphs [0501, 0509]). Zhang teaches that these cells may be engineered with multiple regulatory elements (claim 1), and therefore, can be directed towards multiple factors (genes). As above, Zhang teaches that modifications can be directed towards either MYB or PTEN (claim 1; paragraph [0044]; paragraphs [0504, 507]; paragraph [0445], Table A, p48, table C, p52; paragraph [0450]). A person of ordinary skill in the art would have been motivated to further target these genes in order to study their effect on T cells. Furthermore, because Zhang teaches that they may be targets for T cell genetic modification, it could have been done with predictable results and a reasonable expectation of success.
In regards to the various properties in regards to increases/decreases in expression of CTLA4, IL2, IL2RA, as above, Applicant should note that these are natural properties of the cells themselves (see MPEP 2112).
In the instant case, the claims suggest that genetic modification of T cell in regards to MED12 and MYB/PTEN is sufficient to cause both subsequent decreases or increases in CTLA1, IL2, or IL2RA (which are different genes from MYB of PTEN). Thus, since the T cell as taught above, comprises that genetic modification of T cell in regards to MED12 and PTEN it would be expected to naturally possess the property of exhibiting respective decreased/increased CTLA4, IL2, or IL2RA expression.
Furthermore, as evidenced by Arce et al. (Nature, 2025), perturbance (knockout) of MED12 results in both increases and decreases in CTLA4, IL2, and IL2RA over time (Extended Data Fig. 2g; Extended Data Figs. 4c and 4d; Fig. 2b, p932).
Thus, inhibition of MED12 in T cells itself is sufficient to cause subsequent respective decreases or increases in CTLA4 or IL2 in T cells.
Response to Arguments
In regards to the rejection of claim 4 under 35 USC 112(a), Applicant argues that the claim satisfies the written description requirement (Remarks, p15-16).
Specifically, Applicant argues that, as the Examiner acknowledges, the present application demonstrates that knockout of ETS1, MYBL2, MYB, TP53, SATB1, MBD2, ZBTB7A, DNMT1, TFDP1, SMARCB1 or MAF increased expression of FOXP3 (citing Figs. 4B and 7F, Table 3; Remarks, p15).
However, Applicant contends that MED12 does not affect FOXP3 expression (citing Fig. 4B) and therefore, argues that it follows that a T cell comprising knocking of both MED12 and ETS1, MYBL2, MYB, TP53, SATB1, MBD2, ZBTB7A, DNMT1, TFDP1, SMARCB1 or MAF would still result in an increase in relative expression of FOXP3 (Remarks, p15).
Applicant’s arguments filed 02/02/2026 has been fully considered but it not found persuasive.
It is noted that Applicant does not address the matter of written description in regards to option (b) as discussed above.
As discussed above, the specification explicitly states that knockout of TAF5L, FOXP3, GATA3, STAT5B, FOXP1, STAT5A, PTEN or FOXO1 decreases expression of FOXP3 (paragraph [0241]).
As the specification also indicates that these genes may be knocked out with at CRISPR constructs to establish heterologous polynucleotides (paragraphs [0008, 0028]), taken together, it would suggest that heterologous polynucleotides encoding TAF5L, FOXP3, GATA3, STAT5B, FOXP1, STAT5A, PTEN or FOXO1 would be expected to decrease, not increase, expression of FOXP3.
Turning to the art, as evidenced by Yonekura et al. (BMC Research Notes, 2018), heterologous polynucleotides such as siRNAs directed to FOXP3 (a claimed embodiment) results in knockdown of FOXP3 in T cells (Title, Abstract, p1; Methods, p1).
Thus, directing a heterologous polynucleotide that knocks out FOXP3 would in fact be expected to result in decreased (not increased) relative expression of that gene.
In regards to the effects of knock-out of MED12, while post-filing, as evidenced by Arce et al. (Nature, 2025), knockout of MED12, leads a negative fold-change in gene expression of FOXP3 for resting Treg and stimulated T effector cells and does not indicate that it leads to a positive fold-change in FOXP3 for any cell type (Fig. 4c, p935).
The art is completely silent on whether a genetic modification of heterologous polypeptide directed towards MED12 and a subsequent genetic modification of heterologous polypeptide directed towards any of the genes as in claim 4 results in increased expression of FOXP3.
As a result, the state of the art indicates that making the claimed T cell with the claimed property is not well-established, would require undue experimentation, and a person of ordinary skill in the art would neither expect nor predict the claimed increase in FOXP3 in a T cell comprising a modified or heterologous MED12 gene and a further modified or heterologous gene from options (a) or (b) in claim 4.
In regards to Applicant’s reliance on Fig. 4b to demonstrate that MED12 does not affect FOXP3 expression (see Remarks, p15), it is unclear if Fig. 4b actually demonstrates this. While Fig. 4b describes gRNA enrichment of validation genes including MED12, compared to target screens (including FOXP3), the figure does not clearly describe which targets correlate with MED12 and how that affects expression of MED12. Indeed, assuming arguendo that Fig. 4b demonstrates a relationship between MED12 knockout and expression levels of FOXP3, at least some instances demonstrate negative enrichment and therefore, it unclear if the relationship between knockout of MED12 does not affect FOXP3 expression as alleged by Applicant.
Therefore, the rejection of claim 4 under 35 USC 112(a) for lacking written description is maintained as discussed above.
Applicant argues that Arce is improperly cited a prior art reference in the rejection under 35 USC 103 (Remarks, p16). Applicant argues that Arce does not show a universal fact (Remarks, p16).
Applicant’s arguments filed 02/02/2026 has been fully considered but it not found persuasive.
It is first noted thar Acre is not cited as a prior art reference (Arce is explicitly cited as an evidentiary reference) and is not relied upon to provide motivation or predictability.
Rather, as discussed above, Arce is only relied upon to demonstrate a cellular property of the effect of knocking out/down MED12 in cells.
As discussed in MPEP 2124, in certain circumstances, references cited to show a universal fact need not be available as prior art before the effective filing date of applicant’s claimed invention. In re Wilson, 311 F.2d 266, 135 USPQ 442 (CCPA 1962). Such facts include the characteristics and properties of a material or a scientific truism.
As discussed above, Arce is relied upon to demonstrate that the resultant effect (the property, or natural consequence) of knocking out/down MED12 in a cell is a correlation with decreases or increases in FOXP3, CTLA4, IL-2, or IL-2RA expression in those cells.
Thus, Arce is appropriately applied as an evidentiary reference.
Applicant argues that the claims as amended are not prima facie obvious over Zhang and Heikkinen (Remarks, p16-19).
Continuing, Applicant argues that the claims, as amended, require that the at least one nuclear factor comprise MED12 and that the T cell is a CD4-CD8+ T cell or a CD4+CD8- T cell (Remarks, p17).
Specifically, Applicant argues that Zhang only describes MED12 in the context of creating cancer models and does not disclose or suggest a method wherein the at least one nuclear factor comprises MED12 and wherein the T cell is a CD4-CD8+ T cell or a CD4+CD8- T cell as required in claim 1 as amended (Remarks, p17).
Applicant also argues that Heikkinen does not cure the deficiencies of Zhang (Remarks, p17). Rather, Applicant argues that Heikkinen describes MED12 mutations as associated with cancers, but does not disclose a CD4-CD8+ T cell or a CD4+CD8- T cell as required in claim 1 as amended (Remarks, p17-18).
Relatedly, in regards to claim 5, Applicant argues that Yonekura does not teach a CD4-CD8+ cell (Remarks, p18-19).
Applicant’s arguments filed 02/02/2026 has been fully considered but it not found persuasive.
As discussed above, Zhang teaches that the MED12 (which is a nuclear factor) gene can be specifically targeted for modification (paragraphs [0501, 0509]).
In regards to the specific T cell type, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
As discussed above, in regards to the phenotype of the T cell being CD4-CD8+ specifically, a person of ordinary skill in the art would have been motivated to choose this phenotype because as taught by Zhang YC, CD4-CD8+ T cells (referred to as “CD8+ CD4-“) are a leukemic T-ALL cell subpopulation with distinct properties compared to other phenotypes (specifically, CD8+CD4+ cell) (Title, Abstract, p1592). More specifically, a person of ordinary skill in the art would have been motivated to use CD4-CD8+ T cells because Zhang YC teaches that CD4-CD8+ T cells are less susceptible to rapamycin (Title, Abstract, p1592), and therefore, would want to test knock out/down of a gene essential in a leukemic cell subpopulation with drug resistance.
Furthermore, because as above, Zhang teaches that an object the invention is to provide compositions related to generating models to study proliferative disorders and can be used to study hematopoietic tumors of lymphoid lineage (of which T-ALL is a type and of which of CD8+CD4- are a known subpopulation of), it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 11, Applicant argues that Vlierberghe does not teach a CD4-CD8+ cell (Remarks, p19).
Applicant’s arguments filed 02/02/2026 has been fully considered (see Remarks, p19) but are moot because Vlierberghe is not relied upon for any teachings or matter specifically challenged in the argument.
In regards to non-statutory double-patenting, Applicant requests that the rejection be held in abeyance (Remarks, p20).
Applicant’s request is noted. However, Applicant’s request is not a proper response to the rejections of record as it neither traverses the grounds of rejection by providing specific arguments, nor indicates that a terminal disclaimer has been filed to overcome the rejection. As such, the rejections of record stand.
Conclusion
No claims are allowed.
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.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631